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WUSTL Neuroscience Publications Archive - January 2016

January 2016

January 29, 2015

Hermanstyne, T.O.a , Simms, C.L.b , Carrasquillo, Y.a c , Herzog, E.D.b , Nerbonne, J.M.a
Distinct Firing Properties of Vasoactive Intestinal Peptide-Expressing Neurons in the Suprachiasmatic Nucleus
(2016) Journal of Biological Rhythms, 31 (1), pp. 57-67. 

DOI: 10.1177/0748730415619745


a Departments of Developmental Biology and Medicine, Washington University, School of Medicine, Box 8086, 660 South Euclid Avenue, Saint Louis, MO, United States
b Department of Biology, Washington University, St. Louis, MO, United States
c National Center for Complementary and Alternative Medicine, NIH 35 Convent Drive Building 35A, Bethesda, MD, United States


Abstract
The suprachiasmatic nucleus (SCN) regulates daily rhythms in physiology and behavior. Previous studies suggest a critical role for neurons expressing vasoactive intestinal peptide (VIP) in coordinating rhythmicity and synchronization in the SCN. Here we examined the firing properties of VIP-expressing SCN neurons in acute brain slices. Active and passive membrane properties were measured in VIP and in non-VIP neurons during the day and at night. Current-clamp recordings revealed that both VIP and non-VIP neurons were spontaneously active, with higher firing rates during the day than at night. Average firing frequencies, however, were higher in VIP neurons (3.1 ± 0.2 Hz, day and 2.4 ± 0.2 Hz, night) than in non-VIP neurons (1.8 ± 0.2 Hz, day and 0.9 ± 0.2 Hz, night), both day and night. The waveforms of individual action potentials in VIP and non-VIP neurons were also distinct. Action potential durations (APD50) were shorter in VIP neurons (3.6 ± 0.1 ms, day and 2.9 ± 0.1 ms, night) than in non-VIP neurons (4.4 ± 0.3 ms, day and 3.5 ± 0.2 ms, night) throughout the light-dark cycle. In addition, afterhyperpolarization (AHP) amplitudes were larger in VIP neurons (21 ± 0.8 mV, day and 24.9 ± 0.9 mV, night) than in non-VIP neurons (17.2 ± 1.1 mV, day and 20.5 ± 1.2 mV, night) during the day and at night. Furthermore, significant day/night differences were observed in APD50 and AHP amplitudes in both VIP and non-VIP SCN neurons, consistent with rhythmic changes in ionic conductances that contribute to shaping the firing properties of both cell types. The higher day and night firing rates of VIP neurons likely contribute to synchronizing electrical activity in the SCN. © 2015 The Author(s).


Author Keywords
action potential waveforms;  circadian rhythms;  membrane excitability;  rhythmic firing;  SCN;  VIP neuropeptide


Document Type: Article
Source: Scopus




Cato, M.A.a , Mauras, N.b , Mazaika, P.c , Kollman, C.d , Cheng, P.d , Aye, T.e , Ambrosino, J.f , Beck, R.W.d , Ruedy, K.J.d , Reiss, A.L.c g h , Tansey, M.i , White, N.H.a j , Hershey, T.a k l m , For The Diabetes Research In Children Network (Direcnet)n
Longitudinal Evaluation of Cognitive Functioning in Young Children with Type 1 Diabetes over 18 Months
(2016) Journal of the International Neuropsychological Society, pp. 1-10. Article in Press. 

DOI: 10.1017/S1355617715001289


a Division of Neurology, Nemours Children’s Health System, Jacksonville, Florida
b Division of Endocrinology, Nemours Children’s Health System, Jacksonville, Florida
c Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, California
d Jaeb Center for Health Research, Tampa, Florida
e Division of Pediatrics Endocrinology and Diabetes, Stanford University, Stanford, California
f Yale Children’s Diabetes Program, Yale University, New Haven, Connecticut
g Department of Radiology, Stanford University, Stanford, California
h Department of Pediatrics, Stanford University, Stanford, California
i Division of Pediatric Psychology, University of Iowa Children’s Hospital, Iowa City, Iowa
j Departments of Pediatrics, Washington University, St. Louis, Missouri
k Department of Psychiatry, Washington University, St. Louis, Missouri
l Department of Neurology, Washington University, St. Louis, Missouri
m Department of Radiology, Washington University, St. Louis, Missouri


Abstract
Objectives: Decrements in cognitive function may already be evident in young children with type 1 diabetes (T1D). Here we report prospectively acquired cognitive results over 18 months in a large cohort of young children with and without T1D. Methods: A total of 144 children with T1D (mean HbA1c: 7.9%) and 70 age-matched healthy controls (mean age both groups 8.5 years; median diabetes duration 3.9 years; mean age of onset 4.1 years) underwent neuropsychological testing at baseline and after 18-months of follow-up. We hypothesized that group differences observed at baseline would be more pronounced after 18 months, particularly in those T1D patients with greatest exposure to glycemic extremes. Results: Cognitive domain scores did not differ between groups at the 18 month testing session and did not change differently between groups over the follow-up period. However, within the T1D group, a history of diabetic ketoacidosis (DKA) was correlated with lower Verbal IQ and greater hyperglycemia exposure (HbA1c area under the curve) was inversely correlated to executive functions test performance. In addition, those with a history of both types of exposure performed most poorly on measures of executive function. Conclusions: The subtle cognitive differences between T1D children and nondiabetic controls observed at baseline were not observed 18 months later. Within the T1D group, as at baseline, relationships between cognition (Verbal IQ and executive functions) and glycemic variables (chronic hyperglycemia and DKA history) were evident. Continued longitudinal study of this T1D cohort and their carefully matched healthy comparison group is planned. (JINS, 2016, 21, 1–10) Copyright © The International Neuropsychological Society 2016


Author Keywords
Children;  Cognition;  Early onset;  Hyperglycemia;  Longitudinal;  T1D


Document Type: Article in Press
Source: Scopus




Welch, R.D.a , Ayaz, S.I.a , Lewis, L.M.b , Unden, J.c , Chen, J.Y.d , Mika, V.H.a , Saville, B.e , Tyndall, J.A.f , Nash, M.g , Buki, A.h , Barzo, P.i , Hack, D.j , Tortella, F.C.k , Schmid, K.l , Hayes, R.L.m , Vossough, A.n , Sweriduk, S.T.o , Bazarian, J.J.p
Ability of serum glial fibrillary acidic protein, ubiquitin C-Terminal Hydrolase-L1, and S100B to differentiate normal and abnormal head computed tomography findings in patients with suspected mild or moderate traumatic brain injury
(2016) Journal of Neurotrauma, 33 (2), pp. 203-214. 

DOI: 10.1089/neu.2015.4149


a Department of Emergency Medicine, Wayne State University, Detroit, MI, United States
b Department of Emergency Medicine, Washington University, St. Louis, MO, United States
c Department of Anesthesiology and Intensive Care, Clinical Sciences in Malmo, Malmo, Sweden
d Department of Radiology, University of California San Diego Health System, San Diego, CA, United States
e Berry Consultants, Austin, TX, United States
f Department of Emergency Medicine, University of Florida, Gainesville, FL, United States
g Neurostudies.net, Decatur, GA, United States
h Department of Neurosurgery, Pecs University, Pecs, Hungary
i Department of Neurosurgery, University of Szeged, Szeged, Hungary
j U.S. Army Medical Research and Materiel Command, Fort Detrick, MD, United States
k Applied Neurobiology, Silver Spring, MD, United States
l Center for Military Psychiatry and Neuroscience, Walter Reed Army Institute of Research, Silver Spring, MD, United States
m Center of Innovative Research, Banyan Biomarkers Inc., Alachua, FL, United States
n Department of Radiology, University of Pennsylvania, Philadelphia, PA, United States
o Department of Radiology, Shields Health Care Group, Brockton, MA, United States
p Department of Emergency Medicine, University of Rochester, School of Medicine, Rochester, NY, United States


Abstract
Head computed tomography (CT) imaging is still a commonly obtained diagnostic test for patients with minor head injury despite availability of clinical decision rules to guide imaging use and recommendations to reduce radiation exposure resulting from unnecessary imaging. This prospective multicenter observational study of 251 patients with suspected mild to moderate traumatic brain injury (TBI) evaluated three serum biomarkers' (glial fibrillary acidic protein [GFAP], ubiquitin C-terminal hydrolase-L1 [UCH-L1] and S100B measured within 6 h of injury) ability to differentiate CT negative and CT positive findings. Of the 251 patients, 60.2% were male and 225 (89.6%) had a presenting Glasgow Coma Scale score of 15. A positive head CT (intracranial injury) was found in 36 (14.3%). UCH-L1 was 100% sensitive and 39% specific at a cutoff value >40 pg/mL. To retain 100% sensitivity, GFAP was 0% specific (cutoff value 0 pg/mL) and S100B had a specificity of only 2% (cutoff value 30 pg/mL). All three biomarkers had similar values for areas under the receiver operator characteristic curve: 0.79 (95% confidence interval; 0.70-0.88) for GFAP, 0.80 (0.71-0.89) for UCH-L1, and 0.75 (0.65-0.85) for S100B. Neither GFAP nor UCH-L1 curve values differed significantly from S100B (p = 0.21 and p = 0.77, respectively). In our patient cohort, UCH-L1 outperformed GFAP and S100B when the goal was to reduce CT use without sacrificing sensitivity. UCH-L1 values <40 pg/mL could potentially have aided in eliminating 83 of the 215 negative CT scans. These results require replication in other studies before the test is used in actual clinical practice. © Robert D. Welch, et al. 2015; Published by Mary Ann Liebert, Inc. 2016.


Document Type: Article
Source: Scopus




Ju, Y.-E.
Clocking in to the brain's activity
(2016) Science Translational Medicine, 8 (321), art. no. 321ec6, . 

DOI: 10.1126/scitranslmed.aaf0854


Department of Neurology, Washington University, School of Medicine, Saint Louis, MO, United States


Document Type: Editorial
Source: Scopus




Piccio, L.a c , Deming, Y.b , Del-Águila, J.L.b , Ghezzi, L.a e , Holtzman, D.M.a c d , Fagan, A.M.a c d , Fenoglio, C.e , Galimberti, D.e , Borroni, B.f , Cruchaga, C.b c d
Cerebrospinal fluid soluble TREM2 is higher in Alzheimer disease and associated with mutation status
(2016) Acta Neuropathologica, pp. 1-9. Article in Press. 

DOI: 10.1007/s00401-016-1533-5


a Department of Neurology, Washington University School of Medicine, 660 S. Euclid Avenue, Campus Box 8111, Saint Louis, MO, United States
b Department of Psychiatry, Washington University School of Medicine, 660 South Euclid Avenue B8134, Saint Louis, MO, United States
c Hope Center for Neurological Disorders, Washington University School of Medicine, Saint Louis, MO, United States
d Knight Alzheimer’s disease Research Center, Washington University School of Medicine, Saint Louis, MO, United States
e Neurology Unit, Department of Pathophysiology and Transplantation, University of Milan, Fondazione Cà Granda, IRCCS Ospedale Policlinico, Milan, Italy
f Neurology Unit, University of Brescia, Piazza Spedali Civili 1, Brescia, Italy


Abstract
Low frequency coding variants in TREM2 are associated with increased Alzheimer disease (AD) risk, while loss of functions mutations in the gene lead to an autosomal recessive early-onset dementia, named Nasu-Hakola disease (NHD). TREM2 can be detected as a soluble protein in cerebrospinal fluid (CSF) and plasma, and its CSF levels are elevated in inflammatory CNS diseases. We measured soluble TREM2 (sTREM2) in the CSF of a large AD case–control dataset (n = 180) and 40 TREM2 risk variant carriers to determine whether CSF sTREM2 levels are associated with AD status or mutation status. We also performed genetic studies to identify genetic variants associated with CSF sTREM2 levels. CSF, but not plasma, sTREM2 was highly correlated with CSF total tau and phosphorylated-tau levels (r = 0.35, P &lt; 1×10−4; r = 0.40, P &lt; 1×10−4, respectively), but not with CSF Aβ42. AD cases presented higher CSF sTREM2 levels than controls (P = 0.01). Carriers of NHD-associated TREM2 variants presented significantly lower CSF sTREM2 levels, supporting the hypothesis that these mutations lead to reduced protein production/function (R136Q, D87N, Q33X or T66M; P = 1×10−3). In contrast, CSF sTREM2 levels were significantly higher in R47H carriers compared to non-carriers (P = 6×10−3), suggesting that this variant does not impact protein expression and increases AD risk through a different pathogenic mechanism than NHD variants. In GWAS analyses for CSF sTREM2 levels the most significant signal was located on the MS4A gene locus (P = 5.45 × 10−07) corresponding to one of the SNPs reported to be associated with AD risk in this locus. Furthermore, SNPs involved in pathways related to virus cellular entry and vesicular trafficking were overrepresented, suggesting that CSF sTREM2 levels could be an informative phenotype for AD. © 2016 Springer-Verlag Berlin Heidelberg


Author Keywords
Alzheimer disease;  Cerebrospinal fluid;  Soluble TREM2


Document Type: Article in Press
Source: Scopus




JERGER, S.a , DAMIAN, M.F.b , TYE-MURRAY, N.c , ABDI, H.d
Children perceive speech onsets by ear and eye*
(2016) Journal of Child Language, pp. 1-31. Article in Press. 

DOI: 10.1017/S030500091500077X


a School of Behavioral and Brain Sciences, GR4·1, University of Texas at Dallas, and Callier Center for Communication Disorders, Richardson, Texas
b School of Experimental Psychology, University of Bristol
c Department of Otolaryngology–Head and Neck Surgery, Washington University School of Medicine
d School of Behavioral and Brain Sciences, GR4·1, University of Texas at Dallas


Abstract
Adults use vision to perceive low-fidelity speech; yet how children acquire this ability is not well understood. The literature indicates that children show reduced sensitivity to visual speech from kindergarten to adolescence. We hypothesized that this pattern reflects the effects of complex tasks and a growth period with harder-to-utilize cognitive resources, not lack of sensitivity. We investigated sensitivity to visual speech in children via the phonological priming produced by low-fidelity (non-intact onset) auditory speech presented audiovisually (see dynamic face articulate consonant/rhyme b/ag; hear non-intact onset/rhyme: –b/ag) vs. auditorily (see still face; hear exactly same auditory input). Audiovisual speech produced greater priming from four to fourteen years, indicating that visual speech filled in the non-intact auditory onsets. The influence of visual speech depended uniquely on phonology and speechreading. Children – like adults – perceive speech onsets multimodally. Findings are critical for incorporating visual speech into developmental theories of speech perception. Copyright © Cambridge University Press 2016


Document Type: Article in Press
Source: Scopus




Welch, T.P., Wallendorf, M.J., Kharasch, E.D., Leonard, J.R., Doctor, A., Pineda, J.A.
Fentanyl and Midazolam Are Ineffective in Reducing Episodic Intracranial Hypertension in Severe Pediatric Traumatic Brain Injury
(2016) Critical Care Medicine, . Article in Press. 

DOI: 10.1097/CCM.0000000000001558


1Division of Critical Care Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO. 2Department of Anesthesiology, Washington University School of ­Medicine, St. Louis, MO. 3Division of Biostatistics, Washington University School of Medicine, St. Louis, MO. 4Department of Neurosurgery, Nationwide Children’s Hospital, Ohio State University College of Medicine, Columbus, OH.


Abstract
OBJECTIVE:: To evaluate the clinical effectiveness of bolus-dose fentanyl and midazolam to treat episodic intracranial hypertension in children with severe traumatic brain injury. DESIGN:: Retrospective cohort. SETTING:: PICU in a university-affiliated children’s hospital level I trauma center. PATIENTS:: Thirty-one children aged 0–18 years with severe traumatic brain injury (Glasgow Coma Scale score of ≤ 8) who received bolus doses of fentanyl and/or midazolam for treatment of episodic intracranial hypertension. INTERVENTIONS:: None. MEASUREMENTS AND MAIN RESULTS:: The area under the curve from high-resolution intracranial pressure-time plots was calculated to represent cumulative intracranial hypertension exposure: area under the curve for intracranial pressure above 20 mm Hg (area under the curve-intracranial hypertension) was calculated in 15-minute epochs before and after administration of fentanyl and/or midazolam for the treatment of episodic intracranial hypertension. Our primary outcome measure, the difference between predrug and postdrug administration epochs (Δarea under the curve-intracranial hypertension), was calculated for all occurrences. We examined potential covariates including age, injury severity, mechanism, and time after injury; time after injury correlated with Δarea under the curve-intracranial hypertension. In a mixed-effects model, with patient as a random effect, drug/dose combination as a fixed effect, and time after injury as a covariate, intracranial hypertension increased after administration of fentanyl and/or midazolam (overall aggregate mean Δarea under the curve-intracranial hypertension = +17 mm Hg × min, 95% CI, 0–34 mm Hg × min; p = 0.04). The mean Δarea under the curve-intracranial hypertension increased significantly after administration of high-dose fentanyl (p = 0.02), low-dose midazolam (p = 0.006), and high-dose fentanyl plus low-dose midazolam (0.007). Secondary analysis using age-dependent thresholds showed no significant impact on cerebral perfusion pressure deficit (mean Δarea under the curve-cerebral perfusion pressure). CONCLUSIONS:: Bolus dosing of fentanyl and midazolam fails to reduce the intracranial hypertension burden when administered for episodic intracranial hypertension. Paradoxically, we observed an overall increase in intracranial hypertension burden following drug administration, even after accounting for within-subject effects and time after injury. Future work is needed to confirm these findings in a prospective study design. Copyright © by 2016 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.


Document Type: Article in Press
Source: Scopus




Lynch, S.M.a b , Peek, M.K.c , Mitra, N.a , Ravichandran, K.d , Branas, C.a , Spangler, E.a , Zhou, W.a , Paskett, E.D.e , Gehlert, S.f , Degraffinreid, C.e , Rebbeck, T.R.a g , Riethman, H.c h
Race,ethnicity, psychosocial factors, and telomere length in a multicenter setting
(2016) PLoS ONE, 11 (1), art. no. e0146723, . 

DOI: 10.1371/journal.pone.0146723


a United States of America, University of Pennsylvania, Philadelphia, PA, United States
b Fox Chase Cancer Center, United States of America, Philadelphia, PA, United States
c United States of America, University of Texas Medical Branch, Galveston, TX, United States
d United States of America, Wistar Institute, Philadelphia, PA, United States
e United States of America, Ohio State University, Columbus, OH, United States
f United States of America, Washington University, St. Louis, MO, United States
g United States of America, Dana Farber Cancer Institute and Harvard University, Boston, MA, United States
h United States of America, Old Dominion University, Norfolk, VA, United States


Abstract
Background Leukocyte telomere length(LTL) has been associated with age, self-reported race/ethnicity, gender, education, and psychosocial factors, including perceived stress, and depression. However, inconsistencies in associations of LTL with disease and other phenotypes exist across studies. Population characteristics, including race/ethnicity, laboratory methods, and statistical approaches in LTL have not been comprehensively studied and could explain inconsistent LTL associations. Methods LTL was measured using Southern Blot in 1510 participants from a multi-ethnic, multi-center study combining data from 3 centers with different population characteristics and laboratory processing methods. Main associations between LTL and psychosocial factors and LTL and race/ethnicity were evaluated and then compared across generalized estimating equations(GEE) and linear regression models. Statistical models were adjusted for factors typically associated with LTL(age, gender, cancer status) and also accounted for factors related to center differences, including laboratory methods(i.e., DNA extraction). Associations between LTL and psychosocial factors were also evaluated within race/ethnicity subgroups (Non-hispanic Whites, African Americans, and Hispanics). Results Beyond adjustment for age, gender, and cancer status, additional adjustments for DNA extraction and clustering by center were needed given their effects on LTL measurements. In adjusted GEE models, longer LTL was associated with African American race (Beta(β) (standard error(SE)) = 0.09(0.04), p-value = 0.04) and Hispanic ethnicity (β(SE) = 0.06 (0.01), p-value = 0.02) compared to Non-Hispanic Whites. Longer LTL was also associated with less than a high school education compared to having greater than a high school education (β(SE) = 0.06(0.02), p-value = 0.04). LTL was inversely related to perceived stress (β(SE) = -0.02(0.003), p<0.001). In subgroup analyses, there was a negative association with LTL in African Americans with a high school education versus those with greater than a high school education(β(SE) = -0.11(0.03), p-value<0.001). Conclusions Laboratory methods and population characteristics that differ by center can influence telomere length associations in multicenter settings, but these effects could be addressed through statistical adjustments. Proper evaluation of potential sources of bias can allow for combined multicenter analyses and may resolve some inconsistencies in reporting of LTL associations. Further, biologic effects on LTL may differ under certain psychosocial and racial/ethnic circumstances and could impact future health disparity studies. © 2016 Lynch et al.This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Document Type: Article
Source: Scopus




Sergin, I.a , Bhattacharya, S.a , Emanuel, R.a , Esen, E.b , Stokes, C.J.a , Evans, T.D.a , Arif, B.c , Curci, J.A.d , Razani, B.a e
Inclusion bodies enriched for p62 and polyubiquitinated proteins in macrophages protect against atherosclerosis
(2016) Science Signaling, 9 (409), art. no. ra2, . 

DOI: 10.1126/scisignal.aad5614


a Cardiovascular Division, Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States
b Department of Orthopedic Surgery, Washington University School of Medicine, St. Louis, MO, United States
c Department of Surgery, Washington University School OfMedicine, St. Louis, MO, United States
d Department of Surgery, Vanderbilt University Medical Center, Nashville, TN, United States
e Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States


Abstract
Autophagy is a catabolic cellular mechanism that degrades dysfunctional proteins and organelles. Atherosclerotic plaque formation is enhanced in mice with macrophages deficient for the critical autophagy protein ATG5.We showed that exposure ofmacrophages to lipids that promote atherosclerosis increased the abundance of the autophagy chaperone p62 and that p62 colocalized with polyubiquitinated proteins in cytoplasmic inclusions, which are characterized by insoluble protein aggregates. ATG5-null macrophages developed further p62 accumulation at the sites of large cytoplasmic ubiquitin-positive inclusion bodies. Aortas from atherosclerotic mice and plaques from human endarterectomy samples showed increased abundance of p62 and polyubiquitinated proteins that colocalized with plaque macrophages, suggesting that p62-enriched protein aggregates were characteristic of atherosclerosis. The formation of the cytoplasmic inclusions depended on p62 because lipid-loaded p62-null macrophages accumulated polyubiquitinated proteins in a diffuse cytoplasmic pattern. Lipid-loaded p62-null macrophages also exhibited increased secretion of interleukin-1β (IL-1β) and had an increased tendency to undergo apoptosis, which depended on the p62 ubiquitin-binding domain and at least partly involved p62-mediated clearance ofNLRP3 inflammasomes. Consistent with our in vitro observations, p62-deficient mice formed greater numbers of more complex atherosclerotic plaques, and p62 deficiency further increased atherosclerotic plaque burden in mice with amacrophage-specific ablation of ATG5. Together, these data suggested that sequestration of cytotoxic ubiquitinated proteins by p62 protects against atherogenesis, a condition inwhich the clearance of protein aggregates is disrupted.


Document Type: Article
Source: Scopus




Feczko, E.J.a b , Bliss-Moreau, E.c , Walum, H.a b , Pruett, J.R.d , Parr, L.A.a b e
The Macaque Social Responsiveness Scale (mSRS): A rapid screening tool for assessing variability in the social responsiveness of rhesus monkeys (Macaca mulatta)
(2016) PLoS ONE, 11 (1), art. no. e0145956, . 

DOI: 10.1371/journal.pone.0145956


a Yerkes National Primate Research Center, Atlanta, GA, United States
b Center for Translational Social Neuroscience, Emory University, Atlanta, GA, United States
c Department of Psychiatry and Behavioral Science, California National Primate Research Center, University of California, Davis, CA, United States
d Department of Psychiatry, Washington University, School of Medicine, St. Louis, MO, United States
e Department of Psychiatry and Behavioral Science, Emory University, Atlanta, GA, United States


Abstract
Understanding the biological mechanisms underlying human neuropsychiatric disorders, such as autism spectrum disorder (ASD), has been hindered by the lack of a robust, translational animal model. Rhesus monkeys (Macaca mulatta) display many of the same social behaviors that are affected in ASD, making them an excellent animal species in which to model social impairments. However, the social impairments associated with ASD may reflect extreme ends of a continuous distribution of traits. Thus, to validate the rhesus monkey as an animal model for studying social impairments that has strong translational relevance for ASD, researchers need an easily-implemented measurement tool that can quantify variation in social behavior dimensionally. The Social Responsiveness Scale (SRS) is a 65-item survey that identifies both typical and atypical social behaviors in humans that covary with ASD symptom severity. A chimpanzee SRS has already been validated and the current study adapted this tool for use in the rhesus monkey (mSRS). Fifteen raters completed the mSRS for 105 rhesus monkeys living at the Yerkes National Primate Research Center. The mSRS scores showed a unimodal distribution with a positive skew that identified 6 statistical outliers. Inter-rater reliability was very strong, but only 17 of the 36 questions showed positive intra-item reliability. The results of an exploratory factor analysis identified 3 factors that explained over 60% of the variance, with 12 items significantly loading onto the primary factor. These items reflected behaviors associated with social avoidance, social anxiety or inflexibility and social confidence. These initial findings are encouraging and suggest that variability in the social responsiveness of rhesus monkeys can be quantified using the mSRS: a tool that has strong translational relevance for human disorders. With further modification, the mSRS may provide an promising new direction for research on the biological mechanisms underlying social impairments. © 2016 Feczko et al.This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Document Type: Article
Source: Scopus




Washington, C.W.a b , Derdeyn, C.P.a b c , Chicoine, M.R.a , Cross, D.T.a b , Dacey, R.G.a , Moran, C.J.a b , Rich, K.M.a b , Zipfel, G.J.a c
Comparing routine versus selective use of intraoperative cerebral angiography in aneurysm surgery: A prospective study
(2016) Journal of NeuroInterventional Surgery, 8 (1), pp. 75-80. 

DOI: 10.1136/neurintsurg-2014-011515


a Department of Neurological Surgery, Washington University School of Medicine, 660 S Euclid Avenue, St Louis, MO, United States
b Department of Radiology, Washington University Center for Stroke and Cerebrovascular Disease, Washington University School of Medicine, Saint Louis, MO, United States
c Department of Neurology, Washington University Center for Stroke and Cerebrovascular Disease, Washington University School of Medicine, Saint Louis, MO, United States


Abstract
Introduction While the use of intraoperative angiography (IA) has been shown to be a useful adjunct in aneurysm surgery, its routine use remains controversial. Objective We wished to determine if IA is required in all patients undergoing aneurysm surgery (ie, routine IA) or if intraoperative assessment can reliably predict the need for IA (ie, select IA). Methods We prospectively evaluated all patients undergoing craniotomy for aneurysm clipping. In these patients, the treating surgeons were asked to record whether they felt IA was required at two time points: (1) prior to surgery and (2) immediately after clip application but before IA. All patients underwent IA as per the institutional protocol. IA results and the need for post-IA clip adjustments were recorded. Results Of the 200 patients enrolled, 197 were included for analysis. IA was deemed necessary on preoperative assessment in 144 cases (73%) and on post-clip assessment in 116 cases (59%). Post-clip IA demonstrated 47 (24%) positive findings and post-IA clip adjustments were made in 19 of 198 cases (10%). On preoperative assessment, there were four cases where IA was deemed unnecessary, yet post-IA clip adjustment was required, resulting in a sensitivity of 79% and false negative rate of 8%. Regarding post-clip assessment, there were five cases where IA was thought to be unnecessary and clip adjustment was required, resulting in a sensitivity of 73% and false negative rate of 6%. Conclusions The accuracy of a strategy of select IA was not improved by assessing the need for IA immediately after aneurysm clipping versus prior to surgery onset. This suggests that intraoperative assessment regarding the adequacy of aneurysm clip application should be viewed with caution.


Document Type: Article
Source: Scopus




Luby, J.L.a , Belden, A.C.a , Jackson, J.J.b , Lessov-Schlaggar, C.N.a , Harms, M.P.a , Tillman, R.a , Botteron, K.a c , Whalen, D.a , Barch, D.M.a b c d
Early childhood depression and alterations in the trajectory of gray matter maturation in middle childhood and early adolescence
(2016) JAMA Psychiatry, 73 (1), pp. 31-38. 

DOI: 10.1001/jamapsychiatry.2015.2356


a Department of Psychiatry, Washington University School of Medicine, Campus Box 8134, St Louis, MO, United States
b Department of Psychology, Washington University, St Louis, MO, United States
c Department of Radiology, Washington University School of Medicine, St Louis, MO, United States
d Program in Neuroscience, Washington University School of Medicine, St Louis, United States


Abstract
IMPORTANCE The trajectory of cortical gray matter development in childhood has been characterized by early neurogenesis and volume increase, peaking at puberty followed by selective elimination andmyelination, resulting in volume loss and thinning. This inverted U-shaped trajectory, as well as cortical thickness, has been associated with cognitive and emotional function. Synaptic pruning-based volume decline has been related to experience-dependent plasticity in animals. To date, there have been no data to inform whether and how childhood depression might be associated with this trajectory. OBJECTIVE To examine the effects of early childhood depression, from the preschool age to the school age period, on cortical gray matter development measured across 3 waves of neuroimaging from late school age to early adolescence. DESIGN, SETTING, AND PARTICIPANTS Datawere collected in an academic research setting from September 22, 2003, to December 13, 2014, on 193 children aged 3 to 6 years from the St Louis, Missouri, metropolitan area who were observed for up to 11 years in a longitudinal behavioral and neuroimaging study of childhood depression. Multilevel modeling was applied to explore the association between the number of childhood depression symptoms and prior diagnosis of major depressive disorder and the trajectory of gray matter change across 3 scan waves. Data analysis was conducted from October 29, 2014, to September 28, 2015. MAIN OUTCOMES AND MEASURES Volume, thickness, and surface area of cortical gray matter measured using structural magnetic resonance imaging at 3 scan waves. RESULTS Of the 193 children, 90 had a diagnosis of major depressive disorder; 116 children had 3 full waves of neuroimaging scans. Findings demonstrated marked alterations in cortical gray matter volume loss (slope estimate, -0.93 cm3; 95%CI, -1.75 to -0.10 cm3 per scan wave) and thinning (slope estimate, -0.0044 mm; 95%CI, -0.0077 to -0.0012mmper scan wave) associated with experiencing an episode of major depressive disorder before the first magnetic resonance imaging scan. In contrast, no significant associations were found between development of gray matter and family history of depression or experiences of traumatic or stressful life events during this period. CONCLUSIONS AND RELEVANCE This study demonstrates an association between early childhood depression and the trajectory of cortical gray matter development in late school age and early adolescence. These findings underscore the significance of early childhood depression on alterations in neural development. Copyright 2016 American Medical Association. All rights reserved.


Document Type: Article
Source: Scopus




Wang, D.a b , Patel, A.a , Mello, M.a , Shriver, A.c , Gyawali, C.P.a
Esophagogastric junction contractile integral (EGJ-CI) quantifies changes in EGJ barrier function with surgical intervention
(2016) Neurogastroenterology and Motility, . Article in Press. 

DOI: 10.1111/nmo.12757


a Division of Gastroenterology Washington University School of Medicine St. Louis MO USA
b Gastroenterology Department The First Hospital of Jilin University Changchun Jilin China
c Division of Gastroenterology University of Virginia in Charlottesville Charlottesville VA USA


Abstract
Background: Esophagogastric junction contractile integral (EGJ-CI) assesses EGJ barrier function on esophageal high resolution manometry (HRM). We assessed EGJ-CI values in achalasia and gastroesophageal reflux disease (GERD) to determine if postoperative EGJ-CI changes reflected surgical intervention. Methods: Twenty-one achalasia patients (42.8 ± 3.2 years, 62% F) with HRM before and after Heller myotomy (HM) and 68 GERD patients (53.9 ± 1.8 years, 66% F) undergoing antireflux surgery (ARS) were compared to 21 healthy controls (27.6 ± 0.6 years, 52% F). Esophagogastric junction contractile integral (mmHg.cm) was calculated using the distal contractile integral measurement across the EGJ, measured above the gastric baseline and corrected for respiration. Pre and postsurgical EGJ-CI and conventional lower esophageal sphincter pressure (LESP) metrics were compared within and between these groups using non-parametric tests. Correlation between EGJ-CI and conventional LESP metrics was assessed. Key Results: Baseline EGJ-CI was higher in achalasia compared to GERD (p < 0.001) or controls (p = 0.03). Esophagogastric junction contractile integral declined by 59.2% after HM in achalasia (p = 0.001), and increased by 26.3% after ARS in GERD (p = 0.005). End-expiratory and basal LESP decreased by 74.5% and 64.5% with HM, but increased by only 17.8% and 4.3% with ARS. Differences were noted between Dor vs Toupet fundoplication in achalasia (p = 0.007), and partial vs complete ARS in GERD (p = 0.03). Esophagogastric junction contractile integral correlated modestly with both end-expiratory and basal LESP (Pearson's r of 0.8 for all), but was less robust in GERD (0.7). Conclusions & Inferences: Esophagogastric junction contractile integral has clinical utility in assessing EGJ barrier function at baseline and after surgical intervention to the EGJ, and could complement conventional EGJ metrics. © 2016 John Wiley & Sons Ltd.


Author Keywords
Antireflux surgery;  Esophagogastric junction;  High-resolution manometry;  Myotomy


Document Type: Article in Press
Source: Scopus




Wassif, C.A.a b , Cross, J.L.a b , Iben, J.a , Sanchez-Pulido, L.c , Cougnoux, A.a , Platt, F.M.b , Ory, D.S.d , Ponting, C.P.c , Bailey-Wilson, J.E.e , Biesecker, L.G.f , Porter, F.D.a
High incidence of unrecognized visceral/neurological late-onset Niemann-Pick disease, type C1, predicted by analysis of massively parallel sequencing data sets
(2016) Genetics in Medicine, 18 (1), pp. 41-48. 

DOI: 10.1038/gim.2015.25


a Program in Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, United States
b Department of Pharmacology, University of Oxford, Oxford, United Kingdom
c Department of Physiology,Anatomy and Genetics, MRC Functional Genomics Unit, University of Oxford, Oxford, United Kingdom
d Diabetic Cardiovascular Disease Center, Washington University, School of Medicine, St Louis, MO, United States
e Statistical Genetics Section, National Human Genome Research Institute, US Department of Health and Human Services, Bethesda, MD, United States
f Clinical Genomics Section, National Human Genome Research Institute, US Department of Health and Human Services, Bethesda, MD, United States


Abstract
Purpose:Niemann-Pick disease type C (NPC) is a recessive, neurodegenerative, lysosomal storage disease caused by mutations in either NPC1 or NPC2. The diagnosis is difficult and frequently delayed. Ascertainment is likely incomplete because of both these factors and because the full phenotypic spectrum may not have been fully delineated. Given the recent development of a blood-based diagnostic test and the development of potential therapies, understanding the incidence of NPC and defining at-risk patient populations are important.Method:We evaluated data from four large, massively parallel exome sequencing data sets. Variant sequences were identified and classified as pathogenic or nonpathogenic based on a combination of literature review and bioinformatic analysis. This methodology provided an unbiased approach to determining the allele frequency.Results:Our data suggest an incidence rate for NPC1 and NPC2 of 1/92,104 and 1/2,858,998, respectively. Evaluation of common NPC1 variants, however, suggests that there may be a late-onset NPC1 phenotype with a markedly higher incidence, on the order of 1/19,000-1/36,000.Conclusion:We determined a combined incidence of classical NPC of 1/89,229, or 1.12 affected patients per 100,000 conceptions, but predict incomplete ascertainment of a late-onset phenotype of NPC1. This finding strongly supports the need for increased screening of potential patients. © 2016 American College of Medical Genetics and Genomics.


Author Keywords
allele frequency;  next-generation sequence study;  Niemann-Pick disease;  NPC;  type C


Document Type: Article
Source: Scopus




Wang, S.a , Vafabakhsh, R.b , Borschel, W.F.a , Ha, T.b c d , Nichols, C.G.a
Structural dynamics of potassium-channel gating revealed by single-molecule FRET
(2016) Nature Structural and Molecular Biology, 23 (1), pp. 31-36. 

DOI: 10.1038/nsmb.3138


a Center for Investigation of Membrane Excitability Diseases, Department of Cell Biology and Physiology, Washington University, St. Louis, MO, United States
b Department of Physics, Center for the Physics of Living Cells, University of Illinois at Urbana-Champaign, Urbana, IL, United States
c Howard Hughes Medical Institute, Baltimore, MD, United States
d Department of Biophysics and Biophysical Chemistry, Johns Hopkins University, Baltimore, MD, United States


Abstract
Crystallography has provided invaluable insights regarding ion-channel selectivity and gating, but to advance understanding to a new level, dynamic views of channel structures within membranes are essential. We labeled tetrameric KirBac1.1 potassium channels with single donor and acceptor fluorophores at different sites and then examined structural dynamics within lipid membranes by single-molecule fluorescence resonance energy transfer (FRET). We found that the extracellular region is structurally rigid in both closed and open states, whereas the N-terminal slide helix undergoes marked conformational fluctuations. The cytoplasmic C-terminal domain fluctuates between two major structural states, both of which become less dynamic and move away from the pore axis and away from the membrane in closed channels. Our results reveal mobile and rigid conformations of functionally relevant KirBac1.1 channel motifs, implying similar dynamics for similar motifs in eukaryotic Kir channels and in cation channels in general. © 2016 Nature America, Inc.


Document Type: Article
Source: Scopus




McDaniel, M.A.a , Cahill, M.J.a b , Bugg, J.M.a
The curious case of orthographic distinctiveness: Disruption of categorical processing
(2016) Journal of Experimental Psychology: Learning Memory and Cognition, 42 (1), pp. 104-113. 

DOI: 10.1037/xlm0000160


a Department of Psychology, Washington University, St. Louis, United States
b Center for Integrative Research on Cognition, Learning, and Education, Washington University, St. Louis, United States


Abstract
How does orthographic distinctiveness affect recall of structured (categorized) word lists? On one theory, enhanced item-specific information (e.g., more distinct encoding) in concert with robust relational information (e.g., categorical information) optimally supports free recall. This predicts that for categorically structured lists, orthographically distinct (OD) word lists should be recalled better than orthographically common (OC) word lists. Another possibility is that OD items produce a far-reaching impairment in relational processing, including that of categorical information. This view anticipates an advantage in recall for OC items relative to OD lists. In Experiment 1 categorically structured OC lists produced better recall performance and higher clustering than did categorically structured OD lists. When words were presented in capital letters, thereby minimizing orthographic distinctiveness, OC and OD lists showed equivalent recall and category clustering (Experiment 2). When recall was cued with category labels, OC items were still better recalled than OD items (Experiment 3). These patterns, along with category access and items-per-category recalled, are consistent with the interpretation that orthographic distinctiveness creates a disruption in encoding of inter-item associations within a category. This interpretation expands previous work indicating that orthographic distinctiveness disrupts encoding of serial order information, another kind of inter-item association. © 015 American Psychological Association.


Author Keywords
Disruption of categorical processing;  Mnemonic effects;  Orthographic distinctiveness;  Recall of categorized lists;  Relational processing


Document Type: Article
Source: Scopus




Few, L.R.a , Grant, J.D.a , Trull, T.J.c , Oltmanns, T.F.d , Lynskey, M.T.f , Miller, J.D.b , Maples, J.b , Nelson, E.C.a , Martin, N.G.e , Agrawal, A.a
Trait-based assessment of borderline personality disorder using the NEO five-factor inventory: Phenotypic and genetic support
(2016) Psychological Assessment, 28 (1), pp. 39-50. 

DOI: 10.1037/pas0000142


a Department of Psychiatry, Washington University School of Medicine, United States
b Department of Psychology, University of Georgia, United States
c Department of Psychological Sciences, University of Missouri, United States
d Department of Psychology, Washington University, United States
e QIMR Medical Research Institute, Brisbane, Australia
f Institute of Psychiatry, Psychology and Neuroscience, King's College London, United Kingdom


Abstract
The aim of the current study was to examine the reliability and validity of a trait-based assessment of borderline personality disorder (BPD) using the NEO Five-Factor Inventory. Correlations between the Five-Factor Inventory-BPD composite (FFI-BPD) and explicit measures of BPD were examined across 6 samples, including undergraduate, community, and clinical samples. The median correlation was .60, which was nearly identical to the correlation between measures of BPD and a BPD composite generated from the full Revised NEO Personality Inventory (i.e., NEO-BPD; r = .61). Correlations between FFI-BPD and relevant measures of psychiatric symptomatology and etiology (e.g., childhood abuse, drug use, depression, and personality disorders) were also examined and compared to those generated using explicit measures of BPD and NEO-BPD. As expected, the FFI-BPD composite correlated most strongly with measures associated with high levels of Neuroticism, such as depression, anxiety, and emotion dysregulation, and the pattern of correlations generated using the FFI-BPD was highly similar to those generated using explicit measures of BPD and NEO-BPD. Finally, genetic analyses estimated that FFI-BPD is 44% heritable, which is comparable to meta-analytic research examining genetics associated with BPD, and revealed that 71% of the genetic influences are shared between FFI-BPD and a self-report measure assessing BPD (Personality Assessment Inventory-Borderline subscale; Morey, 1991). Generally, these results support the use of FFI-BPD as a reasonable proxy for BPD, which has considerable implications, particularly for potential gene-finding efforts in large, epidemiological datasets that include the NEO FFI. © 2015 American Psychological Association.


Author Keywords
5-factor model;  Borderline personality disorder;  Genetics


Document Type: Article
Source: Scopus




Madaelil, T.P.a , Dhar, R.b
Posterior reversible encephalopathy syndrome with thalamic involvement during vasopressor treatment of vertebrobasilar vasospasm after subarachnoid hemorrhage
(2015) BMJ Case Reports, 2015, pp. 1-3. 

DOI: 10.1136/bcr-2015-012103


a Department of Neuroradiology, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, MO, United States
b Department of Neurology, Washington University School of Medicine, St Louis, MO, United States


Abstract
Hemodynamic augmentation is the primary medical intervention employed to reverse neurological deficits associated with vasospasm and delayed cerebral ischemia following aneurysmal subarachnoid hemorrhage. Failure to improve despite induced hypertension (IH) may raise concern for persistent hypoperfusion and prompt even more aggressive blood pressure augmentation. However, posterior reversible encephalopathy syndrome (PRES) is a hyperperfusion syndrome reported as a rare complication of IH that may confound this picture. We report a case of PRES with prominent thalamic involvement and impaired level of consciousness secondary to blood pressure augmentation for the treatment of symptomatic vertebrobasilar vasospasm. Recognition of this syndrome in distinction to worsening ischemia is particularly critical, as normalization of blood pressure should lead to rapid clinical improvement. © 2015 BMJ Publishing Group. All rights reserved.


Document Type: Article
Source: Scopus




Khanijow, V.a b , Prakash, P.a b , Emsellem, H.A.c d , Borum, M.L.b e f , Doman, D.B.g
Sleep dysfunction and gastrointestinal diseases
(2015) Gastroenterology and Hepatology, 11 (12), pp. 817-825. 


a Division of Gastroenterology and Liver Diseases, George Washington University Medical Center, Washington, DC, United States
b Medical Faculty, Washington, DC, United States
c George Washington University Medical Center, United States
d Center for Sleep and Wake Disorders in Chevy Chase, Maryland, United States
e George Washington University, School of Medicine, Washington, DC, United States
f Division of Gastroenterology and Liver Diseases, George Washington University Medical Center, United States
g George Washington University, School of Medicine, 12012 Veirs Mill Road, Silver Spring, MD, United States


Abstract
Sleep deprivation and impaired sleep quality have been associated with poor health outcomes. Many patients experience sleep disturbances, which can increase the risk of medical conditions such as hypertension, obesity, stroke, and heart disease as well as increase overall mortality. Recent studies have suggested that there is a strong association between sleep disturbances and gastrointestinal diseases. Proinflammatory cytokines, such as tumor necrosis factor, interleukin-1, and interleukin-6, have been associated with sleep dysfunction. Alterations in these cytokines have been seen in certain gastrointestinal diseases, such as gastroesophageal reflux disease, inflammatory bowel disease, liver disorders, and colorectal cancer. It is important for gastroenterologists to be aware of the relationship between sleep disorders and gastrointestinal illnesses to ensure good care for patients. This article reviews the current research on the interplay between sleep disorders, immune function, and gastrointestinal diseases.


Author Keywords
Circadian rhythm;  Cytokine;  Gastrointestinal disorders;  Immune system;  Irritable bowel syndrome;  Sleep


Document Type: Article
Source: Scopus




Ju, Y.-E.
Big dipper, little dipper
(2015) Science Translational Medicine, 7 (315), art. no. 5912, . 

DOI: 10.1126/scitranslmed.aad5912


Department of Neurology, Washington University, School of Medicine, Saint Louis, MO, United States


Document Type: Note
Source: Scopus




Chaddha, A.a , Kline-Rogers, E.a , Braverman, A.C.b , Erickson, S.R.a , Jackson, E.A.a , Franklin, B.A.c , Woznicki, E.M.a , Jabara, J.T.a , Montgomery, D.G.a , Eagle, K.A.a
Survivors of aortic dissection: Activity, mental health, and sexual function
(2015) Clinical Cardiology, 38 (11), pp. 652-659. 

DOI: 10.1002/clc.22418


a Michigan Clinical Outcomes Research and Reporting Program (MCORRP), University of Michigan, Frankel Cardiovascular Center, Domino's Farm Lobby A 3201, STE 3700 24 Frank Lloyd Wright Dr., Ann Arbor, MI, United States
b Cardiovascular Division, Washington University, St. Louis, MO, United States
c Preventive Cardiology and Cardiology and Cardiac Rehabilitation, William Beaumont Hospital, Royal Oak, MO, United States


Abstract
Background Currently no research exists assessing lifestyle modifications and emotional state of acute aortic dissection (AAD) survivors. We sought to assess activity, mental health, and sexual function in AAD survivors. Hypothesis Physical and sexual activity will decrease in AAD survivors compared to pre-dissection. Incidence of anxiety and depression will be significant after AAD. Methods A cross sectional survey was mailed to 197 subjects from a single academic medical center (part of larger IRAD database). Subjects were ≥18 years of age surviving a type A or B AAD between 1996 and 2011. 82 surveys were returned (overall response rate 42%). Results Mean age ± SD was 59.5 ± 13.7 years, with 54.9% type A and 43.9% type B patients. Walking remained the most prevalent form of physical activity (49 (60%) pre-dissection and 47 (57%) post-dissection). Physical inactivity increased from 14 (17%) before AAD to 20 (24%) after AAD; sexual activity decreased from 31 (38%) to 9 (11%) mostly due to fear. Most patients (66.7%) were not exerting themselves physically or emotionally at AAD onset. Systolic blood pressure (SBP) at 36 months post-discharge for patients engaging in ≥2 sessions of aerobic activity/week was 126.67 ± 10.30 vs. 141.10 ± 11.87 (p-value 0.012) in those who did not. Self-reported new-onset depression after AAD was 32% and also 32% for new-onset anxiety. Conclusions Alterations in lifestyle and emotional state are frequent in AAD survivors. Clinicians should screen for unfounded fears or beliefs after dissection that may reduce function and/or quality of life for AAD survivors. © 2015 Wiley Periodicals, Inc.


Document Type: Article
Source: Scopus




Cole, M.W.a b , Ito, T.a , Braver, T.S.b
Lateral prefrontal cortex contributes to fluid intelligence through multinetwork connectivity
(2015) Brain Connectivity, 5 (8), pp. 497-504. 

DOI: 10.1089/brain.2015.0357


a Center for Molecular and Behavioral Neuroscience, Rutgers University, 197 University Avenue, Newark, NJ, United States
b Psychology Department, Washington University in St. Louis, St. Louis, MO, United States


Abstract
Our ability to effectively adapt to novel circumstances - as measured by general fluid intelligence - has recently been tied to the global connectivity of lateral prefrontal cortex (LPFC). Global connectivity is a broad measure that summarizes both within-network connectivity and across-network connectivity. We used additional graph theoretical measures to better characterize the nature of LPFC connectivity and its relationship with fluid intelligence. We specifically hypothesized that LPFC is a connector hub with an across-network connectivity that contributes to fluid intelligence independent of within-network connectivity. We verified that LPFC was in the top 10% of brain regions in terms of across-network connectivity, suggesting it is a strong connector hub. Importantly, we found that the LPFC across-network connectivity predicted individuals' fluid intelligence and this correlation remained statistically significant when controlling for global connectivity (which includes within-network connectivity). This supports the conclusion that across-network connectivity independently contributes to the relationship between LPFC connectivity and intelligence. These results suggest that LPFC contributes to fluid intelligence by being a connector hub with a truly global multisystem connectivity throughout the brain. © Mary Ann Liebert, Inc. 2015.


Author Keywords
fMRI;  functional connectivity;  graph theory;  individual differences;  intelligence;  prefrontal cortex;  resting-state functional connectivity


Document Type: Article
Source: Scopus




Murata, T.a , Dietrich, H.H.b c , Horiuchi, T.a , Hongo, K.a , Dacey, R.G.b
Mechanisms of magnesium-induced vasodilation in cerebral penetrating arterioles
(2015) Neuroscience Research, . Article in Press. 

DOI: 10.1016/j.neures.2015.12.005


a Department of Neurosurgery, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
b Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO 63110, United States
c Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, United States


Abstract
We investigated in cerebral penetrating arterioles the signaling mechanisms and dose-dependency of extracellular magnesium-induced vasodilation and also its vasodilatory effects in vessels preconstricted with agonists associated with delayed cerebral vasospasm following SAH. Male rat penetrating arterioles were cannulated. Their internal diameters were monitored. To investigate mechanisms of magnesium-induced vasodilation, inhibitors of endothelial function, potassium channels and endothelial impairment were tested. To simulate cerebral vasospasm we applied several spasmogenic agonists. Increased extracellular magnesium concentration produced concentration-dependent vasodilation, which was partially attenuated by non-specific calcium-sensitive potassium channel inhibitor tetraethylammonium, but not by other potassium channel inhibitors. Neither the nitric oxide synthase inhibitor L-NNA nor endothelial impairment induced by air embolism reduced the dilation. Although the magnesium-induced vasodilation was slightly attenuated by the spasmogen ET-1, neither application of PF2α nor TXA2 analog effect the vasodilation. Magnesium induced a concentration- and smooth muscle cell-dependent dilation in cerebral penetrating arterioles. Calcium-sensitive potassium channels of smooth muscle cells may play a key role in magnesium-induced vasodilation. Magnesium also dilated endothelium-impaired vessels as well as vessels preconstricted with spasmogenic agonists. These results provide a fundamental background for the clinical use of magnesium, especially in treatment against delayed cerebral ischemia or vasospasm following SAH. © 2015 Elsevier Ireland Ltd and the Japan Neuroscience Society.


Author Keywords
Cerebral penetrating arterioles;  Delayed cerebral vasospasm;  Magnesium;  Potassium channels;  Subarachnoid hemorrhage


Document Type: Article in Press
Source: Scopus




Corbetta, M.
Functional brain imaging and neurological recovery
(2015) Cognitive Neurorehabilitation, pp. 162-181. 

DOI: 10.1017/CBO9781316529898.013


Department of Neurology, Radiology, Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, MO, United States


Abstract
It is unwise to prophesy either death or recovery in acute diseases. (Hippocrates: Aphorisms II-19 c. 500 BC) Neurological recovery occurs commonly, and is mediated by many mechanisms from cells to systems. Research is currently trying to clarify which neural mechanisms of recovery are behaviorally significant. It is a common observation on neurology wards that most patients improve after a stroke or a traumatic brain injury. About 80-90% of all stroke patients have motor deficits (or hemiparesis) at onset, while only 40-60% of them have a persistent deficit at 6 months to 1 year (Dobkin, 2005). Similar degrees of recovery occur for language and visuospatial perception (Sarno & Levita, 1971; Stone et al., 1993). Whereas early (1-3 days) recovery may be explained by vascular changes, such as early canalization of an obstructed vessel or reduction in the amount of edema surrounding an ischemic area, recovery that occurs in the weeks and months following the stroke must be explained by different mechanisms. The central nervous system reacts to injuries (stroke, trauma) through changes that occur at the level of brain networks, areas, neurons, connections, molecules and even genes (Carmichael, 2003a; Nudo, 1999; Weiller, 1998). Many of these changes represent "house-keeping" operations unrelated to behavioral recovery. For instance, in the area of ischemic damage an inflammatory reaction is mounted within 24-48 hours that leads to the elimination of vascular and cellular debris. At the level of brain networks, damage to one area may lead to a decrement of synaptic activity downstream in a connected area, which will in turn downregulate its metabolic demands (diaschisis) (Baron et al., 1980). © Cambridge University Press 2008.


Author Keywords
Neurology and clinical neuroscience;  Neuropsychology


Document Type: Book Chapter
Source: Scopus




Fong, M.W.M.a , Lee, E.-J.b , Sheppard-Jones, K.c , Bishop, M.d
Home functioning profiles in people with multiple sclerosis and their relation to disease characteristics and psychosocial functioning
(2015) Work, 52 (4), pp. 767-776. 

DOI: 10.3233/WOR-152204


a Department of Neurology, Washington University, St. Louis, MO, United States
b Department of Psychology, Illinois Institute of Technology, Chicago, IL, United States
c Human Development Institute, University of Kentucky, Lexington, KY, United States
d Department of Early Childhood, Special Education, and Rehabilitation Counseling, University of Kentucky, Lexington, KY, United States


Abstract
BACKGROUND:For people with multiple sclerosis (MS), limitations in performing activities of daily living can have a significant impact on personal independence, residential safety, and quality of life. In this study we explored the utility of theHomeFunctioning Scale in identifying home functioning profiles and generating rehabilitation interventions. OBJECTIVE: The objective of this study was to determine whether distinctive and meaningful home functioning profiles could be identified among adults with MS based on Home Functioning Scale scores. METHODS: Home Functioning Scale scores and additional data from a representative national sample of 3,834 adults were analyzed. We used cluster analysis and MANOVA to identify and evaluate group differences. RESULTS: Three distinct home functioning profiles emerged in the analysis: (1) minimal impairment (31.1% of participants); (2) moderate impairment (52.4%); and (3) severe impairment (16.5%). The three groups exhibited significant differences on demographic and MS related characteristics, perceived cognitive function, perceived MS impact on physical and psychological function, and life satisfaction. CONCLUSION: The profile characteristics of the identified groups are presented and the implications of the results for rehabilitation practitioners and the investigation of home functioning in activities of daily living are discussed. © 2015 - IOS Press and the authors. All rights reserved.


Author Keywords
Activities of daily living;  Cluster analysis


Document Type: Article
Source: Scopus




Fowler, P.J.a , McGrath, L.M.b , Henry, D.B.c , Schoeny, M.d , Chavira, D.e , Taylor, J.J.f , Day, O.g
Housing mobility and cognitive development: Change in verbal and nonverbal abilities
(2015) Child Abuse and Neglect, 48, pp. 104-118. 

DOI: 10.1016/j.chiabu.2015.06.002


a Washington University in St. Louis, 1 Brookings Drive, Campus Box 1196, St. Louis, MO, United States
b American University, 4400 Massachusetts Avenue, NW, Washington, DC, United States
c University of Illinois at Chicago, 1747 West Roosevelt Road, Chicago, IL, United States
d University of Chicago, 969 E. 60th Street, Chicago, IL, United States
e DePaul University, 2219 N Kenmore Avenue, Chicago, IL, United States
f Collaborative for Academic, Social, and Emotional Learning, 815 W. Van Buren St. Ste. 210, Chicago, IL, United States
g Research Triangle International, 3040 East Cornwallis Road, Research Triangle Park, NC, United States


Abstract
This study investigates the influence of housing instability on verbal and nonverbal cognitive development among at-risk children and adolescents involved in the child welfare system. Frequent residential changes threaten child mental health, especially among low-income families. Little is known regarding disruptions to cognitive growth, specifically the impact on verbal and nonverbal abilities. The study tests whether developmental timing of housing mobility affects cognitive development beyond individual and family risks. A nationally representative study of families (n =2,442) susceptible to housing and family instability tracked children and adolescents aged 4-14 years (M =8.95 years) over 36 months following investigation by the child welfare system. Youth completed standardized cognitive assessments while caregivers reported on behavior problems and family risk at three time points. Latent growth models examined change in cognitive abilities over time. Housing mobility in the 12 months prior to baseline predicts lower verbal cognitive abilities that improve marginally. Similar effects emerge for all age groups; however, frequent moves in infancy diminish the influence of subsequent housing mobility on verbal tasks. Housing instability threatened cognitive development beyond child maltreatment, family changes, poverty, and other risks. Findings inform emerging research on environmental influences on neurocognitive development, as well as identify targets for early intervention. Systematic assessment of family housing problems, including through the child welfare system, provides opportunities for coordinated responses to prevent instability and cognitive threats. © 2015 Elsevier Ltd.


Author Keywords
Child welfare;  Cognitive development;  Developmental timing;  Family stability;  Housing mobility


Document Type: Article
Source: Scopus




Darken, R.S., Gutmann, D.H.
Neuroibromatosis type I
(2015) Molecular Oncology: Causes of Cancer and Targets for Treatment, pp. 679-685. 

DOI: 10.1017/CBO9781139046947.061


Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States


Abstract
Introduction The neurofibromatoses are composed of several related tumor predisposition syndromes, and include neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2), and segmental forms of NF1 and NF2. NF2 affects ~1:38 000 individuals worldwide. Individuals with NF2 harbor Schwann-cell tumors called schwannomas that affect cranial and peripheral nerves, as well as meningiomas and ependymomas. NF1, also known as Von Recklinghausen disease, is one of the most common neurogenetic disorders, affecting 1 in ~2500 people worldwide (1,2). It is an autosomal dominant cancer syndrome with complete penetrance, but variable phenotypic expression. In this regard, individuals within the same family may exhibit different clinical features and associated medical problems. Although NF1 is frequently inherited from a parent with NF1, 30–50% of affected individuals lack a family history of NF1. Non-tumor features of the syndrome include axillary and groin (skinfold) freckling, hyperpigmented macules (café-au-lait spots), bony abnormalities (skeletal dysplasias, dystrophic scoliosis, and tibial pseudarthrosis), and hamartomas of the iris (Lisch nodules), as well as cognitive impairment (3–5). © Cambridge University Press 2014.


Document Type: Book Chapter
Source: Scopus




Zarling, J.A.a , Brunt, V.E.b , Vallerga, A.K.c , Li, W.c , Tao, A.d , Zarling, D.A.c , Minson, C.T.b
Nitroxide pharmaceutical development for age-related degeneration and disease
(2015) Frontiers in Genetics, 6 (NOV), art. no. 00325, . 

DOI: 10.3389/fgene.2015.00325


a Department of Biology, University of Oregon, Eugene, OR, United States
b Department of Human Physiology, University of Oregon, Eugene, OR, United States
c Colby Pharmaceutical Company, Menlo Park, CA, United States
d Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, United States


Abstract
Nitroxide small molecule agents are in development as preventative or therapeutic pharmaceutical drugs for age-related macular degeneration (AMD) and cardiovascular disease, which are two major diseases of aging. These aging diseases are associated with patient genetics, smoking, diet, oxidative stress, and chronic inflammation. Nitroxide drugs preventing aging-, smoking-, high sugar or high fat diet-, or radiation- and other environmental-induced pathophysiological conditions in aging disease are reviewed. Tempol (TP), Tempol Hydroxylamine (TP-H), and TP-H prodrug (OT-551) are evaluated in (1) non-smokers versus smokers with cutaneous microvascular dysfunction, rapidly reversed by cutaneous TP; (2) elderly cancer patients at risk for radiation-induced skin burns or hair loss, prevented by topical TP; and (3) elderly smoker or non-smoker AMD patients at risk for vision loss, prevented by daily eye drops of OT-551. The human data indicates safety and efficacy for these nitroxide drugs. Both TP and TP-H topically penetrate and function in skin or mucosa, protecting and treating radiation burns and hair loss or smoking-induced cutaneous vascular dysfunction. TP and TP-H do not penetrate the cornea, while OT-551 does effectively penetrate and travels to the back of the eye, preserving visual acuity and preserving normal and low light luminance in dry AMD smokers and non-smoker patients. Topical, oral, or injectable drug formulations are discussed. © 2015 Zarling, Brunt, Vallerga, Li, Tao, Zarling and Minson.


Author Keywords
Aging;  AMD;  CVD;  Hydroxylamine;  Inflammation;  Smoking;  Tempol


Document Type: Review
Source: Scopus




Zorumski, C.F.a b , Nagele, P.b c , Mennerick, S.a b , Conway, C.R.a b
Treatment-resistant major depression: Rationale for NMDA receptors as targets and nitrous oxide as therapy
(2015) Frontiers in Psychiatry, 6 (DEC), art. no. 172, . 

DOI: 10.3389/fpsyt.2015.00172


a Department of Psychiatry, Washington University, School of Medicine, St. Louis, MO, United States
b Taylor Family Institute for Innovative Psychiatric Research, Washington University, School of Medicine, St. Louis, MO, United States
c Department of Anesthesiology, Washington University, School of Medicine, St. Louis, MO, United States


Abstract
Major depressive disorder (MDD) remains a huge personal and societal encumbrance. Particularly burdensome is a virulent subtype of MDD, treatment resistant major depression (TMRD), which afflicts 15-30% of MDD patients. There has been recent interest in N-methyl-D-aspartate receptors (NMDARs) as targets for treatment of MDD and perhaps TMRD. To date, most pre-clinical and clinical studies have focused on ketamine, although psychotomimetic and other side effects may limit ketamine's utility. These considerations prompted a recent promising pilot clinical trial of nitrous oxide, an NMDAR antagonist that acts through a mechanism distinct from that of ketamine, in patients with severe TRMD. In this paper, we review the clinical picture of TRMD as a subtype of MDD, the evolution of ketamine as a fast-acting antidepressant, and clinical and basic science studies supporting the possible use of nitrous oxide as a rapid antidepressant. © 2015 Zorumski, Nagele, Mennerick and Conway.


Author Keywords
Antidepressant;  Hippocampus;  Ketamine;  Metaplasticity;  NMDA receptors;  Suicide

 


Document Type: Review
Source: Scopus

January 25, 2016

Documents


Carvalho, J.O.a , Long, J.D.b c an , Westervelt, H.J.d , Smith, M.M.e , Bruce, J.M.f , Kim, J.-I.b an , Mills, J.A.b , Paulsen, J.S.b g h , De Soriano, I.i , Shadrick, C.i , Miller, A.i , Chiu, E.j , Preston, J.j , Goh, A.j , Antonopoulos, S.j , Loi, S.j , Chua, P.k , Komiti, A.k , Raymond, L.l , Decolongon, J.l , Fan, M.l , Coleman, A.l , Ross, C.A.m , Varvaris, M.m , Ong, M.m , Yoritomo, N.m , Mallonee, W.M.n , Suter, G.n , Samii, A.o , Freney, E.P.o , Macaraeg, A.o , Jones, R.p , Wood-Siverio, C.p , Factor, S.A.p , Barker, R.A.q , Mason, S.q , Guzman, N.V.q , McCusker, E.r , Griffith, J.r , Loy, C.r , McMillan, J.r , Gunn, D.r , Orth, M.s , Süßmuth, S.s , Barth, K.s , Trautmann, S.s , Schwenk, D.s , Eschenbach, C.s , Quaid, K.t , Wesson, M.t , Wojcieszek, J.t , Guttman, M.u , Sheinberg, A.u , Law, A.u , Karmalkar, I.u , Perlman, S.v , Clemente, B.v , Geschwind, M.D.w , Sha, S.w , Winer, J.w , Satris, G.w , Warner, T.x , Burrows, M.x , Rosser, A.y , Price, K.y , Hunt, S.y , Marshall, F.z , Chesire, A.z , Wodarski, M.z , Hickey, C.z , Panegyres, P.aa , Lee, J.aa , Tedesco, M.aa , Maxwell, B.aa , Perlmutter, J.ab , Barton, S.ab , Smith, S.ab , Miedzybrodzka, Z.ac , Rae, D.ac , Vaughan, V.ac , D'Alessandro, M.ac , Craufurd, D.ad , Bek, J.ad , Howard, E.ad , Mazzoni, P.ae , Marder, K.ae , Wasserman, P.ae , Kumar, R.af , Erickson, D.af , Reeves, C.af , Nickels, B.af , Wheelock, V.ag , Kjer, L.ag , Martin, A.ag , Farias, S.ag , Martin, W.ah , Suchowersky, O.ah , King, P.ah , Wieler, M.ah , Sran, S.ah , Ahmed, A.ai , Rao, S.ai am , Reece, C.ai , Bura, A.ai , Mourany, L.ai , Danzer, P.ar , Montross, K.ar , Harrington, D.aj , Westervalt, H.ak , Aylward, E.al , Moser, D.J.an , Williams, J.an , Downing, N.an , Magnotta, V.A.an , Johnson, H.J.an , Brashers-Krug, T.an , Vaidya, J.an , O'Leary, D.an , Young Kim, E.an , Lourens, S.an , Zhang, Y.ao , Lu, W.ao , Erwin, C.ap , Nance, M.aq , Bockholt, H.J.an , Evans, J.an , Zschiegner, R.an
The impact of oculomotor functioning on neuropsychological performance in Huntington disease
(2016) Journal of Clinical and Experimental Neuropsychology, 38 (2), pp. 217-226. 

DOI: 10.1080/13803395.2015.1101054


a Department of Psychology, Bridgewater State University, Bridgewater, MA, United States
b Department of Psychiatry, Carver College of Medicine, University of Iowa, 500 Newton Road MEB 1-305, Iowa City, IA, United States
c Department of Biostatistics, College of Public Health, University of Iowa, Iowa City, IA, United States
d Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, United States
e Department of Neuropsychology, VA Maryland Healthcare System, Baltimore, MD, United States
f Department of Psychology, University of Missouri-Kansas City, Kansas City, MO, United States
g Department of Neurology, Carver College of Medicine, University of Iowa, Iowa City, IA, United States
h Department of Psychology, University of Iowa, Iowa City, IA, United States
i University of Iowa, Iowa City, IA, United States
j St. Vincent's Hospital, University of Melbourne, Kew, VIC, Australia
k University of Melbourne, Royal Melbourne Hospital, Melbourne, VIC, Australia
l University of British Columbia, Vancouver, BC, Canada
m Johns Hopkins University, Baltimore, MD, United States
n Hereditary Neurological Disease Centre, Wichita, KS, United States
o University of Washington, VA Puget Sound Health Care System, Seattle, WA, United States
p Emory University School of Medicine, Atlanta, GA, United States
q John Van Geest Centre for Brain Repair, Cambridge, United Kingdom
r Westmead Hospital, Sydney, NSW, Australia
s University of Ulm, Ulm, Germany
t Indiana University School of Medicine, Indianapolis, IN, United States
u Centre for Addiction and Mental Health, University of Toronto, Markham, ON, Canada
v UCLA Medical Center, Los Angeles, CA, United States
w University of California, San Francisco, CA, United States
x National Hospital for Neurology and Neurosurgery, London, United Kingdom
y Cardiff University, Cardiff, United Kingdom
z University of Rochester, Rochester, NY, United States
aa Neurosciences Unit, Graylands, Selby-Lemnos and Special Care Health Services, Perth, WA, Australia
ab Washington University, St. Louis, MO, United States
ac Clinical Genetics Centre, Aberdeen, United Kingdom
ad University of Manchester, Manchester, United Kingdom
ae Columbia University Medical Center, New York, NY, United States
af Colorado Neurological Institute, Englewood, CO, United States
ag University of California, Davis, Sacramento, CA, United States
ah University of Alberta, Edmonton, AB, Canada
ai Cleveland Clinic Foundation, Cleveland, OH, United States
aj University of California, San Diego, United States
ak Rhode Island Hospital, Alpert Medical School of Brown University, United States
al Seattle Children's Research Institute, United States
am Cleveland Clinic, United States
an University of Iowa, United States
ao University of Indiana, United States
ap Texas Tech University Health Sciences Center, United States
aq University of Minnesota, United States


Abstract
Huntington disease (HD) is a neurodegenerative condition with prominent motor (including oculomotor), cognitive, and psychiatric effects. While neuropsychological deficits are present in HD, motor impairments may impact performance on neuropsychological measures, especially those requiring a speeded response, as has been demonstrated in multiple sclerosis and schizophrenia. The current study is the first to explore associations between oculomotor functions and neuropsychological performance in HD. Participants with impaired oculomotor functioning performed worse than those with normal oculomotor functioning on cognitive tasks requiring oculomotor involvement, particularly on psychomotor speed tasks, controlling for covariates. Consideration of oculomotor dysfunction on neuropsychological performance is critical, particularly for populations with motor deficits. © 2016 Taylor & Francis.


Author Keywords
Huntington disease;  Neuropsychology;  Oculomotor functioning;  PREDICT-HD;  Processing speed


Document Type: Article
Source: Scopus


Gaffrey, M.S.a , Barch, D.M.a b c , Luby, J.L.a
Amygdala reactivity to sad faces in preschool children: An early neural marker of persistent negative affect
(2016) Developmental Cognitive Neuroscience, 17, pp. 94-100. 

DOI: 10.1016/j.dcn.2015.12.015


a Washington University in St. Louis, Department of Psychiatry, Campus Box: 8511, 660 South Euclid Avenue, Saint Louis, MO, United States
b Washington University in St. Louis, Department of Psychology, Campus Box: 8511, 660 South Euclid Avenue, Saint Louis, MO, United States
c Washington University in St. Louis, Department of Radiology, Campus Box: 8511, 660 South Euclid Avenue, Saint Louis, MO, United States


Abstract
Background Elevated negative affect is a highly salient risk factor for later internalizing disorders. Very little is known about the early neurobiological correlates of negative affect and whether they associate with developmental changes in negative emotion. Such information may prove critical for identifying children deviating from normative developmental trajectories of negative affect and at increased risk for later internalizing disorders. The current study examined the relationship between amygdala activity and negative affect measured concurrently and approximately 12 months later in preschool-age children. Method Amygdala activity was assessed using functional magnetic resonance imaging in 31 medication-naive preschool age children. Negative affect was measured using parent report both at the time of scan and 12 months later. Results Negative affect at baseline was positively correlated with right amygdala activity to sad faces, right amygdala activity to happy faces, and left amygdala activity to happy faces. Right amygdala activity to sad faces also positively predicted parent-reported negative affect 12 months later even when negative affect reported at baseline was controlled. Conclusions The current findings provide preliminary evidence for amygdala activity as a potential biomarker of persistent negative affect during early childhood and suggest future work examining the origins and long-term implications of this relationship is necessary. © 2016 Published by Elsevier Ltd.


Author Keywords
Amygdala;  Child;  Development;  fMRI;  Irritability;  Negative affect


Document Type: Article
Source: Scopus


Kim, M.M.a , Camelo-Piragua, S.b , Schipper, M.a c , Tao, Y.a c , Normolle, D.h , Junck, L.d , Mammoser, A.d , Betz, B.L.b , Cao, Y.a e f , Kim, C.J.a , Heth, J.g , Sagher, O.g , Lawrence, T.S.a , Tsien, C.I.i
Gemcitabine Plus Radiation Therapy for High-Grade Glioma: Long-Term Results of a Phase 1 Dose-Escalation Study
(2016) International Journal of Radiation Oncology Biology Physics, 94 (2), pp. 305-311. 

DOI: 10.1016/j.ijrobp.2015.10.032


a Department of Radiation Oncology, University of Michigan, 1301 Catherine St, Ann Arbor, MI, United States
b Department of Pathology, University of Michigan, Ann Arbor, MI, United States
c Department of Biostatistics, University of Michigan, Ann Arbor, MI, United States
d Department of Neurology, University of Michigan, Ann Arbor, MI, United States
e Department of Radiology, University of Michigan, Ann Arbor, MI, United States
f Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, United States
g Department of Neurosurgery, University of Michigan, Ann Arbor, MI, United States
h Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA, United States
i Department of Radiation Oncology, Washington University, St. Louis, MO, United States


Abstract
Purpose To evaluate the tolerability and efficacy of gemcitabine plus radiation therapy (RT) in this phase 1 study of patients with newly diagnosed malignant glioma (HGG). Patients and Methods Between 2004 and 2012, 29 adults with HGG were enrolled. After any extent of resection, RT (60 Gy over 6 weeks) was given concurrent with escalating doses of weekly gemcitabine. Using a time-to-event continual reassessment method, 5 dose levels were evaluated starting at 500 mg/m2 during the last 2 weeks of RT and advanced stepwise into earlier weeks. The primary objective was to determine the recommended phase 2 dose of gemcitabine plus RT. Secondary objectives included progression-free survival, overall survival (OS), and long-term toxicity. Results Median follow-up was 38.1 months (range, 8.9-117.5 months); 24 patients were evaluable for toxicity. After 2005 when standard practice changed, patients with World Health Organization grade 4 tumors were no longer enrolled. Median progression-free survival for 22 patients with grade 3 tumors was 26.0 months (95% confidence interval [CI] 15.6-inestimable), and OS was 48.5 months (95% CI 26.8-inestimable). In 4 IDH mutated, 1p/19q codeleted patients, no failures occurred, with all but 1 alive at time of last follow-up. Seven with IDH mutated, non-codeleted tumors with ATRX loss had intermediate OS of 73.5 months (95% CI 32.8-inestimable). Six nonmutated, non-codeleted patients had a median OS of 26.5 months (95% CI 25.4-inestimable). The recommended phase 2 dose of gemcitabine plus RT was 750 mg/m2/wk given the last 4 weeks of RT. Dose reductions were most commonly due to grade 3 neutropenia; no grade 4 or 5 toxicities were seen. Conclusions Gemcitabine concurrent with RT is well-tolerated and yields promising outcomes, including in patients with adverse molecular features. It is a candidate for further study, particularly for poor-prognosis patient subgroups with HGG.


Document Type: Article
Source: Scopus


Honda, M.a g , Minami, I.b , Tooi, N.b , Morone, N.b , Nishioka, H.b , Uemura, K.c , Kinoshita, A.d , Heuser, J.E.b e , Nakatsuji, N.b f , Aiba, K.a b
The modeling of Alzheimer's disease by the overexpression of mutant Presenilin 1 in human embryonic stem cells
(2016) Biochemical and Biophysical Research Communications, 469 (3), pp. 587-592. 

DOI: 10.1016/j.bbrc.2015.12.025


a Stem Cell and Drug Discovery Institute, Kyoto, Japan
b Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Kyoto,Yoshida-Ushinomiyacho, Sakyo-ku, Japan
c Department of Neurology, Kyoto University Graduate School of Medicine, Kyoto, Japan
d School of Human Health Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan
e Department of Cell Biology, Washington University, St. Louis, MO, United States
f Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan
g ReproCELL Inc., Yokohama, Kanagawa, Japan


Abstract
Cellular disease models are useful tools for Alzheimer's disease (AD) research. Pluripotent stem cells, including human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs), are promising materials for creating cellular models of such diseases. In the present study, we established cellular models of AD in hESCs that overexpressed the mutant Presenilin 1 (PS1) gene with the use of a site-specific gene integration system. The overexpression of PS1 did not affect the undifferentiated status or the neural differentiation ability of the hESCs. We found increases in the ratios of amyloid-β 42 (Aβ42)/Aβ40 and Aβ43/Aβ40. Furthermore, synaptic dysfunction was observed in a cellular model of AD that overexpressed mutant PS1. These results suggest that the AD phenotypes, in particular, the electrophysiological abnormality of the synapses in our AD models might be useful for AD research and drug discovery. © 2015 The Authors.


Author Keywords
Alzheimer's disease;  Cellular disease model;  Human embryonic stem cell;  Presenilin 1;  Synaptic dysfunction


Document Type: Article
Source: Scopus


Boles, R.E.a , Halbower, A.C.a , Daniels, S.a , Gunnarsdottir, T.b , Whitesell, N.a , Johnson, S.L.a
Family Chaos and Child Functioning in Relation to Sleep Problems Among Children at Risk for Obesity
(2016) Behavioral Sleep Medicine, pp. 1-15. Article in Press. 

DOI: 10.1080/15402002.2015.1104687


a Department of Pediatrics, University of Colorado–Anschutz Medical Campus, Aurora, Colorado, USA
b Department of Psychiatry, Washington University, St. Louis, Missouri, USA


Abstract
This study evaluated the influence of child and family functioning on child sleep behaviors in low-income minority families who are at risk for obesity. A cross-sectional study was utilized to measure child and family functioning from 2013 to 2014. Participants were recruited from Head Start classrooms while data were collected during home visits. A convenience sample of 72 low-income Hispanic (65%) and African American (32%) families of preschool-aged children were recruited for this study. We assessed the association of child and family functioning with child sleep behaviors using a multivariate multiple linear regression model. Bootstrap mediation analyses examined the effects of family chaos between child functioning and child sleep problems. Poorer child emotional and behavioral functioning related to total sleep behavior problems. Chaos associated with bedtime resistance significantly mediated the relationship between Behavioral and Emotional Screening System (BESS) and Bedtime Resistance. Families at high risk for obesity showed children with poorer emotional and behavioral functioning were at higher risk for problematic sleep behaviors, although we found no link between obesity and child sleep. Family chaos appears to play a significant role in understanding part of these relationships. Future longitudinal studies are necessary to establish causal relationships between child and family functioning and sleep problems to further guide obesity interventions aimed at improving child sleep routines and increasing sleep duration. © 2016, Routledge. All rights reserved.


Document Type: Article in Press
Source: Scopus


Carney, R.M.a , Freedland, K.E.a , Steinmeyer, B.a , Rubin, E.H.a , Mann, D.L.b , Rich, M.W.b
Cardiac risk markers and response to depression treatment in patients with coronary heart disease
(2016) Psychosomatic Medicine, 78 (1), pp. 49-59. 

DOI: 10.1097/PSY.0000000000000245


a Department of Psychiatry, United States
b Department of Medicine, Washington University School of Medicine, St Louis, MO, United States


Abstract
Background: Depression is associated with an increased risk of mortality in patients with coronary heart disease. There is evidence that this risk may be reduced in patients who respond to depression treatment. The purpose of this study was to determine whether cardiac risk markers predict poor response to depression treatment and, second, whether they improve with successful treatment. Methods: One hundred fifty-seven patients with stable coronary heart disease who met the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria for a moderate to severe major depressive episode were treated with cognitive behavior therapy, either alone or combined with an antidepressant, for up to 16 weeks. Depression, physical activity, sleep quality, thyroid hormones (total thyroxine [T4] and free T4), and inflammatory blood markers (C-reactive protein, interleukin-6, tumor necrosis factor) were assessed at baseline and after 16 weeks of treatment. Results: Themean (SD)Beck Depression Inventory scoreswere 30.2 (8.5) at baseline and 8.5 (7.8) at 16weeks.More than50% of the participants met the criteria for depression remission (17-item Hamilton Rating Scale for Depression ≤7) at 16 weeks. Only free T4 thyroid hormone at baseline predicted poor response to depression treatment after adjustment for potential confounders (p=.004). Improvement in sleep quality (p =.012) and physical activity level (p=.041) correlated withimprovement in depression. None of the inflammatory markers predicted posttreatment depression or changed with depression. Conclusions: Thyroid hormone (T4) level predicted depression treatment outcome, and improvement in depression correlated with improvement in sleep and physical activity. More detailed studies of thyroid function and objective assessments of sleep and physical activity in relation to depression improvement and cardiac outcomes are needed. © 2015 by the American Psychosomatic Society.


Author Keywords
Cardiac risk markers;  Depressive disorder;  Treatment


Document Type: Article
Source: Scopus


Kunkle, B.W.a , Jaworski, J.a , Barral, S.b c d , Vardarajan, B.b c f g , Beecham, G.W.a , Martin, E.R.a , Cantwell, L.S.h , Partch, A.h , Bird, T.D.i j , Raskind, W.H.j k , Destefano, A.L.l , Carney, R.M.a m , Cuccaro, M.a n , Vance, J.M.a n , Farrer, L.A.k o p q r , Goate, A.M.f g , Foroud, T.s , Mayeux, R.P.b c d e t , Schellenberg, G.D.h , Haines, J.L.u , Pericak-Vance, M.A.a n
Genome-wide linkage analyses of non-Hispanic white families identify novel loci for familial late-onset Alzheimer's disease
(2016) Alzheimer's and Dementia, 12 (1), pp. 2-10. 

DOI: 10.1016/j.jalz.2015.05.020


a John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL, United States
b Taub Institute of Research on Alzheimer's Disease, College of Physicians and Surgeons, Columbia University, New York, NY, United States
c Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York, NY, United States
d Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, NY, United States
e Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, NY, United States
f Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
g Hope Center for Neurological Disorders, Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
h Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
i Department of Neurology, University of Washington, Seattle, WA, United States
j Department of Medicine, University of Washington, Seattle, WA, United States
k Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, United States
l Department of Biostatistics, Boston University School of Public Health, Boston, MA, United States
m Department of Psychiatry and Behavioral Sciences, Miller School of Medicine, University of Miami, Miami, FL, United States
n Dr. John T. MacDonald Foundation Department of Human Genetics, Miller School of Medicine, University of Miami, Miami, FL, United States
o Department of Medicine (Biomedical Genetics), Boston University School of Medicine and Public HealthMA, United States
p Department of Neurology, Boston University School of Medicine and Public HealthMA, United States
q Department of Ophthalmology, Boston University School of Medicine and Public HealthMA, United States
r Department of Epidemiology, Boston University School of Public HealthMA, United States
s Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, United States
t Department of Epidemiology, School of Public Health, Columbia University, New York, NY, United States
u Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH, United States


Abstract
Introduction Few high penetrance variants that explain risk in late-onset Alzheimer's disease (LOAD) families have been found. Methods We performed genome-wide linkage and identity-by-descent (IBD) analyses on 41 non-Hispanic white families exhibiting likely dominant inheritance of LOAD, and having no mutations at known familial Alzheimer's disease (AD) loci, and a low burden of APOE ε4 alleles. Results Two-point parametric linkage analysis identified 14 significantly linked regions, including three novel linkage regions for LOAD (5q32, 11q12.2-11q14.1, and 14q13.3), one of which replicates a genome-wide association LOAD locus, the MS4A6A-MS4A4E gene cluster at 11q12.2. Five of the 14 regions (3q25.31, 4q34.1, 8q22.3, 11q12.2-14.1, and 19q13.41) are supported by strong multipoint results (logarithm of odds [LOD
] ≥1.5). Nonparametric multipoint analyses produced an additional significant locus at 14q32.2 (LOD = 4.18). The 1-LOD confidence interval for this region contains one gene, C14orf177, and the microRNA Mir-320, whereas IBD analyses implicates an additional gene BCL11B, a regulator of brain-derived neurotrophic signaling, a pathway associated with pathogenesis of several neurodegenerative diseases. Discussion Examination of these regions after whole-genome sequencing may identify highly penetrant variants for familial LOAD. © 2016 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.


Author Keywords
Familial;  Genetics;  High penetrance;  Identity by descent;  Late-onset Alzheimer's disease;  Linkage;  Non-Hispanic white


Document Type: Article
Source: Scopus


Halstead, M.E.
Pharmacologic Therapies for Pediatric Concussions
(2016) Sports Health, 8 (1), pp. 50-52. Cited 1 time.

DOI: 10.1177/1941738115622158


Departments of Orthopedics and Pediatrics, Washington University School of Medicine, St Louis, MO, United States


Abstract
Context: Pediatric concussions are common, and emphasis on correct diagnosis and management is stressed in consensus guidelines. Medications may have a role in management of concussion, but no consensus exists regarding appropriate pharmacologic therapy. Evidence Acquisition: Nonsystematic review. Study Design: Clinical review. Level of Evidence: Level 4. Results: There is limited evidence for hypertonic saline to improve posttraumatic headache in the emergency department setting. There is essentially no evidence for the use of any other medication in management of pediatric sport-related concussion. Conclusion: Further research is necessary to determine whether there is benefit to the use of any pharmacotherapy in the management of pediatric-aged athletes with concussions. © 2015, © 2015 The Author(s).


Author Keywords
concussion;  medication;  pediatric;  pharmacology


Document Type: Article
Source: Scopus

Nicol, G.E.a , Campagna, E.J.b , Garfield, L.D.c , Newcomer, J.W.d , Parks, J.J.e f , Morrato, E.H.b

The role of clinical setting and management approach in metabolic testing among youths and adults treated with antipsychotics
(2016) Psychiatric Services, 67 (1), pp. 128-132. 

DOI: 10.1176/appi.ps.201400428


a Department of Psychiatry, Washington University, School of Medicine, St. Louis, MO, United States
b Adult and Child Center for Health Outcomes Research and Delivery Science, University of Colorado, Anschutz Medical Campus, Denver, United States
c Mercy Virtual Care Center, St. Louis, United States
d Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, United States
e Missouri Department of Social Services, Jefferson City, United States
f Missouri Institute of Mental Health, University of Missouri, St. Louis, United States


Abstract
Objective: This study compared metabolic screening among patients who received antipsychotic treatment at community mental health centers (CMHCs), with or without case management, and patients treated elsewhere. Methods: Rates of glucose and lipid testing among youths and adults in Missouri Medicaid (N=9,473) who received antipsychotic treatment at CMHCs, with and without case management, were evaluated. Multivariable logistic regressions determined which characteristics were independently associated with metabolic testing. Results: A total of 37.0% and 17.3% of youths and 68.7% and 34.9% of adults had glucose and lipid testing, respectively. Compared with treatment elsewhere, treatment at CMHCs, with or without casemanagement, respectively, was associated with higher odds of glucose testing (youths, adjusted odds ratio [AOR]=1.68 and 1.89; adults, AOR=1.43 and 1.44) and lipid testing (youths, AOR=2.40 and 2.35; adults, AOR=1.97 and 1.48). Conclusions: CMHCs had higher rates of metabolic testing, possibly reflecting Missouri's efforts to promote testing in these settings.


Document Type: Article
Source: Scopus


Diao, F.a , Mena, W.b , Shi, J.c , Park, D.c , Diao, F.a , Taghert, P.c , Ewer, J.b , White, B.H.a
The splice isoforms of the Drosophila ecdysis triggering hormone receptor have developmentally distinct roles
(2016) Genetics, 202 (1), pp. 175-189. 

DOI: 10.1534/genetics.115.182121


a Laboratory of Molecular Biology, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, United States
b Centro Interdisciplinario de Neurociencia, Universidad de Valparaiso, Playa Ancha, Valparaiso, Chile
c Department of Anatomy and Neurobiology, Washington University School of Medicine, St Louis, MO, United States


Abstract
To grow, insects must periodically shed their exoskeletons. This process, called ecdysis, is initiated by the endocrine release of Ecdysis Trigger Hormone (ETH) and has been extensively studied as a model for understanding the hormonal control of behavior. Understanding how ETH regulates ecdysis behavior, however, has been impeded by limited knowledge of the hormone’s neuronal targets. An alternatively spliced gene encoding a G-protein-coupled receptor (ETHR) that is activated by ETH has been identified, and several lines of evidence support a role in ecdysis for its A-isoform. The function of a second ETHR isoform (ETHRB) remains unknown. Here we use the recently introduced “Trojan exon” technique to simultaneously mutate the ETHR gene and gain genetic access to the neurons that express its two isoforms. We show that ETHRA and ETHRB are expressed in largely distinct subsets of neurons and that ETHRA- but not ETHRB-expressing neurons are required for ecdysis at all developmental stages. However, both genetic and neuronal manipulations indicate an essential role for ETHRB at pupal and adult, but not larval, ecdysis. We also identify several functionally important subsets of ETHR-expressing neurons including one that coexpresses the peptide Leucokinin and regulates fluid balance to facilitate ecdysis at the pupal stage. The general strategy presented here of using a receptor gene as an entry point for genetic and neuronal manipulations should be useful in establishing patterns of functional connectivity in other hormonally regulated networks. © 2016 by the Genetics Society of America.


Author Keywords
Behavior;  Ecdysis;  Hormones;  Neural circuit;  Transgene targeting


Document Type: Article
Source: Scopus

Urano, F.a b

Wolfram Syndrome: Diagnosis, Management, and Treatment
(2016) Current Diabetes Reports, 16 (1), art. no. 6, pp. 1-8. 

DOI: 10.1007/s11892-015-0702-6


a Department of Medicine, Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, St. Louis, MO, United States
b Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States


Abstract
Wolfram syndrome is a rare genetic disorder characterized by juvenile-onset diabetes mellitus, diabetes insipidus, optic nerve atrophy, hearing loss, and neurodegeneration. Although there are currently no effective treatments that can delay or reverse the progression of Wolfram syndrome, the use of careful clinical monitoring and supportive care can help relieve the suffering of patients and improve their quality of life. The prognosis of this syndrome is currently poor, and many patients die prematurely with severe neurological disabilities, raising the urgency for developing novel treatments for Wolfram syndrome. In this article, we describe natural history and etiology, provide recommendations for diagnosis and clinical management, and introduce new treatments for Wolfram syndrome. © 2016, The Author(s).


Author Keywords
Blindness;  Deafness;  Endoplasmic reticulum stress;  Genetic disorder;  Neurodegeneration;  Type 1 diabetes;  Type 2 diabetes;  Wolfram syndrome;  β cells


Document Type: Review
Source: Scopus


Hambardzumyan, D.a , Gutmann, D.H.b , Kettenmann, H.c
The role of microglia and macrophages in glioma maintenance and progression
(2015) Nature Neuroscience, 19 (1), pp. 20-27. 

DOI: 10.1038/nn.4185


a Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States
b Department of Neurology, Washington University, School of Medicine, St. Louis, MO, United States
c Max Delbrück Center for Molecular Medicine, Berlin, Germany


Abstract
There is a growing recognition that gliomas are complex tumors composed of neoplastic and non-neoplastic cells, which each individually contribute to cancer formation, progression and response to treatment. The majority of the non-neoplastic cells are tumor-associated macrophages (TAMs), either of peripheral origin or representing brain-intrinsic microglia, that create a supportive stroma for neoplastic cell expansion and invasion. TAMs are recruited to the glioma environment, have immune functions, and can release a wide array of growth factors and cytokines in response to those factors produced by cancer cells. In this manner, TAMs facilitate tumor proliferation, survival and migration. Through such iterative interactions, a unique tumor ecosystem is established, which offers new opportunities for therapeutic targeting. © 2016 Nature America, Inc.


Document Type: Review
Source: Scopus


Zhang, B.a b , Guan, F.a f g , Chen, G.b , Lin, H.c , Zhang, T.d , Feng, J.e , Li, L.b , Fu, D.b g
Common variants in SLC1A2 and schizophrenia: Association and cognitive function in patients with schizophrenia and healthy individuals
(2015) Schizophrenia Research, 169 (1-3), pp. 128-134. Cited 1 time.

DOI: 10.1016/j.schres.2015.10.012


a Department of Forensic Psychiatry, School of Medicine and Forensics, Xi'an Jiaotong University, Xi'an, China
b Key Laboratory of National Ministry of Health for Forensic Sciences, School of Medicine and Forensics, Xi'an Jiaotong University, Xi'an, Shaanxi, China
c Xi'an Mental Health Center, Xi'an, Shannxi, China
d Department of Biology and Biomedical Sciences, Washington University in Saint LouisMO, United States
e School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, Shaanxi, China
f Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, China
g Institute of Human Genomics and Forensic Sciences, Xi'an, China


Abstract
SLC1A2 is reported to be responsible for the majority of glutamate uptake, which has a crucial role in neural development and synaptic plasticity, and a disturbance in glutamatergic transmission has been suggested to be involved in the pathophysiology of schizophrenia (SCZ) and cognition. To evaluate the relationship of common variants within SLC1A2 with SCZ and cognition in Han Chinese, 28 tag SNPs were genotyped in the discovery stage, which included 1117 cases and 2289 controls; significantly associated markers were genotyped in the replication stage with 2128 cases and 3865 controls. The rs4354668 SNP was identified to be significantly associated with SCZ in both datasets, and a similar pattern was also observed in the two-stage study on conducting imputation and haplotype association analyses. In addition, significant associations between the rs4354668 SNP and cognition were observed when processing the perseverative error of the Wisconsin Card Sorting Test in patients and controls. Our results provide supportive evidence for an effect of SLC1A2 on the etiology of SCZ, suggesting that genetic variation (rs4354668 and its haplotypes) in SLC1A2 may be involved in impaired executive function, which adds to the current body of knowledge regarding the risk of SCZ and the impairment of cognitive performance. © 2015 Elsevier B.V.


Author Keywords
Cognitive performance;  Glutamate uptake;  Perseverative errors;  Schizophrenia susceptibility;  SLC1A2 gene


Document Type: Article
Source: Scopus


Mamah, D.a , Wen, J.b , Luo, J.b , Ulrich, X.b , Barch, D.M.a c d , Yablonskiy, D.b
Subcomponents of brain T2* relaxation in schizophrenia, bipolar disorder and siblings: A Gradient Echo Plural Contrast Imaging (GEPCI) study
(2015) Schizophrenia Research, 169 (1-3), pp. 36-45. 

DOI: 10.1016/j.schres.2015.10.004


a Department of Psychiatry, Washington University Medical School, St. Louis, United States
b Department of Radiology, Washington University Medical School, St. Louis, United States
c Department of Psychology, Washington University, St. Louis, United States
d Department of Anatomy and Neurobiology, Washington University, St. Louis, United States


Abstract
Investigating brain tissue T2* relaxation properties in vivo can potentially guide the uncovering of neuropathology in psychiatric illness, which is traditionally examined post mortem. We use an MRI-based Gradient Echo Plural Contrast Imaging (GEPCI) technique that produces inherently co-registered images allowing quantitative assessment of tissue cellular and hemodynamic properties. Usually described as R2* (=1/T2*) relaxation rate constant, recent developments in GEPCI allow the separation of cellular-specific (R2*C) and hemodynamic (BOLD) contributions to the MRI signal decay. We characterize BOLD effect in terms of tissue concentration of deoxyhemoglobin, i.e. CDEOXY, which reflects brain activity. 17 control (CON), 17 bipolar disorder (BPD), 16 schizophrenia (SCZ), and 12 unaffected schizophrenia sibling (SIB) participants were scanned and post-processed using GEPCI protocols. A MANOVA of 38gray matter regions ROIs showed significant group effects for CDEOXY but not for R2*C. In the three non-control groups, 71-92% of brain regions had increased CDEOXY. Group effects were observed in the superior temporal cortex and the thalamus. Increased superior temporal cortex CDEOXY was found in SCZ (p=0.01), BPD (p=0.01) and SIB (p=0.02), with bilateral effects in SCZ and only left hemisphere effects in BPD and SIB. Thalamic CDEOXY abnormalities were observed in SCZ (p=0.003), BPD (p=0.03) and SIB (p=0.02). Our results suggest that increased activity in certain brain regions is part of the underlying pathophysiology of specific psychiatric disorders. High CDEOXY in the superior temporal cortex suggests abnormal activity with auditory, language and/or social cognitive processing. Larger studies are needed to clarify the clinical significance of relaxometric abnormalities. © 2015 Elsevier B.V.


Author Keywords
Bipolar;  Brain;  GEPCI;  MRI;  Relaxometry;  Schizophrenia;  Siblings;  T2*


Document Type: Article
Source: Scopus


Sahlein, D.H.a b , Fouladvand, M.c d , Becske, T.e f , Saatci, I.g , McDougall, C.G.h , Szikora, I.i , Lanzino, G.j , Moran, C.J.k , Woo, H.H.l , Lopes, D.K.m , Berez, A.L.n , Cher, D.J.o , Siddiqui, A.H.p , Levy, E.I.q , Albuquerque, F.C.r , Fiorella, D.J.s , Berentei, Z.t , Marosfoi, M.u , Cekirge, S.H.v , Kallmes, D.F.w , Nelson, P.K.x y
Neuroophthalmological outcomes associated with use of the Pipeline Embolization Device: analysis of the PUFS trial results
(2015) Journal of neurosurgery, 123 (4), pp. 897-905. 

DOI: 10.3171/2014.12.JNS141777


a Departments of 1 Neurology
b Radiology
c Departments of 1 Neurology
d Ophthalmology, and
e Departments of 1 Neurology
f Radiology
g Department of Interventional Neuroradiology, Koru Hospitals, Ankara;
h Division of Neurological Surgery, Barrow Neurological Institute, Phoenix, Arizona;
i National Institute of Neurosciences, Budapest, Hungary;
j Department of Neurosurgery, Mayo Clinic, Rochester, Minnesota;
k Division of Interventional Neuroradiology, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri;
l Department of Neurological Surgery, Stony Brook University, Stony Brook;
m Department of Neurological Surgery, Rush University, Chicago, Illinois;
n Alembic LLC, Mountain View, California
o Wild Iris Consulting LLC, Palo Alto; and
p Department of Neurosurgery, University at Buffalo, Buffalo, New York;
q Department of Neurosurgery, University at Buffalo, Buffalo, New York;
r Division of Neurological Surgery, Barrow Neurological Institute, Phoenix, Arizona;
s Department of Neurological Surgery, Stony Brook University, Stony Brook;
t National Institute of Neurosciences, Budapest, Hungary;
u National Institute of Neurosciences, Budapest, Hungary;
v Department of Interventional Neuroradiology, Bayindir Hospitals, Ankara/Istanbul, Turkey;
w Department of Neurosurgery, Mayo Clinic, Rochester, Minnesota;
x Radiology
y Neurosurgery, New York University Langone Medical Center, New York;


Abstract
OBJECT: Neuroophthalmological morbidity is commonly associated with large and giant cavernous and supraclinoid internal carotid artery (ICA) aneurysms. The authors sought to evaluate the neuroophthalmological outcomes after treatment of these aneurysms with the Pipeline Embolization Device (PED).

METHODS: The Pipeline for Uncoilable or Failed Aneurysms (PUFS) trial was an international, multicenter prospective trial evaluating the safety and efficacy of the PED. All patients underwent complete neuroophthalmological examinations both before the PED procedure and at a 6-month follow-up. All examinations were performed for the purpose of this study and according to study criteria.

RESULTS: In total, 108 patients were treated in the PUFS trial, 98 of whom had complete neuroophthalmological follow-up. Of the patients with complete follow-up, 39 (40%) presented with a neuroophthalmological baseline deficit that was presumed to be attributable to the aneurysm, and patients with these baseline deficits had significantly larger aneurysms. In 25 of these patients (64%), the baseline deficit showed at least some improvement 6 months after PED treatment, whereas in 1 patient (2.6%), the deficits only worsened. In 5 patients (5%), new deficits had developed at the 6-month follow-up, while in another 6 patients (6%), deficits that were not originally assumed to be related to the aneurysm had improved by that time. A history of diabetes was associated with failure of the baseline deficits to improve after the treatment. The aneurysm maximum diameter was significantly larger in patients with a new deficit or a worse baseline deficit at 6 months postprocedure.

CONCLUSIONS: Patients treated with the PED for large and giant ICA aneurysms had excellent neuroophthalmological outcomes 6 months after the procedure, with deficits improving in most of the patients, very few deficits worsening, and few new deficits developing.


Author Keywords
aneurysm;  aneurysm embolization;  APD = afferent pupillary defect;  CN = cranial nerve;  flow diversion;  ICA = internal carotid artery;  neuroophthalmology;  PED = Pipeline Embolization Device;  Pipeline Embolization Device;  PUFS = Pipeline for Uncoilable or Failed Aneurysms;  VA = visual acuity;  vascular disorders;  VF = visual field


Document Type: Article
Source: Scopus



Reynolds, M.R.a , Buckley, R.T.b , Indrakanti, S.S.c , Turkmani, A.H.d , Oh, G.e , Crobeddu, E.f , Fargen, K.M.g , El Ahmadieh, T.Y.h , Naidech, A.M.i , Amin-Hanjani, S.j , Lanzino, G.k , Hoh, B.L.l , Bendok, B.R.m , Zipfel, G.J.n
The safety of vasopressor-induced hypertension in subarachnoid hemorrhage patients with coexisting unruptured, unprotected intracranial aneurysms
(2015) Journal of neurosurgery, 123 (4), pp. 862-871. 

DOI: 10.3171/2014.12.JNS141201


a Department of Neurological Surgery, Washington University Medical School, St. Louis, Missouri;
b Department of Neurological Surgery, Washington University Medical School, St. Louis, Missouri;
c Department of Neurological Surgery, Washington University Medical School, St. Louis, Missouri;
d Department of Neurological Surgery, University of Illinois at Chicago, Illinois;
e Department of Neurological Surgery, University of Illinois at Chicago, Illinois;
f Department of Neurological Surgery, Mayo Clinic, Rochester, Minnesota;
g Department of Neurological Surgery, University of Florida, Gainesville, Florida; and
h Department of Neurosurgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois
i Department of Neurosurgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois
j Department of Neurological Surgery, University of Illinois at Chicago, Illinois;
k Department of Neurological Surgery, Mayo Clinic, Rochester, Minnesota;
l Department of Neurological Surgery, University of Florida, Gainesville, Florida; and
m Department of Neurosurgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois
n Department of Neurological Surgery, Washington University Medical School, St. Louis, Missouri;


Abstract
OBJECT: Vasopressor-induced hypertension (VIH) is an established treatment for patients with aneurysmal subarachnoid hemorrhage (SAH) who develop vasospasm and delayed cerebral ischemia (DCI). However, the safety of VIH in patients with coincident, unruptured, unprotected intracranial aneurysms is uncertain.

METHODS: This retrospective multiinstitutional study identified 1) patients with aneurysmal SAH and 1 or more unruptured, unprotected aneurysms who required VIH therapy (VIH group), and 2) patients with aneurysmal SAH and 1 or more unruptured, unprotected aneurysms who did not require VIH therapy (non-VIH group). All patients had previously undergone surgical or endovascular treatment for the presumed ruptured aneurysm. Comparisons between the VIH and non-VIH patients were made in terms of the patient characteristics, clinical and radiographic severity of SAH, total number of aneurysms, number of ruptured/unruptured aneurysms, aneurysm location/size, number of unruptured and unprotected aneurysms during VIH, severity of vasospasm, degree of hypervolemia, and degree and duration of VIH therapy.

RESULTS: For the VIH group (n = 176), 484 aneurysms were diagnosed, 231 aneurysms were treated, and 253 unruptured aneurysms were left unprotected during 1293 total days of VIH therapy (5.12 total years of VIH therapy for unruptured, unprotected aneurysms). For the non-VIH group (n = 73), 207 aneurysms were diagnosed, 93 aneurysms were treated, and 114 unruptured aneurysms were left unprotected. For the VIH and non-VIH groups, the mean sizes of the ruptured (7.2 ± 0.3 vs 7.8 ± 0.6 mm, respectively; p = 0.27) and unruptured (3.4 ± 0.2 vs 3.2 ± 0.2 mm, respectively; p = 0.40) aneurysms did not differ. The authors observed 1 new SAH from a previously unruptured, unprotected aneurysm in each group (1 of 176 vs 1 of 73 patients; p = 0.50). Baseline patient characteristics and comorbidities were similar between groups. While the degree of hypervolemia was similar between the VIH and non-VIH patients (fluid balance over the first 10 days of therapy: 3146.2 ± 296.4 vs 2910.5 ± 450.7 ml, respectively; p = 0.67), VIH resulted in a significant increase in mean arterial pressure (mean increase over the first 10 days of therapy relative to baseline: 125.1% ± 1.0% vs 98.2% ± 1.2%, respectively; p < 0.01) and systolic blood pressure (125.6% ± 1.1% vs. 104.1% ± 5.2%, respectively; p < 0.01).

CONCLUSIONS: For small, unruptured, unprotected intracranial aneurysms in SAH patients, the frequency of aneurysm rupture during VIH therapy is rare. The authors do not recommend withholding VIH therapy from these patients.


Author Keywords
ACA = anterior cerebral artery;  DCI = delayed cerebral ischemia;  delayed cerebral ischemia;  DVT/PE = deep vein thrombosis/pulmonary embolism;  ICA = internal carotid artery;  induced hypertension;  intracranial aneurysm;  MAP = mean arterial pressure;  MCA = middle cerebral artery;  SAH = subarachnoid hemorrhage;  SBP = systolic blood pressure;  SEM = standard error of the mean;  subarachnoid hemorrhage;  triple-H therapy;  unprotected;  unruptured;  vascular disorders;  vasospasm;  VIH = vasopressor-induced hypertension;  WFNS = World Federation of Neurosurgical Societies


Document Type: Article
Source: Scopus



Scheets, P.L., Sahrmann, S.A., Norton, B.J., Stith, J.S., Crowner, B.E.
What is backward disequilibrium and how do i treat it? A complex patient case study
(2015) Journal of neurologic physical therapy : JNPT, 39 (2), pp. 119-126. 

DOI: 10.1097/NPT.0000000000000084


Quality and Clinical Outcomes, Infinity Rehab, Wilsonville, Oregon (P.L.S.); Physical Therapy/Neurology/Cell Biology & Physiology (S.A.S.), Program in Physical Therapy, Washington University School of Medicine, St. Louis, MO; Physical Therapy and Neurology (B.J.N.), Postprofessional Education in Physical Therapy, Program in Physical Therapy, Washington University School of Medicine, St. Louis, MO; Physical Therapy and Neurology, Education, and Professional Curriculum (J.S.S.), Washington University School of Medicine, St. Louis, MO; Clinical Practice (B.E.C.), Physical Therapy and Neurology, Program in Physical Therapy, Washington University School of Medicine, St. Louis, MO


Abstract
BACKGROUND AND PURPOSE: Postural vertical refers to a component of an individual's perception of verticality that is derived from information about the direction of gravitational forces. Backward disequilibrium (BD) is a postural disorder observed in some older adults who have a distortion in their perception of postural vertical. Individuals with BD sustain their center of mass (COM) posterior to their base of support and resist correction of COM alignment. The purposes of this case study are to describe a patient with BD and propose a physical therapy management program for this condition.

CASE DESCRIPTION AND INTERVENTION: The patient was an 83-year-old woman admitted for home care services 4 months after falling and sustaining a displaced right femoral neck fracture and subsequent hemiarthroplasty. Details of the clinical examination, diagnosis, and intervention are provided and a treatment protocol for physical therapy management is suggested.

OUTCOMES: During the episode of care, the patient (1) decreased her dependence on caregivers, (2) surpassed minimal detectable change or minimal clinically important improvements in gait speed and on the Short Physical Performance Battery and Performance-Oriented Mobility Assessment, and (3) achieved her primary goal of staying in her own apartment at an assisted living facility.

DISCUSSION: Knowledge of BD coupled with a thorough clinical examination may assist physical therapists in identifying this condition and employing the specific intervention we have proposed. We believe that failure to recognize and manage our patient's condition appropriately would have led to nursing home placement.Video Abstract available for more insights from the authors (see Supplemental Digital Content 1, http://links.lww.com/JNPT/A94).


Document Type: Article
Source: Scopus


Constantino, J.N.
Child Maltreatment Prevention and the Scope of Child and Adolescent Psychiatry
(2015) Child and Adolescent Psychiatric Clinics of North America, . Article in Press. 

DOI: 10.1016/j.chc.2015.11.003


Division of Child Psychiatry, Department of Psychiatry, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8504, St Louis, MO 63110, USA


Abstract
Child maltreatment is one of the most deleterious known influences on the mental health and development of children. This article briefly reviews a complement of methods that are ready to incorporate into child and adolescent psychiatric practice, by having been validated either with respect to the prevention of child maltreatment or with respect to adverse outcomes associated with maltreatment (and primarily focused on enhancing the caregiving environment); they are feasible for integration into clinical decision making, and most importantly, can be included in the training of the next generation of clinicians. © 2015 The Author.


Author Keywords
Abuse;  Child;  Maltreatment;  Neglect;  Prevention;  Psychiatry


Document Type: Article in Press
Source: Scopus

 

JANUARY 20, 2016

Tonge, N.A., Rodebaugh, T.L., Fernandez, K.C., Lim, M.H.
Self-reported social skills impairment explains elevated autistic traits in individuals with generalized social anxiety disorder
(2016) Journal of Anxiety Disorders, 38, pp. 31-36. 

DOI: 10.1016/j.janxdis.2015.12.005


Department of Psychology, Washington University in St. Louis, St. Louis, MO, United States


Abstract
Screening for autism in individuals with generalized social anxiety disorder (GSAD) is complicated by symptom overlap between GSAD and autism spectrum disorder (ASD). We examined the prevalence of self-reported autistic traits within a sample of participants with a diagnosis of GSAD (n= 37) compared to individuals without a GSAD diagnosis (NOSAD; n=26). Of the GSAD sample participants, 70.84% self-reported autistic traits above a cut-off of 65 on the Autism Quotient-Short (AQ-S) and reported significantly more autistic traits on 3 of 5 AQ-S subscales compared to the NOSAD group. Diagnosis uniquely predicted variation in the social skills subscale above and beyond the other subscales and other predictors. Furthermore, variation in the social skills subscale largely explained group differences on the other subscales. Our results suggest caution in utilizing measures like the AQ-S with clinical populations characterized by social difficulties such as individuals with a GSAD diagnosis. © 2015 Elsevier Ltd.


Author Keywords
Anxiety;  Assessment;  Measurement;  Social anxiety;  Theory of mind


Document Type: Article
Source: Scopus



Ambike, S.a , Mattos, D.b , Zatsiorsky, V.M.c , Latash, M.L.c
Synergies in the space of control variables within the equilibrium-point hypothesis
(2016) Neuroscience, 315, pp. 150-161. 

DOI: 10.1016/j.neuroscience.2015.12.012


a Department of Health and Kinesiology, Purdue University, West Lafayette, IN, United States
b Washington University School of Medicine, Saint Louis, MO, United States
c Department of Kinesiology, The Pennsylvania State University, University Park, PA, United States


Abstract
We use an approach rooted in the recent theory of synergies to analyze possible co-variation between two hypothetical control variables involved in finger force production based on the equilibrium-point (EP) hypothesis. These control variables are the referent coordinate (R) and apparent stiffness (C) of the finger. We tested a hypothesis that inter-trial co-variation in the {R; C} space during repeated, accurate force production trials stabilizes the fingertip force. This was expected to correspond to a relatively low amount of inter-trial variability affecting force and a high amount of variability keeping the force unchanged. We used the "inverse piano" apparatus to apply small and smooth positional perturbations to fingers during force production tasks. Across trials, R and C showed strong co-variation with the data points lying close to a hyperbolic curve. Hyperbolic regressions accounted for over 99% of the variance in the {R; C} space. Another analysis was conducted by randomizing the original {R; C} data sets and creating surrogate data sets that were then used to compute predicted force values. The surrogate sets always showed much higher force variance compared to the actual data, thus reinforcing the conclusion that finger force control was organized in the {R; C} space, as predicted by the EP hypothesis, and involved co-variation in that space stabilizing total force. © 2015 IBRO.


Author Keywords
Apparent stiffness;  Equilibrium-point hypothesis;  Finger force;  Isometric;  Synergy;  Uncontrolled manifold hypothesis


Document Type: Article
Source: Scopus



Craig, B.M.a , Brown, D.S.b , Reeve, B.B.c
Valuation of child behavioral problems from the perspective of us adults
(2016) Medical Decision Making, 36 (2), pp. 199-209. 

DOI: 10.1177/0272989X15594370


a Health Outcomes and Behavior, Moffitt Cancer Center, University of South Florida, 12902 Magnolia Drive, Tampa, FL, United States
b Brown School and Institute for Public Health, Washington University in St. Louis, St Louis, MO, United States
c Lineberger Comprehensive Cancer Center, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States


Abstract
Objective. To assess preferences between child behavioral problems and estimate their value on a quality-adjusted life year (QALY) scale. Methods. Respondents, age 18 or older, drawn from a nationally representative panel between August 2012 and February 2013 completed a series of paired comparisons, each involving a choice between 2 different behavioral problems described using the Behavioral Problems Index (BPI), a 28-item instrument with 6 domains (Anxious/Depressed, Headstrong, Hyperactive, Immature Dependency, Anti-social, and Peer Conflict/Social Withdrawal). Each behavioral problem lasted 1 or 2 years for an unnamed child, age 7 or 10 years, with no suggested relationship to the respondent. Generalized linear model analyses estimated the value of each problem on a QALY scale, considering its duration and the child's age. Results. Among 5207 eligible respondents, 4155 (80%) completed all questions. Across the 6 domains, problems relating to antisocial behavior were the least preferred, particularly the items related to cheating, lying, bullying, and cruelty to others. Conclusions. The findings are the first to produce a preference-based summary measure of child behavioral problems on a QALY scale. The results may inform both clinical practice and resource allocation decisions by enhancing our understanding of difficult tradeoffs in how adults view child behavioral problems. Understanding US values also promotes national health surveillance by complementing conventional measures of surveillance, survival, and diagnoses. © 2015 The Author(s).


Author Keywords
Behavioral Problems Index;  discrete choice experiments;  patient-reported outcomes;  QALY;  quality-adjusted life years


Document Type: Review
Source: Scopus



Weston, S.J., Jackson, J.J.
How do people respond to health news? The role of personality traits
(2016) Psychology and Health, pp. 1-18. Article in Press. 

DOI: 10.1080/08870446.2015.1119274


Department of Psychological and Brain Sciences, Washington University in St. Louis, St. Louis, MO, USA


Abstract
When a patient receives a health diagnosis, their response (e.g. changes in behaviour, seeking support) can have significant consequences for long-term health and well-being. Characteristics of health news are known to influence these responses, but personality traits have been omitted from this line of research. The current study examines the role of personality traits in predicting response to health news. Participants (N = 298) read scenarios in which they received health news that was manipulated to vary in severity, controllability and likelihood of outcomes. Participants then rated how likely they were to engage in a number of response behaviours. We examined the main effects and interaction of situational manipulations and personality traits on ratings of these behaviours. Both situations and personality traits influenced behavioural responses to health events. In particular, conscientiousness predicted taking action and seeking social support. Neuroticism predicted both maladaptive and adaptive behavioural responses, providing support for the ‘healthy neurotic’ hypothesis. Moreover, personality traits predicted best in weak (unlikely, controllable) situations. Both personality traits and situational characteristics contribute to behavioural responses to health news. © 2016 Taylor & Francis


Author Keywords
bad news response model;  conscientiousness;  health;  health behaviors;  personality;  situation


Document Type: Article in Press
Source: Scopus



Ances, B.M.a , Hoare, J.b
Perinatal HIV in the brain
(2016) Neurology, 86 (1), pp. 13-14. 

DOI: 10.1212/WNL.0000000000002211


a Department of Neurology, Washington University in Saint Louis, Saint Louis, MO, United States
b Department of Psychiatry and Mental Health, University of Cape Town, Cape Town, South Africa


Document Type: Editorial
Source: Scopus



Cui, J.
Voltage-Dependent Gating: Novel Insights from KCNQ1 Channels
(2016) Biophysical Journal, 110 (1), pp. 14-25. 

DOI: 10.1016/j.bpj.2015.11.023


Department of Biomedical Engineering, Cardiac Bioelectricity and Arrhythmia Center, Center for the Investigation of Membrane Excitability Disorders, Washington University, St. Louis, MO, United States


Abstract
Gating of voltage-dependent cation channels involves three general molecular processes: voltage sensor activation, sensor-pore coupling, and pore opening. KCNQ1 is a voltage-gated potassium (Kv) channel whose distinctive properties have provided novel insights on fundamental principles of voltage-dependent gating. 1) Similar to other Kv channels, KCNQ1 voltage sensor activation undergoes two resolvable steps; but, unique to KCNQ1, the pore opens at both the intermediate and activated state of voltage sensor activation. The voltage sensor-pore coupling differs in the intermediate-open and the activated-open states, resulting in changes of open pore properties during voltage sensor activation. 2) The voltage sensor-pore coupling and pore opening require the membrane lipid PIP2 and intracellular ATP, respectively, as cofactors, thus voltage-dependent gating is dependent on multiple stimuli, including the binding of intracellular signaling molecules. These mechanisms underlie the extraordinary KCNE1 subunit modification of the KCNQ1 channel and have significant physiological implications. © 2016 Biophysical Society.


Document Type: Article
Source: Scopus



Mendez, J.S.a , Govindan, A.b , Leong, J.b , Gao, F.c , Huang, J.d , Campian, J.L.b
Association between treatment-related lymphopenia and overall survival in elderly patients with newly diagnosed glioblastoma
(2016) Journal of Neuro-Oncology, pp. 1-7. Article in Press. 

DOI: 10.1007/s11060-015-2037-1


a Department of Neurology, Washington University School of Medicine, St Louis, MO, United States
b Department of Medicine, Oncology Division, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8056, St Louis, MO, United States
c Department of Surgery, Division of Public Health Sciences, Washington University School of Medicine, St Louis, MO, United States
d Department of Radiation Oncology, Washington University School of Medicine, St Louis, MO, United States


Abstract
Management of patients with glioblastoma (GBM) often includes radiation (RT) and temozolomide (TMZ). The association between severe treatment-related lymphopenia (TRL) after the standard chemoradiation and reduced survival has been reported in GBM patients with the median age of 57. Similar findings were described in patients with head and neck, non-small cell lung, and pancreatic cancers. This retrospective study is designed to evaluate whether elderly GBM patients (age ≥65) develop similar TRL after RT/TMZ and whether such TRL is associated with decreased survival. Serial total lymphocyte counts (TLC) were retrospectively reviewed in patients (age ≥65) with newly diagnosed GBM undergoing RT/TMZ and associated with treatment outcomes. Seventy-two patients were eligible: median KPS 70, median age 71 years (range 65–86) with 56 % of patients &gt;70 years, 53 % female, 31 % received RT ≤45 Gy. Baseline median TLC was 1100 cells/mm3 which fell by 41 % to 650 cells/mm3 2 months after initiating RT/TMZ (p &lt; 0.0001). Patients with TLC &lt;500 cells/mm3 at 2 months had a shorter survival than those with higher TLCs with a median overall survival of 4.6 versus 11.6 months, respectively. Multivariate analysis revealed a significant association between TRL and survival (HR 2.76, 95 % CI 1.30–5.86, p = 0.008). Treatment-related lymphopenia is frequent, severe, and an independent predictor for survival in elderly patients with GBM. These findings add to the body of evidence that immunosuppression induced by chemoradiation is associated with inferior clinical outcomes. Prospective studies are needed to confirm these findings suggesting that immune preservation is important in this cancer. © 2016 Springer Science+Business Media New York


Author Keywords
Chemotherapy;  Glioblastoma;  Lymphopenia;  Radiation;  Treatment-related toxicities


Document Type: Article in Press
Source: Scopus



Deming, Y.a , Xia, J.b , Cai, Y.d , Lord, J.e , Del-Aguila, J.L.g , Fernandez, M.V.h , Carrell, D.i , Black, K.a , Budde, J.a , Ma, S.b , Saef, B.c , Howells, B.d , Bertelsen, S.e , Bailey, M.a , Ridge, P.G.a , Holtzman, D.h , Morris, J.C.b , Bales, K.f , Pickering, E.H.g , Lee, J.-M.h , Heitsch, L.i , Kauwe, J.c , Goate, A.a , Piccio, L.b , Cruchaga, C.a
Genetic studies of plasma analytes identify novel potential biomarkers for several complex traits
(2016) Scientific Reports, 6, art. no. 18092, . 

DOI: 10.1038/srep18092


a Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave. B8134, St. Louis, MO, United States
b Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, China
c Human Genetics Programme, Wellcome Trust Sanger Institute, Cambridge, United Kingdom
d Department of Biology, Brigham Young University, Provo, UT, United States
e Department of Neurology, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, MO, United States
f Department of Developmental Biology, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, MO, United States
g Knight Alzheimer's Disease Research Center, Washington University School of Medicine, 4488 Forest Park Ave, St Louis, MO, United States
h Hope Center for Neurological Disorders, Washington University School of Medicine, 660 S. Euclid Ave. B8111, St. Louis, MO, United States
i Neuroscience Research Unit, Worldwide Research and Development, Groton, CT, United States


Abstract
Genome-wide association studies of 146 plasma protein levels in 818 individuals revealed 56 genome-wide significant associations (28 novel) with 47 analytes. Loci associated with plasma levels of 39 proteins tested have been previously associated with various complex traits such as heart disease, inflammatory bowel disease, Type 2 diabetes, and multiple sclerosis. These data suggest that these plasma protein levels may constitute informative endophenotypes for these complex traits. We found three potential pleiotropic genes: ABO for plasma SELE and ACE levels, FUT2 for CA19-9 and CEA plasma levels, and APOE for ApoE and CRP levels. We also found multiple independent signals in loci associated with plasma levels of ApoH, CA19-9, FetuinA, IL6r, and LPa. Our study highlights the power of biological traits for genetic studies to identify genetic variants influencing clinically relevant traits, potential pleiotropic effects, and complex disease associations in the same locus.


Document Type: Article
Source: Scopus



Hammond, E.R.a b , Crum, R.M.a b , Treisman, G.J.b c , Mehta, S.H.a , Clifford, D.B.d , Ellis, R.J.e , Gelman, B.B.f , Grant, I.g , Letendre, S.L.h , Marra, C.M.i , Morgello, S.j k , Simpson, D.M.j , Mcarthur, J.C.a c l , For The Charter Groupm
Persistent CSF but not plasma HIV RNA is associated with increased risk of new-onset moderate-to-severe depressive symptoms; a prospective cohort study
(2016) Journal of NeuroVirology, pp. 1-9. Article in Press. 

DOI: 10.1007/s13365-015-0416-1


a Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States
b Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Baltimore, MD, United States
c Department of Internal Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States
d Department of Neurology, Washington University, St. Louis, MO, United States
e Department of Neurology, University of California, San Diego, CA, United States
f Department of Pathology, University of Texas, Medical Branch, Galveston, TX, United States
g Department of Psychiatry, University of California, San Diego, CA, United States
h Department of Medicine, University of California, San Diego, CA, United States
i Department of Neurology, University of Washington, Seattle, WA, United States
j Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
k Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
l Departments of Neurology and Pathology, Johns Hopkins University, Baltimore, MD, United States


Abstract
Major depressive disorder is the most common neuropsychiatric complication in human immunodeficiency virus (HIV) infections and is associated with worse clinical outcomes. We determined if detectable cerebrospinal fluid (CSF) HIV ribonucleic acid (RNA) at threshold ≥50 copies/ml is associated with increased risk of depression. The CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) cohort is a six-center US-based prospective cohort with bi-annual follow-up of 674 participants. We fit linear mixed models (N = 233) and discrete-time survival models (N = 154; 832 observations) to evaluate trajectories of Beck Depression Inventory (BDI) II scores and the incidence of new-onset moderate-to-severe depressive symptoms (BDI ≥ 17) among participants on combination antiretroviral therapy (cART), who were free of depression at study entry and received a minimum of three CSF examinations over 2496 person-months follow-up. Detectable CSF HIV RNA (threshold ≥50 copies/ml) at any visit was associated with a 4.7-fold increase in new-onset depression at subsequent visits adjusted for plasma HIV RNA and treatment adherence; hazard ratio (HR) = 4.76, (95 % CI 1.58–14.3); P = 0.006. Depression (BDI) scores were 2.53 points higher (95 % CI 0.47–4.60; P = 0.02) over 6 months if CSF HIV RNA was detectable at a prior study visit in fully adjusted models including age, sex, race, education, plasma HIV RNA, duration and adherence of CART, and lifetime depression diagnosis by Diagnostic Statistical Manual (DSM-IV) criteria. Persistent CSF but not plasma HIV RNA is associated with an increased risk for new-onset depression. Further research evaluating the role of immune activation and inflammatory markers may improve our understanding of this association. © 2016 Journal of NeuroVirology, Inc.


Author Keywords
Cerebrospinal fluid;  Depression;  Psychiatry;  Viral load


Document Type: Article in Press
Source: Scopus



Tajdaran, K.a b , Gordon, T.a d e , Wood, M.D.f , Shoichet, M.S.b c , Borschel, G.H.a b d e
A glial cell line-derived neurotrophic factor delivery system enhances nerve regeneration across acellular nerve allografts
(2016) Acta Biomaterialia, 29, pp. 62-70. 

DOI: 10.1016/j.actbio.2015.10.001


a Division of Plastic and Reconstructive Surgery, Hospital for Sick Children, 555 University Ave, Toronto, ON, Canada
b Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON, Canada
c Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, ON, Canada
d Division of Plastic and Reconstructive Surgery, Department of Surgery, University of Toronto, Toronto, ON, Canada
e Program in Neuroscience, Hospital for Sick Children Research Institute, Toronto, ON, Canada
f Division of Plastic and Reconstructive Surgery, Washington University School of Medicine, St. Louis, MO, United States


Abstract
Acellular nerve allografts (ANAs) are used clinically to bridge nerve gaps but these grafts, lacking Schwann cells and therapeutic levels of neurotrophic factors, do not support regeneration to the same extent as autografts. Here we investigated a local drug delivery system (DDS) for glial cell line-derived neurotrophic factor (GDNF) controlled release to implanted ANAs in rats using drug-loaded polymeric microspheres (MSs) embedded in a fibrin gel. In a rat hindlimb nerve gap model, a 10 mm ANA was used to bridge a 5 mm common peroneal (CP) nerve gap. Experimental groups received DDS treatment at both suture sites of the allografts releasing GDNF for either 2 weeks or 4 weeks. In negative control groups, rats received no DDS treatment or empty DDS. Rats receiving nerve isografts served as the positive control group. The numbers of motor and sensory neurons that regenerated their axons in all the groups with GDNF MS and isograft treatment were indistinguishable and significantly higher as compared to the negative control groups. Nerve histology distal to the nerve graft demonstrated increased axon counts and a shift to larger fiber diameters due to GDNF MS treatment. The sustained delivery of GDNF to the implanted ANA achieved in this study demonstrates the promise of this DDS for the management of severe nerve injuries in which allografts are placed. Statement of Significance This work addresses the common clinical situation in which a nerve gap is bridged using acellular nerve allografts. However, these allografts are not as effective in supporting nerve regeneration as the gold standard method of autografting. The novel local drug delivery system used in this study provides sustained and controlled release of glial cell line-derived neurotrophic factor (GDNF), one of the most potent neurotrophic factors, which significantly improves nerve regeneration following severe nerve injuries. Results from this research will provide a mean of improving nerve allografts with locally delivered GDNF. This strategy may lead to a novel "off the shelf" alternative to the current management of severe nerve injuries. © 2015 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.


Author Keywords
Acellular nerve allografts;  Biomaterials;  Drug delivery;  Fibrinogen;  Glial cell line-derived neurotrophic factor;  Nerve injury;  Poly(lactic-co-glycolic) acid;  Regenerative medicine


Document Type: Article
Source: Scopus



Kovacs, G.G.a , Ferrer, I.b , Grinberg, L.T.c d , Alafuzoff, I.e , Attems, J.f , Budka, H.g , Cairns, N.J.h , Crary, J.F.i ag , Duyckaerts, C.j , Ghetti, B.k , Halliday, G.M.l , Ironside, J.W.m , Love, S.n , Mackenzie, I.R.o , Munoz, D.G.p , Murray, M.E.q , Nelson, P.T.r , Takahashi, H.s , Trojanowski, J.Q.t , Ansorge, O.u , Arzberger, T.v , Baborie, A.w , Beach, T.G.x , Bieniek, K.F.q , Bigio, E.H.y , Bodi, I.z , Dugger, B.N.x aa , Feany, M.ab , Gelpi, E.ac , Gentleman, S.M.ad , Giaccone, G.ae , Hatanpaa, K.J.af , Heale, R.f , Hof, P.R.ag , Hofer, M.u , Hortobágyi, T.ah , Jellinger, K.ai , Jicha, G.A.aj , Ince, P.ak , Kofler, J.al , Kövari, E.am , Kril, J.J.an , Mann, D.M.ao , Matej, R.ap , McKee, A.C.aq , McLean, C.ar , Milenkovic, I.a as , Montine, T.J.at , Murayama, S.au , Lee, E.B.t , Rahimi, J.a , Rodriguez, R.D.av , Rozemüller, A.aw , Schneider, J.A.ax ay , Schultz, C.az , Seeley, W.c , Seilhean, D.j , Smith, C.m , Tagliavini, F.ae , Takao, M.ba , Thal, D.R.bb bc , Toledo, J.B.t , Tolnay, M.bd , Troncoso, J.C.be , Vinters, H.V.bf bg , Weis, S.bh , Wharton, S.B.ak , White, C.L., IIIaf , Wisniewski, T.bi bj bk , Woulfe, J.M.bl , Yamada, M.bm , Dickson, D.W.q
Aging-related tau astrogliopathy (ARTAG): harmonized evaluation strategy
(2016) Acta Neuropathologica, 131 (1), pp. 87-102. 

DOI: 10.1007/s00401-015-1509-x


a Institute of Neurology, Medical University of Vienna, AKH 4J, Währinger Gürtel 18-20, Vienna, Austria
b Institute of Neuropathology, Bellvitge University Hospital, University of Barcelona, Hospitalet de Llobregat, Barcelona, Spain
c Department of Neurology, Memory and Aging Center, University of California, San Francisco, United States
d Department of Pathology, LIM-22, University of Sao Paulo Medical School, Sao Paulo, Brazil
e Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
f Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, United Kingdom
g Institute of Neuropathology, University Hospital Zürich, Zurich, Switzerland
h Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States
i Department of Pathology, Friedman Brain Institute, and the Ronald M. Loeb Center for Alzheimer’s Disease, Icahn School of Medicine at Mount Sinai, New York, United States
j Neuropathology Department, Hopital de La Salpetrière, AP-HP, UPMC-Sorbonne-University, Paris, France
k Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, United States
l GMH-Neuroscience Research Australia and the University of New South Wales, Sydney, NSW, Australia
m Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom
n Institute of Clinical Neurosciences, University of Bristol, Learning and Research Level 2, Southmead Hospital, Bristol, United Kingdom
o Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada
p Division of Pathology, St. Michael’s Hospital, 30 Bond St, Toronto, ON, Canada
q Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, United States
r Department of Pathology and Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, United States
s Department of Pathology, Brain Research Institute, Niigata University, Niigata, Japan
t Department of Pathology and Laboratory Medicine of the Perelman School of Medicine, Center for Neurodegenerative Disease Research, Institute On Aging, University of Pennsylvania, Philadelphia, United States
u Department of Neuropathology, John Radcliffe Hospital, Oxford, United Kingdom
v Department of Psychiatry and Psychotherapy, Centre for Neuropathology and Prion Research, Ludwig-Maximilians-University Munich, Munich, Germany
w Department of Neuropathology, Walton Centre, Liverpool, United Kingdom
x Civin Laboratory for Neuropathology, Banner Sun Health Research Institute, Sun City, AZ, United States
y Northwestern ADC Neuropathology Core, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
z Clinical Neuropathology, King’s College Hospital, London Neurodegenerative Brain Bank, London, United Kingdom
aa Institute for Neurodegenerative Diseases, University of California San Francisco, San Francisco, CA, United States
ab Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
ac Neurological Tissue Bank of the Biobank-Hospital Clinic-IDIBAPS, Institut d’Investigacions Biomediques August Pi i Sunyer, Barcelona, Spain
ad Department of Medicine, Imperial College London, London, United Kingdom
ae IRCCS Foundation “Carlo Besta” Neurological Institute, Milan, Italy
af Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, United States
ag Fishberg Department of Neuroscience, Friedman Brain Institute, and Ronald M. Loeb Center for Alzheimer’s Disease, Icahn School of Medicine at Mount Sinai, New York, NY, United States
ah Department of Neuropathology, Institute of Pathology, University of Debrecen, Nagyerdei krt. 98, Debrecen, Hungary
ai Institute of Clinical Neurobiology, Alberichgasse 5/13, Vienna, Austria
aj Department of Neurology and Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, United States
ak Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, United Kingdom
al Department of Pathology, University of Pittsburgh, Pittsburgh, PA, United States
am Department of Mental Health and Psychiatry, University Hospitals and University of Geneva School of Medicine, Geneva, Switzerland
an Discipline of Pathology, Sydney Medical School, The University of Sydney, Sydney, NSW, Australia
ao Institute of Brain, Behaviour and Mental Health, Manchester University Faculty of Medical and Health Sciences, Manchester, United Kingdom
ap Department of Pathology and Molecular Medicine, Thomayer Hospital, Prague 4, Czech Republic
aq Department of Neurology and Pathology, Boston University School of Medicine and VA Healthcare System, Boston, MA, United States
ar Department of Anatomical Pathology, Alfred Hospital, Prahran, VIC, Australia
as Department of Neurology, Medical University of Vienna, Vienna, Austria
at Department of Pathology, University of Washington, Seattle, WA, United States
au Department of Neuropathology (The Brain Bank for Aging Research), Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Tokyo, Japan
av Physiopathology in Aging Lab/Brazilian Aging Brain Study Group-LIM22, University of Sao Paulo Medical School, Sao Paulo, Brazil
aw Netherlands Brainbank and Department of Pathology, VU University Medical Center, Amsterdam, Netherlands
ax Department of Pathology, Rush University Medical Center, Chicago, IL, United States
ay Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, United States
az Institute of Neuroanatomy, Centre for Biomedicine and Medical Technology Mannheim, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany
ba Department of Neurology, Saitama Medical University International Medical Center, Saitama, Japan
bb Laboratory of Neuropathology, Institute of Pathology, University of Ulm, Ulm, Germany
bc Department of Neuroscience, KU-Leuven, Louvain, Belgium
bd Institute of Pathology, University Hospital Basel, Basel, Switzerland
be Division of Neuropathology, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
bf Section of Neuropathology, Department of Pathology and Laboratory Medicine, Brain Research Institute, University of California, Los Angeles (UCLA) Medical Center and David Geffen School of Medicine, Los Angeles, CA, United States
bg Department of Neurology, Brain Research Institute, University of California, Los Angeles (UCLA) Medical Center and David Geffen School of Medicine, Los Angeles, CA, United States
bh Department of Pathology and Neuropathology, Laboratory of Neuropathology, Neuromed Campus, Kepler University Hospital, Medical School, Johannes Kepler University, Linz, Austria
bi Department of Neurology, Center for Cognitive Neurology, New York University School of Medicine, ERSP, 450 East 29th Street, New York, NY, United States
bj Department of Pathology, Center for Cognitive Neurology, New York University School of Medicine, ERSP, 450 East 29th Street, New York, NY, United States
bk Department of Psychiatry, Center for Cognitive Neurology, New York University School of Medicine, ERSP, 450 East 29th Street, New York, NY, United States
bl Department of Pathology and Laboratory Medicine, Centre for Cancer Therapeutics, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Canada
bm Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan


Abstract
Pathological accumulation of abnormally phosphorylated tau protein in astrocytes is a frequent, but poorly characterized feature of the aging brain. Its etiology is uncertain, but its presence is sufficiently ubiquitous to merit further characterization and classification, which may stimulate clinicopathological studies and research into its pathobiology. This paper aims to harmonize evaluation and nomenclature of aging-related tau astrogliopathy (ARTAG), a term that refers to a morphological spectrum of astroglial pathology detected by tau immunohistochemistry, especially with phosphorylation-dependent and 4R isoform-specific antibodies. ARTAG occurs mainly, but not exclusively, in individuals over 60 years of age. Tau-immunoreactive astrocytes in ARTAG include thorn-shaped astrocytes at the glia limitans and in white matter, as well as solitary or clustered astrocytes with perinuclear cytoplasmic tau immunoreactivity that extends into the astroglial processes as fine fibrillar or granular immunopositivity, typically in gray matter. Various forms of ARTAG may coexist in the same brain and might reflect different pathogenic processes. Based on morphology and anatomical distribution, ARTAG can be distinguished from primary tauopathies, but may be concurrent with primary tauopathies or other disorders. We recommend four steps for evaluation of ARTAG: (1) identification of five types based on the location of either morphologies of tau astrogliopathy: subpial, subependymal, perivascular, white matter, gray matter; (2) documentation of the regional involvement: medial temporal lobe, lobar (frontal, parietal, occipital, lateral temporal), subcortical, brainstem; (3) documentation of the severity of tau astrogliopathy; and (4) description of subregional involvement. Some types of ARTAG may underlie neurological symptoms; however, the clinical significance of ARTAG is currently uncertain and awaits further studies. The goal of this proposal is to raise awareness of astroglial tau pathology in the aged brain, facilitating communication among neuropathologists and researchers, and informing interpretation of clinical biomarkers and imaging studies that focus on tau-related indicators. © 2015, Springer-Verlag Berlin Heidelberg.


Author Keywords
Aging;  ARTAG;  Tau;  Tau astrogliopathy


Document Type: Article
Source: Scopus



Reiman, E.M.a , Langbaum, J.B.a , Tariot, P.N.a , Lopera, F.b , Bateman, R.J.c , Morris, J.C.c , Sperling, R.A.d , Aisen, P.S.e , Roses, A.D.f , Welsh-Bohmer, K.A.f , Carrillo, M.C.g , Weninger, S.h
CAP-advancing the evaluation of preclinical Alzheimer disease treatments
(2016) Nature Reviews Neurology, 12 (1), pp. 56-61. 

DOI: 10.1038/nrneurol.2015.177


a Banner Alzheimer's Institute, 901 E. Willetta Street, Phoenix, AZ, United States
b Grupo de Neurosciencias, Universidad de Antioquia, Calle 62 #52-59, Medellin, Colombia
c Department of Neurology, Washington University, 660 South Euclid Avenue, St Louis, MO, United States
d Department of Neurology, Brigham and Women's Hospital, 221 Longwood Avenue, Boston, MA, United States
e University of Southern California, Alzheimer's Therapeutic Research Institute, 10182 Telesis Court, San Diego, CA, United States
f Joseph and Kathleen Bryan Alzheimer's Disease Research Center, Department of Neurology, Duke University Medical Center, 2200 West Main Street, Durham, NC, United States
g Alzheimer's Association, Medical and Scientific Relations Division, 225 North Michigan Avenue, Chicago, IL, United States
h Fidelity Biosciences Research Initiative, One Main Street, Cambridge, MA, United States


Abstract
If we are to find treatments to postpone, reduce the risk of, or completely prevent the clinical onset of Alzheimer disease (AD), we need faster methods to evaluate promising preclinical AD treatments, new ways to work together in support of common goals, and a determination to expedite the initiation and performance of preclinical AD trials. In this article, we note some of the current challenges, opportunities and emerging strategies in preclinical AD treatment. We describe the Collaboration for Alzheimer's Prevention (CAP) - a convening, harmonizing and consensus-building initiative to help stakeholders advance AD prevention research with rigour, care and maximal impact - and we demonstrate the impact of CAP on the goals and design of new preclinical AD trials. © 2016 Macmillan Publishers Limited.


Document Type: Review
Source: Scopus



Deng, P.-Y., Klyachko, V.A.
Genetic upregulation of BK channel activity normalizes multiple synaptic and circuit defects in a mouse model of fragile X syndrome
(2016) Journal of Physiology, 594 (1), pp. 83-97. 

DOI: 10.1113/JP271031


Departments of Cell Biology and Physiology, Biomedical Engineering, CIMED, Washington University, St Louis, MO, United States


Abstract
Loss of fragile X mental retardation protein (FMRP) causes fragile X syndrome (FXS), yet the mechanisms underlying the pathophysiology of FXS are incompletely understood. Recent studies identified important new functions of FMRP in regulating neural excitability and synaptic transmission via both translation-dependent mechanisms and direct interactions of FMRP with a number of ion channels in the axons and presynaptic terminals. Among these presynaptic FMRP functions, FMRP interaction with large-conductance calcium-activated K+ (BK) channels, specifically their auxiliary β4 subunit, regulates action potential waveform and glutamate release in hippocampal and cortical pyramidal neurons. Given the multitude of ion channels and mechanisms that mediate presynaptic FMRP actions, it remains unclear, however, to what extent FMRP-BK channel interactions contribute to synaptic and circuit defects in FXS. To examine this question, we generated Fmr1/β4 double knockout (dKO) mice to genetically upregulate BK channel activity in the absence of FMRP and determine its ability to normalize multilevel defects caused by FMRP loss. Single-channel analyses revealed that FMRP loss reduced BK channel open probability, and this defect was compensated in dKO mice. Furthermore, dKO mice exhibited normalized action potential duration, glutamate release and short-term dynamics during naturalistic stimulus trains in hippocampal pyramidal neurons. BK channel upregulation was also sufficient to correct excessive seizure susceptibility in an in vitro model of seizure activity in hippocampal slices. Our studies thus suggest that upregulation of BK channel activity normalizes multi-level deficits caused by FMRP loss. © 2016 The Physiological Society.


Document Type: Article
Source: Scopus



Christensen, D.L.a , Bilder, D.A.b , Zahorodny, W.c , Pettygrove, S.d , Durkin, M.S.e f g , Fitzgerald, R.T.h , Rice, C.a , Kurzius-Spencer, M.d , Baio, J.a , Yeargin-Allsopp, M.a
Prevalence and characteristics of autism spectrum disorder among 4-year-old children in the autism and developmental disabilities monitoring network
(2016) Journal of Developmental and Behavioral Pediatrics, 37 (1), pp. 1-8. Cited 1 time.

DOI: 10.1097/DBP.0000000000000235


a Division of Birth Defects and Developmental Disabilities, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, 4770 Buford Highway, MS E-86, Atlanta, GA, United States
b Department of Psychiatry, University of Utah, Salt Lake City, UT, United States
c Department of Pediatrics, Rutgers-New Jersey Medical School, Newark, NJ, United States
d Department of Pediatrics, University of Arizona, Tucson, AZ, United States
e Department of Population Health Sciences, University of Wisconsin-Madison, Madison, WI, United States
f Department of Pediatrics, University of Wisconsin-Madison, Madison, WI, United States
g Waisman Center, University of Wisconsin-Madison, Madison, WI, United States
h Department of Psychiatry, Washington University School of Medicine, St Louis, MO, United States


Abstract
Objective: Early identification of children with autism spectrum disorder (ASD) facilitates timely access to intervention services. Yet, few population-based data exist on ASD identification among preschoolaged children. The authors aimed to describe ASD prevalence and characteristics among 4-year-old children in 5 of 11 sites participating in the 2010 Autism and Developmental Disabilities Monitoring Network. Method: Children with ASD were identified through screening of health and education records for ASD indicators, data abstraction and compilation for each child, and clinician review of records. ASD prevalence estimates, ages at first evaluation and ASD diagnosis, cognitive test scores, and demographics were compared for 4-year-old children and 8-year-old children living in the same areas. Results: Among 58,467 children in these 5 sites, 4-year-old ASD prevalence was 13.4 per 1000, which was 30% lower than 8-year-old ASD prevalence. Prevalence of ASD without cognitive impairment was 40% lower among 4-year-olds compared with 8-year-olds, but prevalence of ASD with cognitive impairment was 20% higher among 4-year-olds compared with 8-year-olds. Among 4-year-olds with ASD, female and non-Hispanic white children were more likely to receive their first comprehensive evaluation by age 36 months compared with male and non-Hispanic black children, respectively. Among children diagnosed with ASD by age 48 months, median age at first comprehensive evaluation was 27 months for 4-year-olds compared with 32 months for 8-year-olds. Conclusion: Population-based ASD surveillance among 4-year-old children provides valuable information about the early identification of children with ASD and suggests progression toward lowering the age of first ASD evaluation within participating Autism and Developmental Disabilities Monitoring communities. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.


Author Keywords
Autism spectrum disorder;  Developmental disabilities;  Population-based surveillance;  Prevalence


Document Type: Article
Source: Scopus



Edwin, N.C.a d , Khoury, M.N.b e f , Sohal, D.c , McCrae, K.R.c , Ahluwalia, M.S.b , Khorana, A.A.c
Recurrent venous thromboembolism in glioblastoma
(2016) Thrombosis Research, 137, pp. 184-188. 

DOI: 10.1016/j.thromres.2015.11.027


a Division of Hematology and Medical Oncology, Washington University, St Louis School of Medicine, Campus Box 8056, 660 S Euclid Avenue, St Louis, MO, United States
b Burkhardt Brain Tumor and Neuro Oncology Center, Neurological Institute Cleveland Clinic, 9500 Euclid Avenue, S73 ClevelandOH, United States
c Department of Hematology and Medical Oncology, Taussig Cancer Institute Cleveland Clinic, 9500 Euclid Avenue, R35 ClevelandOH, United States
d Department of Hematology and Medical Oncology, Washington University, St. Louis School of Medicine, 660 S Euclid Avenue, St. Louis, MO, United States
e Department of Neuro Oncology, H Lee Moffitt Cancer Center, Research Institute, Tampa, FL, United States
f Department of Oncological Sciences, University of South Florida, 12902 Magnolia Drive, Tampa, FL, United States


Abstract
Background Patients with glioblastoma (GBM) are at increased risk of initial and recurrent venous thromboembolism (VTE) but rates of recurrence and real-world treatment choices are incompletely understood. Objectives We aim to describe the treatment of incident VTE, report incidence and risk factors for recurrence. Patients/methods We conducted a retrospective cohort study of consecutive Cleveland Clinic patients with GBM presenting with objectively diagnosed deep vein thrombosis (DVT) or pulmonary embolism (PE) from 2007 to 2013 with at least 6-month follow-up. We collected information on patient demographics, VTE incidence, treatment and recurrence. Data were analyzed using multivariate logistic regression analysis. Results Of 450 patients with GBM, 145 (32.2%) developed VTE and comprised the study population. Of these, 11 (7.6%) experienced PE, 117 (80.7%) had DVT and 16 (11%) had DVT as well as PE. Fifty five (37.9%) VTE events occurred in the first 30 post-operative days and 56 (38.6%) during chemotherapy. Thirty one (21.4%) patients were untreated. Treatments included enoxaparin (N = 36, 24.8%), warfarin (15, 10.3%) or vena cava filters either alone (N = 39, 26.9%) or in combination with anticoagulation (N = 21, 14.5%). Recurrent VTE occurred in 39 patients (26.9%).In multivariate analysis, lack of long term anticoagulation (HR 11.2, CI 1.5-86.3, p < 0.05) and the presence of second primary malignancy (HR 3.69, CI 1.2-11.1, p < 0.05) were significantly associated with recurrent VTE. Conclusion VTE and recurrent VTE are highly prevalent throughout the disease course among patients with GBM. Long term anticoagulation is associated with reduced risk of recurrent VTE but is often not utilized. © 2015 Elsevier Ltd. All rights reserved.


Author Keywords
Cancer associated thrombosis;  Deep vein thrombosis;  Glioblastoma multiforme;  Pulmonary embolism;  Venous thromboembolism


Document Type: Article
Source: Scopus



McCutcheon, V.V.a , Luke, D.A.b , Lessov-Schlaggar, C.N.a
Reduced Social Network Drinking is Associated with Improved Response Inhibition in Women During Early Recovery from Alcohol Use Disorders: A Pilot Study
(2016) Alcoholism: Clinical and Experimental Research, 40 (1), pp. 170-177. 

DOI: 10.1111/acer.12925


a Department of Psychiatry, Washington University School of Medicine, St. Louis, MI, United States
b Brown School of Social Work, Washington University in St. Louis, St. Louis, MI, United States


Abstract
Background: Social support for recovery from alcohol use disorders (AUDs) is associated with improvements in self-reported impulsive behavior in individuals treated for AUDs. We build on these findings using a behavioral task-based measure of response inhibition, a well-defined component of impulsivity, to examine the association of disinhibition with alcohol-specific social network characteristics during early recovery. Methods: Women (n=28) were recruited from treatment for AUD within 3 to 4 weeks of their last drink and were assessed at baseline and again 3 months later. Outcome measures were level of disinhibition at baseline and change in disinhibition from baseline to follow-up, measured using a computer-based continuous performance test. The primary independent variables were level of drinking in the social network at baseline and change in network drinking from baseline to follow-up. Results: The sample [50% black, age M (SD)=42.3 (9.5)] reported high rates of physical and sexual abuse before age 13 (43%), psychiatric disorder (71%), drug use disorder (78%), and previous treatment (71%). More drinking in participants' social networks was associated with greater disinhibition at baseline (β=12.5, 95% CI=6.3, 18.7). A reduction in network drinking from baseline to follow-up was associated with reduced disinhibition (β=-6.0, 95% CI=-11.3, -0.78) independent of IQ, recent alcohol consumption, and self-reported negative urgency. Conclusions: This study extends previous findings of an association between social networks and self-reported impulsivity to a neurobehavioral phenotype, response inhibition, suggesting that abstinence-supporting social networks may play a role in cognitive change during early recovery from AUDs. Women in treatment for alcohol use disorder who reported decreased drinking among their social network members over 3 months showed larger reductions in behavioral disinhibition than women who reported unchanged or increased drinking among network members, independent of IQ, drinking between assessments, and self-reported negative urgency. Results extend previous findings that abstinence-supporting social networks are associated with decreased self-reported impulsivity, and suggest social networks may play a role in cognitive change during early recovery from alcohol use disorders. © 2016 Research Society on Alcoholism.


Author Keywords
Alcohol use disorder;  Impulsivity;  Response inhibition;  Social networks;  Substance use


Document Type: Article
Source: Scopus



An, H.a , Ford, A.L.b , Eldeniz, C.a , Chen, Y.b , Vo, K.D.a , Zhu, H.c , Powers, W.J.d , Lin, W.d e , Lee, J.-M.a b
Reperfusion beyond 6 hours reduces infarct probability in moderately ischemic brain tissue
(2016) Stroke, 47 (1), pp. 99-105. 

DOI: 10.1161/STROKEAHA.115.010656


a Mallinckrodt Institute of Radiology, Washington University, School of Medicine, United States
b Department of Neurology, Washington University, School of Medicine, 600 South Euclid Ave, Saint Louis, MO, United States
c Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
d Department of Neurology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
e Department of Radiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States


Abstract
Background and Purpose - We aimed to examine perfusion changes between 3 and 6 and 6 and 24 hours after stroke onset and their impact on tissue outcome. Methods - Acute ischemic stroke patients underwent perfusion magnetic resonance imaging at 3, 6, and 24 hours after stroke onset and follow-up fluid-attenuated inversion recovery at 1 month to assess tissue fate. Mean transit time prolongation maps (MTTp=MTT-[median MTT of contralateral hemisphere]) were obtained at 3 (MTTp3 h), 6 (MTTp6 h), and 24 hours (MTTp24 h). Perfusion changes between 3 and 6 hours (ΔMTTp3-6) and 6 and 24 hours (ΔMTTp6-24) were calculated. A 2-step analysis was performed to evaluate the impact of ΔMTTp3-6 and ΔMTTp6-24 on tissue fate. First, a voxel-based multivariable logistic regression was performed for each individual patient with MTTp3 h, ΔMTTp3-6, and ΔMTT6-24 as independent variables and tissue fate as outcome. Second, Wilcoxon signed-rank tests on logistic regression coefficients were performed across patients to evaluate whether ΔMTTp3-6 and ΔMTT6-24 had significant impact on tissue fate for varying severities of baseline perfusion. Results - Perfusion change was common during both time periods: 85% and 81% of patients had perfusion improvement during 3- to 6- and 6- and 24-hour time intervals, respectively. ΔMTT3-6 significantly influenced 1-month infarct probability across a wide range of baseline perfusion (MTTp 0-15 s). ΔMTT6-24 also impacted 1-month infarct probability, but its influence was restricted to tissue with milder baseline ischemia (MTTp 0-10 s). Conclusions - Brain tissue with mild to moderate ischemia can be salvaged by reperfusion even after 6 hours. Such tissue could be targeted for intervention beyond current treatment windows. © 2015 American Heart Association, Inc.


Author Keywords
brain;  ischemia;  MR perfusion imaging;  reperfusion;  stroke;  tissue outcome


Document Type: Article
Source: Scopus



Chiew, K.S.a , Braver, T.S.b
Reward favors the prepared: Incentive and task-informative cues interact to enhance attentional control
(2016) Journal of Experimental Psychology: Human Perception and Performance, 42 (1), pp. 52-66. 

DOI: 10.1037/xhp0000129


a Center for Cognitive Neuroscience, Duke University, United States
b Department of Psychology, Washington University in St. Louis, United States


Abstract
The dual mechanisms of control account suggests that cognitive control may be implemented through relatively proactive mechanisms in anticipation of stimulus onset, or through reactive mechanisms, triggered in response to changing stimulus demands. Reward incentives and task-informative cues (signaling the presence/absence of upcoming cognitive demand) have both been found to influence cognitive control in a proactive or preparatory fashion; yet, it is currently unclear whether and how such cue effects interact. We investigated this in 2 experiments using an adapted flanker paradigm, where task-informative and reward incentive cues were orthogonally manipulated on a trial-by-trial basis. In Experiment 1, results indicated that incentives not only speed reaction times, but specifically reduce both interference and facilitation effects when combined with task-informative cues, suggesting enhanced proactive attentional control. Experiment 2 manipulated the timing of incentive cue information, demonstrating that such proactive control effects were only replicated with sufficient time to process the incentive cue (early incentive); when incentive signals were presented close to target onset (late incentive) the primary effect was a speed-accuracy trade-off. Together, results suggest that advance cueing may trigger differing control strategies, and that these strategies may critically depend on both the timing-and the motivational incentive-to use such cues. © 2015 American Psychological Association.


Author Keywords
Cognitive control;  Flanker;  Incentive;  Informative cueing;  Preparation


Document Type: Article
Source: Scopus



Best, J.R.a , Goldschmidt, A.B.b , Mockus-Valenzuela, D.S.c , Stein, R.I.d , Epstein, L.H.e , Wilfley, D.E.a
Shared weight and dietary changes in parent-child dyads following family-based obesity treatment
(2016) Health Psychology, 35 (1), pp. 92-95. 

DOI: 10.1037/hea0000247


a Department of Psychiatry, Washington University, School of MedicineWA, United States
b Department of Psychiatry and Behavioral Neuroscience, The University of Chicago, Chicago, IL, United States
c Behavioral Health Services, County of San Diego, San Diego, CA, United States
d Department of Internal Medicine, Washington University, School of MedicineWA, United States
e Department of Pediatrics, University at BuffaloNY, United States


Abstract
Objectives: The primary objective was to determine whether children and their participating parents undergoing family-based behavioral treatment (FBT) for obesity show similar dietary changes following treatment, and if so, whether these shared dietary changes explain the similarity in weight change within the parent- child dyad. Method: Data come from a randomized controlled trial of 148 parent- child dyads who completed FBT and were followed over a 2-year maintenance phase. Energy-dense, nutrient-poor foods ("RED" foods) and fruit and vegetable intake were assessed across time. Results: Maintenance of lower RED food intake following FBT predicted weight maintenance in children and in parents (ps <.01), and dietary and weight changes were correlated within parent- child dyads (ps <.01). Most interesting, the similarity in long-term weight maintenance between children and their parents was predicted by the similarity in long-term changes in RED food intake between children and their parents (p <.001). Conclusions: These findings point to the important role of maintaining low energy-dense, nutrient-poor food intake for long-term weight maintenance in children and parents. Furthermore, these results suggest that the correlation between parent and child weight maintenance can be explained in part by similar long-term changes in energy-dense, nutrient-poor food intake. © 2015 American Psychological Association.


Author Keywords
Childhood obesity;  Dietary intake;  Family-based treatment;  Long-term weight maintenance;  Parent- child dynamics


Document Type: Article
Source: Scopus



Karlsson, P.a d , Haroutounian, S.a b , Polydefkis, M.c , Nyengaard, J.R.d , Jensen, T.S.a e
Structural and functional characterization of nerve fibres in polyneuropathy and healthy subjects
(2016) Scandinavian Journal of Pain, 10, pp. 28-35. Cited 1 time.

DOI: 10.1016/j.sjpain.2015.08.007


a Danish Pain Research Center, Aarhus University Hospital, Aarhus, Denmark
b Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, United States
c Department of Neurology, The Johns Hopkins Hospital, Baltimore, MD, United States
d Stereology and Electron Microscopy Laboratory, Centre for Stochastic Geometry and Advanced Bioimaging, Aarhus University Hospital, Aarhus, Denmark
e Department of Neurology, Aarhus University Hospital, Aarhus, Denmark


Abstract
Objectives: Quantification of intraepidermal nerve fibre density (IENFD) is an important small fibre measure in distal symmetric polyneuropathies (DSP), but quantitative evaluation of additional structural and functional factors may help in elucidating the underlying mechanisms, and in improving the diagnostic accuracy in DSP. The literature reports a weak or moderate relationship between IENFD and spontaneous and evoked pain in neuropathies, but the relationship between functional and structural small fibre parameters in patients with DSP is unclear. The objectives of the current study, therefore, were to determine morphological and functional parameters related to small nerve fibres in subjects with distal symmetric polyneuropathy (DSP) and healthy controls, and to characterize the interplay among these parameters in these two groups. Materials and Methods: 17 patients with painful DSP (≥4 on 0-10 numerical rating scale) and with symptoms and signs of small fibre abnormality (with or without large fibre involvement) and 19 healthy control subjects underwent comprehensive functional and structural small fibre assessments that included quantitative sensory testing, response to 30. min topical application of 10% capsaicin and analysis of skin biopsy samples taken from the distal leg (IENFD, epidermal and dermal nerve fibre length densities (eNFLD, dNFLD) using global spatial sampling and axonal swelling ratios (swellings/IENFD and swellings/NFLD)). Results: DSP patients had reduced sensitivity to cold (median -11.07. °C vs. -2.60, P≤. 0.001) and heat (median 46.7 vs. 37.70, P≤. 0.001), diminished neurovascular (median 184 vs. 278 mean flux on laser Doppler, P=. 0.0003) and pain response to topical capsaicin (median 10 vs. 35 on 0-100 VAS, P=. 0.0002), and lower IENFD, eNFLD and dNFLD values combined with increased swelling ratios (all P<. 0.001) compared to healthy controls. The correlation between structural and functional parameters was poor in DSP patients, compared with healthy controls. In healthy controls eNFLD and dNFLD, IENFD and eNFLD, IENFD and dNFLD all correlated well with each other (. r=. 0.81; P≤. 0.001, r=. 0.58; P=. 0.009, r=. 0.60; P=. 0.007, respectively). In DSP, on the other hand, only eNFLD and dNFLD showed significant correlation (. r=. 0.53, P=. 0.03). A diagnostic approach of combined IENFD and eNFLD utilization increased DSP diagnostic sensitivity from 82.0% to 100% and specificity from 84.0% to 89.5%. Conclusions: This study presents a rigorous comparison between functional and morphological parameters, including parameters such as eNFDL and dNFLD that have not been previously evaluated in this context. The correlation pattern between functional and structural small fibre parameters is different in patients with DSP when compared to healthy controls. The findings suggest a more direct relationship between structure and function of nerve fibres in healthy controls compared to DSP. Furthermore, the findings suggest that combining IENFD with measurement of NFLD improves the diagnostic sensitivity and specificity of DSP. Implications: Combining small fibre parameters may improve the diagnostic accuracy of DSP. © 2015 Scandinavian Association for the Study of Pain.


Author Keywords
Global spatial sampling;  IENFD;  Nerve fibre length density;  Polyneuropathy;  Skin biopsy


Document Type: Article
Source: Scopus



McKee, A.C.a b c d e , Cairns, N.J.f , Dickson, D.W.g , Folkerth, R.D.h , Dirk Keene, C.i , Litvan, I.j , Perl, D.P.k , Stein, T.D.b c d e , Vonsattel, J.-P.l , Stewart, W.m , Tripodis, Y.c n , Crary, J.F.o , Bieniek, K.F.g , Dams-O’Connor, K.p , Alvarez, V.E.a b c d , Gordon, W.A.p
The first NINDS/NIBIB consensus meeting to define neuropathological criteria for the diagnosis of chronic traumatic encephalopathy
(2016) Acta Neuropathologica, 131 (1), pp. 75-86. 

DOI: 10.1007/s00401-015-1515-z


a Department of Neurology, Boston University School of Medicine, 72 East Concord Street, Boston, MA, United States
b Department of Pathology, Boston University School of Medicine, 72 East Concord Street, Boston, MA, United States
c Alzheimer’s Disease Center, CTE Program, Boston University School of Medicine, 72 East Concord Street, Boston, MA, United States
d VA Boston Healthcare System, 150 South Huntington Avenue, Boston, MA, United States
e Department of Veteran Affairs Medical Center, 200 Springs Road, Bedford, MA, United States
f Department of Neurology, Washington University School of Medicine, 660 South Euclid Avenue, Saint Louis, MO, United States
g Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, United States
h Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis Street, Boston, MA, United States
i Department of Pathology, University of Washington School of Medicine, 325 Ninth Avenue, Seattle, WA, United States
j Department of Neurosciences, University of California San Diego School of Medicine, 9500 Gilman Drive, La Jolla, CA, United States
k Department of Pathology, Center for Neuroscience and Regenerative Medicine, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD, United States
l Taub Institute for Research on Alzheimer’s disease and the Aging Brain, Columbia University Medical Center, 710 West 168th Street, New York, NY, United States
m Department of Neuropathology, University of Glasgow Institute of Neuroscience and Psychology and Queen Elizabeth University Hospital, 1345 Govan Road, Glasgow, United Kingdom
n Department of Biostatistics, Boston University School of Public Health, 801 Massachusetts Avenue, Boston, MA, United States
o Department of Pathology, Fishberg Department of Neuroscience, Friedman Brain Institute, Ronald M. Loeb Center for Alzheimer’s Disease, Icahn School of Medicine at Mount Sinai School, One Gustave L. Levy Place, New York, NY, United States
p Department of Rehabilitation Medicine, Icahn School of Medicine at Mount Sinai, 3 East 101st Street, New York, NY, United States


Abstract
Chronic traumatic encephalopathy (CTE) is a neurodegeneration characterized by the abnormal accumulation of hyperphosphorylated tau protein within the brain. Like many other neurodegenerative conditions, at present, CTE can only be definitively diagnosed by post-mortem examination of brain tissue. As the first part of a series of consensus panels funded by the NINDS/NIBIB to define the neuropathological criteria for CTE, preliminary neuropathological criteria were used by 7 neuropathologists to blindly evaluate 25 cases of various tauopathies, including CTE, Alzheimer’s disease, progressive supranuclear palsy, argyrophilic grain disease, corticobasal degeneration, primary age-related tauopathy, and parkinsonism dementia complex of Guam. The results demonstrated that there was good agreement among the neuropathologists who reviewed the cases (Cohen’s kappa, 0.67) and even better agreement between reviewers and the diagnosis of CTE (Cohen’s kappa, 0.78). Based on these results, the panel defined the pathognomonic lesion of CTE as an accumulation of abnormal hyperphosphorylated tau (p-tau) in neurons and astroglia distributed around small blood vessels at the depths of cortical sulci and in an irregular pattern. The group also defined supportive but non-specific p-tau-immunoreactive features of CTE as: pretangles and NFTs affecting superficial layers (layers II–III) of cerebral cortex; pretangles, NFTs or extracellular tangles in CA2 and pretangles and proximal dendritic swellings in CA4 of the hippocampus; neuronal and astrocytic aggregates in subcortical nuclei; thorn-shaped astrocytes at the glial limitans of the subpial and periventricular regions; and large grain-like and dot-like structures. Supportive non-p-tau pathologies include TDP-43 immunoreactive neuronal cytoplasmic inclusions and dot-like structures in the hippocampus, anteromedial temporal cortex and amygdala. The panel also recommended a minimum blocking and staining scheme for pathological evaluation and made recommendations for future study. This study provides the first step towards the development of validated neuropathological criteria for CTE and will pave the way towards future clinical and mechanistic studies. © 2015, The Author(s).


Author Keywords
Brain trauma;  Chronic traumatic encephalopathy;  Neurodegenerative disorders;  Tauopathy;  Traumatic brain injury


Document Type: Article
Source: Scopus



Kharasch, E.D.a b c , Eisenach, J.C.d
Wherefore Gabapentinoids?: Was There Rush Too Soon to Judgment?
(2016) Anesthesiology, 124 (1), pp. 10-12. 

DOI: 10.1097/ALN.0000000000000914


a Division of Clinical and Translational Research, Department of Anesthesiology, Washington University in St. Louis, St. Louis, MI, United States
b Department of Biochemistry and Molecular Biophysics, Washington University in St. Louis, St. Louis, MI, United States
c Center for Clinical Pharmacology, St. Louis College of Pharmacy and Washington University in St. Louis, St. Louis, MI, United States
d Department of Anesthesiology, Wake Forest School of Medicine, Winston-Salem, NC, United States


Document Type: Editorial
Source: Scopus



Diringer, M.N.a b , Dhar, R.a , Scalfani, M.e , Zazulia, A.R.a c , Chicoine, M.b , Powers, W.J.d , Derdeyn, C.P.a b c
Effect of High-Dose Simvastatin on Cerebral Blood Flow and Static Autoregulation in Subarachnoid Hemorrhage
(2015) Neurocritical Care, pp. 1-8. Article in Press. 

DOI: 10.1007/s12028-015-0233-7


a Department of Neurology, Washington University, Campus Box 8111, 660 S Euclid Ave, St Louis, MO, United States
b Department of Neurological Surgery, Washington University, St. Louis, MO, United States
c Department of Radiology, Washington University, St. Louis, MO, United States
d Department of Neurology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
e Kansas City University of Medicine and Biosciences, Kansas City, MO, United States


Abstract
Background: Statins may promote vasodilation following subarachnoid hemorrhage (SAH) and improve the response to blood pressure elevation. We sought to determine whether simvastatin increases cerebral blood flow (CBF) and alters the response to induced hypertension after SAH. Methods: Statin-naïve patients admitted &lt;72 h after WFNS ≥2 aneurysmal SAH were randomly assigned to 80 mg simvastatin/day or placebo for 21 days. Regional CBF was measured with quantitative 15O PET on SAH day 7–10 before and after raising mean arterial pressure (MAP) 20–25 %. Autoregulatory index (AI) was calculated as the ratio of % change in resistance (MAP/CBF) to % change in MAP. Angiography was performed within 24 h of PET. Results are presented as simvastatin vs. placebo. Results: Thirteen patients received simvastatin and 12 placebo. Clinical characteristics were similar. Moderate or severe angiographic vasospasm occurred in 42 vs. 45 % and delayed cerebral ischemia in 14 vs. 55 % (p = 0.074). During PET studies, MAP (110 ± 10 vs. 111 ± 12), global CBF (41 ± 12 vs. 43 ± 13), and CVR (2.95 ± 1.0 vs. 2.81 ± 1.0) did not differ at baseline. When MAP was raised to 135 ± 7 mm Hg vs. 137 ± 15, global CBF did not change. Global AI did not differ (107 ± 59 vs. 0. 89 ± 52 %, p = 0.68). CBF did not change in regions with low baseline flow or in regions supplied by vessels with angiographic vasospasm in either group. Six-month modified Rankin Scale scores did not differ. Conclusions: Our data indicate that initiation of therapy with high-dose simvastatin does not alter baseline CBF or response to induced hypertension. © 2015 Springer Science+Business Media New York


Author Keywords
Blood pressure;  Delayed cerebral ischemia;  Induced hypertension;  Positon emission tomography;  Vasopressors;  Vasospasm


Document Type: Article in Press
Source: Scopus



Sorkin, D.L., Buchman, C.A.
Cochlear Implant Access in Six Developed Countries
(2015) Otology and Neurotology, . Article in Press. 

DOI: 10.1097/MAO.0000000000000946


*American Cochlear Implant Alliance, McLean, Virginia †Department of Otolaryngology–Head and Neck Surgery, Washington University School of Medicine, St. Louis, Missouri, U.S.A.


Abstract
BACKGROUND:: Access to cochlear implantation varies greatly around the world. It is affected by factors that are specific to each country's health care system, by awareness, and by societal attitudes regarding deafness. METHODS:: Cochlear implant clinicians and researchers from six countries explored and discussed these variations and their likely causes: Robert Briggs from Australia; Wolfe-Dieter Baumgartner from Austria; Thomas Lenarz from Germany; Eva Koltharp from Sweden; Christopher Raine from the United Kingdom, and Craig Buchman, Donna Sorkin, and Christine Yoshinago from the United States. RESULTS:: Utilization rates are quite different for the pediatric and adult demographics in all six countries. Pediatric utilization ranges in the six countries (all in the developed world) ranged from a low of 50% in the United States to a high of 97% in Australia. Adult utilization is less than 10% everywhere in the world. CONCLUSIONS:: Pediatric access to care was excellent for children with the exception of Germany and the United States where there is an inadequate referral system. Adult utilization was low everywhere because of the lack of screening for adults and the fact that primary care physicians and even audiologists are unfamiliar with CI candidacy criteria and outcomes, and hence typically do not make patient referrals. Copyright © 2015 by Otology & Neurotology, Inc. Image copyright © 2010 Wolters Kluwer Health/Anatomical Chart Company


Document Type: Article in Press
Source: Scopus



Razafsky, D., Potter, C., Hodzic, D.
Validation of a mouse model to disrupt LINC complexes in a cell-specific manner
(2015) Journal of Visualized Experiments, 2015 (106), art. no. e53318, . 

DOI: 10.3791/53318


Department of Ophthalmology and Visual Sciences, Washington University in St. Louis School of Medicine, United States


Abstract
Nuclear migration and anchorage within developing and adult tissues relies heavily upon large macromolecular protein assemblies called LInkers of the Nucleoskeleton and Cytoskeleton (LINC complexes). These protein scaffolds span the nuclear envelope and connect the interior of the nucleus to components of the surrounding cytoplasmic cytoskeleton. LINC complexes consist of two evolutionary-conserved protein families, Sun proteins and Nesprins that harbor C-terminal molecular signature motifs called the SUN and KASH domains, respectively. Sun proteins are transmembrane proteins of the inner nuclear membrane whose N-terminal nucleoplasmic domain interacts with the nuclear lamina while their C-terminal SUN domains protrudes into the perinuclear space and interacts with the KASH domain of Nesprins. Canonical Nesprin isoforms have a variable sized N-terminus that projects into the cytoplasm and interacts with components of the cytoskeleton. This protocol describes the validation of a dominant-negative transgenic mouse strategy that disrupts endogenous SUN/KASH interactions in a cell-type specific manner. Our approach is based on the Cre/Lox system that bypasses many drawbacks such as perinatal lethality and cell nonautonomous phenotypes that are associated with germline models of LINC complex inactivation. For this reason, this model provides a useful tool to understand the role of LINC complexes during development and homeostasis in a wide array of tissues. © 2015 Journal of Visualized Experiments.


Author Keywords
Cerebellum;  Issue 106;  KASH;  LINC complex;  Molecular Biology;  Nesprin;  Nuclear envelope;  Nucleus;  Purkinje cells;  Sun


Document Type: Article
Source: Scopus



Lenze, E.J.a , Mulsant, B.H.b , Blumberger, D.M.b , Karp, J.F.c , Newcomer, J.W.d , Anderson, S.J.e , Dew, M.A.c , Butters, M.A.c , Stack, J.A.c , Begley, A.E.c , Reynolds, C.F., IIIc e
Efficacy, safety, and tolerability of augmentation pharmacotherapy with aripiprazole for treatment-resistant depression in late life: A randomised, double-blind, placebo-controlled trial
(2015) The Lancet, 386 (10011), pp. 2404-2412. 

DOI: 10.1016/S0140-6736(15)00308-6


a Washington University School of Medicine, St Louis, MO, United States
b Centre for Addiction and Mental Health, Department of Psychiatry, University of Toronto, Toronto, ON, Canada
c University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
d Charles e Schmidt College of Medicine, Florida Atlantic University, Boca Raton, FL, United States
e University of Pittsburgh, Graduate School of Public Health, Pittsburgh, PA, United States


Abstract
Background Treatment-resistant major depression is common and potentially life-threatening in elderly people, in whom little is known about the benefits and risks of augmentation pharmacotherapy. We aimed to assess whether aripiprazole is associated with a higher probability of remission than is placebo. Methods We did a randomised, double-blind, placebo-controlled trial at three centres in the USA and Canada to test the efficacy and safety of aripiprazole augmentation for adults aged older than 60 years with treatment-resistant depression (Montgomery Asberg Depression Rating Scale [MADRS] score of ≥15). Patients who did not achieve remission during a pre-trial with venlafaxine extended-release (150-300 mg/day) were randomly assigned (1:1) to the addition of aripiprazole (target dose 10 mg [maximum 15 mg] daily) daily or placebo for 12 weeks. The computer-generated randomisation was done in blocks and stratified by site. Only the database administrator and research pharmacists had knowledge of treatment assignment. The primary endpoint was remission, defined as an MADRS score of 10 or less (and at least 2 points below the score at the start of the randomised phase) at both of the final two consecutive visits, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00892047. Findings From July 20, 2009, to Dec 30, 2013, we recruited 468 eligible participants, 181 (39%) of whom did not remit and were randomly assigned to aripiprazole (n=91) or placebo (n=90). A greater proportion of participants in the aripiprazole group achieved remission than did those in the placebo group (40 [44%] vs 26 [29%] participants; odds ratio [OR] 2·0 [95% CI 1·1-3·7], p=0·03; number needed to treat [NNT] 6·6 [95% CI 3·5-81·8]). Akathisia was the most common adverse effect of aripiprazole (reported in 24 [26%] of 91 participants on aripiprazole vs 11 [12%] of 90 on placebo). Compared with placebo, aripiprazole was also associated with more Parkinsonism (15 [17%] of 86 vs two [2%] of 81 participants), but not with treatment-emergent suicidal ideation (13 [21%] of 61 vs 19 [29%] of 65 participants) or other measured safety variables. Interpretation In adults aged 60 years or older who do not achieve remission from depression with a first-line antidepressant, the addition of aripiprazole is effective in achieving and sustaining remission. Tolerability concerns include the potential for akathisia and Parkinsonism. Funding National Institute of Mental Health, UPMC Endowment in Geriatric Psychiatry, Taylor Family Institute for Innovative Psychiatric Research, National Center for Advancing Translational Sciences, and the Campbell Family Mental Health Research Institute. © 2015 Elsevier Ltd.


Document Type: Article
Source: Scopus



Mukherjee, S.a eb , Walter, S.b eb eb , Kauwe, J.S.K.c eb eb , Saykin, A.J.d , Bennett, D.A.e , Larson, E.B.f , Crane, P.K.a , Glymour, M.M.b , Albert, M.S.g , Albin, R.L.h i j , Apostolova, L.G.k , Arnold, S.E.l , Asthana, S.m n o , Atwood, C.S.m o , Baldwin, C.T.p , Barber, R.C.q , Barmada, M.M.r , Barnes, L.L.s t , Beach, T.G.u , Becker, J.T.v , Beecham, G.W.w x , Beekly, D.y , Bigio, E.H.z aa , Bird, T.D.ab ac , Blacker, D.ad ae , Boeve, B.F.af , Bowen, J.D.ag , Boxer, A.ah , Burke, J.R.ai , Buxbaum, J.D.aj ak al , Cairns, N.J.am , Cantwell, L.B.an , Cao, C.ao , Carlson, C.S.ap , Carlsson, C.M.n , Carney, R.M.aq , Carrasquillo, M.M.ar , Carroll, S.L.as , Chui, H.C.at , Clark, D.G.au , Corneveaux, J.av , Cribbs, D.H.aw , Crocco, E.A.aq , Cruchaga, C.ax , De Jager, P.L.ay az , DeCarli, C.ba , Demirci, F.Y.r , Dick, M.bb , Dickson, D.W.ar , Duara, R.bc , Ertekin-Taner, N.ar bd , Evans, D.be , Faber, K.M.bf , Fallon, K.B.as , Farlow, M.R.bl , Farrer, L.A.bg bh bi bj bk , Ferris, S.bm , Foroud, T.M.bf , Frosch, M.P.bn , Galasko, D.R.bo , Gearing, M.bp bq , Geschwind, D.H.br , Ghetti, B.bs , Gilbert, J.R.w x , Glass, J.D.bt , Goate, A.M.ax , Graff-Radford, N.R.ar bd , Green, R.C.bu , Growdon, J.H.bv , Haines, J.L.bw , Hakonarson, H.bx , Hamilton, R.L.by , Hamilton-Nelson, K.L.w , Hardy, J.bz , Harrell, L.E.au , Head, E.ca , Honig, L.S.cb , Huebinger, R.M.cc , Huentelman, M.J.av , Hulette, C.M.cd , Hyman, B.T.bv , Jarvik, G.P.ce cf , Jicha, G.A.cg , Jin, L.-W.ch , Jun, G.p bg bk , Kamboh, M.I.r ci , Karydas, A.ah , Kaye, J.A.cj ck , Kim, R.cl , Kowall, N.W.bj cm , Kramer, J.H.cn , Kukull, W.A.co , Kunkle, B.W.w , LaFerla, F.M.cp , Lah, J.J.bt , Leverenz, J.B.cq , Levey, A.I.bt , Li, G.cr , Lieberman, A.P.cs , Lin, C.-F.an , Lopez, O.L.ci , Lunetta, K.L.bg , Lyketsos, C.G.ct , Mack, W.J.cu , Marson, D.C.au , Martin, E.R.w x , Martiniuk, F.cv , Mash, D.C.cw , Masliah, E.bo cx , Mayeux, R.cb cy cz , McCormick, W.C.a , McCurry, S.M.da , McDavid, A.N.ap , McKee, A.C.bj cm , Mesulam, M.z db , Miller, B.L.ah , Miller, C.A.dc , Miller, J.W.ch , Montine, T.J.dd , Morris, J.C.am de , Murrell, J.R.bf bs , Myers, A.J.aq , Naj, A.C.an , Olichney, J.M.ba , Pankratz, V.S.df , Parisi, J.E.dg , Partch, A.an , Paulson, H.L.dh , Pericak-Vance, M.A.w x , Perry, W.w , Peskind, E.cr , Petersen, R.C.af , Pierce, A.aw , Poon, W.W.bb , Potter, H.di , Quinn, J.F.cj , Raj, A.ao , Raskind, M.cr , Reiman, E.M.av dj dk dl , Reisberg, B.bm dm , Reitz, C.cb cy cz , Ringman, J.M.k , Roberson, E.D.au , Rogaeva, E.dn , Rosen, H.J.ah , Rosenberg, R.N.do , Sager, M.A.n , Sano, M.ak , Schellenberg, G.D.an , Schneider, J.A.s dp , Schneider, L.S.at dq , Seeley, W.W.ah , Smith, A.G.ao , Sonnen, J.A.dd , Spina, S.bs , George-Hyslop, P.St.dn dr , Stern, R.A.bj , Tanzi, R.E.bv , Thornton-Wells, T.A.ds , Trojanowski, J.Q.an , Troncoso, J.C.dt , Tsuang, D.W.ac cr , Valladares, O.an , Van Deerlin, V.M.an , Van Eldik, L.J.du , Vardarajan, B.N.cb cy cz , Vinters, H.V.k dv , Vonsattel, J.P.dw , Wang, L.-S.an , Weintraub, S.z dx , Welsh-Bohmer, K.A.ai dy , Williamson, J.cb , Wishnek, S.w , Woltjer, R.L.dz , Wright, C.B.ea , Younkin, S.G.ar , Yu, C.-E.a , Yu, L.s
Genetically predicted body mass index and Alzheimer's disease-related phenotypes in three large samples: Mendelian randomization analyses
(2015) Alzheimer's and Dementia, 11 (12), pp. 1439-1451. 

DOI: 10.1016/j.jalz.2015.05.015


a Department of Medicine, University of Washington, Seattle, WA, United States
b Department of Epidemiology and Biostatistics, University of California at San Francisco, San Francisco, CA, United States
c Department of Biology, Brigham Young University, Provo, UT, United States
d Department of Radiology, Indiana University, Indianapolis, IN, United States
e Department of Neurology, Rush University, Chicago, IL, United States
f Group Health Research Institute, Seattle, WA, United States
g Department of Neurology, Johns Hopkins University, Baltimore, MD, United States
h Department of Neurology, University of Michigan, Ann Arbor, MI, United States
i Geriatric Research, Education and Clinical Center (GRECC), VA Ann Arbor Healthcare System (VAAAHS), Ann Arbor, MI, United States
j Michigan Alzheimer Disease Center, Ann Arbor, MI, United States
k Department of Neurology, University of California Los Angeles, Los Angeles, CA, United States
l Department of Psychiatry, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, United States
m Geriatric Research, Education and Clinical Center (GRECC), University of Wisconsin, Madison, WI, United States
n Department of Medicine, University of Wisconsin, Madison, WI, United States
o Wisconsin Alzheimer's Institute, Madison, WI, United States
p Department of Medicine, Genetics Program, Boston University, Boston, MA, United States
q Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX, United States
r Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, United States
s Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, United States
t Department of Behavioral Sciences, Rush University Medical Center, Chicago, IL, United States
u Civin Laboratory for Neuropathology, Banner Sun Health Research Institute, Phoenix, AZ, United States
v Departments of Psychiatry, Neurology, and Psychology, University of Pittsburgh, School of Medicine, Pittsburgh, PA, United States
w John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL, United States
x Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami, Miami, FL, United States
y National Alzheimer's Coordinating Center, University of Washington, Seattle, WA, United States
z Cognitive Neurology and Alzheimer's Disease Center, Northwestern University Feinberg, School of Medicine, Chicago, IL, United States
aa Department of Pathology, Northwestern University Feinberg, School of Medicine, Chicago, IL, United States
ab Department of Neurology, University of Washington, Seattle, WA, United States
ac VA Puget Sound Health Care System/GRECC, Seattle, WA, United States
ad Department of Epidemiology, Harvard School of Public Health, Boston, MA, United States
ae Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
af Department of Neurology, Mayo Clinic, Rochester, MN, United States
ag Swedish Medical Center, Seattle, WA, United States
ah Department of Neurology, University of California San Francisco, San Francisco, CA, United States
ai Department of Medicine, Duke University, Durham, NC, United States
aj Department of Neuroscience, Mount Sinai School of Medicine, New York, NY, United States
ak Department of Psychiatry, Mount Sinai School of Medicine, New York, NY, United States
al Departments of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, NY, United States
am Department of Pathology and Immunology, Washington University, St. Louis, MO, United States
an Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman, School of Medicine, Philadelphia, PA, United States
ao USF Health Byrd Alzheimer's Institute, University of South Florida, Tampa, FL, United States
ap Fred Hutchinson Cancer Research Center, Seattle, WA, United States
aq Department of Psychiatry and Behavioral Sciences, Miller School of Medicine, University of Miami, Miami, FL, United States
ar Department of Neuroscience, Mayo Clinic, Jacksonville, FL, United States
as Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, United States
at Department of Neurology, University of Southern California, Los Angeles, CA, United States
au Department of Neurology, University of Alabama at Birmingham, Birmingham, AL, United States
av Neurogenomics Division, Translational Genomics Research Institute, Phoenix, AZ, United States
aw Department of Neurology, University of California Irvine, Irvine, CA, United States
ax Department of Psychiatry, Hope Center Program on Protein Aggregation and Neurodegeneration, Washington University, School of Medicine, St. Louis, MO, United States
ay Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Department of Neurology and Psychiatry, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States
az Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, United States
ba Department of Neurology, University of California Davis, Sacramento, CA, United States
bb Institute for Memory Impairments and Neurological Disorders, University of California Irvine, Irvine, CA, United States
bc Wien Center for Alzheimer's Disease and Memory Disorders, Mount Sinai Medical Center, Miami Beach, FL, United States
bd Department of Neurology, Mayo Clinic, Jacksonville, FL, United States
be Rush Institute for Healthy Aging, Department of Internal Medicine, Rush University Medical Center, Chicago, IL, United States
bf Department of Medical and Molecular Genetics, Indiana University, Indianapolis, IN, United States
bg Department of Biostatistics, Boston University, Boston, MA, United States
bh Department of Epidemiology, Boston University, Boston, MA, United States
bi Department of Medicine (Biomedical Genetics), Boston University, Boston, MA, United States
bj Department of Neurology, Boston University, Boston, MA, United States
bk Department of Ophthalmology, Boston University, Boston, MA, United States
bl Department of Neurology, Indiana University, Indianapolis, IN, United States
bm Department of Psychiatry, New York University, New York, NY, United States
bn C.S. Kubik Laboratory for Neuropathology, Massachusetts General Hospital, Charlestown, MA, United States
bo Department of Neurosciences, University of California San Diego, La Jolla, CA, United States
bp Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA, United States
bq Emory Alzheimer's Disease Center, Emory University, Atlanta, GA, United States
br Neurogenetics Program, University of California Los Angeles, Los Angeles, CA, United States
bs Department of Pathology and Laboratory Medicine, Indiana University, Indianapolis, IN, United States
bt Department of Neurology, Emory University, Atlanta, GA, United States
bu Division of Genetics, Department of Medicine, Partners Center for Personalized Genetic Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States
bv Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
bw Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH, United States
bx Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, United States
by Department of Pathology (Neuropathology), University of Pittsburgh, Pittsburgh, PA, United States
bz Institute of Neurology, University College London, Queen Square, London, United Kingdom
ca Sanders-Brown Center on Aging, Department of Molecular and Biomedical Pharmacology, University of Kentucky, Lexington, KY, United States
cb Taub Institute on Alzheimer's Disease and the Aging Brain, Department of Neurology, Columbia University, New York, NY, United States
cc Department of Surgery, University of Texas, Southwestern Medical Center, Dallas, TX, United States
cd Department of Pathology, Duke University, Durham, NC, United States
ce Department of Genome Sciences, University of Washington, Seattle, WA, United States
cf Department of Medicine (Medical Genetics), University of Washington, Seattle, WA, United States
cg Sanders-Brown Center on Aging, Department Neurology, University of Kentucky, Lexington, KY, United States
ch Department of Pathology and Laboratory Medicine, University of California Davis, Sacramento, CA, United States
ci University of Pittsburgh Alzheimer's Disease Research Center, Pittsburgh, PA, United States
cj Department of Neurology, Oregon Health and Science University, Portland, OR, United States
ck Department of Neurology, Portland Veterans Affairs Medical Center, Portland, OR, United States
cl Department of Pathology and Laboratory Medicine, University of California Irvine, Irvine, CA, United States
cm Department of Pathology, Boston University, Boston, MA, United States
cn Department of Neuropsychology, University of California San Francisco, San Francisco, CA, United States
co Department of Epidemiology, University of Washington, Seattle, WA, United States
cp Department of Neurobiology and Behavior, University of California Irvine, Irvine, CA, United States
cq Cleveland Clinic Lou Ruvo Center for Brain Health, Cleveland Clinic, Cleveland, OH, United States
cr Department of Psychiatry and Behavioral Sciences, University of Washington, School of Medicine, Seattle, WA, United States
cs Department of Pathology, University of Michigan, Ann Arbor, MI, United States
ct Department of Psychiatry, Johns Hopkins University, Baltimore, MD, United States
cu Department of Preventive Medicine, University of Southern California, Los Angeles, CA, United States
cv Department of Medicine-Pulmonary, New York University, New York, NY, United States
cw Department of Neurology, University of Miami, Miami, FL, United States
cx Department of Pathology, University of California San Diego, La Jolla, CA, United States
cy Department of Neurology, Columbia University, New York, NY, United States
cz Gertrude H. Sergievsky Center, Columbia University, New York, NY, United States
da School of Nursing Northwest Research Group on Aging, University of Washington, Seattle, WA, United States
db Department of Neurology, Northwestern University Feinberg, School of Medicine, Chicago, IL, United States
dc Department of Pathology, University of Southern California, Los Angeles, CA, United States
dd Department of Pathology, University of Washington, Seattle, WA, United States
de Department of Neurology, Washington University, St. Louis, MO, United States
df Department of Biostatistics, Mayo Clinic, Rochester, MN, United States
dg Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States
dh Michigan Alzheimer's Disease Center, Department of Neurology, University of Michigan, Ann Arbor, MI, United States
di Department of Neurology, University of Colorado, School of Medicine, Aurora, CO, United States
dj Arizona Alzheimer's Consortium, Phoenix, AZ, United States
dk Department of Psychiatry, University of Arizona, Phoenix, AZ, United States
dl Banner Alzheimer's Institute, Phoenix, AZ, United States
dm Alzheimer's Disease Center, New York University, New York, NY, United States
dn Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, ON, Canada
do Department of Neurology, University of Texas Southwestern, Dallas, TX, United States
dp Department of Pathology (Neuropathology), Rush University Medical Center, Chicago, IL, United States
dq Department of Psychiatry, University of Southern California, Los Angeles, CA, United States
dr Cambridge Institute for Medical Research, Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom
ds Center for Human Genetics and Research, Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, United States
dt Department of Pathology, Johns Hopkins University, Baltimore, MD, United States
du Sanders-Brown Center on Aging, Department of Anatomy and Neurobiology, University of Kentucky, Lexington, KY, United States
dv Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, CA, United States
dw Taub Institute on Alzheimer's Disease and the Aging Brain, Department of Pathology, Columbia University, New York, NY, United States
dx Department of Psychiatry, Northwestern University Feinberg, School of Medicine, Chicago, IL, United States
dy Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC, United States
dz Department of Pathology, Oregon Health and Science University, Portland, OR, United States
ea Evelyn F. McKnight Brain Institute, Department of Neurology, Miller School of Medicine, University of Miami, Miami, FL, United States


Abstract
Observational research shows that higher body mass index (BMI) increases Alzheimer's disease (AD) risk, but it is unclear whether this association is causal. We applied genetic variants that predict BMI in Mendelian randomization analyses, an approach that is not biased by reverse causation or confounding, to evaluate whether higher BMI increases AD risk. We evaluated individual-level data from the AD Genetics Consortium (ADGC: 10,079 AD cases and 9613 controls), the Health and Retirement Study (HRS: 8403 participants with algorithm-predicted dementia status), and published associations from the Genetic and Environmental Risk for AD consortium (GERAD1: 3177 AD cases and 7277 controls). No evidence from individual single-nucleotide polymorphisms or polygenic scores indicated BMI increased AD risk. Mendelian randomization effect estimates per BMI point (95% confidence intervals) were as follows: ADGC, odds ratio (OR) = 0.95 (0.90-1.01); HRS, OR = 1.00 (0.75-1.32); GERAD1, OR = 0.96 (0.87-1.07). One subscore (cellular processes not otherwise specified) unexpectedly predicted lower AD risk. © 2015 The Alzheimer's Association.


Author Keywords
Alzheimer's disease;  Dementia;  Mendelian randomization;  Obesity


Document Type: Article
Source: Scopus



Ferenc, G.a , Zsuzsanna, M.a , András, V.a , Zsuzsanna, K.a , Sándor, R.b , Zoltán, V.a , Tamás, K.c
Risk and protective factors of drug use in schoolchildren and adolescents: Results of a representative study [Iskolás- és serdülokorúak droghasználata: Kockázati és védo faktorok egy reprezentatív vizsgálat tükrében]
(2015) Mentalhigiene es Pszichoszomatika, 16 (4), pp. 297-330. 

DOI: 10.1556/0406.16.2015.4.1


a Károli Gáspár Reformatus Egyetem, Pszichólogiai Intézet, Bécsi út 324., Budapest, Hungary
b Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
c Nemzeti Család- és Szociálpolitikai Intezet, Nemzeti Drogmegelozési Iroda, Budapest, Hungary


Abstract
Background: Drug use has been widespread and in recent years, initiation has been occurring at earlier ages. More and more studies have the aim to identify main risk and protective factors. Aim: The IEUD (School Health Development and Universal Drug Prevention) project was launched by the National Institute for Family and Social Policy, Hungary. On basis of representative data, we wanted to investigate mental health in 6-18 year old schoolage children and to gain data about substance use (smoking, alcohol, and illegal drugs). The main focus of the study was to analyze environmental-relational determinants of substance use. Methods: 7623 schoolchildren (grades 1, 3, 5, 7, 9, 11) participated. A comprehensive questionnaire was administered during a school lesson. In addition to studying substance use habits, the test battery included items for relational models and patterns, and a set of other variables (e.g., Big Five personality dimensions, mood and deviance). Results: Data on substance use frequency and initiation were in accordance with former representative studies. About 51 percent of our Global Substance Use Index could be explained by psychosocial variables. Deviance, maternal attitude, family and peer models, particular personality dimensions (extraversion, neuroticism) and perceived popularity in opposite-sex peers were significant determinants. Conclusions: Findings can be used to develop more effective preventive initiatives. Focused efforts should be directed toward groups at risk (e.g., adolescents with deviant behavior and high neuroticism). Also, support of parental monitoring techniques as well as interventions based on peer support seem to be promising directions. © 2015 Akadémiai Kiadó, Budapest.


Author Keywords
Adolescence;  Deviance;  Family relations;  Parental monitoring;  Peer relations;  Personality traits;  Risk and protective factors;  Substance use


Document Type: Review
Source: Scopus



Mattos, D.a b d , Schöner, G.c , Zatsiorsky, V.M.d , Latash, M.L.d
Task-specific stability of abundant systems: Structure of variance and motor equivalence
(2015) Neuroscience, 310, pp. 600-615. 

DOI: 10.1016/j.neuroscience.2015.09.071


a University of Delaware, Newark, DE, United States
b Washington University, Saint Louis, MO, United States
c Institut für Neuroinformatik, Rühr University Bochum, Bochum, Germany
d Department of Kinesiology, The Pennsylvania State University, University Park, PA, United States


Abstract
Our main goal was to test a hypothesis that transient changes in performance of a steady-state task would result in motor equivalence. We also estimated effects of visual feedback on the amount of reorganization of motor elements. Healthy subjects performed two variations of a four-finger pressing task requiring accurate production of total pressing force (FTOT) and total moment of force (MTOT). In the Jumping-Target task, a sequence of target jumps required transient changes in either FTOT or MTOT. In the Step-Perturbation task, the index finger was lifted by 1cm for 0.5s leading to a change in both FTOT and MTOT. Visual feedback could have been frozen for one of these two variables in both tasks. Deviations in the space of finger modes (hypothetical commands to individual fingers) were quantified in directions of unchanged FTOT and MTOT (motor equivalent - ME) and in directions that changed FTOT and MTOT (non-motor equivalence - nME). Both the ME and nME components increased when the performance changed. After transient target jumps leading to the same combination of FTOT and MTOT, the changes in finger modes had a large residual ME component with only a very small nME component. Without visual feedback, an increase in the nME component was observed without consistent changes in the ME component. Results from the Step-Perturbation task were qualitatively similar. These findings suggest that both external perturbations and purposeful changes in performance trigger a reorganization of elements of an abundant system, leading to large ME change. These results are consistent with the principle of motor abundance corroborating the idea that a family of solutions is facilitated to stabilize values of important performance variables. © 2015.


Author Keywords
Finger force;  Motor equivalence;  Perturbation;  Synergy;  Uncontrolled manifold hypothesis


Document Type: Article
Source: Scopus



Huang, J.a , Liu, Y.a , Filas, B.a , Gunhaga, L.c , Beebe, D.C.a b
Negative and positive auto-regulation of BMP expression in early eye development
(2015) Developmental Biology, 407 (2), pp. 256-264. 

DOI: 10.1016/j.ydbio.2015.09.009


a Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO, United States
b Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO, United States
c Umeå Centre for Molecular Medicine, Umeå University, Umeå, Sweden


Abstract
Previous results have shown that Bone Morphogenetic Protein (BMP) signaling is essential for lens specification and differentiation. How BMP signals are regulated in the prospective lens ectoderm is not well defined. To address this issue we have modulated BMP activity in a chicken embryo pre-lens ectoderm explant assay, and also studied transgenic mice, in which the type I BMP receptors, Bmpr1a and Acvr1, are deleted from the prospective lens ectoderm. Our results show that chicken embryo pre-lens ectoderm cells express BMPs and require BMP signaling for lens specification in vitro, and that in vivo inhibition of BMP signals in the mouse prospective lens ectoderm interrupts lens placode formation and prevents lens invagination. Furthermore, our results provide evidence that BMP expression is negatively auto-regulated in the lens-forming ectoderm, decreasing when the tissue is exposed to exogenous BMPs and increasing when BMP signaling is prevented. In addition, eyes lacking BMP receptors in the prospective lens placode develop coloboma in the adjacent wild type optic cup. In these eyes, Bmp7 expression increases in the ventral optic cup and the normal dorsal-ventral gradient of BMP signaling in the optic cup is disrupted. Pax2 becomes undetectable and expression of Sfrp2 increases in the ventral optic cup, suggesting that increased BMP signaling alter their expression, resulting in failure to close the optic fissure. In summary, our results suggest that negative and positive auto-regulation of BMP expression is important to regulate early eye development. © 2015.


Author Keywords
Auto-regulation;  BMP;  Coloboma;  Development;  Lens;  Specification


Document Type: Article
Source: Scopus



Kelsey, M., Prior, F.W., Larson-Prior, L.J.
Spatiotemporal analysis of the appearance of gamma-band Microstates in resting state MEG
(2015) Proceedings of the Annual International Conference of the IEEE Engineering in Medicine and Biology Society, EMBS, 2015-November, art. no. 7318933, pp. 2637-2640. 

DOI: 10.1109/EMBC.2015.7318933


Mallinckrodt Institute of Radiology, Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States


Abstract
Spatiotemporal analysis of EEG signal has revealed a rich set of methods to quantify neuronal activity using spatially global topographic templates, called Microstates. These methods complement more traditional spectral analysis, which uses band limited source data to determine defining differences in band power and peak characteristics. The high sampling rate and increased resistance to high frequency noise of MEG data offers an opportunity to explore the utility of spatiotemporal analysis over a wider spectrum than in EEG. In this work, we explore the utility of representing band limited MEG source data using established microstate techniques, especially in gamma frequency bands - a range yet unexplored using these techniques. We develop methods for gauging the goodness-offit achieved by resultant microstate templates and demonstrate sensor-level dispersion characteristics across wide-band signals as well as across signals filtered by canonical bands. These analyses reveal that, while high-frequency-band derived microstate templates are visually lawful, they fail to exhibit important explained variance and dispersion characteristics present in low- and full- band data necessary to meet the requirements of a microstate model. © 2015 IEEE.


Document Type: Conference Paper
Source: Scopus



Hong Lee, S.a b , Byrne, E.M.a , Hultman, C.M.c , Kähler, A.c , Vinkhuyzen, A.A.a , Ripke, S.d e f , Andreassen, O.A.g h , Frisell, T.i , Gusev, A.j k l , Hu, X.m n o p , Karlsson, R.c , Mantzioris, V.X.a , McGrath, J.J.a q , Mehta, D.a , Stahl, E.A.r , Zhao, Q.a , Kendler, K.S.s t u , Sullivan, P.F.v , Price, A.L.j k l , O'Donovan, M.w x , Okada, Y.y z aa ab , Mowry, B.J.a ac , Raychaudhuri, S.y z aa ad ae , Wray, N.R.a , Agartz, I.af ag , Amin, F.ah , Azevedo, M.H.ai , Bass, N.aj , Black, D.W.ak , Blackwood, D.H.R.al , Bruggeman, R.am , Buccola, N.G.an , Choudhury, K.aj , Cloninger, C.R.ao , Corvin, A.ap , Craddock, N.aq ar , Daly, M.J.as at , Datta, S.au , Donohoe, G.J.av , Duan, J.aw , Dudbridge, F.ax , Fanous, A.ay az , Freedman, R.ba , Freimer, N.B.bb , Friedl, M.bc , Gill, M.ap , Gurling, H.aj , Haan, L.D.bd , Hamshere, M.L.aq be , Hartmann, A.M.bc , Holmans, P.A.aq be , Kahn, R.S.bf , Keller, M.C.bg , Kenny, E.ap , Kirov, G.K.aq ar , Krabbendam, L.bh , Krasucki, R.aj , Lawrence, J.aj , Lencz, T.bi bj bk , Levinson, D.F.bl , Lieberman, J.A.bm , Lin, D.-Y.bn , Linszen, D.H.bo , Magnusson, P.K.E.bp , Maier, W.bq , Malhotra, A.K.bi bj bk , Mattheisen, M.br bs bt bu , Mattingsdal, M.af bv , McCarroll, S.A.at , Medeiros, H.bw , Melle, I.af bx , Milanova, V.by , Myin-Germeys, I.bh , Neale, B.M.as at , Ophoff, R.A.bb bz ca , Owen, M.J.aq ar , Pimm, J.ak , Purcell, S.M.n o cb , Puri, V.ak , Quested, D.J.cc , Rossin, L.at , Ruderfer, D.cb , Sanders, A.R.aw , Shi, J.cd , Sklar, P.cb , St Clair, D.ce , Scott Stroup, T.cf , Van Os, J.bh , Visscher, P.M.cg ch , Wiersma, D.am , Zammit, S.aq ar , Byerley, W.ci cj , Cahn, W.ck , Cantor, R.M.cl , Cichon, S.cm cn co , Cormican, P.cp , Curtis, D.cq , Djurovic, S.cr dq , Escott-Price, V.cs ct , Gejman, P.V.cu , Georgieva, L.cs cv , Giegling, I.cw , Hansen, T.F.cx cy , Ingason, Andréscx cy , Kim, Y.cz , Konte, B.cw , Lee, P.H.da , McIntosh, A.db dc , McQuillin, A.dd , Morris, D.W.de , Nöthen, M.M.cm df , O'Dushlaine, C.dg , Olincy, A.dh , Olsen, L.cx cy , Pato, C.N.di , Pato, M.T.di , Pickard, B.S.db dc , Posthuma, D.dj , Rasmussen, H.B.cx cy , Rietschel, M.dk , Rujescu, D.cv , Schulze, T.G.dl dm , Silverman, J.M.dn , Thirumalai, S.do , Werge, T.cw cx dp , Louis Bridges, S., Jr.dr , Choi, H.K.ds dt du , Coenen, M.J.H.dv , De Vries, N.dw , Dieud, P.dx dy , Greenberg, J.D.dz , Huizinga, T.W.J.ea , Padyukov, L.eb , Siminovitch, K.A.ec ed ee , Tak, P.P.ef eg eh , Worthington, J.ei ej , De Jager, P.L.ek el em , Denny, J.C.en eo , Gregersen, P.K.ep , Klareskog, L.eq , Mariette, X.er , Plenge, R.M.ek el es , Van Laar, M.et , Van Riel, P.eu
New data and an old puzzle: The negative association between schizophrenia and rheumatoid arthritis
(2015) International Journal of Epidemiology, 44 (5), art. no. dyv136, pp. 1706-1721. 

DOI: 10.1093/ije/dyv136


a The University of Queensland, Queensland Brain Institute, Brisbane, QLD, Australia
b School of Environmental and Rural Science, University of New England, Armidale, NSW, Australia
c Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
d Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
e Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, United States
f Department of Psychiatry and Psychotherapy, Charité-Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany
g NORMENT KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
h Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway
i Clinical Epidemiology Unit, Karolinska Institutet, Stockholm, Sweden
j Department of Epidemiology, Harvard School of Public Health, Boston, MA, United States
k Department of Biostatistics, Harvard School of Public Health, Boston, MA, United States
l Medical and Population Genetics Program, Broad Institute, Cambridge, MA, United States
m Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States
n Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States
o Medical and Population Genetics Group, Broad Institute, Cambridge, MA, United States
p Health Science and Technology MD Program, Harvard University and Massachusetts Institute of Technology, Boston, MA, United States
q Queensland Centre for Mental Health Research, Park Centre for Mental Health, Richlands, QLD, Australia
r Division of Psychiatric Genomics, Mt Sinai School of Medicine, New York, NY, United States
s Virginia Institute of Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, United States
t Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA, United States
u Department of Psychiatry, Virginia Commonwealth University, Richmond, VA, United States
v Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
w Medical Research Council (MRC) Centre for Neuropsychiatric Genetics and Genomics, CardiffUniversity School of Medicine, Cardiff, United Kingdom
x Institute of Psychological Medicine and Clinical Neurosciences, CardiffUniversity School of Medicine, Cardiff, United Kingdom
y Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States
z Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States
aa Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, United States
ab Department of Human Genetics and Disease Diversity, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
ac Queensland Centre for Mental Health Research, Wacol, QLD, Australia
ad Partners Center for Personalized Genetic Medicine, Boston, MA, United States
ae Faculty of Medical and Human Sciences, University of Manchester, Manchester, United Kingdom
af KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
ag Department of Research, Diakonhjemmet Hospital, Oslo, Norway
ah Department of Psychiatry and Behavioral Sciences, Atlanta Veterans Affairs Medical Center, Emory University, Atlanta, GA, United States
ai Faculty of Medicine, University of Coimbra, Coimbra, Portugal
aj Mental Health Sciences Unit, University College London, London, United Kingdom
ak Department of Psychiatry, University of Iowa, Iowa City, IA, United States
al Division of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, United Kingdom
am Department of Psychiatry, University Medical Center Groningen, Groningen, Netherlands
an School of Nursing, Louisiana State University Health Sciences Center, New Orleans, LA, United States
ao Department of Psychiatry, Washington University School of Medicine, St Louis, MO, United States
ap Department of Psychiatry, Trinity College Dublin, Dublin, Ireland
aq Medical Research Council (MRC) Centre for Neuropsychiatric Genetics and Genomics, CardiffUniversity School of Medicine, Cardiff, United Kingdom
ar Institute of Psychological Medicine and Clinical Neurosciences, CardiffUniversity School of Medicine, Cardiff, United Kingdom
as Analytic and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
at Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, United States
au Genetics Institute, University College London, London, United Kingdom
av Cognitive Genetics and Therapy Group, Discipline of Biochemistry and School of Psychology, National University of Ireland, Galway, Ireland
aw Department of Psychiatry and Behavioral Sciences, North Shore University Health System and University of Chicago, Evanston, IL, United States
ax Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, United Kingdom
ay Department of Psychiatry, Georgetown University School of Medicine, Washington, DC, United States
az Virginia Institute of Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, United States
ba Department of Psychiatry, University of Colorado Denver, Aurora, CO, United States
bb Center for Neurobehavioral Genetics, University of California, Los Angeles, CA, United States
bc Department of Psychiatry, University of Halle, Halle, Germany
bd Department of Psychiatry, Academic Medical Centre, University of Amsterdam, Amsterdam, Netherlands
be Biostatistics and Bioinformatics Unit, CardiffUniversity, Cardiff, United Kingdom
bf Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Center, Utrecht, Netherlands
bg Department of Psychology, University of Colorado, Boulder, CO, United States
bh Department of Psychiatry and Neuropsychology, Maastricht University Medical Centre, South Limburg Mental Health Research and Teaching Network, Maastricht, Netherlands
bi Department of Psychiatry, Long Island Jewish Health System, Glen Oaks, New York, NY, United States
bj Center for Psychiatric Neuroscience, Feinstein Institute of Medical Research, Manhasset, New York, NY, United States
bk Department of Psychiatry and Behavioral Science, Albert Einstein College of Medicine of Yeshiva University, Bronx, NY, United States
bl Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, United States
bm New York State Psychiatric Institute, Columbia University, New York, NY, United States
bn Department of Biostatistics, University of North Carolina, Chapel Hill, NC, United States
bo Department of Psychiatry, Academic Medical Centre University of Amsterdam, Amsterdam, Netherlands
bp Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
bq Department of Psychiatry, University of Bonn, Bonn, Germany
br Institute of Human Genetics, University of Bonn, Bonn, Germany
bs Lundbeck Initiative for Integrative Psychiatric Research, IPSYCH, Roskilde, Denmark
bt Department of Biomedicine, Aarhus University, Aarhus, Denmark
bu Department of Genomic Mathematics, University of Bonn, Bonn, Germany
bv Sørlandet Hospital, Kristiansand, Norway
bw Department of Psychiatry, Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, CA, United States
bx Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway
by Department of Psychiatry, Alexander University Hospital, Sofia, Bulgaria
bz Department of Human Genetics, University of California, Los Angeles, CA, United States
ca Department of Psychiatry, University Medical Center Utrecht, Utrecht, Netherlands
cb Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, United States
cc Academic Department of Psychiatry, University of Oxford, Oxford, United Kingdom
cd Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, United States
ce Institute of Medical Sciences, University of Aberdeen, Aberdeen, United Kingdom
cf Department of Psychiatry, Columbia University, New York, NY, United States
cg Queensland Brain Institute, University of Queensland, Brisbane, QLD, Australia
ch Diamantina Institute, University of Queensland, Brisbane, QLD, Australia
ci Department of Psychiatry, University of California, San Francisco, CA, United States
cj NCIRE (Northern California Institute of Q Research and Education), San Francisco, CA, United States
ck Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Center, Utrecht, Netherlands
cl David Geffen School of Medicine, University of California, Los Angeles, CA, United States
cm Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany
cn Division of Medical Genetics, Department of Biomedicine, University of Basel, Basel, Switzerland
co Institute of Neuroscience and Medicine (INM-1), Research Center Juelich, Juelich, Germany
cp Department of Psychiatry, Trinity College Dublin, Dublin, Ireland
cq UCL Genetics Institute, University College London, London, United Kingdom
cr NORMENT, KG Jebsen Centre for Psychosis Research, Department of Clinical Science, University of Bergen, Bergen, Norway
cs Medical Research Council (MRC) Centre for Neuropsychiatric Genetics and Genomics, CardiffUniversity School of Medicine, Cardiff, United Kingdom
ct Biostatistics and Bioinformatics Unit, CardiffUniversity, Cardiff, United Kingdom
cu Department of Psychiatry and Behavioral Sciences, North Shore University Health System and University of Chicago, Evanston, IL, United States
cv Institute of Psychological Medicine and Clinical Neurosciences, CardiffUniversity School of Medicine, Cardiff, United Kingdom
cw Department of Psychiatry, University of Halle, Halle, Germany
cx Institute of Biological Psychiatry, Copenhagen University Hospital, Roskilde, Denmark
cy Lundbeck Initiative for Integrative Psychiatric Research, Ipsych, Roskilde, Denmark
cz Department of Genetics, University of North Carolina, Chapel Hill, NC, United States
da Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, MA, United States
db Division of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, United Kingdom
dc Molecular Medicine Centre, University of Edinburgh, Edinburgh, United Kingdom
dd Mental Health Sciences Unit, University College London, London, United Kingdom
de Cognitive Genetics and Therapy Group, Discipline of Biochemistry and School of Psychology, National University of Ireland, Galway, Ireland
df Institute of Human Genetics, University of Bonn, Bonn, Germany
dg Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, United States
dh Department of Psychiatry, University of Colorado Denver, Aurora, CO, United States
di Department of Psychiatry, Zilkha Neurogenetic Institute, University of Southern California, Keck School of Medicine, Los Angeles, CA, United States
dj Department of Complex Trait Genetics, VU University, Amsterdam, Netherlands
dk Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
dl Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, MD, United States
dm Department of Psychiatry and Psychotherapy, University of Göttingen, Göttingen, Germany
dn Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, United States
do Oxford Health NHS Foundation Trust, Marlborough House Secure Unit, Milton Keynes, United Kingdom
dp Faculty of Health and Medical Science, University of Copenhagen, Copenhagen, Denmark
dq Department of Medical Genetics, Oslo University Hospital, Oslo, Norway
dr Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
ds Channing Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States
dt Section of Rheumatology, Boston University School of Medicine, Boston, MA, United States
du Clinical Epidemiology Research and Training Unit, Boston University School of Medicine, Boston, MA, United States
dv Department of Human Genetics, Radboud University Medical Centre, Nijmegen, Netherlands
dw Amsterdam Rheumatology and Immunology Center, Amsterdam Medical Center, Amsterdam, Netherlands
dx Service de Rhumatologie Hôpital Bichat Claude Bernard, Assistance Publique des Hôpitaux de Paris, Paris, France
dy Rheumatology Department, Université Paris Diderot, Paris, France
dz New York University Hospital for Joint Diseases, New York, NY, United States
ea Department of Rheumatology, Leiden University Medical Center, Leiden, Netherlands
eb Rheumatology Unit, Karolinska Institutet, Stockholm, Sweden
ec Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
ed Toronto General Research Institute, Toronto, ON, Canada
ee Department of Medicine, University of Toronto, Toronto, ON, Canada
ef Academic Medical Centre, University of Amsterdam, Amsterdam, Netherlands
eg School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom
eh Immunoinflammation Therapy Unit GlaxoSmithKline, Stevenage, United Kingdom
ei Arthritis Research UK Epidemiology Unit, Centre for Musculoskeletal Research, University of Manchester, Manchester, United Kingdom
ej Musculoskeletal Biomedical Research Unit, Manchester Academic Health Sciences Centre, United Kingdom
ek Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States
el Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, United States
em Program in Translational Neuropsychiatric Genomics, Department of Neurology, Brigham and Women's Hospital, Boston, MA, United States
en Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, TN, United States
eo Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, United States
ep Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, New York, NY, United States
eq Rheumatology Unit, Karolinska Institutet, Stockholm, Sweden
er Institut National de la Santé et de la Recherche Médicale, Hôpitaux Universitaires Paris-Sud, Rhumatologie, Paris, France
es Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States
et Department of Rheumatology and Clinical Immunology, University Twente and Medisch Spectrum Twente, Enschede, Netherlands
eu Scientific Institute for Quality of Healthcare, Radboud University Medical Centre, Nijmegen, Netherlands


Abstract
Background: A long-standing epidemiological puzzle is the reduced rate of rheumatoid arthritis (RA) in those with schizophrenia (SZ) and vice versa. Traditional epidemiological approaches to determine if this negative association is underpinned by genetic factors would test for reduced rates of one disorder in relatives of the other, but sufficiently powered data sets are difficult to achieve. The genomics era presents an alternative paradigm for investigating the genetic relationship between two uncommon disorders. Methods: We use genome-wide common single nucleotide polymorphism (SNP) data from independently collected SZ and RA case-control cohorts to estimate the SNP correlation between the disorders. We test a genotype X environment (GxE) hypothesis for SZ with environment defined as winter- vs summer-born. Results: We estimate a small but significant negative SNP-genetic correlation between SZ and RA (-0.046, s.e. 0.026, P = 0.036). The negative correlation was stronger for the SNP set attributed to coding or regulatory regions (-0.174, s.e. 0.071, P = 0.0075). Our analyses led us to hypothesize a gene-environment interaction for SZ in the form of immune challenge. We used month of birth as a proxy for environmental immune challenge and estimated the genetic correlation between winter-born and non-winter born SZ to be significantly less than 1 for coding/regulatory region SNPs (0.56, s.e. 0.14, P = 0.00090).Conclusions: Our results are consistent with epidemiological observations of a negative relationship between SZ and RA reflecting, at least in part, genetic factors. Results of the month of birth analysis are consistent with pleiotropic effects of genetic variants dependent on environmental context. © The Author 2015; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.


Author Keywords
genetic relationship;  pleiotropy;  rheumatoid arthritis;  Schizophrenia


Document Type: Article
Source: Scopus



Ray, W.Z.a , Chang, J.a , Hawasli, A.a , Wilson, T.J.b , Yang, L.b
Motor nerve transfers: A comprehensive review
(2015) Neurosurgery, 78 (1), pp. 1-25. 

DOI: 10.1227/NEU.0000000000001029


a Department of Neurological Surgery, Washington University, School of Medicine, 660 S Euclid Ave, St. Louis, MO, United States
b Department of Neurological Surgery, University of Michigan, School of Medicine, Ann Arbor, MI, United States


Abstract
Brachial plexus and peripheral nerve injuries are exceedingly common. Traditional nerve grafting reconstruction strategies and techniques have not changed significantly over the last 3 decades. Increased experience and wider adoption of nerve transfers as part of the reconstructive strategy have resulted in a marked improvement in clinical outcomes. We review the options, outcomes, and indications for nerve transfers to treat brachial plexus and upper- and lower-extremity peripheral nerve injuries, and we explore the increasing use of nerve transfers for facial nerve and spinal cord injuries. Each section provides an overview of donor and recipient options for nerve transfer and of the relevant anatomy specific to the desired function. © 2015 by the Congress of Neurological Surgeons.


Author Keywords
Brachial plexus injury;  Nerve transfer;  Spinal cord injury


Document Type: Review
Source: Scopus



Medina, R.G.a , Dempsher, D.P.b , Gauvain, K.M.c , Geller, T.J.d , Elbabaa, S.K.e
Resolution of precocious puberty following resection of fourth ventricular medulloblastoma: case report
(2015) Journal of neurosurgery. Pediatrics, 16 (3), pp. 287-290. 

DOI: 10.3171/2015.1.PEDS14358


a School of Medicine, Saint Louis University;
b Department of Pediatrics, Division of Endocrinology;
c Department of Pediatrics, Division of Hematology-Oncology, Washington University in St. Louis School of Medicine, Saint Louis, Missouri
d Department of Neurology and Psychiatry, Division of Child Neurology; and
e Department of Neurosurgery, Division of Pediatric Neurosurgery, Saint Louis University School of Medicine; and


Abstract
Medulloblastoma is a malignant embryonal tumor that arises in the cerebellum and invades the fourth ventricle, often resulting in obstructive hydrocephalus. Patients typically present with symptoms related to increased intracranial pressure and cerebellar dysfunction. The authors report a rare case of classic medulloblastoma with central precocious puberty (CPP) as its only presenting symptom. A 7-year-old boy with no prior history of medulloblastoma presented with Tanner Stage IV testicular enlargement and a 4-month history of acne and pubic hair. Laboratory tests of blood samples demonstrated highly elevated luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone. Admission MRI of the brain revealed a mass in the posterior fossa, which bordered and compressed the fourth ventricle. The patient also exhibited mild lateral and third ventriculomegaly. Surgical options were discussed with the neurosurgical department. A suboccipital craniotomy and C-1 laminectomy were performed. A large mass was seen arising from the inferior surface of the vermis, and lying within the fourth ventricle. Gross-total microsurgical resection of the mass was performed. Histopathological investigation characterized the tumor as classic medulloblastoma. Follow-up laboratory tests of blood samples demonstrated a reduction of LH, FSH, and testosterone back to prepubertal levels. The patient then began radiation and chemotherapy. This report demonstrates that mild obstructive hydrocephalus due to a posterior fossa tumor may present with unexpected symptoms, such as CPP. To the authors' knowledge, precocious puberty has not yet been associated with medulloblastoma, although it has been found with other posterior fossa tumors. Extensive imaging of the CNS for patients presenting with CPP is recommended.


Author Keywords
CPP = central precocious puberty;  FSH = follicle-stimulating hormone;  GnRH = gonadotropin-releasing hormone;  HPA = hypothalamic-pituitary axis;  hydrocephalus;  LH = luteinizing hormone;  medulloblastoma;  MMC = myelomeningocele;  oncology;  pediatric neurosurgery;  posterior fossa tumor;  precocious puberty;  TS = Tanner Stage


Document Type: Article
Source: Scopus



Zhang, B., Zou, J., Rensing, N.R., Yang, M., Wong, M.
Inflammatory mechanisms contribute to the neurological manifestations of tuberous sclerosis complex
(2015) Neurobiology of Disease, 80, pp. 70-79. 

DOI: 10.1016/j.nbd.2015.04.016


Department of Neurology and the Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, United States


Abstract
Epilepsy and other neurological deficits are common, disabling manifestations of the genetic disorder, tuberous sclerosis complex (TSC). Brain inflammation has been implicated in contributing to epileptogenesis in acquired epilepsy due to brain injury, but the potential role of inflammatory mechanisms in genetic epilepsies is relatively unexplored. In this study, we investigated activation of inflammatory mediators and tested the effects of anti-inflammatory treatment on epilepsy in the Tsc1-GFAP conditional knock-out mouse model of TSC (Tsc1GFAPCKO mice). Real-time quantitative RT-PCR, immunohistochemistry, and Western blotting demonstrated increased expression of specific cytokines and chemokines, particularly IL-1β and CXCL10, in the neocortex and hippocampus of Tsc1GFAPCKO mice, which was reversed by treatment with a mammalian target of rapamycin complex 1 (mTORC1) inhibitor. Double-labeling immunohistochemical studies indicated that the increased IL-1β was localized primarily to astrocytes. Importantly, the increase in inflammatory markers was also observed in astrocyte culture in vitro and at 2weeks of age in Tsc1GFAPCKO mice before the onset of epilepsy in vivo, indicating that the inflammatory changes were not secondary to seizures. Epicatechin-3-gallate, an inhibitor of IL-1β and CXCL10, at least partially reversed the elevated cytokine and chemokine levels, reduced seizure frequency, and prolonged survival of Tsc1GFAPCKO mice. These findings suggest that mTOR-mediated inflammatory mechanisms may be involved in epileptogenesis in the genetic epilepsy, TSC. © 2015 Elsevier Inc..


Author Keywords
Chemokine;  Cytokine;  Epilepsy;  Inflammation;  Interleukin;  Mice;  Seizure;  Tuberous sclerosis


Document Type: Article
Source: Scopus



Deming, Y.a , Xia, J.a , Cai, Y.a , Lord, J.a , Holmans, P.b , Bertelsen, S.a , Holtzman, D.c d e f , Morris, J.C.c d e f , Bales, K.g , Pickering, E.H.g , Kauwe, J.h , Goate, A.a e f , Cruchaga, C.a f
A potential endophenotype for Alzheimer's disease: Cerebrospinal fluid clusterin
(2015) Neurobiology of Aging, . Article in Press. 

DOI: 10.1016/j.neurobiolaging.2015.09.009


a Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA
b Institute of Psychological Medicine and Clinical Neurosciences, MRC Center for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Cardiff, UK
c Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA
d Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, USA
e Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA
f Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA
g Neuroscience Research Unit, Worldwide Research and Development, Pfizer, Inc., Groton, CT, USA
h Department of Biology, Brigham Young University, Provo, UT, USA


Abstract
Genome-wide association studies have associated clusterin (CLU) variants with Alzheimer's disease (AD). However, the role of CLU on AD pathogenesis is not totally understood. We used cerebrospinal fluid (CSF) and plasma CLU levels as endophenotypes for genetic studies to understand the role of CLU in AD. CSF, but not plasma, CLU levels were significantly associated with AD status and CSF tau/amyloid-beta ratio, and highly correlated with CSF apolipoprotein E (APOE) levels. Several loci showed almost genome-wide significant associations including LINC00917 (p = 3.98 × 10-7) and interleukin 6 (IL6, p = 9.94 × 10-6, in the entire data set and in the APOE ε4- individuals p = 7.40 × 10-8). Gene ontology analyses suggest that CSF CLU levels may be associated with wound healing and immune response which supports previous functional studies that demonstrated an association between CLU and IL6. CLU may play a role in AD by influencing immune system changes that have been observed in AD or by disrupting healing after neurodegeneration. © 2015 Elsevier Inc.


Author Keywords
Alzheimer's disease;  APOE;  Cerebrospinal fluid;  Clusterin;  Gene ontology;  Immune response


Document Type: Article in Press
Source: Scopus



Gilmore, A.W.a , Nelson, S.M.c d , McDermott, K.B.a b
A parietal memory network revealed by multiple MRI methods
(2015) Trends in Cognitive Sciences, 19 (9), pp. 534-543. Cited 1 time.

DOI: 10.1016/j.tics.2015.07.004


a Department of Psychology, Washington University in St Louis, St Louis, MO, United States
b Department of Radiology, Washington University in St Louis, St Louis, MO, United States
c VISN 17 Center of Excellence for Research on Returning War Veterans, Waco, TX, United States
d Center for Vital Longevity, School of Behavioral and Brain Sciences, University of Texas at Dallas, Dallas, TX, United States


Abstract
The manner by which the human brain learns and recognizes stimuli is a matter of ongoing investigation. Through examination of meta-analyses of task-based functional MRI and resting state functional connectivity MRI, we identified a novel network strongly related to learning and memory. Activity within this network at encoding predicts subsequent item memory, and at retrieval differs for recognized and unrecognized items. The direction of activity flips as a function of recent history: from deactivation for novel stimuli to activation for stimuli that are familiar due to recent exposure. We term this network the 'parietal memory network' (PMN) to reflect its broad involvement in human memory processing. We provide a preliminary framework for understanding the key functional properties of the network. © 2015 Elsevier Ltd.


Author Keywords
Encoding;  Familiarity;  Functional networks;  Memory;  Parietal cortex;  Retrieval


Document Type: Review
Source: Scopus



Abrams, R.
Beyond the immediate: Academic dishonesty
(2015) Ethical Challenges in the Behavioral and Brain Sciences, pp. 3-4. 

DOI: 10.1007/9781139626491.002


Washington University, St Louis, United States


Abstract
It was 1988 and I had been out of graduate school for two years when I encountered my first case of academic dishonesty (at least I had not suspected any dishonesty before that). The course was Experimental Psychology-a laboratory course like those at many universities where the centerpiece of the course is an independent experimental project of the student’s own design culminating in the submission of a complete write-up (in APA style, of course) of the experiment. (These days there are PowerPoint presentations in addition to the paper-and a relaxation of the APA style rules.) A student who had been performing at an average level in the class turned in a report of an experiment on some aspect of memory. (At least I think it was about memory-isn’t that what people studied in the 1980s?) The paper was excellent-and that was the problem. How could someone who can write so well, think so clearly, and present results so succinctly receive only a C on my tests, where the biggest challenge is to remember the distinction between a Type I and a Type II error? I knew that something was amiss when one of the dependent variables that he reported revealed a grain of analysis finer than what would be possible with the reported number of participants. He reported the percentage of participants who responded in a particular way, but when converted to a number, the value was not a whole number. In other words, the data had come from a study with a greater number of participants than what he had reported. Eventually I found the article on which his paper was “based.” © Cambridge University Press 2015.


Document Type: Book Chapter
Source: Scopus



Godinez, D.A.a , Willcutt, E.G.b c , Burgess, G.C.a d , Depue, B.E.a e , Andrews-Hanna, J.R.a , Banich, M.T.a c
Familial risk and ADHD-specific neural activity revealed by case-control, discordant twin pair design
(2015) Psychiatry Research - Neuroimaging, 233 (3), pp. 458-465. 

DOI: 10.1016/j.pscychresns.2015.07.019


a Institute of Cognitive Science, University of Colorado, Boulder, CO, United States
b Institute for Behavioral Genetics, University of Colorado, Boulder, CO, United States
c Department of Psychology and Neuroscience, University of Colorado, Boulder, CO, United States
d Washington University School of Medicine, St. Louis, MO, United States
e University of Louisville, Louisville, KY, United States


Abstract
Individuals with ADHD, as well as their family members who do not meet clinical criteria, have shown deficits in executive function. However, it remains unclear whether underlying neural alterations are familial or ADHD-specific. To investigate this issue, neural activation underlying executive function was assessed using functional magnetic resonance imaging during performance of a Stroop task in three groups of individuals: 20 young adults who were diagnosed with ADHD in childhood, their 20 dizygotic co-twins without ADHD in childhood, and 20 unrelated controls selected from dizygotic twin pairs in which neither twin had ADHD in childhood (total n=60). Implicating the frontoparietal network as a location of effects specific to ADHD, activation in the superior frontal (Brodmann's Area - BA 6) and parietal regions (BA 40) was significantly reduced in twins with childhood ADHD compared to both their control co-twins and unrelated control twins. Consistent with familial influences, activity in the anterior cingulate and insula was significantly reduced in both the twins with ADHD and their co-twins compared to the unrelated controls. These results show that both ADHD-specific and familial influences related to an ADHD diagnosis impact neural systems underlying executive function. © 2015 Elsevier Ireland Ltd.


Author Keywords
Attention;  Cognitive control;  Executive function;  Familial influences;  fMRI;  Neuroimaging;  Twins


Document Type: Article
Source: Scopus



Kurby, C.A.a , Zacks, J.M.b
Situation models in naturalistic comprehension
(2015) Cognitive Neuroscience of Natural Language Use, pp. 59-76. 

DOI: 10.1017/CBO9781107323667.004


a Grand Valley State University, Allendale, MI, United States
b Washington University, St. Louis, MO, United States


Abstract
Reading a discourse often leads to the construction of a situation model – a mental representation of the state of affairs described by the text. Situation model construction is associated with specific behavioral and neural markers. In this chapter, we consider the following questions: How does reading that involves constructing a situation model differ from other kinds of reading? Do the behavioral and neurophysiological data support a distinction between incremental updating of situation model components and global updating by abandoning an old situation model to form a new one? Do situation models represent information about sensory and motor features in analog representational formats during normal reading for comprehension? The available results indicate that specific mechanisms underlie different forms of situation model updating, that situation model-based reading is qualitatively different from reading without forming situation models, and that readers routinely deploy perceptual and motor representations to understand features of the situations described by a narrative. © Cambridge University Press 2015.


Document Type: Book Chapter
Source: Scopus



Duvekot, J.a b , van der Ende, J.a , Constantino, J.N.c , Verhulst, F.C.a , Greaves-Lord, K.a b
Symptoms of autism spectrum disorder and anxiety: Shared familial transmission and cross-assortative mating
(2015) Journal of Child Psychology and Psychiatry and Allied Disciplines, . Article in Press. 

DOI: 10.1111/jcpp.12508


a Department of Child and Adolescent Psychiatry/Psychology Erasmus Medical Center RotterdamThe Netherlands
b Yulius Mental Health Dordrecht The Netherlands
c Department of Psychiatry Washington University School of Medicine St. Louis MO USA


Abstract
Background: In order to shed more light on the frequent co-occurrence of Autism Spectrum Disorder (ASD) and anxiety in children, the aims of the study were (a) to examine whether ASD and anxiety share familial transmission indicated by cross-symptom associations between parental and children's symptoms (e.g., parental anxiety predicting children's ASD) in addition to associations for similar symptoms; (b) to investigate the possibility that cross-assortative mating (i.e., whether ASD symptoms in one parent are positively associated with anxiety symptoms in the other parent) increases the risk for both ASD and anxiety in children. Method: In 231 families of clinically referred children, parents rated both their own and the other parent's ASD and anxiety symptoms and one parent those of the index child and siblings (n = 447, aged 2.5-18 years). ASD symptoms were assessed using the Social Responsiveness Scale (SRS-2) and anxiety symptoms using the Achenbach System of Empirically Based Assessment (ASEBA) instruments. Results: Parental ASD and anxiety symptoms predicted similar symptoms in children, dependent on the informant type. Additionally, parental anxiety symptoms across both self-report and informant-report predicted children's ASD symptoms and maternal self-reported ASD symptoms predicted children's anxiety symptoms. ASD and anxiety symptoms were correlated within parents, but we found only one cross-symptom association between parents. Conclusions: Cross-symptom associations between parental and children's ASD and anxiety symptoms suggest shared familial transmission of ASD and anxiety, but further research is needed to clarify the underlying mechanisms. Cross-assortative mating does not seem a likely explanation for the co-occurrence of ASD and anxiety in children. © 2015 Association for Child and Adolescent Mental Health.


Author Keywords
Anxiety;  Autism spectrum disorder;  Cross-assortative mating;  Familial transmission


Document Type: Article in Press
Source: Scopus


Bittner, T.a , Zetterberg, H.b c , Teunissen, C.E.d , Ostlund, R.E.e , Militello, M.f , Andreasson, U.b , Hubeek, I.d , Gibson, D.e , Chu, D.C.f , Eichenlaub, U.a , Heiss, P.a , Kobold, U.a , Leinenbach, A.a , Madin, K.a , Manuilova, E.a , Rabe, C.a , Blennow, K.b
Technical performance of a novel, fully automated electrochemiluminescence immunoassay for the quantitation of β-amyloid (1-42) in human cerebrospinal fluid
(2015) Alzheimer's and Dementia, . Article in Press. 

DOI: 10.1016/j.jalz.2015.09.009


a Roche Diagnostics GmbH, Penzberg, Germany
b Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden
c UCL Institute of Neurology, London, UK
d Clinical Chemistry, VU University Medical Center, Amsterdam, the Netherlands
e Washington University School of Medicine, St. Louis, MO, USA
f Covance Central Laboratory Services, Indianapolis, IN, USA


Abstract
Introduction: Available assays for quantitation of the Alzheimer's disease (AD) biomarker amyloid-beta 1-42 (Aβ [1-42]) in cerebrospinal fluid demonstrate significant variability and lack of standardization to reference measurement procedures (RMPs). We report analytical performance data for the novel Elecsys β-amyloid (1-42) assay (Roche Diagnostics). Methods: Lot-to-lot comparability was tested using method comparison. Performance parameters were measured according to Clinical & Laboratory Standards Institute (CLSI) guidelines. The assay was standardized to a Joint Committee for Traceability in Laboratory Medicine (JCTLM) approved RMP. Results: Limit of quantitation was <11.28 pg/mL, and the assay was linear throughout the measuring range (200-1700 pg/mL). Excellent lot-to-lot comparability was observed (correlation coefficients [Pearson's r] >0.995; bias in medical decision area <2%). Repeatability coefficients of variation (CVs) were 1.0%-1.6%, intermediate CVs were 1.9%-4.0%, and intermodule CVs were 1.1%-3.9%. Estimated total reproducibility was 2.0%-5.1%. Correlation with the RMP was good (Pearson's r, 0.93). Discussion: The Elecsys β-amyloid (1-42) assay has high analytical performance that may improve biomarker-based AD diagnosis. © 2015 The Authors.


Author Keywords
Alzheimer's disease;  Amyloid;  Amyloid-beta 1-42;  Assay;  Biomarker;  Cerebrospinal fluid;  Dementia;  Diagnosis;  Electrochemiluminescence;  Immunoassay;  Method comparison;  Precision;  Repeatability;  Reproducibility;  Variability


Document Type: Article in Press

Source: Scopus 

Figueroa-Romero C.a , Hur J.a e , Lunn J.S.a f , Paez-Colasante X.a , Bender D.E.a g , Yung R.b c , Sakowski S.A.d , Feldman E.L.a d
Expression of microRNAs in human post-mortem amyotrophic lateral sclerosis spinal cords provides insight into disease mechanisms
(2016) Molecular and Cellular Neuroscience, 71, pp. 34-45. 

DOI: 10.1016/j.mcn.2015.12.008


a Department of Neurology, University of Michigan, Ann Arbor, MI, United States
b Division of Geriatrics and Palliative Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, United States
c Geriatric Research, Education and Clinical Care Center, VA Ann Arbor Health System, Ann Arbor, MI, United States
d A. Alfred Taubman Medical Research Institute, University of Michigan, Ann Arbor, MI, United States
e Department of Basic Sciences, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND, United States
f Renovo Neural, Inc, Cleveland, OH, United States
g Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO, United States


Abstract
Amyotrophic lateral sclerosis is a late-onset and terminal neurodegenerative disease. The majority of cases are sporadic with unknown causes and only a small number of cases are genetically linked. Recent evidence suggests that post-transcriptional regulation and epigenetic mechanisms, such as microRNAs, underlie the onset and progression of neurodegenerative disorders; therefore, altered microRNA expression may result in the dysregulation of key genes and biological pathways that contribute to the development of sporadic amyotrophic lateral sclerosis. Using systems biology analyses on postmortem human spinal cord tissue, we identified dysregulated mature microRNAs and their potential targets previously implicated in functional process and pathways associated with the pathogenesis of ALS. Furthermore, we report a global reduction of mature microRNAs, alterations in microRNA processing, and support for a role of the nucleotide binding protein, TAR DNA binding protein 43, in regulating sporadic amyotrophic lateral sclerosis-associated microRNAs, thereby offering a potential underlying mechanism for sporadic amyotrophic lateral sclerosis. © 2015 Elsevier Inc.


Author Keywords
Amyotrophic lateral sclerosis;  Epigenetics;  MicroRNA


Document Type: Article
Source: Scopus




Brown W.J.a , Bruce S.E.a b , Buchholz K.R.a , Artime T.M.c , Hu E.a , Sheline Y.I.b
Affective Dispositions and PTSD Symptom Clusters in Female Interpersonal Trauma Survivors
(2016) Journal of Interpersonal Violence, 31 (3), pp. 407-424. 

DOI: 10.1177/0886260514555866


a University of Missouri–St. LouisMO, United States
b Washington University, St. Louis, MO, United States
c Saint Martin’s University, Lacey, WA, United States


Abstract
Interpersonal trauma (IPT) against women can have dire psychological consequences including persistent maladaptive changes in the subjective experience of affect. Contemporary literature has firmly established heightened negative affect (NA) as a risk and maintenance factor for posttraumatic stress disorder (PTSD). However, the relationship between NA and PTSD symptoms is not well understood within IPT survivors, the majority of whom are female, as much of this research has focused on combat veterans. In addition, the connection between positive affect (PA) and PTSD symptoms has yet to be examined. With increased emphasis on “negative alterations in cognitions and mood..” as an independent symptom cluster of PTSD in the Diagnostic and Statistical Manual of Mental Disorders (5th ed.; DSM-5), understanding the relationship between self-reported affectivity and the classic PTSD symptom clusters may be increasingly useful in differentiating symptom presentations of trauma-related psychopathology. The current study directly compared self-reported trait NA and PA with total severity and frequency cluster scores from the Clinician-Administered PTSD Scale (CAPS) in 54 female survivors of IPT who met criteria for PTSD. Results identify NA (but not PA) as a consistent predictor of total PTSD symptoms and, specifically, re-experiencing symptoms. © 2014, © The Author(s) 2014.


Author Keywords
affect;  interpersonal trauma;  PTSD


Document Type: Article
Source: Scopus




Sheffield J.M.a , Barch D.M.a b c
Cognition and resting-state functional connectivity in schizophrenia
(2016) Neuroscience and Biobehavioral Reviews, 61, pp. 108-120. 

DOI: 10.1016/j.neubiorev.2015.12.007


a Washington University in St Louis, Department of Psychology, 1 Brookings Drive, St Louis, MO, United States
b Washington University in St Louis, Department of Psychiatry, 4940 Childrens Place, St Louis, MO, United States
c Washington University in St Louis, Department of Radiology, 224 Euclid Ave, St Louis, MO, United States


Abstract
Individuals with schizophrenia consistently display deficits in a multitude of cognitive domains, but the neurobiological source of these cognitive impairments remains unclear. By analyzing the functional connectivity of resting-state functional magnetic resonance imaging (rs-fcMRI) data in clinical populations like schizophrenia, research groups have begun elucidating abnormalities in the intrinsic communication between specific brain regions, and assessing relationships between these abnormalities and cognitive performance in schizophrenia. Here we review studies that have reported analysis of these brain-behavior relationships. Through this systematic review we found that patients with schizophrenia display abnormalities within and between regions comprising (1) the cortico-cerebellar-striatal-thalamic loop and (2) task-positive and task-negative cortical networks. Importantly, we did not observe unique relationships between specific functional connectivity abnormalities and distinct cognitive domains, suggesting that the observed functional systems may underlie mechanisms that are shared across cognitive abilities, the disturbance of which could contribute to the "generalized" cognitive deficit found in schizophrenia. We also note several areas of methodological change that we believe will strengthen this literature. © 2015 Elsevier Ltd.


Author Keywords
Cognition;  Cognitive dysmetria;  Default mode network;  Executive functioning;  Functional brain networks;  Functional connectivity;  Generalized cognitive deficit;  Go/NoGo;  IQ;  Reinforcement learning;  Resting-state fMRI;  Schizophrenia;  Task-positive networks


Document Type: Review
Source: Scopus




King N.O.a b , Anderson C.J.a , Dorval A.D.a
Deep brain stimulation exacerbates hypokinetic dysarthria in a rat model of Parkinson's disease
(2016) Journal of Neuroscience Research, 94 (2), pp. 128-138. 

DOI: 10.1002/jnr.23679


a Department of Bioengineering, University of Utah, Salt Lake City, UT, United States
b Department of Biomedical Engineering, Washington University, St. Louis, MO, United States


Abstract
Motor symptoms of Parkinson's disease (PD) follow the degeneration of dopaminergic neurons in the substantia nigra pars compacta. Deep brain stimulation (DBS) treats some parkinsonian symptoms, such as tremor, rigidity, and bradykinesia, but may worsen certain medial motor symptoms, including hypokinetic dysarthria. The mechanisms by which DBS exacerbates dysarthria while improving other symptoms are unclear and difficult to study in human patients. This study proposes an animal model of DBS-exacerbated dysarthria. We use the unilateral, 6-hydroxydopamine (6-OHDA) rat model of PD to test the hypothesis that DBS exacerbates quantifiable aspects of vocalization. Mating calls were recorded from sexually experienced male rats under healthy and parkinsonian conditions and during DBS of the subthalamic nucleus. Relative to healthy rats, parkinsonian animals made fewer calls with shorter and less complex vocalizations. In the parkinsonian rats, putatively therapeutic DBS further reduced call frequency, duration, and complexity. The individual utterances of parkinsonian rats spanned a greater bandwidth than those of healthy rats, potentially reducing the effectiveness of the vocal signal. This utterance bandwidth was further increased by DBS. We propose that the parkinsonism-associated changes in call frequency, duration, complexity, and dynamic range combine to constitute a rat analog of parkinsonian dysarthria. Because DBS exacerbates the parkinsonism-associated changes in each of these metrics, the subthalamic stimulated 6-OHDA rat is a good model of DBS-induced hypokinetic dysarthria in PD. This model will help researchers examine how DBS alleviates many motor symptoms of PD while exacerbating parkinsonian speech deficits that can greatly diminish patient quality of life. © 2016 Wiley Periodicals, Inc.


Author Keywords
Deep brain stimulation;  Dysarthria;  Hypokinesia;  Parkinson's disease


Document Type: Article
Source: Scopus




Gyawali C.P.
Achalasia: New perspectives on an old disease
(2016) Neurogastroenterology and Motility, 28 (1), pp. 4-11. 

DOI: 10.1111/nmo.12750


Division of Gastroenterology, Washington University School of Medicine, St. Louis, MO, United States


Abstract
Achalasia is defined by esophageal outflow obstruction from abnormal relaxation of the lower esophageal sphincter (LES) due to deranged inhibitory control. In genetically predisposed individuals, an autoimmune response to an unknown inciting agent, perhaps a viral infection, results in inflammation and sometimes loss of myenteric plexus ganglia and neurons. The net result is varying degrees of inhibitory dysfunction, at times associated with imbalanced and exaggerated excitatory function, with manometrically distinct achalasia phenotypes on high resolution manometry. There is new evidence in the current issue of this Journal suggesting that type 1 achalasia, with esophageal outflow obstruction and absent esophageal body contractility, is an end-stage phenotype from progression of type 2 achalasia, which is characterized by panesophageal compartmentalization of pressure in the untreated patient, and partial recovery of peristalsis after treatment. Esophageal outflow obstruction with premature peristalsis (type 3 achalasia) or intact peristalsis may result from plexitis in the myenteric plexus but can also be encountered in other settings including chronic opioid medication usage and structural processes at the esophagogastric junction and distally. In most instances when idiopathic esophageal outflow obstruction is confirmed, some form of pharmacologic manipulation or disruption of the LES provides durable symptom relief. This review will focus on current understanding of pathophysiology, diagnosis, and principles of management of achalasia in light of emerging literature on the topic. © 2015 John Wiley & Sons Ltd.


Author Keywords
Achalasia;  Esophageal outflow obstruction;  High resolution manometry


Document Type: Short Survey
Source: Scopus




Ward C.M.a , Rogers C.S.a , Van Engen K.J.b , Peelle J.E.a
Effects of Age, Acoustic Challenge, and Verbal Working Memory on Recall of Narrative Speech
(2016) Experimental Aging Research, 42 (1), pp. 126-144. Cited 1 time.

DOI: 10.1080/0361073X.2016.1108785


a Department of Otolaryngology, Washington University in St. Louis, 660 South Euclid, St. Louis, MO, United States
b Department of Psychology, Washington University in St. Louis, St. Louis, MO, United States


Abstract
A common goal during speech comprehension is to remember what we have heard. Encoding speech into long-term memory frequently requires processes such as verbal working memory that may also be involved in processing degraded speech. Here the authors tested whether young and older adult listeners memory for short stories was worse when the stories were acoustically degraded, or whether the additional contextual support provided by a narrative would protect against these effects. Methods: The authors tested 30 young adults (aged 18-28 years) and 30 older adults (aged 65-79 years) with good self-reported hearing. Participants heard short stories that were presented as normal (unprocessed) speech or acoustically degraded using a noise vocoding algorithm with 24 or 16 channels. The degraded stories were still fully intelligible. Following each story, participants were asked to repeat the story in as much detail as possible. Recall was scored using a modified idea unit scoring approach, which included separately scoring hierarchical levels of narrative detail.Results: Memory for acoustically degraded stories was significantly worse than for normal stories at some levels of narrative detail. Older adults memory for the stories was significantly worse overall, but there was no interaction between age and acoustic clarity or level of narrative detail. Verbal working memory (assessed by reading span) significantly correlated with recall accuracy for both young and older adults, whereas hearing ability (better ear pure tone average) did not.Conclusion: The present findings are consistent with a framework in which the additional cognitive demands caused by a degraded acoustic signal use resources that would otherwise be available for memory encoding for both young and older adults. Verbal working memory is a likely candidate for supporting both of these processes. © Taylor and Francis Group, LLC.


Document Type: Conference Paper
Source: Scopus




Fritz B.A.a , Kalarickal P.L.a , Maybrier H.R.a , Muench M.R.a , Dearth D.a , Chen Y.a , Escallier K.E.a , Ben Abdallah A.a , Lin N.b , Avidan M.S.a
Intraoperative Electroencephalogram Suppression Predicts Postoperative Delirium
(2016) Anesthesia and Analgesia, 122 (1), pp. 234-242. 

DOI: 10.1213/ANE.0000000000000989


a Department of Anesthesiology, Washington University, School of Medicine, 660 S. Euclid Ave., St. Louis, MO, United States
b Department of Mathematics, Washington University, St. Louis, MO, United States


Abstract
BACKGROUND: Postoperative delirium is a common complication associated with increased morbidity and mortality, longer hospital stays, and greater health care expenditures. Intraoperative electroencephalogram (EEG) slowing has been associated previously with postoperative delirium, but the relationship between intraoperative EEG suppression and postoperative delirium has not been investigated. METHODS: In this observational cohort study, 727 adult patients who received general anesthesia with planned intensive care unit admission were included. Duration of intraoperative EEG suppression was recorded from a frontal EEG channel (FP1 to F7). Delirium was assessed twice daily on postoperative days 1 through 5 with the Confusion Assessment Method for the intensive care unit. Thirty days after surgery, quality of life, functional independence, and cognitive ability were measured using the Veterans RAND 12-item survey, the Barthel index, and the PROMIS Applied Cognition-Abilities-Short Form 4a survey. RESULTS: Postoperative delirium was observed in 162 (26%) of 619 patients assessed. When we compared patients with no EEG suppression with those divided into quartiles based on duration of EEG suppression, patients with more suppression were more likely to experience delirium (χ2(4) = 25, P &lt; 0.0001). This effect remained significant after we adjusted for potential confounders (odds ratio for log(EEG suppression) 1.22 [99% confidence interval, 1.06-1.40, P = 0.0002] per 1-minute increase in suppression). EEG suppression may have been associated with reduced functional independence (Spearman partial correlation coefficient-0.15, P = 0.02) but not with changes in quality of life or cognitive ability. Predictors of EEG suppression included greater end-tidal volatile anesthetic concentration and lower intraoperative opioid dose. CONCLUSIONS: EEG suppression is an independent risk factor for postoperative delirium. Future studies should investigate whether anesthesia titration to minimize EEG suppression decreases the incidence of postoperative delirium. This is a substudy of the Systematic Assessment and Targeted Improvement of Services Following Yearlong Surgical Outcomes Surveys (SATISFY-SOS) surgical outcomes registry (NCT02032030). © 2015 International Anesthesia Research Society.


Document Type: Article
Source: Scopus




Peelle J.E.
Introduction to Special Issue on Age, Hearing, and Speech Comprehension
(2016) Experimental Aging Research, 42 (1), pp. 1-3. 

DOI: 10.1080/0361073X.2016.1108714


Department of Otolaryngology, Washington University in St. Louis, 660 South Euclid, St. Louis, MO, United States


Document Type: Conference Paper
Source: Scopus




Nemanich S.T.a , Earhart G.M.a b c
Reduced after-effects following podokinetic adaptation in people with Parkinson's disease and freezing of gait
(2016) Parkinsonism and Related Disorders, 22, pp. 93-97. 

DOI: 10.1016/j.parkreldis.2015.11.024


a Washington University School of Medicine in St. Louis, 4444 Forest Park Ave., Campus Box 8502, St. Louis, MO, United States
b Department of Anatomy and Neurobiology, Washington University School of Medicine in St. Louis, 660S. Euclid Ave., Campus Box 8108, St. Louis, MO, United States
c Department of Neurology, Washington University School of Medicine in St. Louis, 660S. Euclid Ave., Campus Box 8111, St. Louis, MO, United States


Abstract
Introduction: Gait dysfunction is common in people with Parkinson's disease (PD). Freezing of gait (FOG) is one such gait disturbance that significantly impacts mobility and quality of life in PD. Recent evidence suggests that cerebellar connectivity may differ in people with PD and FOG (PD+FOG) relative to those without FOG (PD-FOG). Investigation of gait adaptation, or the ability to change gait patterns in response to external perturbations, is cerebellum-dependent, is a practical means of probing cerebellar integrity and may provide additional insights regarding the FOG phenomenon. Methods: In this study, we investigated gait adaptation in PD and FOG by measuring after-effects, namely whole-body rotation, following stepping on a rotating disc in PD+FOG compared to PD-FOG and older healthy adults. We refer to the period of stepping on the rotating disc as the podokinetic (PK) stimulation and after-effects as podokinetic after-rotation (PKAR). Our primary measure of adaptation was the magnitude and rate of decay of the after-effects. Results: We noted that PKAR was diminished in PD+FOG compared to the other groups, indicating reduced storage of the adapted gait pattern in PD+FOG. In the PD groups, FOG explained about 20% of the variability in peak velocity. Furthermore, these differences were independent of stepping cadence or motor sign severity. Conclusion: Our results show that gait adaptation is impaired in PD+FOG, suggesting the cerebellum may be differentially impacted in PD+FOG compared to PD-FOG. This supports previous neuroimaging evidence of cerebellar dysfunction in PD+FOG. Overall, these data further our understanding of gait deficits in PD+FOG. © 2015 Elsevier Ltd.


Author Keywords
After-effects;  Freezing of gait;  Locomotor adaptation;  Parkinson disease


Document Type: Article
Source: Scopus




Ning B.a , Sun N.a , Cao R.a , Chen R.b , Shung K.K.b , Hossack J.A.a , Lee J.-M.c , Zhou Q.b , Hu S.a
Ultrasound-aided Multi-parametric Photoacoustic Microscopy of the Mouse Brain
(2015) Scientific Reports, 5, art. no. 18775, . 

DOI: 10.1038/srep18775


a Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, United States
b Department of Biomedical Engineering, University of Southern California, Los Angeles, CA, United States
c Department of Neurology, Washington University, School of Medicine, St. Louis, MO, United States


Abstract
High-resolution quantitative imaging of cerebral oxygen metabolism in mice is crucial for understanding brain functions and formulating new strategies to treat neurological disorders, but remains a challenge. Here, we report on our newly developed ultrasound-aided multi-parametric photoacoustic microscopy (PAM), which enables simultaneous quantification of the total concentration of hemoglobin (CHb), the oxygen saturation of hemoglobin (sO2), and cerebral blood flow (CBF) at the microscopic level and through the intact mouse skull. The three-dimensional skull and vascular anatomies delineated by the dual-contrast (i.e., ultrasonic and photoacoustic) system provide important guidance for dynamically focused contour scan and vessel orientation-dependent correction of CBF, respectively. Moreover, bi-directional raster scan allows determining the direction of blood flow in individual vessels. Capable of imaging all three hemodynamic parameters at the same spatiotemporal scale, our ultrasound-aided PAM fills a critical gap in preclinical neuroimaging and lays the foundation for high-resolution mapping of the cerebral metabolic rate of oxygen (CMRO2) - a quantitative index of cerebral oxygen metabolism. This technical innovation is expected to shed new light on the mechanism and treatment of a broad spectrum of neurological disorders, including Alzheimer's disease and ischemic stroke.


Document Type: Article
Source: Scopus




Escott-Price V.a , Sims R.a , Bannister C.a , Harold D.b , Vronskaya M.a , Majounie E.a , Badarinarayan N.a , Morgan K.c , Passmore P.d , Holmes C.e , Powell J.f , Brayne C.g , Gill M.h , Mead S.i , Goate A.j , Cruchaga C.k , Lambert J.-C.l m n , Van Duijn C.o , Maier W.p q , Ramirez A.p r , Holmans P.a , Jones L.a , Hardy J.s , Seshadri S.t , Schellenberg G.D.u , Amouyel P.l m n v , Williams J.a
Common polygenic variation enhances risk prediction for Alzheimer's disease
(2015) Brain, 138 (12), pp. 3673-3684. Cited 1 time.

DOI: 10.1093/brain/awv268


a Institute of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, United Kingdom
b School of Medicine, Trinity College Dublin, College Green, Dublin, 2, Ireland
c Institute of Genetics, Queens Medical Centre, University of Nottingham, United Kingdom
d Ageing Group, Centre for Public Health, School of Medicine, Dentistry and Biomedical Sciences, Queens University Belfast, United Kingdom
e Division of Clinical Neurosciences, School of Medicine, University of Southampton, Southampton, United Kingdom
f Kings College London, Institute of Psychiatry, Department of Neuroscience, De Crespigny Park, Denmark Hill, London, United Kingdom
g Institute of Public Health, University of Cambridge, Cambridge, United Kingdom
h Mercers Institute for Research on Aging, St. James Hospital and Trinity College, Dublin, Ireland
i MRC Prion Unit, Department of Neurodegenerative Disease, UCL Institute of Neurology, London, United Kingdom
j Neuroscience Department, Icahn School of Medicine at Mount Sinai, New York, United States
k Departments of Psychiatry, Neurology and Genetics, Washington University School of Medicine, St Louis, MO, United States
l Inserm U744, Lille, France
m Université Lille 2, Lille, France
n Institut Pasteur de Lille, Lille, France
o Department of Epidemiology, Erasmus Medical Centre, Rotterdam, Netherlands
p Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany
q German Centre for Neurodegenerative Diseases (DZNE), Bonn, Germany
r Institute of Human Genetics, University of Bonn, Bonn, Germany
s Department of Molecular Neuroscience, Reta Lilla Weston Laboratories, Institute of Neurology, London, United Kingdom
t Department of Neurology, Boston University School of Medicine, Boston, MA, United States
u Department of Pathology and Laboratory Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, United States
v Centre Hospitalier Régional, Universitaire de Lille, Lille, France


Abstract
The identification of subjects at high risk for Alzheimer's disease is important for prognosis and early intervention. We investigated the polygenic architecture of Alzheimer's disease and the accuracy of Alzheimer's disease prediction models, including and excluding the polygenic component in the model. This study used genotype data from the powerful dataset comprising 17 008 cases and 37 154 controls obtained from the International Genomics of Alzheimer's Project (IGAP). Polygenic score analysis tested whether the alleles identified to associate with disease in one sample set were significantly enriched in the cases relative to the controls in an independent sample. The disease prediction accuracy was investigated in a subset of the IGAP data, a sample of 3049 cases and 1554 controls (for whom APOE genotype data were available) by means of sensitivity, specificity, area under the receiver operating characteristic curve (AUC) and positive and negative predictive values. We observed significant evidence for a polygenic component enriched in Alzheimer's disease (P = 4.9 × 10-26). This enrichment remained significant after APOE and other genome-wide associated regions were excluded (P = 3.4 × 10-19). The best prediction accuracy AUC = 78.2% (95% confidence interval 77-80%) was achieved by a logistic regression model with APOE, the polygenic score, sex and age as predictors. In conclusion, Alzheimer's disease has a significant polygenic component, which has predictive utility for Alzheimer's disease risk and could be a valuable research tool complementing experimental designs, including preventative clinical trials, stem cell selection and high/low risk clinical studies. In modelling a range of sample disease prevalences, we found that polygenic scores almost doubles case prediction from chance with increased prediction at polygenic extremes.


Author Keywords
Alzheimer's disease;  polygenic score;  predictive model


Document Type: Article
Source: Scopus




Marquardt L.M.a , Ee X.b , Iyer N.a , Hunter D.b , Mackinnon S.E.b , Wood M.D.b , Sakiyama-Elbert S.E.a b b
Finely Tuned Temporal and Spatial Delivery of GDNF Promotes Enhanced Nerve Regeneration in a Long Nerve Defect Model
(2015) Tissue Engineering - Part A, 21 (23-24), pp. 2852-2864. 

DOI: 10.1089/ten.tea.2015.0311


a Department of Biomedical Engineering, Washington University in St. Louis, 1097 Brookings Drive, St. Louis, MO, United States
b Divison of Plastic and Reconstructive Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, MO, United States


Abstract
The use of growth factors, such as glial cell line-derived neurotrophic factor (GDNF), for the treatment of peripheral nerve injury has been useful in promoting axon survival and regeneration. Unfortunately, finding a method that delivers the appropriate spatial and temporal release profile to promote functional recovery has proven difficult. Some release methods result in burst release profiles too short to remain effective over the regeneration period; however, prolonged exposure to GDNF can result in axonal entrapment at the site of release. Thus, GDNF was delivered in both a spatially and temporally controlled manner using a two-phase system comprised of an affinity-based release system and conditional lentiviral GDNF overexpression from Schwann cells (SCs). Briefly, SCs were transduced with a tetracycline-inducible (Tet-On) GDNF overexpressing lentivirus before transplantation. Three-centimeter acellular nerve allografts (ANAs) were modified by injection of a GDNF-releasing fibrin scaffold under the epineurium and then used to bridge a 3 cm sciatic nerve defect. To encourage growth past the ANA, GDNF-SCs were transplanted into the distal nerve and doxycycline was administered for 4, 6, or 8 weeks to determine the optimal duration of GDNF expression in the distal nerve. Live imaging and histomorphometric analysis determined that 6 weeks of doxycycline treatment resulted in enhanced regeneration compared to 4 or 8 weeks. This enhanced regeneration resulted in increased gastrocnemius and tibialis anterior muscle mass for animals receiving doxycycline for 6 weeks. The results of this study demonstrate that strategies providing spatial and temporal control of delivery can improve axonal regeneration and functional muscle reinnervation. © Mary Ann Liebert, Inc. 2015.


Document Type: Article
Source: Scopus




Vo K.D.a , Yoo A.J.b , Gupta A.c , Qiao Y.d , Vagal A.S.e , Hirsch J.A.f , Yousem D.M.g , Lum C.h
Multimodal diagnostic imaging for hyperacute stroke
(2015) American Journal of Neuroradiology, 36 (12), pp. 2206-2213. 

DOI: 10.3174/ajnr.A4530


a Mallinckrodt Institute of Radiology, Washington University School of Medicine, 510 South Kingshighway Blvd, St. Louis, MO, United States
b Division of Neurointervention, Texas Stroke Institute, Plano, TX, United States
c Department of Radiology, Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY, United States
d Department of Radiology, Johns Hopkins School of Medicine, Baltimore, MD, United States
e Department of Radiology, University of Cincinnati Medical Center, Cincinnati, OH, United States
f NeuroInterventional Radiology, Massachusetts General Hospital, Boston, MA, United States
g Department of Radiology, Johns Hopkins Medical Institution, Baltimore, MD, United States
h Interventional Neuroradiology, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, ON, Canada


Abstract
In April 2015, the American Roentgen Ray Society and the American Society of Neuroradiology cosponsored a unique program designed to evaluate the state of the art in the imaging work-up of acute stroke. This topic has grown in importance because of the recent randomized controlled trials demonstrating the clear efficacy of endovascular stroke treatment. The authors, who were participants in that symposium, will highlight the points of emphasis in this article.


Document Type: Review
Source: Scopus




Mamah D.a , Wen J.b , Luo J.b , Ulrich X.b , Barch D.M.a c d , Yablonskiy D.b
Subcomponents of brain T2* relaxation in schizophrenia, bipolar disorder and siblings: A Gradient Echo Plural Contrast Imaging (GEPCI) study
(2015) Schizophrenia Research, . Article in Press. 

DOI: 10.1016/j.schres.2015.10.004


a Department of Psychiatry, Washington University Medical School, St. Louis, United States
b Department of Radiology, Washington University Medical School, St. Louis, United States
c Department of Psychology, Washington University in St. Louis, United States
d Department of Anatomy and Neurobiology, Washington University in St. Louis, United States


Abstract
Investigating brain tissue T2* relaxation properties in vivo can potentially guide the uncovering of neuropathology in psychiatric illness, which is traditionally examined post mortem. We use an MRI-based Gradient Echo Plural Contrast Imaging (GEPCI) technique that produces inherently co-registered images allowing quantitative assessment of tissue cellular and hemodynamic properties. Usually described as R2* (=1/T2*) relaxation rate constant, recent developments in GEPCI allow the separation of cellular-specific (R2*C) and hemodynamic (BOLD) contributions to the MRI signal decay. We characterize BOLD effect in terms of tissue concentration of deoxyhemoglobin, i.e. CDEOXY, which reflects brain activity. 17 control (CON), 17 bipolar disorder (BPD), 16 schizophrenia (SCZ), and 12 unaffected schizophrenia sibling (SIB) participants were scanned and post-processed using GEPCI protocols. A MANOVA of 38gray matter regions ROIs showed significant group effects for CDEOXY but not for R2*C. In the three non-control groups, 71-92% of brain regions had increased CDEOXY. Group effects were observed in the superior temporal cortex and the thalamus. Increased superior temporal cortex CDEOXY was found in SCZ (p=0.01), BPD (p=0.01) and SIB (p=0.02), with bilateral effects in SCZ and only left hemisphere effects in BPD and SIB. Thalamic CDEOXY abnormalities were observed in SCZ (p=0.003), BPD (p=0.03) and SIB (p=0.02). Our results suggest that increased activity in certain brain regions is part of the underlying pathophysiology of specific psychiatric disorders. High CDEOXY in the superior temporal cortex suggests abnormal activity with auditory, language and/or social cognitive processing. Larger studies are needed to clarify the clinical significance of relaxometric abnormalities. © 2015 Elsevier B.V.


Author Keywords
Bipolar;  Brain;  GEPCI;  MRI;  Relaxometry;  Schizophrenia;  Siblings;  T2


Document Type: Article in Press
Source: Scopus




Sartor C.E.a b , Grant J.D.b , Agrawal A.b , Sadler B.a b b , Madden P.A.F.b , Heath A.C.b , Bucholz K.K.b
Genetic and environmental contributions to initiation of cigarette smoking in young African-American and European-American women
(2015) Drug and Alcohol Dependence, . Article in Press. 

DOI: 10.1016/j.drugalcdep.2015.10.002


a Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA
b Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA


Abstract
Background: Distinctions in the relative contributions of genetic and environmental factors to initiation of cigarette smoking may explain, in part, the differences between African Americans and European Americans in the prevalence of smoking. The current investigation is the first to compare heritable and environmental influences on smoking initiation between African-American and European-American women. Methods: Data were drawn from Missouri Adolescent Female Twin Study participants and female Missouri Family Study participants (n = 4498; 21% African-American, the remainder European-American). Mean ages at first and last assessments were 17.0 (SD. = 3.5) and 24.0 (SD. = 3.2), respectively. Twin-sibling modeling was conducted to estimate the proportion of variance in smoking initiation (i.e., ever trying a cigarette) attributable to additive genetic, shared environmental, special twin environmental, and unique environmental factors. Results: Additive genetic influences accounted for approximately half of the variance in smoking initiation in both African-American and European-American women. In the African-American subsample, the remaining variance was attributable primarily to unique environmental factors (46%; 95% CI: 28-71%). In the European-American subsample, only 12% (95% CI: 8-16%) of the variance was attributable to unique environmental factors, with the remainder accounted for by shared environmental (13%; 95% CI: 0-41%) and special twin environmental (24%; 95% CI: 0-52%) factors. Conclusions: The estimated heritability of smoking initiation is substantial and nearly identical for African-American and European-American women, but the type of environmental factors that contribute to risk differ by race/ethnicity. Whereas the primary environmental influences on European-American women's smoking initiation are at the family level, those that impact African-American women's smoking initiation are primarily individual-specific. © 2015 Elsevier Ireland Ltd.


Author Keywords
African Americans;  Smoking;  Twins;  Women


Document Type: Article in Press
Source: Scopus




Tajdaran K.a b , Gordon T.a d e , Wood M.D.f , Shoichet M.S.b c , Borschel G.H.a b d e
A glial cell line-derived neurotrophic factor delivery system enhances nerve regeneration across acellular nerve allografts
(2015) Acta Biomaterialia, . Article in Press. 

DOI: 10.1016/j.actbio.2015.10.001


a Division of Plastic and Reconstructive Surgery, The Hospital for Sick Children, 555 University Ave, Toronto, Ontario M5G1X8, Canada
b Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada
c Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, Ontario, Canada
d Division of Plastic and Reconstructive Surgery, Department of Surgery, University of Toronto, Toronto, Ontario, Canada
e Program in Neuroscience, The Hospital for Sick Children Research Institute, Toronto, Ontario, Canada
f Division of Plastic and Reconstructive Surgery, Washington University School of Medicine, St. Louis, MO, USA


Abstract
Acellular nerve allografts (ANAs) are used clinically to bridge nerve gaps but these grafts, lacking Schwann cells and therapeutic levels of neurotrophic factors, do not support regeneration to the same extent as autografts. Here we investigated a local drug delivery system (DDS) for glial cell line-derived neurotrophic factor (GDNF) controlled release to implanted ANAs in rats using drug-loaded polymeric microspheres (MSs) embedded in a fibrin gel. In a rat hindlimb nerve gap model, a 10. mm ANA was used to bridge a 5. mm common peroneal (CP) nerve gap. Experimental groups received DDS treatment at both suture sites of the allografts releasing GDNF for either 2. weeks or 4. weeks. In negative control groups, rats received no DDS treatment or empty DDS. Rats receiving nerve isografts served as the positive control group. The numbers of motor and sensory neurons that regenerated their axons in all the groups with GDNF MS and isograft treatment were indistinguishable and significantly higher as compared to the negative control groups. Nerve histology distal to the nerve graft demonstrated increased axon counts and a shift to larger fiber diameters due to GDNF MS treatment. The sustained delivery of GDNF to the implanted ANA achieved in this study demonstrates the promise of this DDS for the management of severe nerve injuries in which allografts are placed. Statement of Significance: This work addresses the common clinical situation in which a nerve gap is bridged using acellular nerve allografts. However, these allografts are not as effective in supporting nerve regeneration as the gold standard method of autografting. The novel local drug delivery system used in this study provides sustained and controlled release of glial cell line-derived neurotrophic factor (GDNF), one of the most potent neurotrophic factors, which significantly improves nerve regeneration following severe nerve injuries. Results from this research will provide a mean of improving nerve allografts with locally delivered GDNF. This strategy may lead to a novel "off the shelf" alternative to the current management of severe nerve injuries. © 2015 Acta Materialia Inc.


Author Keywords
Acellular nerve allografts;  Biomaterials;  Drug delivery;  Fibrinogen;  Glial cell line-derived neurotrophic factor;  Nerve injury;  Poly(lactic-co-glycolic) acid;  Regenerative medicine


Document Type: Article in Press
Source: Scopus




Crapnell T.L.a , Woodward L.J.b , Rogers C.E.c d , Inder T.E.b , Pineda R.G.a c
Neurodevelopmental Profile, Growth, and Psychosocial Environment of Preterm Infants with Difficult Feeding Behavior at Age 2 Years
(2015) Journal of Pediatrics, . Article in Press. 

DOI: 10.1016/j.jpeds.2015.09.022


a Program in Occupational Therapy, Washington University School of Medicine, St Louis, MO
b Department of Pediatric Newborn Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
c Department of Pediatrics, Washington University School of Medicine, St Louis, MO
d Department of Psychiatry, Washington University School of Medicine, St Louis, MO


Abstract
Objective: To examine the association of difficult feeding behaviors in very preterm infants at age 2 years with growth and neurodevelopmental outcomes and family factors and functioning. Study design: Eighty children born ≤30 weeks gestation were studied from birth until age 2 years. Feeding difficulties were assessed using the Eating Subscale of the Infant-Toddler Social Emotional Assessment at age 2 years, along with growth measurement and developmental testing. Maternal mental health and family factors were assessed using standardized questionnaires. ANOVA and χ2 analyses were performed to determine associations between feeding difficulties and growth, neurodevelopmental outcomes, and family characteristics. Results: Twenty-one children (26%) were at risk for feeding difficulties, and an additional 18 (23%) had definite feeding difficulties at age 2 years. Those with feeding difficulties were more likely to be subject to a range of neurodevelopmental problems, including impaired cognition (P = .02), language (P = .04), motor (P = .01), and socioemotional (P &lt; .007) skills. Compared with the parents of children with fewer feeding difficulties, parents of the children with feeding difficulties had higher parenting stress (P = .02) and reported more difficulty managing their child's behavior (P = .002) and more frequent parent-child interaction problems (P = .002). No associations were found between difficult feeding behaviors and growth, maternal mental health, or family factors. Conclusion: Difficult feeding behaviors in children born very preterm appear to be highly comorbid with other developmental and family challenges, including neurodevelopmental impairment and parent-child interaction difficulties. Focusing on improving feeding skills, in conjunction with supporting positive parent-child interactions, may be beneficial for improving outcomes. © 2015 Elsevier Inc.


Document Type: Article in Press
Source: Scopus




Davis A.A.a , Andruska K.M.a , Benitez B.A.b , Racette B.A.a c d , Perlmutter J.S.a c e f g , Cruchaga C.b c
Variants in GBA, SNCA, and MAPT influence Parkinson disease risk, age at onset, and progression
(2015) Neurobiology of Aging, . Article in Press. 

DOI: 10.1016/j.neurobiolaging.2015.09.014


a Department of Neurology, Washington University, St. Louis, MO, USA
b Department of Psychiatry, Washington University, School of Medicine, St. Louis, MO, USA
c Hope Center Program on Protein Aggregation and Neurodegeneration, Washington University, St. Louis, MO, USA
d School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Parktown, South Africa
e Department of Radiology, Washington University, St. Louis, MO, USA
f Department of Anatomy and Neurobiology, Washington University, St. Louis, MO, USA
g Programs in Physical Therapy and Occupational Therapy, Washington University, St. Louis, MO, USA


Abstract
Multiple genetic variants have been linked to risk of Parkinson disease (PD), but known mutations do not explain a large proportion of the total PD cases. Similarly, multiple loci have been associated with PD risk by genome-wide association studies (GWAS). The influence that genetic factors confer on phenotypic diversity remains unclear. Few studies have been performed to determine whether the GWAS loci are also associated with age at onset (AAO) or motor progression. We used 2 PD case-control data sets (Washington University and the Parkinson's Progression Markers Initiative) to determine whether polymorphisms located at the GWAS top hits (GBA, ACMSD/TMEM163, STK39, MCCC1/LAMP3, GAK/TMEM175, SNCA, and MAPT) show association with AAO or motor progression. We found associations between single nucleotide polymorphisms at the GBA and MAPT loci and PD AAO and progression. These findings reinforce the complex genetic basis of PD and suggest that distinct genes and variants explain the genetic architecture of PD risk, onset, and progression. © 2015 Elsevier Inc.


Author Keywords
Age at onset;  GBA;  MAPT;  Motor progression;  Parkinson disease;  SNCA


Document Type: Article in Press
Source: Scopus




Cho Y.a c , Shin J.b , Ewan E.a , Oh Y.a , Pita-Thomas W.a , Cavalli V.a
Activating Injury-Responsive Genes with Hypoxia Enhances Axon Regeneration through Neuronal HIF-1α
(2015) Neuron, . Article in Press. 

DOI: 10.1016/j.neuron.2015.09.050


a Department of Anatomy and Neurobiology, School of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA
b Department of Developmental Biology, School of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA
c School of Life Sciences and Biotechnology, Korea University, Seoul 136-701, Republic of Korea


Abstract
Injured peripheral neurons successfully activate a proregenerative transcriptional program to enable axon regeneration and functional recovery. How transcriptional regulators coordinate the expression of such program remains unclear. Here we show that hypoxia-inducible factor 1α (HIF-1α) controls multiple injury-induced genes in sensory neurons and contribute to the preconditioning lesion effect. Knockdown of HIF-1α in vitro or conditional knock out in vivo impairs sensory axon regeneration. The HIF-1α target gene Vascular Endothelial Growth Factor A (VEGFA) is expressed in injured neurons and contributes to stimulate axon regeneration. Induction of HIF-1α using hypoxia enhances axon regeneration in vitro and in vivo in sensory neurons. Hypoxia also stimulates motor neuron regeneration and accelerates neuromuscular junction re-innervation. This study demonstrates that HIF-1α represents a critical transcriptional regulator in regenerating neurons and suggests hypoxia as a tool to stimulate axon regeneration. Cho et al. show that HIF-1α controls multiple injury-induced genes in sensory neurons and contributes to stimulate axon regeneration. Induction of HIF-1α using hypoxia enhances axon regeneration in sensory neurons and stimulates motor neuron regeneration, accelerating neuromuscular junction reinnervation. © 2015 Elsevier Inc.


Document Type: Article in Press
Source: Scopus




Salpekar J.A.a , Joshi P.T.b c , Axelson D.A.e , Reinblatt S.P.a , Yenokyan G.d , Sanyal A.d , Walkup J.g , Vitiello B.i , Luby J.h , Wagner K.D.f , Nusrat N.b , Riddle M.A.a
Depression and Suicidality Outcomes in the Treatment of Early Age Mania Study
(2015) Journal of the American Academy of Child and Adolescent Psychiatry, . Article in Press. 

DOI: 10.1016/j.jaac.2015.09.016


a Kennedy Krieger Institute and Johns Hopkins University School of Medicine, Baltimore
b Children's National Medical Center and George Washington University, Washington, DC
c American Academy of Child and Adolescent Psychiatry (AACAP) and with the American Board of Psychiatry and Neurology (ABPN)
d Johns Hopkins Biostatistics Center at Johns Hopkins Bloomberg School of Public Health
e Nationwide Children's Hospital and The Ohio State University, Columbus
f University of Texas Medical Branch at Galveston
g New York Presbyterian Hospital-Weill Cornell Medical College, New York
h Washington University in St. Louis
i Dr. Vitiello is with the National Institute of Mental Health (NIMH), Bethesda, MD


Abstract
Objective: To assess the efficacy of mood-stabilizing medications for depression and suicidality in pediatric bipolar disorder. Method: The Treatment of Early Age Mania (TEAM) study is a multicenter, prospective, randomized, masked comparison of divalproex sodium (VAL), lithium carbonate (LI), and risperidone (RISP) in an 8-week parallel clinical trial. A total of 279 children and adolescents with. DSM-IV diagnoses of bipolar I disorder, mixed or manic, aged 6 to 15 years were enrolled. The primary outcome measure was improvement on the Clinical Global Impression scale for depression (CGI-BP-I-D). Secondary outcome measures included the Children's Depression Rating Scale (CDRS-R) and suicidality status. Statistics included longitudinal analysis of outcomes using generalized linear mixed models with random intercept both for the complete data set and by using last observation carried forward. Results: CGI-BP-I-D ratings were better in the RISP group (60.7%) as compared to the LI (42.2%;. p = .03) or VAL (35.0%;. p = .003) groups from baseline to the end of the study. CDRS scores in all treatment groups improved equally by study end. In week 1, scores were lower with RISP compared to VAL (mean = 4.72, 95% CI = 2.67, 6.78), and compared to LI (mean = 3.63, 95% CI = 1.51, 5.74), although group differences were not present by the end of the study. Suicidality was infrequent, and there was no overall effect of treatment on suicidality ratings. Conclusion: Depressive symptoms, present in the acutely manic or mixed phase of pediatric bipolar disorder, improved with all 3 medications, though RISP appeared to yield more rapid improvement than LI or VAL and was superior using a global categorical outcome + Clinical trial registration information-Treatment of Early Age Mania;. http://www.clinicaltrials.gov;. NCT00057681. © 2015 American Academy of Child and Adolescent Psychiatry.


Author Keywords
Bipolar;  Clinical trial;  Depression;  Pediatrics;  Treatment


Document Type: Article in Press
Source: Scopus




Constantino J.N.a , Charman T.b
Diagnosis of autism spectrum disorder: Reconciling the syndrome, its diverse origins, and variation in expression
(2015) The Lancet Neurology, . Article in Press. 

DOI: 10.1016/S1474-4422(15)00151-9


a Department of Psychiatry, Washington University in St Louis, St Louis, MO, USA
b Department of Psychology, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK


Abstract
Recent discoveries about the pathogenesis and symptom structure of autism spectrum disorders (ASDs) are challenging traditional nosology and driving efforts to reconceptualise the diagnosis of autism, a goal made all the more pressing by new prospects for early identification, targeted intervention, and personalised-medicine approaches to specific autistic syndromes. Recognition that ASD represents the severe end of a continuous distribution of social communication abilities in the general population has stimulated attempts to standardise the measurement of autistic traits and to set appropriate clinical thresholds for diagnosis. Over the next decade, rapid advances in our understanding of symptom structure and the diversity of causes of ASD could be incorporated into the next evolution in the diagnosis of autism, with important implications for research, clinical practice, public health, and policy. As differential effects of personalised therapies are identified in relation to specific causes of autism, the benefits of an updated diagnostic nosology will translate into the delivery of more effective care for patients. © 2015 Elsevier Ltd.


Document Type: Article in Press
Source: Scopus




Sylvester C.M.a , Barch D.M.a , Harms M.P.a , Belden A.C.a , Oakberg T.J.b , Gold A.L.c , White L.K.c , Benson B.E.c , Troller-Renfree S.d , Degnan K.A.d , Henderson H.A.e , Luby J.L.a , Fox N.A.d , Pine D.S.c
Early Childhood Behavioral Inhibition Predicts Cortical Thickness in Adulthood
(2015) Journal of the American Academy of Child and Adolescent Psychiatry, . Article in Press. 

DOI: 10.1016/j.jaac.2015.11.007


a Washington University School of Medicine, St. Louis
b University of Colorado Denver
c National Institute of Mental Health (NIMH) Intramural Research Program, Bethesda, MD
d University of Maryland, College Park
e University of Waterloo, Waterloo, ON, Canada


Abstract
Objective: Behavioral inhibition (BI) during early childhood predicts risk for anxiety disorders and altered cognitive control in adolescence. Although BI has been linked to variation in brain function through adulthood, few studies have examined relations between early childhood BI and adult brain structure. Method: The relation between early childhood BI and cortical thickness in adulthood was examined in a cohort of individuals followed since early childhood (N = 53, mean age 20.5 years). Analyses tested whether anxiety and/or cognitive control during adolescence moderated relations between BI and cortical thickness. Cognitive control was measured with the Eriksen Flanker Task. Initial analyses examined cortical thickness in regions of interest previously implicated in BI, anxiety disorders, and cognitive control: dorsal anterior cingulate (dACC), anterior insula (aI), and subgenual anterior cingulate (sgACC); and volumes of the amygdala and hippocampus. Exploratory analyses examined relations across the prefrontal cortex. Results: BI during early childhood related to thinner dACC in adulthood. Neither anxiety nor cognitive control moderated this relation. A stronger congruency effect on the Eriksen Flanker Task during adolescence independently related to thinner dACC in adulthood. Higher anxiety during adolescence related to thicker cortex in the right ventrolateral prefrontal cortex (VLPFC) in adulthood among those with low BI as children. Conclusion: Temperament in early childhood and the interaction between temperament and later anxiety relate to adult brain structure. These results are consistent with prior work associating BI and anxiety with functional brain variability in the dACC and VLPFC. © 2015 American Academy of Child and Adolescent Psychiatry.


Author Keywords
Anxiety;  Behavioral inhibition;  Cingulate;  Cortical thickness;  Structural MRI


Document Type: Article in Press
Source: Scopus




Ben-Shahar Y.
Editorial overview: Neuroscience: How nervous systems generate behavior: Lessons from insects
(2015) Current Opinion in Insect Science, . Article in Press. 

DOI: 10.1016/j.cois.2015.10.005


Department of Biology, Washington University in St. Louis, MO 63130, USA


Document Type: Article in Press
Source: Scopus




Hochstein E.
Giving up on convergence and autonomy: Why the theories of psychology and neuroscience are codependent as well as irreconcilable
(2015) Studies in History and Philosophy of Science Part A, . Article in Press. 

DOI: 10.1016/j.shpsa.2015.10.001


Washington University, St. Louis, United States


Abstract
There is a long-standing debate in the philosophy of mind and philosophy of science regarding how best to interpret the relationship between neuroscience and psychology. It has traditionally been argued that either the two domains will evolve and change over time until they converge on a single unified account of human behaviour, or else that they will continue to work in isolation given that they identify properties and states that exist autonomously from one another (due to the multiple-realizability of psychological states). In this paper, I argue that progress in psychology and neuroscience is contingent on the fact that both of these positions are false. Contra the convergence position, I argue that the theories of psychology and the theories of neuroscience are scientifically valuable as representational tools precisely because they cannot be integrated into a single account. However, contra the autonomy position, I propose that the theories of psychology and neuroscience are deeply dependent on one another for further refinement and improvement. In this respect, there is an irreconcilable codependence between psychology and neuroscience that is necessary for both domains to improve and progress. The two domains are forever linked while simultaneously being unable to integrate. © 2015 Elsevier Ltd.


Author Keywords
Autonomy;  Convergence;  Idealization;  Neuroscience;  Psychology;  Theory reduction


Document Type: Article in Press
Source: Scopus




Stepan K.O.a , Sharma A.b , Chicoine M.R.c , Uppaluri R.a , Dahiya S.d
Juvenile xanthogranuloma of supra-sellar region: A rare presentation
(2015) Clinical Neuropathology, 34 (6), pp. 368-370. 


a Department of Otolaryngology, Washington University School of Medicine, St. Louis, MO, United States
b Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States
c Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, United States
d Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States


Document Type: Letter
Source: Scopus

Montine T.J.a , Monsell S.E.b , Beach T.G.c , Bigio E.H.d e , Bu Y.b , Cairns N.J.f , Frosch M.g , Henriksen J.a , Kofler J.h , Kukull W.A.b , Lee E.B.i j k , Nelson P.T.l m , Schantz A.M.a , Schneider J.A.n o p , Sonnen J.A.a , Trojanowski J.Q.i j k , Vinters H.V.q r , Zhou X.-H.b , Hyman B.T.s t

Multisite assessment of NIA-AA guidelines for the neuropathologic evaluation of Alzheimer's disease
(2015) Alzheimer's and Dementia, . Article in Press. 

DOI: 10.1016/j.jalz.2015.07.492


a Department of Pathology, University of Washington, Seattle, WA, USA
b National Alzheimer Coordinating Center, University of Washington, Seattle, WA, USA
c Banner Sun Health Research Institute, Civin Laboratory for Neuropathology, Sun City, AZ, USA
d Cognitive Neurology and Alzheimer's Disease Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
e Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
f Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA
g Department of Pathology, C.S. Kubik Laboratory for Neuropathology, Massachusetts General Hospital, Charleston, MA, USA
h Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA
i Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
j Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
k Institute on Aging, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
l Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA
m Pathology Department, University of Kentucky, Lexington, KY, USA
n Department of Pathology Rush University Medical Center, Chicago, IL, USA
o Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA
p Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA
q Department of Pathology and Laboratory Medicine (Neuropathology) David Geffen School of Medicine at UCLA, and Ronald Reagan UCLA Medical Center, Los Angeles, CA, USA
r Department of Neurology, David Geffen School of Medicine at UCLA, and Ronald Reagan UCLA Medical Center, Los Angeles, CA, USA
s Department of Neurology, Massachusetts General Hospital, Charleston, MA, USA
t Massachusetts Alzheimer's Disease Research Center, Massachusetts General Hospital, Charleston, MA, USA


Abstract
Introduction: Neuropathologic assessment is the current "gold standard" for evaluating the Alzheimer's disease (AD), but there is no consensus on the methods used. Methods: Fifteen unstained slides (8 brain regions) from each of the 14 cases were prepared and distributed to 10 different National Institute on Aging AD Centers for application of usual staining and evaluation following recently revised guidelines for AD neuropathologic change. Results: Current practice used in the AD Centers Program achieved robustly excellent agreement for the severity score for AD neuropathologic change (average weighted κ = .88, 95% confidence interval: 0.77-0.95) and good-to-excellent agreement for the three supporting scores. Some improvement was observed with consensus evaluation but not with central staining of slides. Evaluation of glass slides and digitally prepared whole-slide images was comparable. Discussion: AD neuropathologic evaluation as performed across AD Centers yields data that have high agreement with potential modifications for modest improvements. © 2015 The Alzheimer's Association.


Author Keywords
Alzheimer's disease;  Methods;  Multisite;  Neuropathology;  Whole-slide imaging


Document Type: Article in Press
Source: Scopus

 January 7, 2016

 

Figueroa-Romero C.a , Hur J.a e , Lunn J.S.a f , Paez-Colasante X.a , Bender D.E.a g , Yung R.b c , Sakowski S.A.d , Feldman E.L.a d 
Expression of microRNAs in human post-mortem amyotrophic lateral sclerosis spinal cords provides insight into disease mechanisms
(2016) Molecular and Cellular Neuroscience, 71, pp. 34-45. 

DOI: 10.1016/j.mcn.2015.12.008


a Department of Neurology, University of Michigan, Ann Arbor, MI, United States
b Division of Geriatrics and Palliative Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, United States
c Geriatric Research, Education and Clinical Care Center, VA Ann Arbor Health System, Ann Arbor, MI, United States
d A. Alfred Taubman Medical Research Institute, University of Michigan, Ann Arbor, MI, United States
e Department of Basic Sciences, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND, United States
f Renovo Neural, Inc, Cleveland, OH, United States
g Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO, United States


Abstract
Amyotrophic lateral sclerosis is a late-onset and terminal neurodegenerative disease. The majority of cases are sporadic with unknown causes and only a small number of cases are genetically linked. Recent evidence suggests that post-transcriptional regulation and epigenetic mechanisms, such as microRNAs, underlie the onset and progression of neurodegenerative disorders; therefore, altered microRNA expression may result in the dysregulation of key genes and biological pathways that contribute to the development of sporadic amyotrophic lateral sclerosis. Using systems biology analyses on postmortem human spinal cord tissue, we identified dysregulated mature microRNAs and their potential targets previously implicated in functional process and pathways associated with the pathogenesis of ALS. Furthermore, we report a global reduction of mature microRNAs, alterations in microRNA processing, and support for a role of the nucleotide binding protein, TAR DNA binding protein 43, in regulating sporadic amyotrophic lateral sclerosis-associated microRNAs, thereby offering a potential underlying mechanism for sporadic amyotrophic lateral sclerosis. © 2015 Elsevier Inc.


Author Keywords
Amyotrophic lateral sclerosis;  Epigenetics;  MicroRNA


Document Type: Article
Source: Scopus




Brown W.J.a , Bruce S.E.a b , Buchholz K.R.a , Artime T.M.c , Hu E.a , Sheline Y.I.b 
Affective Dispositions and PTSD Symptom Clusters in Female Interpersonal Trauma Survivors
(2016) Journal of Interpersonal Violence, 31 (3), pp. 407-424. 

DOI: 10.1177/0886260514555866


a University of Missouri–St. LouisMO, United States
b Washington University, St. Louis, MO, United States
c Saint Martin’s University, Lacey, WA, United States


Abstract
Interpersonal trauma (IPT) against women can have dire psychological consequences including persistent maladaptive changes in the subjective experience of affect. Contemporary literature has firmly established heightened negative affect (NA) as a risk and maintenance factor for posttraumatic stress disorder (PTSD). However, the relationship between NA and PTSD symptoms is not well understood within IPT survivors, the majority of whom are female, as much of this research has focused on combat veterans. In addition, the connection between positive affect (PA) and PTSD symptoms has yet to be examined. With increased emphasis on “negative alterations in cognitions and mood..” as an independent symptom cluster of PTSD in the Diagnostic and Statistical Manual of Mental Disorders (5th ed.; DSM-5), understanding the relationship between self-reported affectivity and the classic PTSD symptom clusters may be increasingly useful in differentiating symptom presentations of trauma-related psychopathology. The current study directly compared self-reported trait NA and PA with total severity and frequency cluster scores from the Clinician-Administered PTSD Scale (CAPS) in 54 female survivors of IPT who met criteria for PTSD. Results identify NA (but not PA) as a consistent predictor of total PTSD symptoms and, specifically, re-experiencing symptoms. © 2014, © The Author(s) 2014.


Author Keywords
affect;  interpersonal trauma;  PTSD


Document Type: Article
Source: Scopus




Sheffield J.M.a , Barch D.M.a b c 
Cognition and resting-state functional connectivity in schizophrenia
(2016) Neuroscience and Biobehavioral Reviews, 61, pp. 108-120. 

DOI: 10.1016/j.neubiorev.2015.12.007


a Washington University in St Louis, Department of Psychology, 1 Brookings Drive, St Louis, MO, United States
b Washington University in St Louis, Department of Psychiatry, 4940 Childrens Place, St Louis, MO, United States
c Washington University in St Louis, Department of Radiology, 224 Euclid Ave, St Louis, MO, United States


Abstract
Individuals with schizophrenia consistently display deficits in a multitude of cognitive domains, but the neurobiological source of these cognitive impairments remains unclear. By analyzing the functional connectivity of resting-state functional magnetic resonance imaging (rs-fcMRI) data in clinical populations like schizophrenia, research groups have begun elucidating abnormalities in the intrinsic communication between specific brain regions, and assessing relationships between these abnormalities and cognitive performance in schizophrenia. Here we review studies that have reported analysis of these brain-behavior relationships. Through this systematic review we found that patients with schizophrenia display abnormalities within and between regions comprising (1) the cortico-cerebellar-striatal-thalamic loop and (2) task-positive and task-negative cortical networks. Importantly, we did not observe unique relationships between specific functional connectivity abnormalities and distinct cognitive domains, suggesting that the observed functional systems may underlie mechanisms that are shared across cognitive abilities, the disturbance of which could contribute to the "generalized" cognitive deficit found in schizophrenia. We also note several areas of methodological change that we believe will strengthen this literature. © 2015 Elsevier Ltd.


Author Keywords
Cognition;  Cognitive dysmetria;  Default mode network;  Executive functioning;  Functional brain networks;  Functional connectivity;  Generalized cognitive deficit;  Go/NoGo;  IQ;  Reinforcement learning;  Resting-state fMRI;  Schizophrenia;  Task-positive networks


Document Type: Review
Source: Scopus




King N.O.a b , Anderson C.J.a , Dorval A.D.a 
Deep brain stimulation exacerbates hypokinetic dysarthria in a rat model of Parkinson's disease
(2016) Journal of Neuroscience Research, 94 (2), pp. 128-138. 

DOI: 10.1002/jnr.23679


a Department of Bioengineering, University of Utah, Salt Lake City, UT, United States
b Department of Biomedical Engineering, Washington University, St. Louis, MO, United States


Abstract
Motor symptoms of Parkinson's disease (PD) follow the degeneration of dopaminergic neurons in the substantia nigra pars compacta. Deep brain stimulation (DBS) treats some parkinsonian symptoms, such as tremor, rigidity, and bradykinesia, but may worsen certain medial motor symptoms, including hypokinetic dysarthria. The mechanisms by which DBS exacerbates dysarthria while improving other symptoms are unclear and difficult to study in human patients. This study proposes an animal model of DBS-exacerbated dysarthria. We use the unilateral, 6-hydroxydopamine (6-OHDA) rat model of PD to test the hypothesis that DBS exacerbates quantifiable aspects of vocalization. Mating calls were recorded from sexually experienced male rats under healthy and parkinsonian conditions and during DBS of the subthalamic nucleus. Relative to healthy rats, parkinsonian animals made fewer calls with shorter and less complex vocalizations. In the parkinsonian rats, putatively therapeutic DBS further reduced call frequency, duration, and complexity. The individual utterances of parkinsonian rats spanned a greater bandwidth than those of healthy rats, potentially reducing the effectiveness of the vocal signal. This utterance bandwidth was further increased by DBS. We propose that the parkinsonism-associated changes in call frequency, duration, complexity, and dynamic range combine to constitute a rat analog of parkinsonian dysarthria. Because DBS exacerbates the parkinsonism-associated changes in each of these metrics, the subthalamic stimulated 6-OHDA rat is a good model of DBS-induced hypokinetic dysarthria in PD. This model will help researchers examine how DBS alleviates many motor symptoms of PD while exacerbating parkinsonian speech deficits that can greatly diminish patient quality of life. © 2016 Wiley Periodicals, Inc.


Author Keywords
Deep brain stimulation;  Dysarthria;  Hypokinesia;  Parkinson's disease


Document Type: Article
Source: Scopus




Gyawali C.P.
Achalasia: New perspectives on an old disease
(2016) Neurogastroenterology and Motility, 28 (1), pp. 4-11. 

DOI: 10.1111/nmo.12750


Division of Gastroenterology, Washington University School of Medicine, St. Louis, MO, United States


Abstract
Achalasia is defined by esophageal outflow obstruction from abnormal relaxation of the lower esophageal sphincter (LES) due to deranged inhibitory control. In genetically predisposed individuals, an autoimmune response to an unknown inciting agent, perhaps a viral infection, results in inflammation and sometimes loss of myenteric plexus ganglia and neurons. The net result is varying degrees of inhibitory dysfunction, at times associated with imbalanced and exaggerated excitatory function, with manometrically distinct achalasia phenotypes on high resolution manometry. There is new evidence in the current issue of this Journal suggesting that type 1 achalasia, with esophageal outflow obstruction and absent esophageal body contractility, is an end-stage phenotype from progression of type 2 achalasia, which is characterized by panesophageal compartmentalization of pressure in the untreated patient, and partial recovery of peristalsis after treatment. Esophageal outflow obstruction with premature peristalsis (type 3 achalasia) or intact peristalsis may result from plexitis in the myenteric plexus but can also be encountered in other settings including chronic opioid medication usage and structural processes at the esophagogastric junction and distally. In most instances when idiopathic esophageal outflow obstruction is confirmed, some form of pharmacologic manipulation or disruption of the LES provides durable symptom relief. This review will focus on current understanding of pathophysiology, diagnosis, and principles of management of achalasia in light of emerging literature on the topic. © 2015 John Wiley & Sons Ltd.


Author Keywords
Achalasia;  Esophageal outflow obstruction;  High resolution manometry


Document Type: Short Survey
Source: Scopus




Ward C.M.a , Rogers C.S.a , Van Engen K.J.b , Peelle J.E.a 
Effects of Age, Acoustic Challenge, and Verbal Working Memory on Recall of Narrative Speech
(2016) Experimental Aging Research, 42 (1), pp. 126-144. Cited 1 time.

DOI: 10.1080/0361073X.2016.1108785


a Department of Otolaryngology, Washington University in St. Louis, 660 South Euclid, St. Louis, MO, United States
b Department of Psychology, Washington University in St. Louis, St. Louis, MO, United States


Abstract
A common goal during speech comprehension is to remember what we have heard. Encoding speech into long-term memory frequently requires processes such as verbal working memory that may also be involved in processing degraded speech. Here the authors tested whether young and older adult listeners memory for short stories was worse when the stories were acoustically degraded, or whether the additional contextual support provided by a narrative would protect against these effects. Methods: The authors tested 30 young adults (aged 18-28 years) and 30 older adults (aged 65-79 years) with good self-reported hearing. Participants heard short stories that were presented as normal (unprocessed) speech or acoustically degraded using a noise vocoding algorithm with 24 or 16 channels. The degraded stories were still fully intelligible. Following each story, participants were asked to repeat the story in as much detail as possible. Recall was scored using a modified idea unit scoring approach, which included separately scoring hierarchical levels of narrative detail.Results: Memory for acoustically degraded stories was significantly worse than for normal stories at some levels of narrative detail. Older adults memory for the stories was significantly worse overall, but there was no interaction between age and acoustic clarity or level of narrative detail. Verbal working memory (assessed by reading span) significantly correlated with recall accuracy for both young and older adults, whereas hearing ability (better ear pure tone average) did not.Conclusion: The present findings are consistent with a framework in which the additional cognitive demands caused by a degraded acoustic signal use resources that would otherwise be available for memory encoding for both young and older adults. Verbal working memory is a likely candidate for supporting both of these processes. © Taylor and Francis Group, LLC.


Document Type: Conference Paper
Source: Scopus




Fritz B.A.a , Kalarickal P.L.a , Maybrier H.R.a , Muench M.R.a , Dearth D.a , Chen Y.a , Escallier K.E.a , Ben Abdallah A.a , Lin N.b , Avidan M.S.a 
Intraoperative Electroencephalogram Suppression Predicts Postoperative Delirium
(2016) Anesthesia and Analgesia, 122 (1), pp. 234-242. 

DOI: 10.1213/ANE.0000000000000989


a Department of Anesthesiology, Washington University, School of Medicine, 660 S. Euclid Ave., St. Louis, MO, United States
b Department of Mathematics, Washington University, St. Louis, MO, United States


Abstract
BACKGROUND: Postoperative delirium is a common complication associated with increased morbidity and mortality, longer hospital stays, and greater health care expenditures. Intraoperative electroencephalogram (EEG) slowing has been associated previously with postoperative delirium, but the relationship between intraoperative EEG suppression and postoperative delirium has not been investigated. METHODS: In this observational cohort study, 727 adult patients who received general anesthesia with planned intensive care unit admission were included. Duration of intraoperative EEG suppression was recorded from a frontal EEG channel (FP1 to F7). Delirium was assessed twice daily on postoperative days 1 through 5 with the Confusion Assessment Method for the intensive care unit. Thirty days after surgery, quality of life, functional independence, and cognitive ability were measured using the Veterans RAND 12-item survey, the Barthel index, and the PROMIS Applied Cognition-Abilities-Short Form 4a survey. RESULTS: Postoperative delirium was observed in 162 (26%) of 619 patients assessed. When we compared patients with no EEG suppression with those divided into quartiles based on duration of EEG suppression, patients with more suppression were more likely to experience delirium (χ2(4) = 25, P &lt; 0.0001). This effect remained significant after we adjusted for potential confounders (odds ratio for log(EEG suppression) 1.22 [99% confidence interval, 1.06-1.40, P = 0.0002] per 1-minute increase in suppression). EEG suppression may have been associated with reduced functional independence (Spearman partial correlation coefficient-0.15, P = 0.02) but not with changes in quality of life or cognitive ability. Predictors of EEG suppression included greater end-tidal volatile anesthetic concentration and lower intraoperative opioid dose. CONCLUSIONS: EEG suppression is an independent risk factor for postoperative delirium. Future studies should investigate whether anesthesia titration to minimize EEG suppression decreases the incidence of postoperative delirium. This is a substudy of the Systematic Assessment and Targeted Improvement of Services Following Yearlong Surgical Outcomes Surveys (SATISFY-SOS) surgical outcomes registry (NCT02032030). © 2015 International Anesthesia Research Society.


Document Type: Article
Source: Scopus




Peelle J.E.
Introduction to Special Issue on Age, Hearing, and Speech Comprehension
(2016) Experimental Aging Research, 42 (1), pp. 1-3. 

DOI: 10.1080/0361073X.2016.1108714


Department of Otolaryngology, Washington University in St. Louis, 660 South Euclid, St. Louis, MO, United States


Document Type: Conference Paper
Source: Scopus




Nemanich S.T.a , Earhart G.M.a b c 
Reduced after-effects following podokinetic adaptation in people with Parkinson's disease and freezing of gait
(2016) Parkinsonism and Related Disorders, 22, pp. 93-97. 

DOI: 10.1016/j.parkreldis.2015.11.024


a Washington University School of Medicine in St. Louis, 4444 Forest Park Ave., Campus Box 8502, St. Louis, MO, United States
b Department of Anatomy and Neurobiology, Washington University School of Medicine in St. Louis, 660S. Euclid Ave., Campus Box 8108, St. Louis, MO, United States
c Department of Neurology, Washington University School of Medicine in St. Louis, 660S. Euclid Ave., Campus Box 8111, St. Louis, MO, United States


Abstract
Introduction: Gait dysfunction is common in people with Parkinson's disease (PD). Freezing of gait (FOG) is one such gait disturbance that significantly impacts mobility and quality of life in PD. Recent evidence suggests that cerebellar connectivity may differ in people with PD and FOG (PD+FOG) relative to those without FOG (PD-FOG). Investigation of gait adaptation, or the ability to change gait patterns in response to external perturbations, is cerebellum-dependent, is a practical means of probing cerebellar integrity and may provide additional insights regarding the FOG phenomenon. Methods: In this study, we investigated gait adaptation in PD and FOG by measuring after-effects, namely whole-body rotation, following stepping on a rotating disc in PD+FOG compared to PD-FOG and older healthy adults. We refer to the period of stepping on the rotating disc as the podokinetic (PK) stimulation and after-effects as podokinetic after-rotation (PKAR). Our primary measure of adaptation was the magnitude and rate of decay of the after-effects. Results: We noted that PKAR was diminished in PD+FOG compared to the other groups, indicating reduced storage of the adapted gait pattern in PD+FOG. In the PD groups, FOG explained about 20% of the variability in peak velocity. Furthermore, these differences were independent of stepping cadence or motor sign severity. Conclusion: Our results show that gait adaptation is impaired in PD+FOG, suggesting the cerebellum may be differentially impacted in PD+FOG compared to PD-FOG. This supports previous neuroimaging evidence of cerebellar dysfunction in PD+FOG. Overall, these data further our understanding of gait deficits in PD+FOG. © 2015 Elsevier Ltd.


Author Keywords
After-effects;  Freezing of gait;  Locomotor adaptation;  Parkinson disease


Document Type: Article
Source: Scopus




Ning B.a , Sun N.a , Cao R.a , Chen R.b , Shung K.K.b , Hossack J.A.a , Lee J.-M.c , Zhou Q.b , Hu S.a 
Ultrasound-aided Multi-parametric Photoacoustic Microscopy of the Mouse Brain
(2015) Scientific Reports, 5, art. no. 18775, . 

DOI: 10.1038/srep18775


a Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, United States
b Department of Biomedical Engineering, University of Southern California, Los Angeles, CA, United States
c Department of Neurology, Washington University, School of Medicine, St. Louis, MO, United States


Abstract
High-resolution quantitative imaging of cerebral oxygen metabolism in mice is crucial for understanding brain functions and formulating new strategies to treat neurological disorders, but remains a challenge. Here, we report on our newly developed ultrasound-aided multi-parametric photoacoustic microscopy (PAM), which enables simultaneous quantification of the total concentration of hemoglobin (CHb), the oxygen saturation of hemoglobin (sO2), and cerebral blood flow (CBF) at the microscopic level and through the intact mouse skull. The three-dimensional skull and vascular anatomies delineated by the dual-contrast (i.e., ultrasonic and photoacoustic) system provide important guidance for dynamically focused contour scan and vessel orientation-dependent correction of CBF, respectively. Moreover, bi-directional raster scan allows determining the direction of blood flow in individual vessels. Capable of imaging all three hemodynamic parameters at the same spatiotemporal scale, our ultrasound-aided PAM fills a critical gap in preclinical neuroimaging and lays the foundation for high-resolution mapping of the cerebral metabolic rate of oxygen (CMRO2) - a quantitative index of cerebral oxygen metabolism. This technical innovation is expected to shed new light on the mechanism and treatment of a broad spectrum of neurological disorders, including Alzheimer's disease and ischemic stroke.


Document Type: Article
Source: Scopus




Escott-Price V.a , Sims R.a , Bannister C.a , Harold D.b , Vronskaya M.a , Majounie E.a , Badarinarayan N.a , Morgan K.c , Passmore P.d , Holmes C.e , Powell J.f , Brayne C.g , Gill M.h , Mead S.i , Goate A.j , Cruchaga C.k , Lambert J.-C.l m n , Van Duijn C.o , Maier W.p q , Ramirez A.p r , Holmans P.a , Jones L.a , Hardy J.s , Seshadri S.t , Schellenberg G.D.u , Amouyel P.l m n v , Williams J.a 
Common polygenic variation enhances risk prediction for Alzheimer's disease
(2015) Brain, 138 (12), pp. 3673-3684. Cited 1 time.

DOI: 10.1093/brain/awv268


a Institute of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, United Kingdom
b School of Medicine, Trinity College Dublin, College Green, Dublin, 2, Ireland
c Institute of Genetics, Queens Medical Centre, University of Nottingham, United Kingdom
d Ageing Group, Centre for Public Health, School of Medicine, Dentistry and Biomedical Sciences, Queens University Belfast, United Kingdom
e Division of Clinical Neurosciences, School of Medicine, University of Southampton, Southampton, United Kingdom
f Kings College London, Institute of Psychiatry, Department of Neuroscience, De Crespigny Park, Denmark Hill, London, United Kingdom
g Institute of Public Health, University of Cambridge, Cambridge, United Kingdom
h Mercers Institute for Research on Aging, St. James Hospital and Trinity College, Dublin, Ireland
i MRC Prion Unit, Department of Neurodegenerative Disease, UCL Institute of Neurology, London, United Kingdom
j Neuroscience Department, Icahn School of Medicine at Mount Sinai, New York, United States
k Departments of Psychiatry, Neurology and Genetics, Washington University School of Medicine, St Louis, MO, United States
l Inserm U744, Lille, France
m Université Lille 2, Lille, France
n Institut Pasteur de Lille, Lille, France
o Department of Epidemiology, Erasmus Medical Centre, Rotterdam, Netherlands
p Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany
q German Centre for Neurodegenerative Diseases (DZNE), Bonn, Germany
r Institute of Human Genetics, University of Bonn, Bonn, Germany
s Department of Molecular Neuroscience, Reta Lilla Weston Laboratories, Institute of Neurology, London, United Kingdom
t Department of Neurology, Boston University School of Medicine, Boston, MA, United States
u Department of Pathology and Laboratory Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, United States
v Centre Hospitalier Régional, Universitaire de Lille, Lille, France


Abstract
The identification of subjects at high risk for Alzheimer's disease is important for prognosis and early intervention. We investigated the polygenic architecture of Alzheimer's disease and the accuracy of Alzheimer's disease prediction models, including and excluding the polygenic component in the model. This study used genotype data from the powerful dataset comprising 17 008 cases and 37 154 controls obtained from the International Genomics of Alzheimer's Project (IGAP). Polygenic score analysis tested whether the alleles identified to associate with disease in one sample set were significantly enriched in the cases relative to the controls in an independent sample. The disease prediction accuracy was investigated in a subset of the IGAP data, a sample of 3049 cases and 1554 controls (for whom APOE genotype data were available) by means of sensitivity, specificity, area under the receiver operating characteristic curve (AUC) and positive and negative predictive values. We observed significant evidence for a polygenic component enriched in Alzheimer's disease (P = 4.9 × 10-26). This enrichment remained significant after APOE and other genome-wide associated regions were excluded (P = 3.4 × 10-19). The best prediction accuracy AUC = 78.2% (95% confidence interval 77-80%) was achieved by a logistic regression model with APOE, the polygenic score, sex and age as predictors. In conclusion, Alzheimer's disease has a significant polygenic component, which has predictive utility for Alzheimer's disease risk and could be a valuable research tool complementing experimental designs, including preventative clinical trials, stem cell selection and high/low risk clinical studies. In modelling a range of sample disease prevalences, we found that polygenic scores almost doubles case prediction from chance with increased prediction at polygenic extremes.


Author Keywords
Alzheimer's disease;  polygenic score;  predictive model


Document Type: Article
Source: Scopus




Marquardt L.M.a , Ee X.b , Iyer N.a , Hunter D.b , Mackinnon S.E.b , Wood M.D.b , Sakiyama-Elbert S.E.a b b 
Finely Tuned Temporal and Spatial Delivery of GDNF Promotes Enhanced Nerve Regeneration in a Long Nerve Defect Model
(2015) Tissue Engineering - Part A, 21 (23-24), pp. 2852-2864. 

DOI: 10.1089/ten.tea.2015.0311


a Department of Biomedical Engineering, Washington University in St. Louis, 1097 Brookings Drive, St. Louis, MO, United States
b Divison of Plastic and Reconstructive Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, MO, United States


Abstract
The use of growth factors, such as glial cell line-derived neurotrophic factor (GDNF), for the treatment of peripheral nerve injury has been useful in promoting axon survival and regeneration. Unfortunately, finding a method that delivers the appropriate spatial and temporal release profile to promote functional recovery has proven difficult. Some release methods result in burst release profiles too short to remain effective over the regeneration period; however, prolonged exposure to GDNF can result in axonal entrapment at the site of release. Thus, GDNF was delivered in both a spatially and temporally controlled manner using a two-phase system comprised of an affinity-based release system and conditional lentiviral GDNF overexpression from Schwann cells (SCs). Briefly, SCs were transduced with a tetracycline-inducible (Tet-On) GDNF overexpressing lentivirus before transplantation. Three-centimeter acellular nerve allografts (ANAs) were modified by injection of a GDNF-releasing fibrin scaffold under the epineurium and then used to bridge a 3 cm sciatic nerve defect. To encourage growth past the ANA, GDNF-SCs were transplanted into the distal nerve and doxycycline was administered for 4, 6, or 8 weeks to determine the optimal duration of GDNF expression in the distal nerve. Live imaging and histomorphometric analysis determined that 6 weeks of doxycycline treatment resulted in enhanced regeneration compared to 4 or 8 weeks. This enhanced regeneration resulted in increased gastrocnemius and tibialis anterior muscle mass for animals receiving doxycycline for 6 weeks. The results of this study demonstrate that strategies providing spatial and temporal control of delivery can improve axonal regeneration and functional muscle reinnervation. © Mary Ann Liebert, Inc. 2015.


Document Type: Article
Source: Scopus




Vo K.D.a , Yoo A.J.b , Gupta A.c , Qiao Y.d , Vagal A.S.e , Hirsch J.A.f , Yousem D.M.g , Lum C.h 
Multimodal diagnostic imaging for hyperacute stroke
(2015) American Journal of Neuroradiology, 36 (12), pp. 2206-2213. 

DOI: 10.3174/ajnr.A4530


a Mallinckrodt Institute of Radiology, Washington University School of Medicine, 510 South Kingshighway Blvd, St. Louis, MO, United States
b Division of Neurointervention, Texas Stroke Institute, Plano, TX, United States
c Department of Radiology, Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY, United States
d Department of Radiology, Johns Hopkins School of Medicine, Baltimore, MD, United States
e Department of Radiology, University of Cincinnati Medical Center, Cincinnati, OH, United States
f NeuroInterventional Radiology, Massachusetts General Hospital, Boston, MA, United States
g Department of Radiology, Johns Hopkins Medical Institution, Baltimore, MD, United States
h Interventional Neuroradiology, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, ON, Canada


Abstract
In April 2015, the American Roentgen Ray Society and the American Society of Neuroradiology cosponsored a unique program designed to evaluate the state of the art in the imaging work-up of acute stroke. This topic has grown in importance because of the recent randomized controlled trials demonstrating the clear efficacy of endovascular stroke treatment. The authors, who were participants in that symposium, will highlight the points of emphasis in this article.


Document Type: Review
Source: Scopus




Mamah D.a , Wen J.b , Luo J.b , Ulrich X.b , Barch D.M.a c d , Yablonskiy D.b 
Subcomponents of brain T2* relaxation in schizophrenia, bipolar disorder and siblings: A Gradient Echo Plural Contrast Imaging (GEPCI) study
(2015) Schizophrenia Research, . Article in Press. 

DOI: 10.1016/j.schres.2015.10.004


a Department of Psychiatry, Washington University Medical School, St. Louis, United States
b Department of Radiology, Washington University Medical School, St. Louis, United States
c Department of Psychology, Washington University in St. Louis, United States
d Department of Anatomy and Neurobiology, Washington University in St. Louis, United States


Abstract
Investigating brain tissue T2* relaxation properties in vivo can potentially guide the uncovering of neuropathology in psychiatric illness, which is traditionally examined post mortem. We use an MRI-based Gradient Echo Plural Contrast Imaging (GEPCI) technique that produces inherently co-registered images allowing quantitative assessment of tissue cellular and hemodynamic properties. Usually described as R2* (=1/T2*) relaxation rate constant, recent developments in GEPCI allow the separation of cellular-specific (R2*C) and hemodynamic (BOLD) contributions to the MRI signal decay. We characterize BOLD effect in terms of tissue concentration of deoxyhemoglobin, i.e. CDEOXY, which reflects brain activity. 17 control (CON), 17 bipolar disorder (BPD), 16 schizophrenia (SCZ), and 12 unaffected schizophrenia sibling (SIB) participants were scanned and post-processed using GEPCI protocols. A MANOVA of 38gray matter regions ROIs showed significant group effects for CDEOXY but not for R2*C. In the three non-control groups, 71-92% of brain regions had increased CDEOXY. Group effects were observed in the superior temporal cortex and the thalamus. Increased superior temporal cortex CDEOXY was found in SCZ (p=0.01), BPD (p=0.01) and SIB (p=0.02), with bilateral effects in SCZ and only left hemisphere effects in BPD and SIB. Thalamic CDEOXY abnormalities were observed in SCZ (p=0.003), BPD (p=0.03) and SIB (p=0.02). Our results suggest that increased activity in certain brain regions is part of the underlying pathophysiology of specific psychiatric disorders. High CDEOXY in the superior temporal cortex suggests abnormal activity with auditory, language and/or social cognitive processing. Larger studies are needed to clarify the clinical significance of relaxometric abnormalities. © 2015 Elsevier B.V.


Author Keywords
Bipolar;  Brain;  GEPCI;  MRI;  Relaxometry;  Schizophrenia;  Siblings;  T2


Document Type: Article in Press
Source: Scopus




Sartor C.E.a b , Grant J.D.b , Agrawal A.b , Sadler B.a b b , Madden P.A.F.b , Heath A.C.b , Bucholz K.K.b 
Genetic and environmental contributions to initiation of cigarette smoking in young African-American and European-American women
(2015) Drug and Alcohol Dependence, . Article in Press. 

DOI: 10.1016/j.drugalcdep.2015.10.002


a Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA
b Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA


Abstract
Background: Distinctions in the relative contributions of genetic and environmental factors to initiation of cigarette smoking may explain, in part, the differences between African Americans and European Americans in the prevalence of smoking. The current investigation is the first to compare heritable and environmental influences on smoking initiation between African-American and European-American women. Methods: Data were drawn from Missouri Adolescent Female Twin Study participants and female Missouri Family Study participants (n = 4498; 21% African-American, the remainder European-American). Mean ages at first and last assessments were 17.0 (SD. = 3.5) and 24.0 (SD. = 3.2), respectively. Twin-sibling modeling was conducted to estimate the proportion of variance in smoking initiation (i.e., ever trying a cigarette) attributable to additive genetic, shared environmental, special twin environmental, and unique environmental factors. Results: Additive genetic influences accounted for approximately half of the variance in smoking initiation in both African-American and European-American women. In the African-American subsample, the remaining variance was attributable primarily to unique environmental factors (46%; 95% CI: 28-71%). In the European-American subsample, only 12% (95% CI: 8-16%) of the variance was attributable to unique environmental factors, with the remainder accounted for by shared environmental (13%; 95% CI: 0-41%) and special twin environmental (24%; 95% CI: 0-52%) factors. Conclusions: The estimated heritability of smoking initiation is substantial and nearly identical for African-American and European-American women, but the type of environmental factors that contribute to risk differ by race/ethnicity. Whereas the primary environmental influences on European-American women's smoking initiation are at the family level, those that impact African-American women's smoking initiation are primarily individual-specific. © 2015 Elsevier Ireland Ltd.


Author Keywords
African Americans;  Smoking;  Twins;  Women


Document Type: Article in Press
Source: Scopus




Tajdaran K.a b , Gordon T.a d e , Wood M.D.f , Shoichet M.S.b c , Borschel G.H.a b d e 
A glial cell line-derived neurotrophic factor delivery system enhances nerve regeneration across acellular nerve allografts
(2015) Acta Biomaterialia, . Article in Press. 

DOI: 10.1016/j.actbio.2015.10.001


a Division of Plastic and Reconstructive Surgery, The Hospital for Sick Children, 555 University Ave, Toronto, Ontario M5G1X8, Canada
b Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada
c Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, Ontario, Canada
d Division of Plastic and Reconstructive Surgery, Department of Surgery, University of Toronto, Toronto, Ontario, Canada
e Program in Neuroscience, The Hospital for Sick Children Research Institute, Toronto, Ontario, Canada
f Division of Plastic and Reconstructive Surgery, Washington University School of Medicine, St. Louis, MO, USA


Abstract
Acellular nerve allografts (ANAs) are used clinically to bridge nerve gaps but these grafts, lacking Schwann cells and therapeutic levels of neurotrophic factors, do not support regeneration to the same extent as autografts. Here we investigated a local drug delivery system (DDS) for glial cell line-derived neurotrophic factor (GDNF) controlled release to implanted ANAs in rats using drug-loaded polymeric microspheres (MSs) embedded in a fibrin gel. In a rat hindlimb nerve gap model, a 10. mm ANA was used to bridge a 5. mm common peroneal (CP) nerve gap. Experimental groups received DDS treatment at both suture sites of the allografts releasing GDNF for either 2. weeks or 4. weeks. In negative control groups, rats received no DDS treatment or empty DDS. Rats receiving nerve isografts served as the positive control group. The numbers of motor and sensory neurons that regenerated their axons in all the groups with GDNF MS and isograft treatment were indistinguishable and significantly higher as compared to the negative control groups. Nerve histology distal to the nerve graft demonstrated increased axon counts and a shift to larger fiber diameters due to GDNF MS treatment. The sustained delivery of GDNF to the implanted ANA achieved in this study demonstrates the promise of this DDS for the management of severe nerve injuries in which allografts are placed. Statement of Significance: This work addresses the common clinical situation in which a nerve gap is bridged using acellular nerve allografts. However, these allografts are not as effective in supporting nerve regeneration as the gold standard method of autografting. The novel local drug delivery system used in this study provides sustained and controlled release of glial cell line-derived neurotrophic factor (GDNF), one of the most potent neurotrophic factors, which significantly improves nerve regeneration following severe nerve injuries. Results from this research will provide a mean of improving nerve allografts with locally delivered GDNF. This strategy may lead to a novel "off the shelf" alternative to the current management of severe nerve injuries. © 2015 Acta Materialia Inc.


Author Keywords
Acellular nerve allografts;  Biomaterials;  Drug delivery;  Fibrinogen;  Glial cell line-derived neurotrophic factor;  Nerve injury;  Poly(lactic-co-glycolic) acid;  Regenerative medicine


Document Type: Article in Press
Source: Scopus




Crapnell T.L.a , Woodward L.J.b , Rogers C.E.c d , Inder T.E.b , Pineda R.G.a c 
Neurodevelopmental Profile, Growth, and Psychosocial Environment of Preterm Infants with Difficult Feeding Behavior at Age 2 Years
(2015) Journal of Pediatrics, . Article in Press. 

DOI: 10.1016/j.jpeds.2015.09.022


a Program in Occupational Therapy, Washington University School of Medicine, St Louis, MO
b Department of Pediatric Newborn Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
c Department of Pediatrics, Washington University School of Medicine, St Louis, MO
d Department of Psychiatry, Washington University School of Medicine, St Louis, MO


Abstract
Objective: To examine the association of difficult feeding behaviors in very preterm infants at age 2 years with growth and neurodevelopmental outcomes and family factors and functioning. Study design: Eighty children born ≤30 weeks gestation were studied from birth until age 2 years. Feeding difficulties were assessed using the Eating Subscale of the Infant-Toddler Social Emotional Assessment at age 2 years, along with growth measurement and developmental testing. Maternal mental health and family factors were assessed using standardized questionnaires. ANOVA and χ2 analyses were performed to determine associations between feeding difficulties and growth, neurodevelopmental outcomes, and family characteristics. Results: Twenty-one children (26%) were at risk for feeding difficulties, and an additional 18 (23%) had definite feeding difficulties at age 2 years. Those with feeding difficulties were more likely to be subject to a range of neurodevelopmental problems, including impaired cognition (P = .02), language (P = .04), motor (P = .01), and socioemotional (P &lt; .007) skills. Compared with the parents of children with fewer feeding difficulties, parents of the children with feeding difficulties had higher parenting stress (P = .02) and reported more difficulty managing their child's behavior (P = .002) and more frequent parent-child interaction problems (P = .002). No associations were found between difficult feeding behaviors and growth, maternal mental health, or family factors. Conclusion: Difficult feeding behaviors in children born very preterm appear to be highly comorbid with other developmental and family challenges, including neurodevelopmental impairment and parent-child interaction difficulties. Focusing on improving feeding skills, in conjunction with supporting positive parent-child interactions, may be beneficial for improving outcomes. © 2015 Elsevier Inc.


Document Type: Article in Press
Source: Scopus




Davis A.A.a , Andruska K.M.a , Benitez B.A.b , Racette B.A.a c d , Perlmutter J.S.a c e f g , Cruchaga C.b c 
Variants in GBA, SNCA, and MAPT influence Parkinson disease risk, age at onset, and progression
(2015) Neurobiology of Aging, . Article in Press. 

DOI: 10.1016/j.neurobiolaging.2015.09.014


a Department of Neurology, Washington University, St. Louis, MO, USA
b Department of Psychiatry, Washington University, School of Medicine, St. Louis, MO, USA
c Hope Center Program on Protein Aggregation and Neurodegeneration, Washington University, St. Louis, MO, USA
d School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Parktown, South Africa
e Department of Radiology, Washington University, St. Louis, MO, USA
f Department of Anatomy and Neurobiology, Washington University, St. Louis, MO, USA
g Programs in Physical Therapy and Occupational Therapy, Washington University, St. Louis, MO, USA


Abstract
Multiple genetic variants have been linked to risk of Parkinson disease (PD), but known mutations do not explain a large proportion of the total PD cases. Similarly, multiple loci have been associated with PD risk by genome-wide association studies (GWAS). The influence that genetic factors confer on phenotypic diversity remains unclear. Few studies have been performed to determine whether the GWAS loci are also associated with age at onset (AAO) or motor progression. We used 2 PD case-control data sets (Washington University and the Parkinson's Progression Markers Initiative) to determine whether polymorphisms located at the GWAS top hits (GBA, ACMSD/TMEM163, STK39, MCCC1/LAMP3, GAK/TMEM175, SNCA, and MAPT) show association with AAO or motor progression. We found associations between single nucleotide polymorphisms at the GBA and MAPT loci and PD AAO and progression. These findings reinforce the complex genetic basis of PD and suggest that distinct genes and variants explain the genetic architecture of PD risk, onset, and progression. © 2015 Elsevier Inc.


Author Keywords
Age at onset;  GBA;  MAPT;  Motor progression;  Parkinson disease;  SNCA


Document Type: Article in Press
Source: Scopus




Cho Y.a c , Shin J.b , Ewan E.a , Oh Y.a , Pita-Thomas W.a , Cavalli V.a 
Activating Injury-Responsive Genes with Hypoxia Enhances Axon Regeneration through Neuronal HIF-1α
(2015) Neuron, . Article in Press. 

DOI: 10.1016/j.neuron.2015.09.050


a Department of Anatomy and Neurobiology, School of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA
b Department of Developmental Biology, School of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA
c School of Life Sciences and Biotechnology, Korea University, Seoul 136-701, Republic of Korea


Abstract
Injured peripheral neurons successfully activate a proregenerative transcriptional program to enable axon regeneration and functional recovery. How transcriptional regulators coordinate the expression of such program remains unclear. Here we show that hypoxia-inducible factor 1α (HIF-1α) controls multiple injury-induced genes in sensory neurons and contribute to the preconditioning lesion effect. Knockdown of HIF-1α in vitro or conditional knock out in vivo impairs sensory axon regeneration. The HIF-1α target gene Vascular Endothelial Growth Factor A (VEGFA) is expressed in injured neurons and contributes to stimulate axon regeneration. Induction of HIF-1α using hypoxia enhances axon regeneration in vitro and in vivo in sensory neurons. Hypoxia also stimulates motor neuron regeneration and accelerates neuromuscular junction re-innervation. This study demonstrates that HIF-1α represents a critical transcriptional regulator in regenerating neurons and suggests hypoxia as a tool to stimulate axon regeneration. Cho et al. show that HIF-1α controls multiple injury-induced genes in sensory neurons and contributes to stimulate axon regeneration. Induction of HIF-1α using hypoxia enhances axon regeneration in sensory neurons and stimulates motor neuron regeneration, accelerating neuromuscular junction reinnervation. © 2015 Elsevier Inc.


Document Type: Article in Press
Source: Scopus




Salpekar J.A.a , Joshi P.T.b c , Axelson D.A.e , Reinblatt S.P.a , Yenokyan G.d , Sanyal A.d , Walkup J.g , Vitiello B.i , Luby J.h , Wagner K.D.f , Nusrat N.b , Riddle M.A.a 
Depression and Suicidality Outcomes in the Treatment of Early Age Mania Study
(2015) Journal of the American Academy of Child and Adolescent Psychiatry, . Article in Press. 

DOI: 10.1016/j.jaac.2015.09.016


a Kennedy Krieger Institute and Johns Hopkins University School of Medicine, Baltimore
b Children's National Medical Center and George Washington University, Washington, DC
c American Academy of Child and Adolescent Psychiatry (AACAP) and with the American Board of Psychiatry and Neurology (ABPN)
d Johns Hopkins Biostatistics Center at Johns Hopkins Bloomberg School of Public Health
e Nationwide Children's Hospital and The Ohio State University, Columbus
f University of Texas Medical Branch at Galveston
g New York Presbyterian Hospital-Weill Cornell Medical College, New York
h Washington University in St. Louis
i Dr. Vitiello is with the National Institute of Mental Health (NIMH), Bethesda, MD


Abstract
Objective: To assess the efficacy of mood-stabilizing medications for depression and suicidality in pediatric bipolar disorder. Method: The Treatment of Early Age Mania (TEAM) study is a multicenter, prospective, randomized, masked comparison of divalproex sodium (VAL), lithium carbonate (LI), and risperidone (RISP) in an 8-week parallel clinical trial. A total of 279 children and adolescents with. DSM-IV diagnoses of bipolar I disorder, mixed or manic, aged 6 to 15 years were enrolled. The primary outcome measure was improvement on the Clinical Global Impression scale for depression (CGI-BP-I-D). Secondary outcome measures included the Children's Depression Rating Scale (CDRS-R) and suicidality status. Statistics included longitudinal analysis of outcomes using generalized linear mixed models with random intercept both for the complete data set and by using last observation carried forward. Results: CGI-BP-I-D ratings were better in the RISP group (60.7%) as compared to the LI (42.2%;. p = .03) or VAL (35.0%;. p = .003) groups from baseline to the end of the study. CDRS scores in all treatment groups improved equally by study end. In week 1, scores were lower with RISP compared to VAL (mean = 4.72, 95% CI = 2.67, 6.78), and compared to LI (mean = 3.63, 95% CI = 1.51, 5.74), although group differences were not present by the end of the study. Suicidality was infrequent, and there was no overall effect of treatment on suicidality ratings. Conclusion: Depressive symptoms, present in the acutely manic or mixed phase of pediatric bipolar disorder, improved with all 3 medications, though RISP appeared to yield more rapid improvement than LI or VAL and was superior using a global categorical outcome + Clinical trial registration information-Treatment of Early Age Mania;. http://www.clinicaltrials.gov;. NCT00057681. © 2015 American Academy of Child and Adolescent Psychiatry.


Author Keywords
Bipolar;  Clinical trial;  Depression;  Pediatrics;  Treatment


Document Type: Article in Press
Source: Scopus




Constantino J.N.a , Charman T.b 
Diagnosis of autism spectrum disorder: Reconciling the syndrome, its diverse origins, and variation in expression
(2015) The Lancet Neurology, . Article in Press. 

DOI: 10.1016/S1474-4422(15)00151-9


a Department of Psychiatry, Washington University in St Louis, St Louis, MO, USA
b Department of Psychology, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK


Abstract
Recent discoveries about the pathogenesis and symptom structure of autism spectrum disorders (ASDs) are challenging traditional nosology and driving efforts to reconceptualise the diagnosis of autism, a goal made all the more pressing by new prospects for early identification, targeted intervention, and personalised-medicine approaches to specific autistic syndromes. Recognition that ASD represents the severe end of a continuous distribution of social communication abilities in the general population has stimulated attempts to standardise the measurement of autistic traits and to set appropriate clinical thresholds for diagnosis. Over the next decade, rapid advances in our understanding of symptom structure and the diversity of causes of ASD could be incorporated into the next evolution in the diagnosis of autism, with important implications for research, clinical practice, public health, and policy. As differential effects of personalised therapies are identified in relation to specific causes of autism, the benefits of an updated diagnostic nosology will translate into the delivery of more effective care for patients. © 2015 Elsevier Ltd.


Document Type: Article in Press
Source: Scopus




Sylvester C.M.a , Barch D.M.a , Harms M.P.a , Belden A.C.a , Oakberg T.J.b , Gold A.L.c , White L.K.c , Benson B.E.c , Troller-Renfree S.d , Degnan K.A.d , Henderson H.A.e , Luby J.L.a , Fox N.A.d , Pine D.S.c 
Early Childhood Behavioral Inhibition Predicts Cortical Thickness in Adulthood
(2015) Journal of the American Academy of Child and Adolescent Psychiatry, . Article in Press. 

DOI: 10.1016/j.jaac.2015.11.007


a Washington University School of Medicine, St. Louis
b University of Colorado Denver
c National Institute of Mental Health (NIMH) Intramural Research Program, Bethesda, MD
d University of Maryland, College Park
e University of Waterloo, Waterloo, ON, Canada


Abstract
Objective: Behavioral inhibition (BI) during early childhood predicts risk for anxiety disorders and altered cognitive control in adolescence. Although BI has been linked to variation in brain function through adulthood, few studies have examined relations between early childhood BI and adult brain structure. Method: The relation between early childhood BI and cortical thickness in adulthood was examined in a cohort of individuals followed since early childhood (N = 53, mean age 20.5 years). Analyses tested whether anxiety and/or cognitive control during adolescence moderated relations between BI and cortical thickness. Cognitive control was measured with the Eriksen Flanker Task. Initial analyses examined cortical thickness in regions of interest previously implicated in BI, anxiety disorders, and cognitive control: dorsal anterior cingulate (dACC), anterior insula (aI), and subgenual anterior cingulate (sgACC); and volumes of the amygdala and hippocampus. Exploratory analyses examined relations across the prefrontal cortex. Results: BI during early childhood related to thinner dACC in adulthood. Neither anxiety nor cognitive control moderated this relation. A stronger congruency effect on the Eriksen Flanker Task during adolescence independently related to thinner dACC in adulthood. Higher anxiety during adolescence related to thicker cortex in the right ventrolateral prefrontal cortex (VLPFC) in adulthood among those with low BI as children. Conclusion: Temperament in early childhood and the interaction between temperament and later anxiety relate to adult brain structure. These results are consistent with prior work associating BI and anxiety with functional brain variability in the dACC and VLPFC. © 2015 American Academy of Child and Adolescent Psychiatry.


Author Keywords
Anxiety;  Behavioral inhibition;  Cingulate;  Cortical thickness;  Structural MRI


Document Type: Article in Press
Source: Scopus




Ben-Shahar Y.
Editorial overview: Neuroscience: How nervous systems generate behavior: Lessons from insects
(2015) Current Opinion in Insect Science, . Article in Press. 

DOI: 10.1016/j.cois.2015.10.005


Department of Biology, Washington University in St. Louis, MO 63130, USA


Document Type: Article in Press
Source: Scopus




Hochstein E.
Giving up on convergence and autonomy: Why the theories of psychology and neuroscience are codependent as well as irreconcilable
(2015) Studies in History and Philosophy of Science Part A, . Article in Press. 

DOI: 10.1016/j.shpsa.2015.10.001


Washington University, St. Louis, United States


Abstract
There is a long-standing debate in the philosophy of mind and philosophy of science regarding how best to interpret the relationship between neuroscience and psychology. It has traditionally been argued that either the two domains will evolve and change over time until they converge on a single unified account of human behaviour, or else that they will continue to work in isolation given that they identify properties and states that exist autonomously from one another (due to the multiple-realizability of psychological states). In this paper, I argue that progress in psychology and neuroscience is contingent on the fact that both of these positions are false. Contra the convergence position, I argue that the theories of psychology and the theories of neuroscience are scientifically valuable as representational tools precisely because they cannot be integrated into a single account. However, contra the autonomy position, I propose that the theories of psychology and neuroscience are deeply dependent on one another for further refinement and improvement. In this respect, there is an irreconcilable codependence between psychology and neuroscience that is necessary for both domains to improve and progress. The two domains are forever linked while simultaneously being unable to integrate. © 2015 Elsevier Ltd.


Author Keywords
Autonomy;  Convergence;  Idealization;  Neuroscience;  Psychology;  Theory reduction


Document Type: Article in Press
Source: Scopus




Stepan K.O.a , Sharma A.b , Chicoine M.R.c , Uppaluri R.a , Dahiya S.d 
Juvenile xanthogranuloma of supra-sellar region: A rare presentation
(2015) Clinical Neuropathology, 34 (6), pp. 368-370. 


a Department of Otolaryngology, Washington University School of Medicine, St. Louis, MO, United States
b Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States
c Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, United States
d Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States


Document Type: Letter
Source: Scopus

Montine T.J.a , Monsell S.E.b , Beach T.G.c , Bigio E.H.d e , Bu Y.b , Cairns N.J.f , Frosch M.g , Henriksen J.a , Kofler J.h , Kukull W.A.b , Lee E.B.i j k , Nelson P.T.l m , Schantz A.M.a , Schneider J.A.no p , Sonnen J.A.a , Trojanowski J.Q.i j k , Vinters H.V.q r , Zhou X.-H.b , Hyman B.T.s t

Multisite assessment of NIA-AA guidelines for the neuropathologic evaluation of Alzheimer's disease
(2015) Alzheimer's and Dementia, . Article in Press. 

DOI: 10.1016/j.jalz.2015.07.492


a Department of Pathology, University of Washington, Seattle, WA, USA
b National Alzheimer Coordinating Center, University of Washington, Seattle, WA, USA
c Banner Sun Health Research Institute, Civin Laboratory for Neuropathology, Sun City, AZ, USA
d Cognitive Neurology and Alzheimer's Disease Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
e Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
f Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA
g Department of Pathology, C.S. Kubik Laboratory for Neuropathology, Massachusetts General Hospital, Charleston, MA, USA
h Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA
i Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
j Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
k Institute on Aging, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
l Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA
m Pathology Department, University of Kentucky, Lexington, KY, USA
n Department of Pathology Rush University Medical Center, Chicago, IL, USA
o Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA
p Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA
q Department of Pathology and Laboratory Medicine (Neuropathology) David Geffen School of Medicine at UCLA, and Ronald Reagan UCLA Medical Center, Los Angeles, CA, USA
r Department of Neurology, David Geffen School of Medicine at UCLA, and Ronald Reagan UCLA Medical Center, Los Angeles, CA, USA
s Department of Neurology, Massachusetts General Hospital, Charleston, MA, USA
t Massachusetts Alzheimer's Disease Research Center, Massachusetts General Hospital, Charleston, MA, USA


Abstract
Introduction: Neuropathologic assessment is the current "gold standard" for evaluating the Alzheimer's disease (AD), but there is no consensus on the methods used. Methods: Fifteen unstained slides (8 brain regions) from each of the 14 cases were prepared and distributed to 10 different National Institute on Aging AD Centers for application of usual staining and evaluation following recently revised guidelines for AD neuropathologic change. Results: Current practice used in the AD Centers Program achieved robustly excellent agreement for the severity score for AD neuropathologic change (average weighted κ = .88, 95% confidence interval: 0.77-0.95) and good-to-excellent agreement for the three supporting scores. Some improvement was observed with consensus evaluation but not with central staining of slides. Evaluation of glass slides and digitally prepared whole-slide images was comparable. Discussion: AD neuropathologic evaluation as performed across AD Centers yields data that have high agreement with potential modifications for modest improvements. © 2015 The Alzheimer's Association.


Author Keywords
Alzheimer's disease;  Methods;  Multisite;  Neuropathology;  Whole-slide imaging


Document Type: Article in Press

January 7, 2016

 

Figueroa-Romero C.a , Hur J.a e , Lunn J.S.a f , Paez-Colasante X.a , Bender D.E.a g , Yung R.b c , Sakowski S.A.d , Feldman E.L.a d 
Expression of microRNAs in human post-mortem amyotrophic lateral sclerosis spinal cords provides insight into disease mechanisms
(2016) Molecular and Cellular Neuroscience, 71, pp. 34-45. 

DOI: 10.1016/j.mcn.2015.12.008


a Department of Neurology, University of Michigan, Ann Arbor, MI, United States
b Division of Geriatrics and Palliative Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, United States
c Geriatric Research, Education and Clinical Care Center, VA Ann Arbor Health System, Ann Arbor, MI, United States
d A. Alfred Taubman Medical Research Institute, University of Michigan, Ann Arbor, MI, United States
e Department of Basic Sciences, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND, United States
f Renovo Neural, Inc, Cleveland, OH, United States
g Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO, United States


Abstract
Amyotrophic lateral sclerosis is a late-onset and terminal neurodegenerative disease. The majority of cases are sporadic with unknown causes and only a small number of cases are genetically linked. Recent evidence suggests that post-transcriptional regulation and epigenetic mechanisms, such as microRNAs, underlie the onset and progression of neurodegenerative disorders; therefore, altered microRNA expression may result in the dysregulation of key genes and biological pathways that contribute to the development of sporadic amyotrophic lateral sclerosis. Using systems biology analyses on postmortem human spinal cord tissue, we identified dysregulated mature microRNAs and their potential targets previously implicated in functional process and pathways associated with the pathogenesis of ALS. Furthermore, we report a global reduction of mature microRNAs, alterations in microRNA processing, and support for a role of the nucleotide binding protein, TAR DNA binding protein 43, in regulating sporadic amyotrophic lateral sclerosis-associated microRNAs, thereby offering a potential underlying mechanism for sporadic amyotrophic lateral sclerosis. © 2015 Elsevier Inc.


Author Keywords
Amyotrophic lateral sclerosis;  Epigenetics;  MicroRNA


Document Type: Article
Source: Scopus




Brown W.J.a , Bruce S.E.a b , Buchholz K.R.a , Artime T.M.c , Hu E.a , Sheline Y.I.b 
Affective Dispositions and PTSD Symptom Clusters in Female Interpersonal Trauma Survivors
(2016) Journal of Interpersonal Violence, 31 (3), pp. 407-424. 

DOI: 10.1177/0886260514555866


a University of Missouri–St. LouisMO, United States
b Washington University, St. Louis, MO, United States
c Saint Martin’s University, Lacey, WA, United States


Abstract
Interpersonal trauma (IPT) against women can have dire psychological consequences including persistent maladaptive changes in the subjective experience of affect. Contemporary literature has firmly established heightened negative affect (NA) as a risk and maintenance factor for posttraumatic stress disorder (PTSD). However, the relationship between NA and PTSD symptoms is not well understood within IPT survivors, the majority of whom are female, as much of this research has focused on combat veterans. In addition, the connection between positive affect (PA) and PTSD symptoms has yet to be examined. With increased emphasis on “negative alterations in cognitions and mood..” as an independent symptom cluster of PTSD in the Diagnostic and Statistical Manual of Mental Disorders (5th ed.; DSM-5), understanding the relationship between self-reported affectivity and the classic PTSD symptom clusters may be increasingly useful in differentiating symptom presentations of trauma-related psychopathology. The current study directly compared self-reported trait NA and PA with total severity and frequency cluster scores from the Clinician-Administered PTSD Scale (CAPS) in 54 female survivors of IPT who met criteria for PTSD. Results identify NA (but not PA) as a consistent predictor of total PTSD symptoms and, specifically, re-experiencing symptoms. © 2014, © The Author(s) 2014.


Author Keywords
affect;  interpersonal trauma;  PTSD


Document Type: Article
Source: Scopus




Sheffield J.M.a , Barch D.M.a b c 
Cognition and resting-state functional connectivity in schizophrenia
(2016) Neuroscience and Biobehavioral Reviews, 61, pp. 108-120. 

DOI: 10.1016/j.neubiorev.2015.12.007


a Washington University in St Louis, Department of Psychology, 1 Brookings Drive, St Louis, MO, United States
b Washington University in St Louis, Department of Psychiatry, 4940 Childrens Place, St Louis, MO, United States
c Washington University in St Louis, Department of Radiology, 224 Euclid Ave, St Louis, MO, United States


Abstract
Individuals with schizophrenia consistently display deficits in a multitude of cognitive domains, but the neurobiological source of these cognitive impairments remains unclear. By analyzing the functional connectivity of resting-state functional magnetic resonance imaging (rs-fcMRI) data in clinical populations like schizophrenia, research groups have begun elucidating abnormalities in the intrinsic communication between specific brain regions, and assessing relationships between these abnormalities and cognitive performance in schizophrenia. Here we review studies that have reported analysis of these brain-behavior relationships. Through this systematic review we found that patients with schizophrenia display abnormalities within and between regions comprising (1) the cortico-cerebellar-striatal-thalamic loop and (2) task-positive and task-negative cortical networks. Importantly, we did not observe unique relationships between specific functional connectivity abnormalities and distinct cognitive domains, suggesting that the observed functional systems may underlie mechanisms that are shared across cognitive abilities, the disturbance of which could contribute to the "generalized" cognitive deficit found in schizophrenia. We also note several areas of methodological change that we believe will strengthen this literature. © 2015 Elsevier Ltd.


Author Keywords
Cognition;  Cognitive dysmetria;  Default mode network;  Executive functioning;  Functional brain networks;  Functional connectivity;  Generalized cognitive deficit;  Go/NoGo;  IQ;  Reinforcement learning;  Resting-state fMRI;  Schizophrenia;  Task-positive networks


Document Type: Review
Source: Scopus




King N.O.a b , Anderson C.J.a , Dorval A.D.a 
Deep brain stimulation exacerbates hypokinetic dysarthria in a rat model of Parkinson's disease
(2016) Journal of Neuroscience Research, 94 (2), pp. 128-138. 

DOI: 10.1002/jnr.23679


a Department of Bioengineering, University of Utah, Salt Lake City, UT, United States
b Department of Biomedical Engineering, Washington University, St. Louis, MO, United States


Abstract
Motor symptoms of Parkinson's disease (PD) follow the degeneration of dopaminergic neurons in the substantia nigra pars compacta. Deep brain stimulation (DBS) treats some parkinsonian symptoms, such as tremor, rigidity, and bradykinesia, but may worsen certain medial motor symptoms, including hypokinetic dysarthria. The mechanisms by which DBS exacerbates dysarthria while improving other symptoms are unclear and difficult to study in human patients. This study proposes an animal model of DBS-exacerbated dysarthria. We use the unilateral, 6-hydroxydopamine (6-OHDA) rat model of PD to test the hypothesis that DBS exacerbates quantifiable aspects of vocalization. Mating calls were recorded from sexually experienced male rats under healthy and parkinsonian conditions and during DBS of the subthalamic nucleus. Relative to healthy rats, parkinsonian animals made fewer calls with shorter and less complex vocalizations. In the parkinsonian rats, putatively therapeutic DBS further reduced call frequency, duration, and complexity. The individual utterances of parkinsonian rats spanned a greater bandwidth than those of healthy rats, potentially reducing the effectiveness of the vocal signal. This utterance bandwidth was further increased by DBS. We propose that the parkinsonism-associated changes in call frequency, duration, complexity, and dynamic range combine to constitute a rat analog of parkinsonian dysarthria. Because DBS exacerbates the parkinsonism-associated changes in each of these metrics, the subthalamic stimulated 6-OHDA rat is a good model of DBS-induced hypokinetic dysarthria in PD. This model will help researchers examine how DBS alleviates many motor symptoms of PD while exacerbating parkinsonian speech deficits that can greatly diminish patient quality of life. © 2016 Wiley Periodicals, Inc.


Author Keywords
Deep brain stimulation;  Dysarthria;  Hypokinesia;  Parkinson's disease


Document Type: Article
Source: Scopus




Gyawali C.P.
Achalasia: New perspectives on an old disease
(2016) Neurogastroenterology and Motility, 28 (1), pp. 4-11. 

DOI: 10.1111/nmo.12750


Division of Gastroenterology, Washington University School of Medicine, St. Louis, MO, United States


Abstract
Achalasia is defined by esophageal outflow obstruction from abnormal relaxation of the lower esophageal sphincter (LES) due to deranged inhibitory control. In genetically predisposed individuals, an autoimmune response to an unknown inciting agent, perhaps a viral infection, results in inflammation and sometimes loss of myenteric plexus ganglia and neurons. The net result is varying degrees of inhibitory dysfunction, at times associated with imbalanced and exaggerated excitatory function, with manometrically distinct achalasia phenotypes on high resolution manometry. There is new evidence in the current issue of this Journal suggesting that type 1 achalasia, with esophageal outflow obstruction and absent esophageal body contractility, is an end-stage phenotype from progression of type 2 achalasia, which is characterized by panesophageal compartmentalization of pressure in the untreated patient, and partial recovery of peristalsis after treatment. Esophageal outflow obstruction with premature peristalsis (type 3 achalasia) or intact peristalsis may result from plexitis in the myenteric plexus but can also be encountered in other settings including chronic opioid medication usage and structural processes at the esophagogastric junction and distally. In most instances when idiopathic esophageal outflow obstruction is confirmed, some form of pharmacologic manipulation or disruption of the LES provides durable symptom relief. This review will focus on current understanding of pathophysiology, diagnosis, and principles of management of achalasia in light of emerging literature on the topic. © 2015 John Wiley & Sons Ltd.


Author Keywords
Achalasia;  Esophageal outflow obstruction;  High resolution manometry


Document Type: Short Survey
Source: Scopus




Ward C.M.a , Rogers C.S.a , Van Engen K.J.b , Peelle J.E.a 
Effects of Age, Acoustic Challenge, and Verbal Working Memory on Recall of Narrative Speech
(2016) Experimental Aging Research, 42 (1), pp. 126-144. Cited 1 time.

DOI: 10.1080/0361073X.2016.1108785


a Department of Otolaryngology, Washington University in St. Louis, 660 South Euclid, St. Louis, MO, United States
b Department of Psychology, Washington University in St. Louis, St. Louis, MO, United States


Abstract
A common goal during speech comprehension is to remember what we have heard. Encoding speech into long-term memory frequently requires processes such as verbal working memory that may also be involved in processing degraded speech. Here the authors tested whether young and older adult listeners memory for short stories was worse when the stories were acoustically degraded, or whether the additional contextual support provided by a narrative would protect against these effects. Methods: The authors tested 30 young adults (aged 18-28 years) and 30 older adults (aged 65-79 years) with good self-reported hearing. Participants heard short stories that were presented as normal (unprocessed) speech or acoustically degraded using a noise vocoding algorithm with 24 or 16 channels. The degraded stories were still fully intelligible. Following each story, participants were asked to repeat the story in as much detail as possible. Recall was scored using a modified idea unit scoring approach, which included separately scoring hierarchical levels of narrative detail.Results: Memory for acoustically degraded stories was significantly worse than for normal stories at some levels of narrative detail. Older adults memory for the stories was significantly worse overall, but there was no interaction between age and acoustic clarity or level of narrative detail. Verbal working memory (assessed by reading span) significantly correlated with recall accuracy for both young and older adults, whereas hearing ability (better ear pure tone average) did not.Conclusion: The present findings are consistent with a framework in which the additional cognitive demands caused by a degraded acoustic signal use resources that would otherwise be available for memory encoding for both young and older adults. Verbal working memory is a likely candidate for supporting both of these processes. © Taylor and Francis Group, LLC.


Document Type: Conference Paper
Source: Scopus




Fritz B.A.a , Kalarickal P.L.a , Maybrier H.R.a , Muench M.R.a , Dearth D.a , Chen Y.a , Escallier K.E.a , Ben Abdallah A.a , Lin N.b , Avidan M.S.a 
Intraoperative Electroencephalogram Suppression Predicts Postoperative Delirium
(2016) Anesthesia and Analgesia, 122 (1), pp. 234-242. 

DOI: 10.1213/ANE.0000000000000989


a Department of Anesthesiology, Washington University, School of Medicine, 660 S. Euclid Ave., St. Louis, MO, United States
b Department of Mathematics, Washington University, St. Louis, MO, United States


Abstract
BACKGROUND: Postoperative delirium is a common complication associated with increased morbidity and mortality, longer hospital stays, and greater health care expenditures. Intraoperative electroencephalogram (EEG) slowing has been associated previously with postoperative delirium, but the relationship between intraoperative EEG suppression and postoperative delirium has not been investigated. METHODS: In this observational cohort study, 727 adult patients who received general anesthesia with planned intensive care unit admission were included. Duration of intraoperative EEG suppression was recorded from a frontal EEG channel (FP1 to F7). Delirium was assessed twice daily on postoperative days 1 through 5 with the Confusion Assessment Method for the intensive care unit. Thirty days after surgery, quality of life, functional independence, and cognitive ability were measured using the Veterans RAND 12-item survey, the Barthel index, and the PROMIS Applied Cognition-Abilities-Short Form 4a survey. RESULTS: Postoperative delirium was observed in 162 (26%) of 619 patients assessed. When we compared patients with no EEG suppression with those divided into quartiles based on duration of EEG suppression, patients with more suppression were more likely to experience delirium (χ2(4) = 25, P &lt; 0.0001). This effect remained significant after we adjusted for potential confounders (odds ratio for log(EEG suppression) 1.22 [99% confidence interval, 1.06-1.40, P = 0.0002] per 1-minute increase in suppression). EEG suppression may have been associated with reduced functional independence (Spearman partial correlation coefficient-0.15, P = 0.02) but not with changes in quality of life or cognitive ability. Predictors of EEG suppression included greater end-tidal volatile anesthetic concentration and lower intraoperative opioid dose. CONCLUSIONS: EEG suppression is an independent risk factor for postoperative delirium. Future studies should investigate whether anesthesia titration to minimize EEG suppression decreases the incidence of postoperative delirium. This is a substudy of the Systematic Assessment and Targeted Improvement of Services Following Yearlong Surgical Outcomes Surveys (SATISFY-SOS) surgical outcomes registry (NCT02032030). © 2015 International Anesthesia Research Society.


Document Type: Article
Source: Scopus




Peelle J.E.
Introduction to Special Issue on Age, Hearing, and Speech Comprehension
(2016) Experimental Aging Research, 42 (1), pp. 1-3. 

DOI: 10.1080/0361073X.2016.1108714


Department of Otolaryngology, Washington University in St. Louis, 660 South Euclid, St. Louis, MO, United States


Document Type: Conference Paper
Source: Scopus




Nemanich S.T.a , Earhart G.M.a b c 
Reduced after-effects following podokinetic adaptation in people with Parkinson's disease and freezing of gait
(2016) Parkinsonism and Related Disorders, 22, pp. 93-97. 

DOI: 10.1016/j.parkreldis.2015.11.024


a Washington University School of Medicine in St. Louis, 4444 Forest Park Ave., Campus Box 8502, St. Louis, MO, United States
b Department of Anatomy and Neurobiology, Washington University School of Medicine in St. Louis, 660S. Euclid Ave., Campus Box 8108, St. Louis, MO, United States
c Department of Neurology, Washington University School of Medicine in St. Louis, 660S. Euclid Ave., Campus Box 8111, St. Louis, MO, United States


Abstract
Introduction: Gait dysfunction is common in people with Parkinson's disease (PD). Freezing of gait (FOG) is one such gait disturbance that significantly impacts mobility and quality of life in PD. Recent evidence suggests that cerebellar connectivity may differ in people with PD and FOG (PD+FOG) relative to those without FOG (PD-FOG). Investigation of gait adaptation, or the ability to change gait patterns in response to external perturbations, is cerebellum-dependent, is a practical means of probing cerebellar integrity and may provide additional insights regarding the FOG phenomenon. Methods: In this study, we investigated gait adaptation in PD and FOG by measuring after-effects, namely whole-body rotation, following stepping on a rotating disc in PD+FOG compared to PD-FOG and older healthy adults. We refer to the period of stepping on the rotating disc as the podokinetic (PK) stimulation and after-effects as podokinetic after-rotation (PKAR). Our primary measure of adaptation was the magnitude and rate of decay of the after-effects. Results: We noted that PKAR was diminished in PD+FOG compared to the other groups, indicating reduced storage of the adapted gait pattern in PD+FOG. In the PD groups, FOG explained about 20% of the variability in peak velocity. Furthermore, these differences were independent of stepping cadence or motor sign severity. Conclusion: Our results show that gait adaptation is impaired in PD+FOG, suggesting the cerebellum may be differentially impacted in PD+FOG compared to PD-FOG. This supports previous neuroimaging evidence of cerebellar dysfunction in PD+FOG. Overall, these data further our understanding of gait deficits in PD+FOG. © 2015 Elsevier Ltd.


Author Keywords
After-effects;  Freezing of gait;  Locomotor adaptation;  Parkinson disease


Document Type: Article
Source: Scopus




Ning B.a , Sun N.a , Cao R.a , Chen R.b , Shung K.K.b , Hossack J.A.a , Lee J.-M.c , Zhou Q.b , Hu S.a 
Ultrasound-aided Multi-parametric Photoacoustic Microscopy of the Mouse Brain
(2015) Scientific Reports, 5, art. no. 18775, . 

DOI: 10.1038/srep18775


a Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, United States
b Department of Biomedical Engineering, University of Southern California, Los Angeles, CA, United States
c Department of Neurology, Washington University, School of Medicine, St. Louis, MO, United States


Abstract
High-resolution quantitative imaging of cerebral oxygen metabolism in mice is crucial for understanding brain functions and formulating new strategies to treat neurological disorders, but remains a challenge. Here, we report on our newly developed ultrasound-aided multi-parametric photoacoustic microscopy (PAM), which enables simultaneous quantification of the total concentration of hemoglobin (CHb), the oxygen saturation of hemoglobin (sO2), and cerebral blood flow (CBF) at the microscopic level and through the intact mouse skull. The three-dimensional skull and vascular anatomies delineated by the dual-contrast (i.e., ultrasonic and photoacoustic) system provide important guidance for dynamically focused contour scan and vessel orientation-dependent correction of CBF, respectively. Moreover, bi-directional raster scan allows determining the direction of blood flow in individual vessels. Capable of imaging all three hemodynamic parameters at the same spatiotemporal scale, our ultrasound-aided PAM fills a critical gap in preclinical neuroimaging and lays the foundation for high-resolution mapping of the cerebral metabolic rate of oxygen (CMRO2) - a quantitative index of cerebral oxygen metabolism. This technical innovation is expected to shed new light on the mechanism and treatment of a broad spectrum of neurological disorders, including Alzheimer's disease and ischemic stroke.


Document Type: Article
Source: Scopus




Escott-Price V.a , Sims R.a , Bannister C.a , Harold D.b , Vronskaya M.a , Majounie E.a , Badarinarayan N.a , Morgan K.c , Passmore P.d , Holmes C.e , Powell J.f , Brayne C.g , Gill M.h , Mead S.i , Goate A.j , Cruchaga C.k , Lambert J.-C.l m n , Van Duijn C.o , Maier W.p q , Ramirez A.p r , Holmans P.a , Jones L.a , Hardy J.s , Seshadri S.t , Schellenberg G.D.u , Amouyel P.l m n v , Williams J.a 
Common polygenic variation enhances risk prediction for Alzheimer's disease
(2015) Brain, 138 (12), pp. 3673-3684. Cited 1 time.

DOI: 10.1093/brain/awv268


a Institute of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, United Kingdom
b School of Medicine, Trinity College Dublin, College Green, Dublin, 2, Ireland
c Institute of Genetics, Queens Medical Centre, University of Nottingham, United Kingdom
d Ageing Group, Centre for Public Health, School of Medicine, Dentistry and Biomedical Sciences, Queens University Belfast, United Kingdom
e Division of Clinical Neurosciences, School of Medicine, University of Southampton, Southampton, United Kingdom
f Kings College London, Institute of Psychiatry, Department of Neuroscience, De Crespigny Park, Denmark Hill, London, United Kingdom
g Institute of Public Health, University of Cambridge, Cambridge, United Kingdom
h Mercers Institute for Research on Aging, St. James Hospital and Trinity College, Dublin, Ireland
i MRC Prion Unit, Department of Neurodegenerative Disease, UCL Institute of Neurology, London, United Kingdom
j Neuroscience Department, Icahn School of Medicine at Mount Sinai, New York, United States
k Departments of Psychiatry, Neurology and Genetics, Washington University School of Medicine, St Louis, MO, United States
l Inserm U744, Lille, France
m Université Lille 2, Lille, France
n Institut Pasteur de Lille, Lille, France
o Department of Epidemiology, Erasmus Medical Centre, Rotterdam, Netherlands
p Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany
q German Centre for Neurodegenerative Diseases (DZNE), Bonn, Germany
r Institute of Human Genetics, University of Bonn, Bonn, Germany
s Department of Molecular Neuroscience, Reta Lilla Weston Laboratories, Institute of Neurology, London, United Kingdom
t Department of Neurology, Boston University School of Medicine, Boston, MA, United States
u Department of Pathology and Laboratory Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, United States
v Centre Hospitalier Régional, Universitaire de Lille, Lille, France


Abstract
The identification of subjects at high risk for Alzheimer's disease is important for prognosis and early intervention. We investigated the polygenic architecture of Alzheimer's disease and the accuracy of Alzheimer's disease prediction models, including and excluding the polygenic component in the model. This study used genotype data from the powerful dataset comprising 17 008 cases and 37 154 controls obtained from the International Genomics of Alzheimer's Project (IGAP). Polygenic score analysis tested whether the alleles identified to associate with disease in one sample set were significantly enriched in the cases relative to the controls in an independent sample. The disease prediction accuracy was investigated in a subset of the IGAP data, a sample of 3049 cases and 1554 controls (for whom APOE genotype data were available) by means of sensitivity, specificity, area under the receiver operating characteristic curve (AUC) and positive and negative predictive values. We observed significant evidence for a polygenic component enriched in Alzheimer's disease (P = 4.9 × 10-26). This enrichment remained significant after APOE and other genome-wide associated regions were excluded (P = 3.4 × 10-19). The best prediction accuracy AUC = 78.2% (95% confidence interval 77-80%) was achieved by a logistic regression model with APOE, the polygenic score, sex and age as predictors. In conclusion, Alzheimer's disease has a significant polygenic component, which has predictive utility for Alzheimer's disease risk and could be a valuable research tool complementing experimental designs, including preventative clinical trials, stem cell selection and high/low risk clinical studies. In modelling a range of sample disease prevalences, we found that polygenic scores almost doubles case prediction from chance with increased prediction at polygenic extremes.


Author Keywords
Alzheimer's disease;  polygenic score;  predictive model


Document Type: Article
Source: Scopus




Marquardt L.M.a , Ee X.b , Iyer N.a , Hunter D.b , Mackinnon S.E.b , Wood M.D.b , Sakiyama-Elbert S.E.a b b 
Finely Tuned Temporal and Spatial Delivery of GDNF Promotes Enhanced Nerve Regeneration in a Long Nerve Defect Model
(2015) Tissue Engineering - Part A, 21 (23-24), pp. 2852-2864. 

DOI: 10.1089/ten.tea.2015.0311


a Department of Biomedical Engineering, Washington University in St. Louis, 1097 Brookings Drive, St. Louis, MO, United States
b Divison of Plastic and Reconstructive Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, MO, United States


Abstract
The use of growth factors, such as glial cell line-derived neurotrophic factor (GDNF), for the treatment of peripheral nerve injury has been useful in promoting axon survival and regeneration. Unfortunately, finding a method that delivers the appropriate spatial and temporal release profile to promote functional recovery has proven difficult. Some release methods result in burst release profiles too short to remain effective over the regeneration period; however, prolonged exposure to GDNF can result in axonal entrapment at the site of release. Thus, GDNF was delivered in both a spatially and temporally controlled manner using a two-phase system comprised of an affinity-based release system and conditional lentiviral GDNF overexpression from Schwann cells (SCs). Briefly, SCs were transduced with a tetracycline-inducible (Tet-On) GDNF overexpressing lentivirus before transplantation. Three-centimeter acellular nerve allografts (ANAs) were modified by injection of a GDNF-releasing fibrin scaffold under the epineurium and then used to bridge a 3 cm sciatic nerve defect. To encourage growth past the ANA, GDNF-SCs were transplanted into the distal nerve and doxycycline was administered for 4, 6, or 8 weeks to determine the optimal duration of GDNF expression in the distal nerve. Live imaging and histomorphometric analysis determined that 6 weeks of doxycycline treatment resulted in enhanced regeneration compared to 4 or 8 weeks. This enhanced regeneration resulted in increased gastrocnemius and tibialis anterior muscle mass for animals receiving doxycycline for 6 weeks. The results of this study demonstrate that strategies providing spatial and temporal control of delivery can improve axonal regeneration and functional muscle reinnervation. © Mary Ann Liebert, Inc. 2015.


Document Type: Article
Source: Scopus




Vo K.D.a , Yoo A.J.b , Gupta A.c , Qiao Y.d , Vagal A.S.e , Hirsch J.A.f , Yousem D.M.g , Lum C.h 
Multimodal diagnostic imaging for hyperacute stroke
(2015) American Journal of Neuroradiology, 36 (12), pp. 2206-2213. 

DOI: 10.3174/ajnr.A4530


a Mallinckrodt Institute of Radiology, Washington University School of Medicine, 510 South Kingshighway Blvd, St. Louis, MO, United States
b Division of Neurointervention, Texas Stroke Institute, Plano, TX, United States
c Department of Radiology, Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY, United States
d Department of Radiology, Johns Hopkins School of Medicine, Baltimore, MD, United States
e Department of Radiology, University of Cincinnati Medical Center, Cincinnati, OH, United States
f NeuroInterventional Radiology, Massachusetts General Hospital, Boston, MA, United States
g Department of Radiology, Johns Hopkins Medical Institution, Baltimore, MD, United States
h Interventional Neuroradiology, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, ON, Canada


Abstract
In April 2015, the American Roentgen Ray Society and the American Society of Neuroradiology cosponsored a unique program designed to evaluate the state of the art in the imaging work-up of acute stroke. This topic has grown in importance because of the recent randomized controlled trials demonstrating the clear efficacy of endovascular stroke treatment. The authors, who were participants in that symposium, will highlight the points of emphasis in this article.


Document Type: Review
Source: Scopus




Mamah D.a , Wen J.b , Luo J.b , Ulrich X.b , Barch D.M.a c d , Yablonskiy D.b 
Subcomponents of brain T2* relaxation in schizophrenia, bipolar disorder and siblings: A Gradient Echo Plural Contrast Imaging (GEPCI) study
(2015) Schizophrenia Research, . Article in Press. 

DOI: 10.1016/j.schres.2015.10.004


a Department of Psychiatry, Washington University Medical School, St. Louis, United States
b Department of Radiology, Washington University Medical School, St. Louis, United States
c Department of Psychology, Washington University in St. Louis, United States
d Department of Anatomy and Neurobiology, Washington University in St. Louis, United States


Abstract
Investigating brain tissue T2* relaxation properties in vivo can potentially guide the uncovering of neuropathology in psychiatric illness, which is traditionally examined post mortem. We use an MRI-based Gradient Echo Plural Contrast Imaging (GEPCI) technique that produces inherently co-registered images allowing quantitative assessment of tissue cellular and hemodynamic properties. Usually described as R2* (=1/T2*) relaxation rate constant, recent developments in GEPCI allow the separation of cellular-specific (R2*C) and hemodynamic (BOLD) contributions to the MRI signal decay. We characterize BOLD effect in terms of tissue concentration of deoxyhemoglobin, i.e. CDEOXY, which reflects brain activity. 17 control (CON), 17 bipolar disorder (BPD), 16 schizophrenia (SCZ), and 12 unaffected schizophrenia sibling (SIB) participants were scanned and post-processed using GEPCI protocols. A MANOVA of 38gray matter regions ROIs showed significant group effects for CDEOXY but not for R2*C. In the three non-control groups, 71-92% of brain regions had increased CDEOXY. Group effects were observed in the superior temporal cortex and the thalamus. Increased superior temporal cortex CDEOXY was found in SCZ (p=0.01), BPD (p=0.01) and SIB (p=0.02), with bilateral effects in SCZ and only left hemisphere effects in BPD and SIB. Thalamic CDEOXY abnormalities were observed in SCZ (p=0.003), BPD (p=0.03) and SIB (p=0.02). Our results suggest that increased activity in certain brain regions is part of the underlying pathophysiology of specific psychiatric disorders. High CDEOXY in the superior temporal cortex suggests abnormal activity with auditory, language and/or social cognitive processing. Larger studies are needed to clarify the clinical significance of relaxometric abnormalities. © 2015 Elsevier B.V.


Author Keywords
Bipolar;  Brain;  GEPCI;  MRI;  Relaxometry;  Schizophrenia;  Siblings;  T2


Document Type: Article in Press
Source: Scopus




Sartor C.E.a b , Grant J.D.b , Agrawal A.b , Sadler B.a b b , Madden P.A.F.b , Heath A.C.b , Bucholz K.K.b 
Genetic and environmental contributions to initiation of cigarette smoking in young African-American and European-American women
(2015) Drug and Alcohol Dependence, . Article in Press. 

DOI: 10.1016/j.drugalcdep.2015.10.002


a Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA
b Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA


Abstract
Background: Distinctions in the relative contributions of genetic and environmental factors to initiation of cigarette smoking may explain, in part, the differences between African Americans and European Americans in the prevalence of smoking. The current investigation is the first to compare heritable and environmental influences on smoking initiation between African-American and European-American women. Methods: Data were drawn from Missouri Adolescent Female Twin Study participants and female Missouri Family Study participants (n = 4498; 21% African-American, the remainder European-American). Mean ages at first and last assessments were 17.0 (SD. = 3.5) and 24.0 (SD. = 3.2), respectively. Twin-sibling modeling was conducted to estimate the proportion of variance in smoking initiation (i.e., ever trying a cigarette) attributable to additive genetic, shared environmental, special twin environmental, and unique environmental factors. Results: Additive genetic influences accounted for approximately half of the variance in smoking initiation in both African-American and European-American women. In the African-American subsample, the remaining variance was attributable primarily to unique environmental factors (46%; 95% CI: 28-71%). In the European-American subsample, only 12% (95% CI: 8-16%) of the variance was attributable to unique environmental factors, with the remainder accounted for by shared environmental (13%; 95% CI: 0-41%) and special twin environmental (24%; 95% CI: 0-52%) factors. Conclusions: The estimated heritability of smoking initiation is substantial and nearly identical for African-American and European-American women, but the type of environmental factors that contribute to risk differ by race/ethnicity. Whereas the primary environmental influences on European-American women's smoking initiation are at the family level, those that impact African-American women's smoking initiation are primarily individual-specific. © 2015 Elsevier Ireland Ltd.


Author Keywords
African Americans;  Smoking;  Twins;  Women


Document Type: Article in Press
Source: Scopus




Tajdaran K.a b , Gordon T.a d e , Wood M.D.f , Shoichet M.S.b c , Borschel G.H.a b d e 
A glial cell line-derived neurotrophic factor delivery system enhances nerve regeneration across acellular nerve allografts
(2015) Acta Biomaterialia, . Article in Press. 

DOI: 10.1016/j.actbio.2015.10.001


a Division of Plastic and Reconstructive Surgery, The Hospital for Sick Children, 555 University Ave, Toronto, Ontario M5G1X8, Canada
b Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada
c Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, Ontario, Canada
d Division of Plastic and Reconstructive Surgery, Department of Surgery, University of Toronto, Toronto, Ontario, Canada
e Program in Neuroscience, The Hospital for Sick Children Research Institute, Toronto, Ontario, Canada
f Division of Plastic and Reconstructive Surgery, Washington University School of Medicine, St. Louis, MO, USA


Abstract
Acellular nerve allografts (ANAs) are used clinically to bridge nerve gaps but these grafts, lacking Schwann cells and therapeutic levels of neurotrophic factors, do not support regeneration to the same extent as autografts. Here we investigated a local drug delivery system (DDS) for glial cell line-derived neurotrophic factor (GDNF) controlled release to implanted ANAs in rats using drug-loaded polymeric microspheres (MSs) embedded in a fibrin gel. In a rat hindlimb nerve gap model, a 10. mm ANA was used to bridge a 5. mm common peroneal (CP) nerve gap. Experimental groups received DDS treatment at both suture sites of the allografts releasing GDNF for either 2. weeks or 4. weeks. In negative control groups, rats received no DDS treatment or empty DDS. Rats receiving nerve isografts served as the positive control group. The numbers of motor and sensory neurons that regenerated their axons in all the groups with GDNF MS and isograft treatment were indistinguishable and significantly higher as compared to the negative control groups. Nerve histology distal to the nerve graft demonstrated increased axon counts and a shift to larger fiber diameters due to GDNF MS treatment. The sustained delivery of GDNF to the implanted ANA achieved in this study demonstrates the promise of this DDS for the management of severe nerve injuries in which allografts are placed. Statement of Significance: This work addresses the common clinical situation in which a nerve gap is bridged using acellular nerve allografts. However, these allografts are not as effective in supporting nerve regeneration as the gold standard method of autografting. The novel local drug delivery system used in this study provides sustained and controlled release of glial cell line-derived neurotrophic factor (GDNF), one of the most potent neurotrophic factors, which significantly improves nerve regeneration following severe nerve injuries. Results from this research will provide a mean of improving nerve allografts with locally delivered GDNF. This strategy may lead to a novel "off the shelf" alternative to the current management of severe nerve injuries. © 2015 Acta Materialia Inc.


Author Keywords
Acellular nerve allografts;  Biomaterials;  Drug delivery;  Fibrinogen;  Glial cell line-derived neurotrophic factor;  Nerve injury;  Poly(lactic-co-glycolic) acid;  Regenerative medicine


Document Type: Article in Press
Source: Scopus




Crapnell T.L.a , Woodward L.J.b , Rogers C.E.c d , Inder T.E.b , Pineda R.G.a c 
Neurodevelopmental Profile, Growth, and Psychosocial Environment of Preterm Infants with Difficult Feeding Behavior at Age 2 Years
(2015) Journal of Pediatrics, . Article in Press. 

DOI: 10.1016/j.jpeds.2015.09.022


a Program in Occupational Therapy, Washington University School of Medicine, St Louis, MO
b Department of Pediatric Newborn Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
c Department of Pediatrics, Washington University School of Medicine, St Louis, MO
d Department of Psychiatry, Washington University School of Medicine, St Louis, MO


Abstract
Objective: To examine the association of difficult feeding behaviors in very preterm infants at age 2 years with growth and neurodevelopmental outcomes and family factors and functioning. Study design: Eighty children born ≤30 weeks gestation were studied from birth until age 2 years. Feeding difficulties were assessed using the Eating Subscale of the Infant-Toddler Social Emotional Assessment at age 2 years, along with growth measurement and developmental testing. Maternal mental health and family factors were assessed using standardized questionnaires. ANOVA and χ2 analyses were performed to determine associations between feeding difficulties and growth, neurodevelopmental outcomes, and family characteristics. Results: Twenty-one children (26%) were at risk for feeding difficulties, and an additional 18 (23%) had definite feeding difficulties at age 2 years. Those with feeding difficulties were more likely to be subject to a range of neurodevelopmental problems, including impaired cognition (P = .02), language (P = .04), motor (P = .01), and socioemotional (P &lt; .007) skills. Compared with the parents of children with fewer feeding difficulties, parents of the children with feeding difficulties had higher parenting stress (P = .02) and reported more difficulty managing their child's behavior (P = .002) and more frequent parent-child interaction problems (P = .002). No associations were found between difficult feeding behaviors and growth, maternal mental health, or family factors. Conclusion: Difficult feeding behaviors in children born very preterm appear to be highly comorbid with other developmental and family challenges, including neurodevelopmental impairment and parent-child interaction difficulties. Focusing on improving feeding skills, in conjunction with supporting positive parent-child interactions, may be beneficial for improving outcomes. © 2015 Elsevier Inc.


Document Type: Article in Press
Source: Scopus




Davis A.A.a , Andruska K.M.a , Benitez B.A.b , Racette B.A.a c d , Perlmutter J.S.a c e f g , Cruchaga C.b c 
Variants in GBA, SNCA, and MAPT influence Parkinson disease risk, age at onset, and progression
(2015) Neurobiology of Aging, . Article in Press. 

DOI: 10.1016/j.neurobiolaging.2015.09.014


a Department of Neurology, Washington University, St. Louis, MO, USA
b Department of Psychiatry, Washington University, School of Medicine, St. Louis, MO, USA
c Hope Center Program on Protein Aggregation and Neurodegeneration, Washington University, St. Louis, MO, USA
d School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Parktown, South Africa
e Department of Radiology, Washington University, St. Louis, MO, USA
f Department of Anatomy and Neurobiology, Washington University, St. Louis, MO, USA
g Programs in Physical Therapy and Occupational Therapy, Washington University, St. Louis, MO, USA


Abstract
Multiple genetic variants have been linked to risk of Parkinson disease (PD), but known mutations do not explain a large proportion of the total PD cases. Similarly, multiple loci have been associated with PD risk by genome-wide association studies (GWAS). The influence that genetic factors confer on phenotypic diversity remains unclear. Few studies have been performed to determine whether the GWAS loci are also associated with age at onset (AAO) or motor progression. We used 2 PD case-control data sets (Washington University and the Parkinson's Progression Markers Initiative) to determine whether polymorphisms located at the GWAS top hits (GBA, ACMSD/TMEM163, STK39, MCCC1/LAMP3, GAK/TMEM175, SNCA, and MAPT) show association with AAO or motor progression. We found associations between single nucleotide polymorphisms at the GBA and MAPT loci and PD AAO and progression. These findings reinforce the complex genetic basis of PD and suggest that distinct genes and variants explain the genetic architecture of PD risk, onset, and progression. © 2015 Elsevier Inc.


Author Keywords
Age at onset;  GBA;  MAPT;  Motor progression;  Parkinson disease;  SNCA


Document Type: Article in Press
Source: Scopus




Cho Y.a c , Shin J.b , Ewan E.a , Oh Y.a , Pita-Thomas W.a , Cavalli V.a 
Activating Injury-Responsive Genes with Hypoxia Enhances Axon Regeneration through Neuronal HIF-1α
(2015) Neuron, . Article in Press. 

DOI: 10.1016/j.neuron.2015.09.050


a Department of Anatomy and Neurobiology, School of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA
b Department of Developmental Biology, School of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA
c School of Life Sciences and Biotechnology, Korea University, Seoul 136-701, Republic of Korea


Abstract
Injured peripheral neurons successfully activate a proregenerative transcriptional program to enable axon regeneration and functional recovery. How transcriptional regulators coordinate the expression of such program remains unclear. Here we show that hypoxia-inducible factor 1α (HIF-1α) controls multiple injury-induced genes in sensory neurons and contribute to the preconditioning lesion effect. Knockdown of HIF-1α in vitro or conditional knock out in vivo impairs sensory axon regeneration. The HIF-1α target gene Vascular Endothelial Growth Factor A (VEGFA) is expressed in injured neurons and contributes to stimulate axon regeneration. Induction of HIF-1α using hypoxia enhances axon regeneration in vitro and in vivo in sensory neurons. Hypoxia also stimulates motor neuron regeneration and accelerates neuromuscular junction re-innervation. This study demonstrates that HIF-1α represents a critical transcriptional regulator in regenerating neurons and suggests hypoxia as a tool to stimulate axon regeneration. Cho et al. show that HIF-1α controls multiple injury-induced genes in sensory neurons and contributes to stimulate axon regeneration. Induction of HIF-1α using hypoxia enhances axon regeneration in sensory neurons and stimulates motor neuron regeneration, accelerating neuromuscular junction reinnervation. © 2015 Elsevier Inc.


Document Type: Article in Press
Source: Scopus




Salpekar J.A.a , Joshi P.T.b c , Axelson D.A.e , Reinblatt S.P.a , Yenokyan G.d , Sanyal A.d , Walkup J.g , Vitiello B.i , Luby J.h , Wagner K.D.f , Nusrat N.b , Riddle M.A.a 
Depression and Suicidality Outcomes in the Treatment of Early Age Mania Study
(2015) Journal of the American Academy of Child and Adolescent Psychiatry, . Article in Press. 

DOI: 10.1016/j.jaac.2015.09.016


a Kennedy Krieger Institute and Johns Hopkins University School of Medicine, Baltimore
b Children's National Medical Center and George Washington University, Washington, DC
c American Academy of Child and Adolescent Psychiatry (AACAP) and with the American Board of Psychiatry and Neurology (ABPN)
d Johns Hopkins Biostatistics Center at Johns Hopkins Bloomberg School of Public Health
e Nationwide Children's Hospital and The Ohio State University, Columbus
f University of Texas Medical Branch at Galveston
g New York Presbyterian Hospital-Weill Cornell Medical College, New York
h Washington University in St. Louis
i Dr. Vitiello is with the National Institute of Mental Health (NIMH), Bethesda, MD


Abstract
Objective: To assess the efficacy of mood-stabilizing medications for depression and suicidality in pediatric bipolar disorder. Method: The Treatment of Early Age Mania (TEAM) study is a multicenter, prospective, randomized, masked comparison of divalproex sodium (VAL), lithium carbonate (LI), and risperidone (RISP) in an 8-week parallel clinical trial. A total of 279 children and adolescents with. DSM-IV diagnoses of bipolar I disorder, mixed or manic, aged 6 to 15 years were enrolled. The primary outcome measure was improvement on the Clinical Global Impression scale for depression (CGI-BP-I-D). Secondary outcome measures included the Children's Depression Rating Scale (CDRS-R) and suicidality status. Statistics included longitudinal analysis of outcomes using generalized linear mixed models with random intercept both for the complete data set and by using last observation carried forward. Results: CGI-BP-I-D ratings were better in the RISP group (60.7%) as compared to the LI (42.2%;. p = .03) or VAL (35.0%;. p = .003) groups from baseline to the end of the study. CDRS scores in all treatment groups improved equally by study end. In week 1, scores were lower with RISP compared to VAL (mean = 4.72, 95% CI = 2.67, 6.78), and compared to LI (mean = 3.63, 95% CI = 1.51, 5.74), although group differences were not present by the end of the study. Suicidality was infrequent, and there was no overall effect of treatment on suicidality ratings. Conclusion: Depressive symptoms, present in the acutely manic or mixed phase of pediatric bipolar disorder, improved with all 3 medications, though RISP appeared to yield more rapid improvement than LI or VAL and was superior using a global categorical outcome + Clinical trial registration information-Treatment of Early Age Mania;. http://www.clinicaltrials.gov;. NCT00057681. © 2015 American Academy of Child and Adolescent Psychiatry.


Author Keywords
Bipolar;  Clinical trial;  Depression;  Pediatrics;  Treatment


Document Type: Article in Press
Source: Scopus




Constantino J.N.a , Charman T.b 
Diagnosis of autism spectrum disorder: Reconciling the syndrome, its diverse origins, and variation in expression
(2015) The Lancet Neurology, . Article in Press. 

DOI: 10.1016/S1474-4422(15)00151-9


a Department of Psychiatry, Washington University in St Louis, St Louis, MO, USA
b Department of Psychology, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK


Abstract
Recent discoveries about the pathogenesis and symptom structure of autism spectrum disorders (ASDs) are challenging traditional nosology and driving efforts to reconceptualise the diagnosis of autism, a goal made all the more pressing by new prospects for early identification, targeted intervention, and personalised-medicine approaches to specific autistic syndromes. Recognition that ASD represents the severe end of a continuous distribution of social communication abilities in the general population has stimulated attempts to standardise the measurement of autistic traits and to set appropriate clinical thresholds for diagnosis. Over the next decade, rapid advances in our understanding of symptom structure and the diversity of causes of ASD could be incorporated into the next evolution in the diagnosis of autism, with important implications for research, clinical practice, public health, and policy. As differential effects of personalised therapies are identified in relation to specific causes of autism, the benefits of an updated diagnostic nosology will translate into the delivery of more effective care for patients. © 2015 Elsevier Ltd.


Document Type: Article in Press
Source: Scopus




Sylvester C.M.a , Barch D.M.a , Harms M.P.a , Belden A.C.a , Oakberg T.J.b , Gold A.L.c , White L.K.c , Benson B.E.c , Troller-Renfree S.d , Degnan K.A.d , Henderson H.A.e , Luby J.L.a , Fox N.A.d , Pine D.S.c 
Early Childhood Behavioral Inhibition Predicts Cortical Thickness in Adulthood
(2015) Journal of the American Academy of Child and Adolescent Psychiatry, . Article in Press. 

DOI: 10.1016/j.jaac.2015.11.007


a Washington University School of Medicine, St. Louis
b University of Colorado Denver
c National Institute of Mental Health (NIMH) Intramural Research Program, Bethesda, MD
d University of Maryland, College Park
e University of Waterloo, Waterloo, ON, Canada


Abstract
Objective: Behavioral inhibition (BI) during early childhood predicts risk for anxiety disorders and altered cognitive control in adolescence. Although BI has been linked to variation in brain function through adulthood, few studies have examined relations between early childhood BI and adult brain structure. Method: The relation between early childhood BI and cortical thickness in adulthood was examined in a cohort of individuals followed since early childhood (N = 53, mean age 20.5 years). Analyses tested whether anxiety and/or cognitive control during adolescence moderated relations between BI and cortical thickness. Cognitive control was measured with the Eriksen Flanker Task. Initial analyses examined cortical thickness in regions of interest previously implicated in BI, anxiety disorders, and cognitive control: dorsal anterior cingulate (dACC), anterior insula (aI), and subgenual anterior cingulate (sgACC); and volumes of the amygdala and hippocampus. Exploratory analyses examined relations across the prefrontal cortex. Results: BI during early childhood related to thinner dACC in adulthood. Neither anxiety nor cognitive control moderated this relation. A stronger congruency effect on the Eriksen Flanker Task during adolescence independently related to thinner dACC in adulthood. Higher anxiety during adolescence related to thicker cortex in the right ventrolateral prefrontal cortex (VLPFC) in adulthood among those with low BI as children. Conclusion: Temperament in early childhood and the interaction between temperament and later anxiety relate to adult brain structure. These results are consistent with prior work associating BI and anxiety with functional brain variability in the dACC and VLPFC. © 2015 American Academy of Child and Adolescent Psychiatry.


Author Keywords
Anxiety;  Behavioral inhibition;  Cingulate;  Cortical thickness;  Structural MRI


Document Type: Article in Press
Source: Scopus




Ben-Shahar Y.
Editorial overview: Neuroscience: How nervous systems generate behavior: Lessons from insects
(2015) Current Opinion in Insect Science, . Article in Press. 

DOI: 10.1016/j.cois.2015.10.005


Department of Biology, Washington University in St. Louis, MO 63130, USA


Document Type: Article in Press
Source: Scopus




Hochstein E.
Giving up on convergence and autonomy: Why the theories of psychology and neuroscience are codependent as well as irreconcilable
(2015) Studies in History and Philosophy of Science Part A, . Article in Press. 

DOI: 10.1016/j.shpsa.2015.10.001


Washington University, St. Louis, United States


Abstract
There is a long-standing debate in the philosophy of mind and philosophy of science regarding how best to interpret the relationship between neuroscience and psychology. It has traditionally been argued that either the two domains will evolve and change over time until they converge on a single unified account of human behaviour, or else that they will continue to work in isolation given that they identify properties and states that exist autonomously from one another (due to the multiple-realizability of psychological states). In this paper, I argue that progress in psychology and neuroscience is contingent on the fact that both of these positions are false. Contra the convergence position, I argue that the theories of psychology and the theories of neuroscience are scientifically valuable as representational tools precisely because they cannot be integrated into a single account. However, contra the autonomy position, I propose that the theories of psychology and neuroscience are deeply dependent on one another for further refinement and improvement. In this respect, there is an irreconcilable codependence between psychology and neuroscience that is necessary for both domains to improve and progress. The two domains are forever linked while simultaneously being unable to integrate. © 2015 Elsevier Ltd.


Author Keywords
Autonomy;  Convergence;  Idealization;  Neuroscience;  Psychology;  Theory reduction


Document Type: Article in Press
Source: Scopus




Stepan K.O.a , Sharma A.b , Chicoine M.R.c , Uppaluri R.a , Dahiya S.d 
Juvenile xanthogranuloma of supra-sellar region: A rare presentation
(2015) Clinical Neuropathology, 34 (6), pp. 368-370. 


a Department of Otolaryngology, Washington University School of Medicine, St. Louis, MO, United States
b Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States
c Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, United States
d Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States


Document Type: Letter
Source: Scopus

Montine T.J.a , Monsell S.E.b , Beach T.G.c , Bigio E.H.d e , Bu Y.b , Cairns N.J.f , Frosch M.g , Henriksen J.a , Kofler J.h , Kukull W.A.b , Lee E.B.i j k , Nelson P.T.l m , Schantz A.M.a , Schneider J.A.no p , Sonnen J.A.a , Trojanowski J.Q.i j k , Vinters H.V.q r , Zhou X.-H.b , Hyman B.T.s t

Multisite assessment of NIA-AA guidelines for the neuropathologic evaluation of Alzheimer's disease
(2015) Alzheimer's and Dementia, . Article in Press. 

DOI: 10.1016/j.jalz.2015.07.492


a Department of Pathology, University of Washington, Seattle, WA, USA
b National Alzheimer Coordinating Center, University of Washington, Seattle, WA, USA
c Banner Sun Health Research Institute, Civin Laboratory for Neuropathology, Sun City, AZ, USA
d Cognitive Neurology and Alzheimer's Disease Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
e Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
f Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA
g Department of Pathology, C.S. Kubik Laboratory for Neuropathology, Massachusetts General Hospital, Charleston, MA, USA
h Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA
i Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
j Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
k Institute on Aging, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
l Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA
m Pathology Department, University of Kentucky, Lexington, KY, USA
n Department of Pathology Rush University Medical Center, Chicago, IL, USA
o Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA
p Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA
q Department of Pathology and Laboratory Medicine (Neuropathology) David Geffen School of Medicine at UCLA, and Ronald Reagan UCLA Medical Center, Los Angeles, CA, USA
r Department of Neurology, David Geffen School of Medicine at UCLA, and Ronald Reagan UCLA Medical Center, Los Angeles, CA, USA
s Department of Neurology, Massachusetts General Hospital, Charleston, MA, USA
t Massachusetts Alzheimer's Disease Research Center, Massachusetts General Hospital, Charleston, MA, USA


Abstract
Introduction: Neuropathologic assessment is the current "gold standard" for evaluating the Alzheimer's disease (AD), but there is no consensus on the methods used. Methods: Fifteen unstained slides (8 brain regions) from each of the 14 cases were prepared and distributed to 10 different National Institute on Aging AD Centers for application of usual staining and evaluation following recently revised guidelines for AD neuropathologic change. Results: Current practice used in the AD Centers Program achieved robustly excellent agreement for the severity score for AD neuropathologic change (average weighted κ = .88, 95% confidence interval: 0.77-0.95) and good-to-excellent agreement for the three supporting scores. Some improvement was observed with consensus evaluation but not with central staining of slides. Evaluation of glass slides and digitally prepared whole-slide images was comparable. Discussion: AD neuropathologic evaluation as performed across AD Centers yields data that have high agreement with potential modifications for modest improvements. © 2015 The Alzheimer's Association.


Author Keywords
Alzheimer's disease;  Methods;  Multisite;  Neuropathology;  Whole-slide imaging

 


Document Type: Article in Press

  January 4, 2016

 Bandt S.K.a , Leuthardt E.C.a b c
Minimally Invasive Neurosurgery for Epilepsy Using Stereotactic MRI Guidance
(2016) Neurosurgery Clinics of North America, 27 (1), pp. 51-58. 

DOI: 10.1016/j.nec.2015.08.005


a Department of Neurological Surgery, Washington University School of Medicine, Campus Box 8057m 660 South Euclid Avenue, St Louis, MO, United States
b Department of Biomedical Engineering, Washington University, St Louis, MO, United States
c Center for Innovation in Neuroscience and Technology, Washington University School of Medicine, St Louis, MO, United States


Abstract
Medically refractory epilepsy is associated with significant morbidity and mortality. Surgery is a safe and effective option for some patients, however the opportunity exists to develop less invasive and more effective surgical options. To this end, multiple minimally invasive, image-guided techniques have been applied to the treatment of epilepsy. These techniques can be divided into thermoablative and disconnective techniques. Each has been described in the treatment of epilepsy only in small case series. Larger series and longer follow up periods will determine each option's place in the surgical armamentarium for the treatment of refractory epilepsy but early results are promising. © 2016 Elsevier Inc..


Author Keywords
Epilepsy surgery;  Laser ablation;  Medically refractory epilepsy;  Stereotactic guidance


Document Type: Review
Source: Scopus

 BRITO N.H.a , MURPHY E.R.b , VAIDYA C.c , BARR R.c
Do bilingual advantages in attentional control influence memory encoding during a divided attention task?*
(2015) Bilingualism, pp. 1-9. Article in Press. 

DOI: 10.1017/S1366728915000851


a Columbia University Medical Center
b Washington University in St. Louis
c Georgetown University


Abstract
The current study examined if bilingual advantages in cognitive control influence memory encoding during a divided attention task. Monolinguals, simultaneous bilinguals, and sequential bilinguals switched between classifying objects and words, then were tested for their recognition memory of stimuli previously seen during the classification task. Compared to bilingual groups, monolinguals made the most errors on the classification task and simultaneous bilinguals committed the fewest errors. On the memory task, however, no differences were found between the three language groups, but significant correlations were found between the number of errors during switch trials on the classification task and recognition memory for both target and non-target stimuli. For bilinguals, their age of second language acquisition partially accounted for the association between attentional control (number of switch errors) and subsequent memory for non-target stimuli only. These results contribute to our understanding of how individual differences in language acquisition influence interactions between cognitive domains. Copyright © Cambridge University Press 2015


Author Keywords
bilingualism;  cognitive control;  divided attention;  memory


Document Type: Article in Press
Source: Scopus

 Kung N.H.a , Bartlett N.L.b , Yaseen N.R.c , Van Stavern G.P.a d , Bucelli R.C.a
A young woman with blurred vision and distal paresthesias
(2015) JAMA Neurology, 72 (12), pp. 1519-1526. 

DOI: 10.1001/jamaneurol.2015.2390


a Department of Neurology, Washington University in St. Louis, 660 South Euclid Ave, St. Louis, MO, United States
b Division of Oncology, Department of Medicine, Washington University in St. Louis, St. Louis, MO, United States
c Department of Pathology and Immunology, Washington University in St. Louis, St. Louis, MO, United States
d Department of Ophthalmology, Washington University in St. Louis, St. Louis, MO, United States


Abstract
A 29-year-old woman presented with blurred vision and distal paresthesias. Her initial evaluation revealed severe bilateral optic disc edema with distal lower-extremity sensory and motor deficits and electrodiagnostic evidence of a length-dependent mixed demyelinating and axonal polyneuropathy. The results of routine diagnostic testing, including laboratory tests, magnetic resonance imaging, and lumbar puncture, were nondiagnostic. A targeted biopsy was ultimately required for diagnosis. In this article, we discuss the differential diagnosis and outline the clinical evaluation indicated for a patient presenting with demyelinating polyneuropathy and concurrent papilledema. Copyright 2015 American Medical Association. All rights reserved.


Document Type: Conference Paper
Source: Scopus

 Gooblar J.a , Roe C.M.b c , Selsor N.J.b , Gabel M.J.d , Morris J.C.b e f g
Attitudes of research participants and the general public regarding disclosure of Alzheimer disease research results
(2015) JAMA Neurology, 72 (12), pp. 1484-1490. 

DOI: 10.1001/jamaneurol.2015.2875


a Department of Psychology, Washington University in St. Louis, St. Louis, MO, United States
b Knight Alzheimer Disease Research Center, Washington University in St. Louis, 4488 Forest Park Ave, St. Louis, MO, United States
c Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
d Department of Political Science, Washington University in St. Louis, St. Louis, MO, United States
e Department of Pathology and Immunology, Washington University in St. Louis, St. Louis, MO, United States
f Department of Physical Therapy, Washington University in St. Louis, St. Louis, MO, United States
g Program in Occupational Therapy, Washington University in St. Louis, St. Louis, MO, United States


Abstract
IMPORTANCE: Results of Alzheimer disease (AD) research assessments typically are not disclosed to participants. Recent research has suggested interest in disclosure, but, to our knowledge, few studies have accounted for awareness of potential benefits and limitations of disclosure. OBJECTIVE: To determine the attitudes of cognitively normal research participants and members of the general public regarding disclosure of AD research results. DESIGN, SETTING, AND PARTICIPANTS: Participants in a longitudinal aging study (Alzheimer Disease Research Center [ADRC]) were given preintervention and postintervention surveys about disclosure attitudes. In a general public sample (The American Panel Survey), participants responded to a similar survey about disclosure attitudes. INTERVENTIONS: Participantsin the ADRC sample were randomly assigned to a group (n = 119) that read an education intervention about the usefulness of AD biomarkers or to a placebo group (n = 100) that read as its intervention general information about the ADRC. Participants in the general public sample read a brief vignette describing participation in a longitudinal AD study. MAINOUTCOME ANDMEASURE: Interest in disclosure of AD research results. RESULTS Cognitively normal ADRC participants (n = 219) were 60.7% (n = 133) female, 83.6% (n = 183) of white race, and reported a mean of 15.91 years of education. Twenty-nine individuals refused participation. The American Panel Survey participants (n = 1418) indicated they did not have AD and were 50.5% (n = 716) female, 76.7% (n = 1087) of white race, and reported a mean of 13.85 years of education. Overall, 77.6% of eligible participants (1583 of 2041) completed the survey in July 2014. Interest in disclosure was high among the ADRC participants (55.1% [119 of 216] were "extremely interested"). Viewing the education intervention predicted lower interest in disclosure (odds ratio, 2.01; 95% CI, 1.15-3.53; P = .02). High subjective risk of AD, a family history of AD, and minimal attendance at research meetings were associated with high interest after the intervention. In the general public, interest was lower overall (12.5% [174 of 1389] were "extremely interested"), but the subset of participants most likely to join an AD research study reported higher interest (43.5% [40 of 92] were extremely interested). CONCLUSIONS AND RELEVANCE: Experience with AD appears to increase interest in disclosure of AD research results. Learning about potential limitations of disclosure somewhat tempered interest. These findings should inform the development of disclosure policies for asymptomatic individuals in AD studies. Copyright 2015 American Medical Association. All rights reserved.


Document Type: Article
Source: Scopus

 Dai H.a , Milkman K.L.b , Riis J.c
Put Your Imperfections Behind You: Temporal Landmarks Spur Goal Initiation When They Signal New Beginnings
(2015) Psychological Science, 26 (12), pp. 1927-1936. 

DOI: 10.1177/0956797615605818


a Organizational Behavior Department, Olin Business School, Washington University in St. Louis, United States
b Operations, Information and Decisions Department, The Wharton School, University of Pennsylvania, United States
c Marketing Department, The Wharton School, University of Pennsylvania, United States


Abstract
People often fail to muster the motivation needed to initiate goal pursuit. Across five laboratory experiments, we explored occasions when people naturally experience enhanced motivation to take actions that facilitate goal pursuit and why certain dates are more likely to spur goal initiation than others. We present causal evidence that emphasizing a temporal landmark denoting the beginning of a new time period increases people’s intentions to initiate goal pursuit. In addition, we propose and show that people’s strengthened motivation to begin pursuing their aspirations following such temporal landmarks originates in part from the psychological disassociation these landmarks induce from a person’s past, imperfect self. © 2015, © The Author(s) 2015.


Author Keywords
goals;  mental accounting;  motivation;  multiple selves;  new beginnings;  open data;  open materials;  temporal landmarks


Document Type: Article
Source: Scopus

 Yaghi S.a b , Boehme A.K.a , Dibu J.c , Guerrero C.R.L.d , Ali S.d , Martin-Schild S.f , Sands K.A.g , Noorian A.R.e h , Blum C.A.i , Chaudhary S.j , Schwamm L.H.k , Liebeskind D.S.h , Marshall R.S.a , Willey J.Z.a
Treatment and outcome of thrombolysis-related hemorrhage: A multicenter retrospective study
(2015) JAMA Neurology, 72 (12), pp. 1451-1457. 

DOI: 10.1001/jamaneurol.2015.2371


a Department of Neurology, Columbia University Medical Center, New York, NY, United States
b Department of Neurology, Brown University, 593 Eddy St, Ambulatory Patient Center, Providence, RI, United States
c Department of Neurology, Cleveland Clinic Foundation, Cleveland, OH, United States
d Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
e Department of Neurology, University of Arkansas for Medical Sciences, Fayetteville, United States
f Department of Neurology, Tulane University, New Orleans, LA, United States
g Department of Neurology, University of Alabama at Birmingham, Birmingham, United States
h Department of Neurology, UCLA (University of California, Los Angeles), for the UCLA Acute Stroke Investigators, Los Angeles, United States
i Department of Neurology, Hospital of the University of Pennsylvania, Philadelphia, United States
j Department of Neurology, University of Oklahoma, Norman, United States
k Department of Neurology, Massachusetts General Hospital, Boston, United States


Abstract
IMPORTANCE: Treatments for symptomatic intracerebral hemorrhage (sICH) are based on expert opinion, with limited data available on efficacy. OBJECTIVE: To better understand the natural history of thrombolysis-related sICH, with a focus on the efficacy of various treatments used. DESIGN, SETTING, AND PARTICIPANTSL: Multicenter retrospective study between January 1, 2009, and April 30, 2014, at 10 primary and comprehensive stroke centers across the United States. Participants were all patients with sICH, using the definition by the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST), which included a parenchymal hematoma type 2 and at least a 4-point increase in the National Institutes of Health Stroke Scale score. MAIN OUTCOMES AND MEASURES: The primary outcome was in-hospital mortality, and the secondary outcome was hematoma expansion, definedas a33% increase inthe hematoma volume on follow-up imaging. RESULTS: Of 3894 patients treated with intravenous recombinant tissue plasminogen activator (rtPA) within 41/2 hours after symptom onset of ischemic stroke, 128 (3.3%) had sICH. The median time from initiation of rtPA therapy to sICH diagnosis was 470 minutes (range, 30-2572 minutes), and the median time from diagnosis to treatment of sICH was 112 minutes (range, 12-628 minutes). The in-hospital mortality rate was 52.3% (67 of 128), and 26.8% (22 of 82) had hematoma expansion. In the multivariable models, code status change to comfort measures after sICH diagnosis was the sole factor associated with increased in-hospital mortality (odds ratio, 3.6; 95% CI, 1.2-10.6). Severe hypofibrinogenemia (fibrinogen level, <150 mg/dL) was associated with hematoma expansion, occurring in 36.3% (8 of 22) of patients without hematoma expansion vs in 25.0% (15 of 60) of patients with hematoma expansion (P =.01), highlighting a role for cryoprecipitate in reversing rtPA coagulopathy. CONCLUSIONS AND RELEVANCE: In this study, treatment of postthrombolysis sICH did not significantly reduce the likelihood of in-hospital mortality or hematoma expansion. Shortening the time to diagnosis and treatment may be a key variable in improving outcomes of patients with sICH. Copyright 2015 American Medical Association. All rights reserved.


Document Type: Article
Source: Scopus

 Honda M.a g , Minami I.b , Tooi N.b , Morone N.b , Nishioka H.b , Uemura K.c , Kinoshita A.d , Heuser J.E.b e , Nakatsuji N.b f , Aiba K.a b
The modeling of Alzheimer's disease by the overexpression of mutant Presenilin 1 in human embryonic stem cells
(2015) Biochemical and Biophysical Research Communications, . Article in Press. 

DOI: 10.1016/j.bbrc.2015.12.025


a Stem Cell and Drug Discovery Institute, Kyoto 600-8813, Japan
b Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Kyoto 606-8501, Japan
c Department of Neurology, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan
d School of Human Health Sciences, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan
e Department of Cell Biology, Washington University, St. Louis, MO 63110, USA
f Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8507, Japan
g ReproCELL Inc., Yokohama, Kanagawa 222-0033, Japan


Abstract
Cellular disease models are useful tools for Alzheimer's disease (AD) research. Pluripotent stem cells, including human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs), are promising materials for creating cellular models of such diseases. In the present study, we established cellular models of AD in hESCs that overexpressed the mutant Presenilin 1 (PS1) gene with the use of a site-specific gene integration system. The overexpression of PS1 did not affect the undifferentiated status or the neural differentiation ability of the hESCs. We found increases in the ratios of amyloid-β 42 (Aβ42)/Aβ40 and Aβ43/Aβ40. Furthermore, synaptic dysfunction was observed in a cellular model of AD that overexpressed mutant PS1. These results suggest that the AD phenotypes, in particular, the electrophysiological abnormality of the synapses in our AD models might be useful for AD research and drug discovery. © 2015 The Authors.


Author Keywords
Alzheimer's disease;  Cellular disease model;  Human embryonic stem cell;  Presenilin 1;  Synaptic dysfunction


Document Type: Article in Press
Source: Scopus

 Hancock D.B.a , Levy J.L.b , Gaddis N.C.b , Glasheen C.a , Saccone N.L.c , Page G.P.d , Bierut L.J.e , Kral A.H.f , Johnson E.O.g
Replication of ZNF804A gene variant associations with risk of heroin addiction
(2015) Genes, Brain and Behavior, . Article in Press. 

DOI: 10.1111/gbb.12254


a Behavioral and Urban Health Program, Behavioral Health and Criminal Justice Division NC USA
b Research Computing Division RTI International Research Triangle Park, NC USA
c Department of Genetics Washington University School of Medicine St. Louis, MO USA
d Fellow Program, Center for Genomics in Public Health and Medicine RTI International Atlanta, GA USA
e Department of Psychiatry Washington University School of Medicine St. Louis, MO USA
f Behavioral and Urban Health Program, Behavioral Health and Criminal Justice Division RTI International San Francisco, CA USA
g Fellow Program and Behavioral Health and Criminal Justice Division RTI International Research Triangle Park, NC USA


Abstract
Heroin addiction is heritable, but few specific genetic variants have been reproducibly associated with this disease. The zinc finger protein 804A (ZNF804A) gene is a biologically plausible susceptibility gene for heroin addiction, given its function as a transcription factor in human brain. Novel associations of two common ZNF804A single nucleotide polymorphisms (SNPs), rs7597593 and rs1344706, with heroin addiction have been reported in Han Chinese. Both SNPs have also been implicated for regulating ZNF804A expression in human brain, including the addiction-relevant dorsolateral prefrontal cortex. In this independent replication study, we tested the rs7597593 and rs1344706 SNP genotypes and their corresponding haplotypes for association with heroin addiction using cases drawn from the Urban Health Study and population controls: total N = 10 757 [7095 European Americans (EAs) and 3662 African Americans (AAs)]. We independently replicated both ZNF804A SNP associations in EAs: the rs7597593-T (P = 0.016) and rs1344706-A (P = 0.029) alleles both being associated with increased risk of heroin addiction, consistent with the prior report. Neither SNP was associated in AAs alone, but meta-analysis across both ancestry groups resulted in significant associations for rs1344706-A [P = 0.016, odds ratio (95% confidence interval) = 1.13 (1.02-1.25)] and its haplotype with rs7597593-T [P = 0.0067, odds ratio (95% confidence interval) = 1.16 (1.04-1.29)]. By showing consistent associations across independent studies and diverse ancestry groups, our study provides evidence that these two ZNF804A SNPs and their risk haplotype are among the few replicable genetic associations with heroin addiction. © 2015 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.


Author Keywords
Ancestry;  Genetic association study;  Haplotype;  Heroin;  Opioid;  Replication;  Rs1344706;  Rs7597593;  Urban Health Study;  ZNF804A


Document Type: Article in Press

Source: Scopus