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WUSTL Neuroscience Publications Archive - March 2015

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March 27, 2015

Kotyuk, E.a b , Duchek, J.a , Head, D.a , Szekely, A.b , Goate, A.M.c , Balota, D.A.a
A genetic variant (COMT) coding dopaminergic activity predicts personality traits in healthy elderly
(2015) Personality and Individual Differences, 82, pp. 61-66. 

DOI: 10.1016/j.paid.2015.03.012


a Department of Psychology, Washington University in St. Louis, One Brookings DriveMO, United States
b Institute of Psychology, Eötvös Loránd University, Izabella u. 46.Budapest, Hungary
c Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid AvenueMO, United States


Abstract
Association studies between the NEO five factor personality inventory and COMT rs4680 have focused on young adults and the results have been inconsistent. However, personality and cortical changes with age may put older adults in a more sensitive range for detecting a relationship. The present study examined associations of COMT rs4680 and personality in older adults.Genetic association analyses were carried out between the NEO and the targeted COMT rs4680 in a large, well-characterized sample of healthy, cognitively normal older adults (. N=. 616, mean age. =. 69.26. years).Three significant associations were found: participants with GG genotype showed lower mean scores on Neuroticism (. p=. 0.039) and higher scores on Agreeableness (. p=. 0.020) and Conscientiousness (. p=. 0.006) than participants with AA or AG genotypes.These results suggest that older adults with higher COMT enzymatic activity (GG), therefore lower dopamine level, have lower Neuroticism scores, and higher Agreeableness and Conscientiousness scores. This is consistent with a recent model of phasic and tonic dopamine release suggesting that even though GG genotype is associated with lower tonic dopamine release, the phasic release of dopamine might be optimal for a more adaptive personality profile. © 2015 Elsevier Ltd.


Author Keywords
COMT rs4680 polymorphism;  Dopamine;  Genetic association;  Older adults;  Personality


Document Type: Article
Source: Scopus




Bennett, R.E.a b , Brody, D.L.a
Array tomography for the detection of non-dilated, injured axons in traumatic brain injury
(2015) Journal of Neuroscience Methods, 245, pp. 25-36. 

DOI: 10.1016/j.jneumeth.2015.02.005


a Department of Neurology, Washington University in St. Louis, 660 S. Euclid AvenueSaint Louis, MO, United States
b Department of Neurology, Massachusetts General Hospital, Harvard Medical School, 114 16th StreetCharlestown, MA, United States


Abstract
Background: Axonal injury is a key feature of several types of brain trauma and neurological disease. However, in mice and humans, many axons are less than 500. nm in diameter which is at or below the resolution of most conventional light microscopic imaging methods. In moderate to severe forms of axon injury, damaged axons become dilated and therefore readily detectible by light microscopy. However, in more subtle forms of injury, the damaged axons may remain undilated and therefore difficult to detect. New method: Here we present a method for adapting array tomography for the identification and quantification of injured axons. In this technique, ultrathin (~70. nm) plastic sections of tissue are prepared, labeled with axon injury-relevant antibodies and imaged using conventional epifluorescence. Results: To demonstrate the use of array-tomography-based methods, we determined that mice that received two closed-skull concussive traumatic brain injury impacts had significantly increased numbers of non-dilated axons that were immunoreactive for non-phosphorylated neurofilament (SMI-32; a marker of axonal injury), compared to sham mice (1682±628 versus 339±52 per mm2, p=0.004, one-tailed Mann-Whitney U test). Tubulin loss was not evident (p=0.2063, one-tailed Mann-Whitney U test). Furthermore, mice that were subjected to more severe injury had a loss of tubulin in addition to both dilated and non-dilated SMI-32 immunoreactive axons indicating that this technique is suitable for the analysis of various injury conditions. Comparison with existing method: With array tomography we could detect similar overall numbers of axons as electron microscopy, but accurate diameter measurements were limited to those with diameters >200. nm. Importantly, array tomography had greater sensitivity for detecting small non-dilated injured axons compared with conventional immunohistochemistry. Conclusion: Imaging of individual axons and quantification of subtle axonal injury is possible using this array tomography method. This method may be most useful for the assessment of concussive injuries and other pathologies in which injured axons are not typically dilated. The ability to process moderately large volumes of tissue, label multiple proteins of interest, and automate analysis support array tomography as a useful alternative to electron microscopy. © 2015 Elsevier B.V.


Author Keywords
Array tomography;  Axonal injury;  Electron microscopy;  Neurofilament;  Traumatic brain injury;  Tubulin


Document Type: Article
Source: Scopus




Rawson, K.S.a , Dixon, D.a , Nowotny, P.a , Ricci, W.M.b , Binder, E.F.c , Rodebaugh, T.L.d , Wendleton, L.a , Doré, P.a , Lenze, E.J.a
Association of functional polymorphisms from brain-derived neurotrophic factor and serotonin-related genes with depressive symptoms after a medical stressor in older adults
(2015) PLoS ONE, 10 (3), art. no. e0120685, . 

DOI: 10.1371/journal.pone.0120685


a Department of Psychiatry, Washington University School of MedicineSaint Louis, MO, United States
b Orthopaedic Trauma Service, Washington University School of Medicine, Barnes-Jewish HospitalSaint Louis, MO, United States
c Department of Internal Medicine, Washington University School of MedicineSaint Louis, MO, United States
d Department of Psychology, Washington University in Saint LouisSaint Louis, MO, United States


Abstract
Depressive symptoms are common in older adults after a disabling medical event and interfere with rehabilitation and recovery from the disability. This prospective study examined the role of genetic polymorphisms implicated in synaptic integrity and stress-associated depression as predictors of depressive symptoms after hip fracture. We recruited healthy comparisons from the community and participants with hip fracture after surgical fixation from Saint Louis, Missouri hospitals. We examined the valine (Val) to methionine (Met) polymorphism in brain-derived neurotrophic factor (BDNF ), serotonin 1A receptor (5HT1a-rs6295) polymorphism, and the serotonin transporter-linked polymorphic region (5HTTLPR) interaction with the rs25531 A to G single nucleotide polymorphism (5HTTLPR-rs25531) as predictors of depressive symptoms. We also examined whether depressive symptoms mediate the influence of BDNF genotype on functional recovery. Among 429 participants with hip fracture, BDNF Met/Met carriers developed significantly more depressive symptoms than Val/Val carriers during a four-week period after the fracture (p = .012). BDNF genotype also predicted functional recovery over the ensuing year, mediated by its effects on depressive symptoms (CI: 0.07-3.37). Unlike prior studies of stressful life events, the S′ 5HTTLPR-rs25531 variant did not predict higher levels of depressive symptoms; instead, we report an exploratory finding of an epistatic effect between BDNF and 5HTTLPR-rs25531 whereby the compounded effects of two LA alleles and BDNF Met/Met genotype elevate risk of depressive symptoms after hip fracture (p = .006). No differences between 5HT1a genotypes were found. Our findings suggest plasticity-related genetic factors contribute to the neural mechanisms of mental and functional well-being after a disabling medical stressor. © 2015 Rawson et al.


Document Type: Article
Source: Scopus




Wallace, A.N.a b , Vyhmeister, R.b , Bagade, S.a b , Chatterjee, A.a b , Hicks, B.a b , Ramirez-Giraldo, J.C.c , McKinstry, R.C.a b
Evaluation of the use of automatic exposure control and automatic tube potential selection in low-dose cerebrospinal fluid shunt head CT
(2015) Neuroradiology, 6 p. Article in Press. 

DOI: 10.1007/s00234-015-1508-6


a Mallinckrodt Institute of Radiology, Barnes Jewish HospitalSt. Louis, MO, United States
b Washington University School of Medicine, 660 S Euclid AveSt. Louis, MO, United States
c Siemens HealthcareMalvern, PA, United States


Abstract
Introduction: Cerebrospinal fluid shunts are primarily used for the treatment of hydrocephalus. Shunt complications may necessitate multiple non-contrast head CT scans resulting in potentially high levels of radiation dose starting at an early age. A new head CT protocol using automatic exposure control and automated tube potential selection has been implemented at our institution to reduce radiation exposure. The purpose of this study was to evaluate the reduction in radiation dose achieved by this protocol compared with a protocol with fixed parameters.

Methods: A retrospective sample of 60 non-contrast head CT scans assessing for cerebrospinal fluid shunt malfunction was identified, 30 of which were performed with each protocol. The radiation doses of the two protocols were compared using the volume CT dose index and dose length product. The diagnostic acceptability and quality of each scan were evaluated by three independent readers.

Results: The new protocol lowered the average volume CT dose index from 15.2 to 9.2 mGy representing a 39 % reduction (P < 0.01; 95 % CI 35–44 %) and lowered the dose length product from 259.5 to 151.2 mGy/cm representing a 42 % reduction (P < 0.01; 95 % CI 34–50 %). The new protocol produced diagnostically acceptable scans with comparable image quality to the fixed parameter protocol.

Conclusion: A pediatric shunt non-contrast head CT protocol using automatic exposure control and automated tube potential selection reduced patient radiation dose compared with a fixed parameter protocol while producing diagnostic images of comparable quality. © 2015 Springer-Verlag Berlin Heidelberg


Author Keywords
Automatic tube current modulation;  Automatic tube potential selection;  CareDose4D;  Cerebrospinal fluid shunt;  Head CT


Document Type: Article in Press
Source: Scopus




Jellinger, K.A.a , Alafuzoff, I.b , Attems, J.c , Beach, T.G.d , Cairns, N.J.e , Crary, J.F.f , Dickson, D.W.g , Hof, P.R.h , Hyman, B.T.i , Jack, C.R., Jr.j , Jicha, G.A.k , Knopman, D.S.l , Kovacs, G.G.m , Mackenzie, I.R.n , Masliah, E.o p , Montine, T.J.q , Nelson, P.T.r , Schmitt, F.k , Schneider, J.A.s t , Serrano-Pozo, A.u , Thal, D.R.v , Toledo, J.B.w , Trojanowski, J.Q.w , Troncoso, J.C.x , Vonsattel, J.P.f , Wisniewski, T.y z aa
PART, a distinct tauopathy, different from classical sporadic Alzheimer disease
(2015) Acta Neuropathologica, 6 p. Article in Press. 

DOI: 10.1007/s00401-015-1407-2


a Institute of Clinical NeurobiologyVienna, Austria
b Department of Immunology, Genetics and Pathology, Uppsala UniversityUppsala, Sweden
c Institute of Neuroscience, Newcastle University, Campus for Ageing and VitalityNewcastle upon Tyne, United Kingdom
d Civin Laboratory for Neuropathology, Banner Sun Health Research InstituteSun City, AZ, United States
e Department of Pathology and Immunology, Washington University School of MedicineSaint Louis, MO, United States
f Department of Pathology and Cell Biology and The Taub Institute for Research on Alzheimer’s Disease and The Aging Brain, Columbia University Medical CenterNew York, NY, United States
g Department of Neuroscience, Mayo Clinic, 4500 San Pablo RoadJacksonville, FL, United States
h Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount SinaiNew York, NY, United States
i Department of Neurology, Harvard Medical School and Massachusetts General HospitalCharlestown, MA, United States
j Department of Radiology, Mayo ClinicRochester, MN, United States
k Department of Neurology and Sanders-Brown Center on Aging, University of KentuckyLexington, KY, United States
l Department of Neurology, Mayo ClinicRochester, MN, United States
m Institute of Neurology, Medical University of ViennaVienna, Austria
n Department of Pathology, University of British Columbia, 855 West 12th AvenueVancouver, BC, Canada
o Department of Neurosciences, University of California San DiegoLa Jolla, CA, United States
p Department of Pathology, University of California San DiegoLa Jolla, CA, United States
q Department of Pathology, University of WashingtonSeattle, WA, United States
r Department of Pathology and Sanders-Brown Center on Aging, University of KentuckyLexington, KY, United States
s Department of Pathology (Neuropathology), Rush University Medical CenterChicago, IL, United States
t Department of Neurological Sciences, Rush University Medical CenterChicago, IL, United States
u Department of Neurology, University of Iowa Hospitals and ClinicsIowa City, IA, United States
v Laboratory of Neuropathology, Institute of Pathology, Center for Biomedical Research, Ulm University, Helmholtzstrasse 8/1Ulm, Germany
w Center for Neurodegenerative Disease Research and Department of Pathology and Laboratory Medicine, Perelman School of Medicine at The University of PennsylvaniaPhiladelphia, PA, United States
x Department of Pathology and Laboratory Medicine, Institute on Aging, Center for Neurodegenerative Disease Research, University of Pennsylvania Perelman School of MedicinePhiladelphia, PA, United States
y Department of Neurology, New York University School of MedicineNew York, NY, United States
z Department of Pathology, New York University School of MedicineNew York, NY, United States
aa Department of Psychiatry, New York University School of MedicineNew York, NY, United States


Document Type: Article in Press
Source: Scopus




Akbari, S.H.A.a , Limbrick, D.D., Jr.a b , McKinstry, R.C.c , Altaye, M.f , Ragan, D.K.b , Yuan, W.d , Mangano, F.T.e , Holland, S.K.d , Shimony, J.S.c
Periventricular hyperintensity in children with hydrocephalus
(2015) Pediatric Radiology, 9 p. Article in Press. 

DOI: 10.1007/s00247-015-3298-8


a Department of Neurological Surgery, St. Louis Children’s Hospital, Washington University School of MedicineSt. Louis, MO, United States
b Department of Neurological Surgery, St. Louis Children’s Hospital, Washington University School of MedicineSt. Louis, MO, United States
c Mallinckrodt Institute of Radiology, St. Louis Children’s Hospital, Washington University School of Medicine, 510 S. Kingshighway Blvd.St. Louis, MO, United States
d Department of Pediatric Radiology, Cincinnati Children’s HospitalCincinnati, OH, United States
e Department of Pediatric Neurological Surgery, Cincinnati Children’s HospitalCincinnati, OH, United States
f Division of Biostatistics and Epidemiology, Cincinnati Children’s HospitalCincinnati, OH, United States


Abstract
Background: Magnetic resonance images of children with hydrocephalus often include a rim of hyperintensity in the periventricular white matter (halo).

Objective: The purpose of this study was to decide between the hypothesis that the halo is caused by cerebrospinal fluid (CSF) flow during the cardiac cycle, and the alternate hypothesis that the halo is caused by anatomical changes (stretching and compression of white matter).

Materials and methods: Participants were selected from a multicenter imaging study of pediatric hydrocephalus. We compared 19 children with hydrocephalus to a group of 52 controls. We quantified ventricle enlargement using the frontal-occipital horn ratio. We conducted qualitative and quantitative analysis of diffusion tensor imaging in the corpus callosum and posterior limb of the internal capsule. Parameters included the fractional anisotropy (FA), mean diffusivity, axial diffusivity and radial diffusivity.

Results: The halo was seen in 16 of the 19 children with hydrocephalus but not in the controls. The corpus callosum of the hydrocephalus group demonstrated FA values that were significantly decreased from those in the control group (P = 4 · 10−6), and highly significant increases were seen in the mean diffusivity and radial diffusivity in the hydrocephalus group. In the posterior limb of the internal capsule the FA values of the hydrocephalus group were higher than those for the control group (P = 0.002), and higher values in the hydrocephalus group were also noted in the axial diffusivity. We noted correlations between the diffusion parameters and the frontal-occipital horn ratio.

Conclusion: Our results strongly support the hypothesis that the halo finding in hydrocephalus is caused by structural changes rather than pulsatile CSF flow. © 2015 Springer-Verlag Berlin Heidelberg


Author Keywords
Children;  Diffusion tensor imaging;  Fractional anisotropy;  Hydrocephalus;  Magnetic resonance imaging;  Periventricular hyperintensity


Document Type: Article in Press
Source: Scopus




Sala-Rabanal, M.a b , Yurtsever, Z.b c d e , Nichols, C.G.a b , Brett, T.J.a b d e f
Secreted CLCA1 modulates TMEM16A to activate Ca2+-dependent chloride currents in human cells
(2015) eLife, 2015 (4), art. no. e05875, 14 p. 

DOI: 10.7554/eLife.05875


a Department of Cell Biology and Physiology, Washington University School of MedicineSt Louis, United States
b Center for the Investigation of Membrane Excitability Diseases, Washington University School of Medicine, St Louis, United States
c Washington University, School of MedicineSt Louis, United States
d Department of Internal Medicine, Washington University School of MedicineSt Louis, United States
e Pulmonary and Critical Care Medicine, Washington University School of MedicineSt Louis, United States
f Department of Biochemistry and Molecular Biophysics, Washington University School of MedicineSt Louis, United States


Abstract
Calcium-activated chloride channel regulator 1 (CLCA1) activates calcium-dependent chloride currents; neither the target, nor mechanism, is known. We demonstrate that secreted CLCA1 activates calcium-dependent chloride currents in HEK293T cells in a paracrine fashion, and endogenous TMEM16A/Anoctamin1 conducts the currents. Exposure to exogenous CLCA1 increases cell surface levels of TMEM16A and cellular binding experiments indicate CLCA1 engages TMEM16A on the surface of these cells. Altogether, our data suggest that CLCA1 stabilizes TMEM16A on the cell surface, thus increasing surface expression, which results in increased calciumdependent chloride currents. Our results identify the first Cl− channel target of the CLCA family of proteins and establish CLCA1 as the first secreted direct modifier of TMEM16A activity, delineating a unique mechanism to increase currents. These results suggest cooperative roles for CLCA and TMEM16 proteins in influencing the physiology of multiple tissues, and the pathology of multiple diseases, including asthma, COPD, cystic fibrosis, and certain cancers. © Sala-Rabanal et al.


Document Type: Article
Source: Scopus




Bussière, M.a , Gupta, M.a , Sharma, M.a , Dowlatshahi, D.a , Fang, J.b , Dhar, R.c
Anaemia on admission is associated with more severe intracerebral haemorrhage and worse outcomes
(2015) International Journal of Stroke, 10 (3), pp. 382-387. 

DOI: 10.1111/j.1747-4949.2012.00951.x


a Division of Neurology, Department of Medicine, The Ottawa HospitalOttawa, ON, Canada
b Institute for Clinical Evaluative SciencesToronto, ON, Canada
c Division of Neurocritical Care, Department of Neurology, Washington University School of MedicineSaint Louis, MO, United States


Abstract
Background: Lower haemoglobin levels may impair cerebral oxygen delivery and threaten tissue viability in the setting of acute brain injury. Few studies have examined the association between haemoglobin levels and outcomes after spontaneous intracerebral haemorrhage. Aims: We evaluated whether anaemia on admission was associated with greater intracerebral haemorrhage severity and worse outcome. Methods: Consecutive patients with spontaneous intracerebral haemorrhage were analyzed from the Registry of the Canadian Stroke Network. Admission haemoglobin was related to stroke severity (using the Canadian Neurological Scale), modified Rankin score at discharge, and one-year mortality. Adjustment was made for potential confounders including age, gender, medical history, warfarin use, glucose, creatinine, blood pressure, and intraventricular haemorrhage. Results: Two thousand four hundred six patients with intracerebral haemorrhage were studied of whom 23% had anaemia (haemoglobin <120g/l) on admission, including 4% with haemoglobin <100g/l. Patients with anaemia were more likely to have severe neurological deficits at presentation [haemoglobin ≤100g/l, adjusted odds ratio 4·04 (95% confidence interval 2·39, 6·84); haemoglobin 101-120g/l, adjusted odds ratio 1·93 (95% confidence interval 1·43, 2·59), both P<0·0001]. In nonanticoagulated patients, severe anaemia was also associated with poor outcome (modified Rankin score 4-6) at discharge [haemoglobin ≤100g/l, adjusted odds ratio 2·42 (95% confidence interval 1·07-5·47), P=0·034] and increased mortality at one-year [haemoglobin ≤100g/l, adjusted hazard ratio 1·73 (95% confidence interval 1·22-2·45), P=0·002]. Conclusions: Anaemia on admission is associated with greater intracerebral haemorrhage severity and worse outcomes. The utility of transfusion remains unclear in this setting. © 2013 World Stroke Organization.


Author Keywords
Anaemia;  Haemoglobin;  Intracerebral haemorrhage;  Outcomes


Document Type: Article
Source: Scopus




Zazulia, A.
Antiplatelet and Anticoagulant Therapy After Intracerebral Hemorrhage
(2015) Neurologic Clinics, . Article in Press. 

DOI: 10.1016/j.ncl.2014.12.005


Department of Neurology, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box8111, St Louis, MO 63110, USA


Abstract
Management of patients with an indication for long-term oral antithrombotic therapy who have an intracerebral hemorrhage (ICH) presents a therapeutic dilemma. Should antithrombotic therapy be resumed, and if so, when, using what agent, and for whom? There is no consensus for answers to these questions. In the absence of randomized trials, management of antithrombotic therapy after ICH is based on a combination of observational data, pathophysiologic concepts, and decision analysis. At the heart of the decision is an assessment of the individual patient's risk of thromboembolism off antithrombotic therapy versus risk of ICH recurrence on antithrombotic therapy. © 2015 Elsevier Inc.


Author Keywords
Anticoagulation;  Antiplatelet therapy;  Atrial fibrillation;  Intracerebral hemorrhage;  Prosthetic heart valve;  Venous thromboembolism


Document Type: Article in Press
Source: Scopus




Kay, K.N.a , Weiner, K.S.b , Grill-Spector, K.b c
Attention reduces spatial uncertainty in human ventral temporal cortex
(2015) Current Biology, 25 (5), pp. 595-600. 

DOI: 10.1016/j.cub.2014.12.050


a Department of Psychology, Washington University in St. LouisSt. Louis, MO, United States
b Department of Psychology, Stanford UniversityStanford, CA, United States
c Stanford Neurosciences Institute, Stanford UniversityStanford, CA, United States


Abstract
Ventral temporal cortex (VTC) is the latest stage of the ventral "what" visual pathway, which is thought to code the identity of a stimulus regardless of its position or size [1, 2]. Surprisingly, recent studies show that position information can be decoded from VTC [3-5]. However, the computational mechanisms by which spatial information is encoded in VTC are unknown. Furthermore, how attention influences spatial representations in human VTC is also unknown because the effect of attention on spatial representations has only been examined in the dorsal "where" visual pathway [6-10]. Here, we fill these significant gaps in knowledge using an approach that combines functional magnetic resonance imaging and sophisticated computational methods. We first develop a population receptive field (pRF) model [11, 12] of spatial responses in human VTC. Consisting of spatial summation followed by a compressive nonlinearity, this model accurately predicts responses of individual voxels to stimuli at any position and size, explains how spatial information is encoded, and reveals a functional hierarchy in VTC. We then manipulate attention and use our model to decipher the effects of attention. We find that attention to the stimulus systematically and selectively modulates responses in VTC, but not early visual areas. Locally, attention increases eccentricity, size, and gain of individual pRFs, thereby increasing position tolerance. However, globally, these effects reduce uncertainty regarding stimulus location and actually increase position sensitivity of distributed responses across VTC. These results demonstrate that attention actively shapes and enhances spatial representations in the ventral visual pathway. © 2015 Elsevier Ltd All rights reserved.


Document Type: Article
Source: Scopus




Stevenson, M.a , Bae, H.b , Schupf, N.c , Andersen, S.d , Zhang, Q.e , Perls, T.d , Sebastiani, P.a
Burden of disease variants in participants of the long life family study
(2015) Aging, 7 (2), pp. 123-132. 


a Department of Biostatistics, Boston University School of Public HealthBoston, MA, United States
b College of Public Health and Human Sciences, Oregon State UniversityOR, United States
c Department of Neurology, Columbia UniversityNew York City, NY, United States
d Section of Geriatrics, Department of Medicine, Boston University School of Medicine and Boston Medical CenterBoston, MA, United States
e Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, Campus Box 8506St. Louis, MO, United States


Abstract
Case control studies of nonagenarians and centenarians provide evidence that long-lived individuals do not differ in the rate of disease associated variants compared to population controls. These results suggest that an enrichment of novel protective variants, rather than a lack of disease associated variants, determine the genetic predisposition to exceptionally long lives. Using data from the Long Life Family Study (LLFS), we sought to replicate these findings and extend them to include a larger number of disease-specific risk alleles. To accomplish this goal, we built a genetic risk score for each of four age-related disease groups: Alzheimer's disease, cardiovascular disease and stroke, type 2 diabetes, and various cancers and compared the distribution of these scores between older participants of the LLFS, their offspring and their spouses. The analyses showed no significant differences in distribution of the genetic risk scores for cardiovascular disease and stroke, type 2 diabetes, or cancer between the groups, while participants of the LLFS appeared to carry an average 1% fewer risk alleles for Alzheimer's disease compared to spousal controls and, while the difference may not be clinically relevant, it was statistically significant. However, the statistical significance between familial longevity and the Alzheimer's disease genetic risk score was lost when a more stringent linkage disequilibrium threshold was imposed to select independent genetic variants. © Stevenson et al.


Author Keywords
Alzheimer's disease;  Disease variants;  Exceptional longevity;  Genetic risk score


Document Type: Article
Source: Scopus




Klein, R.D.a , Hultgren, S.J.a b
Chaos controlled: Discovery of a powerful amyloid inhibitor
(2015) Molecular Cell, 57 (3), pp. 391-393. 

DOI: 10.1016/j.molcel.2015.01.031


a Department of Molecular Microbiology, Washington University School of MedicineSaint Louis, MO, United States
b Center for Women's Infectious Disease Research, Washington University School of MedicineSaint Louis, MO, United States


Abstract
In this issue of Molecular Cell, Evans etal. (2015) report that the hitherto largely unstudied CsgC protein is responsible for the suppression of premature amyloidogenesis within the cellular periplasm, preventing early aggregation and cellular toxicity. © 2015 Elsevier Inc.


Document Type: Short Survey
Source: Scopus




Lueder, G.T., Galli, M.
Comparison of Lateral Rectus Muscle Re-recession and Medial Rectus Muscle Resection for Treatment of Postoperative Exotropia
(2015) American Journal of Ophthalmology, 159 (4), pp. 812-815. 

DOI: 10.1016/j.ajo.2015.01.020


Departments of Ophthalmology and Visual Sciences and Pediatrics, St Louis Children's Hospital, Washington University School of MedicineSt Louis, MO, United States


Abstract
Purpose To compare the outcomes of unilateral lateral rectus muscle re-recession and medial rectus muscle resection for treatment of recurrent or persistent exotropia. Design Retrospective nonrandomized clinical trial. Methods setting: Hospital-based clinical practice. patient population: Forty patients with recurrent or persistent exotropia following bilateral lateral rectus muscle recessions. intervention: Fourteen patients were treated with unilateral medial rectus muscle resection and 26 with unilateral lateral rectus muscle re-recession. main outcome measures: Outcomes were considered successful if the patients had deviations less than 10 prism diopters (PD) at last follow-up. All patients were followed for at least 1 year postoperatively. Results The mean preoperative deviations were 17.4 PD in the medial rectus muscle resection group and 18.1 PD in the lateral rectus muscle re-recession group. Successful outcomes were achieved in 9 of 14 patients (64%) treated with medial rectus muscle resection and 19 of 26 patients (73%) treated with lateral rectus muscle re-recession. There was no statistically significant difference between these outcomes. Mean follow-up was 4.5 years in the medial rectus muscle resection group and 2.9 years in the lateral rectus muscle re-recession group. Conclusions Surgery on a single muscle can be used to treat moderate-angle recurrent or persistent exotropia. Unilateral re-recession of the lateral rectus muscle and medial rectus muscle resection have equivalent success rates. © 2015 Elsevier Inc. All Rights Reserved.


Document Type: Article
Source: Scopus




Brody, D.L.a , Mac Donald, C.L.a , Shimony, J.S.b
Current and future diagnostic tools for traumatic brain injury. CT, conventional MRI, and diffusion tensor imaging
(2015) Handbook of Clinical Neurology, 127, pp. 267-275. 

DOI: 10.1016/B978-0-444-52892-6.00017-9


a Department of Neurology, Washington University School of MedicineSt. Louis, MO, United States
b Department of Radiology, Washington University School of MedicineSt. Louis, MO, United States


Abstract
Brain imaging plays a key role in the assessment of traumatic brain injury. In this review, we present our perspectives on the use of computed tomography (CT), conventional magnetic resonance imaging (MRI), and newer advanced modalities such as diffusion tensor imaging. Specifically, we address assessment for immediately life-threatening intracranial lesions (noncontrast head CT), assessment of progression of intracranial lesions (noncontrast head CT), documenting intracranial abnormalities for medicolegal reasons (conventional MRI with blood-sensitive sequences), presurgical planning for post-traumatic epilepsy (high spatial resolution conventional MRI), early prognostic decision making (conventional MRI with diffusion-weighted imaging), prognostic assessment for rehabilitative planning (conventional MRI and possibly diffusion tensor imaging in the future), stratification of subjects and pharmacodynamic tracking of targeted therapies in clinical trials (specific MRI sequences or positron emission tomography (PET) ligands, e.g., diffusion tensor imaging for traumatic axonal injury). We would like to emphasize that all of these methods, especially the newer research approaches, require careful radiologic-pathologic validation for optimal interpretation. We have taken this approach in a mouse model of pericontusional traumatic axonal injury. We found that the extent of reduction in the diffusion tensor imaging parameter relative anisotropy directly correlated with the number of amyloid precursor protein (APP)-stained axonal varicosities (r2=0.81, p&lt;0.0001, n=20 injured mice). Interestingly, however, the least severe contusional injuries did not result in APP-stained axonal varicosities, but did cause reduction in relative anisotropy. Clearly, both the imaging assessments and the pathologic assessments will require iterative refinement. © 2015 Elsevier B.V.


Author Keywords
Amyloid precursor protein;  Computed tomography;  Diffusion tensor imaging;  Magnetic resonance imaging;  Medicolegal documentation;  Post-traumatic epilepsy;  Prognosis;  Radiological-pathological correlation;  Traumatic brain injury


Document Type: Article
Source: Scopus




Kumar, A.a , Cage, A.b , Dhar, R.c
Dialysis-Induced Worsening of Cerebral Edema in Intracranial Hemorrhage: A Case Series and Clinical Perspective
(2015) Neurocritical Care, 22 (2), pp. 283-287. 

DOI: 10.1007/s12028-014-0063-z


a Department of Neurology, Saint Louis UniversitySaint Louis, MO, United States
b Barnes-Jewish HospitalSaint Louis, MO, United States
c Department of Neurology, Washington University School of Medicine, 660 S. Euclid Ave, Campus Box 8111Saint Louis, MO, United States


Abstract
Background: Intracranial hemorrhage (ICH) is not an uncommon complication of end-stage renal disease (ESRD), and may be complicated by cerebral edema. Hemodialysis (HD) may induce rapid osmolar and fluid shifts, increasing brain water content with the potential to worsen cerebral edema. The dangers of HD in patients with acute ICH have only been highlighted in isolated reports. Methods: Case series and review of relevant literature. Results: Two patients with ESRD presented with acute ICH (one with putaminal hematoma, the other with bilateral subdural hematomas) and developed fatal/near-fatal herniation during HD, associated with malignant worsening of cerebral edema. Both had interruptions in dialysis schedule prior to index event. Both were awake initially, but developed cerebral herniation syndrome toward the end of index HD, confirmed on imaging with worsening edema and effaced basal cisterns. In one case, herniation was reversed with hypertonic saline and hyperventilation, but in the other, the patient progressed to brain death despite these measures. We contrast these cases with a young patient with ESRD and large basal ganglia ICH who had elevated ICPs on admission, but safely underwent continuous veno-venous HD. Conclusions: Hemodialysis may worsen cerebral edema in the setting of ICH sufficient to precipitate cerebral herniation. Caution should be exercised when dialysing a patient with an acute mass lesion and reduced intracranial compliance, especially those in whom HD is new or not routine. Delaying HD till risk of edema is attenuated, or ensuring gradual urea removal (such as with continuous hemofiltration) may be advisable. © 2014, Springer Science+Business Media New York.


Author Keywords
Brain death;  Dialysis disequilibrium syndrome;  Hemodialysis;  Herniation


Document Type: Article
Source: Scopus




Gutmann, D.H.
Microglia in the tumor microenvironment: Taking their TOLL on glioma biology
(2015) Neuro-Oncology, 17 (2), pp. 171-173. 

DOI: 10.1093/neuonc/nou346


Department of Neurology, Washington University School of Medicine, 660 S. Euclid AvenueSt. Louis, MO, United States


Document Type: Review
Source: Scopus




Ostermann, J.a b , Njau, B.c , Mtuy, T.d , Brown, D.S.b e , Mühlbacher, A.b f , Thielman, N.a g
One size does not fit all: HIV testing preferences differ among high-risk groups in Northern Tanzania
(2015) AIDS Care - Psychological and Socio-Medical Aspects of AIDS/HIV, 27 (5), pp. 595-603. 

DOI: 10.1080/09540121.2014.998612


a Duke Global Health Institute, Duke UniversityDurham, NC, United States
b Center for Health Policy and Inequalities Research, Duke UniversityDurham, NC, United States
c Community Health Department, Kilimanjaro Christian Medical CollegeMoshi, Tanzania
d Department of Clinical Research, London School of Hygiene and Tropical MedicineLondon, United Kingdom
e Brown School, Washington University in St. LouisSt. Louis, MO, United States
f Institut Gesundheitsökonomie und Medizinmanagement, Hochschule NeubrandenburgNeubrandenburg, Germany
g School of Medicine, Duke UniversityDurham, NC, United States


Abstract
In order to maximize the effectiveness of "Seek, Test, and Treat" strategies for curbing the HIV epidemic, new approaches are needed to increase the uptake of HIV testing services, particularly among high-risk groups. Low HIV testing rates among such groups suggest that current testing services may not align well with the testing preferences of these populations. Female bar workers and male mountain porters have been identified as two important high-risk groups in the Kilimanjaro Region of Tanzania. We used conventional survey methods and a discrete choice experiment (DCE), a preference elicitation method increasingly applied by economists and policy-makers to inform health policy and services, to analyze trade-offs made by individuals and quantify preferences for HIV testing services. Bivariate descriptive statistics were used to analyze differences in survey responses across groups. Compared to 486 randomly selected community members, 162 female bar workers and 194 male Kilimanjaro porters reported 2-3 times as many lifetime sexual partners (p < 0.001), but similar numbers of lifetime HIV tests (median 1-2 across all groups). For the DCE, participants' stated choices across 12,978 hypothetical HIV testing scenarios (422 female and 299 male participants x 9 choice tasks x 2 alternatives) were analyzed using gender-specific mixed logit models. Direct assessments and the DCE data demonstrated that barworkers were less likely to prefer home testing and were more concerned about disclosure issues compared with their community counterparts. Male porters preferred testing in venues where antiretroviral therapy was readily available. Both high-risk groups were less averse to traveling longer distances to test compared to their community counterparts. These results expose systematic differences in HIV testing preferences across high-risk populations compared to their community peers. Tailoring testing options to the preferences of high-risk populations should be evaluated as a means of improving uptake of testing in these populations. © 2015 Taylor & Francis.


Author Keywords
Discrete choice experiment;  Hiv diagnosis;  Hiv testing;  Preferences;  Tanzania


Document Type: Article
Source: Scopus




Weston, S.J.a , Hill, P.L.b , Jackson, J.J.a
Personality Traits Predict the Onset of Disease
(2015) Social Psychological and Personality Science, 6 (3), pp. 309-317. 

DOI: 10.1177/1948550614553248


a Department of Psychology, Washington University in St. LouisSt. Louis, MO, United States
b Carleton UniversityOttawa, Canada


Abstract
While personality traits have been linked concurrently to health status and prospectively to outcomes such as mortality, it is currently unknown whether traits predict the diagnosis of a number of specific diseases (e.g., lung disease, heart disease, and stroke) that may account for their mortality effects more generally. A sample (N = 6,904) of participants from the Health and Retirement Study, a longitudinal study of older adults, completed personality measures and reported on current health conditions. Four years later, participants were followed up to see if they developed a new disease. Initial cross-sectional analyses replicated past findings that personality traits differ across disease groups. Longitudinal logistic regression analyses predicting new disease diagnosis suggest that traits are associated with the risk of developing disease—most notably the traits of conscientiousness, neuroticism, and openness. Findings are discussed as a means to identify pathways between personality and health. © The Author(s) 2014.


Author Keywords
conscientiousness;  disease;  health;  neuroticism;  openness;  personality


Document Type: Article
Source: Scopus




Pachow, D.a , Wick, W.c , Gutmann, D.H.b , Mawrin, C.a
The mTOR signaling pathway as a treatment target for intracranial neoplasms
(2015) Neuro-Oncology, 17 (2), pp. 189-199. 

DOI: 10.1093/neuonc/nou164


a Department of Neuropathology, Otto-von-Guericke University Magdeburg, Leipziger Strasse 44Magdeburg, Germany
b Department of Neurology, Washington University School of MedicineSt Louis, MO, United States
c Department of Neuro-Oncology Neurology Clinic, University of Heidelberg, German Cancer Research CenterHeidelberg, Germany


Abstract
Inhibition of the mammalian target of rapamycin (mTOR) signaling pathway has become an attractive target for human cancer therapy. Hyperactivation of mTOR has been reported in both sporadic and syndromic (hereditary) brain tumors. In contrast to the large number of successful clinical trials employing mTOR inhibitors in different types of epithelial neoplasms, their use to treat intracranial neoplasms is more limited. In this review, we summarize the role of mTOR activation in brain tumor pathogenesis and growth relevant to new human brain tumor trials currently under way using mTOR inhibitors. © 2014 The Author(s).


Author Keywords
glioblastoma;  meningioma;  mTORC1;  mTORC2


Document Type: Review
Source: Scopus




Jackson, J.J.a , Connolly, J.J.b , Garrison, S.M.c , Leveille, M.M.b , Connolly, S.L.d
Your Friends Know How Long You Will Live: A 75-Year Study of Peer-Rated Personality Traits
(2015) Psychological Science, 26 (3), pp. 335-340. 

DOI: 10.1177/0956797614561800


a Department of Psychology, Washington University in St. Louis, United States
b Connolly ConsultingWaterford, CT, United States
c Department of Psychology and Human Development, Vanderbilt University, United States
d College of Medicine, Touro University California, United States


Abstract
Although self-rated personality traits predict mortality risk, no study has examined whether one’s friends can perceive personality characteristics that predict one’s mortality risk. Moreover, it is unclear whether observers’ reports (compared with self-reports) provide better or unique information concerning the personal characteristics that result in longer and healthier lives. To test whether friends’ reports of personality predict mortality risk, we used data from a 75-year longitudinal study (the Kelly/Connolly Longitudinal Study on Personality and Aging). In that study, 600 participants were observed beginning in 1935 through 1938, when they were in their mid-20s, and continuing through 2013. Male participants seen by their friends as more conscientious and open lived longer, whereas friend-rated emotional stability and agreeableness were protective for women. Friends’ ratings were better predictors of longevity than were self-reports of personality, in part because friends’ ratings could be aggregated to provide a more reliable assessment. Our findings demonstrate the utility of observers’ reports in the study of health and provide insights concerning the pathways by which personality traits influence health. © The Author(s) 2015.


Author Keywords
conscientiousness;  informant reports;  longevity;  mortality;  peers;  personality;  survival analysis


Document Type: Article
Source: Scopus

 

March 20, 2015

Khundrakpam, B.S.a , Tohka, J.b , Evans, A.C.a , Ball, W.S.c , Byars, A.W.c , Schapiro, M.c , Bommer, W.c , Carr, A.c , German, A.c , Dunn, S.c , Rivkin, M.J.d , Waber, D.d , Mulkern, R.d , Vajapeyam, S.d , Chiverton, A.d , Davis, P.d , Koo, J.d , Marmor, J.d , Mrakotsky, C.d , Robertson, R.d , McAnulty, G.d , Brandt, M.E.e , Fletcher, J.M.e , Kramer, L.A.e , Yang, G.e , Cara McCormacke , Hebert, K.M.e , Volero, H.e , Botteron, K.f , McKinstry, R.C.f , Warren, W.f , Nishino, T.f , Robert Almli, C.f , Todd, R.f , Constantino, J.f , McCracken, J.T.g , Levitt, J.g , Alger, J.g , O'Neil, J.g , Toga, A.g , Asarnow, R.g , Fadale, D.g , Heinichen, L.g , Ireland, C.g , Wang, D.-J.h , Moss, E.h , Zimmerman, R.A.h , Bintliff, B.h , Bradford, R.h , Newman, J.h , Arnaoutelis, R.i , Bruce Pike, G.i , Louis Collins, D.i , Leonard, G.i , Paus, T.i , Zijdenbos, A.i , Das, S.i , Fonov, V.i , Fu, L.i , Harlap, J.i , Leppert, I.i , Milovan, D.i , Vins, D.i , Zeffiro, T.j , Van Meter, J.j , Lange, N.k , Froimowitz, M.P.k , Robert Almli, C.l , Rainey, C.l , Henderson, S.l , Edwards, J.L.l , Dubois, D.l , Smith, K.l , Singer, T.l , Wilber, A.A.l , Pierpaoli, C.m , Basser, P.J.m , Chang, L.-C.m , Koay, C.G.m , Walker, L.m , Freund, L.n , Rumsey, J.n , Baskir, L.n , Stanford, L.n , Sirocco, K.n , Gwinn-Hardy, K.o , Spinella, G.o , Alger, J.R.p , O'Neill, J.p
Prediction of brain maturity based on cortical thickness at different spatial resolutions
(2015) NeuroImage, 111, pp. 350-359. 

DOI: 10.1016/j.neuroimage.2015.02.046


a Montreal Neurological Institute, McGill UniversityMontreal, Canada
b Department of Bioengineering and Aerospace Engineering, Universidad Carlos III de Madrid, Spain
c Children's Hospital Medical Center of Cincinnati, United States
d Children's Hospital Boston, United States
e University of Texas Health Science Center at Houston, United States
f Washington University in St. Louis, United States
g University of California Los Angeles, United States
h Children's Hospital of Philadelphia, United States
i McGill University, United States
j Georgetown University, United States
k Neurostatistics Laboratory, Harvard University, McLean Hospital, United States
l Investigator of the Clinical Coordinating Center at Washington University, United States
m Diffusion Tensor Processing Center, United States
n National Institutes of Health, United States
o NIDA and NINDS, United States
p Spectroscopy Processing Center, University of California Los Angeles, United States


Abstract
Several studies using magnetic resonance imaging (MRI) scans have shown developmental trajectories of cortical thickness. Cognitive milestones happen concurrently with these structural changes, and a delay in such changes has been implicated in developmental disorders such as attention-deficit/hyperactivity disorder (ADHD). Accurate estimation of individuals' brain maturity, therefore, is critical in establishing a baseline for normal brain development against which neurodevelopmental disorders can be assessed. In this study, cortical thickness derived from structural magnetic resonance imaging (MRI) scans of a large longitudinal dataset of normally growing children and adolescents (n = 308), were used to build a highly accurate predictive model for estimating chronological age (cross-validated correlation up to R = 0.84). Unlike previous studies which used kernelized approach in building prediction models, we used an elastic net penalized linear regression model capable of producing a spatially sparse, yet accurate predictive model of chronological age. Upon investigating different scales of cortical parcellation from 78 to 10,240 brain parcels, we observed that the accuracy in estimated age improved with increased spatial scale of brain parcellation, with the best estimations obtained for spatial resolutions consisting of 2560 and 10,240 brain parcels. The top predictors of brain maturity were found in highly localized sensorimotor and association areas. The results of our study demonstrate that cortical thickness can be used to estimate individuals' brain maturity with high accuracy, and the estimated ages relate to functional and behavioural measures, underscoring the relevance and scope of the study in the understanding of biological maturity.


Author Keywords
Brain maturation;  Cortical thickness;  Elastic-net regularized regression;  Prediction model;  Structural magnetic resonance imaging


Document Type: Article
Source: Scopus




Dong-Si, T.a , Gheuens, S.a , Gangadharan, A.a , Wenten, M.a , Philip, J.b , McIninch, J.b , Datta, S.b , Richert, N.c , Bozic, C.a , Bloomgren, G.a , Richman, S.a , Weber, T.d , Clifford, D.B.e
Predictors of survival and functional outcomes in natalizumab-associated progressive multifocal leukoencephalopathy
(2015) Journal of NeuroVirology, 8 p. Article in Press. 

DOI: 10.1007/s13365-015-0316-4


a Drug Safety and Risk Management, Biogen Idec Inc., 225 Binney StreetCambridge, MA, United States
b Data Sciences, Biogen Idec Inc.Cambridge, MA, United States
c Neurology Research and Development, Biogen Idec Inc.Cambridge, MA, United States
d Marienkrankenhaus, Academic Teaching Hospital, University of HamburgHamburg, Germany
e Department of Neurology, Washington University School of MedicineSaint Louis, MO, United States


Abstract
Natalizumab, a highly effective therapy for relapsing-remitting multiple sclerosis, is associated with a risk of progressive multifocal leukoencephalopathy (PML). The objective of this analysis was to examine factors predicting survival in a large natalizumab-associated PML global population. Patients with natalizumab-associated PML identified through postmarketing surveillance were followed up for up to 24 months using a structured questionnaire completed by treating physicians. Demographic and clinical characteristics, JC viral load, magnetic resonance imaging (MRI) results, and Expanded Disability Status Scale (EDSS) and Karnofsky Performance Scale (KPS) scores were compared in survivors and nonsurvivors. Kaplan-Meier analysis was used to model survival function. Among the 336 patients included in this analysis, 76 % survived, with mean follow-up time from PML diagnosis of 16.1 months for survivors; mean time from diagnosis to death was 4.7 months for nonsurvivors. Survivors were significantly younger at diagnosis, had significantly lower EDSS scores and higher KPS scores prior to PML diagnosis, and had significantly lower cerebrospinal fluid JC viral load at the time of diagnosis. Patients with less extensive disease on MRI at diagnosis had a higher survival rate than those with widespread disease. Survivors generally had less functional disability pre-PML, at PML diagnosis, and in subsequent months. In survivors, functional disability appeared to stabilize approximately 6 months post-PML diagnosis. In this analysis, younger age at diagnosis, less functional disability prior to PML diagnosis, lower JC viral load at diagnosis, and more localized brain involvement by MRI at the time of diagnosis appeared to predict improved survival in natalizumab-associated PML.


Author Keywords
Expanded Disability Status Scale;  Karnofsky Performance Scale;  Natalizumab;  Progressive multifocal leukoencephalopathy;  Survival


Document Type: Article in Press
Source: Scopus




Bailey, H.R.a , Sargent, J.Q.a , Flores, S.a , Nowotny, P.b , Goate, A.b , Zacks, J.M.a
APOE ε4 genotype predicts memory for everyday activities
(2015) Aging, Neuropsychology, and Cognition, 28 p. Article in Press. 

DOI: 10.1080/13825585.2015.1020916


a Department of Psychology, Washington University, St. Louis, MO, USA
b Department of Psychiatry, Washington University, St. Louis, MO, USA


Abstract
The apolipoprotein E (ApOE) ε4 allele is associated with neuropathological buildup of amyloid in the brain, and with lower performance on some laboratory measures of memory in some populations. In two studies, we tested whether ApOE genotype affects memory for everyday activities. In Study 1, participants aged 20–79 years old (n = 188) watched movies of actors engaged in daily activities and completed memory tests for the activities in the movies. In Study 2, cognitively healthy and demented older adults (n = 97) watched and remembered similar movies, and also underwent structural MRI scanning. All participants provided saliva samples for genetic analysis. In both samples we found that, in older adults, ApOE ε4 carriers demonstrated worse everyday memory performance than did ε4 noncarriers. In Study 2, ApOE ε4 carriers had smaller medial temporal lobes (MTL) volumes, and MTL volume mediated the relationship between ApOE genotype and everyday memory performance. These everyday memory tasks measure genetically determined cognitive decline that can occur prior to a clinical diagnosis of dementia. Further, these tasks are easily administered and may be a useful clinical tool in identifying ε4 carriers who may be at risk for MTL atrophy and further cognitive decline that is a common characteristic of the earliest stages of Alzheimer’s disease.


Author Keywords
aging;  Alzheimer’s disease;  APOE;  episodic memory;  everyday memory


Document Type: Article in Press
Source: Scopus




Reddy, L.V., Miller, T.M.
RNA-targeted Therapeutics for ALS
(2015) Neurotherapeutics, 4 p. Article in Press. 

DOI: 10.1007/s13311-015-0344-z


Department of Neurology, Washington University, 660 S. EuclidSt. Louis, MO, United States


Abstract
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease leading to cell death of predominantly motor neurons. Despite extensive research in this disease, finding a way to slow the progress of the disease has been challenging. RNA-targeted therapeutic approaches, including small interfering RNA and antisense oligonucleotides are being developed for genetic forms of ALS. ALS provides an unique opportunity for the use of RNA inhibition strategies given a well-defined animal model, extensive available information regarding the causative genes, and recent experience in phase 1 clinical trial.


Document Type: Article in Press
Source: Scopus




Wong, A.W.K.a , Lai, J.-S.b , Correia, H.c , Cella, D.c
Evaluating Psychometric Properties of the Spanish-version of the Pediatric Functional Assessment of Chronic Illness Therapy-Perceived Cognitive Function (pedsFACIT-PCF)
(2015) Quality of Life Research, 7 p. Article in Press. 

DOI: 10.1007/s11136-015-0949-z


a Program in Occupational Therapy and Department of Neurology, Washington University School of MedicineSt. Louis, MO, United States
b Departments of Medical Social Sciences and Pediatrics, Northwestern University Feinberg School of Medicine, 633 N St. Clair, #19-039Chicago, IL, United States
c Department of Medical Social Sciences, Northwestern University Feinberg School of MedicineChicago, IL, United States


Abstract
Purpose: The pediatric Functional Assessment of Chronic Illness Therapy-Perceived Cognitive Function (pedsFACIT-PCF) is a 13-item short-form derived from the pediatric Perceived Cognitive Function item bank (pedsPCF), which was developed to measure children’s daily cognitive behaviors and was validated on the US general population and children with cancer. This study evaluated the psychometric properties of Spanish language pedsFACIT-PCF and the measurement equivalence between Spanish and English versions.

Methods: pedsFACIT-PCF items were translated into Spanish using a standard iterative methodology. A total of 1358 English- and 604 Spanish-speaking children aged 8–17 years who completed English and Spanish versions of pedsFACIT-PCF, respectively, were administered through an Internet survey company. Unidimensionality was evaluated using confirmatory factor analysis. Item responses were modeled using item response theory. The presence and impact of differential item functioning (DIF) were evaluated using ordinal logistic regression.

Results: Unidimensionality of the pedsFACIT-PCF was supported. One of the 13 items demonstrated statistically significant DIF by language; however, impacts of language DIF on both individual scores and at the test level were negligible. No Spanish items showed DIF with respect to age and gender.

Conclusions: The 13-item pedsFACIT-PCF demonstrated stable measurement properties on language, gender and age and can be used for future trials.


Author Keywords
Age;  Children;  Differential item functioning;  Gender;  Language;  Perceived Cognitive Function


Document Type: Article in Press
Source: Scopus




McNeely, M.E.a c , Duncan, R.P.a c , Earhart, G.M.a b c
A comparison of dance interventions in people with Parkinson disease and older adults
(2015) Maturitas, . Article in Press. 

DOI: 10.1016/j.maturitas.2015.02.007


a Program in Physical Therapy, Washington University School of Medicine in St. Louis, St. Louis, MO 63108, USA
b Department of Anatomy and Neurobiology, Washington University School of Medicine in St. Louis, St. Louis, MO 63108, USA
c Department of Neurology, Washington University School of Medicine in St. Louis, St. Louis, MO 63108, USA


Abstract
It is important for our aging population to remain active, particularly those with chronic diseases, like Parkinson disease (PD), which limit mobility. Recent studies in older adults and people with PD suggest dance interventions provide various motor benefits. The literature for dance in PD is growing, but many knowledge gaps remain, relative to what is known in older adults. The purpose of this review is to: (1) detail results of dance intervention studies in older adults and in PD, (2) describe limitations of dance research in these populations, and (3) identify directions for future study. Generally, a wide variety of dance styles have been investigated in older adults, while a more limited subset has been evaluated in PD. Measures vary widely across studies and a lack of standardized outcomes measures hinders cross-studies comparisons. Compared to the dance literature in older adults, there is a notable absence of evidence in the PD literature in outcome domains related to cardiovascular health, muscle strength, body composition, flexibility, and proprioception. As a whole, the dance literature supports substantial and wide-ranging benefits in both populations, but additional effort should be dedicated to well-designed comparative studies using standardized outcome measures to identify optimal treatment programs.


Author Keywords
Balance;  Dance;  Exercise;  Gait;  Parkinson disease;  Physical function


Document Type: Article in Press
Source: Scopus




Perez-Torres, C.J.a , Yuan, L.b , Schmidt, R.E.c , Rich, K.M.b , Ackerman, J.J.H.a d e , Garbow, J.R.a e
Perilesional edema in radiation necrosis reflects axonal degeneration
(2015) Radiation Oncology, 10 (1), art. no. 33, . 

DOI: 10.1186/s13014-015-0335-6


a Washington University, Department of Radiology, Campus Box 8227, 4525 Scott AvenueSaint Louis, MO, United States
b Washington University, Department NeurosurgerySaint Louis, MO, United States
c Washington University, Department of NeuropathologySaint Louis, MO, United States
d Washington University, Department of ChemistrySaint Louis, MO, United States
e Washington University School of Medicine, Alvin J Siteman Cancer CenterSt Louis, MO, United States


Abstract
Background: Recently, we characterized a Gamma Knife® radiation necrosis mouse model with various magnetic resonance imaging (MRI) protocols to identify biomarkers useful in differentiation from tumors. Though the irradiation was focal to one hemisphere, a contralateral injury was observed that appeared to be localized in the white matter only. Interestingly, this injury was identifiable in T2-weighted images, apparent diffusion coefficient (ADC), and magnetization transfer ratio (MTR) maps, but not on post-contrast T1-weighted images. This observation of edema independent of vascular changes is akin to the perilesional edema seen in clinical radiation necrosis. Findings: The pathology underlying the observed white-matter MRI changes was explored by performing immunohistochemistry for healthy axons and myelin. The presence of both healthy axons and myelin was reduced in the contralateral white-matter lesion. Conclusions: Based on our immunohistochemical findings, the contralateral white-matter injury is most likely due to axonal degeneration.


Author Keywords
Axonal degeneration;  Radiation necrosis;  White matter injury


Document Type: Article
Source: Scopus




Hsu, P.J.a , Shou, H.f , Benzinger, T.a b , Marcus, D.a , Durbin, T.a , Morris, J.C.c , Sheline, Y.I.a c d e
Amyloid burden in cognitively normal elderly is associated with preferential hippocampal subfield volume loss
(2015) Journal of Alzheimer's Disease, 45 (1), pp. 27-33. 

DOI: 10.3233/JAD-141743


a Department of Radiology, Washington University, School of MedicineSt. Louis, MO, United States
b Department of Neurosurgery, Washington University, School of MedicineSt. Louis, MO, United States
c Department of Neurology, Washington University, School of MedicineSt. Louis, MO, United States
d Department of Psychiatry, Washington University, School of MedicineSt. Louis, MO, United States
e Departments of Radiology, Neurology, and Psychiatry, University of Pennsylvania Perelman, School of MedicinePhiladelphia, PA, United States
f Departments of Biostatistics, University of Pennsylvania Perelman, School of MedicinePhiladelphia, PA, United States


Abstract
The earliest sites of brain atrophy in Alzheimer's disease are in the medial temporal lobe, following widespread cerebral cortical amyloid deposition. We assessed 74 cognitively normal participants with clinical measurements, amyloid-β-PET imaging, MRI, and a newly developed technique for MRI-based hippocampal subfield segmentation to determine the differential association of amyloid deposition and hippocampal subfield volume. Compared to amyloid-negative participants, amyloid-positive participants had significantly smaller hippocampal tail, presubiculum, subiculum, and total hippocampal gray matter volumes. We conclude that, prior to the development of cognitive impairment, atrophy in particular hippocampal subfields occurs preferentially with amyloid-β accumulation.


Author Keywords
Amyloid accumulation;  cognitively normal elderly;  hippocampal subfield volumes;  presubiculum;  subiculum


Document Type: Article
Source: Scopus




Miller, R.L.a , Denny, G.O.a , Knuepfer, M.M.b , Kleyman, T.R.c , Jackson, E.K.d , Salkoff, L.B.a , Loewy, A.D.a e
Blockade of ENaCs by amiloride induces c-Fos activation of the area postrema
(2015) Brain Research, 1601, art. no. 44015, pp. 40-51. 

DOI: 10.1016/j.brainres.2014.12.048


a Department of Anatomy and Neurobiology, Washington University School of Medicine, Box 8108, 660 S. Euclid Ave.St. Louis, MO, United States
b Department of Pharmacological and Physiological Science, St. Louis University School of Medicine, 1402 S. Grand Blvd.St. Louis, MO, United States
c Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh School of MedicinePittsburgh, PA, United States
d Department of Pharmacology and Chemical Biology, University of Pittsburgh School of MedicinePittsburgh, PA, United States
e Department of Anatomy and Neurobiology, Washington University, School of Medicine, Box 8108, 660 S. Euclid Ave.St. Louis, MO, United States


Abstract
Abstract Epithelial sodium channels (ENaCs) are strongly expressed in the circumventricular organs (CVOs), and these structures may play an important role in sensing plasma sodium levels. Here, the potent ENaC blocker amiloride was injected intraperitoneally in rats and 2 h later, the c-Fos activation pattern in the CVOs was studied. Amiloride elicited dose-related activation in the area postrema (AP) but only ~10% of the rats showed c-Fos activity in the organum vasculosum of the lamina terminalis (OVLT) and subfornical organ (SFO). Tyrosine hydroxylase-immunoreactive (catecholamine) AP neurons were activated, but tryptophan hydroxylase-immunoreactive (serotonin) neurons were unaffected. The AP projects to FoxP2-expressing neurons in the dorsolateral pons which include the pre-locus coeruleus nucleus and external lateral part of the parabrachial nucleus; both cell groups were c-Fos activated following systemic injections of amiloride. In contrast, another AP projection target - the aldosterone-sensitive neurons of the nucleus tractus solitarius which express the enzyme 11-β-hydroxysteriod dehydrogenase type 2 (HSD2) were not activated. As shown here, plasma concentrations of amiloride used in these experiments were near or below the IC50 level for ENaCs. Amiloride did not induce changes in blood pressure, heart rate, or regional vascular resistance, so sensory feedback from the cardiovascular system was probably not a causal factor for the c-Fos activity seen in the CVOs. In summary, amiloride may have a dual effect on sodium homeostasis causing a loss of sodium via the kidney and inhibiting sodium appetite by activating the central satiety pathway arising from the AP.


Author Keywords
Amiloride;  Area postrema;  Epithelial sodium channels;  FoxP2;  Parabrachial nucleus;  Pre-locus coeruleus


Document Type: Article
Source: Scopus




Avetisyan, M.a , Schill, E.M.a , Heuckeroth, R.O.b
Building a second brain in the bowel
(2015) Journal of Clinical Investigation, 125 (3), pp. 899-907. Cited 1 time.

DOI: 10.1172/JCI76307


a Washington University School of MedicineSt. Louis, MO, United States
b Children's Hospital of Philadelphia Research Institute, Perelman School of Medicine, Abramson Research Center, Suite 1116iPhiladelphia, PA, United States


Abstract
The enteric nervous system (ENS) is sometimes called the "second brain" because of the diversity of neuronal cell types and complex, integrated circuits that permit the ENS to autonomously regulate many processes in the bowel. Mechanisms supporting ENS development are intricate, with numerous proteins, small molecules, and nutrients that affect ENS morphogenesis and mature function. Damage to the ENS or developmental defects cause vomiting, abdominal pain, constipation, growth failure, and early death. Here, we review molecular mechanisms and cellular processes that govern ENS development, identify areas in which more investigation is needed, and discuss the clinical implications of new basic research.


Document Type: Review
Source: Scopus




Pappu, R.V.
Cell signaling, division, and organization mediated by intrinsically disordered proteins
(2015) Seminars in Cell and Developmental Biology, 37, pp. 1-2. 

DOI: 10.1016/j.semcdb.2015.01.003


Department of Biomedical Engineering and Center for Biological Systems Engineering, Washington University in St. Louis, One Brookings Drive, Box 1097St. Louis, MO, United States


Document Type: Editorial
Source: Scopus




Corbetta, M.a b c e , Ramsey, L.a d , Callejas, A.a , Baldassarre, A.a , Hacker, C.D.e , Siegel, J.S.d , Astafiev, S.V.a , Rengachary, J.a , Zinn, K.a , Lang, C.E.a f g , Connor, L.T.a b g , Fucetola, R.a , Strube, M.h , Carter, A.R.a , Shulman, G.L.a
Common behavioral clusters and subcortical anatomy in stroke
(2015) Neuron, 85 (5), pp. 927-941. Cited 1 time.

DOI: 10.1016/j.neuron.2015.02.027


a Department of Neurology, Washington University School of Medicine, Box 8111, 660 South Euclid AvenueSaint Louis, MO, United States
b Radiology, Washington University School of Medicine, Box 8111, 660 South Euclid AvenueSaint Louis, MO, United States
c Department of Anatomy and Neurobiology, Washington University School of Medicine, Box 8111, 660 South Euclid AvenueSaint Louis, MO, United States
d Division of Biomedical Sciences, Washington University School of Medicine, Box 8111, 660 South Euclid AvenueSaint Louis, MO, United States
e Department of Bioengineering, Washington University School of Medicine, Box 8111, 660 South Euclid AvenueSaint Louis, MO, United States
f Department of Physical Therapy, Washington University School of Medicine, Box 8111, 660 South Euclid AvenueSaint Louis, MO, United States
g Department of Occupational Therapy, Washington University School of Medicine, Box 8111, 660 South Euclid AvenueSaint Louis, MO, United States
h Department of Psychology, Washington University School of Medicine, Box 8111, 660 South Euclid AvenueSaint Louis, MO, United States


Abstract
A long-held view is that stroke causes many distinct neurological syndromes due to damage of specialized cortical and subcortical centers. However, it is unknown if a syndrome-based description is helpful in characterizing behavioral deficits across a large number of patients. We studied a large prospective sample of first-time stroke patients with heterogeneous lesions at 1-2weeks post-stroke. We measured behavior over multiple domains and lesion anatomy with structural MRI and a probabilistic atlasof white matter pathways. Multivariate methods estimated the percentage of behavioral variance explained by structural damage. A few clusters of behavioral deficits spanning multiple functions explained neurological impairment. Stroke topography was predominantly subcortical, and disconnection of white matter tracts critically contributed to behavioral deficits and their correlation. The locus of damage explained more variance for motor and language than memory or attention deficits. Our findings highlight the need for better models of white matter damage on cognition.


Document Type: Article
Source: Scopus




Kwate, N.O.A.a , Goodman, M.S.b
Cross-sectional and longitudinal effects of racism on mental health among residents of Black neighborhoods in New York City
(2015) American Journal of Public Health, 105 (4), pp. 711-718. 

DOI: 10.2105/AJPH.2014.302243


a Departments of Human Ecology and Africana Studies, Rutgers UniversityNew Brunswick, NJ, United States
b Department of Surgery, School of Medicine, Washington University in St. LouisSt. Louis, MO, United States


Abstract
Objectives. We investigated the impact of reported racism on the mental health of African Americans at cross-sectional time points and longitudinally, over the course of 1 year. Methods. The Black Linking Inequality, Feelings, and the Environment (LIFE) Study recruited Black residents (n = 144) from a probability sample of 2 predominantly Black New York City neighborhoods during December 2011 to June 2013. Respondents completed self-report surveys, including multiple measures of racism. We conducted assessments at baseline, 2-month follow-up, and 1-year follow-up. Weighted multivariate linear regression models assessed changes in racism and health over time. Results. Cross-sectional results varied by time point and by outcome, with only some measures associated with distress, and effects were stronger for poor mental health days than for depression. Individuals who denied thinking about their race fared worst. Longitudinally, increasing frequencies of racism predicted worse mental health across all 3 outcomes. Conclusions. These results support theories of racism as a health-defeating stressor and are among the few that show temporal associations with health.


Document Type: Article
Source: Scopus




Satoh, A.a , Brace, C.S.a , Rensing, N.b , Imai, S.-I.a
Deficiency of Prdm13, a dorsomedial hypothalamus-enriched gene, mimics age-associated changes in sleep quality and adiposity
(2015) Aging Cell, 14 (2), pp. 209-218. 

DOI: 10.1111/acel.12299


a Department of Developmental Biology, Washington University School of MedicineSt. Louis, MO, United States
b Department of Neurology, Washington University School of MedicineSt. Louis, MO, United States


Abstract
The dorsomedial hypothalamus (DMH) controls a number of essential physiological responses. We have demonstrated that the DMH plays an important role in the regulation of mammalian aging and longevity. To further dissect the molecular basis of the DMH function, we conducted microarray-based gene expression profiling with total RNA from laser-microdissected hypothalamic nuclei and tried to find the genes highly and selectively expressed in the DMH. We found neuropeptide VF precursor (Npvf), PR domain containing 13 (Prdm13), and SK1 family transcriptional corepressor (Skor1) as DMH-enriched genes. Particularly, Prdm13, a member of the Prdm family of transcription regulators, was specifically expressed in the compact region of the DMH (DMC), where Nk2 homeobox 1 (Nkx2-1) is predominantly expressed. The expression of Prdm13 in the hypothalamus increased under diet restriction, whereas it decreased during aging. Prdm13 expression also showed diurnal oscillation and was significantly upregulated in the DMH of long-lived BRASTO mice. The transcriptional activity of the Prdm13 promoter was upregulated by Nkx2-1, and knockdown of Nkx2-1 suppressed Prdm13 expression in primary hypothalamic neurons. Interestingly, DMH-specific Prdm13-knockdown mice showed significantly reduced wake time during the dark period and decreased sleep quality, which was defined by the quantity of electroencephalogram delta activity during NREM sleep. DMH-specific Prdm13-knockdown mice also exhibited progressive increases in body weight and adiposity. Our findings indicate that Prdm13/Nkx2-1-mediated signaling in the DMC declines with advanced age, leading to decreased sleep quality and increased adiposity, which mimic age-associated pathophysiology, and provides a potential link to DMH-mediated aging and longevity control in mammals.


Author Keywords
Age-associated pathophysiology;  Aging;  DMH-enriched gene;  Dorsomedial hypothalamus;  Nkx2-1;  NREM delta power;  Prdm13


Document Type: Article
Source: Scopus




Hong, J.S., Tillman, R., Luby, J.L.
Disruptive behavior in preschool children: Distinguishing normal misbehavior from markers of current and later childhood conduct disorder
(2015) Journal of Pediatrics, 166 (3), pp. 723-730. 

DOI: 10.1016/j.jpeds.2014.11.041


Department of Psychiatry, Washington University School of Medicine, Campus-Box 8134, 660 South Euclid Ave.St. Louis, MO, United States


Abstract
Objectives To investigate which disruptive behaviors in preschool were normative and transient vs markers of conduct disorder, as well as which disruptive behaviors predicted the persistence of conduct disorder into school age. Study design Data from a longitudinal study of preschool children were used to investigate disruptive behaviors. Caregivers of preschoolers ages 3.0-5.11 years (n = 273) were interviewed using the Preschool Age Psychiatric Assessment to derive the following diagnostic groups: conduct disorder, externalizing disorder without conduct disorder, internalizing disorder without externalizing disorder, and healthy. At school age, participants were again assessed via an age-appropriate diagnostic interview. Logistic and linear regression with pairwise group comparisons was used to investigate clinical markers of preschool conduct disorder and predictors of school age conduct disorder. Results Losing one's temper, low-intensity destruction of property, and low-intensity deceitfulness/stealing in the preschool period were found in both healthy and disordered groups. In contrast, high-intensity argument/defiant behavior, both low- and high-intensity aggression to people/animals, high-intensity destruction of property, high-intensity deceitfulness/stealing, and high-intensity peer problems were markers of preschool conduct disorder and predictors of school age conduct disorder. Inappropriate sexual behavior was not a marker for preschool conduct disorder but was a predictor of school age conduct disorder. Conclusion These findings provide a guide for primary care clinicians to help identify preschoolers with clinical conduct disorder and those who are at risk for persistent conduct disorder in childhood. Preschoolers displaying these symptoms should be targeted for mental health assessment.


Document Type: Article
Source: Scopus




Weidman, A.C.a , Levinson, C.A.b
I'm still socially anxious online: Offline relationship impairment characterizing social anxiety manifests and is accurately perceived in online social networking profiles
(2015) Computers in Human Behavior, 49, art. no. 3126, pp. 12-19. 

DOI: 10.1016/j.chb.2014.12.045


a University of British Columbia, Department of Psychology, 2136 West MallVancouver, BC, Canada
b Washington University in St. Louis, Department of Psychology, 1 Brookings DriveSt. Louis, MO, United States


Abstract
Prior research has identified the offline thoughts, feelings, and behaviors that lead to impaired relationships for individuals high in social anxiety (HSA; e.g., fear of conversation; interpersonal aloofness). We tested whether social anxiety manifests through visible online signals of relationship impairment that mirror these known offline indicators, and whether observers use these signals when judging social anxiety online. Facebook profile owners (n = 77) reported social anxiety, their profiles were coded for objective features, and unacquainted observers (n = 6) rated profile owners' social anxiety after viewing their profiles. HSA individuals' Facebook profiles were shown to contain signs indicating relationship impairment across the domains of social inactivity (e.g., few friends and photographs), close relationship quality (e.g., relationship status of single), and self-disclosure (e.g., absence of status updates), and observers inferred high levels of social anxiety in individuals' whose profiles showed these signs. These findings suggest that offline relationship impairment experienced by HSA individuals carries over into online contexts, and that online relationship impairment can be accurately perceived by unacquainted observers. Discussion considers whether integrating this knowledge into existing treatments - most notably online, self-guided protocols - could improve the identification and treatment of social anxiety.


Author Keywords
Facebook;  Impression formation;  Online;  Person perception;  Relationship impairment;  Social anxiety


Document Type: Article
Source: Scopus




Lee, A.Y.a , Akileswaran, L.b , Tibbetts, M.D.e , Garg, S.J.e , Van Gelder, R.N.b c d
Identification of torque teno virus in culture-negative endophthalmitis by representational deep DNA sequencing
(2015) Ophthalmology, 122 (3), pp. 524-530. 

DOI: 10.1016/j.ophtha.2014.09.001


a Department of Ophthalmology and Visual Science, Washington UniversitySt. Louis, MO, United States
b Department of Ophthalmology, University of Washington Medical School, 325 Ninth AvenueSeattle, WA, United States
c Department of Biological Structure, University of WashingtonSeattle, WA, United States
d Department of Pathology, University of WashingtonSeattle, WA, United States
e Retina Service of Wills Eye Hospital, MidAtlantic RetinaPhiladelphia, PA, United States


Abstract
Purpose To test the hypothesis that uncultured organisms may be present in cases of culture-negative endophthalmitis by use of deep DNA sequencing of vitreous biopsies. Design Single-center, consecutive, prospective, observational study. Participants Aqueous or vitreous biopsies from 21 consecutive patients presenting with presumed infectious endophthalmitis and 7 vitreous samples from patients undergoing surgery for noninfectious retinal disorders. Methods Traditional bacterial and fungal culture, 16S quantitative polymerase chain reaction (qPCR), and a representational deep-sequencing method (biome representational in silico karyotyping [BRiSK]) were applied in parallel to samples to identify DNA sequences corresponding to potential pathogens. Main Outcome Measures Presence of potential pathogen DNA in ocular samples. Results Zero of 7 control eyes undergoing routine vitreous surgery yielded positive results for bacteria or virus by culture or 16S polymerase chain reaction (PCR). A total of 14 of the 21 samples (66.7%) from eyes harboring suspected infectious endophthalmitis were culture-positive, the most common being Staphylococcal and Streptococcal species. There was good agreement among culture, 16S bacterial PCR, and BRiSK methodologies for culture-positive cases (Fleiss' kappa of 0.621). 16S PCR did not yield a recognizable pathogen sequence in any culture-negative sample, whereas BRiSK suggested the presence of Streptococcus in 1 culture-negative sample. With the use of BRiSK, 57.1% of culture-positive and 100% of culture-negative samples demonstrated the presence of torque teno virus (TTV) sequences, compared with none in the controls (P = 0.0005, Fisher exact test). The presence of TTV viral DNA was confirmed in 7 cases by qPCR. No other known viruses or potential pathogens were identified in these samples. Conclusions Culture, 16S qPCR, and BRiSK provide complementary information in presumed infectious endophthalmitis. The majority of culture-negative endophthalmitis samples did not contain significant levels of bacterial DNA. "Culture negativity" does not seem to be due to failure of growth of fastidious bacteria. The small DNA virus TTV was unexpectedly found in all culture-negative samples and some culture-positive samples. This study cannot distinguish whether TTV is a direct intraocular pathogen, an adjuvant for inflammation, a general marker of inflammation, or a commensal virus but provides a testable hypothesis for a pathogenic mechanism in culture-negative endophthalmitis.


Document Type: Article
Source: Scopus




Norris, S.A.a , Derdeyn, C.P.a b c , Perlmutter, J.S.a c d e f
Levodopa-Responsive Hemiparkinsonism Secondary to Cystic Expansion from a Coiled Cerebral Aneurysm
(2015) Journal of Neuroimaging, 25 (2), pp. 316-318. 

DOI: 10.1111/jon.12117


a Department of Neurology, Washington University School of MedicineSt. Louis, MO, United States
b Department of Neurological Surgery, Washington University School of MedicineSt. Louis, MO, United States
c Department of Radiology, Washington University School of MedicineSt. Louis, MO, United States
d Department of Anatomy and Neurobiology, Washington University School of MedicineSt. Louis, MO, United States
e Programs in Occupational Therapy, Washington University School of MedicineSt. Louis, MO, United States
f Department of Physical Therapy, Washington University School of MedicineSt. Louis, MO, United States


Abstract
An 80-year-old woman with longstanding hemifacial spasm had a 1 cm × 1.5 cm internal carotid artery terminus aneurysm treated with endovascularly delivered bare metal coils. Follow-up imaging revealed an expansile perianeurysmal cyst that coincided with development of contralateral dopa-responsive hemiparkinsonism. This is the first report of perianeurysmal cyst expansion causing levodopa-responsive hemiparkinsonism.


Author Keywords
Aneurysm;  Cyst;  Hemifacial spasm;  Levodopa;  Parkinsonism


Document Type: Article
Source: Scopus




Heath, A.C.
Metagenomics: A new frontier for translational research and personalized therapeutics in psychiatry?
(2015) Biological Psychiatry, 77 (7), art. no. 12445, pp. 600-601. 

DOI: 10.1016/j.biopsych.2015.01.013


Alcoholism Research Center, Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid, CB 8134St. Louis, MO, United States


Document Type: Short Survey
Source: Scopus




Lowe, D.A.a , Balsis, S.a , Hughes, M.L.a , Shine, H.E.a , Carpenter, B.D.b
Misconceptions of Alzheimer’s Disease
(2015) Clinical Gerontologist, 38 (2), pp. 149-156. 

DOI: 10.1080/07317115.2014.990600


a Texas A&M University, College StationTX, United States
b Washington University in St. LouisSt. Louis, MO, United States


Abstract
Misconceptions about Alzheimer’s disease (AD) are important to identify because they can interfere with treatment, caregiving, and understanding of the disease. The present study aimed to identify core misconceptions of AD and describe variations in endorsement of these misconceptions between groups (e.g., health care professionals vs. non–health care professionals); 2989 participants completed 10 items that assess AD misconceptions. There were notable differences in the prevalence of these misconceptions, which varied from 8% (prescription drugs can prevent Alzheimer’s disease) to 68% (reminder notes contribute to decline). Health care professionals were less likely to endorse that AD is a normal part of aging compared to non–health care professionals (13% vs. 16%). Understanding which misconceptions are most common is critical for designing and tailoring educational interventions.


Author Keywords
Alzheimer’s disease;  caregiving;  knowledge;  misconceptions


Document Type: Article
Source: Scopus




Goldman, M.D.a , Naismith, R.T.b
Multiple sclerosis, immunomodulation, and immunizations: Balancing the benefits
(2015) Neurology, 84 (9), pp. 864-865. 

DOI: 10.1212/WNL.0000000000001319


a Department of Neurology, University of VirginiaCharlottesville, United States
b Department of Neurology, Washington UniversitySaint Louis, MO, United States


Document Type: Editorial
Source: Scopus




Cooley, S.A.a , Cabeen, R.P.b , Laidlaw, D.H.b , Conturo, T.E.c , Lane, E.M.d , Heaps, J.M.a e , Bolzenius, J.D.a , Baker, L.M.a , Salminen, L.E.a , Scott, S.E.a , Paul, R.H.a e
Posterior brain white matter abnormalities in older adults with probable mild cognitive impairment
(2015) Journal of Clinical and Experimental Neuropsychology, 37 (1), pp. 61-69. 

DOI: 10.1080/13803395.2014.985636


a Department of Psychology, University of Missouri-Saint Louis, Stadler Hall 442B, One University BoulevardSaint Louis, MO, United States
b Computer Science Department, Brown UniversityProvidence, RI, United States
c Mallinckrodt Institute of Radiology, Washington University School of MedicineSaint Louis, MO, United States
d Vanderbilt University Medical CenterNashville, TN, United States
e Missouri Institute of Mental HealthSaint Louis, MO, United States


Abstract
Objective: Much of the mild cognitive impairment (MCI) neuroimaging literature has exclusively focused on regions associated with Alzheimers disease. Little research has examined white matter abnormalities of other brain regions, including those associated with visual processing, despite evidence that other brain abnormalities appear in these regions in early disease stages. Method: Diffusion tensor imaging (DTI) was utilized to examine participants (n = 44) that completed baseline imaging as part of a longitudinal healthy aging study. Participants were divided into two groups based on scores from the Montreal Cognitive Assessment (MoCA), a brief screening tool for MCI. Participants who scored <26 were defined as "probable MCI" while those who scored ≥26 were labeled cognitively healthy. Two DTI indices were analyzed including fractional anisotropy (FA) and mean diffusivity (MD). DTI values for white matter in the lingual gyrus, cuneus, pericalcarine, fusiform gyrus, and all four lobes were compared using multivariate analysis of variance (MANOVA). Regression analyses examined the relationship between DTI indices and total MoCA score. Results: Results revealed significantly lower FA in the probable MCI group in the cuneus, fusiform, pericalcarine, and occipital lobe, and significantly higher MD in the temporal lobe. Fusiform FA and temporal lobe MD were significantly related to total MoCA score after accounting for age and education. Conclusions: Results indicate that there are posterior white matter microstructural changes in individuals with probable MCI. These differences demonstrate that white matter abnormalities are evident among individuals with probable MCI in regions beyond those commonly associated with Alzheimers disease and anterior brain aging patterns.


Author Keywords
Aging;  Diffusion tensor imaging;  Fractional anisotropy;  Mild cognitive impairment;  Occipital lobe


Document Type: Article
Source: Scopus




Allen, M.G.a , Snyder, A.Z.a , Hacker, C.D.b , Mitchell, T.J.a , Leuthardt, E.C.c , Shimony, J.S.a
Presurgical resting-state fMRI
(2015) Medical Radiology, 142, pp. 143-158. 

DOI: 10.1007/978-3-662-45123-6_5


a Shimony Mallinckrodt Institute of Radiology, Washington University School of MedicineSaint Louis, MO, United States
b Department of Biomedical Engineering, Washington University School of MedicineSaint Louis, MO, United States
c Department of Neurosurgery, Washington University School of MedicineSaint Louis, MO, United States


Abstract
Purpose: Task-based fMRI has traditionally been used to locate eloquent regions of the brain that are relevant to specific cognitive tasks. These locations have, in turn, been used successfully to inform surgical planning. Resting-state functional MRI (fMRI) uses alternative methods to find networks, but does not require any task performance by a patient.

Materials and Methods: Resting-state fMRI uses correlations in the blood oxygen level–dependent (BOLD) signal to identify connected regions across the brain that form networks. Several methods of analyzing the data have been applied to calculate resting-state networks. In particular, seed-based correlation mapping and independent component analysis (ICA) are two commonly used techniques.

Results: Several studies using these analysis techniques are described in this chapter. Resting-state data has been used successfully as a presurgical planning tool in tumor patients and epilepsy patients.

Conclusions: Resting-state fMRI has been compared favorably to other methods of determining functional connectivity, including task-based fMRI and electrocortical stimulation. These results demonstrate great promise for the future of resting-state fMRI in presurgical planning.


Document Type: Article
Source: Scopus




Whitlock, E.L.a , Rodebaugh, T.L.b , Hassett, A.L.c , Shanks, A.M.c , Kolarik, E.c , Houghtby, J.c , West, H.M.a , Burnside, B.A.d , Shumaker, E.b , Villafranca, A.e , Edwards, W.A.d , Levinson, C.A.b , Langer, J.K.b , Fernandez, K.C.b , El-Gabalawy, R.f , Zhou, E.Y.d , Sareen, J.f , Jacobsohn, E.e , Mashour, G.A.c , Avidan, M.S.g
Psychological sequelae of surgery in a prospective cohort of patients from three intraoperative awareness prevention trials
(2015) Anesthesia and Analgesia, 120 (1), pp. 87-95. 

DOI: 10.1213/ANE.0000000000000498


a Department of Anesthesiology, Washington University, School of MedicineSt. Louis, MO, United States
b Department of Psychology, Washington University in St. LouisSt. Louis, MO, United States
c Department of Anesthesiology, University of Michigan Medical SchoolAnn Arbor, MI, United States
d Department of Anesthesiology, Washington University in St. LouisSt. Louis, MO, United States
e Department of Anesthesia and Perioperative Medicine, University of ManitobaWinnipeg, MB, Canada
f Department of Psychology and Community Health Sciences, University of ManitobaWinnipeg, MB, Canada
g Department of Anesthesiology and Surgery, School of Medicine, Washington University in St. Louis, 660 S. Euclid Ave.St. Louis, MO, United States


Abstract
BACKGROUND: Elective surgery can have long-term psychological sequelae, especially for patients who experience intraoperative awareness. However, risk factors, other than awareness, for symptoms of posttraumatic stress disorder (PTSD) after surgery are poorly defined, and practical screening methods have not been applied to a broad population of surgical patients. METHODS: The Psychological Sequelae of Surgery study was a prospective cohort study of patients previously enrolled in the United States and Canada in 3 trials for the prevention of intraoperative awareness. The 68 patients who experienced definite or possible awareness were matched with 418 patients who denied awareness based on age, sex, surgery type, and awareness risk. Participants completed the PTSD Checklist-Specific (PCL-S) and/or a modified Mini-International Neuropsychiatric Interview telephone assessment to identify symptoms of PTSD and symptom complexes consistent with a PTSD diagnosis. We then used structural equation modeling to produce a composite PTSD score and examined potential risk factors. RESULTS: One hundred forty patients were unreachable; of those contacted, 303 (88%) participated a median of 2 years postoperatively. Forty-four of the 219 patients (20.1%) who completed the PCL-S exceeded the civilian screening cutoff score for PTSD symptoms resulting from their surgery (15 of 35 [43%] with awareness and 29 of 184 [16%] without). Nineteen patients (8.7%; 5 of 35 [14%] with awareness and 14 of 184 [7.6%] without) both exceeded the cutoff and endorsed a breadth of symptoms consistent with the Diagnostic and Statistical Manual Fourth Edition diagnosis of PTSD attributable to their surgery. Factors independently associated with PTSD symptoms were poor social support, previous PTSD symptoms, previous mental health treatment, dissociation related to surgery, perceiving that one's life was threatened during surgery, and intraoperative awareness (all P ≤ 0.017). Perioperative dissociation was identified as a potential mediator for perioperative PTSD symptoms. CONCLUSIONS: Events in the perioperative period can precipitate psychological symptoms consistent with subsyndromal and syndromal PTSD. We not only confirmed the high rate of postoperative PTSD in awareness patients but also identified a significant rate in matched nonawareness controls. Screening surgical patients, especially those with potentially mediating risk factors such as intraoperative awareness or perioperative dissociation, for postoperative PTSD symptoms with the PCL-S is practical and could promote early referral, evaluation, and treatment.


Document Type: Article
Source: Scopus




Rutherford, M.A.a b
Resolving the structure of inner ear ribbon synapses with STED microscopy
(2015) Synapse, . Article in Press. 

DOI: 10.1002/syn.21812


a Department of OtolaryngologyCentral Institute for the Deaf, Washington University School of Medicine, Washington University School of MedicineSt. Louis, Missouri63110
b Inner Ear LabDepartment of OtolaryngologyUniversity of Göttingen Medical CenterGöttingen, GermanyD-37077


Abstract
Synapses are diverse in form and function; however, the mechanisms underlying this diversity are poorly understood. To illuminate structure/function relationships, robust analysis of molecular composition and morphology is needed. The molecular-anatomical components of synapses-vesicles, clusters of voltage-gated ion channels in presynaptic densities, arrays of transmitter receptors in postsynaptic densities-are only tens to hundreds of nanometers in size. Measuring the topographies of synaptic proteins requires nanoscale resolution of their molecularly specific labels. Super-resolution light microscopy has emerged to meet this need. Achieving 50 nm resolution in thick tissue, we employed stimulated emission depletion (STED) microscopy to image the functionally and molecularly unique ribbon-type synapses in the inner ear that connect mechano-sensory inner hair cells to cochlear nerve fibers. Synaptic ribbons, bassoon protein, voltage-gated Ca2+ channels, and glutamate receptors are inhomogeneous in their spatial distributions within synapses; the protein clusters assume variations of shapes typical for each protein specifically at cochlear afferent synapses. Heterogeneity of substructure among these synapses may contribute to functional differences among auditory nerve fibers. The morphology of synaptic voltage-gated Ca2+ channels matures over development in a way that depends upon bassoon protein, which aggregates in similar form. Functional properties of synaptic transmission appear to depend on voltage-gated Ca2+ channel cluster morphology and position relative to synaptic vesicles. Super-resolution light microscopy is a group of techniques that complement electron microscopy and conventional light microscopy. Although technical hurdles remain, we are beginning to resolve the details of molecular nanoanatomy that relate mechanistically to synaptic function.


Author Keywords
AMPA receptor;  Bassoon;  CaV1.3;  Cochlea;  CtBP2/Ribeye;  Hair cell;  Spiral ganglion neuron;  Stimulated emission depletion;  Stimulus-secretion coupling;  Super-resolution light microscopy


Document Type: Article in Press
Source: Scopus




Kunst, M.a , Tso, M.C.F.b , Ghosh, D.D.a , Herzog, E.D.b , Nitabach, M.N.a
Rhythmic control of activity and sleep by class B1 GPCRs
(2015) Critical Reviews in Biochemistry and Molecular Biology, 50 (1), pp. 18-30. 

DOI: 10.3109/10409238.2014.985815


a Department of Cellular and Molecular Physiology, Yale University School of MedicineNew Haven, CT, United States
b Department of Biology, Washington UniversitySt. Louis, MO, United States


Abstract
Members of the class B1 family of G-protein coupled receptors (GPCRs) whose ligands are neuropeptides have been implicated in regulation of circadian rhythms and sleep in diverse metazoan clades. This review discusses the cellular and molecular mechanisms by which class B1 GPCRs, especially the mammalian VPAC2 receptor and its functional homologue PDFR in Drosophila and C. elegans, regulate arousal and daily rhythms of sleep and wake. There are remarkable parallels in the cellular and molecular roles played by class B1 intercellular signaling pathways in coordinating arousal and circadian timekeeping across multiple cells and tissues in these very different genetic model organisms.


Author Keywords
Circadian;  Drosophila;  G-protein coupled receptor;  Neuropeptides;  Sleep;  Suprachiasmatic nucleus


Document Type: Review
Source: Scopus




Mickle, A.D.a c , Shepherd, A.J.a c , Mohapatra, D.P.a b c
Sensory TRP channels: The key transducers of nociception and pain
(2015) Progress in Molecular Biology and Translational Science, 131, pp. 73-118. 

DOI: 10.1016/bs.pmbts.2015.01.002


a Department of Pharmacology, University of Iowa, Roy J. and Lucile A. Carver College of MedicineIowa City, IA, United States
b Department of Anesthesia, University of Iowa, Roy J. and Lucile A. Carver College of MedicineIowa City, IA, United States
c Department of Anesthesiology, Washington University School of MedicineSt. Louis, MI, United States


Abstract
Peripheral detection of nociceptive and painful stimuli by sensory neurons involves a complex repertoire of molecular detectors and/or transducers on distinct subsets of nerve fibers. The majority of such molecular detectors/transducers belong to the transient receptor potential (TRP) family of cation channels, which comprise both specific receptors for distinct nociceptive stimuli, as well as for multiple stimuli. This chapter discusses the classification, distribution, and functional properties of individual TRP channel types that have been implicated in various nociceptive and/or painful conditions.


Author Keywords
TRP channel Nociception TRPV1 TRPV2 TRPV3 TRPV4 TRPM3 TRPM8 TRPA1 Pain


Document Type: Article
Source: Scopus




Kaplan, S.C.a , Levinson, C.A.a , Rodebaugh, T.L.a , Menatti, A.b , Weeks, J.W.b
Social Anxiety and the Big Five Personality Traits: The Interactive Relationship of Trust and Openness
(2015) Cognitive Behaviour Therapy, 44 (3), pp. 212-222. 

DOI: 10.1080/16506073.2015.1008032


a Department of Psychology, Washington University in St. LouisSt. Louis, United States
b Department of Psychology, Ohio UniversityAthens, United States


Abstract
It is well established that social anxiety (SA) has a positive relationship with neuroticism and a negative relationship with extraversion. However, findings on the relationships between SA and agreeableness, conscientiousness, and openness to experience are mixed. In regard to facet-level personality traits, SA is negatively correlated with trust (a facet of agreeableness) and self-efficacy (a facet of conscientiousness). No research has examined interactions among the Big Five personality traits (e.g., extraversion) and facet levels of personality in relation to SA. In two studies using undergraduate samples (N = 502; N = 698), we examined the relationships between trust, self-efficacy, the Big Five, and SA. SA correlated positively with neuroticism, negatively with extraversion, and had weaker relationships with agreeableness, openness, and trust. In linear regression predicting SA, there was a significant interaction between trust and openness over and above gender. In addition to supporting previous research on SA and the Big Five, we found that openness is related to SA for individuals low in trust. Our results suggest that high openness may protect against the higher SA levels associated with low trust.


Author Keywords
Big Five;  personality;  self-efficacy;  social anxiety;  trust


Document Type: Article
Source: Scopus




Hurth, K.a , Tarawneh, R.b c , Ghoshal, N.b c , Benzinger, T.L.S.b c d , Clifford, D.B.d , Geschwind, M.e , Morris, J.C.b c , Galvin, J.E.f , Schmidt, R.E.a , Cairns, N.J.a b c
Whipple's disease masquerades as dementia with lewy bodies
(2015) Alzheimer Disease and Associated Disorders, 29 (1), pp. 85-89. 

DOI: 10.1097/WAD.0b013e3182a715da


a Department of Pathology and Immunology, Division of Neuropathology, Washington University, 660 South Euclid AvenueSaint Louis, MO, United States
b Charles F. and Joanne Knight Alzheimer's Disease Research Center, United States
c Department of Neurology, United States
d Mallinckrodt Institute of Radiology, Washington University, School of MedicineSaint Louis, MO, United States
e Department of Neurology, University of CaliforniaSan Francisco, CA, United States
f Comprehensive Center on Brain Aging, New York University, Langone School of MedicineNew York, NY, United States


Author Keywords
bacterial infection;  dementia with Lewy bodies;  Whipple's disease


Document Type: Conference Paper
Source: Scopus




Gu, X.a b c , Cantle, J.a b c , Greiner, E.a d , Lee, C.Y.D.a b c , Barth, A.e , Gao, F.a b , Park, C.a b c , Zhang, Z.f g , Sandoval-Miller, S.a b c , Zhang, R.a b c , Diamond, M.f g , Mody, I.e , Coppola, G.a b c e , Yang, X.W.a b c
N17 Modifies Mutant Huntingtin Nuclear Pathogenesis and Severity of Disease in HD BAC Transgenic Mice
(2015) Neuron, . Article in Press. 

DOI: 10.1016/j.neuron.2015.01.008


a Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA 90095, USA
b Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
c Brain Research Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
d Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA 90095, USA
e Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
f Department of Neurology, Washington University School of Medicine St. Louis, MO 63110, USA
g Department of Neurology and Neurotherapeutics, University of Texas, Southwestern Medical Center, Dallas, TX 75390, USA


Abstract
The nucleus is a critical subcellular compartment forthe pathogenesis of polyglutamine disorders, including Huntington's disease (HD). Recent studies suggest the first 17-amino-acid domain (N17) of mutant huntingtin (mHTT) mediates its nuclear exclusion in cultured cells. Here, we test whether N17 could be a molecular determinant of nuclear mHTT pathogenesis invivo. BAC transgenic mice expressing mHTT lacking the N17 domain (BACHD-δN17) show dramatically accelerated mHTT pathology exclusively in the nucleus, which is associatedwith HD-like transcriptionopathy. Interestingly, BACHD-δN17 mice manifest more overt disease-like phenotypes than the original BACHD mice, including body weight loss, movement deficits, robust striatal neuron loss, and neuroinflammation. Mechanistically, N17 is necessary for nuclear exclusion of small mHTT fragments that are part of nuclear pathology in HD. Together, our study suggests that N17 modifies nuclear pathogenesis and disease severity in HD mice by regulating subcellularlocalization of known nuclear pathogenic mHTT species. Huntington's disease (HD) mice expressing mutant huntingtin lacking the N17 domain manifest overt motor deficits and striatal neurodegeneration that mimic those seen in HD patients. The study shows a pivotal role for N17 in modifying disease pathogenesis in the nucleus.


Document Type: Article in Press
Source: Scopus




Chen, Y.-H.a , McGowan, L.a , Cimino, P.b , Dahiya, S.b , Leonard, J.c , Lee, D.a , Gutmann, D.a
Mouse Low-Grade Gliomas Contain Cancer Stem Cells with Unique Molecular and Functional Properties
(2015) Cell Reports, . Article in Press. 

DOI: 10.1016/j.celrep.2015.02.041


a Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA
b Department of Pathology, Washington University School of Medicine, St. Louis, MO 63110, USA
c Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO 63110, USA


Abstract
The availability of adult malignant glioma stem cells (GSCs) has provided unprecedented opportunities to identify the mechanisms underlying treatment resistance. Unfortunately, there is a lack of comparable reagents for the study of pediatric low-grade glioma (LGG). Leveraging a neurofibromatosis 1 (Nf1) genetically engineered mouse LGG model, we report the isolation of CD133+ multi-potent low-grade glioma stem cells (LG-GSCs), which generate glioma-like lesions histologically similar to the parent tumor following injection into immunocompetent hosts. Inaddition, we demonstrate that these LG-GSCs harbor selective resistance to currently employed conventional and biologically targeted anti-cancer agents, which reflect the acquisition of new targetable signaling pathway abnormalities. Using transcriptomic analysis to identify additional molecular properties, we discovered that mouse and human LG-GSCs harbor high levels of Abcg1 expression critical for protecting against ER-stress-induced mouse LG-GSC apoptosis. Collectively, these findings establish that LGG cancer stem cells have unique molecular and functional properties relevant to brain cancer treatment. Leveraging a neurofibromatosis 1 (Nf1) mouse glioma model, Chen etal. identify CD133+ low-grade glioma stem cells (LG-GSCs), which form histologically similar tumors following transplantation and acquire targetable resistance mechanisms to anti-cancer agents. In addition, human and mouse LG-GSCs express Abcg1, critical for protecting against ER-stress-induced mouse LG-GSC apoptosis.


Document Type: Article in Press
Source: Scopus




Duncan, A.E.a b c , Sartor, C.E.b d , Jonson-Reid, M.a , Munn-Chernoff, M.A.b c , Eschenbacher, M.A.f , Diemer, E.W.a , Nelson, E.C.b c , Waldron, M.b e , Bucholz, K.K.b c , Madden, P.A.F.b c , Heath, A.C.b c
Associations between body mass index, post-traumatic stress disorder, and child maltreatment in young women
(2015) Child Abuse and Neglect, . Article in Press. 

DOI: 10.1016/j.chiabu.2015.02.007


a George Warren Brown School of Social Work, Washington University, St. Louis, MO, USA
b Midwest Alcoholism Research Center, Washington University School of Medicine, St. Louis, MO, USA
c Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA
d Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA
e School of Education, Indiana University, Bloomington, IN, USA
f E. Kenneth Hatton Institute for Research and Education, Cincinnati, OH, USA


Abstract
The objective of this study was to examine interrelationships between child maltreatment, post-traumatic stress disorder (PTSD) and body mass index (BMI) in young women. We used multinomial logistic regression models to explore the possibility that PTSD statistically mediates or moderates the association between BMI category and self-reported childhood sexual abuse (CSA), physical abuse (CPA), or neglect among 3,699 young women participating in a population-based twin study. Obese women had the highest prevalence of CSA, CPA, neglect, and PTSD (p <. .001 for all). Although all three forms of child maltreatment were significantly, positively associated with overweight and obesity in unadjusted models, only CSA was significantly associated with obesity after adjusting for other forms of maltreatment and covariates (OR = 2.21, 95% CI: 1.63, 3.00). CSA and neglect, but not CPA, were associated with underweight in unadjusted models; however, after adjusting for other forms of maltreatment and covariates, the associations were no longer statistically significant (OR = 1.43, 95% CI: 0.90-2.28 and OR = 2.16, 95% CI: 0.90-5.16 for CSA and neglect, respectively). Further adjustment for PTSD generally resulted in modest attenuation of effects across associations of child maltreatment forms with BMI categories, suggesting that PTSD may, at most, be only a weak partial mediator of these associations. Future longitudinal studies are needed to elucidate the mechanisms linking CSA and obesity and to further evaluate the role of PTSD in associations between child maltreatment and obesity.


Author Keywords
BMI;  Child maltreatment;  Obesity;  PTSD


Document Type: Article in Press
Source: Scopus




Stewart, S.B.a b , Greene, D.J.b c , Lessov-Schlaggar, C.N.b , Church, J.A.d , Schlaggar, B.L.a b c e f
Clinical Correlates of Parenting Stress in Children with Tourette Syndrome and in Typically Developing Children
(2015) Journal of Pediatrics, . Article in Press. 

DOI: 10.1016/j.jpeds.2015.01.041


a Department of Neurology, School of Medicine, Washington University in St Louis, St Louis, MO
b Department of Psychiatry, School of Medicine, Washington University in St Louis, St Louis, MO
c Department of Radiology, School of Medicine, Washington University in St Louis, St Louis, MO
d Department of Psychology, The University of Texas at Austin, Austin, TX
e Departments of Pediatrics, School of Medicine, Washington University in St Louis, St Louis, MO
f Departments of Anatomy and Neurobiology, School of Medicine, Washington University in St Louis, St Louis, MO


Abstract
Objective: To determine the impact of tic severity in children with Tourette syndrome on parenting stress and the impact of comorbid attention-deficit hyperactivity disorder (ADHD) and obsessive-compulsive disorder (OCD) symptomatology on parenting stress in both children with Tourette syndrome and typically developing children. Study design: Children with diagnosed Tourette syndrome (n = 74) and tic-free typically developing control subjects (n = 48) were enrolled in a cross-sectional study. Results: Parenting stress was greater in the group with Tourette syndrome than the typically developing group. Increased levels of parenting stress were related to increased ADHD symptomatology in both children with Tourette syndrome and typically developing children. Symptomatology of OCD was correlated with parenting stress in Tourette syndrome. Parenting stress was independent of tic severity in patients with Tourette syndrome. Conclusions: For parents of children with Tourette syndrome, parenting stress appears to be related to the child's ADHD and OCD comorbidity and not to the severity of the child's tic. Subthreshold ADHD symptomatology also appears to be related to parenting stress in parents of typically developing children. These findings demonstrate that ADHD symptomatology impacts parental stress both in children with and without a chronic tic disorder.


Document Type: Article in Press
Source: Scopus




Delforterie, M.J.a , Lynskey, M.T.b , Huizink, A.C.a , Creemers, H.E.c , Grant, J.D.d , Few, L.R.d , Glowinski, A.L.d , Statham, D.J.e , Trull, T.J.f , Bucholz, K.K.d , Madden, P.A.F.d , Martin, N.G.e , Heath, A.C.d , Agrawal, A.d
The relationship between cannabis involvement and suicidal thoughts and behaviors
(2015) Drug and Alcohol Dependence, . Article in Press. 

DOI: 10.1016/j.drugalcdep.2015.02.019


a VU University, Department of Developmental Psychology and EMGO Institute for Health and Care Research, Amsterdam, The Netherlands
b Addictions Department, Institute of Psychiatry, King's College London, United Kingdom
c Research Institute of Child Development and Education, University of Amsterdam, Amsterdam, The Netherlands
d Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA
e School of Social Sciences, University of the Sunshine Coast, Queensland, Australia
f University of Missouri, Department of Psychological Sciences, Columbia, MO, USA


Abstract
Background: In the present study, we examined the relationship between cannabis involvement and suicidal ideation (SI), plan and attempt, differentiating the latter into planned and unplanned attempt, taking into account other substance involvement and psychopathology. Methods: We used two community-based twin samples from the Australian Twin Registry, including 9583 individuals (58.5% female, aged between 27 and 40). The Semi-Structured Assessment of the Genetics of Alcoholism (SSAGA) was used to assess cannabis involvement which was categorized into: (0) no cannabis use (reference category); (1) cannabis use only; (2) 1-2 cannabis use disorder symptoms; (3) 3 or more symptoms. Separate multinomial logistic regression analyses were conducted for SI and suicide attempt with or without a plan. Twin analyses examined the genetic overlap between cannabis involvement and SI. Results: All levels of cannabis involvement were related to SI, regardless of duration (odds ratios [ORs] = 1.28-2.00, p <. 0.01). Cannabis use and endorsing ≥3 symptoms were associated with unplanned (SANP; ORs = 1.95 and 2.51 respectively, p <. 0.05), but not planned suicide attempts (p > 0.10). Associations persisted even after controlling for other psychiatric disorders and substance involvement. Overlapping genetic (rG = 0.45) and environmental (rE = 0.21) factors were responsible for the covariance between cannabis involvement and SI. Conclusions: Cannabis involvement is associated, albeit modestly, with SI and unplanned suicide attempts. Such attempts are difficult to prevent and their association with cannabis use and cannabis use disorder symptoms requires further study, including in different samples and with additional attention to confounders.


Author Keywords
Cannabis use;  Cannabis use disorder symptoms;  Suicidal thoughts and behaviors


Document Type: Article in Press
Source: Scopus




Yang, S.a , Sung, J.a b , Kim, J.-H.c , Song, Y.-M.d , Lee, K.e , Kim, H.-N.f , Kim, H.-L.f , Cloninger, C.R.g
Some personality traits converge gradually by long-term partnership through the lifecourse - Genetic and environmental structure of Cloninger's temperament and character dimensions
(2015) Journal of Psychiatric Research, . Article in Press. 

DOI: 10.1016/j.jpsychires.2015.01.020


a Complex Disease and Genome Epidemiology Branch, Department of Epidemiology, School of Public Health, Seoul National University, Korea
b Institute of Environment and Health, Seoul National University, Korea
c Department of Psychiatry, Samsung Medical Center, Sungkyunkwan University School of Medicine, Korea
d Department of Family Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Korea
e Department of Family Medicine, Busan Paik Hospital, Inje University College of Medicine, Korea
f Department of Biochemistry, School of Medicine, Ewha Womans University, Korea
g Departments of Psychiatry, Genetics, and Psychology, Washington University, St. Louis, MO, USA


Abstract
Temperament and Character Inventory (TCI) is a comprehensive personality inventory that is widely used in behavioral genetics. The original theory suggested that temperament traits were under genetic influences, whereas character traits were gradually built by an interaction between temperaments and environment until early adulthood. This study attempted to evaluate TCI by examining the genetic and environmental contributions to personality with particular attention to spousal effects. From 687 families, a total of 3459 Korean adult individuals completed the survey. Among them, there were 542 Monozygotic (MZ) twin pairs and 122 Dizygotic twin pairs. Intraclass correlation coefficients (ICCs) and heritability were calculated to examine the genetic and shared environmental contributions to personality. Moderate genetic contributions (0.17-0.43) were found for all TCI traits along with the evidence of shared environment (0.11-0.31) for harm avoidance (HA) and all characters. The ICCs of TCI in MZ pairs ranged 0.36-0.46. Spouses' had little resemblance for temperament, whereas for character dimensions, spouses (0.27-0.38) were more similar than first degree relatives (0.10-0.29). Resemblance between spouses increased with duration of marriage for most characters and HA. When the growing similarities between spouses were compared with their MZ cotwins' for subgroup of 81 trios, self-directedness (SD) of character showed even more similarities toward their spouses than cotwins as partnership duration increased (r=0.32). Our findings with regard to change in SD into late adulthood support the psychobiological theory of temperament and character, which suggests that both personality domains have distinct developmental trajectories despite equally large genetic influences.


Author Keywords
Heritability;  Personality;  Temperament and character inventory;  Twin-family study


Document Type: Article in Press
Source: Scopus




Agrawal, A.a , Lynskey, M.T.b , Kapoor, M.a , Bucholz, K.K.a , Edenberg, H.J.c , Schuckit, M.d , Brooks, A.e , Hesselbrock, V.f , Kramer, J.g , Saccone, N.h , Tischfield, J.d , Bierut, L.J.a
Are genetic variants for tobacco smoking associated with cannabis involvement?
(2015) Drug and Alcohol Dependence, . Article in Press. 

DOI: 10.1016/j.drugalcdep.2015.02.029


a Washington University School of Medicine, Department of Psychiatry, St. Louis, MO, USA
b Institute of Psychiatry, Addictions Department, London, UK
c Indiana University School of Medicine, Indianapolis, IN, USA
d University of California, San Diego, CA, USA
e Rutgers University, Department of Genetics, Piscataway, NJ, USA
f University of Connecticut Health Center, Department of Psychiatry, Farmington, CT, USA
g University of Iowa Carver College of Medicine, Iowa City, IA, USA
h Washington University School of Medicine, Department of Genetics, St. Louis, MO, USA


Abstract
Background: Cannabis users are highly likely to also be tobacco cigarette smokers and a proportion of this comorbidity is attributable to shared genetic influences. Three large meta-analyses of genomewide association studies (GWAS) of tobacco smoking have identified multiple genomewide significant (p &lt;5×10-8) single nucleotide polymorphisms (SNPs). We examine whether these SNPs are associated with tobacco smoking and with cannabis involvement in an independent sample. Method: Eleven SNPs associated with cigarettes per day (CPD), ever versus never smoking and current smoking/smoking cessation at p &lt;5×10-8 were selected from three published meta-analyses. Association analyses were conducted with similar tobacco smoking measures in 2716 European-American subjects from the Study of Addictions Genes and Environment (SAGE) and with lifetime and current cannabis use and DSM-IV cannabis abuse/dependence. Results: Cannabis use and tobacco smoking correlated at 0.54. Rs16969968 in CHRNA5 (and its proxy, rs1051730 in CHRNA3) and rs1451240, a proxy for rs13280604 in CHRNB3, were associated with CPD after Bonferroni correction (p &lt;. 0.006). rs1451240 was also associated with DSM-IV cannabis abuse/dependence. Rs6265 in BDNF was associated with smoking initiation, as in the original meta-analysis and also with lifetime cannabis use. Associations with cannabis involvement were no longer significant upon adjustment for the tobacco smoking measures. Conclusions: The modest associations between cannabis involvement and SNPs for tobacco smoking were not independent of the comorbidity between tobacco and cannabis involvement. Larger samples of individuals might be required to articulate the specific genetic architecture of cannabis involvement.


Author Keywords
Cannabis;  Chrna5;  Tobacco


Document Type: Article in Press
Source: Scopus




Kantrowitz, J.T.a b , Scaramello, N.a , Jakubovitz, A.a , Lehrfeld, J.M.a , Laukka, P.c , Elfenbein, H.A.d , Silipo, G.a , Javitt, D.C.b
Amusia and protolanguage impairments in schizophrenia
(2014) Psychological Medicine, 44 (13), pp. 2739-2748. Cited 1 time.

DOI: 10.1017/S0033291714000373


a Schizophrenia Research Center, Nathan Kline Institute for Psychiatric Research, 140 Old Orangeburg RoadOrangeburg, NY, United States
b Department of Psychiatry, Columbia UniversityNew York, NY, United States
c Department of Psychology, Stockholm University, Sweden
d Olin Business School, Washington UniversitySt Louis, MO, United States


Abstract
Background Both language and music are thought to have evolved from a musical protolanguage that communicated social information, including emotion. Individuals with perceptual music disorders (amusia) show deficits in auditory emotion recognition (AER). Although auditory perceptual deficits have been studied in schizophrenia, their relationship with musical/protolinguistic competence has not previously been assessed. Method Musical ability was assessed in 31 schizophrenia/schizo-affective patients and 44 healthy controls using the Montreal Battery for Evaluation of Amusia (MBEA). AER was assessed using a novel battery in which actors provided portrayals of five separate emotions. The Disorganization factor of the Positive and Negative Syndrome Scale (PANSS) was used as a proxy for language/thought disorder and the MATRICS Consensus Cognitive Battery (MCCB) was used to assess cognition. Results Highly significant deficits were seen between patients and controls across auditory tasks (p < 0.001). Moreover, significant differences were seen in AER between the amusia and intact music-perceiving groups, which remained significant after controlling for group status and education. Correlations with AER were specific to the melody domain, and correlations between protolanguage (melody domain) and language were independent of overall cognition. Discussion This is the first study to document a specific relationship between amusia, AER and thought disorder, suggesting a shared linguistic/protolinguistic impairment. Once amusia was considered, other cognitive factors were no longer significant predictors of AER, suggesting that musical ability in general and melodic discrimination ability in particular may be crucial targets for treatment development and cognitive remediation in schizophrenia.


Author Keywords
Amusia;  emotion;  language;  music;  schizophrenia;  social cognition


Document Type: Article
Source: Scopus




Sun, S.Q.a , Kim, A.H.b , Cai, C.c , Murphy, R.K.J.b , DeWees, T.d , Sylvester, P.a , Dacey, R.G.b , Grubb, R.L.b , Rich, K.M.b , Zipfel, G.J.b , Dowling, J.L.b , Leuthardt, E.C.b , Leonard, J.R.b , Evans, J.b , Simpson, J.R.d , Robinson, C.G.d , Perrin, R.J.c , Huang, J.d , Chicoine, M.R.b
Management of atypical cranial meningiomas, Part 1: Predictors of recurrence and the role of adjuvant radiation after gross total resection
(2014) Neurosurgery, 75 (4), pp. 347-354. 


a Washington University School of MedicineSt. Louis, MO, United States
b Department of Neurosurgery, School of Medicine, Washington University, CB 8057, 660 S Euclid AveSt. Louis, MO, United States
c Department of Pathology and Immunology, Washington UniversitySt. Louis, MO, United States
d Department of Radiation Oncology, Washington UniversitySt. Louis, MO, United States


Abstract
CONCLUSION: Brain invasion and high mitotic rates may predict recurrence. After GTR of AMs, EBRT appears not to affect progression-free survival and overall survival, suggesting that observation rather than EBRT may be indicated after GTR.

BACKGROUND: Indications for external beam radiation therapy (EBRT) for atypical meningiomas (AMs) remain unclear.

OBJECTIVE: To analyze features associated with recurrence in AM patients after gross total resection (GTR) and to assess the relative benefit of EBRT in a retrospective cohort study.

METHODS: One hundred fifty-one primary AMs after GTR (88 female patients; median follow-up, 45.0 months) were examined for possible predictors of recurrence (age, sex, location, volume, bone involvement, brain invasion). The Fisher exact and Wilcoxon rank-sum tests were used to analyze the association between these predictors and use of EBRT. The impact on recurrence for these predictors and EBRT was analyzed with Kaplan-Meier and Cox regression.

RESULTS: Of 151 patients, 13 (8.6%) experienced recurrence after GTR (median, 47.0 months). Multivariate analysis identified elevated mitotic index (P = .007) and brain invasion (P = .002) as predictors of recurrence. Larger volume (P = .96) was not associated with recurrence but was more likely to prompt EBRT (P = .001). Recurrences occurred in 11 of 112 with GTR (9.8%; median, 44 months) and 2 of 39 with GTR/EBRT (5.1%; median, 133 months). The 2-, 5-, and 10-year progression-free survival rates after GTR vs GTR/ EBRT were 97%, 86%, and 68% vs 100%, 100%, and 78%. Kaplan-Meier analysis demonstrated no difference in progression-free survival or overall survival after GTR vs GTR/ EBRT (P = .8, P . .99).


Author Keywords
Adjuvant;  Local/therapy;  Meningioma/mortality;  Meningioma/pathology;  Meningioma/therapy;  Neoplasm recurrence;  Prognosis;  Radiotherapy;  Retrospective studies


Document Type: Article
Source: Scopus




Sun, S.Q.a , Cai, C.b , Murphy, R.K.J.c , Dewees, T.d , Dacey, R.G.d , Grubb, R.L.c , Rich, K.M.c , Zipfel, G.J.c , Dowling, J.L.c , Leuthardt, E.C.c , Leonard, J.R.c , Evans, J.c , Simpson, J.R.d , Robinson, C.G.d , Perrin, R.J.d , Huang, J.d , Chicoine, M.R.d , Kim, A.H.c
Management of atypical cranial meningiomas, Part 2: Predictors of progression and the role of adjuvant radiation after subtotal resection
(2014) Neurosurgery, 75 (4), pp. 356-363. 

DOI: 10.1227/NEU.0000000000000462


a Washington University School of MedicineSt. Louis, MO, United States
b Departments of Pathology and Immunology, Washington UniversitySt. Louis, MO, United States
c Departments of Neurosurgery, School of Medicine, Washington University, CB 8057, 660 S Euclid AveSt. Louis, MO, United States
d Departments of Radiation Oncology, Washington UniversitySt. Louis, MO, United States


Abstract
BACKGROUND: The efficacies of adjuvant stereotactic radiosurgery (SRS) and external beam radiation therapy (EBRT) for atypical meningiomas (AMs) after subtotal resection (STR) remain unclear.

OBJECTIVE: To analyze the clinical, histopathological, and radiographic features associated with progression in AM patients after STR. METHODS: Fifty-nine primary AMs after STR were examined for predictors of progression, including the impact of SRS and EBRT, in a retrospective cohort study.

RESULTS: Twenty-seven patients (46%) progressed after STR (median, 30 months). On univariate analysis, spontaneous necrosis positively (hazard ratio = 5.2; P = .006) and adjuvant radiation negatively (hazard ratio = 0.3; P = .009) correlated with progression; on multivariate analysis, only adjuvant radiation remained independently significant (hazard ratio = 0.3; P = .006). SRS and EBRT were associated with greater local control (LC; P = .02) and progression-free survival (P = .007). The 2-, 5-, and 10-year actuarial LC rates after STR vs STR/EBRT were 60%, 34%, and 34% vs 96%, 65%, and 45%. The 2-, 5-, and 10-year actuarial progression-free survival rates after STR vs STR/EBRT were 60%, 30%, and 26% vs 96%, 65%, and 45%. Compared with STR alone, adjuvant radiation therapy significantly improved LC in AMs that lack spontaneous necrosis (P = .003) but did not improve LC in AMs with spontaneous necrosis (P = .6).

CONCLUSION: Adjuvant SRS or EBRT improved LC of AMs after STR but only for tumors without spontaneous necrosis. Spontaneous necrosis may aid in decisions to administer adjuvant SRS or EBRT after STR of AMs.


Author Keywords
Adjuvant;  Local/therapy;  Meningioma/mortality;  Meningioma/pathology;  Meningioma/therapy;  Neoplasm recurrence;  Radiation tolerance;  Radiotherapy;  Retrospective studies


Document Type: Article
Source: Scopus




Serletis, D.a , Bulacio, J.b , Alexopoulos, A.b , Najm, I.b , Bingaman, W.b , González-Martínez, J.b
Tailored unilobar and multilobar resections for orbitofrontal-plus epilepsy
(2014) Neurosurgery, 75 (4), pp. 388-397. 

DOI: 10.1227/NEU.0000000000000481


a Departments of Neurosurgery, School of Medicine, Washington University, CB 8057, 660 S Euclid AveSt. Louis, MO, United States
b Epilepsy Center, Cleveland Clinic, Neurological Institute, 9500 Euclid Ave, S60Cleveland, OH, United States


Abstract
BACKGROUND: Surgery for frontal lobe epilepsy often has poor results, likely because of incomplete resection of the epileptogenic zone.

OBJECTIVE: To present our experience with a series of patients manifesting 2 different anatomo-electro-clinical patterns of refractory orbitofrontal epilepsy, necessitating different surgical approaches for resection in each group.

METHODS: Eleven patients with refractory epilepsy involving the orbitofrontal region were consecutively identified over 3 years in whom stereoelectroencephalography identified the epileptogenic zone. All patients underwent preoperative evaluation, stereoelectroencephalography, and postoperative magnetic resonance imaging. Demographic features, seizure semiology, imaging characteristics, location of the epileptogenic zone, surgical resection site, and pathological diagnosis were analyzed. Surgical outcome was correlated with type of resection.

RESULTS: Five patients exhibited orbitofrontal plus frontal epilepsy with the epileptogenic zone consistently residing in the frontal lobe; after surgery, 4 patients were free of disabling seizures (Engel I) and 1 patient improved (Engel II). The remaining 6 patients had multilobar epilepsy with the epileptogenic zone located in the orbitofrontal cortex associated with the temporal polar region (orbitofrontal plus temporal polar epilepsy). After surgery, all 6 patients were free of disabling seizures (Engel I). Pathology confirmed focal cortical dysplasia in all patients. We report no complications or mortalities in this series.

CONCLUSION: Our findings highlight the importance of differentiating between orbitofrontal plus frontal and orbitofrontal plus temporal polar epilepsy in patients afflicted with seizures involving the orbitofrontal cortex. For identified cases of orbitofrontal plus temporal polar epilepsy, a multilobar resection including the temporal pole may lead to improved postoperative outcomes with minimal morbidity or mortality.


Author Keywords
Epilepsy;  Focal cortical dysplasia;  Multilobar resection;  Orbitofrontal;  Stereoelectroencephalography

 


Document Type: Article
Source: Scopus

 

 

March 5, 2015

Sylvester, C.M.a , Hudziak, J.J.b , Gaffrey, M.S.a , Barch, D.M.a c d , Luby, J.L.a
Stimulus-Driven Attention, Threat Bias, and Sad Bias in Youth with a History of an Anxiety Disorder or Depression
(2015) Journal of Abnormal Child Psychology, 13 p. Article in Press. 

DOI: 10.1007/s10802-015-9988-8


a Department of Psychiatry, Washington University School of Medicine, 4444 Forest Park Avenue, Campus Box 8511St. Louis, MO, United States
b Department of Psychiatry, University of Vermont College of Medicine, 1 South Prospect, UHC St. Joseph’s Room 3213Burlington, VT, United States
c Department of Psychology, Washington University School of Medicine, One Brookings Drive, Campus Box 1125St. Louis, MO, United States
d Department of Radiology, Washington University School of Medicine, One Brookings Drive, Campus Box 1125St. Louis, MO, United States


Abstract
Attention biases towards threatening and sad stimuli are associated with pediatric anxiety and depression, respectively. The basic cognitive mechanisms associated with attention biases in youth, however, remain unclear. Here, we tested the hypothesis that threat bias (selective attention for threatening versus neutral stimuli) but not sad bias relies on stimulus-driven attention. We collected measures of stimulus-driven attention, threat bias, sad bias, and current clinical symptoms in youth with a history of an anxiety disorder and/or depression (ANX/DEP; n = 40) as well as healthy controls (HC; n = 33). Stimulus-driven attention was measured with a non-emotional spatial orienting task, while threat bias and sad bias were measured at a short time interval (150 ms) with a spatial orienting task using emotional faces and at a longer time interval (500 ms) using a dot-probe task. In ANX/DEP but not HC, early attention bias towards threat was negatively correlated with later attention bias to threat, suggesting that early threat vigilance was associated with later threat avoidance. Across all subjects, stimulus-driven orienting was not correlated with early threat bias but was negatively correlated with later threat bias, indicating that rapid stimulus-driven orienting is linked to later threat avoidance. No parallel relationships were detected for sad bias. Current symptoms of depression but not anxiety were related to decreased stimulus-driven attention. Together, these results are consistent with the hypothesis that threat bias but not sad bias relies on stimulus-driven attention. These results inform the design of attention bias modification programs that aim to reverse threat biases and reduce symptoms associated with pediatric anxiety and depression.


Author Keywords
Adolescent;  Anxiety;  Attention bias;  Depression;  Sad bias;  Stimulus-driven attention;  Threat bias


Document Type: Article in Press
Source: Scopus




Ferentinos, P.a b , Koukounari, A.c , Power, R.a , Rivera, M.a d , Uher, R.a e , Craddock, N.f , Owen, M.J.f , Korszun, A.g , Jones, L.h , Jones, I.f , Gill, M.i , Rice, J.P.a j , Ising, M.a k , Maier, W.a l , Mors, O.a m , Rietschel, M.a n , Preisig, M.a o , Binder, E.B.a k , Aitchison, K.J.a p , Mendlewicz, J.a q , Souery, D.a r , Hauser, J.a s , Henigsberg, N.b t , Breen, G.a b u , Craig, I.W.a , Farmer, A.E.a , Müller-Myhsok, B.a k , McGuffin, P.a , Lewis, C.M.a b v
Familiality and SNP heritability of age at onset and episodicity in major depressive disorder
(2015) Psychological Medicine, 11 p. Article in Press. 

DOI: 10.1017/S0033291715000215


a MRC Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
b 2nd Department of Psychiatry, Attikon General Hospital, University of Athens, Athens, Greece
c Department of Biostatistics, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
d Centro de Investigación Biomédica en Red de Salud Mental CIBERSAM, University of Granada, Spain
e Dalhousie University Department of Psychiatry, Halifax, Nova Scotia, Canada
f MRC Centre for Neuropsychiatric Genetics and Genomics, Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, UK
g Barts and The London Medical School, Queen Mary University of London, London, UK
h Department of Psychiatry, University of Birmingham, Birmingham, UK
i Department of Psychiatry, Trinity Centre for Health Science, Dublin, Ireland
j Department of Psychiatry, Washington University, St. Louis, Missouri, USA
k Max Planck Institute of Psychiatry, Munich, Germany
l Department of Psychiatry, University of Bonn & German Center of Neurodegenerative Diseases (DZNE), Bonn, Germany
m Centre for Psychiatric Research, Aarhus University Hospital, Risskov, Denmark
n Division of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Mannheim, Germany
o University Hospital Center and University of Lausanne, Lausanne, Switzerland
p Departments of Psychiatry and Medical Genetics, University of Alberta, Edmonton, Alberta, Canada
q Department of Psychiatry, Free University of Brussels, Brussels, Belgium
r Centre Européen de Psychologie Médicale PSY-PLURIEL, Bruxelles, Belgium
s Department of Genetics in Psychiatry, Poznan University of Medical Sciences, Poznan, Poland
t Department of Psychiatry, University of Zagreb, Zagreb, Croatia
u NIHR Biomedical Research Centre for Mental Health, South London and Maudsley NHS Foundation Trust and Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
v Division of Genetics and Molecular Medicine, King's College London, London, UK


Abstract
Background: Strategies to dissect phenotypic and genetic heterogeneity of major depressive disorder (MDD) have mainly relied on subphenotypes, such as age at onset (AAO) and recurrence/episodicity. Yet, evidence on whether these subphenotypes are familial or heritable is scarce. The aims of this study are to investigate the familiality of AAO and episode frequency in MDD and to assess the proportion of their variance explained by common single nucleotide polymorphisms (SNP heritability).

Method: For investigating familiality, we used 691 families with 2–5 full siblings with recurrent MDD from the DeNt study. We fitted (square root) AAO and episode count in a linear and a negative binomial mixed model, respectively, with family as random effect and adjusting for sex, age and center. The strength of familiality was assessed with intraclass correlation coefficients (ICC). For estimating SNP heritabilities, we used 3468 unrelated MDD cases from the RADIANT and GSK Munich studies. After similarly adjusting for covariates, derived residuals were used with the GREML method in GCTA (genome-wide complex trait analysis) software.

Results: Significant familial clustering was found for both AAO (ICC = 0.28) and episodicity (ICC = 0.07). We calculated from respective ICC estimates the maximal additive heritability of AAO (0.56) and episodicity (0.15). SNP heritability of AAO was 0.17 (p = 0.04); analysis was underpowered for calculating SNP heritability of episodicity.

Conclusions: AAO and episodicity aggregate in families to a moderate and small degree, respectively. AAO is under stronger additive genetic control than episodicity. Larger samples are needed to calculate the SNP heritability of episodicity. The described statistical framework could be useful in future analyses.


Author Keywords
Age at onset;  episodicity;  familiality;  GCTA;  heritability;  major depression


Document Type: Article in Press
Source: Scopus




Kaplan, S.C.a , Levinson, C.A.a , Rodebaugh, T.L.a , Menatti, A.b , Weeks, J.W.b
Social Anxiety and the Big Five Personality Traits: The Interactive Relationship of Trust and Openness
(2015) Cognitive Behaviour Therapy, 11 p. Article in Press. 

DOI: 10.1080/16506073.2015.1008032


a Department of Psychology, Washington University in St. Louis, St. Louis, USA
b Department of Psychology, Ohio University, Athens, USA


Abstract
It is well established that social anxiety (SA) has a positive relationship with neuroticism and a negative relationship with extraversion. However, findings on the relationships between SA and agreeableness, conscientiousness, and openness to experience are mixed. In regard to facet-level personality traits, SA is negatively correlated with trust (a facet of agreeableness) and self-efficacy (a facet of conscientiousness). No research has examined interactions among the Big Five personality traits (e.g., extraversion) and facet levels of personality in relation to SA. In two studies using undergraduate samples (N = 502; N = 698), we examined the relationships between trust, self-efficacy, the Big Five, and SA. SA correlated positively with neuroticism, negatively with extraversion, and had weaker relationships with agreeableness, openness, and trust. In linear regression predicting SA, there was a significant interaction between trust and openness over and above gender. In addition to supporting previous research on SA and the Big Five, we found that openness is related to SA for individuals low in trust. Our results suggest that high openness may protect against the higher SA levels associated with low trust.


Author Keywords
Big Five;  personality;  self-efficacy;  social anxiety;  trust


Document Type: Article in Press
Source: Scopus




Izuma, K.a b , Akula, S.c , Murayama, K.d , Wu, D.-A.a , Iacoboni, M.e , Adolphs, R.a
A causal role for posterior medial frontal cortex in choice-induced preference change
(2015) Journal of Neuroscience, 35 (8), pp. 3598-3606. 

DOI: 10.1523/JNEUROSCI.4591-14.2015


a Division of Humanities and Social Sciences, California Institute of TechnologyPasadena, CA, United States
b Brain Science Institute, Tamagawa UniversityMachida, Tokyo, Japan
c Departments of Genetics and Psychiatry, Washington University in St. LouisSt. Louis, MO, United States
d Department of Psychology, University of ReadingWhiteknights Reading, United Kingdom
e Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, University of CaliforniaLos Angeles, CA, United States


Abstract
After a person chooses between two items, preference for the chosen item will increase and preference for the unchosen item will decrease because of the choice made. In other words, we tend to justify or rationalize our past behavior by changing our attitude. This phenomenon of choice-induced preference change has been traditionally explained by cognitive dissonance theory. Choosing something that is disliked or not choosing something that is liked are both cognitively inconsistent and, to reduce this inconsistency, people tend to change their subsequently stated preference in accordance with their past choices. Previously, human neuroimaging studies identified posterior medial frontal cortex (pMFC) as a key brain region involved in cognitive dissonance. However, it remains unknown whether the pMFC plays a causal role in inducing preference change after cognitive dissonance. Here, we demonstrate that 25 min, 1 Hz repetitive transcranial magnetic stimulation applied over the pMFC significantly reduces choice-induced preference change compared with sham stimulation or control stimulation over a different brain region, demonstrating a causal role for the pMFC.


Author Keywords
Attitude;  Choice justification;  Cognitive dissonance;  Medial prefrontal cortex;  Preference change;  TMS


Document Type: Article
Source: Scopus




Soucy, E.A.a , Wessel, L.E.a , Gao, F.b , Albers, A.C.a , Gutmann, D.H.a , Dunn, C.M.a
A pilot study for evaluation of hypotonia in children with neurofibromatosis type 1
(2015) Journal of Child Neurology, 30 (3), pp. 382-385. 

DOI: 10.1177/0883073814531823


a Department of Neurology, Washington University School of MedicineSt Louis, MO, United States
b Department of Biostatistics, Washington University School of MedicineSt Louis, MO, United States


Abstract
There are currently no objective criteria to evaluate pediatric hypotonia. The purpose of this pilot study was to identify diagnostic criteria for assessing hypotonia in children with neurofibromatosis type 1. Fifty-five subjects between the ages of 1 and 7 years with a diagnosis of neurofibromatosis type 1 were evaluated. A physical therapist recorded a subjective tone assessment and objective tone metrics, including ankle dorsiflexion, knee extension, hip abduction, triceps fat percentage, grip strength, and head lag during a pull-to-sit test. Multivariate logistic regression analysis showed the presence of head lag paired with increased hip range of motion was a significant predictor of hypotonia. The presence of head lag on a pull-to-sit test paired with increased hip range of motion is an accurate predictor of hypotonia in children with neurofibromatosis type 1. These objective measures should be prospectively evaluated in other pediatric populations for their ability to predict hypotonia.


Author Keywords
grip strength;  head lag;  hip abduction;  hypotonia;  muscle tone;  neurofibromatosis type 1


Document Type: Article
Source: Scopus




Pruett, J.R.a , Kandala, S.a , Hoertel, S.a , Snyder, A.Z.a , Elison, J.T.b , Nishino, T.a , Feczko, E.c , Dosenbach, N.U.F.a , Nardos, B.a , Power, J.D.d , Adeyemo, B.a , Botteron, K.N.a , McKinstry, R.C.a , Evans, A.C.e , Hazlett, H.C.f , Dager, S.R.g , Paterson, S.h , Schultz, R.T.h , Collins, D.L.e , Fonov, V.S.e , Styner, M.f , Gerig, G.i , Das, S.e , Kostopoulos, P.e , Constantino, J.N.a , Estes, A.M.g , Petersen, S.E.a , Schlaggar, B.L.a , Piven, J.f
Accurate age classification of 6 and 12 month-old infants based on resting-state functional connectivity magnetic resonance imaging data
(2015) Developmental Cognitive Neuroscience, 12, pp. 123-133. 

DOI: 10.1016/j.dcn.2015.01.003


a Washington University School of Medicine in St. Louis, 660 South Euclid AvenueSt. Louis, MO, United States
b University of Minnesota, 51 East River ParkwayMinneapolis, MN, United States
c Emory University, 201 Dowman DriveAtlanta, GA, United States
d National Institute of Mental Health, National Institutes of Health, 10 Center DriveBethesda, MD, United States
e McConnell Brain Imaging Center, Montreal Neurological Institute, McGill University, 3801 University StreetMontreal, QC, Canada
f University of North Carolina at Chapel Hill, 101 Manning DriveChapel Hill, NC, United States
g University of Washington, Seattle, 1410 NE Campus ParkwaySeattle, WA, United States
h Children's Hospital of Philadelphia, University of Pennsylvania, Civic Center BoulevardPhiladelphia, PA, United States
i University of Utah, Salt Lake City, 201 Presidents CircleSalt Lake City, UT, United States


Abstract
Human large-scale functional brain networks are hypothesized to undergo significant changes over development. Little is known about these functional architectural changes, particularly during the second half of the first year of life. We used multivariate pattern classification of resting-state functional connectivity magnetic resonance imaging (fcMRI) data obtained in an on-going, multi-site, longitudinal study of brain and behavioral development to explore whether fcMRI data contained information sufficient to classify infant age. Analyses carefully account for the effects of fcMRI motion artifact. Support vector machines (SVMs) classified 6 versus 12 month-old infants (128 datasets) above chance based on fcMRI data alone. Results demonstrate significant changes in measures of brain functional organization that coincide with a special period of dramatic change in infant motor, cognitive, and social development. Explorations of the most different correlations used for SVM lead to two different interpretations about functional connections that support 6 versus 12-month age categorization.


Author Keywords
Development;  Functional brain networks;  Functional connectivity magnetic resonance imaging (fcMRI);  Infant;  Multivariate pattern analysis (MVPA);  Support vector machine (SVM)


Document Type: Article
Source: Scopus




Duncan, R.P.a h , Leddy, A.L.b , Cavanaugh, J.T.c , Dibble, L.E.d , Ellis, T.D.e , Ford, M.P.f , Foreman, K.B.d , Earhart, G.M.a g h
Detecting and predicting balance decline in Parkinson disease: A prospective cohort study
(2015) Journal of Parkinson's Disease, 5 (1), pp. 131-139. 

DOI: 10.3233/JPD-140478


a Washington University in St. Louis School of Medicine, Program in Physical TherapyMO, United States
b Rehabilitation Hospital of the Pacific, Department of Physical TherapyHI, United States
c Department of Physical Therapy, University of New EnglandME, United States
d Department of Physical Therapy, University of UtahUT, United States
e Department of Physical Therapy and Athletic Training, Boston UniversityMA, United States
f Department of Physical Therapy, Samford UniversityAL, United States
g Department of Anatomy and Neurobiology, Washington University in St. Louis School of MedicineMO, United States
h Department of Neurology, Washington University in St. Louis School of MedicineMO, United States


Abstract
Background: The natural progression of balance decline in individuals with Parkinson disease (PD) is not well understood. Objectives: We aimed to: 1) compare the utility of three standardized clinical measures for detecting balance decline over 1-year, 2) identify components of balance susceptible to decline, and 3) identify factors useful for predicting future balance decline. Methods: Eighty people with PD (59% male; mean age 68.2 ± 9.3; Hoehn & Yahr range I-IV) completed Balance Evaluation Systems Test (BESTest), Mini-BESTest, and Berg Balance Scale (BBS) assessments. Baseline predictor variables included the MDS-UPDRS III sub-score, presence of freezing, 6-month fall history, age, gender, and physical activity. Balance and MDS-UPDRS III assessments were repeated at 6 (n = 51) and 12 months (n = 44). Results: BESTest and Mini-BESTest score declined over 6 and 12 months (P < 0.01). Postural responses, stability limits, and sensory orientation were most susceptible to decline. BBS score did not change (P > 0.01). MDS-UPDRS III score was unchanged over 6 months (P > 0.01), but declined over 12 months (P < 0.01). Change in BESTest score over 6 months was related to baseline MDS-UPDRS III, H&Y, freezing, and fall history (P < 0.05). Change in BESTest score over 12 months was related to baseline MDS-UPDRS III and freezing (P < 0.05). Change in Mini-BESTest over 12 months was related to baseline MDS-UPDRS III and age (P < 0.05). Conclusions: The BESTest and Mini-BESTest were responsive to balance decline in individuals with PD and helped to identify decline in underlying balance components. Disease severity and freezing most consistently predicted balance decline in persons with PD.


Author Keywords
outcome assessment;  Parkinson disease;  physical therapy;  postural balance;  rehabilitation


Document Type: Article
Source: Scopus




Friess, S.H.a , Bruins, B.b , Kilbaugh, T.J.b , Smith, C.c , Margulies, S.S.d
Differing effects when using phenylephrine and norepinephrine to augment cerebral blood flow after traumatic brain injury in the immature brain
(2015) Journal of Neurotrauma, 32 (4), pp. 237-243. 

DOI: 10.1089/neu.2014.3468


a Department of Pediatrics, Washington University in St. Louis School of Medicine, 660 S. Euclid AvenueSt. Louis, MO, United States
b Department of Anesthesiology and Critical Care Medicine, Children's Hospital of PhiladelphiaPhiladelphia, PA, United States
c Department of Neuropathology, Western General HospitalEdinburgh, United Kingdom
d Department of Bioengineering, University of PennsylvaniaPhiladelphia, PA, United States


Abstract
Low cerebral blood flow (CBF) states have been demonstrated in children early after traumatic brain injury (TBI), and have been correlated with poorer outcomes. Cerebral perfusion pressure (CPP) support following severe TBI is commonly implemented to correct cerebral hypoperfusion, but the efficacy of various vasopressors has not been determined. Sixteen 4-week-old female swine underwent nonimpact inertial brain injury in the sagittal plane. Intraparenchymal monitors were placed to measure intracranial pressure (ICP), CBF, brain tissue oxygen tension (PbtO2), and cerebral microdialysis 30&lt;min to 6&lt;h post-injury. One hour after injury, animals were randomized to receive either phenylephrine (PE) or norepinephrine (NE) infusions titrated to a CPP &gt;70&lt;mm Hg for 5&lt;h. Animals were euthanized 6&lt;h post-TBI, and brains were fixed and stained to assess regions of cell and axonal injury. After initiation of CPP augmentation with NE or PE infusions, there were no differences in ICP between the groups or over time. Animals receiving NE had higher PbtO2 than those receiving PE (29.6±10.2 vs. 19.6±6.4 torr at 6&lt;h post-injury, p&lt;0.05). CBF increased similarly in both the NE and PE groups. CPP support with PE resulted in a greater reduction in metabolic crisis than with NE (lactate/pyruvate ratio 16.7±2.4 vs. 42.7±10.2 at 6&lt;h post-injury, p&lt;0.05). Augmentation of CPP to 70&lt;mm Hg with PE resulted in significantly smaller cell injury volumes at 6&lt;h post-injury than CPP support with NE (0.4% vs. 1.4%, p&lt;0.05). Despite similar increases in CBF, CPP support with NE resulted in greater brain tissue oxygenation and hypoxic-ischemic injury than CPP support with PE. Future clinical studies comparing the effectiveness of various vasopressors for CPP support are warranted.


Author Keywords
CBF;  CPP;  NE;  PE;  TBI


Document Type: Article
Source: Scopus




Bieser, S.a , Reis, M.a , Guzman, M.a , Gauvain, K.b , Elbabaa, S.a , Braddock, S.R.a , Abdel-Baki, M.S.a
Grade II pilocytic astrocytoma in a 3-month-old patient with encephalocraniocutaneous lipomatosis (ECCL): Case report and literature review of low grade gliomas in ECCL
(2015) American Journal of Medical Genetics, Part A, . Article in Press. 

DOI: 10.1002/ajmg.a.37017


a Saint Louis University School of MedicineSt. Louis, Missouri
b Washington University School of MedicineSt. Louis, Missouri


Abstract
Encephalocraniocutaneous lipomatosis (ECCL) is a rare congenital syndrome with an unknown etiology. Since 1970, around 60 cases have been reported in English literature. ECCL is usually classified by cutaneous lesions and non-progressive intracranial or spinal lipomas; however three cases of ECCL associated with low grade glioma (LGG) have been described. We report on the fourth case of LGG in a patient with ECCL; a grade II pilocytic astrocytoma with pilomyxoid features in a 3-month-old male, the youngest in literature.


Author Keywords
Encephalocraniocutaneous;  Glioma;  Lipomatosis


Document Type: Article in Press
Source: Scopus




Herzog, E.D.a , Kiss, I.Z.b , Mazuski, C.a
Measuring synchrony in the mammalian central circadian circuit
(2015) Methods in Enzymology, 552, pp. 3-22. 

DOI: 10.1016/bs.mie.2014.10.042


a Department of Biology, Washington UniversitySt. Louis, MO, United States
b Department of Chemistry, Saint Louis UniversitySt. Louis, MO, United States


Abstract
Circadian clocks control daily rhythms in physiology and behavior across all phyla. These rhythms are intrinsic to individual cells that must synchronize to their environment and to each other to anticipate daily events. Recent advances in recording from large numbers of cells for many circadian cycles have enabled researchers to begin to evaluate the mechanisms and consequences of intercellular circadian synchrony. Consequently, methods have been adapted to estimate the period, phase, and amplitude of individual circadian cells and calculate synchrony between cells. Stable synchronization requires that the cells share a common period. As a result, synchronized cells maintain constant phase relationships to each (e.g., with cell 1 peaking an hour before cell 2 each cycle). This chapter reviews how circadian rhythms are recorded from single mammalian cells and details methods for measuring their period and phase synchrony. These methods have been useful, for example, in showing that specific neuropeptides are essential to maintain synchrony among circadian cells.


Document Type: Review
Source: Scopus




Lingle, C.J.
NAVigating a transition from single action potential firing to bursting in chromaffin cells
(2015) Journal of Physiology, 593 (4), pp. 761-762. 

DOI: 10.1113/jphysiol.2014.288464


Department of Anaesthesiology, Washington University School of MedicineSt Louis, MO, United States


Document Type: Note
Source: Scopus




Scoto, M.a , Rossor, A.M.c , Harms, M.B.d , Cirak, S.e , Calissano, M.a , Robb, S.a , Manzur, A.Y.a , Arroyo, A.M.f , Sanz, A.R.f , Mansour, S.g , Fallon, P.g , Hadjikoumi, I.g , Klein, A.h , Yang, M.i , De Visser, M.j , Overweg-Plandsoen, W.C.G.T.j , Baas, F.j , Taylor, J.P.r , Benatar, M.s , Connolly, A.M.d , Al-Lozi, M.T.d , Nixon, J.t , De Goede, C.G.E.L.t , Foley, A.R.a , McWilliam, C.k , Pitt, M.o , Sewry, C.a l , Phadke, R.a , Hafezparast, M.m , Chong, W.K.K.n , Mercuri, E.p , Baloh, R.H.q , Reilly, M.M.c , Muntoni, F.a b
Novel mutations expand the clinical spectrum of DYNC1H1-associated spinal muscular atrophy
(2015) Neurology, 84 (7), pp. 668-679. 

DOI: 10.1212/WNL.0000000000001269


a Dubowitz Neuromuscular Center, UCL Institute of Child HealthLondon, United Kingdom
b MRC Center for Neuromuscular Diseases, UCL Institute of Child HealthLondon, United Kingdom
c MRC Center for Neuromuscular Diseases, UCL Institute of Neurology, Queen SquareLondon, United Kingdom
d Neuromuscular Division, Department of Neurology, Washington University School of MedicineSt. Louis, MO, United States
e Research Center for Genetic Medicine, Children's National Medical CenterWashington, DC, United States
f Galdakao-Usansolo Hospital, Department of Neurology, Barrio Labeaga s/nUsansolo, Vizcaya, Spain
g St George's NHS Health Care TrustLondon, United Kingdom
h Department of Paediatric Neurology, University Children's HospitalZurich, Switzerland
i Department of Pediatrics, University of Colorado Denver, Netherlands
j Department of Neurology, Academic Medical Center, University of Amsterdam, Netherlands
k Human Genetics Unit, Ninewells HospitalDundee, United Kingdom
l Center for Inherited Neuromuscular Diseases, RJAH Orthopaedic NHS Foundation TrustOswestry, United Kingdom
m School of Life Sciences, University of Sussex, John Maynard Smith BuildingBrighton, United Kingdom
n Radiology Department, Great Ormond Street HospitalLondon, United Kingdom
o Neurophysiology Department, Great Ormond Street HospitalLondon, United Kingdom
p Paediatric Neurology Unit, Policlinico GemelliRome, Italy
q Department of Neurology, Cedars Sinai Medical CenterLos Angeles, CA, United States
r Department of Developmental Neurobiology, St. Jude Children's Research HospitalMemphis, TN, United States
s Neurology Department, University of Miami Miller School of MedicineFL, United States
t Department of Neurology, Royal Preston Hospital, United Kingdom


Abstract
Objective: To expand the clinical phenotype of autosomal dominant congenital spinal muscular atrophy with lower extremity predominance (SMA-LED) due to mutations in the dynein, cytoplasmic 1, heavy chain 1 (DYNC1H1) gene. Methods: Patients with a phenotype suggestive of a motor, non-length-dependent neuronopathy predominantly affecting the lower limbs were identified at participating neuromuscular centers and referred for targeted sequencing of DYNC1H1. Results: We report a cohort of 30 cases of SMA-LED from 16 families, carrying mutations in the tail and motor domains of DYNC1H1, including 10 novel mutations. These patients are characterized by congenital or childhood-onset lower limb wasting and weakness frequently associated with cognitive impairment. The clinical severity is variable, ranging from generalized arthrogryposis and inability to ambulate to exclusive and mild lower limb weakness. In many individuals with cognitive impairment (9/30 had cognitive impairment) who underwent brain MRI, there was an underlying structural malformation resulting in polymicrogyric appearance. The lower limb muscle MRI shows a distinctive pattern suggestive of denervation characterized by sparing and relative hypertrophy of the adductor longus and semitendinosus muscles at the thigh level, and diffuse involvement with relative sparing of the anteriormedial muscles at the calf level. Proximal muscle histopathology did not always show classic neurogenic features. Conclusion: Our report expands the clinical spectrum of DYNC1H1-related SMA-LED to include generalized arthrogryposis. In addition, we report that the neurogenic peripheral pathology and the CNS neuronal migration defects are often associated, reinforcing the importance of DYNC1H1 in both central and peripheral neuronal functions.


Document Type: Article
Source: Scopus




Cash, K.J.a c , Li, C.b , Xia, J.b d , Wang, L.V.b , Clark, H.A.a
Optical drug monitoring: Photoacoustic imaging of nanosensors to monitor therapeutic lithium in vivo
(2015) ACS Nano, 9 (2), pp. 1692-1698. 

DOI: 10.1021/nn5064858


a Department of Pharmaceutical Sciences, Northeastern UniversityBoston, MA, United States
b Optical Imaging Laboratory, Department of Biomedical Engineering, Washington University in St. LouisSt. Louis, MO, United States
c Chemical and Biological Engineering Department, Colorado School of MinesGolden, CO, United States
d Department of Biomedical Engineering, University of BuffaloBuffalo, NY, United States


Abstract
Personalized medicine could revolutionize how primary care physicians treat chronic disease and how researchers study fundamental biological questions. To realize this goal, we need to develop more robust, modular tools and imaging approaches for in vivo monitoring of analytes. In this report, we demonstrate that synthetic nanosensors can measure physiologic parameters with photoacoustic contrast, and we apply that platform to continuously track lithium levels in vivo. Photoacoustic imaging achieves imaging depths that are unattainable with fluorescence or multiphoton microscopy. We validated the photoacoustic results that illustrate the superior imaging depth and quality of photoacoustic imaging with optical measurements. This powerful combination of techniques will unlock the ability to measure analyte changes in deep tissue and will open up photoacoustic imaging as a diagnostic tool for continuous physiological tracking of a wide range of analytes.


Author Keywords
bipolar;  continuous monitoring;  diagnostic;  nanomedicine;  nanoparticle


Document Type: Article
Source: Scopus




Moore, A.M., Wagner, I.J., Fox, I.K.
Principles of nerve repair in complex wounds of the upper extremity
(2015) Seminars in Plastic Surgery, 29 (1), pp. 40-47. 

DOI: 10.1055/s-0035-1544169


Division of Plastic and Reconstructive Surgery, Department of Surgery, Washington University School of MedicineSt. Louis, MO, United States


Abstract
Peripheral nerve injuries are common in the setting of complex upper extremity trauma. Early identification of nerve injuries and intervention is critical for maximizing return of function. In this review, the principles of nerve injury, patient evaluation, and surgical management are discussed. An evidence-based approach to nerve reconstruction is reviewed, including the benefits and limitations of direct repair and nerve gap reconstruction with the use of autografts, processed nerve allografts, and conduits. Further, the principles and indications of commonly used nerve transfers in proximal nerve injuries are also addressed.


Author Keywords
mutilating injury of the hand;  nerve conduit;  nerve transfer;  peripheral nerve injury;  processed nerve allograft;  upper extremity trauma


Document Type: Review
Source: Scopus




Winterheld, H.A.a , Simpson, J.A.b
Regulatory Focus and the Interpersonal Dynamics of Romantic Partners' Personal Goal Discussions
(2015) Journal of Personality, . Article in Press. 

DOI: 10.1111/jopy.12158


a Washington University in St. Louis
b University of Minnesota Twin Cities Campus


Abstract
Guided by regulatory focus theory, we examined how romantic partners' chronic concerns with promotion (advancement) and prevention (security) shape the interpersonal dynamics of couples' conversations about different types of personal goals. Members of 95 couples (N=190) first completed chronic regulatory focus measures and then engaged in videotaped discussions of two types of goals that were differentially relevant to promotion and prevention concerns. Participants also completed measures of goal- and partner-relevant perceptions. Independent observers rated the discussions for support-related behaviors. Highly promotion-focused people approached their partners more, perceived greater partner responsiveness, and received more support when discussing goals that were promotion-relevant and that they perceived as less attainable. When partners' responsiveness to promotion-relevant goals was low, highly promotion-focused people reported greater self-efficacy regarding these goals. Highly prevention-focused people perceived more responsiveness when partners were less distancing during discussions of their prevention-relevant goals, and greater responsiveness perceptions reassured them that these goals are less disruptive to the relationship. These findings suggest that chronic concerns with promotion and prevention orient people to their relationship environment in ways that are consistent with these distinct motivational needs, especially when discussing goals that increase the salience of these needs.


Document Type: Article in Press
Source: Scopus




Larsen, D.P.a , Butler, A.C.b , Aung, W.Y.a , Corboy, J.R.c , Friedman, D.I.d , Sperling, M.R.e
The effects of test-enhanced learning on long-term retention in AAN annual meeting courses
(2015) Neurology, 84 (7), pp. 748-754. 

DOI: 10.1212/WNL.0000000000001264


a Department of Neurology, Washington University in St. Louis School of MedicineMO, United States
b Department of Psychology and Neuroscience, Duke UniversityDurham, NC, United States
c Department of Neurology, University of Colorado School of MedicineDenver, United States
d Department of Neurology, University of Texas Southwestern Medical SchoolDallas, United States
e Department of Neurology, Jefferson Medical CollegePhiladelphia, PA, United States


Abstract
Objective: We measured the long-term retention of knowledge gained through selected American Academy of Neurology annual meeting courses and compared the effects of repeated quizzing (known as test-enhanced learning) and repeated studying on that retention. Methods: Participants were recruited from 4 annual meeting courses. All participants took a pretest. This randomized, controlled trial utilized a within-subjects design in which each participant experienced 3 different postcourse activities with each activity performed on different material. Each key information point from the course was randomized in a counterbalanced fashion among participants to one of the 3 activities: repeated short-answer quizzing, repeated studying, and no further exposure to the materials. A final test covering all information points from the course was taken 5.5 months after the course. Results: Thirty-five participants across the 4 courses completed the study. Average score on the pretest was 36%. Performance on the final test showed that repeated quizzing led to significantly greater long-term retention relative to both repeated studying (55% vs 46%; t[34] = 3.28, SEM = 0.03, p = 0.01, d = 0.49) and no further exposure (55% vs 44%; t[34] = 3.16, SEM = 0.03, p = 0.01, d = 0.58). Relative to the pretest baseline, repeated quizzing helped participants to retain almost twice as much of the knowledge acquired from the course compared to repeated studying or no further exposure. Conclusions: Whereas annual meeting continuing medical education (CME) courses lead to longterm gains in knowledge, when repeated quizzing is added, retention is significantly increased. CME planners may consider adding repeated quizzing to increase the impact of their courses.


Document Type: Article
Source: Scopus




Gordon, B.A.a b , Zacks, J.M.a c , Blazey, T.d , Benzinger, T.L.S.a b d e , Morris, J.C.b f , Fagan, A.M.b f g , Holtzman, D.M.b d f g , Balota, D.A.b c
Task-evoked fMRI changes in attention networks are associated with preclinical Alzheimer's disease biomarkers
(2015) Neurobiology of Aging, . Article in Press. 

DOI: 10.1016/j.neurobiolaging.2015.01.019


a Department of Radiology, Washington University in St Louis, St Louis, MO, USA
b Knight Alzheimer's Disease Research Center, Washington University in St Louis, St Louis, MO, USA
c Department of Psychology, Washington University in St Louis, St Louis, MO, USA
d Division of Biology and Biomedical Sciences, Washington University in St Louis, St Louis, MO, USA
e Department of Neurological Surgery, Washington University in St Louis, St Louis, MO, USA
f Department of Neurology, Washington University in St Louis, St Louis, MO, USA
g The Hope Center for Neurodegenerative Disorders, Washington University in St Louis, St Louis, MO, USA


Abstract
There is a growing emphasis on examining preclinical levels of Alzheimer's disease (AD)-related pathology in the absence of cognitive impairment. Previous work examining biomarkers has focused almost exclusively on memory, although there is mounting evidence that attention also declines early in disease progression. In the current experiment, 2 attentional control tasks were used to examine alterations in task-evoked functional magnetic resonance imaging data related to biomarkers of AD pathology. Seventy-one cognitively normal individuals (females= 44, mean age= 63.5 years) performed 2 attention-demanding cognitive tasks in a design that modeled both trial- and task-level functional magnetic resonance imaging changes. Biomarkers included amyloid β42, tau, and phosphorylated tau measured from cerebrospinal fluid and positron emission tomography measures of amyloid deposition. Both tasks elicited widespread patterns of activation and deactivation associated with large task-level manipulations of attention. Importantly, results from both tasks indicated that higher levels of tau and phosphorylated tau pathologies were associated with block-level overactivations of attentional control areas. This suggests early alteration in attentional control with rising levels of AD pathology.


Author Keywords
Alzheimer;  Alzheimer's disease;  Amyloid;  Attention;  Biomarkers;  Dementia;  FMRI;  Ptau;  Tau


Document Type: Article in Press
Source: Scopus




Wang, Y.a e , Cella, M.a , Mallinson, K.b c d , Ulrich, J.b c d , Young, K.b c d , Robinette, M.a , Gilfillan, S.a , Krishnan, G.a , Sudhakar, S.b c d , Zinselmeyer, B.a , Holtzman, D.b c d , Cirrito, J.b c d , Colonna, M.a
TREM2 Lipid Sensing Sustains the Microglial Response in an Alzheimer's Disease Model
(2015) Cell, . Article in Press. 

DOI: 10.1016/j.cell.2015.01.049


a Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
b Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA
c Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO 63110, USA
d Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, USA
e Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA


Abstract
Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial surface receptor that triggers intracellular protein tyrosine phosphorylation. Recent genome-wide association studies have shown that a rare R47H mutation of TREM2 correlates with a substantial increase in the risk of developing Alzheimer's disease (AD). To address the basis for this genetic association, we studied TREM2 deficiency in the 5XFAD mouse model of AD. We found that TREM2 deficiency and haploinsufficiency augment β-amyloid (Aβ) accumulation due to a dysfunctional response of microglia, which fail to cluster around Aβ plaques and become apoptotic. We further demonstrate that TREM2 senses a broad array of anionic and zwitterionic lipids known to associate with fibrillar Aβ in lipid membranes and to be exposed on the surface of damaged neurons. Remarkably, the R47H mutation impairs TREM2 detection of lipid ligands. Thus, TREM2 detects damage-associated lipid patterns associated with neurodegeneration, sustaining the microglial response to Aβ accumulation. TREM2 acts in microglia as a sensor for a wide array of lipids that are associated with β-amyloid accumulation and neuronal loss. The TREM2 mutation that has recently been identified as a risk factor for Alzheimer's disease attenuates microglial detection of damage-associated lipids, providing a mechanistic basis for the genetic association.


Document Type: Article in Press
Source: Scopus




Weihl, C.C.a , Iyadurai, S.b , Baloh, R.H.c , Pittman, S.K.a , Schmidt, R.E.d , Lopate, G.a , Pestronk, A.a , Harms, M.B.a
Autophagic vacuolar pathology in desminopathies
(2015) Neuromuscular Disorders, . Article in Press. 

DOI: 10.1016/j.nmd.2014.12.002


a Department of Neurology and Hope Center for Neurologic Disorders, Washington University School of Medicine, Saint Louis, MO, USA
b Department of Neurology, The Ohio State University College of Medicine, Columbus, OH, USA
c Department of Neurology, Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
d Department of Pathology, Washington University School of Medicine, Saint Louis, MO, USA


Abstract
Autophagic vacuolar myopathies are an emerging group of muscle diseases with common pathologic features. These include autophagic vacuoles containing both lysosomal and autophagosomal proteins sometimes lined with sarcolemmal proteins such as dystrophin. These features have been most clearly described in patients with Danon's disease due to LAMP2 deficiency and X-linked myopathy with excessive autophagy (XMEA) due to mutations in VMA21. Disruptions of these proteins lead to lysosomal dysfunction and subsequent autophagic vacuolar pathology. We performed whole exome sequencing on two families with autosomal dominantly inherited myopathies with autophagic vacuolar pathology and surprisingly identified a p.R454W tail domain mutation and a novel p.S6W head domain mutation in desmin, DES. In addition, re-evaluation of muscle tissue from another family with a novel p.I402N missense DES mutation also identified autophagic vacuoles. We suggest that autophagic vacuoles may be an underappreciated pathology present in desminopathy patient muscle. Moreover, autophagic vacuolar pathology can be due to genetic etiologies unrelated to primary defects in the lysosomes or autophagic machinery. Specifically, cytoskeletal derangement and the accumulation of aggregated proteins such as desmin may activate the autophagic system leading to the pathologic features of an autophagic vacuolar myopathy.


Author Keywords
Autophagy;  Desmin;  Myofibrillar myopathy;  Protein aggregation


Document Type: Article in Press
Source: Scopus




Kay, K.a , Weiner, K.b , Grill-Spector, K.b c
Attention Reduces Spatial Uncertainty in Human Ventral Temporal Cortex
(2015) Current Biology, . Article in Press. 

DOI: 10.1016/j.cub.2014.12.050


a Department of Psychology, Washington University in St. Louis, St. Louis, MO 63130, USA
b Department of Psychology, Stanford University, Stanford, CA94305, USA
c Stanford Neurosciences Institute, Stanford University, Stanford, CA 94305, USA


Abstract
Ventral temporal cortex (VTC) is the latest stage of the ventral "what" visual pathway, which is thought to code the identity of a stimulus regardless of its position or size [1, 2]. Surprisingly, recent studies show that position information can be decoded from VTC [3-5]. However, the computational mechanisms by which spatial information is encoded in VTC are unknown. Furthermore, how attention influences spatial representations in human VTC is also unknown because the effect of attention on spatial representations has only been examined in the dorsal "where" visual pathway [6-10]. Here, we fill these significant gaps inknowledge using an approach that combines functional magnetic resonance imaging and sophisticated computational methods. We first develop a population receptive field (pRF) model [11, 12] of spatial responses in human VTC. Consisting of spatial summation followed by a compressive nonlinearity, this model accurately predicts responses of individual voxels to stimuli at any position and size, explains how spatial information is encoded, and reveals a functional hierarchy in VTC. We then manipulate attention and use our model to decipher the effects of attention. We find that attention to the stimulus systematically and selectively modulates responses in VTC, but not early visual areas. Locally, attention increases eccentricity, size, and gain of individual pRFs, thereby increasing position tolerance. However, globally, these effects reduce uncertainty regarding stimulus location and actually increase position sensitivity of distributed responses across VTC. These results demonstrate that attention actively shapes and enhances spatial representations in the ventral visual pathway. Kay etal. tackle the problem of modeling the final stage in the ventral visual pathway. They do so with a model of visual space, which is surprising since this stage is traditionally viewed as coding form, not space. They show that attention reduces uncertainty in the peripheral visual field where humans and primates are the worst at seeing.


Document Type: Article in Press
Source: Scopus




Lang, C.E.c , Bland, M.D.a c , Cheng, N.b , Corbetta, M.c d , Lee, J.-M.c d
A case-control study of the effectiveness of tissue plasminogen activator on 6 month patients-reported outcomes and health care utilization
(2014) Journal of Stroke and Cerebrovascular Diseases, 23 (10), pp. 2914-2919. 

DOI: 10.1016/j.jstrokecerebrovasdis.2014.07.049


a Program in Physical Therapy, Washington University, Campus Box 8502St. Louis, MO, United States
b Division of Biostatistics, Washington University School of Medicine in St. LouisSt. Louis, MO, United States
c Department of Neurology, Washington University School of Medicine in St. LouisSt. Louis, MO, United States
d Department of Radiology, Washington University School of Medicine in St. LouisSt. Louis, MO, United States


Abstract
We Examined the Benefit of Tissue Plasminogen Activator , Delivered As Part of Usual Stroke Mgmt., on Patient-reported Outcomes and Hlth. Care Utiliz.. Using A Case Contr. Des., Patients Who Received TPA As Part of Usual Stroke Mgmt. Were Compared with Patients Who Would Have Received TPA Had They Arrived to the Hosp. Within the Therapeut. Time Window. Data Were Collected from Surveys 6 Months after Stroke Using Standardized Patient-reported Outcome Measures and Questions about Hlth. Care Utiliz.. Demogr. and Med. Data Were Acquired from Hosp. Records. Patients Were Matched on Stroke Severity, Age, Race, and Gender. Matching Was Done with 1:2 Ratio of TPA to Controls. Results Were Compared between Groups with 1-tailed Tests because of A Directionally Specific Hypothesis in Favor of the TPA Grp.. the TPA and Contr. Groups Were Matched Across Variables, Except for Stroke Severity, Which Was Better in the Contr. Grp.; Subsequent Analyses Controlled for This Mismatch. the TPA Grp. Reported Better Phys. Funct., Commun., Cogn. Ability, Depressive Symptomatology, and Qual. of Life/participation Compared with the Contr. Grp.. Fewer People in the TPA Grp. Reported Skilled Nursing Facil. Stays. Emergency Dept. Visits, and Rehospitalizations after Their Stroke Compared with Controls. Reports of Other Postacute Serv. Were Not Different between Groups. although It is Known That TPA Reduces Disability, This is the First Stud. to Demonstrate the Effectiveness of TPA in Improving Meaningful, Patientreported Outcomes. Thus, Use of TPA Provides A Large Benefit to the Daily Lives of People with Ischemic Stroke.


Author Keywords
Comparative effectiveness;  Function;  Health care utilization;  Patient-reported outcomes;  Stroke;  Tissue plasminogen activator;  tPA


Document Type: Article
Source: Scopus




Lumba-Brown, A.a , Pineda, J.b
Evidence-based assessment of severe pediatric traumatic brain injury and emergent neurocritical care
(2014) Seminars in Pediatric Neurology, 21 (4), pp. 275-283. 

DOI: 10.1016/j.spen.2014.11.001


a Division of Pediatric Emergency Medicine, Washington University School of MedicineSt. Louis, MO, United States
b Pediatric Neurocritical Care, Washington University School of MedicineSt. Louis, MO, United States


Abstract
Pediatric traumatic brain injury accounts for approximately 474,000 emergency department visits, 37,000 hospitalizations, and 3,000 deaths in children 14 years and younger annually in the United States. Acute neurocritical care in children has advanced with specialized pediatric trauma centers and emergency medical services. This article reviews pediatric-specific diagnosis, management, and medical decision making related to the neurocritical care of severe traumatic brain injury.


Document Type: Article
Source: Scopus




Rumalla, K., Karim, A.M., Hullar, T.E.
The effect of hearing aids on postural stability
(2014) Laryngoscope, 125 (3), pp. 720-723. 

DOI: 10.1002/lary.24974


Department of Otolaryngology-Head and Neck Surgery, Washington University in St. Louis, 660 South Euclid Avenue #8115St. Louis, MO, United States


Abstract
Objectives/Hypothesis: In the United States, falls are the leading cause of accidental deaths in adults aged over 65 years. Epidemiologic studies indicate that there is a correlation between hearing loss and the risk of falling among older people. The vestibular, proprioceptive, and visual systems are known to contribute to postural stability, but the contribution of audition to maintaining balance has not yet been determined. Study Design: Cross-sectional study to measure postural stability in bilateral hearing-aid users aged over 65 years in aided and unaided conditions. Methods: Balance was assessed using the Romberg on foam test and the tandem stance test. Tests were administered in the presence of a point-source broadband white-noise sound (0-4 kHz) source in both unaided and aided conditions in the dark. Subjective measures of balance were made using the Activities-specific Balance Confidence Scale. Results: Performance was significantly better in the aided than the unaided condition (P50.005 for both tests). No statistically significant relationship between improvement in balance, and hearing was identified. Participants did not report that they perceived a difference in balance between the two conditions. Conclusion: These results indicate that hearing aids are a novel treatment modality for imbalance in older adults with hearing loss and suggest that wearing hearing aids may offer a significant public-health benefit for avoiding falls in this population.


Author Keywords
Aid;  Audition;  Auditory;  Balance;  Elderly;  Fall;  Hearing;  Landmark;  Posture;  Romberg;  Stability

 


Document Type: Article
Source: Scopus