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WUSTL Neuroscience Publications Archive - June 2015

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June 30, 2015

 

Pierce, L., Balasubramanian, P.
Behavioral field evidence on psychological and social factors in dishonesty and misconduct
(2015) Current Opinion in Psychology, 6, pp. 70-76. 

DOI: 10.1016/j.copsyc.2015.04.002

Olin Business School, Washington University in St. Louis, United States

Abstract
We review recent behavioral field evidence on dishonesty and other unethical behaviors from psychology and related fields. We specifically focus on individual-level studies that use explicitly behavioral data in natural settings, covering research topics relevant to psychology from across disciplines. Our review shows both the paucity and potential of behavioral field evidence on the psychology of dishonesty. -. although such research can provide actionable and realistic conclusions, it presents a host of practical and identification-related challenges that have limited its use. We explain the major methodological approaches, and discuss the multiple identification challenges for researchers using archival and other non-experimental data. © 2015 Elsevier Ltd.


Document Type: Review
Source: Scopus


Pruett, J.R., Jr.a , Kandala, S.a , Petersen, S.E.b c , Povinelli, D.J.d
Brief Report: Theory of Mind, Relational Reasoning, and Social Responsiveness in Children With and Without Autism: Demonstration of Feasibility for a Larger-Scale Study
(2015) Journal of Autism and Developmental Disorders, 45 (7), pp. 2243-2251. 

DOI: 10.1007/s10803-015-2357-1

a Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave, Campus Box 8134, St. Louis, MO, United States
b Department of Neurology, Washington University School of Medicine, 660 S. Euclid Ave, Campus Box 8111, St. Louis, MO, United States
c Department of Psychology, Washington University, One Brookings Drive, St. Louis, MO, United States
d Department of Biology, University of Louisiana, P.O. Box 42451, Lafayette, LA, United States

Abstract
Understanding the underpinnings of social responsiveness and theory of mind (ToM) will enhance our knowledge of autism spectrum disorder (ASD). We hypothesize that higher-order relational reasoning (higher-order RR: reasoning necessitating integration of relationships among multiple variables) is necessary but not sufficient for ToM, and that social responsiveness varies independently of higher-order RR. A pilot experiment tested these hypotheses in n = 17 children, 3–14, with and without ASD. No child failing 2nd-order RR passed a false belief ToM test. Contrary to prediction, Social Responsiveness Scale scores did correlate with 2nd-order RR performance, likely due to sample characteristics. It is feasible to translate this comparative cognition-inspired line of inquiry for full-scale studies of ToM, higher-order RR, and social responsiveness in ASD. © 2015, Springer Science+Business Media New York.

Author Keywords
Analogical reasoning;  Autism;  Cognition;  Relational reasoning;  Social responsiveness;  Theory of mind


Document Type: Article
Source: Scopus


Halladay, A.K.a b , Bishop, S.c , Constantino, J.N.d , Daniels, A.M.e , Koenig, K.f , Palmer, K.g , Messinger, D.h , Pelphrey, K.i , Sanders, S.J.j , Singer, A.T.a , Taylor, J.L.k , Szatmari, P.l m
Sex and gender differences in autism spectrum disorder: Summarizing evidence gaps and identifying emerging areas of priority
(2015) Molecular Autism, 6 (1), art. no. 36, . 

DOI: 10.1186/s13229-015-0019-y

a Autism Science Foundation, 28 W 39th Street #502, New York, NY, United States
b Department of Pharmacology and Toxicology, Rutgers University, 41B Gordon Road, Piscataway, New Brunswick, NJ, United States
c Department of Psychiatry, University of California San Francisco, 401 Parnassus Ave, LangPorter, San Francisco, CA, United States
d William Greenleaf Eliot Division of Child Psychiatry, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8134, St. Louis, MO, United States
e Autism Speaks, 1 E 33rd St 4th Floor, New York, NY, United States
f Initiative for Girls and Women with Autism Spectrum Disorders, Yale Child Study Center, PO Box 207900230 South Frontage Road, New Haven, CT, United States
g Global and Regional Asperger, Syndrome Partnership, Inc., 419 Lafayette Street, New York, NY, United States
h Department of Psychology and Pediatrics, University of Miami, Flipse Building, P.O. Box 249229, Coral Gables, FL, United States
i Child Neuroscience Laboratory, Yale Child Study Center, PO Box 207900230 South Frontage Road, New Haven, CT, United States
j UCSF School of Medicine, Psychiatry, 1550 4th St Bldg 19B, San Francisco, CA, United States
k Pediatrics and Special Education, Vanderbilt Kennedy Center Investigator, PMB 40-230 Appleton Pl., Nashville, TN, United States
l Hospital for Sick Children and Centre for Addiction and Mental Health, Centre for Addiction and Mental Health, University of Toronto, 1001 Queen Street West, Toronto, ON, Canada
m Division of Child and Adolescent Psychiatry, Centre for Addiction and Mental Health, University of Toronto, 1001 Queen Street West, Toronto, ON, Canada

Abstract
One of the most consistent findings in autism spectrum disorder (ASD) research is a higher rate of ASD diagnosis in males than females. Despite this, remarkably little research has focused on the reasons for this disparity. Better understanding of this sex difference could lead to major advancements in the prevention or treatment of ASD in both males and females. In October of 2014, Autism Speaks and the Autism Science Foundation co-organized a meeting that brought together almost 60 clinicians, researchers, parents, and self-identified autistic individuals. Discussion at the meeting is summarized here with recommendations on directions of future research endeavors. © 2015 Halladay et al.

Author Keywords
Autism;  Diagnosis;  Female;  Protection;  Research;  Symposium


Document Type: Article
Source: Scopus


Eisenstein, S.A.a b , Bischoff, A.N.a , Gredysa, D.M.a , Antenor-Dorsey, J.A.V.a , Koller, J.M.a , Al-Lozi, A.a , Pepino, M.Y.c , Klein, S.c , Perlmutter, J.S.b d e f g , Moerlein, S.M.b h , Black, K.J.a b d e , Hershey, T.a b d
Emotional eating phenotype is associated with central dopamine D2 receptor binding independent of body mass index
(2015) Scientific Reports, 5, art. no. 11283, . 

DOI: 10.1038/srep11283

a Departments of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
b Departments of Radiology, Washington University School of Medicine, St. Louis, MO, United States
c Departments of Internal Medicine, Washington University School of Medicine, St. Louis, MO, United States
d Departments of Neurology, Washington University School of Medicine, St. Louis, MO, United States
e Departments of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, MO, United States
f Departments of Physical Therapy, Washington University School of Medicine, St. Louis, MO, United States
g Departments of Occupational Therapy, Washington University School of Medicine, St. Louis, MO, United States
h Departments of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO, United States

Abstract
PET studies have provided mixed evidence regarding central D<inf>2</inf>/D3 dopamine receptor binding and its relationship with obesity as measured by body mass index (BMI). Other aspects of obesity may be more tightly coupled to the dopaminergic system. We characterized obesity-associated behaviors and determined if these related to central D<inf>2</inf> receptor (D<inf>2</inf>R) specific binding independent of BMI. Twenty-two obese and 17 normal-weight participants completed eating- and reward-related questionnaires and underwent PET scans using the D<inf>2</inf>R-selective and nondisplaceable radioligand (N-[ 11 C]methyl)benperidol. Questionnaires were grouped by domain (eating related to emotion, eating related to reward, non-eating behavior motivated by reward or sensitivity to punishment). Normalized, summed scores for each domain were compared between obese and normal-weight groups and correlated with striatal and midbrain D<inf>2</inf>R binding. Compared to normal-weight individuals, the obese group self-reported higher rates of eating related to both emotion and reward (p < 0.001), greater sensitivity to punishment (p = 0.06), and lower non-food reward behavior (p < 0.01). Across normal-weight and obese participants, self-reported emotional eating and non-food reward behavior positively correlated with striatal (p < 0.05) and midbrain (p < 0.05) D<inf>2</inf>R binding, respectively. In conclusion, an emotional eating phenotype may reflect altered central D<inf>2</inf>R function better than other commonly used obesity-related measures such as BMI.


Document Type: Article
Source: Scopus


Mirbaha, H.a , Holmes, B.B.a , Sanders, D.W.a , Bieschke, J.b , Diamond, M.I.a
Tau trimers are the minimal propagation unit spontaneously internalized to seed intracellular aggregation
(2015) Journal of Biological Chemistry, 290 (24), pp. 14893-14903. 

DOI: 10.1074/jbc.M115.652693

a Center for Alzheimer's and Neurodegenerative Diseases, University of Texas Southwestern Medical Center, 6000 Harry Hines Blvd., Dallas, TX, United States
b Department of Biomedical Engineering, Washington University, St. Louis, MO, United States

Abstract
Tau amyloid assemblies propagate aggregation from the outside to the inside of a cell, which may mediate progression of the tauopathies. The critical size of Tau assemblies, or "seeds," responsible for this activity is currently unknown, but this could be important for the design of effective therapies. We studied recombinant Tau repeat domain (RD) and Tau assemblies purified from Alzheimer disease (AD) brain composed largely of full-length Tau. Large RD fibrils were first sonicated to create a range of assembly sizes. We confirmed our ability to resolve stable assemblies ranging from n = 1 to > 100 units of Tau using size exclusion chromatography, fluorescence correlation spectroscopy, cross-linking followed by Western blot, and mass spectrometry. All recombinant Tau assemblies bound heparan sulfate proteoglycans on the cell surface, which are required for Tau uptake and seeding, because they were equivalently sensitive to inhibition by heparin and chlorate. However, cells only internalized RD assemblies of n ≥ 3 units. We next analyzed Tau assemblies from AD or control brains. AD brains contained aggregated species, whereas normal brains had predominantly monomer, and no evidence of large assemblies. HEK293 cells and primary neurons spontaneously internalized Tau of n ≥ 3 units from AD brain in a heparin- and chlorate-sensitive manner. Only n ≥ 3-unit assemblies from AD brain spontaneously seeded intracellular Tau aggregation in HEK293 cells. These results indicate that a clear minimum size (n = 3) of Tau seed exists for spontaneous propagation of Tau aggregation from the outside to the inside of a cell, whereas many larger sizes of soluble aggregates trigger uptake and seeding. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.


Document Type: Article
Source: Scopus


Hargis, M.a , Shah, J.N.b , Mazabob, J.c , Rao, C.V.c , Suarez, J.I.c , Bershad, E.M.c
Barriers to administering intravenous tissue plasminogen activator (tPA) for acute ischemic stroke in the emergency department: A cross-sectional survey of stroke centers
(2015) Clinical Neurology and Neurosurgery, 135, pp. 79-84. 

DOI: 10.1016/j.clineuro.2015.04.027

a Washington University School of Medicine, Saint Louis, United States
b Johns Hopkins University, Baltimore, United States
c Department of Neurology, Baylor College of Medicine, Houston, TX, United States

Abstract
Objective The logistics involved in administration of IV tPA for acute ischemic stroke patients are complex, and may contribute to variability in door-to-needle times between different hospitals. We sought to identify practice patterns in stroke centers related to IV tPA use. We hypothesized that there would be significant variability in logistics related to ancillary staff (i.e. nursing, pharmacists) processes in the emergency room setting. Methods A 21 question survey was distributed to attendees of the AHA/ASA Southwest Affiliate Stroke Coordinators Conference to evaluate potential barriers and delays with regards to thrombolysis for acute strokes patients in the Emergency Department setting. Answers were anonymous and aggregated to examine trends in responses. Results Responses were obtained from 37 of 67 (55%) stroke centers, which were located mainly in the Southwest United States. Logistical processes differed between facilities. Nursing and pharmacy carried stroke pagers in only 19% of the centers, and pharmacy responded to stroke alerts only one-third of centers. Insertion of Foley catheters and nasogastric tubes prior to tPA was routine in some of the sites. Other barriers to IV tPA administration included physician reluctance and inadequate communication between health care providers. Conclusion Practices regarding logistics for giving IV tPA may be variable amongst different stroke centers. Given this potential variability, prospective evaluation to confirm these preliminary findings is warranted. © 2015 Elsevier B.V. All rights reserved.

Author Keywords
Acute ischemic stroke;  Barriers;  Emergency department;  IV tPA;  Stroke centers


Document Type: Article
Source: Scopus


Razafsky, D., Hodzic, D.
Nuclear envelope: Positioning nuclei and organizing synapses
(2015) Current Opinion in Cell Biology, 34, pp. 84-93. 

DOI: 10.1016/j.ceb.2015.06.001

Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, 660 S. Euclid Avenue, St Louis, MO, United States

Abstract
The nuclear envelope plays an essential role in nuclear positioning within cells and tissues. This review highlights advances in understanding the mechanisms of nuclear positioning during skeletal muscle and central nervous system development. New findings, particularly about A-type lamins and Nesprin1, may link nuclear envelope integrity to synaptic integrity. Thus synaptic defects, rather than nuclear mispositioning, may underlie human pathologies associated with mutations of nuclear envelope proteins. © 2015 Elsevier Ltd.


Document Type: Review
Source: Scopus


Munn-Chernoff, M.A.a e , Grant, J.D.a , Agrawal, A.a , Sartor, C.E.a b , Werner, K.B.c , Bucholz, K.K.a , Madden, P.A.F.a , Heath, A.C.a , Duncan, A.E.a d
Genetic overlap between alcohol use disorder and bulimic behaviors in European American and African American women
(2015) Drug and Alcohol Dependence, . Article in Press. 

DOI: 10.1016/j.drugalcdep.2015.05.043

a Department of Psychiatry, Washington University School of Medicine, 660 South Euclid, CB 8134, St. Louis, MO 63110, USA
b Department of Psychiatry, Yale University School of Medicine, VA Connecticut Healthcare System, 950 Campbell Ave. (151D), West Haven, CT 06516, USA
c George Warren Brown School of Social Work, Washington University, 4560 Clayton Ave., CID 1000, St. Louis, MO 63110, USA
d George Warren Brown School of Social Work, Washington University, One Brookings Drive, CB 1196, St. Louis, MO 63130, USA
e Department of Psychiatry, University of North Carolina, 101 Manning Drive, CB 7160, Chapel Hill, NC 27599, USA

Abstract
Background: Despite substantial evidence that alcohol use disorder (AUD) and bulimic behaviors (i.e., binge eating and compensatory behaviors) co-occur, insufficient information exists regarding a possible shared etiology. Moreover, although numerous twin studies of European ancestry individuals have reported moderate heritability estimates for AUD and bulimic behaviors, with little evidence for shared environmental factors, research on genetic and environmental risk in African American (AA) individuals is lacking. Methods: We investigated specific and overlapping genetic and environmental influences on AUD and bulimic behaviors in 3232 European American (EA; 55.38% monozygotic) and 549 AA (42.81% monozygotic) young adult female twins from the Missouri Adolescent Female Twin Study (age range = 18-29 years). A structured clinical interview assessed lifetime DSM-5 AUD (minus craving) and bulimic behaviors. Biometrical twin modeling was conducted to generate age-adjusted estimates of genetic and environmental influences on AUD, bulimic behaviors, and their comorbidity. Results: Estimates of genetic and environmental contributions on AUD and bulimic behaviors could be equated across EA and AA women. Additive genetic effects accounted for 59% (95% CI: 50%, 66%) and 43% (33%, 52%) of the variance in AUD and bulimic behaviors, respectively, with the remainder due to non-shared environmental effects. Shared genetic factors (r <inf> g </inf> =.33 (.18, .49)) were solely responsible for the correlation between phenotypes; the non-shared environmental correlation was not significant (r <inf> e </inf> =.10 (-.05, .25)). Conclusions: Findings indicate similar magnitudes of genetic and environmental effects on AUD and bulimic behaviors for EA and AA women and implicate common genetic mechanisms underlying liability to these problem behaviors. © 2015 Elsevier Ireland Ltd.

Author Keywords
African American;  Alcohol use disorder;  DSM-5;  Eating disorders;  Heritability;  Twins


Document Type: Article in Press
Source: Scopus


Day, B.K., Eisenman, L., Black, J., Maccotta, L., Hogan, R.E.
A case study of voltage-gated potassium channel antibody-related limbic encephalitis with PET/MRI findings
(2015) Epilepsy and Behavior Case Reports, 4, pp. 23-26. 

DOI: 10.1016/j.ebcr.2015.02.002

Department of Neurology, Washington University in St. Louis, Campus Box 8111, 660 South Euclid Avenue, St. Louis, MO, United States

Abstract
Preclinical and clinical studies have demonstrated the significance of inflammation and autoantibodies in epilepsy, and the use of immunotherapies in certain situations has become an established practice. Temporal lobe epilepsy can follow paraneoplastic or nonparaneoplastic limbic encephalitis associated with antibodies directed against brain antigens. Here, we focus on a patient with worsening confusion and temporal lobe seizures despite treatment with antiepileptic medications. Serial brain MRIs did not conclusively reveal structural abnormalities, so the patient underwent brain PET/MRI to simultaneously evaluate brain structure and function, revealing bitemporal abnormalities. The patient was diagnosed with voltage-gated potassium channel antibody-related limbic encephalitis based on clinical presentation, imaging findings, and antibody testing. Treatment included the addition of a second antiepileptic agent and oral steroids. His seizures and cognitive deficits improved and stabilized. © 2015.

Author Keywords
Autoimmune epilepsy;  Limbic encephalitis;  Magnetic resonance imaging;  PET/MRI;  Positron emission tomography;  Voltage-gated potassium channel


Document Type: Article
Source: Scopus


Maddox, G.B.a b , Balota, D.A.a
Retrieval practice and spacing effects in young and older adults: An examination of the benefits of desirable difficulty
(2015) Memory and Cognition, 43 (5), pp. 760-774. 

DOI: 10.3758/s13421-014-0499-6

a Washington University in St. Louis, St. Louis, MO, United States
b Rhodes College, 110 Clough Hall, Memphis, TN, United States

Abstract
In the present study, we examined how the function relating continued retrieval practice (e.g., one, three, or five tests) and long-term memory retention is modulated by desirable difficulty (R. A. Bjork, 1994). Of particular interest was how retrieval difficulty differed across young and older adults and across manipulations of lag (Exp. 1) and spacing (Exp. 2). To extend on previous studies, the acquisition phase response latency was used as a proxy for retrieval difficulty, and our analysis of final-test performance was conditionalized on acquisition phase retrieval success, to more directly examine the influence of desirable difficulty on retention. The results from Experiment 1 revealed that continued testing in the short-lag condition led to consistent increases in retention, whereas continued testing in the long-lag condition led to increasingly smaller benefits in retention for both age groups. The results from Experiment 2 revealed that repeated spaced testing enhanced retention relative to taking one spaced test, for both age groups; however, repeated massed testing only enhanced retention over taking one test for young adults. Across both experiments, the response latency results were overall consistent with an influence of desirable difficulty on retention. The discussion focuses on the role of desirable difficulty during encoding in producing the benefits of lag, spacing, and testing. © 2015, Psychonomic Society, Inc.

Author Keywords
Refreshing;  Retrieval practice aging;  Spacing effect;  Testing effect


Document Type: Article
Source: Scopus


Black, K.J.a , Piccirillo, M.L.b f , Koller, J.M.c , Hseih, T.b g , Wang, L.d , Mintun, M.A.e h
Levodopa effects on [11C]raclopride binding in the resting human brain
(2015) F1000Research, 4, . 

DOI: 10.12688/f1000research.5672.1

a Departments of Psychiatry, Neurology, Radiology, and Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, MO, United States
b School of Arts and Sciences, Washington University, St. Louis, MO, United States
c Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
d Departments of Psychiatry and Behavioral Sciences, and Radiology, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
e Departments of Radiology, Psychiatry, Bioengineering, and Anatomy and Neurobiology, Washington University, St. Louis, MO, United States
f Temple University, Philadelphia, PA, United States
g Department of Ophthalmology, University of Cincinnati, Cincinnati, OH, United States
h Avid Radiopharmaceuticals, Philadelphia, PA, United States

Abstract
Rationale: Synaptic dopamine (DA) release induced by amphetamine or other experimental manipulations can displace [ 11C]raclopride (RAC*) from dopamine D2-like receptors. We hypothesized that exogenous levodopa might increase dopamine release at striatal synapses under some conditions but not others, allowing a more naturalistic assessment of presynaptic dopaminergic function. Presynaptic dopaminergic abnormalities have been reported in Tourette syndrome (TS). Objective: Test whether levodopa induces measurable synaptic DA release in healthy people at rest, and gather pilot data in TS. Methods: This double-blind crossover study used RAC* and positron emission tomography (PET) to measure synaptic dopamine release 4 times in each of 10 carbidopa-pretreated, neuroleptic-naïve adults: before and during an infusion of levodopa on one day and placebo on another (in random order). Five subjects had TS and 5 were matched controls. RAC* binding potential (BP ND) was quantified in predefined anatomical volumes of interest (VOIs). A separate analysis compared BP ND voxel by voxel over the entire brain. Results: DA release declined between the first and second scan of each day (p=0.012), including on the placebo day. Levodopa did not significantly reduce striatal RAC* binding and striatal binding did not differ significantly between TS and control groups. However, levodopa's effect on DA release differed significantly in a right midbrain region (p=0.002, corrected), where levodopa displaced RAC* by 59% in control subjects but increased BP ND by 74% in TS subjects. Discussion: Decreased DA release on the second scan of the day is consistent with the few previous studies with a similar design, and may indicate habituation to study procedures. We hypothesize that mesostriatal DA neurons fire relatively little while subjects rest, possibly explaining the non-significant effect of levodopa on striatal RAC* binding. The modest sample size argues for caution in interpreting the group difference in midbrain DA release with levodopa. © 2015 Black KJ et al.


Document Type: Article
Source: Scopus


Weiner, M.W.a b c d e x , Veitch, D.P.a , Aisen, P.S.f , Beckett, L.A.g , Cairns, N.J.h i , Cedarbaum, J.j , Green, R.C.k , Harvey, D.g , Jack, C.R.l , Jagust, W.m , Luthman, J.n , Morris, J.C.f , Petersen, R.C.o , Saykin, A.J.p q , Shaw, L.r , Shen, L.p , Schwarz, A.s , Toga, A.W.t , Trojanowski, J.Q.r u v w
2014 Update of the Alzheimer's Disease Neuroimaging Initiative: A review of papers published since its inception
(2015) Alzheimer's and Dementia, 11 (6), pp. e1-e120. 

DOI: 10.1016/j.jalz.2014.11.001

a Department of Veterans Affairs Medical Center, Center for Imaging of Neurodegenerative Diseases, San Francisco, CA, United States
b Department of Radiology, University of California, San Francisco, CA, United States
c Department of Medicine, University of California, San Francisco, CA, United States
d Department of Psychiatry, University of California, San Francisco, CA, United States
e Department of Neurology, University of California, San Francisco, CA, United States
f Department of Neurosciences, University of California, San Diego, San Diego, CA, United States
g Division of Biostatistics, Department of Public Health Sciences, University of California, Davis, CA, United States
h Knight Alzheimer's Disease Research Center, Washington University School of Medicine, Saint Louis, MO, United States
i Department of Neurology, Washington University School of Medicine, Saint Louis, MO, United States
j Neurology Early Clinical Development, Biogen Idec, Cambridge, MA, United States
k Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States
l Department of Radiology, Mayo Clinic, Rochester, MN, United States
m Helen Wills Neuroscience Institute, University of California Berkeley, Berkeley, CA, United States
n Neuroscience Clinical Development, Neuroscience and General Medicine Product Creation Unit, Eisai Inc., Philadelphia, PA, United States
o Department of Neurology, Mayo Clinic, Rochester, MN, United States
p Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, United States
q Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, United States
r Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
s Tailored Therapeutics, Eli Lilly and Company, Indianapolis, IN, United States
t Laboratory of Neuroimaging, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
u Institute on Aging, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
v Alzheimer's Disease Core Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
w Udall Parkinson's Research Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States

Abstract
The Alzheimer's Disease Neuroimaging Initiative (ADNI) is an ongoing, longitudinal, multicenter study designed to develop clinical, imaging, genetic, and biochemical biomarkers for the early detection and tracking of Alzheimer's disease (AD). The initial study, ADNI-1, enrolled 400 subjects with early mild cognitive impairment (MCI), 200 with early AD, and 200 cognitively normal elderly controls. ADNI-1 was extended by a 2-year Grand Opportunities grant in 2009 and by a competitive renewal, ADNI-2, which enrolled an additional 550 participants and will run until 2015. This article reviews all papers published since the inception of the initiative and summarizes the results to the end of 2013. The major accomplishments of ADNI have been as follows: (1) the development of standardized methods for clinical tests, magnetic resonance imaging (MRI), positron emission tomography (PET), and cerebrospinal fluid (CSF) biomarkers in a multicenter setting; (2) elucidation of the patterns and rates of change of imaging and CSF biomarker measurements in control subjects, MCI patients, and AD patients. CSF biomarkers are largely consistent with disease trajectories predicted by β-amyloid cascade (Hardy, J Alzheimer's Dis 2006;9(Suppl 3):151-3) and tau-mediated neurodegeneration hypotheses for AD, whereas brain atrophy and hypometabolism levels show predicted patterns but exhibit differing rates of change depending on region and disease severity; (3) the assessment of alternative methods of diagnostic categorization. Currently, the best classifiers select and combine optimum features from multiple modalities, including MRI, [18F]-fluorodeoxyglucose-PET, amyloid PET, CSF biomarkers, and clinical tests; (4) the development of blood biomarkers for AD as potentially noninvasive and low-cost alternatives to CSF biomarkers for AD diagnosis and the assessment of α-syn as an additional biomarker; (5) the development of methods for the early detection of AD. CSF biomarkers, β-amyloid 42 and tau, as well as amyloid PET may reflect the earliest steps in AD pathology in mildly symptomatic or even nonsymptomatic subjects and are leading candidates for the detection of AD in its preclinical stages; (6) the improvement of clinical trial efficiency through the identification of subjects most likely to undergo imminent future clinical decline and the use of more sensitive outcome measures to reduce sample sizes. Multimodal methods incorporating APOE status and longitudinal MRI proved most highly predictive of future decline. Refinements of clinical tests used as outcome measures such as clinical dementia rating-sum of boxes further reduced sample sizes; (7) the pioneering of genome-wide association studies that leverage quantitative imaging and biomarker phenotypes, including longitudinal data, to confirm recently identified loci, CR1, CLU, and PICALM and to identify novel AD risk loci; (8) worldwide impact through the establishment of ADNI-like programs in Japan, Australia, Argentina, Taiwan, China, Korea, Europe, and Italy; (9) understanding the biology and pathobiology of normal aging, MCI, and AD through integration of ADNI biomarker and clinical data to stimulate research that will resolve controversies about competing hypotheses on the etiopathogenesis of AD, thereby advancing efforts to find disease-modifying drugs for AD; and (10) the establishment of infrastructure to allow sharing of all raw and processed data without embargo to interested scientific investigators throughout the world. © 2015, Elsevier Inc. All rights reserved.

Author Keywords
Alzheimer's disease;  Amyloid;  Biomarker;  Mild cognitive impairment;  Tau


Document Type: Review
Source: Scopus


Vernon, E.K.a , Babulal, G.M.a , Head, D.b c d , Carr, D.a e , Ghoshal, N.a , Barco, P.P.f , Morris, J.C.a f g h , Roe, C.M.a
Adults aged 65 and older use potentially distracting electronic devices while driving
(2015) Journal of the American Geriatrics Society, 63 (6), pp. 1251-1253. 

DOI: 10.1111/jgs.13499

a Department of Neurology, School of Medicine, Washington University, St. Louis, MO, United States
b Department of Psychology, Washington University, St. Louis, MO, United States
c Department of Radiology, Washington University, St. Louis, MO, United States
d Department of African and African American Studies, Washington University, St. Louis, MO, United States
e Department of Medicine, School of Medicine, Washington University, St. Louis, MO, United States
f Department of Occupational Therapy, School of Medicine, Washington University, St. Louis, MO, United States
g Department of Physical Therapy, School of Medicine, Washington University, St. Louis, MO, United States
h Department of Pathology and Immunology, School of Medicine, Washington University, St. Louis, MO, United States


Document Type: Letter
Source: Scopus


Tarawneh, R.a b c d , Head, D.c e f , Allison, S.f , Buckles, V.a c , Fagan, A.M.a b c , Ladenson, J.H.g , Morris, J.C.a c g , Holtzman, D.M.a b c h
Cerebrospinal fluid markers of neurodegeneration and rates of brain atrophy in early Alzheimer disease
(2015) JAMA Neurology, 72 (6), pp. 656-665. 

DOI: 10.1001/jamaneurol.2015.0202

a Department of Neurology, Washington University, School of Medicine in St. Louis, 660 S Euclid Ave., Campus Box 8111, St. Louis, MO, United States
b Hope Center for Neurological Disorders, Washington University, School of Medicine in St. Louis, St. Louis, MO, United States
c Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University, School of Medicine in St. Louis, St. Louis, MO, United States
d Department of Neurology, Duke University, Medical Center, Durham, NC, United States
e Department of Radiology, Washington University, School of Medicine in St. Louis, St. Louis, MO, United States
f Department of Psychology, Washington University, School of Medicine in St. Louis, St. Louis, MO, United States
g Department of Pathology and Immunology, Washington University, School of Medicine in St. Louis, St. Louis, MO, United States
h Department of Developmental Biology, Washington University, School of Medicine in St. Louis, St. Louis, MO, United States

Abstract
IMPORTANCE: Measures of neuronal loss are likely good surrogates for clinical and radiological disease progression in Alzheimer disease (AD). Cerebrospinal fluid (CSF) markers of neuronal injury or neurodegeneration may offer usefulness in predicting disease progression and guiding outcome assessments and prognostic decisions in clinical trials of disease-modifying therapies. Visinin-like protein 1 (VILIP-1) has demonstrated potential usefulness as a marker of neuronal injury in AD. OBJECTIVE: To investigate the usefulness of CSF VILIP-1, tau, p-tau181, and Aβ42 levels in predicting rates of whole-brain and regional atrophy in early AD and cognitively normal control subjects over time. DESIGN, SETTING, AND PARTICIPANTS: Longitudinal observational study of brain atrophy in participants with early AD and cognitively normal controls. Study participants had baseline CSF biomarker measurements and longitudinal magnetic resonance imaging assessments for a mean follow-up period of 2 to 3 years. Mixed linear models assessed the ability of standardized baseline CSF biomarker measures to predict rates of whole-brain and regional atrophy over the follow-up period. The setting was The Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine in St Louis. Participants (mean age, 72.6 years) were individuals with a clinical diagnosis of very mild AD (n = 23) and cognitively normal controls (n = 64) who were enrolled in longitudinal studies of healthy aging and dementia. The study dates were 2000 to 2010. MAIN OUTCOMES AND MEASURES: Correlations between baseline CSF biomarker measures and rates of whole-brain or regional atrophy in the AD and control cohorts over the follow-up period. RESULTS: Baseline CSF VILIP-1, tau, and p-tau181 levels (but not Aβ42 levels) predicted rates of whole-brain and regional atrophy in AD over the follow-up period. Baseline CSF VILIP-1 levels predicted whole-brain (P =.006), hippocampal (P =.01), and entorhinal (P =.001) atrophy rates at least as well as tau and p-tau181 in early AD. Cognitively normal controls whose CSF VILIP-1, tau, or p-tau181 levels were in the upper tercile had higher rates of whole-brain (P =.02, P =.003, and P =.02, respectively), hippocampal (P =.001, P =.01, and P =.02, respectively), and entorhinal (P =.007, P =.01, and P =.01, respectively) atrophy compared with those whose levels were in the lower 2 terciles. CONCLUSIONS AND RELEVANCE: Cerebrospinal fluid VILIP-1 levels predict rates of whole-brain and regional atrophy similarly to tau and p-tau181 and may provide a useful CSF biomarker surrogate for neurodegeneration in early symptomatic and preclinical AD. JAMA Neurol.


Document Type: Article
Source: Scopus


Aiyagari, V.a , Diringer, M.N.b
Cognition and quality-of-life outcomes in the targeted temperature management trial for cardiac arrest
(2015) JAMA Neurology, 72 (6), pp. 628-630. 

DOI: 10.1001/jamaneurol.2015.0164

a Department of Neurological Surgery and Neurology and Neurotherapeutics, University of Texas Southwestern, Medical Center, 5323 Harry Hines Blvd., Mail Code 8855, Dallas, TX, United States
b Department of Neurology, Neurosurgery, Anesthesiology, and Occupational Therapy, Washington University, School of Medicine, St. Louis, MO, United States


Document Type: Note
Source: Scopus


Jones, L.a eh eh , Lambert, J.-C.b c d , Wang, L.-S.t , Choi, S.-H.i , Harold, D.ee , Vedernikov, A.a , Escott-Price, V.a , Stone, T.a , Richards, A.a , Bellenguez, C.b c d , Ibrahim-Verbaas, C.A.e , Naj, A.C.f , Sims, R.a , Gerrish, A.a , Jun, G.g h i , DeStefano, A.L.i , Bis, J.C.j , Beecham, G.W.f k , Grenier-Boley, B.b c d , Russo, G.l , Thornton-Wells, T.A.m , Jones, N.a , Smith, A.V.n o , Chouraki, V.b c d , Thomas, C.a , Ikram, M.A.p q , Zelenika, D.r , Vardarajan, B.N.g , Kamatani, Y.s , Lin, C.-F.t , Schmidt, H.u , Kunkle, B.W.f , Dunstan, M.L.a , Ruiz, A.v , Bihoreau, M.-T.r , Reitz, C.w x , Pasquier, F.c y , Hollingworth, P.a , Hanon, O.aa , Fitzpatrick, A.L.j ab , Buxbaum, J.D.ac ad ae , Campion, D.af , Crane, P.K.ag , Becker, T.ah , Gudnason, V.n o , Cruchaga, C.ai , Craig, D.aj , Amin, N.ak , Berr, C.al , Lopez, O.L.am , De Jager, P.L.an ao , Deramecourt, V.b y , Johnston, J.A.aj , Evans, D.ap , Lovestone, S.aq , Letteneur, L.ar ef , Kornhuber, J.as , Tárraga, L.v , Rubinsztein, D.C.at , Eiriksdottir, G.o , Sleegers, K.au av , Goate, A.M.ai , Fiévet, N.b d , Huentelman, M.J.aw , Gill, M.ax , Emilsson, V.n o , Brown, K.ay , Kamboh, M.I.az ba , Keller, L.bb , Barberger-Gateau, P.ar ef , McGuinness, B.aj , Larson, E.B.ag bc , Myers, A.J.bd , Dufouil, C.ar ef , Todd, S.aj , Wallon, D.af , Love, S.be , Kehoe, P.be , Rogaeva, E.bf , Gallacher, J.bg , St George-Hyslop, P.bf bh , Clarimon, J.bi bj , Lleò, A.bi bj , Bayer, A.bg , Tsuang, D.W.bk , Yu, L.bl , Tsolaki, M.bm , Bossù, P.bn , Spalletta, G.bn , Proitsi, P.aq , Collinge, J.bo , Sorbi, S.bp bq , Sanchez Garcia, F.br , Fox, N.bs , Hardy, J.bt , Deniz Naranjo, M.C.br , Razquin, C.dz , Bosco, P.bu , Clarke, R.bv , Brayne, C.bw , Galimberti, D.bx , Mancuso, M.by , Moebus, S.bz , Mecocci, P.ca , Del Zompo, M.cb , Maier, W.cc cz , Hampel, H.cd , Pilotto, A.ce , Bullido, M.cf cg ch , Panza, F.ci , Caffarra, P.cj ck , Nacmias, B.bp bq , Gilbert, J.R.f k , Mayhaus, M.cl , Jessen, F.cc cz , Dichgans, M.dp ec , Lannfelt, L.cm , Hakonarson, H.cn , Pichler, S.cl , Carrasquillo, M.M.co , Ingelsson, M.cm , Beekly, D.cp , Alavarez, V.cq , Zou, F.co , Valladares, O.t , Younkin, S.G.co , Coto, E.cq , Hamilton-Nelson, K.L.f , Mateo, I.cr , Owen, M.J.a , Faber, K.M.cs , Jonsson, P.V.ct , Combarros, O.cr , O'Donovan, M.C.a , Cantwell, L.B.t , Soininen, H.cu cv , Blacker, D.cw cy , Mead, S.bo , Mosley, T.H., Jr.da , Bennett, D.A.bl da , Harris, T.B.db , Fratiglioni, L.dc dd , Holmes, C.de , De Bruijn, R.F.A.G.df , Passmore, P.aj , Montine, T.J.dg , Bettens, K.au av , Rotter, J.I.dh , Brice, A.di dj , Morgan, K.ay , Foroud, T.M.cs , Kukull, W.A.dk , Hannequin, D.af , Powell, J.F.aq , Nalls, M.A.dl , Ritchie, K.al , Lunetta, K.L.i , Kauwe, J.S.K.at , Boerwinkle, E.dm dn , Riemenschneider, M.cl , Boada, M.v , Hiltunen, M.cu cv , Martin, E.R.f k , Pastor, P.ea eb , Schmidt, R.dq , Rujescu, D.dr eg , Dartigues, J.-F.ar ds ef , Mayeux, R.w x , Tzourio, C.do dt , Hofman, A.p q , Nöthen, M.M.du , Graff, C.dd dv , Psaty, B.M.j bc ed , Haines, J.L.m dw , Lathrop, M.r s dx , Pericak-Vance, M.A.f k , Launer, L.J.db , Farrer, L.A.g h i cx dy , Van Duijn, C.M.ak , Van Broeckhoven, C.au av , Ramirez, A.z , Schellenberg, G.D.t , Seshadri, S.dy , Amouyel, P.b c d y , Williams, J.a , Holmans, P.A.a , MRC CFASeh
Convergent genetic and expression data implicate immunity in Alzheimer's disease
(2015) Alzheimer's and Dementia, 11 (6), pp. 658-671. 

DOI: 10.1016/j.jalz.2014.05.1757

a Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff, United Kingdom
b Inserm U744, Lille, France
c Université Lille 2, Lille, France
d Institut Pasteur de Lille, Lille, France
e Department of Epidemiology, Clinical Genetics and Neurology, Erasmus MC University Medical Center, Rotterdam, Netherlands
f John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL, United States
g Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, United States
h Department of Ophthalmology, Boston University School of Medicine, Boston, MA, United States
i Department of Biostatistics, Boston University School of Public Health, Boston, MA, United States
j Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, United States
k Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami, Miami, FL, United States
l Functional Genomics Center, Zurich, Switzerland
m Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, United States
n University of Iceland, Faculty of Pharmaceutical Sciences, Reykjavik, Iceland
o Icelandic Heart Association, Kopavogur, Iceland
p Departments of Epidemiology, Neurology and Radiology, Erasmus MC University Medical Center, Rotterdam, Netherlands
q Netherlands Consortium for Healthy Aging, Leiden, Netherlands
r Centre National de Genotypage, Institut Genomique, Commissariat À l'Énergie Atomique, Evry, France
s Fondation Jean Dausset- CEPH, Paris, France
t Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States
u Institute for Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria
v Memory Clinic of Fundació ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain
w Taub Institute on Alzheimer's Disease and the Aging Brain, Department of Neurology, Columbia University, New York, NY, United States
x Gertrude H. Sergievsky Center, Columbia University, Department of Neurology, New York, NY, United States
y Centre Hospitalier Régional Universitaire de Lille, Lille, France
z Department of Psychiatry and Psychotherapy, Institute of Human Genetics, University of Bonn, Bonn, Germany
aa UMR 894 Inserm, Faculté de Médecine, Université Paris Descartes, Paris, France
ab Departments of Epidemiology and Global Health, University of Washington, Seattle, WA, United States
ac Department of Neuroscience, Mount Sinai School of Medicine, New York, NY, United States
ad Department of Psychiatry, Mount Sinai School of Medicine, New York, NY, United States
ae Departments of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, NY, United States
af INSERM U614, Faculté de Médecine, Centre Hospitalier du Rouvray, Rouen, France
ag Department of Medicine, University of Washington, Seattle, WA, United States
ah German Center for Neurodegenerative Diseases (DZNE, Bonn), Institute for Medical Biometry, Informatics and Epidemiology, University of Bonn, Bonn, Germany
ai Department of Psychiatry, Hope Center Program on Protein Aggregation and Neurodegeneration, Washington University School of Medicine, St. Louis, MO, United States
aj Ageing Group, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, United Kingdom
ak Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, Netherlands
al INSERM U888, Hôpital La Colombière, Montpellier, France
am Departments of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
an Department of Neurology and Psychiatry, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States
ao Program in Medical and Population Genetics, Broad Institute, Boston, MA, United States
ap Rush Institute for Healthy Aging, Department of Internal Medicine, Rush University Medical Center, Chicago, IL, United States
aq King's College London, Institute of Psychiatry, Department of Neuroscience, De Crespigny Park, Denmark Hill, London, United Kingdom
ar Inserm U897, Victor Segalen University, Bordeaux, France
as Department of Psychiatry and Psychotherapy, Friedrich-Alexander-University Erlangen-Nuremberg, Germany
at Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom
au Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerp, Belgium
av Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
aw Neurogenomics Division, Translational Genomics Research Institute, Phoenix, AZ, United States
ax Mercer's Institute for Research on Aging, St. James Hospital, Trinity College, Dublin, Dublin 8, Ireland
ay Institute of Genetics, Queen's Medical Centre, University of Nottingham, United Kingdom
az Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, United States
ba Alzheimer's Disease Research Center, University of Pittsburgh, Pittsburgh, PA, United States
bb Dept. Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm University, Stockholm, Sweden
bc Group Health Research Institute, Group Health, Seattle, WA, United States
bd Department of Psychiatry and Behavioral Sciences, Miller School of Medicine, University of Miami, Miami, FL, United States
be University of Bristol, Clinical Neurosciences, Level 1 Learning and Research Building, United Kingdom
bf Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, ON, Canada
bg Institute of Primary Care and Public Health, Cardiff University, University Hospital of Wales, Neuadd Meirionnydd, Heath Park, Cardiff, United Kingdom
bh Cambridge Institute for Medical Research, Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom
bi Neurology Department, Sant Pau Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain
bj Center for Networker Biomedical Research in Neurodegenerative Diseases (CIBERNED), Barcelona, Spain
bk Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, United States
bl Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, United States
bm Aristotle University of Thessaloniki, Despere 3, Thessaloniki, Greece
bn Clinical and Behavioral Neurology, Fondazione Santa Lucia, Roma, Italy
bo MRC Prion Unit, Department of Neurodegenerative Disease, UCL Institute of Neurology, London, United Kingdom
bp Department of Neurological and Psychiatric Sciences, University of Florence, Florence, Italy
bq Centro di Ricerca, Trasferimento e Alta Formazione DENOTHE, University of Florence, Florence, Italy
br Department of Immunology, Hospital Universitario Dr. Negrin, Las Palmas de Gran Canaria, Spain
bs Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, London, United Kingdom
bt Department of Molecular Neuroscience, Reta Lilla Weston Laboratories, Institute of Neurology, London, United Kingdom
bu IRCCS Associazione Oasi Maria SS, Troina, Italy
bv Oxford Healthy Aging Project (OHAP), Clinical Trial Service Unit, University of Oxford, Oxford, United Kingdom
bw Cognitive Function and Ageing Study (CFAS), Institute of Public Health, University of Cambridge, Cambridge, United Kingdom
bx University of Milan, Fondazione Cà Granda, IRCCS Ospedale Policlinico, Milan, Italy
by Neurological Clinic, University of Pisa, Italy
bz Institute for Medical Informatics, Biometry and Epidemiology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
ca Section of Gerontology and Geriatrics, Department of Clinical and Experimental Medicine, University of Perugia, Perugia, Italy
cb Section of Neuroscience and Clinical Pharmacology, Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy
cc Department of Psychiatry and Psychotherapy, University of Bonn, Germany
cd Université Pierre et Marie Curie, Département de Neurologie, Institut de la Mémoire et de la Maladie d'Alzheimer, Paris, France
ce Gerontology and Geriatrics Research Laboratory, I.R.C.C.S. Casa Sollievo della Sofferenza, San Giovanni Rotondo (FG), Italy
cf Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Madrid, Spain
cg Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
ch Instituto de Investigación Sanitaria Hospital la Paz (IdIPaz), Madrid, Spain
ci Departement of Geriatrics, Center for Aging Brain, University of Bari, Bari, Italy
cj Department of Neuroscience, University of Parma, Parma, Italy
ck Center for Cognitive Disorders AUSL, Parma, Italy
cl Dept. of Psychiatry, University Hospital, Saarland, Germany
cm Dept. of Public Health/Geriatrics, Uppsala University, Uppsala, Sweden
cn Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, United States
co Department of Neuroscience, Mayo Clinic, Jacksonville, FL, United States
cp National Alzheimer's Coordinating Center, University of Washington, Seattle, WA, United States
cq Genetica molecular-Huca-Oviedo, Oviedo, Spain
cr Neurology Service, CIBERNED, Marqués de Valdecilla University Hospital (University of Cantabria and IFIMAV), Santander, Spain
cs Department of Medical and Molecular Genetics, Indiana University, Indianapolis, IN, United States
ct Landspitali University Hospital, Reykjavik, Iceland
cu Institute of Clinical Medicine - Neurology, University of Eastern Finland, Kuopio, Finland
cv Department of Neurology, Kuopio University Hospital, Kuopio, Finland
cw Department of Epidemiology, Harvard School of Public Health, Boston, MA, United States
cx Department of Epidemiology, Boston University School of Public Health, Boston, MA, United States
cy Department of Psychiatry, Massachusetts General Hospital/Harvard Medical School, Boston, MA, United States
cz German Center for Neurodegenerative Diseases (DZNE, Bonn), Bonn, Germany
da Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, United States
db Laboratory of Epidemiology, Demography, and Biometry, National Institute of Health, Bethesda, MD, United States
dc Aging Reasearch Center, Karolinska Institutet, Stockholm University, Stockholm, Sweden
dd Dept. Geriatric Medicine, Genetics Unit, Karolinska University Hospital Huddinge, Stockholm, Sweden
de Division of Clinical Neurosciences, School of Medicine, University of Southampton, Southampton, United Kingdom
df Departments of Neurology and Epidemiology, Erasmus MC University Medical Center, Rotterdam, Netherlands
dg Department of Pathology, University of Washington, Seattle, WA, United States
dh Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States
di CRicm-UMRS975, Paris, France
dj AP-HP, Hôpital de la Pitié-Salpêtrière, Paris, France
dk Department of Epidemiology, University of Washington, Seattle, WA, United States
dl Laboratory of Neurogenetics, Intramural Research Program, National Institute on Aging, Bethesda, MD, United States
dm Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, United States
dn Human Genetics Center, Div. of Epidemiology, University of Texas Health Sciences Center at Houston, Houston, TX, United States
do Inserm U708, Victor Segalen University, Bordeaux, France
dp German Center for Neurodegenerative Diseases (DZNE, Munich), Munich, Germany
dq Department of Neurology, Medical University of Graz, Graz, Austria
dr Department of Psychiatry, University of Munich, Munich, Germany
ds Centre de Mémoire de Ressources et de Recherche de Bordeaux, CHU de Bordeaux, Bordeaux, France
dt Inserm U708, Victor Segalen University, Bordeaux, France
du Institute of Human Genetics, Department of Genomics, University of Bonn, Bonn, Germany
dv Karolinska Institutet, Dept. Neurobiology, Care Sciences and Society, KIADRC, Novum floor 5 S14186, Stockholm, Sweden
dw Vanderbilt Center for Human Genetics Research, Vanderbilt University, Nashville, TN, United States
dx McGill University, Génome Québec Innovation Centre, Montreal, QC, Canada
dy Department of Neurology, Boston University School of Medicine, Boston, MA, United States
dz Division of Neurosciences, Center for Applied Medical Research, University of Navarra School of Medicine, Pamplona, Spain
ea Department of Neurology, Clínica Universidad de Navarra, University of Navarra School of Medicine, Pamplona, Spain
eb CIBERNED, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, Spain
ec Institute for Stroke and Dementia Research, Klinikum der Universität München, Munich, Germany
ed Departments of Epidemiology and Health Services, University of Washington, Seattle, WA, United States
ee Department of Psychiatry, Trinity Centre for Health Sciences, St. James's Hospital, Dublin 8, Ireland
ef Inserm U897, Victor Segalen University, Bordeaux, France
eg University of Halle, Halle, Germany

Abstract
Background: Late-onset Alzheimer's disease (AD) is heritable with 20 genes showing genome-wide association in the International Genomics of Alzheimer's Project (IGAP). To identify the biology underlying the disease, we extended these genetic data in a pathway analysis. Methods: The ALIGATOR and GSEA algorithms were used in the IGAP data to identify associated functional pathways and correlated gene expression networks in human brain. Results: ALIGATOR identified an excess of curated biological pathways showing enrichment of association. Enriched areas of biology included the immune response (P = 3.27 × 10-12 after multiple testing correction for pathways), regulation of endocytosis (P = 1.31 × 10-11), cholesterol transport (P = 2.96 × 10-9), and proteasome-ubiquitin activity (P = 1.34 × 10-6). Correlated gene expression analysis identified four significant network modules, all related to the immune response (corrected P =.002-.05). Conclusions: The immune response, regulation of endocytosis, cholesterol transport, and protein ubiquitination represent prime targets for AD therapeutics. © 2015, Elsevier Inc. All rights reserved.

Author Keywords
ALIGATOR;  Alzheimer's disease;  Cholesterol metabolism;  Dementia;  Endocytosis;  Immune response;  Neurodegeneration;  Pathway analysis;  Ubiquitination;  Weighted gene co-expression network analysis


Document Type: Article
Source: Scopus


Atkinson, E.G.a , Rogers, J.b , Mahaney, M.C.c d , Cox, L.A.d , Cheverud, J.M.a e
Cortical folding of the primate brain: An interdisciplinary examination of the genetic architecture, modularity, and evolvability of a significant neurological trait in pedigreed baboons (genus papio)
(2015) Genetics, 200 (2), pp. 651-665. 

DOI: 10.1534/genetics.114.173443

a Department of Anatomy and Neurobiology, Washington University in St. Louis School of Medicine, St. Louis, MO, United States
b Human Genome Sequencing Center and Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States
c South Texas Diabetes and Obesity Institute, University of Texas Health Science Center at San Antonio and Regional Academic Health Center, Harlingen, TX, United States
d Department of Genetics and Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, TX, United States
e Department of Biology, Loyola University, Chicago, IL, United States

Abstract
Folding of the primate brain cortex allows for improved neural processing power by increasing cortical surface area for the allocation of neurons. The arrangement of folds (sulci) and ridges (gyri) across the cerebral cortex is thought to reflect the underlying neural network. Gyrification, an adaptive trait with a unique evolutionary history, is affected by genetic factors different from those affecting brain volume. Using a large pedigreed population of ~1000 Papio baboons, we address critical questions about the genetic architecture of primate brain folding, the interplay between genetics, brain anatomy, development, patterns of cortical–cortical connectivity, and gyrification’s potential for future evolution. Through Mantel testing and cluster analyses, we find that the baboon cortex is quite evolvable, with high integration between the genotype and phenotype. We further find significantly similar partitioning of variation between cortical development, anatomy, and connectivity, supporting the predictions of tension-based models for sulcal development. We identify a significant, moderate degree of genetic control over variation in sulcal length, with gyrus-shape features being more susceptible to environmental effects. Finally, through QTL mapping, we identify novel chromosomal regions affecting variation in brain folding. The most significant QTL contain compelling candidate genes, including gene clusters associated with Williams and Down syndromes. The QTL distribution suggests a complex genetic architecture for gyrification with both polygeny and pleiotropy. Our results provide a solid preliminary characterization of the genetic basis of primate brain folding, a unique and biomedically relevant phenotype with significant implications in primate brain evolution. © 2015 by the Genetics Society of America.

Author Keywords
Cerebral cortex;  Evolution;  Gyrification;  Heritability;  Modularity;  Papio hamadryas;  Primate brain;  Qtl


Document Type: Article
Source: Scopus


Campbell, M.C.a b , Koller, J.M.c , Snyder, A.Z.b , Buddhala, C.a , Kotzbauer, P.T.a , Perlmutter, J.S.a b d e f
CSF proteins and resting-state functional connectivity in Parkinson disease
(2015) Neurology, 84 (24), pp. 2413-2421. Cited 1 time.

DOI: 10.1212/WNL.0000000000001681

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

Abstract
Objective: The purpose of this study was to investigate the relationship between disruption of MRI-measured resting-state functional connectivity (rs-fcMRI) brain networks and CSF levels of potentially pathogenic proteins that reflect brain pathology in Parkinson disease (PD). Methods: PD participants without dementia (n = 43) and age-matched controls (n = 22) had lumbar punctures to measure CSF protein levels, Pittsburgh compound B (PiB)-PET imaging, and rs-fcMRI while off medication. Imaging analyses focused on 5 major resting-state networks as well as the striatum. Results: Participants with PD had significantly reduced sensorimotor functional connectivity, which correlated with reduced CSF levels of a-synuclein. The PD group also had significantly stronger default mode network functional connectivity that did not correlate with CSF β-amyloid (Aβ)<inf>42</inf> or PiB uptake. In contrast, default mode network functional connectivity in the control group did correlate with CSF Aβ<inf>42</inf> levels. Functional connectivity was similar between groups in the dorsal attention, control, and salience networks. Conclusion: These results suggest that abnormal a-synuclein accumulation, but not Ab, contributes to the disruption of motor-related functional connectivity in PD. Furthermore, correlating CSF protein measures with the strength of resting-state networks provides a direct link between abnormal a-synuclein metabolism and disrupted brain function in PD. © 2015 American Academy of Neurology.


Document Type: Article
Source: Scopus


Ford, A.L.a , Leker, R.R.b
MRI in acute stroke: Good times are coming
(2015) Neurology, 84 (24), pp. 2394-2395. 

DOI: 10.1212/WNL.0000000000001690

a Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
b Department of Neurology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

Abstract
When considering IV tissue plasminogen activator (tPA) for ischemic stroke, acute imaging must ensure neurologic deficits are not due to intracerebral hemorrhage and ascertain the presence of early ischemic changes in the 3- to 4.5-hour window. The National Institute of Neurological Disorders and Stroke IV tPA study required a CT for this purpose, but the European Cooperative Acute Stroke Study (ECASS) III trial allowed both CT and MRI for screening for treatment in the 3- to 4.5-hour window.1,2 However, of the 821 patients enrolled in ECASS III, only 50 (6%) were screened with MRI before randomization.1 Thus, our success with IV tPA has occurred in the setting of a simple, noncontrast CT. Furthermore, the pooled IV tPA data, including more than 6,000 patients, demonstrate the convincing positive consequences of early treatment to enable a good functional outcome.2 Every 15 minutes earlier that tPA is given provides an additional 1 month of disability-free life indicating real-world public health implications of early treatment.3 Therefore, using MRI as a screening tool for IV tPA decision-making, which, at present, comes at the expense of time and brain, should be approached with utmost caution.


Document Type: Review
Source: Scopus


Blum, K.a b c d , Thanos, P.K.e , Badgaiyan, R.D.f , Febo, M.a , Oscar-Berman, M.g , Fratantonio, J.b , Demotrovics, Z.h , Gold, M.S.a i j k
Neurogenetics and gene therapy for reward deficiency syndrome: Are we going to the Promised Land?
(2015) Expert Opinion on Biological Therapy, 15 (7), pp. 973-985. 

DOI: 10.1517/14712598.2015.1045871

a Department of Psychiatry, McKnight Brain Institute, University of Florida College of Medicine, Gainesville, FL, United States
b Division of Applied Clinical Research and Education, Dominion Diagnostics, LLC, North Kingstown, RI, United States
c Department of Psychiatry, University of Vermont, Burlington, United States
d Department of Addiction Research and Therpy, Malibu Beach Recovery Center, Malibu Beach, CA, United States
e Behavior Neuropharmacology and Neuroimaging Lab, Department of Psychology, State University of New York, Stony Brook, NY, United States
f Department of Psychiatry, University of Minnesota School of Medicine, Minneapolis, MN, United States
g Boston University, School of Medicine and VA Boston Healthcare System, Boston, MA, United States
h Eotvos Lorand University, Institute of Psychology, Department of Clinical Psychology and Addiction, Izabella utca 46, Budapest, Hungary
i Rivermend, LLC, New York, NY, United States
j Departments of Psychiatry and Behavioral Sciences, Keck School of Medicine of USC, Los Angeles, CA, United States
k Department of Psychiatry, Washington University School of Medicine, St. Louis, Mo, United States

Abstract
Introduction: Addiction is a substantial health issue with limited treatment options approved by the FDA and as such currently available. The advent of neuroimaging techniques that link neurochemical and neurogenetic mechanisms to the reward circuitry brain function provides a framework for potential genomic-based therapies.Areas Covered: Through candidate and genome-wide association studies approaches, many gene polymorphisms and clusters have been implicated in drug, food and behavioral dependence linked by the common rubric reward deficiency syndrome (RDS). The results of selective studies that include the role of epigenetics, noncoding micro RNAs in RDS behaviors especially drug abuse involving alcohol, opioids, cocaine, nicotine, pain and feeding are reviewed in this article. New targets for addiction treatment and relapse prevention, treatment alternatives such as gene therapy in animal models, and pharmacogenomics and nutrigenomics methods to manipulate transcription and gene expression are explored.Expert Opinion: The recognition of the clinical benefit of early genetic testing to determine addiction risk stratification and dopaminergic agonistic, rather than antagonistic therapies are potentially the genomic-based wave of the future. In addition, further development, especially in gene transfer work and viral vector identification, could make gene therapy for RDS a possibility in the future. © 2015 Informa UK, Ltd.

Author Keywords
Antisense;  Gene therapy;  Gene transfer;  Hypodopaminergic;  Neurogenetics;  Neuroimaging;  Reward deficiency syndrome


Document Type: Review
Source: Scopus


Valnegri, P.a b , Puram, S.V.b c , Bonni, A.a b
Regulation of dendrite morphogenesis by extrinsic cues
(2015) Trends in Neurosciences, . Article in Press. 

DOI: 10.1016/j.tins.2015.05.003

a Department of Anatomy and Neurobiology, Washington University in St Louis School of Medicine, St Louis, MO 63110, USA
b Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA
c Department of Otolaryngology, Massachusetts Eye and Ear Infirmary and Harvard Medical School, Boston, MA 02114, USA

Abstract
Dendrites play a central role in the integration and flow of information in the nervous system. The morphogenesis and maturation of dendrites is hence an essential step in the establishment of neuronal connectivity. Recent studies have uncovered crucial functions for extrinsic cues in the development of dendrites. We review the contribution of secreted polypeptide growth factors, contact-mediated proteins, and neuronal activity in distinct phases of dendrite development. We also highlight how extrinsic cues influence local and global intracellular mechanisms of dendrite morphogenesis. Finally, we discuss how these studies have advanced our understanding of neuronal connectivity and have shed light on the pathogenesis of neurodevelopmental disorders. © 2015 Elsevier Ltd.

Author Keywords
Calcium signaling;  Contact-mediated regulators;  Dendrite morphogenesis;  Neuronal activity;  Secreted polypeptide growth factors


Document Type: Article in Press
Source: Scopus


Walker, L.a , Chang, L.-C.a , Nayak, A.a , Irfanoglu, M.O.a , Botteron, K.N.b , McCracken, J.c , McKinstry, R.C.d , Rivkin, M.J.e , Wang, D.-J.f , Rumsey, J.g , Pierpaoli, C.a
The diffusion tensor imaging (DTI) component of the NIH MRI study of normal brain development (PedsDTI)
(2015) NeuroImage, . Article in Press. 

DOI: 10.1016/j.neuroimage.2015.05.083

a Program on Pediatric Imaging and Tissue Sciences, NICHD, NIH, Bethesda, MD, USA
b Washington University in St. Louis, Department of Psychiatry, Saint Louis, MO, USA
c Department of Child Psychiatry, University of California in Los Angeles, Los Angeles, CA, USA
d Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, USA
e Departments of Neurology, Psychiatry and Radiology, Boston Children's Hospital, Boston, MA, USA
f The Children's Hospital of Philadelphia, Philadelphia, PA, USA
g Clinical Neuroscience Research Branch, Division of Translational Research, NIMH, NIH, Bethesda, MD, USA

Abstract
The NIH MRI Study of normal brain development sought to characterize typical brain development in a population of infants, toddlers, children and adolescents/young adults, covering the socio-economic and ethnic diversity of the population of the United States. The study began in 1999 with data collection commencing in 2001 and concluding in 2007. The study was designed with the final goal of providing a controlled-access database; open to qualified researchers and clinicians, which could serve as a powerful tool for elucidating typical brain development and identifying deviations associated with brain-based disorders and diseases, and as a resource for developing computational methods and image processing tools.This paper focuses on the DTI component of the NIH MRI study of normal brain development. In this work, we describe the DTI data acquisition protocols, data processing steps, quality assessment procedures, and data included in the database, along with database access requirements. For more details, visit http://www.pediatricmri.nih.gov.This longitudinal DTI dataset includes raw and processed diffusion data from 498 low resolution (3. mm) DTI datasets from 274 unique subjects, and 193 high resolution (2.5. mm) DTI datasets from 152 unique subjects. Subjects range in age from 10. days (from date of birth) through 22. years. Additionally, a set of age-specific DTI templates are included. This forms one component of the larger NIH MRI study of normal brain development which also includes T1-, T2-, proton density-weighted, and proton magnetic resonance spectroscopy (MRS) imaging data, and demographic, clinical and behavioral data. © 2015.

Author Keywords
Database;  Diffusion;  DTI;  Longitudinal;  MRI;  Multicenter;  NIH;  Pediatric


Document Type: Article in Press
Source: Scopus


Watkins, J.W.a , Schwarz, E.S.a , Arroyo-Plasencia, A.M.b , Mullins, M.E.a
The Use of Physostigmine by Toxicologists in Anticholinergic Toxicity
(2015) Journal of Medical Toxicology, 11 (2), pp. 179-184. 

DOI: 10.1007/s13181-014-0452-x

a Division of Emergency Medicine, Washington University in St Louis, 660 S. Euclid Ave., Campus Box 8072, St. Louis, MO, United States
b Department of Internal Medicine, Washington University in St Louis, St. Louis, MO, United States

Abstract
The anticholinergic toxidrome is well described and relatively common. Despite controversy, studies have shown that physostigmine is relatively safe and effective in reversing this toxidrome. We would expect toxicologists would be liberal in its use. We retrospectively analyzed data in the Toxicology Investigators Consortium (ToxIC) registry, representing data from medical toxicologists in multiple institutions nationwide, searching for patients who exhibited an anticholinergic toxidrome, determining what treatment(s) they received, and classifying the treatments as physostigmine, benzodiazepines, physostigmine and benzodiazepines, antipsychotics, or no definitive treatment. The causal agents of the toxidrome were as reported by the treating toxicologist. Eight hundred fifteen consecutive patients with anticholinergic toxidromes were analyzed. Benzodiazepines alone were given in 28.7 %, 12.4 % were given physostigmine alone, 8.8 % received both physostigmine and benzodiazepines, 2.7 % were given antipsychotics, and 47.4 % were given no definitive treatment. In patients who received only physostigmine, there was a significant difference in the rate of intubation (1.9 vs. 8.4 %, OR 0.21, 95 % CI 0.05–0.87) versus other treatment groups. Physostigmine was given at varying rates based on causative agent with use in agents with mixed or unknown effects (15.1 %) being significantly lower than those with primarily anticholinergic effects (26.6 %) (p < 0.001). Patients with anticholinergic toxicity were more likely to receive benzodiazepines than physostigmine. Those patients who received only physostigmine had a significantly lower rate of intubation. Physostigmine was more likely to be used with agents exerting primarily anticholinergic toxicity than in those agents with multiple actions. © 2014, American College of Medical Toxicology.

Author Keywords
Anticholinergic syndrome;  Antidepressive agents;  Antidotes;  Intubation;  Physostigmine;  Tricyclic


Document Type: Article
Source: Scopus


Fowler, P.J.a , Henry, D.B.b , Schoeny, M.c , Gorman-Smith, D.d , Tolan, P.H.e
Effects of the SAFE Children preventive intervention on developmental trajectories of attention-deficit/hyperactivity disorder symptoms
(2014) Development and psychopathology, 26 (4), pp. 1161-1179. 

DOI: 10.1017/S0954579414000170

a Washington University in St. Louis
b University of Illinois at Chicago
c University of Chicago
d University of Chicago
e University of Virginia

Abstract
This study examined whether a family-based preventive intervention for inner-city children entering the first grade could alter the developmental course of attention-deficit/hyperactivity disorder (ADHD) symptoms. Participants were 424 families randomly selected and randomly assigned to a control condition (n = 192) or Schools and Families Educating Children (SAFE) Children (n = 232). SAFE Children combined family-focused prevention with academic tutoring to address multiple developmental-ecological needs. A booster intervention provided in the 4th grade to randomly assigned children in the initial intervention (n =101) evaluated the potential of increasing preventive effects. Follow-up occurred over 5 years with parents and teachers reporting on attention problems. Growth mixture models identified multiple developmental trajectories of ADHD symptoms. The initial phase of intervention placed children on more positive developmental trajectories for impulsivity and hyperactivity, demonstrating the potential for ADHD prevention in at-risk youth, but the SAFE Children booster had no additional effect on trajectory or change in ADHD indicators.


Document Type: Article
Source: Scopus

June 23, 2015

 

Hassanpour, M.S.a , Eggebrecht, A.T.b , Culver, J.P.a b , Peelle, J.E.c
Mapping cortical responses to speech using high-density diffuse optical tomography
(2015) NeuroImage, 117, pp. 319-326. 

DOI: 10.1016/j.neuroimage.2015.05.058

a Department of Physics, Washington University in Saint Louis, United States
b Department of Radiology, Washington University in Saint Louis, United States
c Department of Otolaryngology, Washington University in Saint Louis, United States

Abstract
The functional neuroanatomy of speech processing has been investigated using positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) for more than 20. years. However, these approaches have relatively poor temporal resolution and/or challenges of acoustic contamination due to the constraints of echoplanar fMRI. Furthermore, these methods are contraindicated because of safety concerns in longitudinal studies and research with children (PET) or in studies of patients with metal implants (fMRI). High-density diffuse optical tomography (HD-DOT) permits presenting speech in a quiet acoustic environment, has excellent temporal resolution relative to the hemodynamic response, and provides noninvasive and metal-compatible imaging. However, the performance of HD-DOT in imaging the brain regions involved in speech processing is not fully established. In the current study, we use an auditory sentence comprehension task to evaluate the ability of HD-DOT to map the cortical networks supporting speech processing. Using sentences with two levels of linguistic complexity, along with a control condition consisting of unintelligible noise-vocoded speech, we recovered a hierarchically organized speech network that matches the results of previous fMRI studies. Specifically, hearing intelligible speech resulted in increased activity in bilateral temporal cortex and left frontal cortex, with syntactically complex speech leading to additional activity in left posterior temporal cortex and left inferior frontal gyrus. These results demonstrate the feasibility of using HD-DOT to map spatially distributed brain networks supporting higher-order cognitive faculties such as spoken language. © 2015 Elsevier Inc.


Document Type: Article
Source: Scopus


Peelle, J.E.a , Sommers, M.S.b
Prediction and constraint in audiovisual speech perception
(2015) Cortex, 68, pp. 169-181. Cited 1 time.

DOI: 10.1016/j.cortex.2015.03.006

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

Abstract
During face-to-face conversational speech listeners must efficiently process a rapid and complex stream of multisensory information. Visual speech can serve as a critical complement to auditory information because it provides cues to both the timing of the incoming acoustic signal (the amplitude envelope, influencing attention and perceptual sensitivity) and its content (place and manner of articulation, constraining lexical selection). Here we review behavioral and neurophysiological evidence regarding listeners' use of visual speech information. Multisensory integration of audiovisual speech cues improves recognition accuracy, particularly for speech in noise. Even when speech is intelligible based solely on auditory information, adding visual information may reduce the cognitive demands placed on listeners through increasing the precision of prediction. Electrophysiological studies demonstrate that oscillatory cortical entrainment to speech in auditory cortex is enhanced when visual speech is present, increasing sensitivity to important acoustic cues. Neuroimaging studies also suggest increased activity in auditory cortex when congruent visual information is available, but additionally emphasize the involvement of heteromodal regions of posterior superior temporal sulcus as playing a role in integrative processing. We interpret these findings in a framework of temporally-focused lexical competition in which visual speech information affects auditory processing to increase sensitivity to acoustic information through an early integration mechanism, and a late integration stage that incorporates specific information about a speaker's articulators to constrain the number of possible candidates in a spoken utterance. Ultimately it is words compatible with both auditory and visual information that most strongly determine successful speech perception during everyday listening. Thus, audiovisual speech perception is accomplished through multiple stages of integration, supported by distinct neuroanatomical mechanisms. © 2015 Elsevier Ltd.

Author Keywords
Audiovisual speech;  Multisensory integration;  Predictive coding;  Predictive timing;  Speech perception


Document Type: Review
Source: Scopus


Campian, J.L.a b , Ye, X.b , Gladstone, D.E.b , Ambady, P.c , Nirschl, T.R.b , Borrello, I.b , Golightly, M.d , King, K.E.b , Holdhoff, M.b , Karp, J.b , Drake, C.G.b , Grossman, S.A.b
Pre-radiation lymphocyte harvesting and post-radiation reinfusion in patients with newly diagnosed high grade gliomas
(2015) Journal of Neuro-Oncology, 10 p. Article in Press. 

DOI: 10.1007/s11060-015-1841-y

a Departments of Medicine, Oncology Division, Washington University in St. Louis, 660 South Euclid Avenue, Campus Box 8056, St. Louis, MO, United States
b Departments of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD, United States
c Departments of Neurology, Oregon Health & Science University, Portland, OR, United States
d Departments of Pathology, Stony Brook School of Medicine, Stony Brook, NY, United States

Abstract
Radiation (RT), temozolomide (TMZ), and dexamethasone in newly diagnosed high grade gliomas (HGG) produces severe treatment-related lymphopenia (TRL) that is associated with early cancer-related deaths. This TRL may result from inadvertent radiation to circulating lymphocytes. This study reinfused lymphocytes, harvested before chemo-radiation, and assessed safety, feasibility, and trends in lymphocyte counts. Patients with newly diagnosed HGG and total lymphocyte counts (TLC) ≥ 1000 cells/mm3 underwent apheresis. Cryopreserved autologous lymphocytes were reinfused once radiation was completed. Safety, feasibility, and trends in TLC, T cell subsets and cytokines were studied. Serial TLC were also compared with an unreinfused matched control group. Ten patients were harvested (median values: age 56 years, dexamethasone 3 mg/day, TLC/CD4 1980/772 cells/mm3). After 6 weeks of RT/TMZ, TLC fell 69 % (p < 0.0001) with similar reductions in CD4, CD8 and NK cells but not Tregs. Eight patients received lymphocyte reinfusions (median = 7.0 × 107 lymphocytes/kg) without adverse events. A post-reinfusion TLC rise of ≥300 cells/mm3 was noted in 3/8 patients at 4 weeks and 7/8 at 14 weeks which was similar to 23 matched controls. The reduced CD4/CD8 ratio was not restored by lymphocyte reinfusion. Severe lymphopenia was not accompanied by elevated serum interleukin-7 (IL-7) levels. This study confirms that severe TRL is common in HGG and is not associated with high plasma IL-7 levels. Although lymphocyte harvesting/reinfusion is feasible and safe, serial lymphocyte counts are similar to unreinfused matched controls. Studies administering higher lymphocyte doses and/or IL-7 should be considered to restore severe treatment-related lymphopenia in HGG. © 2015 Springer Science+Business Media New York

Author Keywords
High grade glioma;  IL-7;  Lymphocyte reinfusion;  Lymphopenia;  Radiation


Document Type: Article in Press
Source: Scopus


Anderson, A.M.a , Fennema-Notestine, C.b h , Umlauf, A.b h , Taylor, M.J.b h , Clifford, D.B.c , Marra, C.M.d , Collier, A.C.d , Gelman, B.B.e , McArthur, J.C.f , McCutchan, J.A.b h , Simpson, D.M.g , Morgello, S.g , Grant, I.b h , Letendre, S.L.b h , For The Charter Groupi
CSF biomarkers of monocyte activation and chemotaxis correlate with magnetic resonance spectroscopy metabolites during chronic HIV disease
(2015) Journal of NeuroVirology, 9 p. Article in Press. 

DOI: 10.1007/s13365-015-0359-6

a Emory School of Medicine, Emory University, Atlanta, GA, United States
b University of California, San Diego, La Jolla, CA, United States
c Washington University School of Medicine, Washington University, St. Louis, MO, United States
d University of Washington, Seattle, WA, United States
e University of Texas Medical Branch, University of Texas System, Galveston, TX, United States
f John Hopkins School of Medicine, Johns Hopkins University, Baltimore, MD, United States
g The Mount Sinai Hospital, New York, NY, United States
h HIV Neurobehavioral Research Center and Antiviral Research Center, University of California, San Diego, 220 Dickinson Street, Suite A, San Diego, CA, United States

Abstract
Human immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND) persist despite combination antiretroviral therapy (cART), supporting the need to better understand HIV neuropathogenesis. Magnetic resonance spectroscopy (MRS) of the brain has demonstrated abnormalities in HIV-infected individuals despite cART. We examined the associations between MRS metabolites and selected cerebrospinal fluid (CSF) biomarkers reflecting monocyte/macrophage activation and chemotaxis. A multicenter cross-sectional study involving five sites in the USA was conducted. The following CSF biomarkers were measured: soluble CD14 (sCD14), monocyte chemotactic protein-1 (MCP-1), interferon inducible protein 10 (IP-10), and stromal cell-derived growth factor 1 alpha (SDF-1α). The following MRS metabolites were measured from basal ganglia (BG), frontal white matter (FWM), and frontal gray matter (FGM): N-acetylaspartate (NAA), myo-inositol (MI), choline (Cho), and creatine (Cr). CSF biomarkers were compared to absolute MRS metabolites as well as metabolite/Cr ratios using linear regression. Eighty-three HIV-infected individuals were included, 78 % on cART and 37 % with HAND. The most robust positive correlations were between MCP-1 and Cho in BG (R2 0.179, p < 0.001) as well as MCP-1 and MI in FWM (R2 0.137, p = 0.002). Higher Cr levels in FWM were associated with MCP-1 (R2 0. 075, p = 0.01) and IP-10 (R2 0.106, p = 0.003). Comparing biomarkers to MRS metabolite/Cr ratios impacted some relationships, e.g., higher sCD14 levels were associated with lower Cho/Cr ratios in FGM (R2 0.224, p < 0.001), although higher MCP-1 levels remained associated with Cho/Cr in BG. These findings provide evidence that monocyte activation and chemotaxis continue to contribute to HIV-associated brain abnormalities in cART-treated individuals. © 2015 Journal of NeuroVirology, Inc.

Author Keywords
Acquired immunodeficiency syndrome;  Biomarkers;  Cerebrospinal fluid;  HIV-associated neurocognitive disorder;  Human immunodeficiency virus


Document Type: Article in Press
Source: Scopus


Armstrong, R.A.a , Cairns, N.J.b c
Erratum to: Comparative quantitative study of ‘signature’ pathological lesions in the hippocampus and adjacent gyri of 12 neurodegenerative disorders
(2015) Journal of Neural Transmission, 2 p. Article in Press. 

DOI: 10.1007/s00702-015-1412-6

a Vision Sciences, Aston University, Birmingham, United Kingdom
b Department of Neurology, Washington University School of Medicine, Saint Louis, MO, United States
c Department Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO, United States


Document Type: Article in Press
Source: Scopus


Zaninotto, L.a b , Souery, D.c , Calati, R.d , Di Nicola, M.a , Montgomery, S.e , Kasper, S.f , Zohar, J.g , Mendlewicz, J.h , Robert Cloninger, C.i , Serretti, A.b , Janiri, L.a
Temperament and character profiles in bipolar I, bipolar II and major depressive disorder: Impact over illness course, comorbidity pattern and psychopathological features of depression
(2015) Journal of Affective Disorders, 184, pp. 51-59. 

DOI: 10.1016/j.jad.2015.05.036

a Institute of Psychiatry and Psychology, Catholic University of the Sacred Heart, Rome, Italy
b Department of Biomedical and Neuro-Motor Sciences, University of Bologna, Viale Carlo Pepoli 5, Bologna, Italy
c Laboratoire de Psychologie Medicale, Université Libre de Bruxelles and Psy Pluriel, Centre Européen de Psychologie Medicale, Brussels, Belgium
d INSERM U1061, University of Montpellier, FondaMental Foundation, Montpellier, France
e Imperial College, University of London, London, United Kingdom
f Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria
g Chaim Sheba Medical Center, Tel-Hashomer, Israel
h Université Libre de Bruxelles, Brussels, Belgium
i Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO, United States

Abstract
Background Studies comparing temperament and character traits between patients with mood disorders and healthy individuals have yielded variable results. Methods The Temperament and Character Inventory (TCI) was administered to 101 bipolar I (BP-I), 96 bipolar II (BP-II), 123 major depressive disorder (MDD) patients, and 125 HS. A series of generalized linear models were performed in order to: (a) compare the TCI dimensions across groups; (b) test any effect of the TCI dimensions on clinical features of mood disorders; and (c) detect any association between TCI dimensions and the psychopathological features of a major depressive episode. Demographic and clinical variables were also included in the models as independent variables. Results Higher Harm Avoidance was found in BP-II and MDD, but not in BP-I. Higher Self-Transcendence was found in BP-I. Our models also showed higher Self-Directedness in HS, either vs MDD or BP-II. No association was found between any TCI dimension and the severity of symptoms. Conversely, a positive association was found between Harm Avoidance and the overall burden of depressive episodes during lifetime. Limitations The cross-sectional design and the heterogeneity of the sample may be the main limitations of our study. Conclusion In general, our sample seems to support the view of a similar profile of temperament and character between MDD and BP-II, characterized by high Harm Avoidance and low Self-Directedness. In contrast, patients with BP-I only exhibit high Self-Transcendence, having a near-normal profile in terms of Harm Avoidance or Self-Directedness. © 2015 Elsevier B.V. All rights reserved.

Author Keywords
Bipolar disorder;  Character;  Depression;  Depressive disorder;  Mood disorders;  Temperament


Document Type: Article
Source: Scopus


Diwakar, M.a , Harrington, D.L.a b , Maruta, J.c , Ghajar, J.c d , El-Gabalawy, F.a , Muzzatti, L.a , Corbetta, M.e , Huang, M.-X.a b f , Lee, R.R.a b
Filling in the gaps: Anticipatory control of eye movements in chronic mild traumatic brain injury
(2015) NeuroImage: Clinical, 8, pp. 210-223. 

DOI: 10.1016/j.nicl.2015.04.011

a Department of Radiology, University of California, San Diego, San Diego, CA, United States
b Radiology and Research Services, VA San Diego Healthcare System, San Diego, CA, United States
c Brain Trauma Foundation, New York, NY, United States
d Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, United States
e Department of Neurology, Washington University, St. Louis, MO, United States
f Radiology Imaging Laboratory, University of California at San Diego, 3510 Dunhill Street, San Diego, CA, United States

Abstract
A barrier in the diagnosis of mild traumatic brain injury (mTBI) stems from the lack of measures that are adequately sensitive in detecting mild head injuries. MRI and CT are typically negative in mTBI patients with persistent symptoms of post-concussive syndrome (PCS), and characteristic difficulties in sustaining attention often go undetected on neuropsychological testing, which can be insensitive to momentary lapses in concentration. Conversely, visual tracking strongly depends on sustained attention over time and is impaired in chronic mTBI patients, especially when tracking an occluded target. This finding suggests deficient internal anticipatory control in mTBI, the neural underpinnings of which are poorly understood. The present study investigated the neuronal bases for deficient anticipatory control during visual tracking in 25 chronic mTBI patients with persistent PCS symptoms and 25 healthy control subjects. The task was performed while undergoing magnetoencephalography (MEG), which allowed us to examine whether neural dysfunction associated with anticipatory control deficits was due to altered alpha, beta, and/or gamma activity. Neuropsychological examinations characterized cognition in both groups. During MEG recordings, subjects tracked a predictably moving target that was either continuously visible or randomly occluded (gap condition). MEG source-imaging analyses tested for group differences in alpha, beta, and gamma frequency bands. The results showed executive functioning, information processing speed, and verbal memory deficits in the mTBI group. Visual tracking was impaired in the mTBI group only in the gap condition. Patients showed greater error than controls before and during target occlusion, and were slower to resynchronize with the target when it reappeared. Impaired tracking concurred with abnormal beta activity, which was suppressed in the parietal cortex, especially the right hemisphere, and enhanced in left caudate and frontaloral areas. Regional beta-amplitude demonstrated high classification accuracy (92%) compared to eye-tracking (65%) and neuropsychological variables (80%). These findings show that deficient internal anticipatory control in mTBI is associated with altered beta activity, which is remarkably sensitive given the heterogeneity of injuries. © 2015 Published by Elsevier Ltd.

Author Keywords
Anticipatory control;  Attention;  Magnetoencephalography;  Mild traumatic brain injury;  Visual tracking


Document Type: Article
Source: Scopus


Gordon, B.A.a b c , Najmi, S.d , Hsu, P.e , Roe, C.M.c f , Morris, J.C.c f , Benzinger, T.L.S.a c g
The effects of white matter hyperintensities and amyloid deposition on Alzheimer dementia
(2015) NeuroImage: Clinical, 8, pp. 246-252. 

DOI: 10.1016/j.nicl.2015.04.017

a Department of Radiology, Washington University, St. Louis, United States
b Department of Psychology, Washington University, St. Louis, United States
c Knight Alzheimer's Disease Research Center, Washington University, St. Louis, United States
d Department of Neurology, Tabriz University of Medical Science, Iran
e Pritzker School of Medicine, University of Chicago, United States
f Department of Neurology, Washington University, St. Louis, United States
g Department of Neurosurgery, Washington University, St. Louis, United States

Abstract
Background and purpose Elevated levels of amyloid deposition as well as white matter damage are thought to be risk factors for Alzheimer Disease (AD). Here we examined whether qualitative ratings of white matter damage predicted cognitive impairment beyond measures of amyloid. Materials and methods The study examined 397 cognitively normal, 51 very mildly demented, and 11 mildly demented individuals aged 42-90 (mean 68.5). Participants obtained a T<inf>2</inf>-weighted scan as well as a positron emission tomography scan using 11[C] Pittsburgh Compound B. Periventricular white matter hyperintensities (PVWMHs) and deep white matter hyperintensities (DWMHs) were measured on each T<inf>2</inf> scan using the Fazekas rating scale. The effects of amyloid deposition and white matter damage were assessed using logistic regressions. Results Levels of amyloid deposition (ps < 0.01), as well as ratings of PVWMH (p < 0.01) and DWMH (p < 0.05) discriminated between cognitively normal and demented individuals. Conclusions The amount of amyloid deposition and white matter damage independently predicts cognitive impairment. This suggests a diagnostic utility of qualitative white matter scales in addition to measuring amyloid levels. © 2015 Published by Elsevier Inc.

Author Keywords
Alzheimer's;  Amyloid;  Biomarkers;  Myelin;  Vascular;  White matter


Document Type: Article
Source: Scopus


Song, W., Cho, Y., Watt, D., Cavalli, V.
Tubulin-tyrosine ligase (TTL)-mediated increase in tyrosinated α-tubulin in injured axons is required for retrograde injury signaling and axon regeneration
(2015) Journal of Biological Chemistry, 290 (23), pp. 14765-14775. 

DOI: 10.1074/jbc.M114.622753

Department of Anatomy and Neurobiology, Washington University in St. Louis, School of Medicine, 660 S. Euclid Ave., St. Louis, MO, United States

Abstract
Injured peripheral neurons successfully activate a pro-regenerative program to enable axon regeneration and functional recovery. The microtubule-dependent retrograde transport of injury signals from the lesion site in the axon back to the cell soma stimulates the increased growth capacity of injured neurons. However, the mechanisms initiating this retrograde transport remain poorly understood. Here we show that tubulin-tyrosine ligase (TTL) is required to increase the levels of tyrosinated α-tubulin at the axon injury site and plays an important role in injury signaling. Preventing the injury-induced increase in tyrosinated α-tubulin by knocking down TTL impairs retrograde organelle transport and delays activation of the pro-regenerative transcription factor c-Jun. In the absence of TTL, axon regeneration is reduced severely. We propose a model in which TTL increases the levels of tyrosinated α-tubulin locally at the injury site to facilitate the retrograde transport of injury signals that are required to activate a pro-regenerative program. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.


Document Type: Article
Source: Scopus


Rowe, R.A.a , Pryse, K.M.b , Asnes, C.F.b , Elson, E.L.a b , Genin, G.M.a c
Collective Matrix Remodeling by Isolated Cells: Unionizing Home Improvement Do-It-Yourselfers
(2015) Biophysical Journal, 108 (11), art. no. 6547, pp. 2611-2612. 

DOI: 10.1016/j.bpj.2015.04.026

a Department of Mechanical Engineering and Materials Science, Washington University in St. Louis, St. Louis, MO, United States
b Department of Biochemistry and Molecular Biophysics, Washington University, School of Medicine, St. Louis, MO, United States
c Department of Neurological Surgery, Washington University, School of Medicine, St. Louis, MO, United States


Document Type: Article
Source: Scopus


Bischoff, A.N.a , Reiersen, A.M.a , Buttlaire, A.a , Al-Lozi, A.a , Doty, T.a , Marshall, B.A.b c , Hershey, T.a d e , Austin, P.f , Earhart, G.f , Eisenstein, S.f , Hoekel, J.f , Tychsen, L.f , Hullar, T.f , Karzon, R.f , Manwaring, L.f , Paciorkowski, A.R.f , Pepino De Gruev, Y.f , Pickett, K.f , Shimony, J.f , Viehoever, A.f , White, N.H.f , Urano, F.f , Ranck, S.f , Beato, B.f , Bihun, E.f , Koller, J.M.f , Lugar, H.M.f , Rutlin, J.f , Semenkovich, K.f
Selective cognitive and psychiatric manifestations in Wolfram Syndrome
(2015) Orphanet Journal of Rare Diseases, 10 (1), art. no. 66, . 

DOI: 10.1186/s13023-015-0282-1

a Department of Psychiatry, Washington University School of Medicine, Campus Box 8225, 4525 Scott Avenue, St. Louis, MO, United States
b Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
c Department of Cell Biology, Washington University School of Medicine, St. Louis, MO, United States
d Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
e Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Background: Wolfram Syndrome (WFS) is known to involve diabetes mellitus, diabetes insipidus, optic nerve atrophy, vision loss, hearing impairment, motor abnormalities, and neurodegeneration, but has been less clearly linked to cognitive, sleep, and psychiatric abnormalities. We sought to determine whether these abnormalities are present in children, adolescents, and young adults with WFS compared to age- and gender-matched individuals with and without type 1 diabetes using standardized measures. Methods: Individuals with genetically-confirmed WFS (n = 19, ages 7-27) were compared to age- and gender- equivalent groups of individuals with type 1 diabetes (T1DM; n = 25), and non-diabetic healthy controls (HC: n = 25). Cognitive performance across multiple domains (verbal intelligence, spatial reasoning, memory, attention, smell identification) was assessed using standardized tests. Standardized self- and parent-report questionnaires on psychiatric symptoms and sleep disturbances were acquired from all groups and an unstructured psychiatric interview was performed within only the WFS group. Results: The three groups were similar demographically (age, gender, ethnicity, parental IQ). WFS and T1DM had similar duration of diabetes but T1DM had higher Hb<inf>A1C</inf> levels than WFS and as expected both groups had higher levels than HC. The WFS group was impaired on smell identification and reported sleep quality, but was not impaired in any other cognitive or self-reported psychiatric domain. In fact, the WFS group performed better than the other two groups on selected memory and attention tasks. However, based upon a clinical evaluation of only WFS patients, we found that psychiatric and behavioral problems were present and consisted primarily of anxiety and hypersomnolence. Conclusions: This study found that cognitive performance and psychological health were relatively preserved WFS patients, while smell and sleep abnormalities manifested in many of the WFS patients. These findings contradict past case and retrospective reports indicating significant cognitive and psychiatric impairment in WFS. While many of these patients were diagnosed with anxiety and hypersomnolence, self-reported measures of psychiatric symptoms indicated that the symptoms were not of grave concern to the patients. It may be that cognitive and psychiatric issues become more prominent later in life and/or in later stages of the disease, but this requires standardized assessment and larger samples to determine. In the relatively early stages of WFS, smell and sleep-related symptoms may be useful biomarkers of disease and should be monitored longitudinally to determine if they are good markers of progression as well. © 2015 Bischoff et al.

Author Keywords
Behavior;  Cognition;  Development;  Diabetes mellitus;  Psychiatry;  Wolfram syndrome


Document Type: Article
Source: Scopus


Kim, T.a b , Soto, F.a , Kerschensteiner, D.a c d
An excitatory amacrine cell detects object motion and provides feature-selective input to ganglion cells in the mouse retina
(2015) eLife, 4 (MAY), 31 p. 

DOI: 10.7554/eLife.08025

a Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, 660 S. Euclid Avenue, Saint Louis, MO, United States
b Washington University School of Medicine, 660 S. Euclid Avenue, Saint Louis, MO, United States
c Department of Anatomy and Neurobiology, Washington University School of Medicine, 660 S. Euclid Avenue, Saint Louis, MO, United States
d Hope Center for Neurological Disorders, Washington University School of Medicine, 660 S. Euclid Avenue, Saint Louis, MO, United States

Abstract
Retinal circuits detect salient features of the visual world and report them to the brain through spike trains of retinal ganglion cells. The most abundant ganglion cell type in mice, the so-called W3 ganglion cell, selectively responds to movements of small objects. Where and how object motion sensitivity arises in the retina is incompletely understood. Here, we use 2-photon-guided patch clamp recordings to characterize responses of VGluT3-expressing amacrine cells to a broad set of visual stimuli. We find that VG3-ACs are object motion sensitive and analyze the synaptic mechanisms underlying this computation. Anatomical circuit reconstructions suggest that VGluT3-expressing amacrine cells form glutamatergic synapses with W3 ganglion cells and targeted recordings show that the tuning of W3 ganglion cells’ excitatory input matches that of VGluT3-expressing amacrine cells’ responses. Synaptic excitation of W3 ganglion cells is diminished and responses to object motion are suppressed in mice lacking VGluT3. Object motion thus is first detected by VGluT3-expressing amacrine cells, which provide feature-selective excitatory input to W3 ganglion cells. © 2015, eLife Sciences Publications Ltd. All rights reserved.


Document Type: Article
Source: Scopus


Shepperd, J.A.a , Waters, E.A.b , Weinstein, N.D.c , Klein, W.M.P.d
A Primer on Unrealistic Optimism
(2015) Current Directions in Psychological Science, 24 (3), pp. 232-237. 

DOI: 10.1177/0963721414568341

a Department of Psychology, University of Florida, United States
b Department of Surgery, Division of Public Health Sciences, Washington University in St. Louis, United States
c Department of Human Ecology, Rutgers University, United States
d National Cancer Institute, Bethesda, MD, United States

Abstract
People display unrealistic optimism in their predictions about countless events, believing that their personal future outcomes will be more desirable than can possibly be true. We summarize the vast literature on unrealistic optimism by focusing on four broad questions: What is unrealistic optimism, when does it occur, why does it occur, and what are its consequences? Unrealistic optimism can be operationalized in multiple ways; is commonplace yet has well-established boundary conditions; occurs for a variety of reasons; and has consequences for affect, decision making, and behavior. © The Author(s) 2015.

Author Keywords
comparative optimism;  optimistic bias;  risk judgments;  risk perception;  unrealistic optimism


Document Type: Article
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, 45, pp. 154-162. 

DOI: 10.1016/j.chiabu.2015.02.007

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

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. © 2015 Elsevier Ltd.

Author Keywords
BMI;  Child maltreatment;  Obesity;  PTSD


Document Type: Article
Source: Scopus


Padoa-Schioppa, C.
Commentary: Utility-free heuristic models of two-option choice can mimic predictions of utility-stage models under many conditions
(2015) Frontiers in Neuroscience, 9 (MAY), p. 188. 

DOI: 10.3389/fnins.2015.00188

Departments of Anatomy and Neurobiology, Economics, and Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, United States

Author Keywords
Decision making;  Dimensional prioritization;  Heuristics;  Neuroeconomics;  Subjective value;  Utility;  Value comparison;  Value correlate


Document Type: Note
Source: Scopus


Vilupuru, S.a , Lin, L.a , Pepose, J.S.b
Comparison of contrast sensitivity and through focus in small-aperture inlay, accommodating intraocular lens, or multifocal intraocular lens subjects
(2015) American Journal of Ophthalmology, 160 (1), pp. 150-162.e1. 

DOI: 10.1016/j.ajo.2015.04.023

a AcuFocus Inc, Irvine, CA, United States
b Pepose Vision Institute, Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, 1815 Clarkson Road, Chesterfield, MO, United States

Abstract
Purpose To compare monocular and binocular mesopic contrast sensitivity and through focus following monocular implantation with KAMRA small-aperture inlay (AcuFocus, Irvine, California, USA) vs binocular implantation with an accommodating or multifocal intraocular lens (IOL) implant. Design Three-treatment randomized clinical trial of presbyopia-correcting IOLs with comparison to results from a previous nonrandomized multicenter clinical trial on the KAMRA corneal inlay. Methods Study population of 507 subjects with KAMRA inlays; predetermined subgroups included 327 subjects that underwent contrast sensitivity testing and another 114 subjects for defocus curve testing, along with 78 subjects randomized between bilateral Crystalens Advanced Optics (AO) (Bausch + Lomb Surgical, Aliso Viejo, California, USA), AcrySof IQ ReSTOR +3.0 D (Alcon Laboratories, Fort Worth, Texas, USA), or Tecnis +4D Multifocal (MF) (Abbott Medical Optics, Santa Ana, California, USA) IOL. Results KAMRA inlay subjects demonstrated improved intermediate and near vision with minimal to no change to distance vision, better contrast sensitivity in the inlay eye when compared to the multifocals, and better binocular contrast sensitivity when compared to all 3 intraocular lenses. Crystalens AO was superior in uncorrected intermediate vision compared to the KAMRA inlay, but not in distance-corrected intermediate, and was worse in near vision. The multifocals were superior in near vision at their respective optimum near focus points, but worse in intermediate vision compared to both KAMRA inlay and Crystalens AO. Conclusions The demonstrated performance of these devices should be considered, along with subjects' visual demands and expectations, degree of crystalline lens dysfunction, and other ocular characteristics, in guiding the selection of small-aperture corneal inlay or specific intraocular lens in the correction of presbyopia. © 2015 BY ELSEVIER INC. ALL RIGHTS RESERVED.


Document Type: Article
Source: Scopus


Dissel, S.a , Seugnet, L.a b , Thimgan, M.S.a , Silverman, N.c , Angadi, V.a , Thacher, P.V.d , Burnham, M.M.e , Shaw, P.J.a
Differential activation of immune factors in neurons and glia contribute to individual differences in resilience/vulnerability to sleep disruption
(2015) Brain, Behavior, and Immunity, 47, pp. 75-85. 

DOI: 10.1016/j.bbi.2014.09.019

a Department of Anatomy and Neurobiology, Washington University in St. Louis, 660 S. Euclid Ave, St. Louis, MO, United States
b Centre for Research in Neurosciences de Lyon, U1028/UMR 5292-Team WAKING, Université Claude Bernard, 8 avenue Rockefeller, Lyon Cedex 08, France
c Division of Infectious Diseases, Department of Medicine, University of Massachusetts Medical School, 364 Plantation St., Worcester, MA, United States
d Department of Psychology, St Lawrence University, 23 Romoda Drive, Canton, NY, United States
e College of Education, University of Nevada, Reno, Reno, NV, United States

Abstract
Individuals frequently find themselves confronted with a variety of challenges that threaten their wellbeing. While some individuals face these challenges efficiently and thrive (resilient) others are unable to cope and may suffer persistent consequences (vulnerable). Resilience/vulnerability to sleep disruption may contribute to the vulnerability of individuals exposed to challenging conditions. With that in mind we exploited individual differences in a fly's ability to form short-term memory (STM) following 3 different types of sleep disruption to identify the underlying genes. Our analysis showed that in each category of flies examined, there are individuals that form STM in the face of sleep loss (resilient) while other individuals show dramatic declines in cognitive behavior (vulnerable). Molecular genetic studies revealed that Antimicrobial Peptides, factors important for innate immunity, were candidates for conferring resilience/vulnerability to sleep deprivation. Specifically, Metchnikowin (Mtk), drosocin (dro) and Attacin (Att) transcript levels seemed to be differentially increased by sleep deprivation in glia (Mtk), neurons (dro) or primarily in the head fat body (Att). Follow-up genetic studies confirmed that expressing Mtk in glia but not neurons, and expressing dro in neurons but not glia, disrupted memory while modulating sleep in opposite directions. These data indicate that various factors within glia or neurons can contribute to individual differences in resilience/vulnerability to sleep deprivation. © 2014 Elsevier Inc..

Author Keywords
Glia;  Immunity;  Individual differences;  Resilience/vulnerability;  Short term memory;  Sleep disruption


Document Type: Article
Source: Scopus


Wilson, M.B.a , Kallogjeri, D.a , Joplin, C.N.a b , Gorman, M.D.a c , Krings, J.G.a d , Lenze, E.J.e , Nicklaus, J.E.a , Spitznagel, E.E.f , Piccirillo, J.F.a
Ecological momentary assessment of tinnitus using smartphone technology: A pilot study
(2015) Otolaryngology - Head and Neck Surgery (United States), 152 (5), pp. 897-903. Cited 1 time.

DOI: 10.1177/0194599815569692

a Department of Otolaryngology-Head and Neck Surgery, Washington University in St Louis, School of Medicine, 660 South Euclid Avenue, Saint Louis, MO, United States
b School of Engineering, Vanderbilt University, Nashville, TN, United States
c Kansas City University of Medicine and Biosciences, Kansas City, MO, United States
d Stanford University School of Medicine, Palo Alto, CA, United States
e Department of Psychiatry, Washington University in St Louis, School of Medicine, St Louis, MO, United States
f Department of Mathematics, Washington University in St Louis, St Louis, MO, United States

Abstract
Objective. To explore the feasibility of ecological momentary assessments (EMAs) as a tool to more accurately assess the level of bother from tinnitus. Study Design. Longitudinal observational study. Setting. Washington University Department of Otolaryngology- Head and Neck Surgery faculty practice plan. Subjects and Methods. Twenty participants with moderately to severely bothersome tinnitus were enrolled. All participants owned a smartphone device, and all communications were conducted via email, phone, and text messaging. Participants received 4 EMAs per day for 2 weeks via text message and a final survey on the 15th day. In each survey, participants recorded their level of tinnitus bother, their location at the time of response, their stress level, how they were feeling, and what they were doing. Response rates as a proxy for the feasibility of the program. Results. There were a total of 1120 surveys sent to 20 participants (56 surveys per participant), and 889 (79.4%) of the surveys were completed and returned. The median time to response from the moment of receiving the text message was 7 minutes. The distribution of responses to the EMA question, In the last 5 minutes, how bothered have you been by your tinnitus displayed both high between- and within-subject variability. At the end of 2 weeks, the median score on the Tinnitus Handicap Inventory was 37, with a range of 10 to 82 points; the median Tinnitus Functional Index score was 43, with a range of 10 to 82 points. Conclusion. This study suggests bothered tinnitus patients will use smartphones as part of EMA. © 2015 American Academy of Otolaryngology-Head and Neck Surgery Foundation.

Author Keywords
ecological momentary assessment;  outcome measure;  tinnitus


Document Type: Article
Source: Scopus


Liao, F.a b c , Zhang, T.J.a b c , Mahan, T.E.a b c , Jiang, H.a b c , Holtzman, D.M.a b c
Effects of growth hormone-releasing hormone on sleep and brain interstitial fluid amyloid-β in an APP transgenic mouse model
(2015) Brain, Behavior, and Immunity, 47, pp. 163-171. Cited 1 time.

DOI: 10.1016/j.bbi.2014.09.005

a Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
b Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, United States
c Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by impairment of cognitive function, extracellular amyloid plaques, intracellular neurofibrillary tangles, and synaptic and neuronal loss. There is substantial evidence that the aggregation of amyloid β (Aβ) in the brain plays a key role in the pathogenesis of AD and that Aβ aggregation is a concentration dependent process. Recently, it was found that Aβ levels in the brain interstitial fluid (ISF) are regulated by the sleep-wake cycle in both humans and mice; ISF Aβ is higher during wakefulness and lower during sleep. Intracerebroventricular infusion of orexin increased wakefulness and ISF Aβ levels, and chronic sleep deprivation significantly increased Aβ plaque formation in amyloid precursor protein transgenic (APP) mice. Growth hormone-releasing hormone (GHRH) is a well-documented sleep regulatory substance which promotes non-rapid eye movement sleep. GHRHR. lit/lit mice that lack functional GHRH receptor have shorter sleep duration and longer wakefulness during light periods. The current study was undertaken to determine whether manipulating sleep by interfering with GHRH signaling affects brain ISF Aβ levels in APPswe/PS1δE9 (PS1APP) transgenic mice that overexpress mutant forms of APP and PSEN1 that cause autosomal dominant AD. We found that intraperitoneal injection of GHRH at dark onset increased sleep and decreased ISF Aβ and that delivery of a GHRH antagonist via reverse-microdialysis suppressed sleep and increased ISF Aβ. The diurnal fluctuation of ISF Aβ in PS1APP/GHRHR. lit/lit mice was significantly smaller than that in PS1APP/GHRHR. lit/+ mice. However despite decreased sleep in GHRHR deficient mice, this was not associated with an increase in Aβ accumulation later in life. One of several possibilities for the finding is the fact that GHRHR deficient mice have GHRH-dependent but sleep-independent factors which protect against Aβ deposition. © 2014 Elsevier Inc..

Author Keywords
Alzheimer's disease;  Amyloid-β;  Growth hormone-releasing hormone;  Sleep


Document Type: Article
Source: Scopus


Roland, L.T.a , Lenze, E.J.b , Hardin, F.M.a , Kallogjeri, D.a , Nicklaus, J.a , Wineland, A.M.a , Fendell, G.b , Peelle, J.E.a , Piccirillo, J.F.a
Effects of mindfulness based stress reduction therapy on subjective bother and neural connectivity in chronic tinnitus
(2015) Otolaryngology - Head and Neck Surgery (United States), 152 (5), pp. 919-926. 

DOI: 10.1177/0194599815571556

a Department of Otolaryngology-Head and Neck Surgery, Washington University, St Louis School of Medicine, 660 South Euclid Ave, St. Louis, MO, United States
b Department of Psychiatry, Washington University, St Louis School of Medicine, St Louis, MO, United States

Abstract
Objective. To evaluate the impact of a Mindfulness Based Stress Reduction (MBSR) program in patients with chronic bothersome tinnitus on the (1) severity of symptoms of tinnitus and (2) functional connectivity in neural attention networks. Study Design. Open-label interventional pilot study. Setting. Outpatient academic medical center. Subjects. A total of 13 adult participants with a median age of 55 years, suffering from bothersome tinnitus. Methods. An 8-week MBSR program was conducted by a trained MBSR instructor. The primary outcome measure was the difference in patient-reported tinnitus symptoms using the Tinnitus Handicap Index (THI) and Tinnitus Functional Index (TFI) between pre-intervention, post- MBSR, and 4-week post-MBSR assessments. Secondary outcomes included change in measurements of depression, anxiety, mindfulness, and cognitive abilities. Functional connectivity magnetic resonance imaging (MRI) was performed at pre- and post-MBSR intervention time points to serve as a neuroimaging biomarker of critical cortical networks. Results. Scores on the THI and TFI showed statistically significant and clinically meaningful improvement over the course of the study with a median DTHI of 216 and median DTFI of 214.8 between baseline and 4-week follow-up scores. Except for depression, there was no significant change in any of the secondary outcome measures. Analysis of the resting state functional connectivity MRI (rs-fcMRI) data showed increased connectivity in the post-MBSR group in attention networks but not the default network. Conclusion. Participation in an MBSR program is associated with decreased severity in tinnitus symptoms and depression and connectivity changes in neural attention networks. MBSR is a promising treatment option for chronic bothersome tinnitus that is both noninvasive and inexpensive. © 2015 American Academy of Otolaryngology-Head and Neck Surgery Foundation.

Author Keywords
functional connectivity MRI;  neuroplasticity;  tinnitus


Document Type: Article
Source: Scopus


Yao, J.a , Yang, J.-M.a , Waiig, L.a , Zou, J.b , Waug, L.Y.a
Fast functional photoacoustic microscopy of mouse brain
(2015) Optics and the Brain, BRAIN 2015, . 

a Washington University in St. Louis, St Louis, MO, United States
b Texas A and M University, College Station, TX, United States

Abstract
We have developed fast functional photoacoustic microscopy (ffPAM). which can be utilized for three-dimensional morphological, functional, flow dynamic and metabolic mouse brain imaging through an intact skull with endogenous contrast only. © OSA 2015.


Document Type: Conference Paper
Source: Scopus


Urbin, M.A.a , Harris-Love, M.L.b , Carter, A.R.c , Lang, C.E.a c
High-intensity, unilateral resistance training of a non-paretic muscle group increases active range of motion in a severely paretic upper extremity muscle group after stroke
(2015) Frontiers in Neurology, 6 (MAY), art. no. 00119, . 

DOI: 10.3389/fneur.2015.00119

a Washington University School of Medicine, St. Louis, MO, United States
b Georgetown University Medical Center, MedStar National Rehabilitation Hospital, Washington, DC, United States
c Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Limited rehabilitation strategies are available for movement restoration when paresis is too severe following stroke. Previous research has shown that high-intensity resistance training of one muscle group enhances strength of the homologous, contralateral muscle group in neurologically intact adults. How this "cross education" phenomenon might be exploited to moderate severe weakness in an upper extremity muscle group after stroke is not well understood. The primary aim of this study was to examine adaptations in force-generating capacity of severely paretic wrist extensors resulting from high intensity, dynamic contractions of the non-paretic wrist extensors. A secondary, exploratory aim was to probe neural adaptations in a subset of participants from each sample using a single-pulse, transcranial magnetic stimulation (TMS) protocol. Separate samples of neurologically intact controls (n = 7) and individuals ≥4 months post stroke (n = 6) underwent 16 sessions of training. Following training, one-repetition maximum of the untrained wrist extensors in the control group and active range of motion of the untrained, paretic wrist extensors in the stroke group were significantly increased. No changes in corticospinal excitability, intracortical inhibition, or interhemispheric inhibition were observed in control participants. Both stroke participants who underwent TMS testing, however, exhibited increased voluntary muscle activation following the intervention. In addition, motor-evoked potentials that were unobtainable prior to the intervention were readily elicited afterwards in a stroke participant. Results of this study demonstrate that high-intensity resistance training of a non-paretic upper extremity muscle group can enhance voluntary muscle activation and force-generating capacity of a severely paretic muscle group after stroke. There is also preliminary evidence that corticospinal adaptations may accompany these gains. © 2015 Urbin, Harris-Love, Carter and Lang.

Author Keywords
Cross education;  Electrophysiology;  Rehabilitation;  Resistance training;  Stroke;  Upper extremity


Document Type: Article
Source: Scopus


Larsen, D.P.a , Santini, V.E.b
Increasing student recruitment into neurology: Joining the family
(2015) Neurology, 84 (23), pp. 2302-2303. 

DOI: 10.1212/WNL.0000000000001668

a Department of Neurology, Washington University, School of Medicine, St. Louis, MO, United States
b Department of Neurology and Neurological Sciences, Stanford University, School of Medicine, Stanford, CA, United States


Document Type: Editorial
Source: Scopus


Bollich, K.L.a , Rogers, K.H.b , Vazire, S.c
Knowing more than we can tell: People are aware of their biased self-perceptions
(2015) Personality and Social Psychology Bulletin, 41 (7), pp. 918-929. 

DOI: 10.1177/0146167215583993

a Washington University in St. Louis, St. Louis, MO, United States
b University of British Columbia, Vancouver, BC, Canada
c University of California, Davis, CA, United States

Abstract
There is no question that biases exist in self-perceptions of personality. To what extent do people have insight into their positive and negative self-biases? In two samples (total N = 130), people with positive biases (i.e., self-perceptions that are more positive than a reputation-based criterion measure) accurately described themselves as positively biased, and people with negative biases accurately described themselves as negatively biased. Furthermore, people were able to distinguish which traits they were more or less biased about. These findings suggest that people may know more about themselves than they initially admit. Implications for the use of self-reports and the study of self-knowledge are discussed. © 2015 by the Society for Personality and Social Psychology, Inc.

Author Keywords
Bias;  Individual differences;  Personality;  Self-knowledge


Document Type: Article
Source: Scopus


Akk, G.
Meet our editorial board member
(2015) Current Neuropharmacology, 13 (2), p. 161. 

Department of Anesthesiology, Washington University School of Medicine, Campus Box 8054, 660 S. Euclid Ave, St. Louis, MO, United States


Document Type: Editorial
Source: Scopus


Monk, K.R.a , Feltri, M.L.b , Taveggia, C.c
New insights on schwann cell development
(2015) GLIA, 63 (8), pp. 1376-1393. 

DOI: 10.1002/glia.22852

a Department of Developmental Biology, Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, United States
b Department of Biochemistry and Neurology, Hunter James Kelly Research Institute, University at Buffalo, State University of New York, Buffalo, NY, United States
c Division of Neuroscience and INSPE, San Raffaele Scientific Institute, Milan, Italy

Abstract
In the peripheral nervous system, Schwann cells are glial cells that are in intimate contact with axons throughout development. Schwann cells generate the insulating myelin sheath and provide vital trophic support to the neurons that they ensheathe. Schwann cell precursors arise from neural crest progenitor cells, and a highly ordered developmental sequence controls the progression of these cells to become mature myelinating or nonmyelinating Schwann cells. Here, we discuss both seminal discoveries and recent advances in our understanding of the molecular mechanisms that drive Schwann cell development and myelination with a focus on cell-cell and cell-matrix signaling events. © 2015 Wiley Periodicals, Inc.

Author Keywords
Immature Schwann cell;  Myelinating Schwann cell;  Neural crest;  Peripheral nervous system;  Radial sorting;  Remak Schwann cell;  Schwann cell;  Schwann cell precursor


Document Type: Review
Source: Scopus


Culver, J.P.a b c
Optical imaging of functional connectivity
(2015) Optics and the Brain, BRAIN 2015, . 

a Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States
b Department of Biomedical Engineering, Washington University, St. Louis, MO, United States
c Department of Physics, Washington University, St. Louis, MO, United States

Abstract
Optical imaging of spontaneous brain activity provides a potent assay of brain functions and networks. We are developing neurophotonics for non-invasive imaging of humans in the clinic and for imaging mouse models of disease. © OSA 2015.


Document Type: Conference Paper
Source: Scopus


Grant, J.D.a , Waldron, M.a b , Sartor, C.E.a c , Scherrer, J.F.d , Duncan, A.E.a e , Mccutcheon, V.a , Haber, J.R.f , Jacob, T.f , Heath, A.C.a , Bucholz, K.a
Parental Separation and Offspring Alcohol Involvement: Findings from Offspring of Alcoholic and Drug Dependent Twin Fathers
(2015) Alcoholism: Clinical and Experimental Research, . Article in Press. 

DOI: 10.1111/acer.12766

a Midwest Alcoholism Research Center Department of Psychiatry Washington University School of Medicine St. Louis, Missouri
b Department of Counseling and Educational Psychology Indiana University School of Education Bloomington, Indiana
c Department of Psychiatry Yale School of Medicine New Haven, Connecticut
d Department of Family and Community Medicine Saint Louis University St. Louis, Missouri
e George Warren Brown School of Social Work Washington University St. Louis, Missouri
f Palo Alto Department of Veterans Affairs Medical Center Palo Alto, California

Abstract
Background: We examined associations between parental separation during childhood and offspring alcohol involvement, adjusting for genetic and environmental risks specific to parental alcohol (AD) and cannabis/other illicit drug dependence (DD). Methods: The sample consisted of 1,828 offspring of male twins from the Vietnam Era Twin (VET) Registry, who completed a telephone diagnostic interview. Cox proportional hazards regression analyses were conducted predicting onset of first use, transition from first use to first AD symptom, and transition from first use to AD diagnosis from paternal and avuncular AD and DD history, parental separation, and offspring and family background characteristics. Paternal/avuncular DD/AD was based on the DSM-III-R; offspring and maternal AD were based on DSM-IV criteria. Results: Paternal DD/AD predicted increased offspring risk for all transitions, with genetic effects suggested on rate of transitioning to AD diagnosis. Parental separation was predictive of increased risk for early alcohol use, but a reduced rate of transition to both AD symptom onset and onset of AD. No interactions between separation and familial risk (indexed by paternal or avuncular DD/AD) were found. Conclusions: Findings highlight the contribution of both parental separation and paternal substance dependence in predicting timing of offspring alcohol initiation and problems across adolescence into early adulthood. © 2015 by the Research Society on Alcoholism.

Author Keywords
Alcohol Involvement;  Offspring of Twins;  Parental Alcohol Dependence;  Parental Drug Dependence;  Parental Separation or Divorce


Document Type: Article in Press
Source: Scopus


Cherry-Allen, K.M.a , Gidday, J.M.b c d , Lee, J.-M.e , Hershey, T.e f g , Lang, C.E.a e h
Remote limb ischemic conditioning enhances motor learning in healthy humans
(2015) Journal of Neurophysiology, 113 (10), pp. 3708-3719. 

DOI: 10.1152/jn.01028.2014

a Washington University School of Medicine, St. Louis, MO, United States
b Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, United States
c Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO, United States
d Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO, United States
e Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
f Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
g Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States
h Washington University School of Medicine, St. Louis, MO, United States

Abstract
Brief bouts of sublethal ischemia have been shown to protect exposed tissue (ischemic conditioning) and tissues at remote sites (remote ischemic conditioning) against subsequent ischemic challenges. Given that the mechanisms of this protective phenomenon are multifactorial and epigenetic, we postulated that remote limb ischemic conditioning (RLIC) might enhance mechanisms responsible for neural plasticity, and thereby facilitate learning. Specifically, we hypothesized that conditioning of the nervous system with RLIC, achieved through brief repetitive limb ischemia prior to training, would facilitate the neurophysiological processes of learning, thus making training more effective and more long-lasting. Eighteen healthy adults participated in this study; nine were randomly allocated to RLIC and nine to sham conditioning. All subjects underwent seven consecutive weekday sessions and 2-wk and 4-wk follow-up sessions. We found that RLIC resulted in significantly greater motor learning and longer retention of motor performance gains in healthy adults. Changes in motor performance do not appear to be due to a generalized increase in muscle activation or muscle strength and were not associated with changes in serum brain-derived neurotrophic factor (BDNF) concentration. Of note, RLIC did not enhance cognitive learning on a hippocampusdependent task. While future research is needed to establish optimal conditioning and training parameters, this inexpensive, clinically feasible paradigm might ultimately be implemented to enhance motor learning in individuals undergoing neuromuscular rehabilitation for brain injury and other pathological conditions. © 2015 the American Physiological Society.

Author Keywords
Behavioral training;  Motor learning;  Remote limb ischemic conditioning


Document Type: Article
Source: Scopus


Zhu, D.a , Bungart, B.L.b , Yang, X.c d , Zhumadilov, Z.e , Lee, J.C.-M.f , Askarova, S.e
Role of membrane biophysics in Alzheimer's-related cell pathways
(2015) Frontiers in Neuroscience, 9 (MAY), art. no. 186, . 

DOI: 10.3389/fnins.2015.00186

a Department of Chemical, Biological and Bioengineering, North Carolina A and T State University, Greensboro, NC, United States
b Indiana University School of Medicine Medical Scientist Training Program, Indiana University School of Medicine, Indianapolis, IN, United States
c Department of Clinical Neuroscience and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
d The Hope Center for Neurological Disorders, Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
e Department of Bioengineering and Regenerative Medicine, Center for Life Sciences, Nazarbayev University, Astana, Kazakhstan
f Department of Bioengineering, University of Illinois at Chicago, Chicago, IL, United States

Abstract
Cellular membrane alterations are commonly observed in many diseases, including Alzheimer's disease (AD). Membrane biophysical properties, such as membrane molecular order, membrane fluidity, organization of lipid rafts, and adhesion between membrane and cytoskeleton, play an important role in various cellular activities and functions. While membrane biophysics impacts a broad range of cellular pathways, this review addresses the role of membrane biophysics in amyloid-β peptide aggregation, Aβ-induced oxidative pathways, amyloid precursor protein processing, and cerebral endothelial functions in AD. Understanding the mechanism(s) underlying the effects of cell membrane properties on cellular processes should shed light on the development of new preventive and therapeutic strategies for this devastating disease. © 2015 Zhu, Bungart, Yang, Zhumadilov, Lee and Askarova.

Author Keywords
Amyloid precursor protein;  Amyloid-βpeptide;  Cerebral endothelium;  Membrane fluidity;  Membrane molecular order


Document Type: Article
Source: Scopus


Thio, L.L.a , Wainwright, M.S.b
Status epilepticus: For what are we waiting?
(2015) Neurology, 84 (23), pp. 2296-2297. 

DOI: 10.1212/WNL.0000000000001670

a Pediatric Epilepsy Center, Washington University, St. Louis Children's Hospital, St. Louis, MO, United States
b Northwestern University, Feinberg School of Medicine, Chicago, IL, United States


Document Type: Editorial
Source: Scopus


Ein-Dor, T.a , Coan, J.A.b , Reizer, A.c , Gross, E.B.b , Dahan, D.d , Wegener, M.A.b , Carel, R.e f , Cloninger, C.R.g , Zohar, A.H.d
Sugarcoated isolation: Evidence that social avoidance is linked to higher basal glucose levels and higher consumption of glucose
(2015) Frontiers in Psychology, 6 (APR), art. no. 492, . 

DOI: 10.3389/fpsyg.2015.00492

a School of Psychology, Interdisciplinary Center Herzliya, Herzliya, Israel
b University of Virginia, Charlottesville, VA, United States
c Ariel University Center of Samaria, Ariel, Israel
d Ruppin Academic Center, Ruppin, Israel
e Machon Mor Medical Center, Haifa, Israel
f Haifa University, Haifa, Israel
g Washington University, St. Louis, MO, United States

Abstract
Objective: The human brain adjusts its level of effort in coping with various life stressors as a partial function of perceived access to social resources. We examined whether people who avoid social ties maintain a higher fasting basal level of glucose in their bloodstream and consume more sugar-rich food, reflecting strategies to draw more on personal resources when threatened. Methods: In Study 1 (N = 60), we obtained fasting blood glucose and adult attachment orientations data. In Study 2 (N = 285), we collected measures of fasting blood glucose and adult attachment orientations from older adults of mixed gender, using a measure of attachment style different from Study 1. In Study 3 (N = 108), we examined the link between trait-like attachment avoidance, manipulation of an asocial state, and consumption of sugar-rich food. In Study 4 (N = 115), we examined whether manipulating the social network will moderate the effect of attachment avoidance on consumption of sugar-rich food. Results: In Study 1, fasting blood glucose levels corresponded with higher attachment avoidance scores after statistically adjusting for time of assessment and interpersonal anxiety. For Study 2, fasting blood glucose continued to correspond with higher adult attachment avoidance even after statistically adjusting for interpersonal anxiety, stress indices, age, gender, social support and body mass. In Study 3, people high in attachment avoidance consume more sugar-rich food, especially when reminded of asocial tendencies. Study 4 indicated that after facing a stressful task in the presence of others, avoidant people gather more sugar-rich food than more socially oriented people. Conclusion: Results are consistent with the suggestion that socially avoidant individuals upwardly adjust their basal glucose levels and consume more glucose-rich food with the expectation of increased personal effort because of limited access to social resources. Further investigation of this link is warranted. © 2015 Ein-Dor, Coan, Reizer, Gross, Dahan, Wegener, Carel, Cloninger and Zohar.

Author Keywords
Attachment;  Avoidance;  Glucose;  Metabolic resources;  Social baseline theory;  Social support;  Stress


Document Type: Article
Source: Scopus


Arias, E.J.a , Dunn, G.P.a , Washington, C.W.a , Derdeyn, C.P.a b c , Chicoine, M.R.a , Grubb, R.L., Jr.a b , Moran, C.J.a b , Cross, D.T., IIIa b , Dacey, R.G., Jr.a , Zipfel, G.J.a c
Surgical revascularization in North American adults with moyamoya phenomenon: Long-term angiographic follow-up
(2015) Journal of Stroke and Cerebrovascular Diseases, 24 (7), pp. 1597-1608. 

DOI: 10.1016/j.jstrokecerebrovasdis.2015.03.053

a Department of Neurological Surgery, Washington University School of Medicine, Box 8057, 660 South Euclid Avenue, St. Louis, MO, United States
b Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States
c Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Background North American and Asian forms of moyamoya have distinct clinical characteristics. Asian adults with moyamoya are known to respond better to direct versus indirect revascularization. It is unclear whether North American adults with moyamoya have a similar long-term angiographic response to direct versus indirect bypass. Methods A retrospective review of surgical revascularization for adult moyamoya phenomenon was performed. Preoperative and postoperative cerebral angiograms underwent consensus review, with degree of revascularization quantified as extent of new middle cerebral artery (MCA) territory filling. Results Late angiographic follow-up was available in 15 symptomatic patients who underwent 20 surgical revascularization procedures. In 10 hemispheres treated solely with indirect arterial bypass, 3 had 2/3 revascularization, 4 had 1/3 revascularization, and 3 had no revascularization of the MCA territory. In the 10 hemispheres treated with direct arterial bypass (8 as a stand-alone procedure and 2 in combination with an indirect procedure), 2 had complete revascularization, 7 had 2/3 revascularization, and 1 had 1/3 revascularization. Direct bypass provided a higher rate of "good" angiographic outcome (complete or 2/3 revascularization) when compared with indirect techniques (P =.0198). Conclusions Direct bypass provides a statistically significant, more consistent, and complete cerebral revascularization than indirect techniques in this patient population. This is similar to that reported in the Asian literature, which suggests that the manner of presentation (ischemia in North American adults versus hemorrhage in Asian adults) is likely not a contributor to the extent of revascularization achieved after surgical intervention. © 2015 by National Stroke Association.

Author Keywords
EDAMS;  EDAS;  Moyamoya;  revascularization;  STA-MCA


Document Type: Article
Source: Scopus


North, C.S.a b , Pollio, D.E.c , Hong, B.A.d , Pandya, A.e , Smith, R.P.f , Pfefferbaum, B.g
The postdisaster prevalence of major depression relative to PTSD in survivors of the 9/11 attacks on the world trade center selected from affected workplaces
(2015) Comprehensive Psychiatry, 60, pp. 119-125. 

DOI: 10.1016/j.comppsych.2015.02.009

a Program in Trauma and Disaster and Staff Psychiatrist, VA North Texas Health Care System, Dallas, TX, United States
b Departments of Psychiatry and Emergency Medicine, University of Texas, Southwestern Medical Center, 6363 Forest Park Rd., Dallas, TX, United States
c University of Alabama at Birmingham, Department of Social Work, College of Arts and Sciences, Birmingham, AL, United States
d Washington University, School of Medicine, Department of Psychiatry, St. Louis, MO, United States
e Keck School of Medicine, Department of Psychiatry and Behavioral Sciences, University of California, Los Angeles, CA, United States
f Ichan School of Medicine at Mt. Sinai, New York Harbor Health Care System - Manhattan VA, New York, NY, United States
g University of Oklahoma, Department of Psychiatry and Behavioral Sciences, College of Medicine, Oklahoma City, OK, United States

Abstract
Background Studies of survivors of the September 11, 2001 attacks on the World Trade Center in New York City suggest that postdisaster depressive disorders may be at least as prevalent, or even more prevalent, than posttraumatic stress disorder (PTSD), unlike findings from most other disaster studies. The relative prevalence and incidence of major depressive disorder (MDD) and PTSD were examined after the 9/11 attacks relative to trauma exposures. Methods This study used full diagnostic assessment methods and careful categorization of exposure groups based on DSM-IV-TR criteria for PTSD to examine 373 employees of 9/11-affected New York City workplaces. Results Postdisaster new MDD episode (26%) in the entire sample was significantly more prevalent (p <.001) than 9/11-related PTSD (14%). Limiting the comparison to participants with 9/11 trauma exposures, the prevalence of postdisaster new MDD episode and 9/11-related PTSD did not differ (p =.446). The only 9/11 trauma exposure group with a significant difference in relative prevalence of MDD and PTSD were those with a 9/11 trauma-exposed close associate, for whom postdisaster new MDD episode (45%) was more prevalent (p =.046) than 9/11-related PTSD (31%). Conclusions Because of the conditional definition of PTSD requiring trauma exposure that is not part of MDD criteria, prevalence comparisons of these two disorders must be limited to groups with qualifying trauma exposures to be meaningful. Findings from this study suggest distinct mechanisms underlying these two disorders that differentially relate to direct exposure to trauma vs. the magnitude of the disaster and personal connectedness to disaster and community-wide effects. © 2015 Elsevier Inc.


Document Type: Article
Source: Scopus


Ju, Y.-E.
The slow road to memory loss
(2015) Science Translational Medicine, 7 (291), art. no. 96, . 

DOI: 10.1126/scitranslmed.aac5095

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


Document Type: Note
Source: Scopus


Xiang, X.a , An, R.b , Gehlert, S.c
Trends in antidepressant use among U.S. cancer survivors, 1999-2012
(2015) Psychiatric Services, 66 (6), p. 564. 

DOI: 10.1176/appi.ps.201500007

a School of Social Work, University of Illinois, Urbana-Champaign, IL, United States
b Department of Kinesiology and Community Health, University of Illinois at Urbana-ChampaignIL, United States
c George Warren Brown School of Social Work, Washington University, St. Louis, WA, United States


Document Type: Short Survey
Source: Scopus


Werner, R.A.a b c d , Franzblau, A.c , Evanoff, B.e , Ulin, S.d
Ulnar Neuropathy Among Active Workers Based Upon Hand Diagram Ratings
(2015) PM and R, 7 (6), pp. 571-575. 

DOI: 10.1016/j.pmrj.2014.12.014

a Department of Physical Medicine and Rehabilitation, Veterans Administration Health System, 2215 Fuller Rd. (117), Ann Arbor, MI, United States
b Department of Physical Medicine and Rehabilitation, University of Michigan Health Systems, Ann Arbor, MI, United States
c Department of Environmental Health Sciences, School of Public Health, University of Michigan, Ann Arbor, MI, United States
d Center for Ergonomics, College of Engineering, University of Michigan, Ann Arbor, MI, United States
e Department of Public Health, Washington University, St. Louis, MO, United States

Abstract
Background: Limited studies have estimated the prevalence of ulnar neuropathy (UN) in the workplace. Hand diagrams have been demonstrated to have a good sensitivity and specificity when attempting to identify patients with UN. Objective: To determine the prevalence and associated risk factors for UN among active workers based on results of a hand diagram, and to determine the reliability of hand diagram scoring. Design: Cross-sectional study. Setting: Seven different industrial and clerical work sites. Methods: A total of 501 active workers were screened. Subjects completed a hand diagram and the Job Content Questionnaire, and had ergonomic assessment of their job. Each hand diagram was scored independently by 2 raters. Main Outcome Measures: Rating of the hand diagram for UN. Results: Interrater reliability of scoring the hand diagram for UN was very high. The estimated prevalence of UN was 3.6%. Suspected UN was associated with positioning of the elbow but not by contact stress at the elbow or force at the hand. Smokers had a lower prevalence, but smokers with suspected UN had higher-pack year histories. Workers with suspected UN had a greater sense of job insecurity and lower job satisfaction rating. Conclusions: Hand diagram rating has a high interrater reliability. Suspected UN has a relatively high prevalence among active workers in comparison to prior estimates of the prevalence of UN among the general population and is not strongly associated with ergonomic factors. © 2015 American Academy of Physical Medicine and Rehabilitation.


Document Type: Article
Source: Scopus


Ghoshal, N.a , Perry, A.b , McKeel, D.b , Schmidt, R.E.b , Carter, D.b , Norton, J.a , Zou, W.-Q.c , Xiao, X.c , Puoti, G.c , Notari, S.c , Gambetti, P.c , Morris, J.C.a b , Cairns, N.J.a b
Variably protease-sensitive prionopathy in an apparent cognitively normal 93-year-old
(2015) Alzheimer Disease and Associated Disorders, 29 (2), pp. 173-176. 

DOI: 10.1097/WAD.0000000000000049

a Department of Neurology, Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine, 660 S. Euclid Avenue, St Louis, MO, United States
b Pathology and Immunology, Washington University School of Medicine, St Louis, MO, United States
c Department of Pathology, National Prion Disease Pathology Surveillance Center, Case Western Reserve University, Cleveland, OH, United States

Author Keywords
clinical case presentation;  cognitively normal;  Creutzfeldt-Jakob disease;  dementia;  neuropathology;  prion disease;  Western blot


Document Type: Article
Source: Scopus


Mao, D.D.a , Gujar, A.D.a , Mahlokozera, T.a b , Chen, I.a , Pan, Y.a , Luo, J.c , Brost, T.d , Thompson, E.A.a , Turski, A.a , Leuthardt, E.C.a , Dunn, G.P.a e f g , Chicoine, M.R.a e , Rich, K.M.a e , Dowling, J.L.a e , Zipfel, G.J.a e , Dacey, R.G.a e , Achilefu, S.h , Tran, D.D.e i , Yano, H.a e j k , Kim, A.H.a e j l
A CDC20-APC/SOX2 Signaling Axis Regulates Human Glioblastoma Stem-like Cells
(2015) Cell Reports, . Article in Press. 

DOI: 10.1016/j.celrep.2015.05.027

a Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA
b Program in Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, USA
c Division of Biostatistics, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
d Program in Molecular Cell Biology, Washington University School of Medicine, St. Louis, MO 63110, USA
e Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA
f Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO 63110, USA
g Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
h Molecular Imaging Center, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO 63110, USA
i Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
j Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA
k Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA
l Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA

Abstract
Glioblastoma harbors a dynamic subpopulation of glioblastoma stem-like cells (GSCs) that can propagate tumors invivo and is resistant to standard chemoradiation. Identification of the cell-intrinsic mechanisms governing this clinically important cell state may lead to the discovery of therapeutic strategies for this challenging malignancy. Here, we demonstrate that the mitotic E3 ubiquitin ligase CDC20-anaphase-promoting complex (CDC20-APC) drives invasiveness and self-renewal in patient tumor-derived GSCs. Moreover, CDC20 knockdown inhibited and CDC20 overexpression increased the ability of human GSCs to generate brain tumors in an orthotopic xenograft model invivo. CDC20-APC control of GSC invasion and self-renewal operates through pluripotency-related transcription factor SOX2. Our results identify a CDC20-APC/SOX2 signaling axis that controls key biological properties of GSCs, with implications for CDC20-APC-targeted strategies in the treatment of glioblastoma. Mao etal. report that E3 ubiquitin ligase CDC20-APC is required for invasiveness, self-renewal, and invivo tumorigenicity of human glioblastoma stem-like cells (GSCs). CDC20-APC interacts with and regulates SOX2 protein to promote SOX2-dependent transcription and drive GSC invasiveness and self-renewal. Using the Cancer Genome Atlas dataset, the authors find that high CDC20 expression in proneural glioblastomas is associated with shorter overall survival. © 2015 The Authors.


Document Type: Article in Press
Source: Scopus

 

June 17, 2015

 

Tanenbaum, A.B., Snyder, A.Z., Brier, M.R., Ances, B.M.
A method for reducing the effects of motion contamination in arterial spin labeling magnetic resonance imaging
(2015) Journal of Cerebral Blood Flow and Metabolism, . Article in Press. 

DOI: 10.1038/jcbfm.2015.124

Department of Neurology, Washington University in St. Louis, St. Louis, Missouri, USA

Abstract
Arterial spin labeling (ASL) is a noninvasive method to measure cerebral blood flow (CBF). Arterial spin labeling is susceptible to artifact generated by head motion; this artifact is propagated through the subtraction procedure required to calculate CBF. We introduce a novel strategy for mitigating this artifact based on weighting tag/control volumes according to a noise estimate. We evaluated this strategy (DVARS weighting) in application to both pulsed ASL (PASL) and pseudo-continuous ASL (pCASL) in a cohort of normal adults (N=57). Application of DVARS weighting significantly improved test–retest repeatability as assessed by the intra-class correlation coefficient. Before the application of DVARS weighting, mean gray matter intra-class correlation (ICC) between subsequent ASL runs was 0.48 and 0.51 in PASL and pCASL, respectively. With weighting, ICC was significantly improved to 0.63 and 0.58.Journal of Cerebral Blood Flow & Metabolism advance online publication, 3 June 2015; doi:10.1038/jcbfm.2015.124. © 2015 International Society for Cerebral Blood Flow &amp; Metabolism, Inc.


Document Type: Article in Press
Source: Scopus


Naidoo, S.D.a , Skolnick, G.B.a , Patel, K.B.a , Woo, A.S.a , Cheng, A.-L.b
Long-term outcomes in treatment of deformational plagiocephaly and brachycephaly using helmet therapy and repositioning: a longitudinal cohort study
(2015) Child's Nervous System, 6 p. Article in Press. 

DOI: 10.1007/s00381-015-2769-4

a Cleft Palate and Craniofacial Deformities Institute, Division of Plastic and Reconstructive Surgery, Washington University School of Medicine, 660 S. Euclid Avenue, Campus Box 8238, St. Louis, MO, United States
b School of Nursing and Health Studies, University of Missouri–Kansas City, 2464 Charlotte, Kansas City, MO, United States

Abstract
Objectives: Deformational plagiocephaly and/or brachycephaly (DPB) is a misshapen head presenting at birth or shortly thereafter, caused by extrinsic forces on an infant’s malleable cranium. There are two treatment methods available for DPB: helmeting and repositioning. Little is known about the long-term outcomes of these two treatment options. The purpose of this study was to examine children who received helmeting or repositioning therapy for DPB as infants and compare the long-term head shape outcomes of the two groups. Methods: A longitudinal cohort study design was used to evaluate change in head shape of the two groups. One hundred children (50 helmeted, 50 repositioned) were initially evaluated at 6 months or younger for DPB. Anthropometric skull measurements taken as infants before treatment were compared with measurements taken for this study. Inclusion criteria included initial clinic visit at age 6 months or younger, evaluation by the same practitioner, and current age 2–10 years. Cephalic index and cranial vault asymmetry were calculated based on caliper measurements. Results: Data from 100 children were evaluated for this study. Significant differences between the treatment groups in the mean change in cephalic index (p = 0.003) and cranial vault asymmetry (p < 0.001) were found; the children that used helmet therapy demonstrated greater improvement. Conclusions: This is one of the larger published long-term outcome studies comparing children that used helmets and repositioning to treat their DPB as infants. The data suggest that infants will have more improvement in head shape with a helmet than with repositioning. © 2015 Springer-Verlag Berlin Heidelberg

Author Keywords
Brachycephaly;  Deformational plagiocephaly;  Long-term outcomes;  Non-synostotic plagiocephaly;  Plagiocephaly treatment;  Positional plagiocephaly


Document Type: Article in Press
Source: Scopus


Bourgault, S.a b , Baril, C.a b , Vincent, A.c d , Héon, E.c d , Ali, A.c d , MacDonald, I.e , Lueder, G.T.f , Colleaux, K.M.g h , Laliberté, I.a i
Retinal degeneration in autoimmune polyglandular syndrome type 1: A case series
(2015) British Journal of Ophthalmology, . Article in Press. 

DOI: 10.1136/bjophthalmol-2014-305897

a Département d'ophtalmologie et ORL-Chirurgie cervico-faciale, Faculté de médecine, Université Laval, Québec, Quebec, Canada
b Centre universitaire d'ophtalmologie, Hôpital du Saint-Sacrement, CHU de Québec, Québec, Quebec, Canada
c Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, Ontario, Canada
d Department of Ophthalmology and Vision Sciences, The Hospital for Sick Children, Toronto, Ontario, Canada
e Department of Ophthalmology and Visual Sciences, University of Alberta, Edmonton, Canada
f Departments of Ophthalmology and Visual Sciences and Pediatrics, Washington University School of Medicine, St Louis, Missouri, USA
g Department of Ophthalmology, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
h Saskatoon Retina Consultants, Saskatoon, Saskatchewan, Canada
i Centre mére-enfant Soleil, CHUL, CHU de Québec, Québec, Quebec, Canada

Abstract
Background Autoimmune polyglandular syndrome type 1 (APS1) is a rare autosomal recessive disorder due to mutations in the AIRE gene. Aim To report the ocular features and characterise the retinal phenotype in molecularly confirmed APS1. Method This retrospective case series reviewed five molecularly confirmed cases with APS1 known to have ocular involvement (age range: 19 months-44 years; mean follow-up of 8 years). The medical history, ocular history and evaluation, visual field testing, full-field electroretinogram (ERG) and antiretinal antibody results were reviewed. Results All but one case had decreased vision at first presentation. All cases had peripheral pigmentary retinal changes; macular atrophy was noted in 80% of cases. The most common feature on spectral-domain optical coherence tomography was a disruption of the external limiting membrane and inner segment ellipsoid band (n=3). Fundus autofluorescence imaging demonstrated a parafoveal ring of hyper-autofluorescence (n=1) or a stippled and patchy autofluorescence pattern in the macula (n=1). The visual fields were constricted in all tested patients (n=3). The rod ERG was abnormal in all cases; the relative involvement of rods and cones differed. Four patients who were tested for antiretinal antibodies were found positive by immunohistochemistry (n=3) and/or western blot (n=2). Conclusions Photoreceptor degeneration is part of APS1 phenotype and the presence of antiretinal antibodies strongly supports an aetiology similar to that of non-paraneoplastic autoimmune retinopathy. Periodic retinal evaluation and imaging, visual field testing and ERG would assist in monitoring the retinopathy in APS1-related disease. © 2015 by the BMJ Publishing Group Ltd.


Document Type: Article in Press
Source: Scopus


Goyal, N.A.a , Cash, T.M.a , Alam, U.a , Enam, S.a , Tierney, P.a , Araujo, N.a , Mozaffar, F.H.a , Pestronk, A.b c , Mozaffar, T.a d
Seropositivity for NT5c1A antibody in sporadic inclusion body myositis predicts more severe motor, bulbar and respiratory involvement
(2015) Journal of Neurology, Neurosurgery and Psychiatry, . Article in Press. 

DOI: 10.1136/jnnp-2014-310008

a Department of Neurology, University of California, Irvine, California, USA
b Department of Neurology, Washington University, St. Louis, Missouri, USA
c Department of Pathology, Washington University, St. Louis, Missouri, USA
d Department of Orthopaedic Surgery, University of California, Irvine, California, USA

Abstract
Objectives To explore phenotypic differences between individuals with sporadic inclusion body myositis (sIBM) who are seropositive for the NT5c1A antibody compared with those who are seronegative. Methods Cross-sectional clinical, serological and functional analysis in 25 consecutive participants with sIBM. Results All participants met criteria for clinically defined or probable sIBM. 18 of 25 participants with sIBM (72%) were seropositive for the NT5c1A antibody. No differences between median age and duration of illness between the two groups were seen. Females have higher odds of being seropositive (OR=2.30). Participants with seropositive sIBM took significantly longer to get up and stand (p=0.012). There were no significant differences between the two groups in terms of distance covered on a 6 min walk. Seropositive participants were more likely to require assistive devices such as a walker or wheelchair for mobility (OR=23.00; p=0.007). A number of secondary (exploratory) outcomes were assessed. NT5c1A seropositive sIBM cases had lower total Medical Research Council (MRC) sum score and MRC sum score on the right (p=0.03 and 0.02, respectively). Participants with the NT5c1A antibody were significantly more likely to have symptoms of dysphagia (OR=10.67; p=0.03) and reduced forced vital capacity (p=0.005). Facial weakness occurred in 50% of seropositive participants while it was only seen in 14% of seronegative participants. Conclusions Even though the small sample size limits definite conclusions, our cross-sectional study showed seropositivity to the NT5c1A antibody is associated with greater motor and functional disability in sIBM. The study also suggests more prominent bulbar, facial and respiratory involvement in individuals positive for NT5c1A antibodies. © 2015 by the BMJ Publishing Group Ltd.


Document Type: Article in Press
Source: Scopus


Sun, M.a , Hu, X.b , Zhang, W.a , Guo, R.a , Hu, A.a , Mwansisya, T.E.c , Zhou, L.a , Liu, C.a , Chen, X.a , Huang, X.a , Shi, J.d , Chiu, H.F.K.e , Liu, Z.a
Psychotic-like experiences and associated socio-demographic factors among adolescents in China
(2015) Schizophrenia Research, . Article in Press. 

DOI: 10.1016/j.schres.2015.05.031

a Institute of Mental Health, The Second Xiangya Hospital of Central South University, Changsha, China
b School of Medicine and Institute for Public Health, Washington University, St. Louis, USA
c College of Health Sciences, University of Dodoma, P.O. Box 395, Dodoma, Tanzania
d School of Public Health, Central South University, Changsha, China
e Department of Psychiatry, Chinese University of Hong Kong, Hong Kong, China

Abstract
Objective: Adolescents with persistent psychotic-like experiences (PLEs) may be at high risk for later development of psychoses. Exploring early age risk factors for PLEs may provide useful information for prevention of mental disorders and improvement of mental health. Method: A total of 5427 adolescents (aged between 10 and 16) participated in a cross-sectional survey, with social and demographic information collected. The Positive Subscale of Community Assessment of Psychic Experiences (CAPE) was used to measure PLEs, and the CAPE Depressive and Negative Subscales were used to examine depressive and negative experiences. The Trauma History Questionnaire (child version) was used to assess experiences of previous traumatic events. Results: In our study, 95.7% of the adolescents reported more than one episode of PLEs, while 17.2% reported "nearly always" having PLEs. High positive correlations were shown both between frequency scores among experiences of three dimensions (PLEs, depressive and negative experiences), and between frequency and distress scores. Factors associated with a higher risk for more frequent and distressing PLEs include: urban setting, family history of psychiatric illnesses, and higher impact from previous traumatic events at present. Conclusions: Episodes of PLEs are common in Chinese adolescents, however only a small proportion have persistent PLEs, with worsening distress as the frequency increased. PLEs shared similar environmental and genetic risk factors not only with the clinical phenotypes, which is consistent with the continuity model of PLEs, but also with depressive and negative experiences, which may imply etiologic relation between different dimensions of psychosis at the subclinical level. © 2015 Elsevier B.V.

Author Keywords
CAPE;  Left-behind children;  Psychosis;  Trauma history


Document Type: Article in Press
Source: Scopus


Constantino, J.N.a b , Zhang, Y.a , Holzhauer, K.c , Sant, S.a , Long, K.a , Vallorani, A.d , Malik, L.a , Gutmann, D.H.d
Distribution and Within-Family Specificity of Quantitative Autistic Traits inPatients with Neurofibromatosis Type I
(2015) Journal of Pediatrics, . Article in Press. 

DOI: 10.1016/j.jpeds.2015.04.075

a Department of Psychiatry, Washington University School of Medicine, St. Louis, MO
b Department of Pediatrics, Washington University School of Medicine, St. Louis, MO
c University of Illinois, Chicago, IL
d Department of Neurology, Washington University School of Medicine, St. Louis, MO

Abstract
Objective: To examine the distribution of quantitative autistic traits (QATs) in an independent neurofibromatosis type I (NF1) sample, the relationships between QAT, sex, and attention deficit hyperactivity disorder (ADHD) symptomatology, and to explore evidence for QAT mutational specificity within families. Study design: Age-appropriate versions of the Social Responsiveness Scale, second edition and the Conners Adult ADHD Rating Scales were completed for 103 patients with NF1 from the Washington University Neurofibromatosis Center. Results: Patients with NF1 exhibited a pathologically shifted unimodal distribution for QAT. Forty-four percent of the subjects exhibited a QAT burden at or above 1 SD from the population mean; 13% scored at or above the extreme first percentile of the general population distribution. Elevations in ADHD symptomatology exhibited a distinct bimodal distribution; however, mean ADHD index scores were equivalent in patients who had been diagnosed in the community with ADHD compared with those who had not. We observed striking within-family associations for QAT, reflected by an Social Responsiveness Scale, second edition intraclass correlation of 0.77 in pairings of first degree relatives with NF1. Conclusions: Impairments in reciprocal social behavior and attention affect a large proportion of patients with NF1 throughout life and are often clinically unrecognized. Further exploration of genotype-phenotype correlation is strongly warranted for the purpose of gaining insights into mechanisms by which specific mutational variations in the NF1 gene may influence autistic trait severity. © 2015 Elsevier Inc.


Document Type: Article in Press
Source: Scopus


Zalewski, M.a , Stepp, S.D.b , Whalen, D.J.c d , Scott, L.N.b
A Qualitative assessment of the parenting challenges and treatment needs of mothers with borderline personality disorder
(2015) Journal of Psychotherapy Integration, 25 (2), pp. 71-89. 

DOI: 10.1037/a0038877

a University of Oregon, United States
b University of Pittsburgh Medical Center, United States
c University of Pittsburgh, United States
d Washington University, School of Medicine, United States

Abstract
There are currently no empirically supported interventions to target parenting among mothers who have borderline personality disorder (BPD). The current study uses Consensus Qualitative Research (CQR) methodology to (a) learn about mothers' experiences of parenting with BPD, and (b) identify treatment modifications to dialectical behavior therapy (DBT) as suggested by mothers with BPD who are currently engaged in DBT skills training. Twenty-three mothers were recruited from intensive outpatient and partial hospitalization programs that teach DBT skills. A total of 9 focus groups that met 1 time were conducted, asking women a series of questions regarding their experiences of parenting with BPD and how they would modify DBT to address parenting issues. Using the CQR approach, we coded domains and categories that were discussed by mothers in the focus groups. Coding revealed that mothers with BPD wished parenting was integrated more in their current DBT skills groups. In addition, one of the most prominent themes to emerge was that parenting is particularly stressful to mothers with BPD and is associated with guilt, uncertainty, and worry. Finally, mothers offered many ideas for how to integrate parenting-focused interventions into DBT. The CQR method revealed gaps in current treatment for mothers with BPD and provided useful ideas for how to modify DBT to target parenting and integrate these modifications into other approaches for treating mothers with BPD. © 2015 American Psychological Association.

Author Keywords
Borderline personality disorder;  Consensus qualitative research;  Dialectical behavior therapy;  Parenting;  Treatment development


Document Type: Article
Source: Scopus


Grucza, R.A.a , Hur, M.a , Agrawal, A.a , Krauss, M.J.a , Plunk, A.D.b , Cavazos-Rehg, P.A.a , Chaloupka, F.J.c , Bierut, L.J.a d
A reexamination of medical marijuana policies in relation to suicide risk
(2015) Drug and Alcohol Dependence, 152, pp. 68-72. 

DOI: 10.1016/j.drugalcdep.2015.04.014

a Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
b Department of Pediatrics, Eastern Virginia Medical School, Norfolk, VA, United States
c Department of Economics and Health Policy Center, University of Illinois at Chicago, Chicago, IL, United States
d Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Objectives: Previous research has suggested that medical marijuana policies lead to reductions in suicide rates. In this study, we further investigate the association between these policies and within-state changes in suicide risk. Methods: Data on suicide deaths (n=662,993) from the National Vital Statistics System Multiple Cause of Death files were combined with living population data. Fixed-effects regression methods were employed to control for state differences in suicide rates and national and state secular trends. Analyses extended prior research that suggested a protective effect of medical marijuana policies by incorporating newer data and additional covariates. Results: After adjustment for race/ethnicity, tobacco control policies, and other covariates, we found no association between medical marijuana policy and suicide risk in the population ages 15 and older (OR. =1.000; 95% CI: 0.956, 1.045; p=0.98), among men overall (OR. =0.996; 95% CI: 0.951, 1.043; p=0.87) or for any other age-by-sex groups. Conclusion: We find no statistically significant association between medical marijuana policy and suicide risk. These results contradict prior analyses which did not control for race/ethnicity and certain state characteristics such as tobacco control policies. Failure to control for these factors in future analyses would likely bias estimates of the associations between medical marijuana policy and health outcomes. © 2015 Elsevier Ireland Ltd.

Author Keywords
Epidemiology;  Marijuana;  Medical marijuana;  Policy;  Suicide


Document Type: Article
Source: Scopus


Yang, M.L.a , Shin, J.a b , Kearns, C.A.a , Langworthy, M.M.a , Snell, H.a c , Walker, M.B.a , Appel, B.a
CNS myelination requires cytoplasmic dynein function
(2015) Developmental Dynamics, 244 (2), pp. 134-145. 

DOI: 10.1002/dvdy.24238

a Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, United States
b Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, United States
c Meharry Medical College, Nashville, TN, United States

Abstract
Background: Cytoplasmic dynein provides the main motor force for minus-end-directed transport of cargo on microtubules. Within the vertebrate central nervous system (CNS), proliferation, neuronal migration, and retrograde axon transport are among the cellular functions known to require dynein. Accordingly, mutations of DYNC1H1, which encodes the heavy chain subunit of cytoplasmic dynein, have been linked to developmental brain malformations and axonal pathologies. Oligodendrocytes, the myelinating glial cell type of the CNS, migrate from their origins to their target axons and subsequently extend multiple long processes that ensheath axons with specialized insulating membrane. These processes are filled with microtubules, which facilitate molecular transport of myelin components. However, whether oligodendrocytes require cytoplasmic dynein to ensheath axons with myelin is not known. Results: We identified a mutation of zebrafish dync1h1 in a forward genetic screen that caused a deficit of oligodendrocytes. Using in vivo imaging and gene expression analyses, we additionally found evidence that dync1h1 promotes axon ensheathment and myelin gene expression. Conclusions: In addition to its well known roles in axon transport and neuronal migration, cytoplasmic dynein contributes to neural development by promoting myelination. © 2014 Wiley Periodicals, Inc.

Author Keywords
Axon;  Dynein;  Myelination;  Oligodendrocyte;  Zebrafish


Document Type: Article
Source: Scopus


Kubanek, J.a b , Mooshagian, E.a
Cognitive and action-based aspects of developing decisions in parietal cortex
(2015) Journal of Neuroscience, 35 (22), pp. 8382-8383. 

DOI: 10.1523/JNEUROSCI.1181-15.2015

a Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, MO, United States
b Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, United States


Document Type: Article
Source: Scopus


Piccirillo, J.F.a b , Hardin, F.M.b , Nicklaus, J.b , Kallogjeri, D.b , Wilson, M.b , Ma, C.X.a g , Coalson, R.S.c d , Shimony, J.d , Schlaggar, B.L.c d e f
Cognitive impairment after chemotherapy related to atypical network architecture for executive control
(2015) Oncology (Switzerland), 88 (6), pp. 360-368. 

DOI: 10.1159/000370117

a Alvin J. Siteman Cancer Center, Barnes-Jewish Hospital, Washington University School of Medicine in St. Louis, United States
b Departments of Otolaryngology - Head and Neck Surgery, Washington University, School of Medicine in St. Louis, 660 South Euclid Av., St. Louis, MO, United States
c Departments of Neurology, United States
d Departments of Radiology, United States
e Departments of Pediatrics, United States
f Departments of Anatomy and Neurobiology, United States
g Division of Medical Oncology, Department of Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO, United States

Abstract
Objectives: A common complaint of cancer patients is the experience of cognitive difficulty during and after chemotherapy. We hypothesized that cognitive impairment may result from dysfunction in large-scale brain networks, particularly those involved in attentional control. Methods: Using a case-control design, this study includes women with a history of invasive ductal or lobular triple-negative breast cancer who completed standard adjuvant chemotherapy within 2 years of study entry. Women who reported cognitive impairment by the Global Rating of Cognition question were considered to be cases (n = 15). Women who reported no cognitive impairment were considered to be controls (n = 13). All enrolled participants were eligible for MRI investigation and underwent resting-state functional connectivity MRI. Results: Women who self-reported cognitive impairment were found to have disrupted resting-state functional connectivity, as measured by MRI, when compared to women who did not self-report cognitive impairment. These findings suggest that some women may be more sensitive to the standard treatments for breast cancer and that this increased sensitivity may result in functional connectivity alterations in the brain networks supporting attention and executive function. Conclusions: Neuroimaging analyses confirmed self-reported cognitive deficits in women with breast cancer treated with chemotherapy. © 2015 S. Karger AG, Basel.

Author Keywords
Breast neoplasms;  Chemotherapy;  Cognitive disorders;  Complications;  Diagnostic imaging;  Neuroimaging


Document Type: Article
Source: Scopus


Kapoor, M.a , Agrawal, A.b
Commentary: Sex Differences in the Pathways to Symptoms of Alcohol Use Disorder: A Study of Opposite-Sex Twin Pairs
(2015) Alcoholism: Clinical and Experimental Research, 39 (6), pp. 950-952. 

DOI: 10.1111/acer.12736

a Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York City, NY, United States
b Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, United States


Document Type: Note
Source: Scopus


Friess, S.H.a , Lapidus, J.B.a , Brody, D.L.b
Decompressive Craniectomy Reduces White Matter Injury after Controlled Cortical Impact in Mice
(2015) Journal of Neurotrauma, 32 (11), pp. 791-800. 

DOI: 10.1089/neu.2014.3564

a Department of Pediatrics, Washington University, St. Louis School of Medicine, Campus Box 8028, 5th Floor MPRB 660 S. Euclid Avenue, St. Louis, MO, United States
b Department of Neurology, Washington University, St. Louis School of Medicine, St. Louis, MO, United States

Abstract
Abstract Reduction and avoidance of increases in intracranial pressure (ICP) after severe traumatic brain injury (TBI) continue to be the mainstays of treatment. Traumatic axonal injury is a major contributor to morbidity after TBI, but it remains unclear whether elevations in ICP influence axonal injury. Here we tested the hypothesis that reduction in elevations in ICP after experimental TBI would result in decreased axonal injury and white matter atrophy in mice. Six-week-old male mice (C57BL/6J) underwent either moderate controlled cortical impact (CCI) (n=48) or Sham surgery (Sham, n=12). Immediately after CCI, injured animals were randomized to a loose fitting plastic cap (Open) or replacement of the previously removed bone flap (Closed). Elevated ICP was observed in Closed animals compared with Open and Sham at 15 min (21.4±4.2 vs. 12.3±2.9 and 8.8±1.8 mm Hg, p<0.0001) and 1 day (17.8±3.7 vs. 10.6±2.0 and 8.9±1.9 mm Hg, p<0.0001) after injury. Beta amyloid precursor protein staining in the corpus callosum and ipsilateral external capsule revealed reduced axonal swellings and bulbs in Open compared with Closed animals (32% decrease, p<0.01 and 40% decrease, p<0.001 at 1 and 7 days post-injury, respectively). Open animals were also found to have decreased neurofilament-200 stained axonal swellings at 7 days post-injury compared with Open animals (32% decrease, p<0.001). At 4 weeks post-injury, Open animals had an 18% reduction in white matter volume compared with 34% in Closed animals (p<0.01). Thus, our results indicate that CCI with decompressive craniectomy was associated with reductions in ICP and reduced pericontusional axonal injury and white matter atrophy. If similar in humans, therapeutic interventions that ameliorate intracranial hypertension may positively influence white matter injury severity. © Copyright 2015, Mary Ann Liebert, Inc.

Author Keywords
Axonal injury;  Controlled cortical impact;  Intracranial pressure;  Traumatic brain injury;  White matter


Document Type: Article
Source: Scopus


Longbrake, E.E., Cross, A.H.
Dimethyl fumarate associated lymphopenia in clinical practice
(2015) Multiple Sclerosis, 21 (6), pp. 796-797. 

DOI: 10.1177/1352458514559299

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

Author Keywords
Dimethyl fumarate;  lymphopenia;  multiple sclerosis


Document Type: Letter
Source: Scopus


Anastasaki, C.a , Woo, A.S.b , Messiaen, L.M.c , Gutmann, D.H.a
Elucidating the impact of neurofibromatosis-1 germline mutations on neurofibromin function and dopamine-based learning
(2015) Human Molecular Genetics, 24 (12), art. no. ddv103, pp. 3518-3528. 

DOI: 10.1093/hmg/ddv103

a Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
b Department of Surgery, Washington University School of Medicine, St. Louis, MO, United States
c Department of Genetics, University of Alabama, Birmingham, Birmingham, AL, United States

Abstract
Neurofibromatosis type 1 (NF1) is a common autosomal dominant neurologic condition characterized by significant clinical heterogeneity, ranging from malignant cancers to cognitive deficits. Recent studies have begun to reveal rare genotype- phenotype correlations, suggesting that the specific germline NF1 gene mutation may be one factor underlying disease heterogeneity. The purpose of this study was to define the impact of the germline NF1 gene mutation on brain neurofibromin function relevant to learning. Herein, we employ human NF1-patient primary skin fibroblasts, induced pluripotent stem cells and derivative neural progenitor cells (NPCs) to demonstrate that NF1 germline mutations have dramatic effects on neurofibromin expression. Moreover, while all NF1-patient NPCs exhibit increased RAS activation and reduced cyclic AMP generation, there was a neurofibromin dose-dependent reduction in dopamine (DA) levels. Additionally, we leveraged two complementary Nf1 genetically-engineered mouse strains in which hippocampal-based learning and memory is DAdependent to establish that neuronal DA levels and signaling as well as mouse spatial learning are controlled in an Nf1 gene dose-dependent manner. Collectively, this is the first demonstration that different germline NF1 gene mutations differentially dictate neurofibromin function in the brain. © The Author 2015. Published by Oxford University Press. All rights reserved.


Document Type: Article
Source: Scopus


Arloth, J.a , Bogdan, R.c , Weber, P.a , Frishman, G.d , Menke, A.a , Wagner, K.V.j , Balsevich, G.j , Schmidt, M.V.j , Karbalai, N.a , Czamara, D.a , Altmann, A.i , Trümbach, D.d , Wurst, W.a d f g , Mehta, D.a , Uhr, M.a , Klengel, T.a , Erhardt, A.a , Carey, C.E.c , Conley, E.D.e , Ruepp, A.d , Müller-Myhsok, B.a , Hariri, A.R.b , Binder, E.B.a h
Genetic Differences in the Immediate Transcriptome Response to Stress Predict Risk-Related Brain Function and Psychiatric Disorders
(2015) Neuron, 86 (5), pp. 1189-1202. 

DOI: 10.1016/j.neuron.2015.05.034

a Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany
b Department of Psychology and Neuroscience, Institute for Genome Sciences and Policy, Duke University, Durham, NC, United States
c Department of Psychology, Washington University in St. Louis, St. Louis, MO, United States
d Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany
e 23 and Me, Mountain View, CA, United States
f Technische Universität München, C/o Helmholtz Zentrum München, German Research Centre for Environmental Health, Institute of Developmental Genetics, Neuherberg, Germany
g Deutsches Zentrum für Neurodegenerative Erkrankungen e. V. (DZNE), Site Munich, Munich, Germany
h Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, United States
i Department of Neurology and Neurological Sciences, School of Medicine, Stanford University, Palo Alto, CA, United States
j Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany

Abstract
Depression risk is exacerbated by genetic factors and stress exposure; however, the biological mechanisms through which these factors interact to confer depression risk are poorly understood. One putative biological mechanism implicates variability in the ability of cortisol, released in response to stress, to trigger a cascade of adaptive genomic and non-genomic processes through glucocorticoid receptor (GR) activation. Here, we demonstrate that common genetic variants in long-range enhancer elements modulate the immediate transcriptional response to GR activation in human blood cells. These functional genetic variants increase risk for depression and co-heritable psychiatric disorders. Moreover, these risk variants are associated with inappropriate amygdala reactivity, a transdiagnostic psychiatric endophenotype and an important stress hormone response trigger. Network modeling and animal experiments suggest that these genetic differences in GR-induced transcriptional activation may mediate the risk for depression and other psychiatric disorders by altering a network of functionally related stress-sensitive genes in blood and brain. © 2015 The Authors.


Document Type: Article
Source: Scopus


Macauley, S.L.a , Stanley, M.a , Caesar, E.E.a , Yamada, S.A.a , Raichle, M.E.a b , Perez, R.a , Mahan, T.E.a , Sutphen, C.L.a , Holtzman, D.M.a
Hyperglycemia modulates extracellular amyloid-β concentrations and neuronal activity in vivo
(2015) Journal of Clinical Investigation, 125 (6), pp. 2463-2467. 

DOI: 10.1172/JCI79742

a Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Campus Box 8111, 660 S. Euclid Avenue, St. Louis, MO, United States
b Department of Radiology, Washington University, School of Medicine, St. Louis, MO, United States

Abstract
Epidemiological studies show that patients with type 2 diabetes (T2DM) and individuals with a diabetes-independent elevation in blood glucose have an increased risk for developing dementia, specifically dementia due to Alzheimer's disease (AD). These observations suggest that abnormal glucose metabolism likely plays a role in some aspects of AD pathogenesis, leading us to investigate the link between aberrant glucose metabolism, T2DM, and AD in murine models. Here, we combined two techniques - glucose clamps and in vivo microdialysis - as a means to dynamically modulate blood glucose levels in awake, freely moving mice while measuring real-time changes in amyloid-β (Aβ), glucose, and lactate within the hippocampal interstitial fluid (ISF). In a murine model of AD, induction of acute hyperglycemia in young animals increased ISF Aβ production and ISF lactate, which serves as a marker of neuronal activity. These effects were exacerbated in aged AD mice with marked Aβ plaque pathology. Inward rectifying, ATP-sensitive potassium (K<inf>ATP</inf>) channels mediated the response to elevated glucose levels, as pharmacological manipulation of K<inf>ATP</inf> channels in the hippocampus altered both ISF Aβ levels and neuronal activity. Taken together, these results suggest that K<inf>ATP</inf> channel activation mediates the response of hippocampal neurons to hyperglycemia by coupling metabolism with neuronal activity and ISF Aβ levels.


Document Type: Article
Source: Scopus


Low, P.A.a , Reich, S.G.c , Jankovic, J.d , Shults, C.W.e , Stern, M.B.f , Novak, P.g , Tanner, C.M.h , Gilman, S.i , Marshall, F.J.j , Wooten, F.k , Racette, B.l m , Chelimsky, T.n , Singer, W.a , Sletten, D.M.a , Sandroni, P.a , Mandrekar, J.b
Natural history of multiple system atrophy in the USA: A prospective cohort study
(2015) The Lancet Neurology, 14 (7), pp. 710-719. 

DOI: 10.1016/S1474-4422(15)00058-7

a Department of Neurology, Mayo Clinic, Rochester, MN, United States
b Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, United States
c Department of Neurology, University of Maryland School of Medicine, Baltimore, MD, United States
d Department of Neurology, Baylor College of Medicine, Houston, TX, United States
e Department of Neurosciences, University of California, San Diego, La Jolla, CA, United States
f Parkinson's Disease and Movement Disorders Center, Pennsylvania Hospital, Philadelphia, PA, United States
g Department of Neurology, University of Massachusetts, Worcester, MA, United States
h Department of Neurology, University of California, San Francisco, CA, United States
i Department of Neurology, University of Michigan, Ann Arbor, MI, United States
j Department of Neurology, University of Rochester, Rochester, NY, United States
k Department of Neurology, University of Virginia Health System, Charlottesville, VA, United States
l Department of Neurology, Washington University School of Medicine, St Louis, MO, United States
m School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Parktown, South Africa
n Department of Neurology, Medical College of Wisconsin, Milwaukee, WI, United States

Abstract
Background: Multiple system atrophy is a rare, fatal neurodegenerative disorder with symptoms of autonomic failure plus parkinsonism, cerebellar ataxia, or both. We report results of the first prospective natural history study of multiple system atrophy in the USA, and the effects of phenotype and autonomic failure on prognosis. Methods: We recruited participants with probable multiple system atrophy-of either the parkinsonism subtype (MSA-P) or the cerebellar ataxia subtype (MSA-C)-at 12 neurology centres in the USA specialising in movement or autonomic disorders. We followed up patients every 6 months for 5 years and assessed them with the Unified Multiple System Atrophy Rating Scale part I (UMSARS I; a functional score of symptoms and ability to undertake activities of daily living), UMSARS II (neurological motor evaluation), and the Composite Autonomic Symptoms Scale (COMPASS)-select (a measure of autonomic symptoms and autonomic functional status). We assessed potential predictors of outcome. We used Cox proportional hazards models to calculate univariate hazard ratios for shorter survival using age at disease onset as a continuous variable and sex, clinical phenotype, and early development of neurological and autonomic manifestations as categorical variables. Findings: We recruited 175 participants. Mean age at study entry was 63·4 years (SD 8·6). Median survival from symptom onset was 9·8 years (95% CI 8·8-10·7) and median survival from enrolment was 1·8 years (0·9-2·7). Participants with severe symptomatic autonomic failure (symptomatic orthostatic hypotension, urinary incontinence, or both) at diagnosis (n=62) had a worse prognosis than those without severe disease (n=113; median survival 8·0 years, 95% CI 6·5-9·5 vs 10·3 years, 9·3-11·4; p=0·021). At baseline, patients with MSA-P (n=126) and MSA-C (n=49) had much the same symptoms and functional status: mean UMSARS I 25·2 (SD 8·08) versus 24·6 (8·34; p=0·835); mean UMSARS II 26·4 (8·8) versus 25·4 (10·5; p=0·764); COMPASS-select 43·5 (18·7) versus 42·8 (19·6; p=0·835). Progression over 5 years, assessed by change in UMSARS I, UMSARS II, and COMPASS-select, was modest. Interpretation: Probable multiple system atrophy is a late-stage disease with short survival. The natural histories of MSA-P and MSA-C are similar and severe symptomatic autonomic failure at diagnosis is associated with worse prognosis. Funding: US National Institutes of Health, Mayo Clinic, and Kathy Shih Memorial Foundation. © 2015 Elsevier Ltd.


Document Type: Article
Source: Scopus


Iacovino, J.M., Bogdan, R., Oltmanns, T.F.
Personality Predicts Health Declines Through Stressful Life Events During Late Mid-Life
(2015) Journal of Personality, . Article in Press. 

DOI: 10.1111/jopy.12179

Washington University in St. Louis

Abstract
Personality predicts the occurrence of dependent stressful life events (SLE; i.e., events reliant, at least in part, on an individual's behavior). This process, termed stress generation, contributes to psychiatric outcomes, but its role in physical health is unknown. Data were included from 998 participants (aged 55-64) in the St. Louis Personality and Aging Network (SPAN) study. Assessments occurred every 6 months for 18 months. Neuroticism, impulsivity, and agreeableness were measured with the Revised NEO Personality Inventory. Dependent (e.g., divorce) and independent (e.g., family death) SLE occurring within 6 months following baseline were assessed with the List of Threatening Experiences and confirmed by interviews. Health problems occurring within a year after SLE were the outcome. Analyses examined whether neuroticism, impulsivity, and agreeableness indirectly predict the onset of new health problems through exposure to dependent SLE. Each personality trait was associated with dependent, but not independent, SLE. Only dependent SLE predicted new health problems. Each personality trait indirectly predicted the onset of new health problems through dependent SLE. Findings suggest that personality-driven stress generation influences physical health during late mid-life. Addressing personality in interventions may reduce the occurrence of SLE, in turn decreasing health risks. © 2015 Wiley Periodicals, Inc.


Document Type: Article in Press
Source: Scopus


Van Essen, D.C.a , Barch, D.M.b
The human connectome in health and psychopathology
(2015) World Psychiatry, 14 (2), pp. 154-157. Cited 1 time.

DOI: 10.1002/wps.20228

a Department of Anatomy and Neurobiology, Washington University, St. Louis, MO, United States
b Departments of Psychology, Psychiatry, and Radiology, Washington University, St. Louis, MO, United States


Document Type: Review
Source: Scopus


Qualls, D.a , Leonard, J.R.a c , Keller, M.a b , Pineda, J.a b , Leonard, J.C.a c
Utility of magnetic resonance imaging in diagnosing cervical spine injury in children with severe traumatic brain injury
(2015) Journal of Trauma and Acute Care Surgery, 78 (6), pp. 1122-1128. 

DOI: 10.1097/TA.0000000000000646

a Washington University in St. Louis School of Medicine, St. Louis, MO, United States
b St. Louis Children's Hospital, St. Louis, MO, United States
c Nationwide Children's Hospital, Ohio State University College of Medicine, 700 Children's Drive, RB III, Columbus, United States

Abstract
BACKGROUND Evaluation of children for cervical spine injuries (CSIs) after blunt trauma is complicated, particularly if the patient is unresponsive because of severe traumatic brain injury. Plain radiography and computed tomography (CT) are commonly used, but CT combined with magnetic resonance imaging (MRI) is still considered the gold standard in CSI detection. However, MRI is expensive and can delay cervical clearance. The purpose of this study is to determine the added benefit of MRI as an adjunct to CT in the clearance of children with severe head trauma. METHODS We performed a retrospective chart review of pediatric head trauma patients admitted to the pediatric intensive care unit at St. Louis Children's Hospital from 2002 to 2012. Patients who received both cervical spine CT and MRI and presented with a Glasgow Coma Scale score of 8 or lower were included in the study. Imaging was analyzed by two pediatric trauma subspecialists and classified as demonstrating "no injury," "stable injury," or "unstable injury." Results were compared, and discrepancies between CT and MRI findings were noted. RESULTS A total of 1,196 head-injured children were admitted to the pediatric intensive care unit between January 2002 and December 2012. Sixty-three children underwent CT and MRI and met Glasgow Coma Scale criteria. Seven children were identified with negative CT and positive MRI findings, but none of these injuries were considered unstable by our criteria. Five children were determined to have unstable injuries, and all were detected on CT. CONCLUSION The results of this study suggest that MRI does not detect unstable CSIs in the setting of negative CT imaging. Given the limited patient population for this study, further and more extensive studies investigating the utility of MRI in the head-injured pediatric patient are warranted. © Copyright 2015 Wolters Kluwer Health, Inc. All rights reserved.

Author Keywords
cervical clearance;  cervical spine injury;  magnetic resonance imaging;  Pediatric;  traumatic brain injury


Document Type: Conference Paper
Source: Scopus

 

June 1, 2015

Criswell, S.R.a , Nelson, G.b , Gonzalez-Cuyar, L.F.c , Huang, J.d , Shimony, J.S.e , Checkoway, H.f , Simpson, C.D.g , Dills, R.g , Seixas, N.S.g , Racette, B.A.a b
Ex vivo magnetic resonance imaging in South African manganese mine workers
(2015) NeuroToxicology, 49, pp. 8-14. 

DOI: 10.1016/j.neuro.2015.04.002


a Department of Neurology, Washington University School of Medicine, 660 South Euclid Ave., Box 8111, St. Louis, MO, United States
b School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, 27 St Andrews Rd, Parktown, South Africa
c Department of Pathology, University of Washington, UW Medicine Pathology, Box 357470, Seattle, WA, United States
d Washington University School of Medicine, 4444 Forest Park Ave., Suite 1101, Box 8502, St. Louis, MO, United States
e Department of Radiology, Washington University School of Medicine, 660 South Euclid Ave., Box 8131, St. Louis, MO, United States
f Department of Family Medicine and Public Health, UC San Diego School of Medicine, 9500 Gilman Drive-0628, La Jolla, CA, United States
g Department of Environmental and Occupational Health Sciences, University of Washington, School of Public Health, Box 357234, Seattle, WA, United States


Abstract
Background: Manganese (Mn) exposure is associated with increased T1-weighted magnetic resonance imaging (MRI) signal in the basal ganglia. T1 signal intensity has been correlated with occupational Mn exposure but not with clinical symptomatology or neuropathology. Objectives: This study investigated predictors of ex vivo T1 MRI basal ganglia signal intensity in neuropathologic tissue obtained from deceased South African mine workers. Methods: A 3.0. T MRI was performed on ex vivo brain tissue obtained from 19 Mn mine workers and 10 race- and sex-matched mine workers of other commodities. Basal ganglia regions of interest were identified for each subject with T1-weighted intensity indices generated for each region. In a pathology subset, regional T1 indices were compared to neuronal and glial cell density and tissue metal concentrations. Results: Intensity indices were higher in Mn mine workers than non-Mn mine workers for the globus pallidus, caudate, anterior putamen, and posterior putamen with the highest values in subjects with the longest cumulative Mn exposure. Intensity indices were inversely correlated with the neuronal cell density in the caudate (p=. 0.040) and putamen (p=. 0.050). Tissue Mn concentrations were similar in Mn and non-Mn mine workers. Tissue iron (Fe) concentration trended lower across all regions in Mn mine workers. Conclusions: Mn mine workers demonstrated elevated basal ganglia T1 indices when compared to non-Mn mine workers. Predictors of ex vivo T1 MRI signal intensity in Mn mine workers include duration of Mn exposure and neuronal density. © 2015 Elsevier Inc.


Author Keywords
Ex vivo;  Manganese;  Miners;  MRI


Document Type: Article
Source: Scopus




Sheffield, J.M.a , Repovs, G.d , Harms, M.P.b , Carter, C.S.e , Gold, J.M.f , MacDonald, A.W., IIIg , Daniel Ragland, J.e , Silverstein, S.M.h i , Godwin, D.j , Barch, D.M.a b c
Fronto-parietal and cingulo-opercular network integrity and cognition in health and schizophrenia
(2015) Neuropsychologia, 73, pp. 82-93. 

DOI: 10.1016/j.neuropsychologia.2015.05.006


a Washington University in St Louis, Department of Psychology, United States
b Washington University in St Louis, Departments of Psychiatry, United States
c Washington University in St Louis, Department of Radiology, United States
d University of Ljubljana, Department of Psychiatry and Behavioral Science, Slovenia
e University of California at Davis, Department of Psychiatry and Behavioral Sciences, United States
f Maryland Psychiatric Research Center, Department of Psychiatry, United States
g University of Minnesota, Department of Psychology, United States
h Rutgers, The State University of New Jersey, University Behavioral Health Care, United States
i Rutgers Robert Wood Johnson Medical School, Department of Psychiatry, United States
j Vanderbilt University, Department of Psychology, United States


Abstract
Growing evidence suggests that coordinated activity within specific functional brain networks supports cognitive ability, and that abnormalities in brain connectivity may underlie cognitive deficits observed in neuropsychiatric diseases, such as schizophrenia. Two functional networks, the fronto-parietal network (FPN) and cingulo-opercular network (CON), are hypothesized to support top-down control of executive functioning, and have therefore emerged as potential drivers of cognitive impairment in disease-states. Graph theoretic analyses of functional connectivity data can characterize network topology, allowing the relationships between cognitive ability and network integrity to be examined. In the current study we applied graph analysis to pseudo-resting state data in 54 healthy subjects and 46 schizophrenia patients, and measured overall cognitive ability as the shared variance in performance from tasks of episodic memory, verbal memory, processing speed, goal maintenance, and visual integration. We found that, across all participants, cognitive ability was significantly positively associated with the local and global efficiency of the whole brain, FPN, and CON, but not with the efficiency of a comparison network, the auditory network. Additionally, the participation coefficient of the right anterior insula, a major hub within the CON, significantly predicted cognition, and this relationship was independent of CON global efficiency. Surprisingly, we did not observe strong evidence for group differences in any of our network metrics. These data suggest that functionally efficient task control networks support better cognitive ability in both health and schizophrenia, and that the right anterior insula may be a particularly important hub for successful cognitive performance across both health and disease. © 2015 Elsevier Ltd.


Author Keywords
Executive control;  Functional brain networks;  Graph theory;  Schizophrenia


Document Type: Article
Source: Scopus




Henriksson, L.a b , Khaligh-Razavi, S.-M.a c , Kay, K.d , Kriegeskorte, N.a
Visual representations are dominated by intrinsic fluctuations correlated between areas
(2015) NeuroImage, 114, pp. 275-286. 

DOI: 10.1016/j.neuroimage.2015.04.026


a MRC Cognition and Brain Sciences Unit, Cambridge, United Kingdom
b Brain Research Unit, Department of Neuroscience and Biomedical Engineering, Aalto University, Espoo, Finland
c Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, United States
d Department of Psychology, Washington University in St. Louis, St. Louis, MO, United States


Abstract
Intrinsic cortical dynamics are thought to underlie trial-to-trial variability of visually evoked responses in animal models. Understanding their function in the context of sensory processing and representation is a major current challenge. Here we report that intrinsic cortical dynamics strongly affect the representational geometry of a brain region, as reflected in response-pattern dissimilarities, and exaggerate the similarity of representations between brain regions. We characterized the representations in several human visual areas by representational dissimilarity matrices (RDMs) constructed from fMRI response-patterns for natural image stimuli. The RDMs of different visual areas were highly similar when the response-patterns were estimated on the basis of the same trials (sharing intrinsic cortical dynamics), and quite distinct when patterns were estimated on the basis of separate trials (sharing only the stimulus-driven component). We show that the greater similarity of the representational geometries can be explained by coherent fluctuations of regional-mean activation within visual cortex, reflecting intrinsic dynamics. Using separate trials to study stimulus-driven representations revealed clearer distinctions between the representational geometries: a Gabor wavelet pyramid model explained representational geometry in visual areas V1-3 and a categorical animate-inanimate model in the object-responsive lateral occipital cortex. © 2015.


Author Keywords
Functional MRI;  Intrinsic dynamics;  Natural images;  Pattern information;  Representational similarity;  Visual cortex


Document Type: Article
Source: Scopus




Sun, T.a , Plutynski, A.b , Ward, S.a , Rubin, J.B.a c d
An integrative view on sex differences in brain tumors
(2015) Cellular and Molecular Life Sciences, 20 p. Article in Press. 

DOI: 10.1007/s00018-015-1930-2


a Department of Pediatrics, Washington University School of Medicine, St Louis, United States
b Department of Philosophy, Washington University in St Louis, St Louis, United States
c Department of Anatomy and Neurobiology, Washington University School of Medicine, 660 South Euclid Ave, St Louis, MO, United States
d Campus Box 8208, 660 South Euclid Ave, St Louis, MO, United States


Abstract
Sex differences in human health and disease can range from undetectable to profound. Differences in brain tumor rates and outcome are evident in males and females throughout the world and regardless of age. These observations indicate that fundamental aspects of sex determination can impact the biology of brain tumors. It is likely that optimal personalized approaches to the treatment of male and female brain tumor patients will require recognizing and understanding the ways in which the biology of their tumors can differ. It is our view that sex-specific approaches to brain tumor screening and care will be enhanced by rigorously documenting differences in brain tumor rates and outcomes in males and females, and understanding the developmental and evolutionary origins of sex differences. Here we offer such an integrative perspective on brain tumors. It is our intent to encourage the consideration of sex differences in clinical and basic scientific investigations. © 2015 The Author(s)


Author Keywords
Cancer;  Evolution;  Immunity;  Metabolism;  Sex determination;  Sexual dimorphism


Document Type: Article in Press
Source: Scopus




Reeder, R.M., Cadieux, J., Firszt, J.B.
Quantification of Speech-in-Noise and Sound Localisation Abilities in Children with Unilateral Hearing Loss and Comparison to Normal Hearing Peers
(2015) Audiology and Neurotology, pp. 31-37. Article in Press. 

DOI: 10.1159/000380745


Department of Otolaryngology, Head and Neck Surgery, Washington University School of Medicine, St. Louis, Mo., USA


Abstract
The study objective was to quantify abilities of children with unilateral hearing loss (UHL) on measures that address known deficits for this population, i.e. speech understanding in quiet and noise, and sound localisation. Noise conditions varied by noise type and source location. Parent reports of real-world abilities were also obtained. Performance was compared to gender- and age-matched normal hearing (NH) peers. UHL performance was poorer and more varied compared to NH peers. Among the findings, age correlated with localisation ability for UHL but not NH participants. Low-frequency hearing in the better ear of UHL children was associated with performance in noise; however, there was no relation for NH children. Considerable variability was evident in the outcomes of children with UHL and needs to be understood as future treatment options are considered. © 2015 S. Karger AG, Basel Copyright © 2015, S. Karger AG. All rights reserved.


Document Type: Article in Press
Source: Scopus




Godzik, J.a , Dardas, A.b , Kelly, M.P.c , Holekamp, T.F.b , Lenke, L.G.c , Smyth, M.D.b d , Park, T.S.b d , Leonard, J.R.b d , Limbrick, D.D.b d
Comparison of spinal deformity in children with Chiari I malformation with and without syringomyelia: matched cohort study
(2015) European Spine Journal, 8 p. Article in Press. 

DOI: 10.1007/s00586-015-4011-1


a Department of Neurosurgery, Barrow Neurological Institute, 350 W. Thomas Road, Phoenix, AZ, United States
b Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO, United States
c Department of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, MO, United States
d Department of Pediatric Neurosurgery, St. Louis Children’s Hospital, St. Louis, MO, United States


Abstract
Purpose: To describe curve patterns in patients with Chiari malformation I (CIM) without syringomyelia, and compare to patients with Chiari malformation with syringomyelia (CIM + SM). Methods: Review of medical records from 2000 to 2013 at a single institution was performed to identify CIM patients with scoliosis. Patients with CIM were matched (1:1) by age and gender to CIM + SM. Radiographic curve patterns, MRI-based craniovertebral junction parameters, and associated neurological signs were compared between the two cohorts. Results: Eighteen patients with CIM-associated scoliosis in the absence of syringomyelia were identified; 14 (78 %) were female, with mean age of 11.5 ± 4.5 years. Mean tonsillar descent was 9.9 ± 4.1 mm in the CIM group and 9.1 ± 3.0 mm in the CIM + SM group (p = 0.57). Average syrinx diameter in the CIM + SM group was 9.0 ± 2.7 mm. CIM patients demonstrated less severe scoliotic curves (32.1° vs. 46.1°, p = 0.04), despite comparable thoracic kyphosis (43.7° vs. 49.6°, p = 0.85). Two (11 %) patients with CIM demonstrated thoracic apex left deformities compared to 9/18 (50 %) in the CIM + SM cohort (p = 0.01). Neurological abnormalities were only observed in the group with syringomyelia (6/18, or 33 %; p = 0.007). Conclusion: In the largest series specifically evaluating CIM and scoliosis, we found that these patients appear to present with fewer atypical curve features, with less severe scoliotic curves, fewer apex left curves, and fewer related neurological abnormalities than CIM + SM. Notably, equivalent thoracic kyphosis was observed in both groups. Future studies are needed to better understand pathogenesis of spinal deformity in CIM with and without SM. © 2015 Springer-Verlag Berlin Heidelberg


Author Keywords
Chiari malformation;  Kyphosis;  Scoliosis;  Spinal deformity;  Syringomyelia


Document Type: Article in Press
Source: Scopus




Nobuta, H.a e , Cilio, M.R.a b , Danhaive, O.a , Tsai, H.-H.a e , Tupal, S.f , Chang, S.M.a e , Murnen, A.a , Kreitzer, F.g , Bravo, V.g , Czeisler, C.i , Gokozan, H.N.i , Gygli, P.i , Bush, S.i , Weese-Mayer, D.E.j , Conklin, B.c g , Yee, S.-P.h , Huang, E.J.d , Gray, P.A.f , Rowitch, D.a c e , Otero, J.J.a d e i
Dysregulation of locus coeruleus development in congenital central hypoventilation syndrome
(2015) Acta Neuropathologica, 13 p. Article in Press. 

DOI: 10.1007/s00401-015-1441-0


a Department of Pediatrics, University of California San Francisco, 35 Medical Center Way, San Francisco, CA, United States
b Department of Neurology, University of California San Francisco, 35 Medical Center Way, San Francisco, CA, United States
c Department of Medicine, University of California San Francisco, 35 Medical Center Way, San Francisco, CA, United States
d Department of Pathology, University of California San Francisco, 35 Medical Center Way, San Francisco, CA, United States
e Department of Howard Hughes Medical Institute, University of California San Francisco, 35 Medical Center Way, San Francisco, CA, United States
f Department of Anatomy and Neurobiology, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, MO, United States
g Gladstone Institutes, 1650 Owens Street, San Francisco, CA, United States
h Department of Genetics and Developmental Biology, University of Connecticut Health Center, 263 Farmington Ave, Farmington, CT, United States
i Department of Pathology, The Ohio State University College of Medicine, 4169 Graves Hall, 333 W 10th Ave, Columbus, OH, United States
j Center for Autonomic Medicine in Pediatrics (CAMP), Ann and Robert H. Lurie Children’s Hospital of Chicago and Stanley Manne Children’s Research Institute, Northwestern University Feinberg School of Medicine, 225 East Chicago Avenue, Box 165, Chicago, IL, United States


Abstract
Human congenital central hypoventilation syndrome (CCHS), resulting from mutations in transcription factor PHOX2B, manifests with impaired responses to hypoxemia and hypercapnia especially during sleep. To identify brainstem structures developmentally affected in CCHS, we analyzed two postmortem neonatal-lethal cases with confirmed polyalanine repeat expansion (PARM) or Non-PARM (PHOX2B?8) mutation of PHOX2B. Both human cases showed neuronal losses within the locus coeruleus (LC), which is important for central noradrenergic signaling. Using a conditionally active transgenic mouse model of the PHOX2B?8 mutation, we found that early embryonic expression (<E10.5) caused failure of LC neuronal specification and perinatal respiratory lethality. In contrast, later onset (E11.5) of PHOX2B?8 expression was not deleterious to LC development and perinatal respiratory lethality was rescued, despite failure of chemosensor retrotrapezoid nucleus formation. Our findings indicate that early-onset mutant PHOX2B expression inhibits LC neuronal development in CCHS. They further suggest that such mutations result in dysregulation of central noradrenergic signaling, and therefore, potential for early pharmacologic intervention in humans with CCHS. © 2015 The Author(s)


Author Keywords
Congenital central hypoventilation syndrome;  Locus coeruleus;  Noradrenergic system;  PHOX2B


Document Type: Article in Press
Source: Scopus




Nemanich, S.T.a , Earhart, G.M.a b c
Prism adaptation in Parkinson disease: comparing reaching to walking and freezers to non-freezers
(2015) Experimental Brain Research, 10 p. Article in Press. 

DOI: 10.1007/s00221-015-4299-4


a Program in Physical Therapy, Washington University School of Medicine in St. Louis, 4444 Forest Park Blvd., Campus Box 8502, St. Louis, MO, United States
b Anatomy and Neurobiology, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
c Neurology, Washington University School of Medicine in St. Louis, St. Louis, MO, United States


Abstract
Visuomotor adaptation to gaze-shifting prism glasses requires recalibration of the relationship between sensory input and motor output. Healthy individuals flexibly adapt movement patterns to many external perturbations; however, individuals with cerebellar damage do not adapt movements to the same extent. People with Parkinson disease (PD) adapt normally, but exhibit reduced after-effects, which are negative movement errors following the removal of the prism glasses and are indicative of true spatial realignment. Walking is particularly affected in PD, and many individuals experience freezing of gait (FOG), an episodic interruption in walking, that is thought to have a distinct pathophysiology. Here, we examined how individuals with PD with (PD + FOG) and without (PD − FOG) FOG, along with healthy older adults, adapted both reaching and walking patterns to prism glasses. Participants completed a visually guided reaching and walking task with and without rightward-shifting prism glasses. All groups adapted at similar rates during reaching and during walking. However, overall walking adaptation rates were slower compared to reaching rates. The PD − FOG group showed smaller after-effects, particularly during walking, compared to PD + FOG, independent of adaptation magnitude. While FOG did not appear to affect characteristics of prism adaptation, these results support the idea that the distinct neural processes governing visuomotor adaptation and storage are differentially affected by basal ganglia dysfunction in PD. © 2015 Springer-Verlag Berlin Heidelberg


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


Document Type: Article in Press
Source: Scopus




Kudesia, R.S., Baer, M., Elfenbein, H.A.
A wandering mind does not stray far from home: The value of metacognition in distant search
(2015) PLoS ONE, 10 (5), art. no. e0126865, . 

DOI: 10.1371/journal.pone.0126865


Department of Organizational Behavior, Olin Business School, Washington University in St. Louis, St. Louis, MO, United States


Abstract
When faced with a problem, how do individuals search for potential solutions? In this article, we explore the cognitive processes that lead to local search (i.e., identifying options closest to existing solutions) and distant search (i.e., identifying options of a qualitatively different nature than existing solutions). We suggest that mind wandering is likely to lead to local search because it operates by spreading activation from initial ideas to closely associated ideas. This reduces the likelihood of accessing a qualitatively different solution. However, instead of getting lost in thought, individuals can also step back and monitor their thoughts from a detached perspective. Such mindful metacognition, we suggest, is likely to lead to distant search because it redistributes activation away from initial ideas to other, less strongly associated, ideas. This hypothesis was confirmed across two studies. Thus, getting lost in thoughts is helpful when one is on the right track and needs only a local search whereas stepping back from thoughts is helpful when one needs distant search to produce a change in perspective. © 2015 Kudesia et al.


Document Type: Article
Source: Scopus




Bouhlel, A.a , Zhou, D.a , Li, A.a , Yuan, L.b , Rich, K.M.b , McConathy, J.a
Synthesis, radiolabeling, and biological evaluation of (R)- and (S)-2-amino-5-[18F]fluoro-2-methylpentanoic acid ((R)-, (S)-[18F]FAMPe) as potential positron emission tomography tracers for brain tumors
(2015) Journal of Medicinal Chemistry, 58 (9), pp. 3817-3829. 

DOI: 10.1021/jm502023y


a Department of Radiology, Washington University in Saint Louis, School of Medicine, St. Louis, MO, United States
b Department of Neurosurgery, Washington University in Saint Louis, School of Medicine, St. Louis, MO, United States


Abstract
A novel 18F-labeled α,α-disubstituted amino acid-based tracer, 2-amino-5-[18F]fluoro-2-methylpentanoic acid ([18F]FAMPe), has been developed for brain tumor imaging with a longer alkyl side chain than previously reported compounds to increase brain availability via system L amino acid transport. Both enantiomers of [18F]FAMPe were obtained in good radiochemical yield (24-52% n = 8) and high radiochemical purity (>99%). In vitro uptake assays in mouse DBT gliomas cells revealed that (S)-[18F]FAMPe enters cells partly via sodium-independent system L transporters and also via other nonsystem A transport systems including transporters that recognize glutamine. Biodistribution and small animal PET/CT studies in the mouse DBT model of glioblastoma showed that both (R)- and (S)-[18F]FAMPe have good tumor imaging properties with the (S)-enantiomer providing higher tumor uptake and tumor to brain ratios. Comparison of the SUVs showed that (S)-[18F]FAMPe had higher tumor to brain ratios compared to (S)-[18F]FET, a well-established system L substrate. © 2015 American Chemical Society.


Document Type: Article
Source: Scopus




Kaur, T.a , Hirose, K.a , Rube, E.W.b , Warchol, M.E.a
Macrophage recruitment and epithelial repair following hair cell injury in the mouse utricle
(2015) Frontiers in Cellular Neuroscience, 9 (APR), 9 p. 

DOI: 10.33S9/fncel.2015.00150


a Department of Otolaryngology, Washington University School of Medicine, St. Louis, MO, United States
b The Virginia Merrill Bloedel Hearing Research Center, Department of Otolaryngology-Head and Neck Surgery, University of Washington School of Medicine, Seattle, WA, United States


Abstract
The sensory organs of the inner ear possess resident populations of macrophages, but the function of those cells is poorly understood. In many tissues, macrophages participate in the removal of cellular debris after injury and can also promote tissue repair. The present study examined injury-evoked macrophage activity in the mouse utricle. Experiments used transgenic mice in which the gene for the human diphtheria toxin receptor (huDTR) was inserted under regulation of the Pou4f3 promoter. Hair cells in such mice can be selectively lesioned by systemic treatment with diphtheria toxin (DT). In order to visualize macrophages, Pou4f3-huDTR mice were crossed with a second transgenic line, in which one or both copies of the gene for the fractalkine receptor CX3CR1 were replaced with a gene for GFP. Such mice expressed GFP in all macrophages, and mice that were CX3CR1GFP/GFP lacked the necessary receptor for fractalkine signaling. Treatment with DT resulted in the death of ~70% of utricular hair cells within 7 days, which was accompanied by increased numbers of macrophages within the utricular sensory epithelium. Many of these macrophages appeared to be actively engulfing hair cell debris, indicating that macrophages participate in the process of 'corpse removal' in the mammalian vestibular organs. However, we observed no apparent differences in injury-evoked macrophage numbers in the utricles of CX3CR1+/GFP mice vs. CX3CR1GFP/GFP mice, suggesting that fractalkine signaling is not necessary for macrophage recruitment in these sensory organs. Finally, we found that repair of sensory epithelia at short times after DT-induced hair cell lesions was mediated by relatively thin cables of F-actin. After 56 days recovery, however, all cell-cell junctions were characterized by very thick actin cables. © 2015, Frontiers Research Foundation. All rights reserved.


Author Keywords
Auditory;  Hair cell;  Neuroimmunology;  Ototoxicity;  Vestbular


Document Type: Article
Source: Scopus




Sharma, A., Chatterjee, A., Goyal, M., Parsons, M.S., Bartel, S.
Location of core diagnostic information across various sequences in brain MRI and implications for efficiency of MRI scanner utilization
(2015) AJR. American journal of roentgenology, 204 (4), pp. 804-809. 

DOI: 10.2214/AJR.14.13494


1 Mallinckrodt Institute of Radiology, Washington University School of Medicine, Campus Box 8131, 510 S Kingshighway Blvd, St. Louis, MO 63110


Abstract
OBJECTIVE: Targeting redundancy within MRI can improve its cost-effective utilization. We sought to quantify potential redundancy in our brain MRI protocols.

MATERIALS AND METHODS: In this retrospective review, we aggregated 207 consecutive adults who underwent brain MRI and reviewed their medical records to document clinical indication, core diagnostic information provided by MRI, and its clinical impact. Contributory imaging abnormalities constituted positive core diagnostic information whereas absence of imaging abnormalities constituted negative core diagnostic information. The senior author selected core sequences deemed sufficient for extraction of core diagnostic information. For validating core sequences selection, four readers assessed the relative ease of extracting core diagnostic information from the core sequences. Potential redundancy was calculated by comparing the average number of core sequences to the average number of sequences obtained.

RESULTS: Scanning had been performed using 9.4±2.8 sequences over 37.3±12.3 minutes. Core diagnostic information was deemed extractable from 2.1±1.1 core sequences, with an assumed scanning time of 8.6±4.8 minutes, reflecting a potential redundancy of 74.5%±19.1%. Potential redundancy was least in scans obtained for treatment planning (14.9%±25.7%) and highest in scans obtained for follow-up of benign diseases (81.4%±12.6%). In 97.4% of cases, all four readers considered core diagnostic information to be either easily extractable from core sequences or the ease to be equivalent to that from the entire study. With only one MRI lacking clinical impact (0.48%), overutilization did not seem to contribute to potential redundancy.

CONCLUSION: High potential redundancy that can be targeted for more efficient scanner utilization exists in brain MRI protocols.


Author Keywords
cost-effectiveness;  health care costs;  MRI;  neuroimaging;  resource utilization


Document Type: Article
Source: Scopus




Lenze, S.N., Rodgers, J., Luby, J.
A pilot, exploratory report on dyadic interpersonal psychotherapy for perinatal depression
(2015) Archives of Women's Mental Health, 18 (3), art. no. 503, pp. 485-491. 

DOI: 10.1007/s00737-015-0503-6


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


Abstract
Perinatal depression is a major public health burden impacting both mothers and their offspring. The purpose of this study was to develop and test the acceptability and feasibility of a novel psychotherapeutic intervention that integrates an evidence-based intervention for depression, interpersonal psychotherapy (IPT), with postpartum dyadic psychotherapy focused on emotional development in the context of the mother-infant relationship. Nine women between 12 and 30 weeks gestation with Edinburgh Depression Scale (EDS) scores >12 were entered into treatment. Three out of nine women dropped out of the study after initiating treatment (one lost to follow-up antepartum; two lost to follow-up postpartum). Seven out of eight women (87 %) reported clinically significant improvements in EDS scores from baseline to 37–39 weeks gestation, and all women had clinically significant improvements at 12 months postpartum. A small randomized controlled trial is underway to further examine the feasibility and acceptability of the intervention. © 2015, Springer-Verlag Wien.


Author Keywords
Depression;  Interpersonal psychotherapy;  Mother-infant interactions;  Postpartum;  Pregnancy


Document Type: Article
Source: Scopus




Liewluck, T.a , Tian, X.b , Wong, L.-J.b , Pestronk, A.c
Dystrophinopathy mimicking metabolic myopathies
(2015) Neuromuscular Disorders, . Article in Press. 

DOI: 10.1016/j.nmd.2015.04.001


a Department of Neurology, Anschutz Medical Campus, Mail Stop B-185, 12631 East 17th Avenue, University of Colorado School of Medicine, Aurora, Colorado 80045, USA
b Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, NAB 2015, Houston, Texas 77030, USA
c Department of Neurology, Washington University School of Medicine, Campus Box8111, 660 South Euclid Avenue, St. Louis, Missouri 63110, USA


Abstract
Recurrent rhabdomyolysis warrants comprehensive evaluations to search for underlying muscle diseases, including metabolic myopathies, LPIN1-myopathy, RYR1-myopathy, and less commonly muscular dystrophies. The absence of weakness and the normal or minimally elevated creatine kinase levels between attacks are typical of metabolic myopathies, LPIN1-myopathy, and RYR1-myopathy, while the presence of weakness and the highly elevated creatine kinase levels between attacks point toward muscular dystrophies. Here we report a 32-year-old man with a one-year history of recurrent rhabdomyolysis, who had normal strength, slightly elevated baseline creatine kinase level, and normal muscle histopathology. All workups for metabolic myopathies, LPIN1-myopathy and RYR1-myopathy were unrevealing. Next generation sequencing of muscular dystrophy-related genes revealed a hemizygous deletion of exons 17-34 of the dystrophin-encoding gene. Immunohistochemical study revealed absent staining for the rod domain of dystrophin. Dystrophinopathy should be considered in patients with recurrent rhabdomyolysis despite the absence of fixed weakness or highly elevated resting creatine kinase level. © 2015 Elsevier B.V.


Author Keywords
Becker muscular dystrophy;  Dystrophin;  Dystrophinopathy;  Metabolic myopathy;  Rhabdomyolysis


Document Type: Article in Press
Source: Scopus




Sun, S.Q.a , Hawasli, A.H.b , Huang, J.c , Chicoine, M.R.b , Kim, A.H.b
An evidence-based treatment algorithm for the management of WHO Grade II and III meningiomas
(2015) Neurosurgical Focus, 38 (3), art. no. E3, . 

DOI: 10.3171/2015.1.FOCUS14757


a Washington University School of Medicine, St. Louis, MO, United States
b Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO, United States
c Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, United States


Abstract
The management of WHO Grade II "atypical" meningiomas (AMs) and Grade III "malignant" meningiomas (MMs) remains controversial and under-investigated in prospective studies. The roles of surgery, radiation therapy, radiosurgery, and chemotherapy have been incompletely delineated. This has left physicians to decipher how they should treat patients on a case-by-case basis. In this study, the authors review the English-language literature on the management and clinical outcomes associated with AMs and MMs diagnosed using the WHO 2000/2007 grading criteria. Twenty-two studies for AMs and 7 studies for MMs were examined in detail. The authors examined clinical decision points using the literature and concepts from evidence-based medicine. Acknowledging the retrospective nature of the studies concerning AM and MM, the authors did find evidence for the following clinical strategies: 1) maximal safe resection of AM and MM; 2) active surveillance after gross-total resection of AM; 3) adjuvant radiation therapy after subtotal resection of AM, especially in the absence of putative radioresistant features; and 4) adjuvant radiation therapy after resection of MM. © AANS, 2015.


Author Keywords
Anaplastic meningioma;  Atypical meningioma;  Malignant meningioma;  Meningioma


Document Type: Article
Source: Scopus




Harp, C.R.P.a , Archambault, A.S.a , Sim, J.b , Ferris, S.T.c , Mikesell, R.J.a , Koni, P.A.d , Shimoda, M.e , Linington, C.f , Russell, J.H.b , Wu, G.F.a c
B cell antigen presentation is sufficient to drive neuroinflammation in an animal model of multiple sclerosis
(2015) Journal of Immunology, 194 (11), pp. 5077-5084. 

DOI: 10.4049/jimmunol.1402236


a Department of Neurology, Washington University School of Medicine, Box 8111, 660 South Euclid Avenue, St. Louis, MO, United States
b Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, United States
c Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States
d Cancer Immunology, Inflammation, and Tolerance Program, Cancer Center and Department of Medicine, Georgia Regents University, Augusta, GA, United States
e Department of Dermatology, University of California, Davis School of Medicine, Sacramento, CA, United States
f Department of Immunology, University of Glasgow, Glasgow, United Kingdom


Abstract
B cells are increasingly regarded as integral to the pathogenesis of multiple sclerosis, in part as a result of the success of B cell- depletion therapy. Multiple B cell-dependent mechanisms contributing to inflammatory demyelination of the CNS have been explored using experimental autoimmune encephalomyelitis (EAE), a CD4 T cell-dependent animal model for multiple sclerosis. Although B cell Ag presentation was suggested to regulate CNS inflammation during EAE, direct evidence that B cells can independently support Ag-specific autoimmune responses by CD4 T cells in EAE is lacking. Using a newly developed murine model of in vivo conditional expression of MHC class II, we reported previously that encephalitogenic CD4 T cells are incapable of inducing EAE when B cells are the sole APC. In this study, we find that B cells cooperate with dendritic cells to enhance EAE severity resulting from myelin oligodendrocyte glycoprotein (MOG) immunization. Further, increasing the precursor frequency of MOG-specific B cells, but not the addition of soluble MOG-specific Ab, is sufficient to drive EAE in mice expressing MHCII by B cells alone. These data support a model in which expansion of Ag-specific B cells during CNS autoimmunity amplifies cognate interactions between B and CD4 T cells and have the capacity to independently drive neuroinflammation at later stages of disease. Copyright © 2015 by The American Association of Immunologists, Inc.


Document Type: Article
Source: Scopus




Maccotta, L.a , Moseley, E.D.a , Benzinger, T.L.b c , Hogan, R.E.a
Beyond the CA1 subfield: Local hippocampal shape changes in MRI-negative temporal lobe epilepsy
(2015) Epilepsia, 56 (5), pp. 780-788. 

DOI: 10.1111/epi.12955


a Department of Neurology, Washington University, Campus-Box 8111, 660 South Euclid Avenue, St. Louis, MO, United States
b Department of Radiology, Washington University, St. Louis, MO, United States
c Department of Neurological Surgery, Washington University, St. Louis, MO, United States


Abstract
Objective Hippocampal atrophy in temporal lobe epilepsy (TLE) can indicate mesial temporal sclerosis and predict surgical success. Yet many patients with TLE do not have significant atrophy (magnetic resonance imaging (MRI) negative), which presents a diagnostic challenge. We used a new variant of high-dimensional large-deformation mapping to assess whether patients with apparently normal hippocampi have local shape changes that mirror those of patients with significant hippocampal atrophy. Methods Forty-seven patients with unilateral TLE and 32 controls underwent structural brain MRI. High-dimensional large-deformation mapping provided hippocampal surface and volume estimates for each participant, dividing patients into low versus high hippocampal atrophy groups. A vertex-level generalized linear model compared local shape changes between groups. Results Patients with low-atrophy TLE (MRI negative) had significant local hippocampal shape changes compared to controls, similar to those in the contralateral hippocampus of high-atrophy patients. These changes primarily involved the subicular and hilar/dentate regions, instead of the classically affected CA1 region. Disease duration instead co-varied with lateral hippocampal atrophy, co-localizing with the CA1 subfield. Significance These findings show that patients with "MRI-negative" TLE have regions of hippocampal atrophy that cluster medially, sparing the lateral regions (CA1) involved in high-atrophy patients. This suggests an overall effect of temporal lobe seizures manifesting as bilateral medial hippocampal atrophy, and a more selective effect of hippocampal seizures leading to disease-proportional CA1 atrophy, potentially reflecting epileptogenesis. © Wiley Periodicals, Inc. © 2015 International League Against Epilepsy.


Author Keywords
Hippocampal subfields;  Morphometry;  Structural MRI;  Subiculum


Document Type: Article
Source: Scopus




Huang, J.a , Liu, Y.a , Oltean, A.c , Beebe, D.C.a b
Bmp4 from the optic vesicle specifies murine retina formation
(2015) Developmental Biology, 402 (1), pp. 119-126. 

DOI: 10.1016/j.ydbio.2015.03.006


a Department of Ophthalmology and Visual Science, United States
b Department of Cell Biology and Physiology, Washington University School of Medicine, United States
c Department of Biomedical Engineering, Washington University, Saint Louis, MO, United States


Abstract
Previous studies of mouse embryos concluded that after the optic vesicle evaginates from the ventral forebrain and contacts the surface ectoderm, signals from the ectoderm specify the distal region of the optic vesicle to become retina and signals from the optic vesicle induce the lens. Germline deletion of Bmp4 resulted in failure of lens formation. We performed conditional deletion of Bmp4 from the optic vesicle to test the function of Bmp4 in murine eye development. The optic vesicle evaginated normally and contacted the surface ectoderm. Lens induction did not occur. The optic cup failed to form and the expression of retina-specific genes decreased markedly in the distal optic vesicle. Instead, cells in the prospective retina expressed genes characteristic of the retinal pigmented epithelium. We conclude that Bmp4 is required for retina specification in mice. In the absence of Bmp4, formation of the retinal pigmented epithelium is the default differentiation pathway of the optic vesicle. Differences in the signaling pathways required for specification of the retina and retinal pigmented epithelium in chicken and mouse embryos suggest major changes in signaling during the evolution of the vertebrate eye. © 2015 Elsevier Inc.


Author Keywords
Bmp4;  Evolution;  Optic cup;  Retina;  Retinal pigmented epithelium


Document Type: Article
Source: Scopus




Yamamoto, K.a , Tanei, Z.-I.a b , Hashimoto, T.a , Wakabayashi, T.a , Okuno, H.c , Naka, Y.a , Yizhar, O.d , Fenno, L.E.d , Fukayama, M.b , Bito, H.c , Cirrito, J.R.e , Holtzman, D.M.e , Deisseroth, K.d , Iwatsubo, T.a
Chronic Optogenetic Activation Augments Aβ Pathology in a Mouse Model of Alzheimer Disease
(2015) Cell Reports, 11 (6), pp. 859-865. 

DOI: 10.1016/j.celrep.2015.04.017


a Department of Neuropathology, Graduate School of Medicine, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo, Japan
b Department of Pathology, Graduate School of Medicine, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo, Japan
c Department of Neurochemistry, Graduate School of Medicine, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo, Japan
d Departments of Bioengineering and Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, United States
e Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University, St. Louis, MO, United States


Abstract
Invivo experimental evidence indicates that acute neuronal activation increases Aβ release from presynaptic terminals, whereas long-term effects ofchronic synaptic activation on Aβ pathology remain unclear. To address this issue, we adopted optogenetics and transduced stabilized step-function opsin, a channelrhodopsin engineered to elicit a long-lasting neuronal hyperexcitability, into the hippocampal perforant pathway of APP transgenic mice. Invivo microdialysis revealed a ~24% increase in the hippocampal interstitial fluid Aβ42 levels immediately after acute light activation. Five months of chronic optogenetic stimulation increased Aβ burden specifically in the projection area of the perforant pathway (i.e., outer molecular layer of the dentate gyrus) of the stimulated side by ~2.5-fold compared with that in the contralateral side. Epileptic seizures were observed during the course of chronic stimulation, which might have partly contributed to the Aβ pathology. These findings implicate functional abnormalities of specific neuronal circuitry in Aβ pathology and Alzheimer disease. © 2015 The Authors.


Document Type: Article
Source: Scopus




McNally, E.M.a , Kaltman, J.R.b , Woodrow Benson, D.c , Canter, C.E.d , Cripe, L.H.e , Duan, D.f , Finder, J.D.g , Hoffman, E.P.h , Judge, D.P.j , Kertesz, N.e , Kinnett, K.k , Kirsch, R.l , Metzger, J.M.m , Pearson, G.D.b , Rafael-Fortney, J.A.n , Raman, S.V.o , Spurney, C.F.i , Targum, S.L.p , Wagner, K.R.q , Markham, L.W.r
Contemporary cardiac issues in Duchenne muscular dystrophy
(2015) Circulation, 131 (18), pp. 1590-1598. 

DOI: 10.1161/CIRCULATIONAHA.114.015151


a Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, 303 E Superior St, 7-123, Chicago, IL, United States
b Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, United States
c Division of Cardiology, Children's Hospital of Wisconsin, Milwaukee, United States
d Department of Pediatrics, Washington University, St. Louis, MO, United States
e Heart Center, Nationwide Children's Hospital, Columbus, OH, United States
f Department of Molecular Microbiology and Immunology, School of Medicine, University of Missouri, Columbia, United States
g Division of Pulmonary Medicine, Children's Hospital, Pittsburgh, PA, United States
h Center for Genetic Medicine Research, Children's National Health System, Washington, DC, United States
i Division of Cardiology, Children's National Heart Institute, Children's National Health System, Washington, DC, United States
j Division of Cardiology, Johns Hopkins School of Medicine, Baltimore, MD, United States
k Parent Project Muscular Dystrophy, Middletown, OH, United States
l Division of Cardiac Critical Care, Children's Hospital, Philadelphia, PA, United States
m Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis, United States
n Department of Molecular and Cellular Biochemistry, Ohio State University, Columbus, United States
o Division of Cardiovascular Medicine, Ohio State University, Columbus, United States
p Division of Cardiovascular and Renal Products, US Food and Drug Administration, Silver Spring, MD, United States
q Hugo W. Moser Research Institute, Kennedy Krieger Institute, Baltimore, MD, United States
r Division of Pediatric Cardiology, Department of Pediatrics, Vanderbilt University, Nashville, TN, United States


Author Keywords
Cardiomyopathy;  Dystrophin;  Heart failure;  Magnetic resonance imaging;  Muscular dystrophy


Document Type: Article
Source: Scopus




Wang, Y.a b f , Sun, P.a , Wang, Q.a , Trinkaus, K.c , Schmidt, R.E.d , Naismith, R.T.e , Cross, A.H.b e , Song, S.-K.a b
Differentiation and quantification of inflammation, demyelination and axon injury or loss in multiple sclerosis
(2015) Brain, 138 (5), pp. 1223-1238. 

DOI: 10.1093/brain/awv046


a Department of Radiology, Washington University, St. Louis, MO, United States
b Hope Centre for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, United States
c Department of Biostatistics, Washington University, St. Louis, MO, United States
d Department of Pathology Washington University, St. Louis, MO, United States
e Department of Neurology, Washington University School of Medicine, Campus-Box 8111, 660 S. Euclid Avenue, St. Louis, MO, United States
f Department of Obstetrics and Gynecology, Washington University, St. Louis, United States


Abstract
Axon injury/loss, demyelination and inflammation are the primary pathologies in multiple sclerosis lesions. Despite the prevailing notion that axon/neuron loss is the substrate of clinical progression of multiple sclerosis, the roles that these individual pathological processes play in multiple sclerosis progression remain to be defined. An imaging modality capable to effectively detect, differentiate and individually quantify axon injury/loss, demyelination and inflammation, would not only facilitate the understanding of the pathophysiology underlying multiple sclerosis progression, but also the assessment of treatments at the clinical trial and individual patient levels. In this report, the newly developed diffusion basis spectrum imaging was used to discriminate and quantify the underlying pathological components in multiple sclerosis white matter. Through the multiple-tensor modelling of diffusion weighted magnetic resonance imaging signals, diffusion basis spectrum imaging resolves inflammation-associated cellularity and vasogenic oedema in addition to accounting for partial volume effects resulting from cerebrospinal fluid contamination, and crossing fibres. Quantitative histological analysis of autopsied multiple sclerosis spinal cord specimens supported that diffusion basis spectrum imaging-determined cellularity, axon and myelin injury metrics closely correlated with those pathologies identified and quantified by conventional histological staining. We demonstrated in healthy control subjects that diffusion basis spectrum imaging rectified inaccurate assessments of diffusion properties of white matter tracts by diffusion tensor imaging in the presence of cerebrospinal fluid contamination and/or crossing fibres. In multiple sclerosis patients, we report that diffusion basis spectrum imaging quantitatively characterized the distinct pathologies underlying gadolinium-enhanced lesions, persistent black holes, non-enhanced lesions and non-black hole lesions, a task yet to be demonstrated by other neuroimaging approaches. Diffusion basis spectrum imaging-derived radial diffusivity (myelin integrity marker) and non-restricted isotropic diffusion fraction (oedema marker) correlated with magnetization transfer ratio, supporting previous reports that magnetization transfer ratio is sensitive not only to myelin integrity, but also to inflammation-associated oedema. Our results suggested that diffusion basis spectrum imaging-derived quantitative biomarkers are highly consistent with histology findings and hold promise to accurately characterize the heterogeneous white matter pathology in multiple sclerosis patients. Thus, diffusion basis spectrum imaging can potentially serve as a non-invasive outcome measure to assess treatment effects on the specific components of underlying pathology targeted by new multiple sclerosis therapies. © 2015 The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.


Author Keywords
Diffusion basis spectrum imaging;  Diffusion tensor imaging;  Inflammation;  Multiple sclerosis;  White matter injury


Document Type: Article
Source: Scopus




Ishikawa, M.a , Yoshitomi, T.a , Zorumski, C.F.b c , Izumi, Y.b c
Experimentally Induced Mammalian Models of Glaucoma
(2015) BioMed Research International, 2015, art. no. 281214, . 

DOI: 10.1155/2015/281214


a Department of Ophthalmology, Akita Graduate University School of Medicine, 1-1-1 Hondo, Akita, Japan
b Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
c Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, St. Louis, MO, United States


Abstract
A wide variety of animal models have been used to study glaucoma. Although these models provide valuable information about the disease, there is still no ideal model for studying glaucoma due to its complex pathogenesis. Animal models for glaucoma are pivotal for clarifying glaucoma etiology and for developing novel therapeutic strategies to halt disease progression. In this review paper, we summarize some of the major findings obtained in various glaucoma models and examine the strengths and limitations of these models. Copyright © 2015 Makoto Ishikawa et al.


Document Type: Review
Source: Scopus




Boden, M.T.a , Thompson, R.J.b
Facets of emotional awareness and associations with emotion regulation and depression
(2015) Emotion, 15 (3), pp. 399-410. 

DOI: 10.1037/emo0000057


a Center for Innovation to Implementation, Veterans Administration Palo Alto Health Care System, Menlo Park, CA, United States
b Department of Psychology, Washington University in St. Louis, United States


Abstract
Emotion theories posit that effective emotion regulation depends upon the nuanced information provided by emotional awareness; attending to and understanding one's own emotions. Additionally, the strong associations between facets of emotional awareness and various forms of psychopathology may be partially attributable to associations with emotion regulation. These logically compelling hypotheses are largely uninvestigated, including which facets compose emotional awareness and how they relate to emotion regulation strategies and psychopathology. We used exploratory structural equation modeling of individual difference measures among a large adult sample (n = 919) recruited online. Results distinguished 4 facets of emotional awareness (type clarity, source clarity, involuntary attention to emotion, and voluntary attention to emotion) that were differentially associated with expressive suppression, acceptance of emotions, and cognitive reappraisal. Facets were associated with depression both directly and indirectly via associations with emotion regulation strategies. We discuss implications for theory and research on emotional awareness, emotion regulation, and psychopathology. © 2014 American Psychological Association.


Author Keywords
Attention to emotions;  Clarity of emotion;  Depression;  Emotion regulation;  Emotional awareness


Document Type: Article
Source: Scopus




Long, E.C.a , Aliev, A.a b , Wang, J.-C.c , Edenberg, H.J.d , Nurnberger, J., Jr.e , Hesselbrock, V.f , Porjesz, B.g , Dick, D.M.a
Further analyses of genetic association between GRM8 and alcohol dependence symptoms among young adults
(2015) Journal of Studies on Alcohol and Drugs, 76 (3), pp. 414-418. 


a Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA, United States
b Department of Actuarial and Risk Management, Karabük University, Karabük, Turkey
c Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, United States
d Departments of Biochemistry and Molecular Biology, Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, United States
e Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, United States
f Department of Psychiatry, University of Connecticut Health Center, Farmington, CT, United States
g Department of Psychiatry and Behavioral Sciences, State University of New York (SUNY) Downstate Medical Center, Brooklyn, NY, United States


Abstract
Objective: The gene GRM8, a metabotropic glutamate receptor, has emerged as a gene of interest for its possible role in the development of alcohol dependence, with evidence of association with an electrophysiological endophenotype and level of response to alcohol as well as suggestive evidence of association with alcohol dependence. Method: The present study further investigated the association between GRM8 and alcohol dependence symptom counts among young adults using a new sample of individuals collected as part of the prospective sample (ages 18–26 years; N = 842) from the Collaborative Study on the Genetics of Alcoholism (COGA). Results: Two single-nucleotide polymorphisms were significantly associated with alcohol dependence in European Americans using the Nyholt corrected p value of .007: rs886003 (β = -.212, p = .0002) and rs17862325 (β = -.234, p < .0001), but not in African Americans, likely because of the lower power to detect association in this group. Conclusions: These results further implicate the role of glutamate receptor genes such as GRM8 in the development of alcohol dependence. © 2015, Alcohol Research Documentation Inc. All rights reserved.


Document Type: Article
Source: Scopus




Blazquez, P.M., Yakusheva, T.A.
GABA-A Inhibition Shapes the Spatial and Temporal Response Properties of Purkinje Cells in the Macaque Cerebellum
(2015) Cell Reports, 11 (7), pp. 1043-1053. 

DOI: 10.1016/j.celrep.2015.04.020


Department of Otolaryngology, Washington University School of Medicine, 4566 Scott Avenue, St. Louis, MO, United States


Abstract
Data from invitro and anesthetized preparations indicate that inhibition plays a major role in cerebellar cortex function. We investigated the role of GABA-A inhibition in the macaque cerebellar ventral-paraflocculus while animals performed oculomotor behaviors that are known to engage the circuit. We recorded Purkinje cell responses to these behaviors with and without application of gabazine, a GABA-A receptor antagonist, near the recorded neuron. Gabazine increased the neuronal responsiveness to saccades in all directions and the neuronal gain to VOR cancellation and pursuit, most significantly the eye and head velocity sensitivity. L-glutamate application indicated that these changes were not the consequence of increases in baseline firing rate. Importantly, gabazine did not affect behavior or efference copy, suggesting that only local computations were disrupted. Our data, collected while the cerebellum performs behaviorally relevant computations, indicate that inhibition is a potent regulatory mechanism for the control of input-output gain and spatial tuning in the cerebellar cortex. © 2015 The Authors.


Document Type: Article
Source: Scopus




O'Bryant, S.E.a , Gupta, V.b , Henriksen, K.c , Edwards, M.d , Jeromin, A.e , Lista, S.f , Bazenet, C.g , Soares, H.h , Lovestone, S.g , Hampel, H.f i j , Montine, T.k , Blennow, K.l , Foroud, T.m , Carrillo, M.n , Graff-Radford, N.o , Laske, C.p , Breteler, M.q r , Shaw, L.q r , Trojanowski, J.Q.q r , Schupf, N.s , Rissman, R.A.t , Fagan, A.M.u , Oberoi, P.v , Umek, R.w , Weiner, M.W.x , Grammas, P.y , Posner, H.z , Martins, R.b
Guidelines for the standardization of preanalytic variables for blood-based biomarker studies in Alzheimer's disease research
(2015) Alzheimer's and Dementia, 11 (5), pp. 549-560. 

DOI: 10.1016/j.jalz.2014.08.099


a Institute for Aging and Alzheimer's Disease Research, Department of Internal Medicine, University of North Texas, Fort Worth, TX, United States
b Centre of Excellence for Alzheimer's Disease Research and Care, School of Medical Sciences, Edith Cowan University, Joondalup, WA, Australia
c Nordic Bioscience Biomarkers and Research, Neurodegenerative Diseases, Herlev, Denmark
d Department of Psychology, University of North Texas, Denton, TX, United States
e Quanterix, Inc., Lexington, MA, United States
f AXA Research Fund, UPMC, Paris, France
g Department of Old Age Psychiatry, King's College London, Institute of Psychiatry, London, United Kingdom
h Bristol-Myers Squibb, Wallingford, CT, United States
i Sorbonne Universités, Institut dela Mémoire et de la Maladie d'Alzheimer (IM2A), Département de Neurologie, Paris, France
j Département de Neurologie, Institut du Cerveau et de la Moelle épinière (ICM), Hôpital de la Pitié-Salpétrière, Paris, France
k Department of Pathology, University of Washington, Seattle, WA, United States
l Clinical Neurochemistry Laboratory, Department of Neuroscience and Physiology, Sahlgrenska University Hospital, Molndal, Sweden
m Department of Medical and Molecular Genetics, Indiana University, School of Medicine, Indianapolis, IN, United States
n Alzheimer's Association, Chicago, IL, United States
o Department of Neurology, Mayo Clinic Jacksonville, Jacksonville, FL, United States
p Department of Neurodegeneration, Hertie-Institute of Clinical Brain Research, University of Tubingen, Tubingen, Germany
q Department of Psychiatry and Psychotherapy, University of Tübingen, Tübingen, Germany
r German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany
s Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
t Department of Epidemiology, Joseph P Mailman School of Public Health, Columbia University, New York, NY, United States
u Alzheimer's Disease Cooperative Study, Department of Neurosciences, UCSD School of Medicine, San Diego, CA, United States
v Department of Neurology, Washington University, School of Medicine, St. Louis, MO, United States
w Meso Scale Discovery, Rockville, MD, United States
x Department of Medicine, Radiology and Psychiatry, University of California, San Francisco, CA, United States
y Texas Tech University, Health Science Center, Garrison Institute on Aging, Lubbock, TX, United States
z Pfizer Inc., New York, NY, United States


Abstract
The lack of readily available biomarkers is a significant hindrance toward progressing to effective therapeutic and preventative strategies for Alzheimer's disease (AD). Blood-based biomarkers have potential to overcome access and cost barriers and greatly facilitate advanced neuroimaging and cerebrospinal fluid biomarker approaches. Despite the fact that preanalytical processing is the largest source of variability in laboratory testing, there are no currently available standardized preanalytical guidelines. The current international working group provides the initial starting point for such guidelines for standardized operating procedures (SOPs). It is anticipated that these guidelines will be updated as additional research findings become available. The statement provides (1) a synopsis of selected preanalytical methods utilized in many international AD cohort studies, (2) initial draft guidelines/SOPs for preanalytical methods, and (3) a list of required methodological information and protocols to be made available for publications in the field to foster cross-validation across cohorts and laboratories. © 2015 The Authors.


Author Keywords
Alzheimer's disease;  Biomarkers;  Blood;  Dementia;  Diagnosis;  Plasma;  Serum;  Treatment


Document Type: Article
Source: Scopus




Chandrasekaran, B.a b c , Van Engen, K.d , Xie, Z.a , Beevers, C.G.b c , Maddox, W.T.b c
Influence of depressive symptoms on speech perception in adverse listening conditions
(2015) Cognition and Emotion, 29 (5), pp. 900-909. 

DOI: 10.1080/02699931.2014.944106


a Department of Communication Sciences & Disorders, The University of Texas at Austin, Austin, TX, United States
b Department of Psychology, The University of Texas at Austin, Austin, TX, United States
c Institute for Mental Health Research, The University of Texas at Austin, Austin, TX, United States
d Department of Psychology and Linguistics Program, Washington University in St. Louis, St. Louis, MO, United States


Abstract
It is widely acknowledged that individuals with elevated depressive symptoms exhibit deficits in inter-personal communication. Research has primarily focused on speech production in individuals with elevated depressive symptoms. Little is known about speech perception in individuals with elevated depressive symptoms, especially in challenging listening conditions. Here, we examined speech perception in young adults with low- or high-depressive (HD) symptoms in the presence of a range of maskers. Maskers were selected to reflect various levels of informational masking (IM), which refers to cognitive interference due to signal and masker similarity, and energetic masking (EM), which refers to peripheral interference due to signal degradation by the masker. Speech intelligibility data revealed that individuals with HD symptoms did not differ from those with low-depressive symptoms during EM, but they exhibited a selective deficit during IM. Since IM is a common occurrence in real-world social settings, this listening deficit may exacerbate communicative difficulties. © 2014 Taylor & Francis.


Author Keywords
CES-D;  Communication;  Depression;  Informational masking;  Speech perception


Document Type: Article
Source: Scopus




Bosch, M.K.a , Carrasquillo, Y.a b , Ransdell, J.L.a b , Kanakamedala, A.a , Ornitz, D.M.a , Nerbonne, J.M.a b
Intracellular FGF14 (iFGF14) is required for spontaneous and evoked firing in cerebellar Purkinje neurons and for motor coordination and balance
(2015) Journal of Neuroscience, 35 (17), pp. 6752-6769. 

DOI: 10.1523/JNEUROSCI.2663-14.2015


a Department of Developmental Biology, Cardiovascular Division, Washington University School of Medicine, St. Louis, MO, United States
b Department of Internal Medicine, Cardiovascular Division, Washington University School of Medicine, St. Louis, MO, United States


Abstract
Mutations in FGF14, which encodes intracellular fibroblast growth factor 14 (iFGF14), have been linked to spinocerebellar ataxia (SCA27). In addition, mice lacking Fgf14 (Fgf14−/−) exhibit an ataxia phenotype resembling SCA27, accompanied by marked changes in the excitability of cerebellar granule and Purkinje neurons. It is not known, however, whether these phenotypes result from defects in neuronal development or if they reflect a physiological requirement for iFGF14 in the adult cerebellum. Here, we demonstrate that the acute and selective Fgf14-targeted short hairpin RNA (shRNA)-mediated in vivo “knock-down” of iFGF14 in adult Purkinje neurons attenuates spontaneous and evoked action potential firing without measurably affecting the expression or localization of voltage-gated Na+ (Nav) channels at Purkinje neuron axon initial segments. The selective shRNA-mediated in vivo “knock-down” of iFGF14 in adult Purkinje neurons also impairs motor coordination and balance. Repetitive firing can be restored in Fgf14-targeted shRNA-expressing Purkinje neurons, as well as in Fgf14−/− Purkinje neurons, by prior membrane hyperpolarization, suggesting that the iFGF14-mediated regulation of the excitability of mature Purkinje neurons depends on membrane potential. Further experiments revealed that the loss of iFGF14 results in a marked hyperpolarizing shift in the voltage dependence of steady-state inactivation of the Nav currents in adult Purkinje neurons. We also show here that expressing iFGF14 selectively in adult Fgf14−/− Purkinje neurons rescues spontaneous firing and improves motor performance. Together, these results demonstrate that iFGF14 is required for spontaneous and evoked action potential firing in adult Purkinje neurons, thereby controlling the output of these cells and the regulation of motor coordination and balance. © 2015 the authors.


Author Keywords
Channel inactivation;  FGF14;  Fibroblast growth factor homologous factor 4 (FHF4);  Intrinsic excitability;  Spinocerebellar ataxia 27;  Voltage-gated sodium (Nav) channels


Document Type: Article
Source: Scopus




Roh, J.H.a , Holtzman, D.M.b c d
Is there a link between the sleep-wake cycle and Alzheimer's pathology?
(2015) Future Neurology, 10 (3), pp. 183-186. 

DOI: 10.2217/fnl.15.15


a Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
b Department of Neurology, Hope Center for Neurological Disorders, Washington University School of MedicineMO, United States
c Hope Center for Neurological Disorders, Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University School of MedicineMO, United States
d Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University School of MedicineMO, United States


Author Keywords
Alzheimer's disease;  amyloid-β;  sleep-wake cycle;  tau


Document Type: Editorial
Source: Scopus




Cloninger, C.R.
Meet our editorial board member
(2015) Current Psychiatry Reviews, 11 (2), p. 85. 


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


Document Type: Editorial
Source: Scopus




Kumar, G.N., Rao, P.K., Apte, R.S.
Microstructural retinal findings by spectral-domain optical coherence tomography after vitrectomy repair of rhegmatogenous retinal detachments
(2015) Ophthalmic Surgery Lasers and Imaging Retina, 46 (4), pp. 493-498. 

DOI: 10.3928/23258160-20150422-17


Department of Ophthalmology and Visual Science, Washington University School of Medicine, 660 S. Euclid Ave, Box 8096, St. Louis, MO, United States


Abstract
BACKGROUND AND OBJECTIVE: To evaluate macular microstructural changes after macula-involving rhegmatogenous retinal detachment repair and correlate with visual recovery. PATIENTS AND METHODS: A prospective, observational study was performed of select patients presenting with macula-involving rhegmatogenous retinal detachments (RRD). Spectral-domain optical coherence tomography (SD-OCT) imaging was performed at postoperative visits over the course of the first year after operative repair of the RRD. RESULTS: The maculas of seven patients were evaluated. Postoperative best corrected visual acuity (BCVA) at the final follow-up ranged from 20/20 to 20/70 for all patients. Eyes with final BCVA greater than 20/40 had intact external limiting membrane and outer photoreceptor structures, while those with BCVA of less than 20/70 had poorer definition to those structures. Serial images showed resolution of irregularities in both the external limiting membrane and outer photoreceptor structures. CONCLUSION: Macular structure and function can progressively improve in the first year after successful RRD repair, including in the external limiting membrane, damage to which has previously been thought to be irreversible. SD-OCT serves as a useful tool to monitor postoperative retinal recovery.


Document Type: Article
Source: Scopus




Musiek, E.S.
Neuroinflammation: Friend or foe?
(2015) Science Translational Medicine, 7 (274), . 

DOI: 10.1126/scitranslmed.aaa8314


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


Document Type: Editorial
Source: Scopus




Clifford, D.B.
Neurological immune reconstitution inflammatory response: Riding the tide of immune recovery
(2015) Current Opinion in Neurology, 28 (3), pp. 295-301. 

DOI: 10.1097/WCO.0000000000000200


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


Abstract
This manuscript reviews current reports about clinical aspects of immune reconstitution inflammatory syndrome (IRIS), with a particular emphasis on IRIS in the setting of progressive multifocal leukoencephalopathy (PML) and to a lesser extent on cryptococcal meningitis and HIV. Recent findings PML prognosis has been radically improved, as it has become possible to provide immune reconstitution, although some remaining morbidity and mortality results from excess inflammation. Similar pathologic responses are seen less often, but remain clinically important in cryptococcal meningitis, and HIV. Early diagnosis and active management of PML results in optimal outcomes with survival of 75% or higher in multiple recent series. These finding apply both to natalizumab and HIV-associated PML. Cryptococcal meningitis is frequently complicated by IRIS, and early treatment with antifungal therapy preceding HIV therapy provides optimal outcomes. HIV IRIS is reduced by early therapy, which is now recommended, but even on therapy, chronic dysregulated immune responses may play important roles in ongoing HIV-associated neurocognitive disease (HAND), which is common, as well as rare but more dramatic subacute encephalopathies. Summary The clinician must actively monitor and treat both opportunistic infection and the inflammatory response that is essential to recovery but may itself augment disease and injury. © 2015 Wolters Kluwer Health, Inc.


Author Keywords
Cryptococcal meningitis;  HIV;  immune reconstitution inflammatory syndrome (IRIS);  JC virus;  progressive multifocal leukoencephalopathy (PML)


Document Type: Review
Source: Scopus




Monosov, I.E.a c , Leopold, D.A.b d , Hikosaka, O.c
Neurons in the primate medial basal forebrain signal combined information about reward uncertainty, value, and punishment anticipation
(2015) Journal of Neuroscience, 35 (19), pp. 7443-7459. 

DOI: 10.1523/JNEUROSCI.0051-15.2015


a Department of Anatomy and Neurobiology, Washington University, School of Medicine, St. Louis, MO, United States
b Section on Cognitive Neurophysiology and Imaging, National Institute of Mental Health, Bethesda, MD, United States
c Laboratory of Sensorimotor Research, National Eye Institute, Bethesda, MD, United States
d Neurophysiology Imaging Facility, National Institute of Mental Health, National Institute of Neurological Disorders and Stroke, National Eye Institute, Bethesda, MD, United States


Abstract
It has been suggested that the basal forebrain (BF) exerts strong influences on the formation of memory and behavior. However, what information is used for the memory-behavior formation is unclear. We found that a population of neurons in the medial BF (medial septum and diagonal band of Broca) of macaque monkeys encodes a unique combination of information: reward uncertainty, expected reward value, anticipation of punishment, and unexpected reward and punishment. The results were obtained while the monkeys were expecting (often with uncertainty) a rewarding or punishing outcome during a Pavlovian procedure, or unexpectedly received an outcome outside the procedure. In vivo anterograde tracing using manganese-enhanced MRI suggested that the major recipient of these signals is the intermediate hippocampal formation. Based on these findings, we hypothesize that the medial BF identifies various contexts and outcomes that are critical for memory processing in the hippocampal formation. © 2015 the authors.


Author Keywords
Basal forebrain;  Electrophysiology;  Emotion;  Learning;  Memory;  Motivation


Document Type: Article
Source: Scopus




Cai, C.a , Stephens, B.H.b , Leonard, J.R.b , Dahiya, S.a
Posterior fossa tumor with distinct choroid plexus papilloma and ependymoma components
(2015) Clinical Neuropathology, 34 (3), pp. 132-135. 

DOI: 10.5414/NP300816


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


Abstract
Synchronous occurrence of multiple primary central nervous system (CNS) tumors of different histological types is uncommon in patients without radiation history or genetic syndrome association. We herein report a sporadic case of posterior fossa tumor with synchronous choroid plexus papilloma (CPP) and ependymoma (EP) components. A 7-year-old girl with no significant past or familial medical history presented with 2 years of migraine type headaches. Brain magnetic resonance imaging showed a cystic mass with a mural enhancing nodule centered within the cerebellar vermis. The patient underwent gross total resection of the tumor. Histologic examination showed a tumor with two distinct components. The predominant component demonstrated classic morphological and immunohistochemical characteristics of choroid plexus papilloma CPP, WHO grade I. However, there were a few discrete foci, where tumor cells showed architectural, cytological, and immunohistochemical features characteristic of an ependymoma, WHO grade II. In addition, there was exuberant piloid gliosis secondary to infiltration of the CPP component into the adjacent brain parenchyma. Followup brain imaging at 14 months after surgery showed no evidence of residual or recurrent tumor. To the best of our knowledge, this is the first reported case of synchronous CPP and EP in the posterior fossa. © 2015 Dustri-Verlag Dr. K. Feistle.


Author Keywords
Choroid plexus papilloma;  Ependymoma;  Posterior fossa;  Synchronous/collision


Document Type: Article
Source: Scopus




Deshields, T.a , Kracen, A.a , Nanna, S.b , Kimbro, L.c
Psychosocial staffing at National Comprehensive Cancer Network member institutions: Data from leading cancer centers
(2015) Psycho-Oncology, . Article in Press. 

DOI: 10.1002/pon.3826


a Siteman Cancer Center, Barnes-Jewish Hospital Washington University School of Medicine St. Louis, MO USA
b American University of the Caribbean School of Medicine Cupecoy St. Maarten, Netherlands Antilles
c National Comprehensive Cancer Network Fort Washington PA USA


Abstract
Objective: The National Comprehensive Cancer Network (NCCN) is comprised of 25 National Cancer Institute-designated cancer centers and arguably could thus set the standard for optimal psychosocial staffing for cancer centers; therefore, information was sought from NCCN Member Institutions about their current staffing for psychosocial services. These findings are put into perspective given the limited existing literature and consensus reports. Methods: The NCCN Best Practices Committee surveyed member institutions about their staffing for psychosocial services. The survey was administered electronically in the winter of 2012. Results: The survey was completed by 20 cancer centers. Across institutions, case managers and mental health therapists, typically social workers, were utilized most frequently to provide psychosocial services (67% of full-time-equivalents (FTEs)), with other psychosocial professionals also represented but less consistently. Most psychosocial services are institutionally funded (ranging from 64 to 100%), although additional sources of support include fee for service and grant funding. Training of psychosocial providers is unevenly distributed across responding sites, ranging from 92% of institutions having training programs for psychiatrists to 36% having training programs for mental health therapists. Conclusions: There was variability among the institutions in terms of patient volume, psychosocial services provided, and psychosocial staff employed. As accreditation standards are implemented that provide impetus for psychosocial services in oncology, it is hoped that greater clarity will develop concerning staffing for psychosocial services and uptake of these services by patients with cancer. © 2015 John Wiley & Sons, Ltd.


Document Type: Article in Press
Source: Scopus




Alankus, G.a , Kelleher, C.b
Reducing compensatory motions in motion-based video games for stroke rehabilitation
(2015) Human-Computer Interaction, 30 (3-4), pp. 232-262. 

DOI: 10.1080/07370024.2014.985826


a Izmir University of Economics, Department of Computer Engineering, Turkey
b Washington University in St. Louis, Department of Computer Engineering, United States


Abstract
Stroke survivors unsupervised therapeutic exercise motions are often accompanied by harmful compensatory motions that prevent proper motor recovery and introduce additional health issues. These compensatory motions are often performed unconsciously and are difficult to prevent. Motion-based games show promise for motivating patients to perform stroke rehabilitation exercises at home by themselves. Currently, exercises with these games are likely to contain undesired compensatory motions. In this article, we provide the design and empirical evaluation of a motion-based game system that addresses the issue of compensation in therapeutic games. We introduce a technique to identify and measure compensation, develop a game that meaningfully uses exercise and compensation as inputs, and use incentives and disincentives to reduce compensation. We show that this technique outperforms existing approaches by significantly reducing compensatory motions during therapeutic exercise. This has important implications for therapeutic games, which can use our findings to improve the quality of motions to be closer to therapist-supervised motions. Our techniques can increase the effectiveness of therapeutic games and reduce the possibility that they may cause harm in long-term use. © 2015 Taylor & Francis Group, LLC.


Document Type: Article
Source: Scopus




Bressler, S.B.a , Almukhtar, T.b , Bhorade, A.c , Bressler, N.M.d , Glassman, A.R.b , Huang, S.S.e , Jampol, L.M.f , Kim, J.E.g , Melia, M.b
Repeated intravitreous ranibizumab injections for diabetic macular edema and the risk of sustained elevation of intraocular pressure OR the need for ocular hypotensive treatment
(2015) JAMA Ophthalmology, 133 (5), pp. 589-597. 

DOI: 10.1001/jamaophthalmol.2015.186


a Wilmer Eye Institute, Johns Hopkins University, School of Medicine, Baltimore, MD, United States
b Jaeb Center for Health Research, 15310 Amberly Dr., Tampa, FL, United States
c Department of Ophthalmology, Washington University, School of Medicine in St Louis, St. Louis, MO, United States
d JAMA Ophthalmology, United States
e Retina Center of Ohio, South Euclid, United States
f Department of Ophthalmology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
g Department of Ophthalmology, Eye Institute, Medical College of Wisconsin, Milwaukee, United States


Abstract
IMPORTANCE: For the management of retinal disease, the use of intravitreous injections of anti-vascular endothelial growth factor has increased. Recent reports have suggested that this therapy may cause sustained elevation of intraocular pressure (IOP) and may potentially increase the risk of glaucoma for patients with retinal disease. OBJECTIVE: To assess the risk of sustained IOP elevation or the need for IOP-lowering treatments for eyes with diabetic macular edema following repeated intravitreous injections of ranibizumab. DESIGN, SETTING, AND PARTICIPANTS: An exploratory analysis was conducted within a Diabetic Retinopathy Clinical Research Network randomized clinical trial. Study enrollment dates were from March 20,2007, to December 17,2008. Of 582 eyes (of 486 participants) with center-involved diabetic macular edema and no preexisting open-angle glaucoma, 260 were randomly assigned to receive a sham injection plus focal/grid laser treatment, and 322 were randomly assigned to receive ranibizumab plus deferred or prompt focal/grid laser treatment. MAIN OUTCOMES AND MEASURES: The cumulative probability of sustained IOP elevation, defined as IOP of at least 22 mm Hgandan increase of at least 6 mm Hgfrom baseline at 2 consecutive visits, or the initiation or augmentation of ocular hypotensive therapy, through 3 years of follow-up. RESULTS: The mean (SD) baseline IOP in both treatment groups was 16 (3) mm Hg (range, 5-24 mm Hg). The cumulative probability of sustained IOP elevation or of initiation or augmentation of ocular hypotensive therapy by 3 years, after repeated ranibizumab injections, was 9.5% for the participants who received ranibizumab plus prompt or deferred focal/grid laser treatment vs 3.4% for the participants who received a sham injection plus focal/grid laser treatment (difference, 6.1% [99% CI, -0.2% to 12.3%]; hazard ratio, 2.9 [99% CI, 1.0-7.9]; P =.01). The distribution of IOP and the change in IOP from baseline at each visit through 3 years were similar in each group. CONCLUSIONS AND RELEVANCE: In eyes with center-involved diabetic macular edema and no prior open-angle glaucoma, repeated intravitreous injections of ranibizumab may increase the risk of sustained IOP elevation or the need for ocular hypotensive treatment. Clinicians should be aware of this risk and should consider this information when following up with patients who have received intravitreous injections of anti-vascular endothelial growth factor for the treatment of diabetic macular edema.


Document Type: Article
Source: Scopus




Dale, A.M.a , Evanoff, B.a , Al-Lozi, M.b
Reply
(2015) PM and R, 7 (5), pp. 550-551. 

DOI: 10.1016/j.pmrj.2015.02.008


a Division of General Medical Sciences, Washington University School of Medicine, St Louis, MO, United States
b Department of Neurology, Washington University School of Medicine, St Louis, MO, United States


Document Type: Letter
Source: Scopus




Baldassarre, A.a b c , Corbetta, M.a b c d e f
Resting state network changes in aging and cognitive decline
(2015) Hearing, Balance and Communication, 13 (2), pp. 58-64. 

DOI: 10.3109/21695717.2015.1022986


a Department of Neurology, Washington University, School of Medicine, 660 South Euclid, St. Louis, MO, United States
b Department of Neuroscience, Imaging and Clinical Sciences, University G. d'Annunzio of Chieti-Pescara, via dei Vestini 33, Chieti, Italy
c Institute for Advanced Biomedical Technologies, University G. d'Annunzio of Chieti-Pescara, Italy
d Department of Radiology, Washington University, School of Medicine, Saint Louis, MO, United States
e Department of Anatomy and Neurobiology, Washington University, School of Medicine, Saint Louis, MO, United States
f Department of Bioengineering, Washington University, School of Medicine, Saint Louis, MO, United States


Abstract
Identifying the neural mechanisms related to aging in the lifespan represents a fundamental goal for clinical neuroscience. Here, we review recent advances in understanding the effects of aging on spontaneous brain activity and behavior. A large body of neuroimaging studies shows that spontaneous brain activity is intrinsically organized in large-scale resting-state networks (RSNs) associated with different cognitive functions such as memory, attention, language, and executive control. Furthermore, recent lines of evidence indicate that aging affects the patterns of correlated brain activity (functional connectivity) within and across RSNs. A common observation is that elderly individuals exhibit decreased functional connectivity within specific RSNs such as the default mode, dorsal attention and executive-control networks. Moreover, aging is associated with increased inter-network functional connectivity between RSNs, i.e. reduction of segregation between functional systems. Finally, some studies show that changes in functional connectivity are behaviorally relevant, i.e. they are correlated with a decline in cognitive abilities, mainly in memory and executive control functions. These findings strongly suggest that robust changes in RSNs occur in aging; hence investigations of spontaneous brain activity may shed light into brain processes related to aging or serve as a sensitive biomarker of cognitive decline and response to therapy. © 2015 Informa Healthcare.


Author Keywords
Aging;  Cognitive decline;  fMRI;  Functional connectivity;  Resting state networks


Document Type: Article
Source: Scopus




Tong, L.a b , Strong, M.K.a b , Kaur, T.f , Juiz, J.M.e , Oesterle, E.C.a b , Hume, C.a b , Warchol, M.E.f , Palmiter, R.D.c , Rubel, E.W.a b d
Selective deletion of cochlear hair cells causes rapid age-dependent changes in spiral ganglion and cochlear nucleus neurons
(2015) Journal of Neuroscience, 35 (20), pp. 7878-7891. 

DOI: 10.1523/JNEUROSCI.2179-14.2015


a Virginia Merrill Bloedel Hearing Research Center, University of Washington, Seattle, WA, United States
b Department of Otolaryngology-Head and Neck Surgery, University of Washington, Seattle, WA, United States
c Department of Biochemistry and Howard Hughes Medical Institute, University of Washington, Seattle, WA, United States
d Department of Physiology and Biophysics, University of Washington, Seattle, WA, United States
e Discapacidades Neurològicas and School of medicine, Universidad de Castilla-La Mancha, Albacete, Spain
f Department of Otolaryngology, Washington University School of Medicine, St Louis, MO, United States


Abstract
During nervous system development, critical periods are usually defined as early periods during which manipulations dramatically change neuronal structure or function, whereas the same manipulations in mature animals have little or no effect on the same property. Neurons in the ventral cochlear nucleus (CN) are dependent on excitatory afferent input for survival during a critical period of development. Cochlear removal in young mammals and birds results in rapid death of target neurons in the CN. Cochlear removal in older animals results in little or no neuron death. However, the extent to which hair-cell-specific afferent activity prevents neuronal death in the neonatal brain is unknown. We further explore this phenomenon using a new mouse model that allows temporal control of cochlear hair cell deletion. Hair cells express the human diphtheria toxin (DT) receptor behind the Pou4f3 promoter. Injections of D Tresulted in nearly complete loss of organ of Corti hair cells within 1 week of injection regardless of the age of injection. Injection of DT did not influence surrounding supporting cells directly in the sensory epithelium or spiral ganglion neurons (SGNs). Loss of hair cells in neonates resulted in rapid and profound neuronal loss in the ventral CN, but not when hair cells were eliminated at a more mature age. In addition, normal survival of SGNs was dependent on hair cell integrity early in development and less so in mature animals. This defines a previously undocumented critical period for SGN survival. © 2015 the authors.


Author Keywords
Cochlea;  Cochlear nucleus;  Critical period;  Diphtheria toxin receptor knock-in;  Neuronal death;  Spiral ganglion


Document Type: Article
Source: Scopus




Sun, S.Q.a , Cai, C.b , Ravindra, V.M.c , Gamble, P.a , Yarbrough, C.K.d , Dacey, R.G.d , Dowling, J.L.d , Zipfel, G.J.d , Wright, N.M.d , Santiago, P.d , Robinson, C.G.e , Schmidt, M.H.c , Kim, A.H.d , Ray, W.Z.d
Simpson grade I-III resection of spinal atypical (world health organization grade II) meningiomas is associated with symptom resolution and low recurrence
(2015) Neurosurgery, 76 (6), pp. 739-746. 

DOI: 10.1227/NEU.0000000000000720


a Washington University School of Medicine, Saint Louis, MO, United States
b Department of Pathology and Immunology, Washington University, St. Louis, MO, United States
c Department of Neurosurgery, University of Utah, Salt Lake City, UT, United States
d Department of Neurosurgery, Washington University, 660 S. Euclid Avenue, St. Louis, MO, United States
e Department of Radiation Oncology, Washington University, St. Louis, MO, United States


Abstract
Background: Because of their rarity, outcomes regarding spinal atypical meningiomas (AMs) remain unclear. OBJECTIVE: To describe the recurrence rate and postoperative outcomes after resection of spinal AMs, and to discuss an appropriate resection strategy and adjuvant therapy for spinal AMs. METHODS: Data from all patients who presented with spinal AMs to 2 tertiary referral centers between 1998 and 2013 were obtained by chart review. RESULTS: From 102 patients with spinal meningioma, 20 AM tumors (7 cervical, 11 thoracic, 2 thoracolumbar) were identified in 18 patients (median age, 50 years [range, 19-75] at time of resection; 11% male; median follow-up, 32 months [range, 1-179] after resection). Before resection, patients had sensory deficits (70%), pain (70%), weakness (60%), ataxia (50%), spasticity (65%), and incontinence (35%). One tumor presented asymptomatically. Simpson grade I, II, III, and IV resection were achieved in 3 (15%), 13 (65%), 2 (10%), and 2 (10%) tumors, respectively. One patient that underwent Simpson grade III resection received adjuvant radiation therapy. After Simpson grade I-III or gross total resection, no tumors recurred (0%; confidence interval, 0%-17.6%). After Simpson grade IV resection, 1 tumor recurred (50%; confidence interval, 1.3%-98.7%). With the exception of 1 patient who had bilateral paraplegia perioperatively, all other patients experienced improvement of preoperative symptoms after surgery (median time, 3.6 months [range, 1-13] after resection). CONCLUSION: Despite published cases suggesting an aggressive clinical course for spinal AMs, this series of spinal AMs reports that gross total resection without adjuvant radiation therapy resulted in symptom resolution and low recurrence.. Copyright © 2015 by the Congress of Neurological Surgeons.


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


Document Type: Article
Source: Scopus




Finley, J.R., Roediger, H.L., III, Hughes, A.D., Wahlheim, C.N., Jacoby, L.L.
Simultaneous versus sequential presentation in testing recognition memory for faces
(2015) American Journal of Psychology, 128 (2), pp. 173-195. 

DOI: 10.5406/amerjpsyc.128.2.0173


Washington University, St. Louis, United States


Abstract
Three experiments examined the issue of whether faces could be better recognized in a simultaneous test format (2-alternative forced choice [2AFC]) or a sequential test format (yes-no). All experiments showed that when target faces were present in the test, the simultaneous procedure led to superior performance (area under the ROC curve), whether lures were high or low in similarity to the targets. However, when a target-absent condition was used in which no lures resembled the targets but the lures were similar to each other, the simultaneous procedure yielded higher false alarm rates (Experiments 2 and 3) and worse overall performance (Experiment 3). This pattern persisted even when we excluded responses that participants opted to withhold rather than volunteer. We conclude that for the basic recognition procedures used in these experiments, simultaneous presentation of alternatives (2AFC) generally leads to better discriminability than does sequential presentation (yes-no) when a target is among the alternatives. However, our results also show that the opposite can occur when there is no target among the alternatives. An important future step is to see whether these patterns extend to more realistic eyewitness lineup procedures. © 2015 by the Board of Trustees of the University of Illinois.


Document Type: Article
Source: Scopus




Dissel, S.a , Angadi, V.a , Kirszenblat, L.c , Suzuki, Y.a , Donlea, J.b , Klose, M.a , Koch, Z.a , English, D.a , Winsky-Sommerer, R.d , Van Swinderen, B.c , Shaw, P.J.a
Sleep restores behavioral plasticity to drosophila mutants
(2015) Current Biology, 25 (10), pp. 1270-1281. 

DOI: 10.1016/j.cub.2015.03.027


a Department of Anatomy and Neurobiology, Washington University in St. Louis, 660 South Euclid Avenue, St. Louis, MO, United States
b Centre for Neural Circuits and Behaviour, University of Oxford, Oxford, United Kingdom
c Queensland Brain Institute, University of Queensland, Brisbane, QLD, Australia
d Surrey Sleep Research Centre, Faculty of Health and Medical Sciences, University of Surrey, Guildford, Surrey, United Kingdom


Abstract
Given the role that sleep plays in modulating plasticity, we hypothesized that increasing sleep would restore memory to canonical memory mutants without specifically rescuing the causal molecular lesion. Sleep was increased using three independent strategies: activating the dorsal fan-shaped body, increasing the expression of Fatty acid binding protein (dFabp), or by administering the GABA-A agonist 4,5,6,7-tetrahydroisoxazolo-[5,4-c]pyridine-3-ol (THIP). Short-term memory (STM) or long-term memory (LTM) was evaluated in rutabaga (rut) and dunce (dnc) mutants using aversive phototaxic suppression and courtship conditioning. Each of the three independent strategies increased sleep and restored memory to rut and dnc mutants. Importantly, inducing sleep also reverses memory defects in a Drosophila model of Alzheimer's disease. Together, these data demonstrate that sleep plays a more fundamental role in modulating behavioral plasticity than previously appreciated and suggest that increasing sleep may benefit patients with certain neurological disorders. © 2015 Elsevier Ltd.


Document Type: Article
Source: Scopus




Yo-El, J.
Sleep well, breathe well, age well
(2015) Science Translational Medicine, 7 (285), art. no. 285ec68, . 

DOI: 10.1126/scitranslmed.aab3134


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


Document Type: Editorial
Source: Scopus




Doyle, F.a , McGee, H.c , Conroy, R.b , Conradi, H.J.d , Meijer, A.e , Steeds, R.f , Sato, H.g , Stewart, D.E.h , Parakh, K.i , Carney, R.j , Freedland, K.j , Anselmino, M.k , Pelletier, R.l , Bos, E.H.e , De Jonge, P.e
Systematic review and individual patient data meta-analysis of sex differences in depression and prognosis in persons with myocardial infarction: A MINDMAPS study
(2015) Psychosomatic Medicine, 77 (4), pp. 419-428. 

DOI: 10.1097/PSY.0000000000000174


a Division of Population Health Sciences (Psychology), Epidemiology and Public Health Medicine, Royal College of Surg. in Ireland, 123 St Stephen's Green, Dublin 2, Ireland
b Population Health Sciences, Epidemiology and Public Health Medicine, Royal College of Surg. in Ireland, Ireland
c Faculty of Medicine and Health Sciences, Royal College of Surg. in Ireland, Ireland
d Department of Clinical Psychology, University of Amsterdam, Amsterdam, Netherlands
e Interdisciplinary Center Psychopathology and Emotion Regulation, University Medical Center Groningen, Groningen, Netherlands
f Department of Cardiology, Queen Elizabeth Hospital, Birmingham, United Kingdom
g School of Human Welfare Studies, Kwansei Gakuin University, Nishinomiya, Japan
h University Health Network, University of Toronto, Toronto, ON, Canada
i Department of Medicine, Johns Hopkins University, School of Medicine, Baltimore, MD, United States
j Department of Psychiatry, Washington University, St Louis, MI, United States
k Division of Cardiology, Department of Medical Sciences, University of Turin, Turin, Italy
l McGill University Health Centre, Montréal, Canada


Abstract
Objective: Using combined individual patient data from prospective studies, we explored sex differences in depression and prognosis post-myocardial infarction (MI) and determined whether disease indices could account for found differences. Methods: Individual patient data analysis of 10,175 MI patients who completed diagnostic interviews or depression questionnaires from 16 prospective studies from the MINDMAPS study was conducted. Multilevel logistic and Cox regression models were used to determine sex differences in prevalence of depression and sex-specific effects of depression on subsequent outcomes. Results: Combined interview and questionnaire data from observational studies showed that 36% (635/1760) of women and 29% (1575/5526) of men reported elevated levels of depression (age-adjusted odds ratio = 0.68, 95% confidence interval [CI] = 0.60-0.77). The risk for all-cause mortality associated with depression was higher in men (hazard ratio = 1.38, 95% CI = 1.30-1.47) than in women (hazard ratio = 1.22, 95% CI = 1.14-1.31; sex by depression interaction: p <.001). Low left ventricular ejection fraction (LVEF) was associated with higher depression scores in men only (sex by LVEF interaction: B = 0.294, 95% CI = 0.090-0.498), which attenuated the sex difference in the association between depression and prognosis. Conclusions: The prevalence of depression post-MI was higher in women than in men, but the association between depression and cardiac prognosis was worse for men. LVEF was associated with depression in men only and accounted for the increased risk of all-cause mortality in depressed men versus women, suggesting that depression in men post-MI may, in part, reflect cardiovascular disease severity. Copyright © 2015 by the American Psychosomatic Society.


Author Keywords
Depression;  Gender differences;  Individual patient data meta-analysis;  Myocardial infarction;  Prognosis


Document Type: Review
Source: Scopus




Del Brutto, O.H.a , Sedler, M.J.b , Mera, R.M.c , Lama, J.d , Gruen, J.A.b , Phelan, K.J.b , Cusick, E.H.b , Zambrano, M.e , Brown, D.L.f
The association of ankle-brachial index with silent cerebral small vessel disease: Results of the Atahualpa Project
(2015) International Journal of Stroke, 10 (4), pp. 589-593. 

DOI: 10.1111/ijs.12450


a School of Medicine, Universidad Espíritu Santo, Guayaquil, Ecuador
b School of Medicine, Stony Brook University, New York, NY, United States
c Gastroenterology Department, Vanderbilt University, Nashville, TN, United States
d Imaging Department, Hospital-Clínica Kennedy, Guayaquil, Ecuador
e Community Center, The Atahualpa Project, Atahualpa, Ecuador
f Cardiovascular Division, Washington University School of Medicine, St. Louis, MO, United States


Abstract
Background: An abnormal ankle-brachial index has been associated with overt stroke and coronary heart disease, but little is known about its relationship with silent cerebral small vessel disease. Aim: To assess the value of ankle-brachial index as a predictor of silent small vessel disease in an Ecuadorian geriatric population. Methods: Stroke-free Atahualpa residents aged ≥60 years were identified during a door-to-door survey. Ankle-brachial index determinations and brain magnetic resonance imaging were performed in consented persons. Ankle-brachial index ≤0·9 and ≥1·4 were proxies of peripheral artery disease and noncompressible arteries, respectively. Using logistic regression models adjusted for age, gender, and cardiovascular health status, we evaluated the association between abnormal ankle-brachial index with silent lacunar infarcts, white matter hyperintensities, and cerebral microbleeds. Results: Mean age of the 224 participants was 70±8 years, 60% were women, and 80% had poor cardiovascular health status. Ankle-brachial index was ≤0·90 in 37 persons and ≥1·4 in 17. Magnetic resonance imaging showed lacunar infarcts in 27 cases, moderate-to-severe white matter hyperintensities in 47, and cerebral microbleeds in 26. Adjusted models showed association of lacunar infarcts with ankle-brachial index≤0·90 (OR: 3·72, 95% CI: 1·35-10·27, P=0·01) and with ankle-brachial index≥1·4 (OR: 3·85, 95% CI: 1·06-14·03, P=0·04). White matter hyperintensities were associated with ankle-brachial index≤0·90 (P=0·03) and ankle-brachial index≥1·4 (P=0·02) in univariate analyses. There was no association between ankle-brachial index groups and cerebral microbleeds. Conclusions: In this population-based study conducted in rural Ecuador, apparently healthy individuals aged ≥60 years with ankle-brachial index values ≤0·90 and ≥1·4 are almost four times more likely to have a silent lacunar infarct. Ankle-brachial index screening might allow recognition of asymptomatic people who need further investigation and preventive therapy. © 2015 World Stroke Organization.


Author Keywords
Ankle-brachial index;  Cerebral small vessel disease;  Peripheral artery disease;  Population-based study;  Silent lacunar strokes;  White matter hyperintensities


Document Type: Article
Source: Scopus




Gooblar, J.a , Carpenter, B.D.a , Coats, M.A.b , Morris, J.C.b c d e f , Snider, B.J.b c
The influence of cerebrospinal fluid (CSF) biomarkers on clinical dementia evaluations
(2015) Alzheimer's and Dementia, 11 (5), pp. 533-540. 

DOI: 10.1016/j.jalz.2014.04.517


a Department of Psychology, St. Louis, MO, United States
b Knight Alzheimer's Disease Research Center, St. Louis, MO, United States
c Department of Neurology, St. Louis, MO, United States
d Department of Pathology and Immunology, St. Louis, MO, United States
e Department of Physical Therapy, St. Louis, MO, United States
f Department of Occupational Therapy, School of Medicine, Washington University, St. Louis, MO, United States


Abstract
Background Cerebrospinal fluid (CSF) proteins have become accepted biomarkers of Alzheimer's disease (AD) in research settings. The extent of their use, perceived utility, and influence on decision making in clinical settings, however, are less well studied. Methods Clinicians who evaluate older adults (N = 193) were randomized to view normal, borderline, AD-consistent, or no CSF information in two vignettes portraying patients with borderline and mild AD symptoms. Clinicians also reported on the use and perceived utility of CSF biomarkers. Results Although clinicians reported infrequent use and low perceived utility of CSF biomarkers, viewing AD-consistent CSF values made clinicians more likely to make an AD-related diagnosis, increased diagnostic confidence, and led clinicians to initiate treatment more often than clinicians who had no CSF information. Conclusions CSF biomarkers influence decision making depending on the extent to which biomarkers reflect AD pathology, consistency between clinical-pathologic information, and the ambiguity of protein values. © 2015 The Alzheimer's Association.


Author Keywords
Alzheimer's disease;  Biomarkers;  Cerebrospinal fluid;  Dementia;  Diagnosis


Document Type: Article
Source: Scopus




Bermel, R.A.a b , Naismith, R.T.a
Using MRI to make informed clinical decisions in multiple sclerosis care
(2015) Current Opinion in Neurology, 28 (3), pp. 244-249. 

DOI: 10.1097/WCO.0000000000000204


a Cleveland Clinic Foundation, Cleveland, OH, United States
b Washington University, St. Louis, MO, United States


Abstract
Patients with multiple sclerosis have benefited from an increasingly large number of choices for anti-inflammatory, disease-modifying therapy. One cannot reliably predict how an individual patient will respond to a particular therapy. MRI has become an integral component of therapy selection and monitoring in multiple sclerosis. Recent findings Number of lesions at baseline and new lesions on therapy have implications for long-term prognosis. To achieve best therapeutic outcomes, patients with accumulating lesions may benefit from a change in their therapy. For patients with established stable disease, MRI may be done less frequently. Summary Practitioners should be obtaining brain MRI scans to supplement their clinical evaluations and assess for subclinical disease activity. In certain circumstances, changing therapy may be warranted based upon MRI alone, despite the appearance of clinical stability. The appearance of two to five T2-weighted lesions or one to two gadolinium-enhancing lesions represents a threshold of concern. © 2015 Wolters Kluwer Health, Inc.


Author Keywords
Disability;  MRI;  multiple sclerosis;  relapse

 


Document Type: Review
Source: Scopus