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Office of Neuroscience Research > Resources and Facilities > WUSTL Neuroscience Publications for the week

WUSTL Neuroscience Publications for the week


The publications below include authors at Washington University and were identified by Scopus search.  These are the most current publications.  For previous lists, visit the WUSTL Neuroscience publications archive.

May 22, 2017 


Müller, S.a , Preische, O.a b , Sohrabi, H.R.c d , Gräber, S.b e , Jucker, M.b f , Dietzsch, J.e , Ringman, J.M.g , Martins, R.N.c d , McDade, E.h , Schofield, P.R.i j , Ghetti, B.k , Rossor, M.l , Graff-Radford, N.R.m n , Levin, J.o p , Galasko, D.q , Quaid, K.A.r , Salloway, S.s , Xiong, C.t , Benzinger, T.u , Buckles, V.u , Masters, C.L.v , Sperling, R.w , Bateman, R.J.u , Morris, J.C.u , Laske, C.b e
Decreased body mass index in the preclinical stage of autosomal dominant Alzheimer's disease
(2017) Scientific Reports, 7 (1), art. no. 1225, . 

DOI: 10.1038/s41598-017-01327-w

a Department of Psychiatry and Psychotherapy, University of Tübingen, Tübingen, Germany
b German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany
c Centre of Excellence for Alzheimer's Disease Research and Care, School of Medical Sciences, Edith Cowan University, Perth, WA, Australia
d School of Psychiatry and Clinical Neurosciences, University of Western Australia, Nedlands, WA, Australia
e Section for Dementia Research, Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, Department of Psychiatry and Psychotherapy, University of Tübingen, Tübingen, Germany
f Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
g Memory and Aging Center, Keck School of Medicine of USC, Los Angeles, CA, United States
h University of Pittsburgh School of Medicine, Department of Neurology, 3471 5th Ave, Suite 811, Pittsburgh, PA, United States
i Neuroscience Research Australia, Randwick, Sydney, NSW, Australia
j School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia
k Department of Pathology and Laboratory Medicine, Indiana University, Indianapolis, IN, United States
l Dementia Research Centre, Department of Neurodegeneration, UCL Institute of Neurology, Queen Square, London, United Kingdom
m Department of Neuroscience, Mayo Clinic, Jacksonville, FL, United States
n Department of Neurology, Mayo Clinic, Jacksonville, FL, United States
o German Center for Neurodegenerative Diseases (DZNE), München, Germany
p Department of Neurology, Ludwig-Maximilians Universität Munich, Munich, Germany
q Shiley-Marcos Alzheimer's Disease Research Center, Department of Neurosciences, University of California, San Diego, CA, United States
r Indiana University Center for Bioethics, 410 West 10th Street, Indianapolis, IN, United States
s Department of Neurology, Warren Alpert Medical School of Brown University, Providence, RI, United States
t Division of Biostatistics, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St Louis, MO, United States
u Department of Neurology, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. LouisMO, United States
v Mental Health Research Institute, University of Melbourne, Level 5, Kenneth Myer Building, 30 Royal Parade, Parkville, VIC, Australia
w Center for Alzheimer Research and Treatment, Department of Neurology, Brigham and Women's Hospital, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States

The relationship between body-mass index (BMI) and Alzheimers disease (AD) has been extensively investigated. However, BMI alterations in preclinical individuals with autosomal dominant AD (ADAD) have not yet been investigated. We analyzed cross-sectional data from 230 asymptomatic members of families with ADAD participating in the Dominantly Inherited Alzheimer Network (DIAN) study including 120 preclinical mutation carriers (MCs) and 110 asymptomatic non-carriers (NCs). Differences in BMI and their relation with cerebral amyloid load and episodic memory as a function of estimated years to symptom onset (EYO) were analyzed. Preclinical MCs showed significantly lower BMIs compared to NCs, starting 11.2 years before expected symptom onset. However, the BMI curves begun to diverge already at 17.8 years before expected symptom onset. Lower BMI in preclinical MCs was significantly associated with less years before estimated symptom onset, higher global Aβ brain burden, and with lower delayed total recall scores in the logical memory test. The study provides cross-sectional evidence that weight loss starts one to two decades before expected symptom onset of ADAD. Our findings point toward a link between the pathophysiology of ADAD and disturbance of weight control mechanisms. Longitudinal follow-up studies are warranted to investigate BMI changes over time. © 2017 The Author(s).

Document Type: Article
Source: Scopus


Schindler, S.E.a b c , Jasielec, M.S.d , Weng, H.d , Hassenstab, J.J.a b , Grober, E.e , McCue, L.M.d , Morris, J.C.a b , Holtzman, D.M.a b c , Xiong, C.a b d , Fagan, A.M.a b c
Neuropsychological measures that detect early impairment and decline in preclinical Alzheimer disease
(2017) Neurobiology of Aging, 56, pp. 25-32. 

DOI: 10.1016/j.neurobiolaging.2017.04.004

a Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
b Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, United States
c Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, United States
d Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, United States
e Department of Neurology, Albert Einstein College of Medicine, New York, NY, United States

Identifying which neuropsychological measures detect early cognitive changes associated with Alzheimer disease (AD), brain pathology would be helpful clinically for the diagnosis of early AD and for the design of clinical trials. We evaluated which neuropsychological measures in our cognitive battery are most strongly associated with cerebrospinal fluid (CSF) biomarkers of AD brain pathology. We studied a large cohort (n = 233) of middle-to older-aged community-dwelling individuals (mean age 61 years) who had no clinical symptoms of dementia and underwent baseline CSF collection at baseline. Participants completed a battery of 9 neuropsychological measures at baseline and then every 1 to 3 years. CSF tau/Aβ42 was associated with baseline performance on 5/9 neuropsychological measures, especially measures of episodic memory, and longitudinal performance on 7/9 neuropsychological measures, especially measures of global cognition. The free recall portion of the Free and Cued Selective Reminding Task (FCSRT-free) detected declining cognition in the high CSF tau/Aβ42 group the earliest, followed by another measure of episodic memory and a sequencing task. © 2017 Elsevier Inc.

Author Keywords
Cerebrospinal fluid;  Neuropsychological measures;  Preclinical Alzheimer disease;  Subtle cognitive decline

Document Type: Article
Source: Scopus


Oh, S.-H.a , Choi, Y.-B.b , Kim, J.-H.b , Weihl, C.C.c , Ju, J.-S.a
Quantification of autophagy flux using LC3 ELISA
(2017) Analytical Biochemistry, 530, pp. 57-67. 

DOI: 10.1016/j.ab.2017.05.003

a Department of Exercise Science, Research Institute of Sports Science, The University of Suwon, 17 Wauan-gil, Bongdam-eup, Hwaseong-si, Gyeonggi-do, South Korea
b Department of Biotechnology and Bioscience, School of Bioindustry, The University of Suwon, 17 Wauan-gil, Bongdam-eup, Hwaseong-si, Gyeonggi-do, South Korea
c Department of Neurology, Washington University School of Medicine, PO Box 8111, 660 South Euclid Avenue, St Louis, MO, United States

Macroautophagy (hereafter referred to as autophagy) is a degradation system that delivers cytoplasmic materials to lysosomes via autophagosomes. Autophagic flux is defined as a measure of autophagic degradation activity. Despite several methods for monitoring autophagic flux being currently utilized, interest in finding a highly accurate, sensitive and well-quantifiable assay is still growing. Therefore, we introduce a new approach analyzing autophagic flux in vitro and in vivo using enzyme-linked immunosorbent assay (ELISA) technique. In order to adapt this assay from LC3-II turnover measured by Western blot in the presence and absence of lysosomal inhibitors, we induced autophagy by starvation or rapamycin and mitophagy (mitochondrial degradation by autophagy) by CCCP in C2C12 myotubes for 8 h and in mice for 48 h with and without Bafilomycin A1 or colchicine treatment, respectively. Following subcellular fractionation of mouse skeletal muscle cells and tissue, cytosolic, membrane, and mitochondrial fractions were analyzed through a sandwich ELISA using two LC3 antibodies, LC3 capture and HRP-conjugated LC3 detection antibodies. Using this ELISA, changes in the membrane-bound or mitochondrion-associated LC3-II levels, and the ratio of the LC3-II from each fraction to LC3-I levels (cytosolic fraction) were evaluated for measuring autophagy and mitophagy flux. This study demonstrates that this ELISA was more sensitive and reliable to measure autophagic/mitophagic flux in both in vitro and in vivo, compared with the most commonly used LC3 turnover assay via Western blot. © 2017 Elsevier Inc.

Author Keywords
Autophagy;  ELISA;  LC3 turnover;  Mitophagy;  Skeletal muscle

Document Type: Article
Source: Scopus


Du, F.a b , Wang, X.a c , Abrams, R.A.d , Zhang, K.a b
Emotional processing is enhanced in peri-hand space
(2017) Cognition, 165, pp. 39-44. 

DOI: 10.1016/j.cognition.2017.04.009

a CAS Key Laboratory of Behavioral Science, Institute of Psychology, Chinese Academy of Sciences, Beijing, China
b University of Chinese Academy of Sciences, Beijing, China
c School of Psychology, Jiangxi Normal University, Nanchang, Jiangxi, China
d Department of Psychological and Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States

The space near the hands, or peri-hand space is a critical multisensory-motor interface between people and the environment. Recent studies have shown that visual processing near the hands is altered compared with stimuli far from the hands. Some results suggest that the changes may be mediated by brain mechanisms involved in evaluating emotional stimuli. Here we show direct evidence for that proposal: we found that both the emotional Stroop effect and the Late Positive Potential (LPP) to unpleasant visual stimuli were enhanced near the hands compared to far from the hands. The results reveal enhanced processing of unpleasant stimuli in peri-hand space, which may facilitate the response to potentially dangerous stimuli. © 2017 Elsevier B.V.

Author Keywords
Emotional Stroop;  Event-related potentials;  Hand-stimulus proximity;  Late positive potential;  Peri-hand space

Document Type: Article
Source: Scopus


Davis, S.A.a , Gan, K.A.a , Dowell, J.A.b , Cairns, N.J.c , Gitcho, M.A.a
TDP-43 expression influences amyloidβ plaque deposition and tau aggregation
(2017) Neurobiology of Disease, 103, pp. 154-162. 

DOI: 10.1016/j.nbd.2017.04.012

a Department of Biological Sciences, Delaware Center for Neuroscience Research, Delaware State University, Dover, DE, United States
b Wisconsin Institute of Discovery, Madison, WI, United States
c Knight Alzheimer's Disease Research Center, Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States

Although the main focus in Alzheimer's disease (AD) has been an investigation of mechanisms causing Aβ plaque deposition and tau tangle formation, recent studies have shown that phosphorylated TDP-43 pathology is present in up to 50% of sporadic cases. Furthermore, elevated phosphorylated TDP-43 has been associated with more severe AD pathology. Therefore, we hypothesized that TDP-43 may regulate amyloid-beta precursor protein (APP) trafficking and tau phosphorylation/aggregation. In order to examine the role of TDP-43 in AD, we developed a transgenic mouse that overexpresses hippocampal and cortical neuronal TDP-43 in a mouse expressing familial mutations (K595N and M596L) in APP and presenilin 1 (PSEN1ΔE9). In our model, increased TDP-43 was related to increased tau aggregation as evidenced by thioflavin S-positive phosphorylated tau, which may implicate TDP-43 expression in pre-tangle formation. In addition, there was increased endosomal/lysosomal localization of APP and reduced Aβ plaque formation with increased TDP-43. Furthermore, there was decreased calcineurin with elevated TDP-43 expression. Since calcineurin is a phosphatase for TDP-43, the decreased calcineurin expression may be one mechanism leading to an increase in accumulation of diffuse phosphorylated TDP-43 in the hippocampus and cortex. We further show that when TDP-43 is knocked down there is an increase in calcineurin. In our model of selective TDP-43 overexpression in an APP/PSEN1 background, we show that TDP-43 decreases Aβ plaque deposition while increasing abnormal tau aggregation. These observations indicate that TDP-43 may play a role in regulating APP trafficking and tau aggregation. Our data suggest that TDP-43 could be a putative target for therapeutic intervention in AD affecting both Aβ plaque formation and tauopathy. © 2017 Elsevier Inc.

Author Keywords
Alzheimer's disease;  APP;  APP/PS1;  Calcineurin;  TARDBP;  Tau;  TDP-43

Document Type: Article
Source: Scopus


Gruber, J.a , Van Meter, A.b , Gilbert, K.E.c , Youngstrom, E.A.d , Youngstrom, J.K.d , Feeny, N.C.e , Findling, R.L.f
Positive Emotion Specificity and Mood Symptoms in an Adolescent Outpatient Sample
(2017) Cognitive Therapy and Research, 41 (3), pp. 393-405. 

DOI: 10.1007/s10608-016-9796-7

a Department of Psychology and Neuroscience, University of Colorado Boulder, 1905 Colorado Avenue, 345 UCB, Muenzinger D321C, Boulder, CO, United States
b Ferkauf Graduate School, Yeshiva University, New York, NY, United States
c Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, United States
d Department of Psychology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
e Case Western Reserve University, Cleveland, OH, United States
f Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, MD, United States

Research on positive emotion disturbance has gained increasing attention, yet it is not clear which specific positive emotions are affected by mood symptoms, particularly during the critical period of adolescence. This is especially pertinent for identifying potential endophenotypic markers associated with mood disorder onset and course. The present study examined self-reported discrete positive and negative emotions in association with clinician-rated manic and depressive mood symptoms in a clinically and demographically diverse group of 401 outpatient adolescents between 11 and 18 years of age. Results indicated that higher self reported joy and contempt were associated with increased symptoms of mania, after controlling for symptoms of depression. Low levels of joy and high sadness uniquely predicted symptoms of depression, after controlling for symptoms of mania. Results were independent of age, ethnicity, gender and bipolar diagnosis. These findings extend work on specific emotions implicated in mood pathology in adulthood, and provide insights into associations between emotions associated with goal driven behavior with manic and depressive mood symptom severity in adolescence. In particular, joy was the only emotion associated with both depressive and manic symptoms across adolescent psychopathology, highlighting the importance of understanding positive emotion disturbance during adolescent development. © 2016, Springer Science+Business Media New York.

Author Keywords
Adolescence;  Depression;  Mania;  Positive emotion

Document Type: Article
Source: Scopus


Meacham, K.a b , Shepherd, A.a b , Mohapatra, D.P.a b , Haroutounian, S.a b
Neuropathic Pain: Central vs. Peripheral Mechanisms
(2017) Current Pain and Headache Reports, 21 (6), art. no. 28, . 

DOI: 10.1007/s11916-017-0629-5

a Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, United States
b Washington University Pain Center, Washington University School of Medicine, St. Louis, MO, United States

Purpose of Review: Our goal is to examine the processes—both central and peripheral—that underlie the development of peripherally-induced neuropathic pain (pNP) and to highlight recent evidence for mechanisms contributing to its maintenance. While many pNP conditions are initiated by damage to the peripheral nervous system (PNS), their persistence appears to rely on maladaptive processes within the central nervous system (CNS). The potential existence of an autonomous pain-generating mechanism in the CNS creates significant implications for the development of new neuropathic pain treatments; thus, work towards its resolution is crucial. Here, we seek to identify evidence for PNS and CNS independently generating neuropathic pain signals. Recent Findings: Recent preclinical studies in pNP support and provide key details concerning the role of multiple mechanisms leading to fiber hyperexcitability and sustained electrical discharge to the CNS. In studies regarding central mechanisms, new preclinical evidence includes the mapping of novel inhibitory circuitry and identification of the molecular basis of microglia-neuron crosstalk. Recent clinical evidence demonstrates the essential role of peripheral mechanisms, mostly via studies that block the initially damaged peripheral circuitry. Clinical central mechanism studies use imaging to identify potentially self-sustaining infra-slow CNS oscillatory activity that may be unique to pNP patients. Summary: While new preclinical evidence supports and expands upon the key role of central mechanisms in neuropathic pain, clinical evidence for an autonomous central mechanism remains relatively limited. Recent findings from both preclinical and clinical studies recapitulate the critical contribution of peripheral input to maintenance of neuropathic pain. Further clinical investigations on the possibility of standalone central contributions to pNP may be assisted by a reconsideration of the agreed terms or criteria for diagnosing the presence of central sensitization in humans. © 2017, Springer Science+Business Media New York.

Author Keywords
Central sensitization;  Chronic pain;  Hyperexcitability;  Neuropathic pain;  Neuroplasticity;  Painful neuropathy;  Peripheral nerve damage

Document Type: Review
Source: Scopus


Ke, Q.a , Zhao, Z.-Y.b , Griggs, R.c , Wiley, V.d , Connolly, A.e , Kwon, J.f , Qi, M.g , Sheehan, D.h , Ciafaloni, E.i , Howell, R.R.j , Furu, P.k , Sazani, P.l , Narayana, A.m , Gatheridge, M.n
Newborn screening for Duchenne muscular dystrophy in China: Follow-up diagnosis and subsequent treatment
(2017) World Journal of Pediatrics, pp. 1-5. Article in Press. 

DOI: 10.1007/s12519-017-0036-3

a Department of Neurology, Zhejiang University School of Medicine, Hangzhou, China
b Department of Child Health Care, Zhejiang University School of Medicine, Hangzhou, China
c Department of Neurology, University of Rochester School of Medicine and Dentistry, Rochester, NY, United States
d Disciplines of Genetic Medicine and Pediatric and Child Health, University of Sydney, Sydney, Australia
e Departments of Neurology and Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
f Departments of Neurology and Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, NY, United States
g Center for Genetic & Genomic Medicine, Zhejiang University School of Medicine and James Watson Institute of Genome Sciences, Hangzhou, China
h Department of Pediatrics, University of Buffalo, Buffalo, NY, United States
i Department of Neurology, University of Rochester School of Medicine and Dentistry, Rochester, NY, United States
j University of Miami, Business Manager Neonatal Screening, PerkinElmer, Turku, Finland
k Senior Direction, Field Medical Affairs, Marathon Pharmaceuticals, Northbrook, IL, United States
l Sr. Medical Director, Sarepta Therapeutics, Cambridge, MA, United States
m Department of Neurology, University of Rochester School of Medicine and Dentistry, Rochester, NY, United States
n Department of Neurology, University of Rochester School of Medicine and Dentistry, 601 Elmwood Ave, Box 673, Rochester, NY, United States

Background: Newborn screening for Duchenne muscular dystrophy (DMD) is currently being initiated in Zhejiang Province, China and is under consideration in other countries, including the United States. As China begins to implement DMD newborn screening (DMDNBS), there is ongoing discussion regarding the steps forward for follow up care of positively identifi ed patients as well as false positive and false negative results. Data sources: Relevant papers related to DMD-NBS, and NBS in China were reviewed in PubMed. Results: The current state of DMD-NBS is discussed, along with the steps needed to effectively screen infants for this disease in China, recommendations for establishment of follow up care in patients with positive and negative screens, and measurement of patient outcomes. Conclusions: Zhejiang Province, China is ready to implement DMD-NBS. Future challenges that exist for this program, and other countries, include the ability to track patients, assist with access to care, and ensure adequate follow-up care according to evidence-based guidelines. In addition, China's large rural population, lack of specialty providers, and difficulty in educating patients regarding the benefi ts of treatment create challenges that will need to be addressed. © 2017 Children's Hospital, Zhejiang University School of Medicine and Springer-Verlag Berlin Heidelberg

Author Keywords
Duchene muscular dystrophy;  neurology;  neuromuscular disorders;  newborn screening

Document Type: Article in Press
Source: Scopus


Yang, C.a , Gonzalez-Perez, V.a , Mukaibo, T.b c , Melvin, J.E.b , Xia, X.-M.a , Lingle, C.J.a
Knockout of the LRRC26 subunit reveals a primary role of LRRC26-containing BK channels in secretory epithelial cells
(2017) Proceedings of the National Academy of Sciences of the United States of America, 114 (18), pp. E3739-E3747. 

DOI: 10.1073/pnas.1703081114

a Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, United States
b Secretory Mechanisms and Dysfunction Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, United States
c Department of Oral Reconstruction and Rehabilitation, Kyushu Dental University, Kitakyushu, Fukuoka, Japan

Leucine-rich-repeat-containing protein 26 (LRRC26) is the regulatory γ1 subunit of Ca2+- and voltage-dependent BK-type K+ channels. BK channels that contain LRRC26 subunits are active near normal resting potentials even without Ca2+, suggesting they play unique physiological roles, likely limited to very specific cell types and cellular functions. By using Lrrc26 KOmicewith a β-gal reporter, Lrrc26 promoter activity is found in secretory epithelial cells, especially acinar epithelial cells in lacrimal and salivary glands, and also goblet and Paneth cells in intestine and colon, although absent from neurons. We establish the presence of LRRC26 protein in eight secretory tissues or tissues with significant secretory epithelium and show that LRRC26 protein coassembles with the pore-forming BK α-subunit in at least three tissues: lacrimal gland, parotid gland, and colon. In lacrimal, parotid, and submandibular gland acinar cells, LRRC26 KO shifts BK gating to be like α-subunit-only BK channels. Finally, LRRC26 KO mimics the effect of SLO1/BK KO in reducing [K+] in saliva. LRRC26-containing BK channels are competent to contribute to resting K+ efflux at normal cell membrane potentials with resting cytosolic Ca2+ concentrations and likely play a critical physiological role in supporting normal secretory function in all secretory epithelial cells.

Author Keywords
BK channels;  LRRC26;  Salivary glands;  Secretory epithelium;  SLO1

Document Type: Article
Source: Scopus


Smolkina, M.a , Morley, K.I.a b , Rijsdijk, F.c , Agrawal, A.d , Bergin, J.E.e , Nelson, E.C.d , Statham, D.f , Martin, N.G.g , Lynskey, M.T.a
Cannabis and Depression: A Twin Model Approach to Co-morbidity
(2017) Behavior Genetics, pp. 1-11. Article in Press. 

DOI: 10.1007/s10519-017-9848-0

a National Addiction Centre, Institute of Psychiatry, Psychology, and Neuroscience, King’s College London, Addiction Sciences Building, 4 Windsor Walk, SE5 8BB, London, United Kingdom
b Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC, Australia
c Social, Genetic & Developmental Psychiatry Centre, Institute of Psychiatry, Psychology, and Neuroscience, King’s College London, London, United Kingdom
d Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
e Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, United States
f Faculty of Arts, Business and Law, School of Social Sciences, University of the Sunshine Coast, Sippy Downs, QLD, Australia
g Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia

Cannabis use disorder (CUD) co-occurs with major depressive disorder (MDD) more frequently than would be expected by chance. However, studies to date have not produced a clear understanding of the mechanisms underlying this co-morbidity. Genetically informative studies can add valuable insight to this problem, as they allow the evaluation of competing models of co-morbidity. This study uses data from the Australian Twin Registry to compare 13 co-morbidity twin models initially proposed by Neale and Kendler (Am J Hum Genet 57:935–953, 1995). The analysis sample comprised 2410 male and female monozygotic and dizygotic twins (average age 32) who were assessed on CUD and MDD using the SSAGA-OZ interview. Data were analyzed in OpenMx. Of the 13 different co-morbidity models, two fit equally well: CUD causes MDD and Random Multiformity of CUD. Both fit substantially better than the Correlated Liabilities model. Although the current study cannot differentiate between them statistically, these models, in combination, suggest that CUD risk factors may causally influence the risk to develop MDD, but only when risk for CUD is high. © 2017 The Author(s)

Author Keywords
Cannabis use disorder;  Co-morbidity;  Genetics;  Major depressive disorder;  Twin model

Document Type: Article in Press
Source: Scopus


Saa, J.P.a b , Doherty, M.a , Young, A.a , Spiers, M.c , Leary, E.d , Wolf, T.J.c
Development and alternate form reliability of the Complex Task Performance Assessment (CTPA) for people with mild stroke
(2017) American Journal of Occupational Therapy, 71 (3), art. no. 024356, . 

DOI: 10.5014/ajot.2017.024356

a Program in Occupational Therapy, Washington University, School of Medicine, St. Louis, MO, United States
b George Warren Brown School of Social Work and Public Health, Washington University, St. Louis, MO, United States
c Department of Occupational Therapy, University of Missouri, Columbia, United States
d Biostatistics and Research Design Unit, University of Missouri, Columbia, United States

Cognitive impairment is a common consequence of mild stroke. Current performance-based assessments for mild stroke can detect mild impairments in executive function but lack alternate forms to be used as outcome measures. This study aimed to develop an alternate form of the Complex Task Performance Assessment (CTPA-Alt), a performance-based assessment of executive function, and to establish the alternate form reliability of the CTPA-Alt. A repeated-measures study was conducted with 26 community participants. Participants were screened for eligibility and administered both forms of the CTPA; administration order was alternated. Overall performance was significantly correlated (rs =.44, p =.03), but pattern of scoring differed by CTPA form and order of administration. Our results indicate that the CTPA forms were similar but that the specific tasks in each form were different. The CTPA may be used as an ecologically valid outcome assessment with further considerations.

Document Type: Article
Source: Scopus


Shaw, J.A.a , Bryant, L.K.b , Malle, B.F.c , Povinelli, D.J.d , Pruett, J.R., Jr.e
The relationship between joint attention and theory of mind in neurotypical adults
(2017) Consciousness and Cognition, 51, pp. 268-278. 

DOI: 10.1016/j.concog.2017.02.012

a Medical Scientist Training Program, Philosophy-Neuroscience-Psychology Program, Washington University in St. Louis, 1 Brookings Drive, St. Louis, MO, United States
b Vanderbilt Brain Institute, Vanderbilt University School of Medicine, 2215 Garland Ave., Nashville, TN, United States
c Department of Cognitive, Linguistic, and Psychological Sciences, Brown University, 190 Thayer Street, Providence, RI, United States
d Department of Biology, University of Louisiana, 104 University Circle, Lafayette, LA, United States
e Department of Psychiatry, Washington University in St. Louis, School of Medicine, 660 S. Euclid Ave., St. Louis, MO, United States

Joint attention (JA) is hypothesized to have a close relationship with developing theory of mind (ToM) capabilities. We tested the co-occurrence of ToM and JA in social interactions between adults with no reported history of psychiatric illness or neurodevelopmental disorders. Participants engaged in an experimental task that encouraged nonverbal communication, including JA, and also ToM activity. We adapted an in-lab variant of experience sampling methods (Bryant et al., 2013) to measure ToM during JA based on participants’ subjective reports of their thoughts while performing the task. This experiment successfully elicited instances of JA in 17/20 dyads. We compared participants’ thought contents during episodes of JA and non-JA. Our results suggest that, in adults, JA and ToM may occur independently. © 2017 The Authors

Author Keywords
Experience sampling;  Joint attention;  Social cognition;  Theory of mind

Document Type: Article
Source: Scopus


Krauss, M.J., Grucza, R.A., Bierut, L.J., Cavazos-Rehg, P.A.
"get drunk. Smoke weed. Have fun.": A Content Analysis of Tweets about Marijuana and Alcohol
(2017) American Journal of Health Promotion, 31 (3), pp. 200-208. 

DOI: 10.4278/ajhp.150205-QUAL-708

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

Purpose. To explore the sentiment and themes of Twitter chatter that mentions both alcohol and marijuana. Design. Cross-sectional analysis of tweets mentioning both alcohol and marijuana during 1 month was performed. Setting. The study setting was Twitter. Participants. Tweets sent from February 4 to March 5, 2014, were studied. Method. A random sample (n = 5000) of tweets that mentioned alcohol and marijuana were qualitatively coded as normalizing both substances, preferring one substance over the other, or discouraging both substances. Other common themes were identified. Results. More than half (54%) of the tweets normalized marijuana and alcohol (without preferring one substance over the other), and 24% preferred marijuana over alcohol. Only 2% expressed a preference for alcohol over marijuana, 7% discouraged the use of both substances, and the sentiment was unknown for 13% of the tweets. Common themes among tweets that normalized both substances included using the substances with friends (17%) and mentioning substance use in the context of sex or romance (14%). Common themes among tweets that preferred marijuana over alcohol were the beliefs that marijuana is safer than alcohol (46%) and preferences for effects of marijuana over alcohol (40%). Conclusion. Tweets normalizing polysubstance use or encouraging marijuana use over alcohol use are common. Both online and offline prevention efforts are needed to increase awareness of the risks associated with polysubstance use and marijuana use. © 2016 by American Journal of Health Promotion, Inc.

Author Keywords
Health focus: social health;  Outcome measure: behavioral;  Research purpose: descriptive;  Setting: national;  Social Media, Alcohol, Marijuana, Twitter, Prevention Research. Manuscript format: research;  Strategy: behavior change;  Study design: content analysis;  Target population age: youth, adults;  Target population circumstances: education/income level

Document Type: Article
Source: Scopus


Colonna, M.a , Butovsky, O.b
Microglia function in the central nervous system during health and neurodegeneration
(2017) Annual Review of Immunology, 35, pp. 441-468. 

DOI: 10.1146/annurev-immunol-051116-052358

a Department of Pathology and Immunology, Washington University, School of Medicine, St. Louis, MO, United States
b Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States

Microglia are resident cells of the brain that regulate brain development, maintenance of neuronal networks, and injury repair. Microglia serve as brain macrophages but are distinct from other tissue macrophages owing to their unique homeostatic phenotype and tight regulation by the central nervous system (CNS) microenvironment. They are responsible for the elimination of microbes, dead cells, redundant synapses, protein aggregates, and other particulate and soluble antigens that may endanger the CNS. Furthermore, as the primary source of proinflammatory cytokines, microglia are pivotal mediators of neuroinflammation and can induce or modulate a broad spectrum of cellular responses. Alterations in microglia functionality are implicated in brain development and aging, as well as in neurodegeneration. Recent observations about microglia ontogeny combined with extensive gene expression profiling and novel tools to study microglia biology have allowed us to characterize the spectrum of microglial phenotypes during development, homeostasis, and disease. In this article, we review recent advances in our understanding of the biology of microglia, their contribution to homeostasis, and their involvement in neurodegeneration. Moreover, we highlight the complexity of targeting microglia for therapeutic intervention in neurodegenerative diseases. © 2017 by Annual Reviews. All rights reserved.

Author Keywords
Homeostasis;  Microglia;  Neurodegeneration;  Phenotypes;  Receptors;  Regulation

Document Type: Review
Source: Scopus


Walter, C.a , Crawford, L.b , Lai, M.c , Toonen, J.A.b , Pan, Y.b , Sakiyama-Elbert, S.d , Gutmann, D.H.b , Pathak, A.a c
Increased Tissue Stiffness in Tumors from Mice with Neurofibromatosis-1 Optic Glioma
(2017) Biophysical Journal, 112 (8), pp. 1535-1538. 

DOI: 10.1016/j.bpj.2017.03.017

a Department of Biomedical Engineering, Washington University, St. Louis, Missouri, United States
b Department of Neurology, Washington University School of Medicine, St. Louis, Missouri, United States
c Department of Mechanical Engineering and Materials Science, Washington University, St. Louis, Missouri, United States
d Department of Biomedical Engineering, University of Texas-Austin, Austin, Texas, United States

Children with neurofibromatosis type 1 (NF1) cancer predisposition syndrome are prone to the development of low-grade brain tumors (gliomas) within the optic pathway (optic gliomas). One of the key obstacles to developing successful therapeutic strategies for these tumors is the striking lack of information about the mechanical properties that characterize these tumors relative to non-neoplastic optic nerve tissue. To study the physical changes that may occur when an optic nerve glioma is present, we employed atomic force microscopy to measure the stiffness of healthy versus tumor-bearing optic nerve tissue. We found that the average elastic moduli of non-neoplastic and tumor-bearing optic nerves were
3 and 6 kPa, respectively. Based on previous studies implicating changes in extracellular matrix remodeling in other, related optic nerve pathological states, we found decreased expression of one major metalloproteinase protein (MMP-2) and unchanged expression of lysyl oxidase and a second metalloproteinase, MMP-9, in murine optic gliomas relative to normal non-neoplastic optic nerve. Collectively, these observations suggest a productive interplay between physical properties of mouse optic nerve gliomas and the extracellular matrix. © 2017 Biophysical Society

Document Type: Article
Source: Scopus


Wong, A.W.K.a b , Ng, S.b c , Dashner, J.a , Baum, M.C.d , Hammel, J.e , Magasi, S.f , Lai, J.-S.g , Carlozzi, N.E.h , Tulsky, D.S.i , Miskovic, A.j , Goldsmith, A.j , Heinemann, A.W.j k
Relationships between environmental factors and participation in adults with traumatic brain injury, stroke, and spinal cord injury: a cross-sectional multi-center study
(2017) Quality of Life Research, pp. 1-13. Article in Press. 

DOI: 10.1007/s11136-017-1586-5

a Program in Occupational Therapy and Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
b Program in Occupational Therapy, Washington University School of Medicine, 4444 Forest Park Ave, Campus Box 8505, St. Louis, MO, United States
c Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore
d Program in Occupational Therapy, Department of Neurology and George Warren Brown School of Social Work, Washington University, St. Louis, MO, United States
e Departments of Occupational Therapy and Disability and Human Development, University of Illinois at Chicago, Chicago, IL, United States
f Department of Occupational Therapy, University of Illinois at Chicago, Chicago, IL, United States
g Departments of Medical Social Science and Pediatric, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
h Department of Physical Medicine and Rehabilitation, University of Michigan Medical School, Ann Arbor, MI, United States
i Department of Physical Therapy, University of Delaware, Newark, DE, United States
j Center for Rehabilitation Outcomes Research, Rehabilitation Institute of Chicago, Chicago, IL, United States
k Department of Physical Medicine and Rehabilitation, Northwestern University Feinberg School of Medicine, Chicago, IL, United States

Purpose: To develop and evaluate a model of environmental factors-participation relationships for persons with traumatic brain injury (TBI), stroke, and spinal cord injury (SCI), and test whether this model differed across three diagnostic groups, as well as other demographic and clinical characteristics. Methods: A cross-sectional observational study included 545 community-dwelling adults with neurological disorders (TBI = 166; stroke = 189; SCI = 190) recruited at three academic medical centers. Participants completed patient-reported measures of environmental factors and participation. Results: The final structural equation model had acceptable fit to the data (CFI = 0.923; TLI = 0.898; RMSEA = 0.085; SRMR = 0.053), explaining 63% of the variance in participation in social roles and activities. Systems, services, and policies had an indirect influence on participation and this relation was mediated by social attitudes and the built and natural environment. Access to information and technology was associated with the built and natural environment which in turn influence on participation (ps < 0.001). The model was consistent across sex, diagnosis, severity/type of injury, education, race, age, marital status, years since injury, wheelchairs use, insurance coverage, personal or household income, and crystallized cognition. Conclusions: Social and physical environments appear to mediate the influence of systems, services, and policies on participation after acquired neurological disorders. These relations are stable across three diagnostic groups and many personal and clinical factors. Our findings inform health and disability policy, and provide guidance for implementing the initiatives in Healthy People 2020 in particular for people with acquired neurological disorders. © 2017 Springer International Publishing Switzerland

Author Keywords
Environment;  Participation;  Spinal cord injury;  Stroke;  Traumatic brain injury

Document Type: Article in Press
Source: Scopus


McCarty, S., Eickmeyer, S.M., Kocherginsky, M., Keeshin, S., Shahpar, S., Semik, P., Wong, A.W.K.
Health-Related Quality of Life and Cancer-Related Symptoms During Interdisciplinary Outpatient Rehabilitation for Malignant Brain Tumor
(2017) American Journal of Physical Medicine and Rehabilitation, . Article in Press. 

DOI: 10.1097/PHM.0000000000000756

From the Department of Physical Medicine and Rehabilitation, Northwestern University Feinberg School of Medicine, Chicago, Illinois (SM, SK, SS); Physical Medicine and Rehabilitation, University of Kansas Medical Center, Kansas City, Kansas (SME); Department of Preventive Medicine, Division of Biostatistics, Northwestern University Feinberg School of Medicine, Chicago, Illinois (MK); Center of Rehabilitation Outcomes Research, Rehabilitation Institute of Chicago, Chicago, Illinois (PS); and Occupational Therapy and Neurology, Washington University School of Medicine, St. Louis, Missouri (AWKW).

OBJECTIVE: The aim of the study was to determine the relationships between functional outcomes, clinical symptoms, and health-related quality of life among patients with malignant brain tumors receiving interdisciplinary outpatient rehabilitation. DESIGN: A prospective study of 49 adults with malignant brain tumors participating in outpatient therapies was performed. Outcome measures included the Functional Assessment of Cancer Therapy-Brain (FACT-Br) for health-related quality of life and the Patient-Reported Outcome Measures Instrument Survey (PROMIS) Depression and Pain Behavior scales measured at admission, discharge, 1 and 3 mos after discharge. Day Rehabilitation Outcome Scale, a functional measure, was measured at admission and discharge. RESULTS: The FACT-Br scores, PROMIS pain, and PROMIS depression scores did not significantly change. There were many negative associations seen between FACT-Br and PROMIS depression (all P < .0001) and less associations with PROMIS pain. There was a positive correlation between Day Rehabilitation Outcome Scale and FACT-Br (P = .0058) and a negative association with PROMIS pain (P = .028), but not with PROMIS depression. There were no correlations between Day Rehabilitation Outcome Scale gains and change in PROMIS depression, FACT-Br total, or PROMIS pain. CONCLUSIONS: Health-related quality of life, pain, and depression did not worsen. Patients who reported less depression and pain had better reported health-related quality of life. Level of function was also associated with HRQOL and pain, but not depression. Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.

Document Type: Article in Press
Source: Scopus


Bauernfeind, A.L.a b , Babbitt, C.C.c
The predictive nature of transcript expression levels on protein expression in adult human brain
(2017) BMC Genomics, 18 (1), art. no. 322, . 

DOI: 10.1186/s12864-017-3674-x

a Washington University Medical School, Department of Neuroscience, St. Louis, MO, United States
b Washington University in St. Louis, Department of Anthropology, St. Louis, MO, United States
c University of Massachusetts Amherst, Department of Biology, Amherst, MA, United States

Background: Next generation sequencing methods are the gold standard for evaluating expression of the transcriptome. When determining the biological implications of such studies, the assumption is often made that transcript expression levels correspond to protein levels in a meaningful way. However, the strength of the overall correlation between transcript and protein expression is inconsistent, particularly in brain samples. Results: Following high-throughput transcriptomic (RNA-Seq) and proteomic (liquid chromatography coupled with tandem mass spectrometry) analyses of adult human brain samples, we compared the correlation in the expression of transcripts and proteins that support various biological processes, molecular functions, and that are located in different areas of the cell. Although most categories of transcripts have extremely weak predictive value for the expression of their associated proteins (R2 values of &lt; 10%), transcripts coding for protein kinases and membrane-associated proteins, including those that are part of receptors or ion transporters, are among those that are most predictive of downstream protein expression levels. Conclusions: The predictive value of transcript expression for corresponding proteins is variable in human brain samples, reflecting the complex regulation of protein expression. However, we found that transcriptomic analyses are appropriate for assessing the expression levels of certain classes of proteins, including those that modify proteins, such as kinases and phosphatases, regulate metabolic and synaptic activity, or are associated with a cellular membrane. These findings can be used to guide the interpretation of gene expression results from primate brain samples. © 2017 The Author(s).

Author Keywords
Chimpanzee;  Gene;  Proteomics;  RNA-Seq

Document Type: Article
Source: Scopus


Ulrich, J.D.a b c , Ulland, T.K.d , Colonna, M.d , Holtzman, D.M.a b c
Elucidating the Role of TREM2 in Alzheimer's Disease
(2017) Neuron, 94 (2), pp. 237-248. 

DOI: 10.1016/j.neuron.2017.02.042

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 Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, United States
d Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States

Alzheimer's disease (AD) is the sixth leading cause of death in the United States and the most common cause of dementia in the elderly. Genetic factors, such as rare variants in the microglial-expressed gene TREM2, strongly impact the lifetime risk of developing AD. Several recent studies have described dramatic TREM2-dependent phenotypes in mouse models of amyloidosis that point to an important role for TREM2 in regulating the response of the innate immune system to Aβ pathology. Furthermore, elevations in the CSF levels of soluble TREM2 fragments implicate changes in inflammatory pathways as occurring coincident with markers of neuronal damage and the onset of clinical dementia in AD. Here, we review the rapidly developing literature surrounding TREM2 in AD that may provide novel insight into the broader role of the innate immune system in neurodegenerative disease. © 2017 Elsevier Inc.

Author Keywords
Alzheimer's disease;  microglia;  TREM2

Document Type: Review
Source: Scopus


Yanamandra, K.a b , Patel, T.K.a , Jiang, H.a , Schindler, S.a , Ulrich, J.D.a , Boxer, A.L.c , Miller, B.L.c , Kerwin, D.R.d , Gallardo, G.a , Stewart, F.a , Finn, M.B.a , Cairns, N.J.a , Verghese, P.B.e , Fogelman, I.e , West, T.e , Braunstein, J.e , Robinson, G.a , Keyser, J.a , Roh, J.a , Knapik, S.S.e , Hu, Y.e , Holtzman, D.M.a
Anti-tau antibody administration increases plasma tau in transgenic mice and patients with tauopathy
(2017) Science Translational Medicine, 9 (386), art. no. eaal2029, . 

DOI: 10.1126/scitranslmed.aal2029

a Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Department of Neurology, Washington University, St. Louis, MO, United States
b AbbVie Inc., Foundational Neuroscience Center, Cambridge, MA, United States
c Clinical Trials Program, Memory and Aging Center, Department of Neurology, University of California, San Francisco, San Francisco, CA, United States
d Texas Alzheimer's and Memory Disorders, Texas Health Presbyterian Hospital Dallas, Dallas, TX, United States
e C2N Diagnostics, Center for Emerging Technologies, 4041 Forest Park Avenue, St. Louis, MO, United States

Tauopathies are a group of disorders in which the cytosolic protein tau aggregates and accumulates in cells within the brain, resulting in neurodegeneration. A promising treatment being explored for tauopathies is passive immunization with anti-tau antibodies. We previously found that administration of an anti-tau antibody to human tau transgenic mice increased the concentration of plasma tau. We further explored the effects of administering an anti-tau antibody on plasma tau. After peripheral administration of an anti-tau antibody to human patients with tauopathy and to mice expressing human tau in the central nervous system, there was a dose-dependent increase in plasma tau. In mouse plasma, we found that tau had a short half-life of 8 min that increased to more than 3 hours after administration of anti-tau antibody. As tau transgenic mice accumulated insoluble tau in the brain, brain soluble and interstitial fluid tau decreased. Administration of anti-tau antibody to tau transgenic mice that had decreased brain soluble tau and interstitial fluid tau resulted in an increase in plasma tau, but this increase was less than that observed in tau transgenic mice without these brain changes. Tau transgenic mice subjected to acute neuronal injury using 3-nitropropionic acid showed increased interstitial fluid tau and plasma tau. These data suggest that peripheral administration of an anti-tau antibody results in increased plasma tau, which correlates with the concentration of extracellular and soluble tau in the brain. 2017 © The Authors.

Document Type: Article
Source: Scopus


Mahdi, J.a , Shah, A.C.c , Sato, A.d , Morris, S.M.a , McKinstry, R.C.b , Listernick, R.e , Packer, R.J.d , Fisher, M.J.c f , Gutmann, D.H.a
A multi-institutional study of brainstem gliomas in children with neurofibromatosis type 1
(2017) Neurology, 88 (16), pp. 1584-1589. 

DOI: 10.1212/WNL.0000000000003881

a Departments of Neurology, United States
b Departments of Radiology, Washington University, School of Medicine, St. Louis, MO, United States
c Division of Oncology, Children's Hospital of PhiladelphiaPA, United States
d Center for Neuroscience of Behavioral Medicine, Children's National Medical Center, Washington, DC, United States
e Division of Academic General Pediatrics, Feinberg School of Medicine, Northwestern University, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, United States
f Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States

Objective: To define the clinical and radiologic features of brainstem gliomas (BSGs) in children with neurofibromatosis type 1 (NF1). Methods: We performed a retrospective cross-sectional study of 133 children with NF1 and concurrent BSGs cared for at 4 NF1 referral centers. BSG was determined using radiographic criteria. Age at diagnosis, tumor location and appearance, clinical symptoms, treatment, and presence of a concurrent optic pathway glioma were assessed. Results: The average age at BSG diagnosis was 7.2 years, and tumors occurred most often in the midbrain and medulla (66%). The majority of children with NF1-BSGs were asymptomatic (54%) and were not treated (88%). Only 9 of the 72 asymptomatic children received treatment because of progressive tumor enlargement. In contrast, 61 children presented with clinical signs/symptoms attributable to their BSG; these individuals were older and more often had focal lesions. Thirty-one patients underwent treatment for their tumor, and 14 received CSF diversion only. Progression-free survival was
3 years shorter for children receiving tumor-directed therapy relative to those who had either no treatment or CSF diversion only. Overall survival was 85% for the tumor-directed therapy group, whereas no deaths were reported in the untreated or CSF diversion groups. Conclusions: Unlike children with sporadically occurring BSGs, most children with NF1-BSGs were asymptomatic, and few individuals died from complications of their tumor. Those requiring tumor-directed treatment tended to be older children with focal lesions, and had clinically more aggressive disease relative to those who were not treated or underwent CSF diversion only. © 2017 American Academy of Neurology.

Document Type: Article
Source: Scopus


Marrie, R.A.a , Salter, A.b , Tyry, T.c , Cutter, G.R.d , Cofield, S.d , Fox, R.J.e
High hypothetical interest in physician-assisted death in multiple sclerosis
(2017) Neurology, 88 (16), pp. 1528-1534. Cited 1 time.

DOI: 10.1212/WNL.0000000000003831

a Departments of Internal Medicine and Community Health Sciences, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada
b Division of Biostatistics, Washington University in St. Louis, St. Louis, MO, United States
c Dignity Health, St. Joseph's Hospital and Medical Center, Phoenix, AZ, United States
d Department of Biostatistics, University of Alabama at Birmingham, United States
e Mellen Center, Department of Neurology, Cleveland ClinicOH, United States

Objective: To assess the opinions of persons with multiple sclerosis (MS) regarding physician-assisted death (PAD). Methods: We surveyed participants in the North American Research Committee on Multiple Sclerosis (NARCOMS) Registry regarding PAD. For each of 5 hypothetical situations, respondents indicated whether they definitely would, probably would, probably would not, or definitely would not consider PAD. They also reported their sociodemographics, disability status using Patient-Determined Disease Steps, depression status, pain status, religiosity, and degree of social support. Using multivariable logistic regression models, we evaluated the factors associated with an individual reporting that he or she would definitely or probably consider PAD in each situation. Results: Of 7,534 respondents, 6,011 (79.8%) were female, and 6,884 (92.9%) were white. Their mean (SD) age was 59.9 (10.2) years. Fifty percent of respondents reported at least moderate disability. Of the 6,792 respondents who responded to any of the PAD questions, 6,400 responded to all questions. Of these, 458 (7.1%) indicated that they would definitely consider PAD in all of the situations listed, while 1,275 (19.9%) indicated that they definitely would not consider PAD in any of the situations listed. If experiencing unbearable pain, 4,383 (65.3%) of respondents would definitely or probably consider PAD. On multivariable analysis, religiosity, social support, depression, pain, disability, sex, and race were associated with considering PAD in some or all of the situations presented. Conclusions: Depending upon the situation, a large proportion of persons with MS would consider PAD. The association of depression with considering PAD emphasizes the importance of diagnosing and treating depression. © 2017 American Academy of Neurology.

Document Type: Article
Source: Scopus


Ghossoub, E.a , Ghandour, L.A.b , Halabi, F.c , Zeinoun, P.d , Shehab, A.A.S.e , Maalouf, F.T.a
Prevalence and correlates of ADHD among adolescents in a Beirut community sample: Results from the BEI-PSY Study
(2017) Child and Adolescent Psychiatry and Mental Health, 11 (1), art. no. 20, . 

DOI: 10.1186/s13034-017-0156-5

a American University of Beirut, Department of Psychiatry, P.O. Box 11-0236, Riad El-Solh/Beirut, Lebanon
b American University of Beirut, Department of Epidemiology and Population Health, Faculty of Health Sciences, Beirut, Lebanon
c Washington University in St. Louis, Department of Psychiatry, St. Louis, United States
d Faculty of Arts and Sciences, American University of Beirut, Department of Psychology, Beirut, Lebanon
e Queens College, City University of New York, Department of PsychologyNY, United States

Background: This study aims to investigate the prevalence, correlates and treatment seeking behavior related to ADHD among adolescents from Lebanon. Methods: Five hundred and ten adolescents were recruited through multistage stratified cluster sampling of households in Beirut, and separately interviewed along with one parent/legal guardian, using the DAWBA. All adolescents completed the PRQ and the SDQ; the parent/legal guardian also completed the SDQ and provided basic demographic information, including attitudes towards seeking mental health services. Results: 10.20% of the adolescents were diagnosed with ADHD. Having ADHD was associated with having academic difficulties and being involved in bullying. Adolescents with ADHD also had higher odds of drinking alcohol, smoking cigarettes, and having comorbid emotional and conduct disorders (compared to those without ADHD). Adolescents with ADHD and their parents reported a higher burden of illness and were more likely to consider seeing a mental health professional than healthy adolescents and their parents. Conclusion: ADHD among adolescents in Lebanon warrants closer attention, mainly increased awareness in the larger public, and stronger commitment to increase treatment resources to the community. © 2017 The Author(s).

Author Keywords
Attention deficit disorder with hyperactivity;  Epidemiology;  Lebanon;  Patient acceptance of health care

Document Type: Article
Source: Scopus


Liu, C.-C.a , Hu, J.a c , Zhao, N.a , Wang, J.a , Wang, N.a c , Cirrito, J.R.b , Kanekiyo, T.a , Holtzman, D.M.b , Bu, G.a c
Astrocytic LRP1 mediates brain Aβ clearance and impacts amyloid deposition
(2017) Journal of Neuroscience, 37 (15), pp. 4023-4031. 

DOI: 10.1523/JNEUROSCI.3442-16.2017

a Department of Neuroscience, Mayo Clinic, Jacksonville, FL, United States
b Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, MO, United States
c Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, Fujian, China

Accumulation and deposition of amyloid-β (Aβ) in the brain represent an early and perhaps necessary step in the pathogenesis of Alzheimer’s disease (AD). Aβ accumulation leads to the formation of Aβ aggregates, which may directly and indirectly lead to eventual neurodegeneration. While Aβ production is accelerated in many familial forms of early-onset AD, increasing evidence indicates that impaired clearance of Aβ is more evident in late-onset AD. To uncover the mechanisms underlying impaired Aβ clearance in AD, we examined the role of low-density lipoprotein receptor-related protein 1 (LRP1) in astrocytes. Although LRP1 has been shown to play critical roles in brain Aβ metabolism in neurons and vascular mural cells, its role in astrocytes, the most abundant cell type in the brain responsible for maintaining neuronal homeostasis, remains unclear. Here, we show that astrocytic LRP1 plays a critical role in brain Aβ clearance. LRP1 knockdown in primary astrocytes resulted in decreased cellular Aβ uptake and degradation. In addition, silencing of LRP1 in astrocytes led to downregulation of several majorAβ-degrading enzymes, including matrix metalloproteasesMMP2,MMP9,and insulin-degrading enzyme. More important, conditional knock-out of the Lrp1 gene in astrocytes in the background of APP/PS1 mice impaired brainAβ clearance, exacerbatedAβ accumulation, and accelerated amyloid plaque deposition without affecting its production. Together, our results demonstrate that astrocyticLRP1plays an important role inAβ metabolism and that restoringLRP1expression and function in the brain could be an effective strategy to facilitate Aβ clearance and counter amyloid pathology in AD. © 2017 the authors.

Author Keywords
Alzheimer’s disease;  Amyloid-β;  LRP1

Document Type: Article
Source: Scopus


Shahim, P.a b c , Tegner, Y.d , Marklund, N.e , Höglund, K.a b c , Portelius, E.a b c , Brody, D.L.f g h , Blennow, K.a , Zetterberg, H.a b c i
Astroglial activation and altered amyloid metabolism in human repetitive concussion
(2017) Neurology, 88 (15), pp. 1400-1407. 

DOI: 10.1212/WNL.0000000000003816

a Institute of Neuroscience and Physiology, United States
b Department of Psychiatry and Neurochemistry, Sahlgrenska Academy, University of Gothenburg, Sweden
c Clinical Neurochemistry Laboratory, Sweden
d Sahlgrenska University Hospital, Division of Medical Sciences, Department of Health Sciences, Sweden
e Luleå University of Technology, Department of Neuroscience, Neurosurgery, Sweden
f Uppsala University, Uppsala, Sweden
g Washington University, School of Medicine, St. Louis, MO, United States
h Department of Molecular Neuroscience, United States
i UCL Institute of Neurology, London, United Kingdom

Objective: To determine whether postconcussion syndrome (PCS) due to repetitive concussive traumatic brain injury (rcTBI) is associated with CSF biomarker evidence of astroglial activation, amyloid deposition, and blood-brain barrier (BBB) impairment. Methods: A total of 47 participants (28 professional athletes with PCS and 19 controls) were assessed with lumbar puncture (median 1.5 years, range 0.25-12 years after last concussion), standard MRI of the brain, and Rivermead Post-Concussion Symptoms Questionnaire (RPQ). The main outcome measures were CSF concentrations of astroglial activation markers (glial fibrillary acidic protein [GFAP] and YKL-40), markers reflecting amyloid precursor protein metabolism (Aβ38, Aβ40, Aβ42, sAPPα, and sAPPβ), and BBB function (CSF:serum albumin ratio). Results: Nine of the 28 athletes returned to play within a year, while 19 had persistent PCS >1 year. Athletes with PCS >1 year had higher RPQ scores and number of concussions than athletes with PCS <1 year. Median concentrations of GFAP and YKL-40 were higher in athletes with PCS >1 year compared with controls, although with an overlap between the groups. YKL-40 correlated with RPQ score and the lifetime number of concussions. Athletes with rcTBI had lower concentrations of Aβ40 and Aβ42 than controls. The CSF:serum albumin ratio was unaltered. Conclusions: This study suggests that PCS may be associated with biomarker evidence of astroglial activation and β-amyloid (Aβ) dysmetabolism in the brain. There was no clear evidence of Aβ deposition as Aβ40 and Aβ42 were reduced in parallel. The CSF:serum albumin ratio was unaltered, suggesting that the BBB is largely intact in PCS. © 2017 American Academy of Neurology.

Document Type: Article
Source: Scopus


Guerriero, R.M., Schlaggar, B.L.
An important step toward a functional biomarker in pediatric TBI recovery and outcome
(2017) Neurology, 88 (15), pp. 1386-1387. 

DOI: 10.1212/WNL.0000000000003822

From the Department of Neurology, Division of Pediatric and Developmental Neurology, Washington University, St. Louis, MO, United States

Document Type: Editorial
Source: Scopus


Takeda, A.a , Perlmutter, J.S.b
Striatal molecular imaging of presynaptic markers
(2017) Neurology, 88 (15), pp. 1388-1389. 

DOI: 10.1212/WNL.0000000000003827

a Department of Neurology, National Hospital Organization, Sendai-Nishitaga Hospital, Sendai, Miyagi, Japan
b Departments of Neurology, Radiology, Washington University, School of Medicine, St. Louis, MO, United States

Document Type: Editorial
Source: Scopus


Lin, T.-H.a , Chiang, C.-W.a g , Perez-Torres, C.J.a h , Sun, P.a , Wallendorf, M.b , Schmidt, R.E.c , Cross, A.H.d e , Song, S.-K.a e f i
Diffusion MRI quantifies early axonal loss in the presence of nerve swelling
(2017) Journal of Neuroinflammation, 14 (1), art. no. 78, . 

DOI: 10.1186/s12974-017-0852-3

a Washington University School of Medicine, Radiology, 660 S Euclid Ave, St. Louis, MO, United States
b Washington University School of Medicine, Biostatistics, 660 S Euclid Ave, St. Louis, MO, United States
c Washington University School of Medicine, Pathology, 660 S Euclid Ave, St. Louis, MO, United States
d Washington University School of Medicine, Neurology, 660 S Euclid Ave, St. Louis, MO, United States
e Washington University School of Medicine, Hope Center for Neurological Disorders, 660 S Euclid Ave, St. Louis, MO, United States
f Washington University, Biomedical Engineering, 1 Brookings Dr, St. Louis, MO, United States
g National Health Research Institute, Institute of Biomedical Engineering and Nanomedicine, 35 Keyan Road, Zhunan, Miaoli County, Taiwan
h Purdue University, School of Health Sciences, 550 W Stadium Ave, West Lafayette, IN, United States
i Washington University School of Medicine, Biomedical MR Laboratory, Campus Box 8227, 4525 Scott Ave, St Louis, MO, United States

Background: Magnetic resonance imaging markers have been widely used to detect and quantify white matter pathologies in multiple sclerosis. We have recently developed a diffusion basis spectrum imaging (DBSI) to distinguish and quantify co-existing axonal injury, demyelination, and inflammation in multiple sclerosis patients and animal models. It could serve as a longitudinal marker for axonal loss, a primary cause of permanent neurological impairments and disease progression. Methods: Eight 10-week-old female C57BL/6 mice underwent optic nerve DBSI, followed by a week-long recuperation prior to active immunization for experimental autoimmune encephalomyelitis (EAE). Visual acuity of all mice was assessed daily. Longitudinal DBSI was performed in mouse optic nerves at baseline (naïve, before immunization), before, during, and after the onset of optic neuritis. Tissues were perfusion fixed after final in vivo scans. The correlation between DBSI detected pathologies and corresponding immunohistochemistry markers was quantitatively assessed. Results: In this cohort of EAE mice, monocular vision impairment occurred in all animals. In vivo DBSI detected, differentiated, and quantified optic nerve inflammation, demyelination, and axonal injury/loss, correlating nerve pathologies with visual acuity at different time points of acute optic neuritis. DBSI quantified, in the presence of optic nerve swelling, ~15% axonal loss at the onset of optic neuritis in EAE mice. Conclusions: Our findings support the notion that axonal loss could occur early in EAE mice. DBSI detected pathologies in the posterior visual pathway unreachable by optical coherence tomography and without confounding inflammation induced optic nerve swelling. DBSI could thus decipher the interrelationship among various pathological components and the role each plays in disease progression. Quantification of the rate of axonal loss could potentially serve as the biomarker to predict treatment outcome and to determine when progressive disease starts. © 2017 The Author(s).

Author Keywords
Axonal loss;  DBSI;  Diffusion MRI;  Multiple sclerosis;  Optic neuritis

Document Type: Article
Source: Scopus


Smith, S.B.a , Lichtenhan, J.T.b , Cone, B.K.a
Contralateral inhibition of click- and chirp-evoked human compound action potentials
(2017) Frontiers in Neuroscience, 11 (APR), art. no. 189, . 

DOI: 10.3389/fnins.2017.00189

a Department of Speech, Language and Hearing Sciences, University of Arizona, Tucson, AZ, United States
b Department of Otolaryngology, Washington University School of Medicine, St. Louis, MO, United States

Cochlear outer hair cells (OHC) receive direct efferent feedback from the caudal auditory brainstem via the medial olivocochlear (MOC) bundle. This circuit provides the neural substrate for the MOC reflex, which inhibits cochlear amplifier gain and is believed to play a role in listening in noise and protection from acoustic overexposure. The human MOC reflex has been studied extensively using otoacoustic emissions (OAE) paradigms; however, these measurements are insensitive to subsequent "downstream" efferent effects on the neural ensembles that mediate hearing. In this experiment, click- and chirp-evoked auditory nerve compound action potential (CAP) amplitudes were measured electrocochleographically from the human eardrum without and with MOC reflex activation elicited by contralateral broadband noise. We hypothesized that the chirp would be a more optimal stimulus for measuring neural MOC effects because it synchronizes excitation along the entire length of the basilar membrane and thus evokes a more robust CAP than a click at low to moderate stimulus levels. Chirps produced larger CAPs than clicks at all stimulus intensities (50-80 dB ppeSPL). MOC reflex inhibition of CAPs was larger for chirps than clicks at low stimulus levels when quantified both in terms of amplitude reduction and effective attenuation. Effective attenuation was larger for chirp- and click-evoked CAPs than for click-evoked OAEs measured from the same subjects. Our results suggest that the chirp is an optimal stimulus for evoking CAPs at low stimulus intensities and for assessing MOC reflex effects on the auditory nerve. Further, our work supports previous findings that MOC reflex effects at the level of the auditory nerve are underestimated by measures of OAE inhibition. © 2017 Smith, Lichtenhan and Cone.

Author Keywords
Chirps;  Compound action potential;  Efferent auditory system;  Electrocochleography;  Medial olivocochlear reflex

Document Type: Article
Source: Scopus


Frontera, W.R.a b , Bean, J.F.c d , Damiano, D.e , Ehrlich-Jones, L.f , Fried-Oken, M.g , Jette, A.h , Jung, R.i , Lieber, R.L.f , Malec, J.F.j , Mueller, M.J.k , Ottenbacher, K.J.l , Tansey, K.E.m , Thompson, A.n
Rehabilitation Research at the National Institutes of Health
(2017) Neurorehabilitation and Neural Repair, 31 (4), pp. 304-314. 

DOI: 10.1177/1545968317698875

a Department of Physical Medicine and Rehabilitation, Vanderbilt University Medical Center, Vanderbilt University School of Medicine, 2201 Children's Way, Nashville, TN, United States
b Department of Physical Medicine, Rehabilitation, and Sports Medicine, University of Puerto Rico, School of Medicine, San Juan, Puerto Rico, Puerto Rico
c Harvard Medical School, Boston, MA, United States
d New England GRECC, VA Boston Healthcare SystemMA, United States
e National Institutes of Health, Bethesda, MD, United States
f Northwestern Feinberg Medical School and Rehabilitation Institute of ChicagoIL, United States
g Oregon Health and Science University, Portland, OR, United States
h Boston UniversityMA, United States
i Florida International University, Miami, FL, United States
j Indiana University, School of Medicine and Rehabilitation, Hospital of Indiana, Indianapolis, IN, United States
k Washington University, School of Medicine, St Louis, MO, United States
l University of Texas Medical Branch, Galveston, TX, United States
m Jackson Veteran's Administration Medical CenterMS, United States
n Medical University of South Carolina, Charleston, SC, United States

Document Type: Article
Source: Scopus


Hawasli, A.H.a , Chacko, R.b , Szrama, N.P.b , Bundy, D.T.b , Pahwa, M.b , Yarbrough, C.K.a , Dlouhy, B.J.c , Limbrick, D.D.a , Barbour, D.L.b , Smyth, M.D.a , Leuthardt, E.C.a b
Electrophysiological sequelae of hemispherotomy in ipsilateral human cortex
(2017) Frontiers in Human Neuroscience, 11, art. no. 149, . 

DOI: 10.3389/fnhum.2017.00149

a Department of Neurological Surgery, Washington University School of Medicine, Saint Louis, MO, United States
b Department of Biomedical Engineering, Washington University School of Medicine, Saint Louis, MO, United States
c Department of Neurosurgery, University of Iowa Hospitals and Clinics, Iowa City, IA, United States

Objectives: Hemispheric disconnection has been used as a treatment of medically refractory epilepsy and evolved from anatomic hemispherectomy to functional hemispherectomies to hemispherotomies. The hemispherotomy procedure involves disconnection of an entire hemisphere with limited tissue resection and is reserved for medically-refractory epilepsy due to diffuse hemispheric disease. Although it is thought to be effective by preventing seizures from spreading to the contralateral hemisphere, the electrophysiological effects of a hemispherotomy on the ipsilateral hemisphere remain poorly defined. The objective of this study was to evaluate the effects of hemispherotomy on the electrophysiologic dynamics in peri-stroke and dysplastic cortex. Methods: Intraoperative electrocorticography (ECoG) was recorded from ipsilateral cortex in 5 human subjects with refractory epilepsy before and after hemispherotomy. Power spectral density, mutual information, and phase-amplitude coupling were measured from the ECoG signals. Results: Epilepsy was a result of remote perinatal stroke in three of the subjects. In two of the subjects, seizures were a consequence of dysplastic tissue: one with hemimegalencephaly and the second with Rasmussen's encephalitis. Hemispherotomy reduced broad-band power spectral density in peri-stroke cortex. Meanwhile, hemispherotomy increased power in the low and high frequency bands for dysplastic cortex. Functional connectivity was increased in lower frequency bands in peri-stroke tissue but not affected in dysplastic tissue after hemispherotomy. Finally, hemispherotomy reduced band-specific phase-amplitude coupling in peristroke cortex but not dysplastic cortex. Significance: Disconnecting deep subcortical connections to peri-stroke cortex via a hemispherotomy attenuates power of oscillations and impairs the transfer of information from large-scale distributed brain networks to the local cortex. Hence, hemispherotomy reduces heterogeneity between neighboring cortex while impairing phase-amplitude coupling. In contrast, dysfunctional networks in dysplastic cortex lack the normal connectivity with distant networks. Therefore hemispherotomy does not produce the same effects. © 2017 Hawasli, Chacko, Szrama, Bundy, Pahwa, Yarbrough, Dlouhy, Limbrick, Barbour, Smyth and Leuthardt.

Author Keywords
Cortical physiology;  Electrocorticography;  Epilepsy;  Hemispherotomy;  Oscillations

Document Type: Article
Source: Scopus


Wang, S.a b , Peterson, D.J.b , Wang, Y.c d e , Wang, Q.d , Grabowski, T.J.b f , Li, W.a , Madhyastha, T.M.b
Empirical comparison of diffusion kurtosis imaging and diffusion basis spectrum imaging using the same acquisition in healthy young adults
(2017) Frontiers in Neurology, 8 (MAR), art. no. 118, . 

DOI: 10.3389/fneur.2017.00118

a Institute of Diagnostic and Interventional Radiology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
b Department of Radiology, University of Washington, Seattle, WA, United States
c Department of Obstetrics and Gynecology, Washington University, St. Louis, MO, United States
d Department of Radiology, Washington University, St. Louis, MO, United States
e Department of Biomedical Engineering, Washington University, St. Louis, MO, United States
f Department of Neurology, University of Washington, Seattle, WA, United States

As diffusion tensor imaging gains widespread use, many researchers have been motivated to go beyond the tensor model and fit more complex diffusion models, to gain a more complete description of white matter microstructure and associated pathology. Two such models are diffusion kurtosis imaging (DKI) and diffusion basis spectrum imaging (DBSI). It is not clear which DKI parameters are most closely related to DBSI parameters,so in the interest of enabling comparisons between DKI and DBSI studies, we conducted an empirical survey of the interrelation of these models in 12 healthy volunteers using the same diffusion acquisition. We found that mean kurtosis is positively associated with the DBSI fiber ratio and negatively associated with the hindered ratio. This was primarily driven by the radial component of kurtosis. The axial component of kurtosis was strongly and specifically correlated with the restricted ratio. The joint spatial distributions of DBSI and DKI parameters are tissue-dependent and stable across healthy individuals. Our contribution is a better understanding of the biological interpretability of the parameters generated by the two models in healthy individuals. © 2017 Wang, Peterson, Wang, Wang, Grabowski, Li and Madhyastha.

Author Keywords
Diffusion basis spectrum imaging;  Diffusion kurtosis imaging;  Diffusion magnetic resonance imaging;  Diffusion tensor imaging;  Model comparison

Document Type: Article
Source: Scopus


Soundararajan, S.a , Narayanan, G.b , Agrawal, A.c , Murthy, P.b
Personality profile and short-term treatment outcome in patients with alcohol dependence: A study from South India
(2017) Indian Journal of Psychological Medicine, 39 (2), pp. 169-175. 

DOI: 10.4103/0253-7176.203127

a Department of Clinical Neurosciences, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, India
b Department of Psychiatry, Centre for Addiction Medicine, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, India
c Department of Psychiatry, Washington University School of Medicine, Saint Louis, MO, United States

Background: Studying personality profiles allows researchers to generate important hypotheses in risk factors and correlates of alcohol use/misuse. Studies examining the association between personality traits and treatment outcome are limited in India. We studied the correlation between personality and treatment outcome in patients with alcohol dependence. Methods: Adult participants with alcohol dependence were recruited from the inpatient and outpatient wards of de-addiction unit of a tertiary care facility in India using a prospective design and followed up after 3 months. Questionnaires administered were revised NEO personality inventory (NEO-PI-R), alcohol use disorders identification test, and advanced warning of alcohol relapse (AWARE). Results: Out of 99 recruited participants (92% males) with mean age of 37 (±8.36) years, 82 (82.8%) patients were followed up to 3 months. E4 (activity) facet of the extraversion domain in the NEO-PI-R significantly correlated with the baseline drinking scores (r = 0.204, P = 0.042, n = 99) and AWARE scores (r = 0.276, P = 0.043, n = 54). There was a significant negative correlation between the E2 (gregariousness) facet and satisfaction with life scores (r = -0.211, P = 0.036, n = 99). Age at first drink was significantly lower among relapsers (P = 0.021). Conclusion: Our study suggests that factors related to extraversion, specifically, high activity might be associated with higher drinking as well as higher risk of alcohol relapse. Predicting alcohol relapse by studying the personality traits would help clinicians in improving treatment outcomes. © 2017 Indian Psychiatric Society.

Author Keywords
Alcohol dependence;  extraversion;  personality;  relapse;  revised NEO personality inventory

Document Type: Article
Source: Scopus


Kober, D.L.a b , Brett, T.J.b c d
TREM2-Ligand Interactions in Health and Disease
(2017) Journal of Molecular Biology, . Article in Press. 

DOI: 10.1016/j.jmb.2017.04.004

a Molecular Microbiology and Microbial Pathogenesis Program, Washington University School of Medicine, St. Louis, MO 63110, USA
b Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
c Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110, USA
d Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110, USA

The protein triggering receptor expressed on myeloid cells-2 (TREM2) is an immunomodulatory receptor with a central role in myeloid cell activation and survival. In recent years, the importance of TREM2 has been highlighted by the identification of coding variants that increase risk for Alzheimer's disease and other neurodegenerative diseases. Animal studies have further shown the importance of TREM2 in neurodegenerative and other inflammatory disease models including chronic obstructive pulmonary disease, multiple sclerosis, and stroke. A mechanistic understanding of TREM2 function remains elusive, however, due in part to the absence of conclusive information regarding the identity of endogenous TREM2 ligands. While many TREM2 ligands have been proposed, their physiological role and mechanism of engagement remain to be determined. In this review, we highlight the suggested roles of TREM2 in these diseases and the recent advances in our understanding of TREM2 and discuss putative TREM2-ligand interactions and their potential roles in signaling during health and disease. We develop a model based on the TREM2 structure to explain how different TREM2 ligands might interact with the receptor and how disease risk variants may alter ligand interactions. Finally, we propose future experimental directions to establish the role and importance of these different interactions on TREM2 function. © 2017 Elsevier Ltd.

Author Keywords
Alzheimer's disease;  Immune signaling;  Inflammation;  Microglia;  Neurodegeneration

Document Type: Article in Press
Source: Scopus


Salas, J.a b , Scherrer, J.F.a b c , Schneider, F.D.a , Sullivan, M.D.d , Bucholz, K.K.e , Burroughs, T.c , Copeland, L.A.f g h , Ahmedani, B.K.i , Lustman, P.J.e j
New-onset depression following stable, slow, and rapid rate of prescription opioid dose escalation
(2017) Pain, 158 (2), pp. 306-312. 

DOI: 10.1097/j.pain.0000000000000763

a Department of Family and Community Medicine, Saint Louis University School of Medicine, 1402 S. Grand Blvd, St Louis, MO, United States
b Harry S. Truman Veterans Administration Medical Center, Columbia, MO, United States
c Saint Louis University Center for Outcomes Research, St. Louis, MO, United States
d Department of Psychiatry and Behavioral Health, University of Washington School of Medicine, Seattle, WA, United States
e Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
f Center for Applied Health Research, Baylor Scott and White Health, Central Texas Veterans Health Care System, Temple, TX, United States
g Texas AandM Health Science Center, Bryan, TX, United States
h UT Health Science Center, San Antonio, TX, United States
i Henry Ford Health System, Center for Health Policy and Health Services Research and Behavioral Health Services DetroitMI, United States
j Bell Street Clinic, VA St. Louis Health Care System-John Cochran Division, St. Louis, MO, United States

Recent studies suggest that longer durations of opioid use, independent of maximum morphine equivalent dose (MED) achieved, is associated with increased risk of new-onset depression (NOD). Conversely, other studies, not accounting for duration, found that higher MED increased probability of depressive symptoms. To determine whether rate of MED increase is associated with NOD, a retrospective cohort analysis of Veterans Health Administration data (2000-2012) was conducted. Eligible patients were new, chronic (>90 days) opioid users, aged 18 to 80, and without depression diagnoses for 2 years before start of follow-up (n = 7051). Mixed regression models of MED across follow-up defined 4 rate of dose change categories: Stable, decrease, slow increase, and rapid increase. Cox proportional hazard models assessed the relationship of rate of dose change and NOD, controlling for pain, duration of use, maximum MED, and other confounders using inverse probability of treatment-weighted propensity scores. Incidence rate for NOD was 14.1/1000PY (person-years) in stable rate, 13.0/1000PY in decreasing, 19.3/1000PY in slow increasing, and 27.5/1000PY in rapid increasing dose. Compared with stable rate, risk of NOD increased incrementally for slow (hazard ratio = 1.22; 95% confidence interval: 1.05-1.42) and rapid (hazard ratio = 1.58; 95% confidence interval: 1.30-1.93) rate of dose increase. Faster rates of MED escalation contribute to NOD, independent of maximum dose, pain, and total opioid duration. Dose escalation may be a proxy for loss of control or undetected abuse known to be associated with depression. Clinicians should avoid rapid dose increase when possible and discuss risk of depression with patients if dose increase is warranted for pain. © 2016 International Association for the Study of Pain.

Author Keywords
Depression;  Epidemiology;  Opioids;  Retrospective cohort

Document Type: Article
Source: Scopus


Jung, M.E.a , Colletta, M.a , Coalson, R.b , Schlaggar, B.L.c , Lieu, J.E.C.a
Differences in interregional brain connectivity in children with unilateral hearing loss
(2017) Laryngoscope, . Article in Press. 

DOI: 10.1002/lary.26587

a Department of Otolaryngology-Head and Neck SurgeryWashington University School of MedicineSt. Louis, Missouri U.S.A
b Departments of Neurology and RadiologyWashington University School of MedicineSt. Louis, Missouri U.S.A
c Departments of NeurologyRadiology, Neuroscience, Psychiatry, and Pediatrics, Washington University School of MedicineSt. Louis, Missouri U.S.A

Objectives: To identify functional network architecture differences in the brains of children with unilateral hearing loss (UHL) using resting-state functional-connectivity magnetic resonance imaging (rs-fcMRI). Study Design: Prospective observational study. Methods: Children (7 to 17 years of age) with severe to profound hearing loss in one ear, along with their normal hearing (NH) siblings, were recruited and imaged using rs-fcMRI. Eleven children had right UHL; nine had left UHL; and 13 had normal hearing. Forty-one brain regions of interest culled from established brain networks such as the default mode (DMN); cingulo-opercular (CON); and frontoparietal networks (FPN); as well as regions for language, phonological, and visual processing, were analyzed using regionwise correlations and conjunction analysis to determine differences in functional connectivity between the UHL and normal hearing children. Results: When compared to the NH group, children with UHL showed increased connectivity patterns between multiple networks, such as between the CON and visual processing centers. However, there were decreased, as well as aberrant connectivity patterns with the coactivation of the DMN and FPN, a relationship that usually is negatively correlated. Conclusion: Children with UHL demonstrate multiple functional connectivity differences between brain networks involved with executive function, cognition, and language comprehension that may represent adaptive as well as maladaptive changes. These findings suggest that possible interventions or habilitation, beyond amplification, might be able to affect some children's requirement for additional help at school. © 2017 The American Laryngological, Rhinological and Otological Society, Inc.

Author Keywords
Children;  MRI;  Unilateral hearing loss

Document Type: Article in Press
Source: Scopus


McPherson, C.a b , Smith, J.R.c
Analgesia in the premature neonate: Walking the tightrope requires a great team
(2017) Journal of Perinatal and Neonatal Nursing, 31 (2), pp. 99-100. 

DOI: 10.1097/JPN.0000000000000245

a Neonatal ICU, St. Louis Children's Hospital, St. Louis, MO, United States
b Department of Pediatrics, Washington University, School of Medicine, St. Louis, MO, United States
c Clinical Quality, Safety and Practice Excellence, St. Louis Children's HospitalMO, United States

Document Type: Note
Source: Scopus


Merz, Z.C.a , Van Patten, R.a , Mulhauser, K.a , Fucetola, R.b
Exploratory factor analysis of the reintegration to normal living index in a stroke population
(2017) Topics in Stroke Rehabilitation, 24 (2), pp. 158-162. 

DOI: 10.1080/10749357.2016.1215398

a Department of Psychology, Saint Louis University, St. Louis, MO, United States
b Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States

Background: The reintegration to normal living index (RNLI) is a global assessment of patient quality of life often utilized in stroke populations. Previous studies in various general disability samples have consistently reported a two-factor solution for the RNLI. Despite its common use with stroke patients, the RNLI has not been psychometrically evaluated in an exclusively stroke sample. This study is believed to represent the first factor analysis of the RNLI using a sample comprised exclusively of individuals who have survived cerebral infarct. Objective: The aim of this study is to evaluate the psychometric properties of the RNLI in assessing quality of life of stroke survivors. Methods: We retrospectively examined RNLI scores of 928 adults with strokes of varying severities as part of a multidisciplinary, interinstitutional collaboration across an academic medical center, acute care hospital, and rehabilitation center. We utilized a principal component factor analysis to evaluate the factor structure of the RNLI. Results: Mean RNLI scores ±SD for the sample were 75.26 ± 19.85, ranging between 20 and 100. The Cronbach α was.94. A scree test for factor retention strongly suggested a single factor solution, explaining 64.50% of the total variance. Conclusions: Previous factor analyses on the RNLI utilizing general disability samples commonly report a twofactor solution. Our data support the presence of a single factor solution across the RNLI within a large sample comprised exclusively of stroke survivors. This suggests that the RNLI acts as more of a unitary measure of quality of life within a stroke sample relative to other disabled samples. © 2016 Informa UK Limited, trading as Taylor & Francis Group.

Author Keywords
Activities of daily living;  Quality of life;  Rehabilitation;  Stroke

Document Type: Article
Source: Scopus


Taylor, S.R.a , Wang, T.J.b , Granados-Fuentes, D.b , Herzog, E.D.b
Resynchronization dynamics reveal that the ventral entrains the dorsal suprachiasmatic nucleus
(2017) Journal of Biological Rhythms, 32 (1), pp. 35-47. 

DOI: 10.1177/0748730416680904

a Department of Computer Science, Colby College, 5855 Mayflower Hill, Waterville, ME, United States
b Department of Biology, Washington University, St. Louis, MO, United States

Although the suprachiasmatic nucleus (SCN) has long been considered the master circadian clock in mammals, the topology of the connections that synchronize daily rhythms among SCN cells is not well understood. We combined experimental and computational methods to infer the directed interactions that mediate circadian synchrony between regions of the SCN. We analyzed PERIOD2 (PER2) expression from SCN slices during and after treatment with tetrodotoxin, allowing us to map connections as cells resynchronized their daily cycling following blockade and restoration of cell-cell communication. Using automated analyses, we found that cells in the dorsal SCN stabilized their periods slower than those in the ventral SCN. A phaseamplitude computational model of the SCN revealed that, to reproduce the experimental results: (1) the ventral SCN had to be more densely connected than the dorsal SCN and (2) the ventral SCN needed strong connections to the dorsal SCN. Taken together, these results provide direct evidence that the ventral SCN entrains the dorsal SCN in constant conditions. © 2016 The Author(s).

Author Keywords
Circadian;  Computational model;  Entrainment;  Period gene;  SCN;  Vasoactive intestinal polypeptide;  Vasopressin

Document Type: Article
Source: Scopus


Lean, R.E.a , Smyser, C.D.b c d , Rogers, C.E.a e
Assessment. The Newborn
(2017) Child and Adolescent Psychiatric Clinics of North America, . Article in Press. 

DOI: 10.1016/j.chc.2017.02.002

a Department of Psychiatry, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8504, St Louis, MO 63110, USA
b Department of Neurology, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8111, St Louis, MO 63110, USA
c Department of Radiology, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8111, St Louis, MO 63110, USA
d Department of Pediatrics, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8111, St Louis, MO 63110, USA
e Department of Pediatrics, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8504, St Louis, MO 63110, USA

Neonatal neurobehavioral assessment has become a standardized component of clinical care provided to newborn infants, guiding neonatal clinical care and subsequent access to early interventions and services. Links between neonatal assessment and neurosensory and motor impairments in high-risk infants have been relatively well established. In contrast, the extent to which newborn neurobehavioral assessment might also facilitate the early identification of infants susceptible to socioemotional impairments in early childhood is less well documented. This review examines longitudinal links between the neonatal neurobehavioral assessment, temperament, and socioemotional outcomes in early childhood. © 2017 Elsevier Inc.

Author Keywords
Assessment;  Neonate;  Neurobehavioral;  Socioemotional impairment;  Temperament

Document Type: Article in Press
Source: Scopus


Mulkey, S.B.a b , Ramakrishnaiah, R.H.b , McKinstry, R.C.c , Chang, T.a , Mathur, A.M.c , Mayock, D.E.d , Van Meurs, K.P.e , Schaefer, G.B.b , Luo, C.b , Bai, S.b , Juul, S.E.d , Wu, Y.W.f
Erythropoietin and Brain Magnetic Resonance Imaging Findings in Hypoxic-Ischemic Encephalopathy: Volume of Acute Brain Injury and 1-Year Neurodevelopmental Outcome
(2016) Journal of Pediatrics, . Article in Press. 

DOI: 10.1016/j.jpeds.2017.03.053

a Division of Fetal and Transitional Medicine, Children's National Health System, Washington, DC
b University of Arkansas for Medical Sciences, Little Rock, AR
c Washington University, St. Louis, MO
d University of Washington, Seattle, WA
e Stanford University, Palo Alto, CA
f University of California San Francisco, San Francisco, CA

In the Neonatal Erythropoietin and Therapeutic Hypothermia Outcomes study, 9/20 erythropoietin-treated vs 12/24 placebo-treated infants with hypoxic-ischemic encephalopathy had acute brain injury. Among infants with acute brain injury, the injury volume was lower in the erythropoietin than the placebo group (P = .004). Higher injury volume correlated with lower 12-month neurodevelopmental scores. Trial registration: NCT01913340. © 2017 Elsevier Inc.

Author Keywords
Brain volumetrics;  Diffusion weighted imaging;  Neuroprotection;  Newborn

Document Type: Article in Press
Source: Scopus


Strahle, J.a b , Maher, C.O.b
Are arachnoid cysts and Chiari malformation type i more common in those with postconcussion syndrome?
(2016) Journal of Neurosurgery, 125 (5), pp. 1320-1321. 

DOI: 10.3171/2016.4.JNS16788

a Washington University in St. Louis, St. Louis, MO, United States
b University of Michigan, Ann Arbor, MI, United States

Document Type: Editorial
Source: Scopus


Sylvester, P.T.a , Moran, C.J.b , Derdeyn, C.P.a b , Cross, D.T.b , Dacey, R.G.a , Zipfel, G.J.a , Kim, A.H.a , Uppaluri, R.c , Haughey, B.H.c , Tempelhoff, R.d , Rich, K.M.a , Schneider, J.c , Chole, R.A.c , Chicoine, M.R.a
Endovascular management of internal carotid artery injuries secondary to endonasal surgery: Case series and review of the literature
(2016) Journal of Neurosurgery, 125 (5), pp. 1256-1276. 

DOI: 10.3171/2015.6.JNS142483

a Department of Neurosurgery, Washington University School of Medicine, Box 8057, 660 S. Euclid Ave., St. Louis, MO, United States
b Division of Neuroradiology, Mallinckrodt Institute, Washington University School of Medicine, St. Louis, MO, United States
c Department of Otolaryngology, United States
d Department of Anesthesia, United States

Objective Internal carotid artery (ICA) injury is a rare but severe complication of endonasal surgery. The authors describe their endovascular experience managing ICA injuries after transsphenoidal surgery; they review and summarize the current literature regarding endovascular techniques; and they propose a treatment algorithm based on the available evidence. MethoDs A retrospective review of 576 transsphenoidal pituitary adenoma resections was performed. Cases of ICA injury occurring at our institution and transfers from other hospitals were evaluated. Endovascular treatments for ICA injury reported in the literature were also reviewed and summarized. resUlts Seven cases were identifed from the institutional cohort (mean age 46.3 years, mean follow-up 43.4 months [1-107 months]) that received endovascular treatment for ICA injury. Five injuries occurred at our institution (5 [0.9%] of 576), and 2 injuries occurred at outside hospitals. Three patients underwent ICA sacrifce by coil placement, 2 underwent lesion embolization (coil or stent-assisted coil placement), and 2 underwent endoluminal reconstruction (both with flow diversion devices). Review of the literature identifed 98 cases of ICA injury treated with endovascular methods. Of the 105 total cases, 46 patients underwent ICA sacrifce, 28 underwent lesion embolization, and 31 underwent endoluminal reconstruction. Sacrifce of the ICA proved a durable solution in all cases; however, the rate of persistent neurological complications was relatively high (10 [21.7%] of 46). Lesion embolization was primarily performed by coil embolization without stenting (16 cases) and stent-assisted coiling (9 cases). Both techniques had a relatively high rate of at least some technical complication (6 [37.5%] of 16 and 5 [55.6%] of 9, respectively) and major technical complications (i.e., injury, new neurological defcit, or ICA sacrifce) (5 [31.3%] of 16 and 2 [22.2%] of 9, respectively). Endoluminal reconstruction was performed by covered stent (24 cases) and flow diverter (5 cases) placement. Covered stents showed a reasonably high rate of technical complications (10 [41.7%] of 24); however, 8 of these problems were resolved, leaving a small percentage with major technical complications (2 [8.3%] of 24). Flow diverter placement was also well tolerated, with only 1 minor technical complication. coNclUsioNs Endovascular treatments including vessel sacrifce, coil embolization (with or without stent assistance), and endoluminal reconstruction offer a tailored approach to ICA injury management after endonasal surgery. Vessel sacrifce remains the defnitive treatment for acute, uncontrolled bleeding; however, vessel preservation techniques should be considered carefully in select patients. Multiple factors including vascular anatomy, injury characteristics, and risk of dual antiplatelet therapy should guide best treatment, but more study is needed (particularly with flow diverters) to refne this decision-making process. Ideally, all endovascular treatment options should be available at institutions performing endonasal surgery. © 2016 AANS.

Author Keywords
Decision making;  Endonasal surgery;  Endovascular procedures;  Internal carotid artery;  Pituitary surgery;  Treatment outcomes

Document Type: Article
Source: Scopus


Lewis, J.D.a , Evans, A.C.a , Pruett, J.R.b c , Botteron, K.N.b c , McKinstry, R.C.c , Zwaigenbaum, L.d , Estes, A.e , Collins, D.L.a , Kostopoulos, P.a , Gerig, G.g , Dager, S.f , Paterson, S.h , Schultz, R.T.h , Styner, M.i j , Hazlett, H.j , Piven, J.j
The Emergence of Network Inefficiencies in Infants With Autism Spectrum Disorder
(2016) Biological Psychiatry, . Article in Press. 

DOI: 10.1016/j.biopsych.2017.03.006

a Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada
b Department of Psychiatry, Washington University School of Medicine, Saint Louis, Missouri
c Department of Radiology, Washington University School of Medicine, Saint Louis, Missouri
d Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada
e Department of Speech and Hearing Sciences, University of Washington, Seattle, Washington
f Department of Radiology, University of Washington, Seattle, Washington
g Tandon School of Engineering, New York University, Brooklyn, New York
h Center for Autism Research, University of Pennsylvania, Philadelphia, Pennsylvania
i Department of Computer Science, University of North Carolina, Chapel Hill, North Carolina
j Carolina Institute for Developmental Disabilities, University of North Carolina, Chapel Hill, North Carolina

Background: Autism spectrum disorder (ASD) is a developmental disorder defined by behavioral features that emerge during the first years of life. Research indicates that abnormalities in brain connectivity are associated with these behavioral features. However, the inclusion of individuals past the age of onset of the defining behaviors complicates interpretation of the observed abnormalities: they may be cascade effects of earlier neuropathology and behavioral abnormalities. Our recent study of network efficiency in a cohort of 24-month-olds at high and low familial risk for ASD reduced this confound; we reported reduced network efficiencies in toddlers classified with ASD. The current study maps the emergence of these inefficiencies in the first year of life. Methods: This study uses data from 260 infants at 6 and 12 months of age, including 116 infants with longitudinal data. As in our earlier study, we use diffusion data to obtain measures of the length and strength of connections between brain regions to compute network efficiency. We assess group differences in efficiency within linear mixed-effects models determined by the Akaike information criterion. Results: Inefficiencies in high-risk infants later classified with ASD were detected from 6 months onward in regions involved in low-level sensory processing. In addition, within the high-risk infants, these inefficiencies predicted 24-month symptom severity. Conclusions: These results suggest that infants with ASD, even before 6 months of age, have deficits in connectivity related to low-level processing, which contribute to a developmental cascade affecting brain organization and eventually higher-level cognitive processes and social behavior. © 2017 Society of Biological Psychiatry.

Author Keywords
Autism;  Connectivity;  Development;  Efficiency;  Infant siblings;  Network analysis

Document Type: Article in Press
Source: Scopus