Arts & Sciences Brown School McKelvey School Medicine Weekly Publications

WashU weekly Neuroscience publications

“Statistical learning and spelling: Evidence from Brazilian prephonological spellers” (2019) Cognition

Statistical learning and spelling: Evidence from Brazilian prephonological spellers
(2019) Cognition, 182, pp. 1-7. 

Treiman, R.a , Cardoso-Martins, C.b , Pollo, T.C.c , Kessler, B.a

a Department of Psychological and Brain Sciences, Washington University in St. Louis, United States
b Departamento de Psicologia, Universidade Federal de Minas Gerais, Brazil
c Departamento de Psicologia, Universidade Federal de São João Del–Rei, Brazil

Abstract
We analyzed the spelling attempts of Brazilian children (age 3 years, 3 months to 6 years, 0 months) who were prephonological spellers, in that they wrote using letters that did not reflect the phonemes in the words they were asked to spell. We tested the hypothesis that children use their statistical-learning skills to learn about the appearance of writing and that older prephonological spellers, who have had on average more exposure to writing, produce more wordlike spellings than younger prephonological spellers. We found that older prephonological spellers produced longer spellings and were more likely to use letters and digrams in proportion to their frequency of occurrence in Portuguese. There were also some age-related differences in children’s tendency to use letters from their own names when writing other words. The results extend previous findings with learners of English to children who are learning a more transparent orthography. © 2018 Elsevier B.V.

Author Keywords
Graphotactics;  Literacy development;  Portuguese;  Spelling;  Statistical learning;  Writing

Document Type: Article
Source: Scopus

“Regionally specific TSC1 and TSC2 gene expression in tuberous sclerosis complex” (2018) Scientific Reports

Regionally specific TSC1 and TSC2 gene expression in tuberous sclerosis complex
(2018) Scientific Reports, 8 (1), art. no. 13373, . 

Li, Y.a , Barkovich, M.J.a , Karch, C.M.b , Nillo, R.M.a , Fan, C.-C.c , Broce, I.J.a , Tan, C.H.a , Cuneo, D.a , Hess, C.P.a , Dillon, W.P.a , Glenn, O.A.a , Glastonbury, C.M.a , Olney, N.d , Yokoyama, J.S.d , Bonham, L.W.d , Miller, B.d , Kao, A.d , Schmansky, N.e , Fischl, B.e f , Andreassen, O.A.g , Jernigan, T.c , Dale, A.c h , Barkovich, A.J.a i , Desikan, R.S.a i , Sugrue, L.P.a

a Neuroradiology Section, Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA 94143, United States
b Department of Psychiatry, Washington University, St. Louis, MO 63110, United States
c Department of Cognitive Sciences, University of California, San Diego, La Jolla, CA 92093, United States
d Memory and Aging Center, Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, United States
e Athinoula A. Martinos Center, Harvard Medical School, Charlestown, MA 02129, United States
f Health Science and Technology Program and Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Boston, MA 02139, United States
g NORMENT Institute of Clinical Medicine, University of Oslo and Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway
h Departments of Radiology and Neurosciences, University of California, San Diego, La Jolla, CA, United States
i Departments of Neurology and Pediatrics, University of California, San Francisco, San Francisco, CA 94143, United States

Abstract
Tuberous sclerosis complex (TSC), a heritable neurodevelopmental disorder, is caused by mutations in the TSC1 or TSC2 genes. To date, there has been little work to elucidate regional TSC1 and TSC2 gene expression within the human brain, how it changes with age, and how it may influence disease. Using a publicly available microarray dataset, we found that TSC1 and TSC2 gene expression was highest within the adult neo-cerebellum and that this pattern of increased cerebellar expression was maintained throughout postnatal development. During mid-gestational fetal development, however, TSC1 and TSC2 expression was highest in the cortical plate. Using a bioinformatics approach to explore protein and genetic interactions, we confirmed extensive connections between TSC1/TSC2 and the other genes that comprise the mammalian target of rapamycin (mTOR) pathway, and show that the mTOR pathway genes with the highest connectivity are also selectively expressed within the cerebellum. Finally, compared to age-matched controls, we found increased cerebellar volumes in pediatric TSC patients without current exposure to antiepileptic drugs. Considered together, these findings suggest that the cerebellum may play a central role in TSC pathogenesis and may contribute to the cognitive impairment, including the high incidence of autism spectrum disorder, observed in the TSC population. © 2018, The Author(s).

Document Type: Article
Source: Scopus
Access Type: Open Access

“The Association Between Racial Discrimination and Suicidality among African-American Adolescents and Young Adults” (2018) Archives of Suicide Research

The Association Between Racial Discrimination and Suicidality among African-American Adolescents and Young Adults
(2018) Archives of Suicide Research, 22 (4), pp. 584-595. 

Arshanapally, S.a , Werner, K.B.b , Sartor, C.E.c , Bucholz, K.K.d

a Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
b George Warren Brown School of Social Work, Washington University, St. Louis, MO, United States
c Department of Psychiatry, Yale University School of Medicine, New Haven, CT, United States
d Department of Psychiatry, Washington University School of Medicine and Alcoholism Research Center, Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States

Abstract
This study assessed the association between racial discrimination and suicidality (ideation, plan, or attempt) in African-American adolescents and young adults (n = 806, mean age = 17.9 years). Structured psychiatric phone interviews were conducted in offspring and their mothers in a high-risk alcoholism family study. Logistic regression analyses using offspring’s own racial discrimination as a predictor revealed elevated odds of suicidality, even after adjusting for correlated psychiatric conditions (OR = 1.76) but was reduced to non-significance after adjusting for maternal experiences of racial discrimination (OR = 3.19 in males), depression, and problem drinking. Findings support a link between racial discrimination and suicidality in African-American youth that, for males, is partially explained by maternal racial discrimination. © 2017, Copyright © International Academy for Suicide Research.

Author Keywords
adolescents;  African-Americans;  racial discrimination;  suicidality;  young adults

Document Type: Article
Source: Scopus

“Assessment of neuroplasticity in late-life depression with transcranial magnetic stimulation” (2018) Journal of Psychiatric Research

Assessment of neuroplasticity in late-life depression with transcranial magnetic stimulation
(2018) Journal of Psychiatric Research, 105, pp. 63-70. 

Bhandari, A.a , Lissemore, J.I.b , Rajji, T.K.a b c , Mulsant, B.H.b c , Cash, R.F.H.d , Noda, Y.e , Zomorrodi, R.a c , Karp, J.F.f g , Lenze, E.J.h , Reynolds, C.F., IIIf i , Daskalakis, Z.J.a b c , Blumberger, D.M.a b c j

a Temerty Centre for Therapeutic Brain Intervention, Centre for Addiction and Mental Health, Toronto, Ontario M6J 1H4, Canada
b Department of Psychiatry, University of Toronto, Toronto, Ontario M5T 1R8, Canada
c Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario M5T 1R8, Canada
d Monash University, Alfred Psychiatry Research Centre, Melbourne, Australia
e Department of Psychiatry, Faculty of Medicine, Keio University, Japan
f Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
g VAPHS, Geriatric Research, Education, and Clinical Center, United States
h Healthy Mind Lab, Department of Psychiatry, Washington University School of Medicine, St Louis, MO, United States
i Department of Psychiatry, Pittsburgh, PA, United States
j Department of Psychiatry, University of Toronto, 1001 Queen St. W. Unit 4, Room 115, Toronto, ON M6J 1H4, Canada

Abstract
Background: Studies using Transcranial Magnetic Stimulation (TMS), a non-invasive method of brain stimulation, have implicated impaired neuroplasticity in the pathophysiology of depression in younger adults. The role of neuroplasticity in late-life depression (LLD) has not yet been explored using TMS. Objective: This study aimed at evaluating motor cortical neuroplasticity using paired associative stimulation (PAS). Single-pulse TMS was used to induce motor-evoked potentials (MEP) in the contralateral hand muscle before and after PAS. The potentiation of MEP amplitudes after PAS was used as an indirect index of associative plasticity and long-term potentiation (LTP) (i.e. PAS-LTP). Results: 48 older adults with depression and 34 age-matched healthy controls (HC) were compared. PAS- LTP was successfully induced in 68.8% of older adults with depression and 47.1% of HC. At the group level, older adults with depression failed to show statistically significant induction of neuroplasticity, which was observed in HC. However, no significant differences were observed between the two groups for PAS-LTP. Conclusion: Our results suggest that associative plasticity does not differ substantially between older adults with depression and age-matched HC. Continued research is needed to more comprehensively understand the role of neuroplasticity in the pathophysiology of LLD. © 2018

Author Keywords
Aging;  Late-life depression;  Long-term potentiation;  N-Methyl-D-Aspartate;  Neuroplasticity;  Paired associative stimulation;  Transcranial magnetic stimulation

Document Type: Article
Source: Scopus

“Palmitoylation enables MAPK-dependent proteostasis of axon survival factors” (2018) Proceedings of the National Academy of Sciences of the United States of America

Palmitoylation enables MAPK-dependent proteostasis of axon survival factors
(2018) Proceedings of the National Academy of Sciences of the United States of America, 115 (37), pp. E8746-E8754. 

Summers, D.W.a b , Milbrandt, J.b c , DiAntonio, A.a c

a Department of Developmental Biology, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, United States
b Department of Genetics, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, United States
c Hope Center for Neurological Disorders, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, United States

Abstract
Axon degeneration is a prominent event in many neurodegenerative disorders. Axon injury stimulates an intrinsic self-destruction program that culminates in activation of the prodegeneration factor SARM1 and local dismantling of damaged axon segments. In healthy axons, SARM1 activity is restrained by constant delivery of the axon survival factor NMNAT2. Elevating NMNAT2 is neuroprotective, while loss of NMNAT2 evokes SARM1-dependent axon degeneration. As a gatekeeper of axon survival, NMNAT2 abundance is an important regulatory node in neuronal health, highlighting the need to understand the mechanisms behind NMNAT2 protein homeostasis. We demonstrate that pharmacological inhibition of the MAP3Ks dual leucine zipper kinase (DLK) and leucine zipper kinase (LZK) elevates NMNAT2 abundance and strongly protects axons from injury-induced degeneration. We discover that MAPK signaling selectively promotes degradation of palmitoylated NMNAT2, as well as palmitoylated SCG10. Conversely, nonpalmitoylated NMNAT2 is degraded by the Phr1/Skp1a/Fbxo45 ligase complex. Combined inactivation of both pathways leads to synergistic accumulation of NMNAT2 in axons and dramatically enhanced protection against pathological axon degeneration. Hence, the subcellular localization of distinct pools of NMNAT2 enables differential regulation of NMNAT2 abundance to control axon survival. © 2018 National Academy of Sciences. All Rights Reserved.

Author Keywords
Axon;  DLK;  NMNAT2;  SARM1;  SCG10

Document Type: Article
Source: Scopus

“The Trem2 R47H Alzheimer’s risk variant impairs splicing and reduces Trem2 mRNA and protein in mice but not in humans” (2018) Molecular Neurodegeneration

The Trem2 R47H Alzheimer’s risk variant impairs splicing and reduces Trem2 mRNA and protein in mice but not in humans
(2018) Molecular Neurodegeneration, 13 (1), art. no. 49, . 

Xiang, X.a b , Piers, T.M.c , Wefers, B.d f , Zhu, K.d e , Mallach, A.c , Brunner, B.d , Kleinberger, G.a e , Song, W.g , Colonna, M.g , Herms, J.d e h , Wurst, W.d e f i , Pocock, J.M.c , Haass, C.a d e

a Metabolic Biochemistry Biomedical Center (BMC), Faculty of Medicine, Ludwig-Maximilians-Universität München, Munich, Germany
b Graduate School of Systemic Neuroscience, Ludwig- Maximilians- University Munich, Munich, Germany
c Department of Neuroinflammation, Cell Signalling Lab, University College London, Institute of Neurology, London, WC1N 1PJ, United Kingdom
d German Center for Neurodegenerative Diseases (DZNE) Munich, Munich, Germany
e Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
f Institute of Developmental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
g Department of Immunology and Pathology, Washington University in St. Louis, St. Louis, MO, United States
h Center for Neuropathology and Prion Research, Ludwig-Maximilians-Universität München, Munich, Germany
i Technische Universität München-Weihenstephan, Neuherberg/Munich, 85764, Germany

Abstract
Background: The R47H variant of the Triggering Receptor Expressed on Myeloid cells 2 (TREM2) significantly increases the risk for late onset Alzheimer’s disease. Mouse models accurately reproducing phenotypes observed in Alzheimer’ disease patients carrying the R47H coding variant are required to understand the TREM2 related dysfunctions responsible for the enhanced risk for late onset Alzheimer’s disease. Methods: A CRISPR/Cas9-assisted gene targeting strategy was used to generate Trem2 R47H knock-in mice. Trem2 mRNA and protein levels as well as Trem2 splicing patterns were assessed in these mice, in iPSC-derived human microglia-like cells, and in human brains from Alzheimer’s patients carrying the TREM2 R47H risk factor. Results: Two independent Trem2 R47H knock-in mouse models show reduced Trem2 mRNA and protein production. In both mouse models Trem2 haploinsufficiency was due to atypical splicing of mouse Trem2 R47H, which introduced a premature stop codon. Cellular splicing assays using minigene constructs demonstrate that the R47H variant induced abnormal splicing only occurs in mice but not in humans. TREM2 mRNA levels and splicing patterns were both normal in iPSC-derived human microglia-like cells and patient brains with the TREM2 R47H variant. Conclusions: The Trem2 R47H variant activates a cryptic splice site that generates miss-spliced transcripts leading to Trem2 haploinsufficiency only in mice but not in humans. Since Trem2 R47H related phenotypes are mouse specific and do not occur in humans, humanized TREM2 R47H knock-in mice should be generated to study the cellular consequences caused by the human TREM2 R47H coding variant. Currently described phenotypes of Trem2 R47H knock-in mice can therefore not be translated to humans. © 2018 The Author(s).

Author Keywords
Alzheimer’s disease;  Human microglia;  Microglia;  Neurodegeneration;  Pre-mRNA splicing;  TREM2

Document Type: Article
Source: Scopus

“The development of purpose in life among adolescents who experience marginalization: Potential opportunities and obstacles” (2018) American Psychologist

The development of purpose in life among adolescents who experience marginalization: Potential opportunities and obstacles
(2018) American Psychologist, 73 (6), pp. 740-752. Cited 1 time.

Sumner, R.a , Burrow, A.L.b , Hill, P.L.c

a Bronfenbrenner Center for Translational Research, Cornell University, United States
b Department of Human Development, Cornell University, United States
c Department of Psychological and Brain Sciences, Washington University, St. Louis, United States

Abstract
In recent decades there has been a dramatic increase in the amount of research focused on purpose in life, demonstrating a host of benefits that emerge for individuals committed to a purpose. As with other constructs in the positive youth development framework, there is a paucity of work investigating how experiences of marginalization impact the development of this psychological asset among adolescents. To catalyze research on this front, we draw attention to potential opportunities and obstacles associated with experiences of marginalization and how they might affect an adolescent developing a purpose in life. Like García Coll and colleagues’ (1996) integrative model, our perspective includes sociocultural factors (e.g., social position, adaptive culture), an emphasis on intragroup variability, and discussion of potentially promoting and inhibiting aspects of marginalization. Following a description of existing research on purpose development during adolescence, we discuss how experiences of marginalization could contour the development of self-integrative, strong, and articulated purpose among adolescents. To conclude, specific considerations for future research are outlined, including how existing definitions of and tools for measuring purpose can be adapted to produce a scientific literature that values and includes the normative purpose development of adolescents who experience marginalization. © 2018 American Psychological Association.

Author Keywords
Adolescence;  Marginalization;  Purpose in life

Document Type: Article
Source: Scopus

“Associations of observed performance monitoring during preschool with obsessive-compulsive disorder and anterior cingulate cortex volume over 12 years” (2018) JAMA Psychiatry

Associations of observed performance monitoring during preschool with obsessive-compulsive disorder and anterior cingulate cortex volume over 12 years
(2018) JAMA Psychiatry, 75 (9), pp. 940-948. 

Gilbert, K.E.a , Barclay, M.E.a , Tillman, R.a , Barch, D.M.a b c d , Luby, J.L.a

a Department of Psychiatry, Washington University School of Medicine in St Louis, 4444 Forest Park, Ste 2100, St Louis, MO 63108, United States
b Program in Neuroscience, Washington University School of Medicine in St Louis, St Louis, MO, United States
c Department of Psychological and Brain Sciences, Washington University School of Medicine in St Louis, St Louis, MO, United States
d Department of Radiology, Washington University School of Medicine in St Louis, St Louis, MO, United States

Abstract
Importance: Monitoring one’s performance is necessary for learning and adaptive behavior; however, heightened performance monitoring is a purported endophenotype of obsessive-compulsive disorder (OCD). The anterior cingulate cortex (ACC), a brain region implicated in the pathogenesis of OCD, is associated with performance monitoring. Whether performance monitoring early in development is an identifiable risk factor for OCD and whether early childhood performance monitoring is associated with later alterations in ACC volume are unknown. Objective: To determine whether an observed indicator of heightened performance monitoring during the preschool age is associated with later onset of OCD and altered dorsal ACC (dACC) volume through adolescence. Design, Setting, and Participants: This longitudinal observational cohort studywas performed at an academic medical center as part of the Preschool Depression Study. A sample of 292 children oversampled for depression from September 22, 2003, through May 12, 2005, completed a performance-based observational task during which they received persistent negative evaluation. Blind raters behaviorally coded child performance monitoring. During the next 12 years, children completed annual diagnostic assessments; 133 completed the final behavioral follow-up and 152 contributed 1 to 3 magnetic resonance imaging scans. Follow-up was completed on August 14, 2017. Main Outcomes and Measures: Onset of DSM-5 diagnosis of OCD from baseline to the final behavioral assessment and whole-brain-adjusted dACC volume at the 3 waves of scanning. Results: Among the 292 preschool children who completed the baseline evaluation (51.4% boys; mean [SD] age, 4.5 [0.8] years), when controlling for demographic and clinical indicators, those who exhibited observed heightened performance monitoring were 2 times more likely to develop OCD (n = 35) during the next 12 years (odds ratio, 2.00; 95% CI, 1.06-3.78; P = .03). Multilevel modeling of dACC volume across the 3 scan waves (n = 152) demonstrated that heightened performance monitoring was associated with smaller right dACC volume (intercept estimate, -0.14; SE, 0.07; t = -2.17; P = .03). Conclusions and Relevance: An ecologically valid indicator of performance monitoring in early childhood was associated with onset of OCD and smaller dACC volumes in later childhood and adolescence. Early childhood observed performance monitoring is a readily observed risk factor of OCD that can be identified in preschool-aged children. © 2018 American Medical Association. All rights reserved.

Document Type: Article
Source: Scopus

“Ethical considerations in the use of Pernkopf’s Atlas of Anatomy: A surgical case study” (2018) Surgery (United States)

Ethical considerations in the use of Pernkopf’s Atlas of Anatomy: A surgical case study
(2018) Surgery (United States), . Article in Press. 

Yee, A.a , Zubovic, E.a , Yu, J.b , Ray, S.b , Hildebrandt, S.c d , Seidelman, W.E.e , Polak, R.J.A.f g h , Grodin, M.A.f g , Coert, J.H.i , Brown, D.b , Kodner, I.J.b , Mackinnon, S.E.a

a Division of Plastic and Reconstructive Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, MO, United States
b Department of Surgery, Washington University School of Medicine, St. Louis, MO, United States
c Division of General Pediatrics, Department of Pediatrics, Boston Children’s HospitalMA, United States
d Department of Global Health and Social Medicine, Harvard Medical School, Boston, MA, United States
e Department of Family and Community Medicine, Faculty of Medicine, University of TorontoON, Canada
f School of Public Health, Boston UniversityMA, United States
g Elie Wiesel Center for Jewish Studies, Boston UniversityMA, United States
h Rabbinical Court of New England, Boston, MA, United States
i Department of Plastic, Reconstructive, and Hand Surgery, Utrecht University Medical Center, Utrecht, Netherlands

Abstract
The use of Eduard Pernkopf’s anatomic atlas presents ethical challenges for modern surgery concerning the use of data resulting from abusive scientific work. In the 1980s and 1990s, historic investigations revealed that Pernkopf was an active National Socialist (Nazi) functionary at the University of Vienna and that among the bodies depicted in the atlas were those of Nazi victims. Since then, discussions persist concerning the ethicality of the continued use of the atlas, because some surgeons still rely on information from this anatomic resource for procedural planning. The ethical implications relevant to the use of this atlas in the care of surgical patients have not been discussed in detail. Based on a recapitulation of the main arguments from the historic controversy surrounding the use of Pernkopf’s atlas, this study presents an actual patient case to illustrate some of the ethical considerations relevant to the decision of whether to use the atlas in surgery. This investigation aims to provide a historic and ethical framework for questions concerning the use of the Pernkopf atlas in the management of anatomically complex and difficult surgical cases, with special attention to implications for medical ethics drawn from Jewish law. © 2018 Elsevier Inc.

Document Type: Article in Press
Source: Scopus

“Using Extracellular Circulating microRNAs to Classify the Etiological Subtypes of Ischemic Stroke” (2018) Translational Stroke Research

Using Extracellular Circulating microRNAs to Classify the Etiological Subtypes of Ischemic Stroke
(2018) Translational Stroke Research, . Article in Press. 

Gui, Y.X.a , Xu, Z.P.b , Jin, T.a , Zhang, L.S.a , Chen, L.L.a , Hong, B.a , Xie, F.a , Lv, W.a , Hu, X.Y.a

a Department of Neurology, Sir Run Run Shaw Hospital, Affiliated with School of Medicine, Zhejiang University, #3 Qingchun East Road, Hangzhou, Zhejiang 310016, China
b Washington University School of Medicine, St. Louis, MO, United States

Abstract
There is no effective biological method to classify ischemic stroke subtypes. In this study, we first performed a systematical gene array study on serum microRNAs with different ischemic stroke subtypes including 13 normal control subjects (NCs) and 87 ischemic stroke (IS) patients including 23 cardioembolism (CARD), 26 large artery atherosclerosis (LAA), 27 lacunar infarct (LAC), and 11 stroke of undetermined etiology (SUE). Validation was performed by using an independent cohort of 20 NCs and 85 IS patients including 28 CARD, 23 LAA, 18 LAC, and 16 SUE. In the pilot discovery gene array study, we found specific serum microRNA signatures between different ischemic stroke subtypes (CARD, LAA, LAC, and SUE). We further validated 6 microRNAs [miR-125b, miR-125a, let-7b, let-7e, miR-7-2-3p, miR-1908] in a different group of ischemic stroke subtypes by using an independent cohort of 20 NCs, 28 CARD, 23 LAA, 18 LAC, and 16 SUE. Moreover, these circulating miRNAs were further detected to be differentially expressed between pre- vs. post-stroke in different ischemic stroke subtypes. The ROC analysis showed that miR-125b, miR-125a, let-7b, and let-7e could discriminate CARD patients from normal controls and other subtypes. Furthermore, ROC curves shown that miR-7-2-3p and miR-1908 showed significant area-under-the-curve values in both LAA and LAC patients. In conclusion, these results demonstrated that circulating miRNAs in sera could be potentially novel risk factors that involve in the pathogenesis of ischemic stroke subtypes. © 2018, Springer Science+Business Media, LLC, part of Springer Nature.

Author Keywords
Ischemic stroke;  MicroRNA;  Subtype

Document Type: Article in Press
Source: Scopus

“Software for web-based tic suppression training – version 2; referees: 2 approved, 1 approved with reservations” (2018) F1000Research

Software for web-based tic suppression training [version 2; referees: 2 approved, 1 approved with reservations]
(2018) F1000Research, 6, art. no. 2150, . 

Black, J.K.a , Black, K.J.b

a Ira A. Fulton College of Engineering and Technology, Brigham Young University, Provo, UT 84602, United States
b Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
Exposure and response prevention (ERP) is a first-line behavior therapy for obsessive-compulsive disorder and Tourette syndrome (TS). However, ERP for tic disorders requires intentional tic suppression, which for some patients is difficult even for brief periods. Additionally, practical access to behavior therapy is difficult for many patients, especially those in rural areas. The authors present a simple, working web platform (TicTrainer) that implements a strategy called reward-enhanced exposure and response prevention (RE–ERP). This strategy sacrifices most expert therapist components of ERP, focusing only on increasing the duration of time for which the user can suppress tics through automated differential reinforcement of tic-free periods (DRO). RE–ERP requires an external tic monitor, such as a parent, during training sessions. The user sees increasing digital rewards for longer and longer periods of successful tic suppression, similar to a video game score. TicTrainer is designed with security in mind, storing no personally identifiable health information, and has features to facilitate research, including optional masked comparison of tics during DRO vs. noncontingent reward conditions. A working instance of TicTrainer is available from https://tictrainer.com/. © 2018 Black JK and Black KJ.

Author Keywords
Behavior therapy;  Reward;  Software;  Tic disorders;  Tourette syndrome

Document Type: Article
Source: Scopus
Access Type: Open Access

“Definition and Consensus Diagnostic Criteria for Neurosarcoidosis: From the Neurosarcoidosis Consortium Consensus Group” (2018) JAMA Neurology

Definition and Consensus Diagnostic Criteria for Neurosarcoidosis: From the Neurosarcoidosis Consortium Consensus Group
(2018) JAMA Neurology, . Article in Press. 

Stern, B.J.a , Royal, W.b , Gelfand, J.M.c , Clifford, D.B.d , Tavee, J.e , Pawate, S.f , Berger, J.R.g , Aksamit, A.J.h , Krumholz, A.i , Pardo, C.A.a , Moller, D.R.j , Judson, M.A.k , Drent, M.l , Baughman, R.P.m

a Department of Neurology, Johns Hopkins University, 601 N Caroline St, Baltimore, MD 21287, United States
b Department of Neurobiology, Neuroscience Institute, Morehouse School of Medicine, Atlanta, GA, United States
c Department of Neurology, University of California, San Francisco, San Francisco, United States
d Department of Neurology, Washington University in St Louis, St Louis, MO, United States
e Department of Neurology, Northwestern University, Chicago, IL, United States
f Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, United States
g Department of Neurology, University of Pennsylvania, Philadelphia, United States
h Department of Neurology, Mayo Clinic, Rochester, MN, United States
i Department of Neurology, University of Maryland, Baltimore, United States
j Department of Medicine, Johns Hopkins University, Baltimore, MD, United States
k Department of Medicine, Albany Medical College, Albany, NY, United States
l Department of Pharmacology and Toxicology, Faculty of Health Medicine and Life Sciences, Maastricht University Maastricht, Interstitial Lung Disease Center of Excellence, St. Antonius Hospital, Nieuwegein, Netherlands
m Department of Medicine, University of Cincinnati, Cincinnati, OH, United States

Abstract
Importance: The Neurosarcoidosis Consortium Consensus Group, an expert panel of physicians experienced in the management of patients with sarcoidosis and neurosarcoidosis, engaged in an iterative process to define neurosarcoidosis and develop a practical diagnostic approach to patients with suspected neurosarcoidosis. This panel aimed to develop a consensus clinical definition of neurosarcoidosis to enhance the clinical care of patients with suspected neurosarcoidosis and to encourage standardization of research initiatives that address this disease. Observations: The work of this collaboration included a review of the manifestations of neurosarcoidosis and the establishment of an approach to the diagnosis of this disorder. The proposed consensus diagnostic criteria, which reflect current knowledge, provide definitions for possible, probable, and definite central and peripheral nervous system sarcoidosis. The definitions emphasize the need to evaluate patients with findings suggestive of neurosarcoidosis for alternate causal factors, including infection and malignant neoplasm. Also emphasized is the need for biopsy, whenever feasible and advisable according to clinical context and affected anatomy, of nonneural tissue to document the presence of systemic sarcoidosis and support a diagnosis of probable neurosarcoidosis or of neural tissue to support a diagnosis of definite neurosarcoidosis. Conclusions and Relevance: Diverse disease presentations and lack of specificity of relevant diagnostic tests contribute to diagnostic uncertainty. This uncertainty is compounded by the absence of a pathognomonic histologic tissue examination. The diagnostic criteria we propose are designed to focus investigations on NS as accurately as possible, recognizing that multiple pathophysiologic pathways may lead to the clinical manifestations we currently term NS. Research recognizing the clinical heterogeneity of this diagnosis may open the door to identifying meaningful biologic factors that may ultimately contribute to better treatments. © 2018 American Medical Association. All rights reserved.

Document Type: Article in Press
Source: Scopus

“Comparison of urologic and non-urologic presentation in interstitial cystitis/bladder pain syndrome patients with and without Hunner lesions” (2018) Neurourology and Urodynamics

Comparison of urologic and non-urologic presentation in interstitial cystitis/bladder pain syndrome patients with and without Hunner lesions
(2018) Neurourology and Urodynamics, . Article in Press. 

Van Moh, F.a , Vetter, J.a , Lai, H.H.a b

a Division of Urologic Surgery, Department of Surgery, St. Louis, MO, United States
b Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Aims: To compare severity and characteristics of urologic pain, other urinary symptoms, sexual pain, psychosocial health, and the distribution and intensity of non-urologic pain between men and women with and without Hunner lesions. Methods: All cystoscopies were performed and documented by the same clinician to ensure uniform recognition of Hunner lesions. Intensity of urologic and sexual pain, nocturia, frequency, urgency, and bladder hypersensitivity features were assessed using validated questionnaires and numeric rating scales. The distribution and intensity of non-urologic pain was assessed using self-reported history, a body map diagram, and numeric rating scales. Somatic symptom burden, depression, and anxiety were compared. Results: Among the 150 participants, 27% (n = 41) had Hunner lesions (36% of men, 25% of women). Participants with Hunner lesions were significantly older (median age 58 vs 41, P < 0.001). They reported less intense urologic pain (5 vs 7, P = 0.024) and more nocturia (ICSI nocturia symptom score: 4 vs 3, P = 0.007). They also were less likely to have a history of irritable bowel syndrome (15% vs 36%, P = 0.013) and anxiety attacks (22% vs 44%, P = 0.013). Close to half of Hunner IC patients had non-urologic pain outside the pelvis. There were no differences in bladder hypersensitivity features (eg, painful bladder filling) between the two groups. Conclusions: Hunner lesions can be identified in both men and women. There are significant overlaps in terms of their urologic and non-urologic presentation. Further investigation is needed on phenotypic and biological distinction between IC/BPS with and without Hunner lesions. © 2018 Wiley Periodicals, Inc.

Author Keywords
chronic prostatitis;  Hunner lesion;  interstitial cystitis;  ulcerative interstitial cystitis

Document Type: Article in Press
Source: Scopus

“ESM-CT: a precise method for localization of DBS electrodes in CT images” (2018) Journal of Neuroscience Methods

ESM-CT: a precise method for localization of DBS electrodes in CT images
(2018) Journal of Neuroscience Methods, . Article in Press. 

Milchenko, M.a , Snyder, A.Z.a b , Campbell, M.C.a b , Dowling, J.L.c , Rich, K.M.c , Brier, L.M.a , Perlmutter, J.S.a b c d e f , Norris, S.A.b

a Mallinckrodt Institute of Radiology, Department of Radiology, Washington University School of Medicine, (CB 8225), 660 S. Euclid Avenue, St. Louis, MO 63110, United States
b Department of Neurology, Washington University School of Medicine, (CB 8111), 660 S. Euclid Avenue, St. Louis, MO 63110, United States
c Department of Neurosurgical Surgery, Washington University School of Medicine, (CB 8057), 660 S. Euclid Avenue, St. Louis, MO 63110, United States
d Department of Neuroscience, Washington University School of Medicine, (CB 8108), 660 S. Euclid Avenue, St. Louis, MO 63110, United States
e Department of Occupational Therapy, CB 8505, 4444 Forest Park Ave, St. Louis, MO 63108, United States
f Department of Physical Therapy, CB 8502, 4444 Forest Park Ave, St. Louis, MO 63108, United States

Abstract
Background: Deep brain stimulation (DBS) of the subthalamic nucleus produces variable effects in Parkinson disease. Variation may result from different electrode positions relative to target. Thus, precise electrode localization is crucial when investigating DBS effects. New method: We developed a semi-automated method, Electrode Shaft Modeling in CT images (ESM-CT) to reconstruct DBS lead trajectories and contact locations. We evaluated methodological sensitivity to operator-dependent steps, robustness to image resampling, and test-retest replicability. ESM-CT was applied in 56 patients to study electrode position change (and relation to time between scans, postoperative subdural air volume, and head tilt during acquisition) between images acquired immediately post-implantation (DBS-CT) and months later (DEL-CT). Results: Electrode tip localization was robust to image resampling and replicable to within 0.2 mm on test-retest comparisons. Systematic electrode displacement occurred rostral-ventral-lateral between DBS-CT and DEL-CT scans. Head angle was a major explanatory factor (p &lt; 0.001,Pearson’s r = 0.46, both sides) and volume of subdural air weakly predicted electrode displacement (p = 0.02,r = 0.29:p = 0.1,r = 0.25 for left:right). Modeled shaft curvature was slightly greater in DEL-CT. Magnitude of displacement and degree of curvature were independent of elapsed time between scans. Comparison with Existing Methods: Comparison of ESM-CT against two existing methods revealed systematic differences in one coordinate (1 ± 0.3 mm,p &lt; 0.001) for one method and in three coordinates for another method (x:0.1 ± 0.1 mm, y:0.4 ± 0.2 mm, z:0.4 ± 0.2 mm, p &lt; 10−10). Within-method coordinate variability across participants is similar. Conclusion: We describe a robust and precise method for CT DBS contact localization. Application revealed that acquisition head angle significantly impacts electrode position. DBS localization schemes should account for head angle. © 2018 Elsevier B.V.

Author Keywords
Brain shift;  Contact localization;  CT;  Deep brain stimulation (DBS);  Subthalamic nucleus (STN)

Document Type: Article in Press
Source: Scopus

“Genetic and environmental influences on gambling disorder liability: A replication and combined analysis of two twin studies” (2018) Psychological Medicine

Genetic and environmental influences on gambling disorder liability: A replication and combined analysis of two twin studies
(2018) Psychological Medicine, . Article in Press. 

Davis, C.N.a , Slutske, W.S.a , Martin, N.G.b , Agrawal, A.c , Lynskey, M.T.d

a University of Missouri, Columbia, MO, United States
b QIMR Berghofer, Brisbane, QLD, Australia
c Washington University, School of Medicine, St. Louis, MO, United States
d King’s College London Institute of Psychiatry, Psychology and Neuroscience, London, United Kingdom

Abstract
BackgroundGambling disorder (GD), recognized in Diagnostic and Statistical Manual of Mental Disorders, Version 5 (DSM-5) as a behavioral addiction, is associated with a range of adverse outcomes. However, there has been little research on the genetic and environmental influences on the development of this disorder. This study reports results from the largest twin study of GD conducted to date.MethodsReplication and combined analyses were based on samples of 3292 (mean age 31.8, born 1972-79) and 4764 (mean age 37.7, born 1964-71) male, female, and unlike-sex twin pairs from the Australian Twin Registry. Univariate biometric twin models estimated the proportion of variation in the latent GD liability that could be attributed to genetic, shared environmental, and unique environmental factors, and whether these differed quantitatively or qualitatively for men and women.ResultsIn the replication study, when using a lower GD threshold, there was evidence for significant genetic (60%; 95% confidence interval (CI) 45-76%) and unique environmental (40%; 95% CI 24-56%), but not shared environmental contributions (0%; 95% CI 0-0%) to GD liability; this did not significantly differ from the original study. In the combined analysis, higher GD thresholds (such as one consistent with DSM-5 GD) and a multiple threshold definitions of GD yielded similar results. There was no evidence for quantitative or qualitative sex differences in the liability for GD.ConclusionsTwin studies of GD are few in number but they tell a remarkably similar story: substantial genetic and unique environmental influences, with no evidence for shared environmental contributions or sex differences in GD liability. Copyright © Cambridge University Press 2018.

Author Keywords
Behavioral genetics;  gambling disorder;  sex differences;  twins

Document Type: Article in Press
Source: Scopus

“Commentary – consensus research priorities for facial palsy: A delphi survey of patients, carers, clinicians and researchers” (2018) Journal of Plastic, Reconstructive and Aesthetic Surgery

Commentary – consensus research priorities for facial palsy: A delphi survey of patients, carers, clinicians and researchers
(2018) Journal of Plastic, Reconstructive and Aesthetic Surgery, . Article in Press. 

Chi, J.J.

Division of Facial Plastic & Reconstructive Surgery, Department of Otolaryngology – Head & Neck Surgery, Washington University School of Medicine, St. Louis, MO, United States

Document Type: Article in Press
Source: Scopus

“The 2018 ISHLT/APM/AST/ICCAC/STSW recommendations for the psychosocial evaluation of adult cardiothoracic transplant candidates and candidates for long-term mechanical circulatory support” (2018) Psychosomatics

The 2018 ISHLT/APM/AST/ICCAC/STSW recommendations for the psychosocial evaluation of adult cardiothoracic transplant candidates and candidates for long-term mechanical circulatory support
(2018) Psychosomatics, . Article in Press. 

Dew, M.A.a , DiMartini, A.F.a , Dobbels, F.b , Grady, K.L.c , Jowsey-Gregoire, S.G.d , Kaan, A.e , Kendall, K.f , Young, Q.-R.e , Abbey, S.E.g , Butt, Z.c , Crone, C.C.h , De Geest, S.b i , Doligalski, C.T.j x , Kugler, C.k , McDonald, L.l , Ohler, L.m y , Painter, L.n , Petty, M.G.o , Robson, D.p , Schlöglhofer, T.q , Schneekloth, T.D.d , Singer, J.P.r , Smith, P.J.s , Spaderna, H.t , Teuteberg, J.J.u , Yusen, R.D.v , Zimbrean, P.C.w

a University of Pittsburgh School of Medicine and Medical Center, Pittsburgh, Pennsylvania, United States
b Katholieke Universiteit Leuven, Leuven, Belgium
c Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
d Mayo Clinic, Rochester, Minnesota, United States
e St. Paul’s Hospital, Vancouver, British Columbia, Canada
f Cleveland Clinic, Cleveland, Ohio, United States
g University of Toronto and University Health Network, Toronto, Ontario, Canada
h INOVA Hospitals, Fairfax, Virginia, United States
i University of Basel, Basel, Switzerland
j Tampa General Hospital, Tampa, Florida, United States
k University of Freiburg, Freiburg, Germany
l University of North Carolina, Chapel Hill, North Carolina, United States
m George Washington University, Washington, DC, United States
n Auckland City Hospital, Auckland, New Zealand
o University of Minnesota, Minneapolis, Minnesota, United States
p St. Vincent’s Hospital, Sydney, New South Wales, Australia
q Medical University of Vienna, Vienna, Austria
r University of California at San Francisco, San Francisco, California, United States
s Duke University, Durham, North Carolina, United States
t Trier University, Trier, Germany
u Stanford University, Stanford, California, United States
v Washington University, St. Louis, Missouri, United States
w Yale University, New Haven, Connecticut, United States
x University of North Carolina, Chapel Hill, NC, United States
y New York University Medical Center, New York, NY, United States

Abstract
The psychosocial evaluation is well-recognized as an important component of the multifaceted assessment process to determine candidacy for heart transplantation, lung transplantation, and long-term mechanical circulatory support (MCS). However, there is no consensus-based set of recommendations for either the full range of psychosocial domains to be assessed during the evaluation, or the set of processes and procedures to be used to conduct the evaluation, report its findings, and monitor patients’ receipt of and response to interventions for any problems identified. This document provides recommendations on both evaluation content and process. It represents a collaborative effort of the International Society for Heart and Lung Transplantation (ISHLT) and the Academy of Psychosomatic Medicine, American Society of Transplantation, International Consortium of Circulatory Assist Clinicians, and Society for Transplant Social Workers. The Nursing, Health Science and Allied Health Council of the ISHLT organized a Writing Committee composed of international experts representing the ISHLT and the collaborating societies. This Committee synthesized expert opinion and conducted a comprehensive literature review to support the psychosocial evaluation content and process recommendations that were developed. The recommendations are intended to dovetail with current ISHLT guidelines and consensus statements for the selection of candidates for cardiothoracic transplantation and MCS implantation. Moreover, the recommendations are designed to promote consistency across programs in the performance of the psychosocial evaluation by proposing a core set of content domains and processes that can be expanded as needed to meet programs’ unique needs and goals. © 2018 The Authors

Author Keywords
heart transplantation;  lung transplantation;  mechanical circulatory support;  psychosocial evaluation;  psychosocial risk factors.

Document Type: Article in Press
Source: Scopus

“Pupillary light reaction in preclinical Alzheimer’s disease subjects compared with normal ageing controls” (2018) British Journal of Ophthalmology

Pupillary light reaction in preclinical Alzheimer’s disease subjects compared with normal ageing controls
(2018) British Journal of Ophthalmology, . Article in Press. 

Van Stavern, G.P., Bei, L., Shui, Y.-B., Huecker, J., Gordon, M.

Department of Ophthalmology and Visual Sciences, Washington University, St. Louis School of Medicine, St. Louis, MO 63110, United States

Abstract
Background/aims: We wished to determine whether the pupillary light reaction can differentiate preclinical Alzheimer’s disease (AD) subjects from normal ageing controls. We performed a prospective study evaluating the pupillary light reaction in a cohort of well-characterised subjects with preclinical AD versus normal ageing controls. Methods: We recruited 57 subjects from our institution’s Memory and Aging Project, part of our Alzheimer’s Disease Research Center. All subjects completed PET-PiB imaging, cerebrospinal fluid analysis and at least 1 neuropsychiatric assessment after their baseline assessment. All participants were assigned a clinical dementia rating and underwent a complete neuro-ophthalmic examination. Participants were divided into a dementia biomarker+ (preclinical AD) and biomarker- (normal ageing) group based on preclinical risk for Alzheimer’s dementia. Pupillometry measurements were performed by using the NeurOptics PLR-200 Pupillometer. Results: A total of 57 subjects were recruited with 24 dementia biomarker+ and 33 dementia biomarker- individuals. A variety of pupil flash response (PLR) parameters were assessed. Comparisons between groups were analysed using generalised estimating equations. None of the pupillary parameters showed a significant difference between groups. Conclusions: We found no significant differences in PLR between preclinical AD subjects and normal ageing controls. This suggests that the disease effect on the PLR may be small and difficult to detect at the earliest stages of the disease. Future studies could include larger sample size and chromatic pupillometry. © Author(s) (or their employer(s)) 2018. No commercial re-use. See rights and permissions. Published by BMJ.

Author Keywords
physiology;  pupil

Document Type: Article in Press
Source: Scopus

“Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight” (2018) Nature Reviews Immunology

Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight
(2018) Nature Reviews Immunology, . Article in Press. 

Shi, Y., Holtzman, D.M.

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

Abstract
Alzheimer disease is more than a pure proteopathy. Chronic neuroinflammation stands out during the pathogenesis of the disease and in turn modulates disease progression. The central nervous system (CNS) is separated from the blood circulation by the blood–brain barrier. In Alzheimer disease, neuroinflammation heavily relies on innate immune responses that are primarily mediated by CNS-resident microglia. APOE (which encodes apolipoprotein E) is the strongest genetic risk factor for Alzheimer disease, and APOE was recently shown to affect the disease in part through its immunomodulatory function. This function of APOE is likely linked to triggering receptor expressed on myeloid cells 2 (TREM2), which is expressed by microglia in the CNS. Here, we review the rapidly growing literature on the role of disease-associated microglia, TREM2 and APOE in the pathogenesis of Alzheimer disease and present an integrated view of innate immune function in Alzheimer disease. © 2018, Springer Nature Limited.

Document Type: Article in Press
Source: Scopus

“Ecopipam, a D1 receptor antagonist, for treatment of tourette syndrome in children: A randomized, placebo-controlled crossover study” (2018) Movement Disorders

Ecopipam, a D1 receptor antagonist, for treatment of tourette syndrome in children: A randomized, placebo-controlled crossover study
(2018) Movement Disorders, . Article in Press. 

Gilbert, D.L.a , Murphy, T.K.b , Jankovic, J.c , Budman, C.L.d , Black, K.J.e , Kurlan, R.M.f , Coffman, K.A.g , McCracken, J.T.h , Juncos, J.i , Grant, J.E.j , Chipkin, R.E.k

a Cincinnati Children’s Hospital Medical Center, Department of Pediatrics, Cincinnati, OH, United States
b University of South Florida, Departments of Pediatrics and Psychiatry, Tampa, FL, United States
c Baylor College of Medicine, Department of Neurology, Houston, TX, United States
d Zucker School of Medicine, Hofstra/Northwell Department of Psychiatry, Northwell Health, Hempstead, NY, United States
e Washington University School of Medicine, Departments of Psychiatry, Neurology, Radiology, and Neuroscience, St. Louis, MO, United States
f Center for Neurological and Neurodevelopmental Health, Voorhees, NJ, United States
g Children’s Mercy Hospital, Kansas City, MO, United States
h UCLA Semel Institute for Neuroscience, Los Angeles, CA, United States
i Emory University School of Medicine, Department of Neurology & Brain Health Center, Atlanta, GA, United States
j University of Chicago, Department of Psychiatry & Behavioral Neuroscience, Chicago, IL, United States
k Psyadon Pharmaceuticals, Inc., Germantown, MD, United States

Abstract
Background: Dopamine D2 receptor antagonists used to treat Tourette syndrome may have inadequate responses or intolerable side effects. We present results of a 4-week randomized, double-blind, placebo-controlled crossover study evaluating the safety, tolerability, and efficacy of the D1 receptor antagonist ecopipam in children and adolescents with Tourette syndrome. Methods: Forty youth aged 7 to 17 years with Tourette syndrome and a Yale Global Tic Severity Scale – total tic score of ≥20 were enrolled and randomized to either ecopipam (50 mg/day for weight of <34 kg, 100 mg/day for weight of >34 kg) or placebo for 30 days, followed by a 2-week washout and then crossed to the alternative treatment for 30 days. Stimulants and tic-suppressing medications were excluded. The primary outcome measure was the total tic score. Secondary outcomes included obsessive compulsive and attention deficit/hyperactivity disorder scales. Results: Relative to changes in placebo, reduction in total tic score was greater for ecopipam at 16 days (mean difference, -3.7; 95% CI, -6.5 to -0.9; P = 0.011) and 30 days (mean difference, -3.2; 95% CI, -6.1 to -0.3; P = 0.033). There were no weight gain, drug-induced dyskinesias, or changes in laboratory tests, electrocardiograms, vital signs, or comorbid symptoms. Dropout rate was 5% (2 of 40). Adverse events reported for both treatments were rated predominantly mild to moderate, with only 5 rated severe (2 for ecopipam and 3 for placebo). Conclusions: Ecopipam reduced tics and was well tolerated. This placebo-controlled study of ecopipam supports further clinical trials in children and adolescents with Tourette syndrome. © 2018 International Parkinson and Movement Disorder Society. © 2018 International Parkinson and Movement Disorder Society

Author Keywords
children;  controlled trial;  dopamine D1 receptor;  ecopipam;  randomized;  Tourette syndrome

Document Type: Article in Press
Source: Scopus

“Facial Animation Surgery for Long-standing Facial Palsy: Opportunities for Shared Decision Making” (2018) JAMA Facial Plastic Surgery

Facial Animation Surgery for Long-standing Facial Palsy: Opportunities for Shared Decision Making
(2018) JAMA Facial Plastic Surgery, . Article in Press. 

Santosa, K.B.a , Keane, A.M.b , Politi, M.c , Snyder-Warwick, A.K.a

a Division of Plastic and Reconstructive Surgery, Department of Surgery, Washington University School of Medicine, Campus Box 8238, 660 S Euclid Ave, St Louis, MO 63110, United States
b Washington University School of Medicine, St Louis, MO, United States
c Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St Louis, MO, United States

Document Type: Article in Press
Source: Scopus

“Occupational exposures and parkinsonism among Shanghai women textile workers” (2018) American Journal of Industrial Medicine

Occupational exposures and parkinsonism among Shanghai women textile workers
(2018) American Journal of Industrial Medicine, . Article in Press. 

Checkoway, H.a b , Ilango, S.a c , Li, W.d , Ray, R.M.d , Tanner, C.M.e , Hu, S.-C.f , Wang, X.g h , Nielsen, S.i , Gao, D.L.j , Thomas, D.B.d k

a Department of Family Medicine and Public Health, University of California, San Diego, CA, United States
b Department of Neurosciences, University of California, San Diego, CA, United States
c Graduate School of Public Health, San Diego State University, San Diego, CA, United States
d Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Epidemiology Division, Seattle, WA, United States
e Department of Neurology, University of California, San Francisco, CA, United States
f Department of Neurology, University of Washington, Seattle, WA, United States
g Department of Neurology, Zhong Shan Hospital, Fudan University, Shanghai, China
h The State Key Laboratory of Medical Neurobiology, The Institutes of Brain Science and the Collaborative Innovation Center for Brain Science, Fudan University, Shanghai, China
i Department of Neurology, Washington University St. Louis, St. Louis, MO, United States
j Department of Epidemiology, Fudan University, Zhong Shan Hospital, Shanghai, China
k Department of Epidemiology, University of Washington, Seattle, WA, United States

Abstract
Background: Endotoxin, a contaminant of cotton dust, is an experimental model for parkinsonism (PS). Methods: We investigated associations between exposures to endotoxin, solvents, magnetic fields, and night shift work, and neurologist-determined PS among Shanghai women textile workers, including 537 retired cotton factory workers ages ≥50 years and an age-matched reference group of 286 retired textile workers not exposed to cotton dust. Repeat exams were conducted 2.5 years after enrollment among 467 cotton workers and 229 reference workers. Results: We identified 39 prevalent PS cases and 784 non-cases. No consistent or statistically significant associations were observed for endotoxin, solvents, magnetic fields, or shift work with PS risk, severity, or progression. Conclusions: Despite the null findings, additional studies of endotoxin exposure and risk of PS in other well-characterized occupational cohorts are warranted in view of toxicological evidence that endotoxin is a pathogenic agent and its widespread occurrence in multiple industries worldwide. © 2018 Wiley Periodicals, Inc.

Author Keywords
endotoxin;  magnetic fields;  parkinsonism;  shift work;  textile industry

Document Type: Article in Press
Source: Scopus

“Astrocytic degeneration in chronic traumatic encephalopathy” (2018) Acta Neuropathologica

Astrocytic degeneration in chronic traumatic encephalopathy
(2018) Acta Neuropathologica, . Article in Press. 

Hsu, E.T.a , Gangolli, M.b , Su, S.b , Holleran, L.a c , Stein, T.D.d e f , Alvarez, V.E.d e f , McKee, A.C.d e f g , Schmidt, R.E.h , Brody, D.L.a b h i j

 a Department of Neurology, Washington University, St. Louis, MO, United States
b Department of Biomedical Engineering, Washington University, St. Louis, MO, United States
c Centre for Neuroimaging and Cognitive Genomics, National University of Ireland, Galway, Ireland
d VA Boston Healthcare System, Boston, MA, United States
e Boston University Alzheimer’s Disease and CTE Center, Boston University School of Medicine, Boston, MA, United States
f Department of Pathology, Boston University School of Medicine, Boston, MA, United States
g Department of Neurology, Boston University School of Medicine, Boston, MA, United States
h Department of Pathology and Immunology, Washington University, St. Louis, MO, United States
i Hope Center for Neurological Disorders, Washington University, St. Louis, MO, United States
j Uniformed Services University of the Health Sciences, Bethesda, MD, United States

Abstract
Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with repeated head traumas. Using immunohistochemistry for glial fibrillary acidic protein as a marker, plus automated quantitative analysis, we examined the characteristics and extent of astrogliosis present in stage III and IV CTE, along with Alzheimer’s disease (AD), and frontotemporal dementia (FTD) cases. Astrogliosis in CTE patients was more diffuse compared to that of AD and FTD patients, which was concentrated in the sulcal depths. Of 14 patients with CTE, 10 exhibited signs of a degenerating astrocyte pathology, characterized by beaded, broken astrocytic processes. This astrocytic degeneration was typically found to be diffuse throughout the white matter, although two cases demonstrated astrocytic degeneration in the gray matter. The degeneration was also observed in 2 of 3 AD and 2 of 3 FTD brains, with overall similar characteristics across diseases. There was minimal to no astrocytic degeneration in six age-matched controls with no neurodegenerative disease. We found that the extent of the white matter astrocytic degeneration was strongly correlated with the level of overall astrogliosis in both the white and gray matter. However, astrocytic degeneration was not correlated with the overall extent of tau pathology. Specifically, there was no correlation between levels of p-tau in the sulcal depths and astrocytic degeneration in the white matter adjacent to the sulcal depths. Thus, astrocytic degeneration and overall astrogliosis appear to represent distinct pathological features of CTE. Further investigation into these astroglial pathologies could provide new insights into underlying disease mechanisms and represent a potential target for in vivo assessment of CTE as well as other neurodegenerative disorders. © 2018, This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.

Author Keywords
Astrocyte;  Chronic traumatic encephalopathy;  Glial fibrillary acidic protein;  Neurodegeneration

Document Type: Article in Press
Source: Scopus

“Association of Preclinical Alzheimer Disease with Optical Coherence Tomographic Angiography Findings” (2018) JAMA Ophthalmology

Association of Preclinical Alzheimer Disease with Optical Coherence Tomographic Angiography Findings
(2018) JAMA Ophthalmology, . Article in Press. 

O’Bryhim, B.E.a , Apte, R.S.a b c , Kung, N.d , Coble, D.e , Van Stavern, G.P.a f

a Department of Ophthalmology and Vision Science, Washington University in St Louis, 660 S Euclid Ave, St Louis, MO 63110, United States
b Department of Medicine, Washington University in St Louis, St Louis, MO, United States
c Department of Developmental Biology, Washington University in St Louis, St Louis, MO, United States
d Blue Sky Neurology, Denver, CO, United States
e Division of Biostatistics, Washington University in St Louis, St Louis, MO, United States
f Department of Neurology, Washington University in St Louis, St Louis, MO, United States

Abstract
Importance: Biomarker testing for asymptomatic, preclinical Alzheimer disease (AD) is invasive and expensive. Optical coherence tomographic angiography (OCTA) is a noninvasive technique that allows analysis of retinal and microvascular anatomy, which is altered in early-stage AD. Objective: To determine whether OCTA can detect early retinal alterations in cognitively normal study participants with preclinical AD diagnosed by criterion standard biomarker testing. Design, Setting, and Participants: This case-control study included 32 participants recruited from the Charles F. and Joanne Knight Alzheimer Disease Research Center, Washington University in St Louis, St Louis, Missouri. Results of extensive neuropsychometric testing determined that all participants were cognitively normal. Participants underwent positron emission tomography and/or cerebral spinal fluid testing to determine biomarker status. Individuals with prior ophthalmic disease, media opacity, diabetes, or uncontrolled hypertension were excluded. Data were collected from July 1, 2016, through September 30, 2017, and analyzed from July 30, 2016, through December 31, 2017. Main Outcomes and Measures: Automated measurements of retinal nerve fiber layer thickness, ganglion cell layer thickness, inner and outer foveal thickness, vascular density, macular volume, and foveal avascular zone were collected using an OCTA system from both eyes of all participants. Separate model III analyses of covariance were used to analyze individual data outcome. Results: Fifty-eight eyes from 30 participants (53% female; mean [SD] age, 74.5 [5.6] years; age range, 62-92 years) were included in the analysis. One participant was African American and 29 were white. Fourteen participants had biomarkers positive for AD and thus a diagnosis of preclinical AD (mean [SD] age, 73.5 [4.7] years); 16 without biomarkers served as a control group (mean [SD] age, 75.4 [6.6] years). The foveal avascular zone was increased in the biomarker-positive group compared with controls (mean [SD], 0.364 [0.095] vs 0.275 [0.060] mm2; P =.002). Mean (SD) inner foveal thickness was decreased in the biomarker-positive group (66.0 [9.9] vs 75.4 [10.6] μm; P =.03). Conclusions and Relevance: This study suggests that cognitively healthy individuals with preclinical AD have retinal microvascular abnormalities in addition to architectural alterations and that these changes occur at earlier stages of AD than has previously been demonstrated. Longitudinal studies in larger cohorts are needed to determine whether this finding has value in identifying preclinical AD. © 2018 American Medical Association. All rights reserved.

Document Type: Article in Press
Source: Scopus