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WashU weekly Neuroscience publications

Age at first birth in women is genetically associated with increased risk of schizophrenia (2018) Scientific Reports

Age at first birth in women is genetically associated with increased risk of schizophrenia
(2018) Scientific Reports, 8 (1), art. no. 10168, . 

Ni, G.a b , Gratten, J.c d , Wray, N.R.c d , Lee, S.H.a b d , Ripke, S.e f , Neale, B.M.e f g h , Corvin, A.i , Walters, J.T.R.j , Farh, K.-H.e , Holmans, P.A.j k , Lee, P.e f h , Bulik-Sullivan, B.e f , Collier, D.A.l m , Huang, H.e g , Pers, T.H.g n o , Agartz, I.p q r , Agerbo, E.s t u , Albus, M.v , Alexander, M.w , Amin, F.x y , Bacanu, S.A.z , Begemann, M.aa , Belliveau, R.A.f , Bene, J.ab ac , Bergen, S.E.f ad , Bevilacqua, E.f , Bigdeli, T.B.z , Black, D.W.ae , Bruggeman, R.af , Buccola, N.G.ag , Buckner, R.L.ah ai aj , Byerley, W.ak , Cahn, W.al , Cai, G.am an , Campion, D.ao , Cantor, R.M.ap , Carr, V.J.aq ar , Carrera, N.j , Catts, S.V.aq as , Chambert, K.D.f , Chan, R.C.K.at , Chen, R.Y.L.au , Chen, E.Y.H.au av , Cheng, W.aw , Cheung, E.F.C.ax , Chong, S.A.ay , Cloninger, C.R.az , Cohen, D.ba , Cohen, N.bb , Cormican, P.i , Craddock, N.j k , Crowley, J.J.bc , Curtis, D.bd be , Davidson, M.bf , Davis, K.L.an , Degenhardt, F.bg bh , Del Favero, J.bi , Demontis, D.u bj bk , Dikeos, D.bl , Dinan, T.bm , Djurovic, S.r bn , Donohoe, G.i bo , Drapeau, E.an , Duan, J.bp bq , Dudbridge, F.br , Durmishi, N.bs , Eichhammer, P.bt , Eriksson, J.bu bv bw , Escott-Price, V.j , Essioux, L.bx , Fanous, A.H.by bz ca cb , Farrell, M.S.bc , Frank, J.cc , Franke, L.cd , Freedman, R.ce , Freimer, N.B.cf , Friedl, M.cg , Friedman, J.I.an , Fromer, M.e f h ch , Genovese, G.f , Georgieva, L.j , Giegling, I.cg ci , Giusti-Rodríguez, P.bc , Godard, S.cj , Goldstein, J.I.e g , Golimbet, V.ck , Gopal, S.cl , Haan, L.D.cm , Hammer, C.aa , Hamshere, M.L.j , Hansen, M.cn , Hansen, T.u co , Haroutunian, V.an cp cq , Hartmann, A.M.cg , Henskens, F.A.aq cr cs , Herms, S.bg bh ct , Hirschhorn, J.N.g o cu , Hoffmann, P.bg bh ct , Hofman, A.bg bh , Hollegaard, M.V.cv , Hougaard, D.M.cv , Ikeda, M.cw , Joa, I.cx , Juliá, A.cy , Kahn, R.S.al , Kalaydjieva, L.cz da , Karachanak-Yankova, S.db , Karjalainen, J.cd , Kavanagh, D.j , Keller, M.C.dc , Kennedy, J.L.dd de df , Khrunin, A.dg , Kim, Y.bc , Klovins, J.dh , Knowles, J.A.di , Konte, B.cg , Kucinskas, V.dj , Kucinskiene, Z.A.dj , Kuzelova-Ptackova, H.dk , Kähler, A.K.ad , Laurent, C.w dl , Keong, J.L.C.ay dm , Legge, S.E.j , Lerer, B.dn , Li, M.au av do , Li, T.dp , Liang, K.-Y.dq , Lieberman, J.dr , Limborska, S.dg , Loughland, C.M.aq ds , Lubinski, J.dt , Lönnqvist, J.du , Macek, M.dk , Magnusson, P.K.E.ad , Maher, B.S.dv , Maier, W.dw , Mallet, J.dx , Marsal, S.cy , Mattheisen, M.u bj bk dy , Mattingsdal, M.r dz , McCarley, R.W.ea eb , McDonald, C.ec , McIntosh, A.M.ed ee , Meier, S.cc , Meijer, C.J.cm , Melegh, B.ab ac , Melle, I.r ef , Mesholam-Gately, R.I.ea eg , Metspalu, A.eh , Michie, P.T.aq ei , Milani, L.eh , Milanova, V.ej , Mokrab, Y.l , Morris, D.W.i bo , Mors, O.u bj ek , Murphy, K.C.el , Murray, R.M.em , Myin-Germeys, I.en , Müller-Myhsok, B.eo ep eq , Nelis, M.eh , Nenadic, I.er , Nertney, D.A.es , Nestadt, G.et , Nicodemus, K.K.eu , Nikitina-Zake, L.dh , Nisenbaum, L.ev , Nordin, A.ew , O’callaghan, E.ex , O’dushlaine, C.f , O’neill, F.A.ey , Oh, S.-Y.ez , Olincy, A.ce , Olsen, L.u co , Os, J.V.en fa , Pantelis, C.aq fb , Papadimitriou, G.N.bl , Papiol, S.aa , Parkhomenko, E.an , Pato, M.T.di , Paunio, T.fc fd , Pejovic-Milovancevic, M.fe , Perkins, D.O.ff , Pietiläinen, O.fd fg , Pimm, J.be , Pocklington, A.J.j , Powell, J.em , Price, A.g fh , Pulver, A.E.et , Purcell, S.M.ch , Quested, D.fi , Rasmussen, H.B.u co , Reichenberg, A.an , Reimers, M.A.fj , Richards, A.L.j , Roffman, J.L.ah aj , Roussos, P.ch fk , Ruderfer, D.M.j ch , Salomaa, V.bw , Sanders, A.R.bp bq , Schall, U.aq ds , Schubert, C.R.fl , Schulze, T.G.cc fm , Schwab, S.G.fn , Scolnick, E.M.f , Scott, R.J.aq fo fp , Seidman, L.J.ea eg , Shi, J.fq , Sigurdsson, E.fr , Silagadze, T.fs , Silverman, J.M.an ft , Sim, K.ay , Slominsky, P.dg , Smoller, J.W.f h , So, H.-C.au , Spencer, C.C.A.fu , Stahl, E.A.g ch , Stefansson, H.fv , Steinberg, S.fv , Stogmann, E.fw , Straub, R.E.fx , Strengman, E.al fy , Strohmaier, J.cc , Stroup, T.S.dr , Subramaniam, M.ay , Suvisaari, J.du , Svrakic, D.M.az , Szatkiewicz, J.P.bc , Söderman, E.p , Thirumalai, S.fz , Toncheva, D.db , Tosato, S.ga , Veijola, J.gb gc , Waddington, J.gd , Walsh, D.ge , Wang, D.cl , Wang, Q.dp , Webb, B.T.z , Weiser, M.bf , Wildenauer, D.B.gf , Williams, N.M.j , Williams, S.bc , Witt, S.H.cc , Wolen, A.R.fj , Wong, E.H.M.au , Wormley, B.K.z , Xi, H.S.gg , Zai, C.C.dd de , Zheng, X.gh , Zimprich, F.fw , Stefansson, K.fv , Visscher, P.M.c , Adolfsson, R.ew , Andreassen, O.A.r ef , Blackwood, D.H.R.ee , Bramon, E.gi , Buxbaum, J.D.am an cp gj , Børglum, A.D.u bj bk ek , Cichon, S.bg bh ct gk , Darvasi, A.gl , Domenici, E.gm , Ehrenreich, H.aa , Esko, T.g o cu eh , Gejman, P.V.bp bq , Gill, M.i , Gurling, H.be , Hultman, C.M.ad , Iwata, N.cw , Jablensky, A.V.aq da gf gn , Jönsson, E.G.p r , Kendler, K.S.go , Kirov, G.j , Knight, J.dd de df , Lencz, T.gp gq gr , Levinson, D.F.w , Li, Q.S.cl , Liu, J.gh gs , Malhotra, A.K.gp gq gr , McCarroll, S.A.f cu , McQuillin, A.be , Moran, J.L.f , Mortensen, P.B.s t u , Mowry, B.J.ch gt , Nöthen, M.M.bg bh , Ophoff, R.A.al ap cf , Owen, M.J.j k , Palotie, A.f h fg , Pato, C.N.di , Petryshen, T.L.f ea gu , Posthuma, D.gv gw gx , Rietschel, M.cc , Riley, B.P.go , Rujescu, D.cg ci , Sham, P.C.au av do , Sklar, P.ch cp fk , Clair, D.S.gy , Weinberger, D.R.fx gz , Wendland, J.R.fl , Werge, T.u co ha , Daly, M.J.e f g , Sullivan, P.F.ad bc ff , O’donovan, M.C.j k

a Australian Center for Precision Health, University of South Australia Cancer Research Institute, University of South Australia, Adelaide, SA, Australia
b School of Environmental and Rural Science, University of New England, Armidale, NSW, Australia
c Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia
d Queensland Brain Institute, University of Queensland, Brisbane, QLD, Australia
e Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, United States
f Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, United States
g Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, MA, United States
h Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, MA, United States
i Neuropsychiatric Genetics Research Group, Department of Psychiatry, Trinity College Dublin, Dublin 8, Ireland
j MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, United Kingdom
k National Centre for Mental Health, Cardiff University, Cardiff, United Kingdom
l Eli Lilly and Company Limited, Erl Wood Manor, Sunninghill Road, Windlesham, Surrey, United Kingdom
m Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King’s College London, London, United Kingdom
n Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Lyngby, Denmark
o Division of Endocrinology and Center for Basic and Translational Obesity Research, Boston Children’s Hospital, Boston, MA, United States
p Department of Clinical Neuroscience, Psychiatry Section, Karolinska Institutet, Stockholm, Sweden
q Department of Psychiatry, Diakonhjemmet Hospital, Oslo, Norway
r NORMENT, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
s Centre for Integrative Register-based Research, CIRRAU, Aarhus University, Aarhus, Denmark
t National Centre for Register-based Research, AarhusUniversity, Aarhus, Denmark
u Lundbeck Foundation Initiative for Integrative Psychiatric Research, IPSYCH, Aarhus, Denmark
v State Mental Hospital, Haar, Germany
w Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, United States
x Department of Psychiatry and Behavioral Sciences, Atlanta Veterans Affairs Medical Center, Atlanta, GA, United States
y Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA, United States
z Virginia Institute for Psychiatric and Behavioral Genetics, Department of Psychiatry, Virginia Commonwealth University, Richmond, VA, United States
aa Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Goettingen, Germany
ab Department of Medical Genetics, University of Pécs, Pécs, Hungary
ac Szentagothai Research Center, University of Pécs Hungary, Pécs, Hungary
ad Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
ae Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, IA, United States
af University Medical Center Groningen, Department of Psychiatry, University of Groningen, Groningen, Netherlands
ag School of Nursing, Louisiana State University Health Sciences Center, New Orleans, LA, United States
ah Athinoula A Martinos Center, Massachusetts General Hospital, Boston, MA, United States
ai Center for Brain Science, Harvard University, Cambridge, MA, United States
aj Department of Psychiatry, Massachusetts General Hospital, Boston, MA, United States
ak Department of Psychiatry, University of California at San Francisco, San Francisco, CA, United States
al University Medical Center Utrecht, Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, Utrecht, Netherlands
am Department of Human Genetics, Icahn School of Medicine at Mount Sinai, New York, NY, United States
an Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, United States
ao Centre Hospitalier du Rouvray and INSERM U1079, Faculty of Medicine, Rouen, France
ap Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA, United States
aq Schizophrenia Research Institute, Sydney, NSW, Australia
ar School of Psychiatry, University of New South Wales, Sydney, NSW, Australia
as Royal Brisbane and Women’s Hospital, University of Queensland, St Lucia, QLD, Australia
at Institute of Psychology, Chinese Academy of Science, Beijing, China
au Department of Psychiatry, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, Hong Kong
av State Key Laboratory for Brain and Cognitive Sciences, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, Hong Kong
aw Department of Computer Science, University of North Carolina, Chapel Hill, NC, United States
ax Castle Peak Hospital, Hong Kong, Hong Kong
ay Institute of Mental Health, Singapore, Singapore
az Department of Psychiatry, Washington University, St. Louis, MI, United States
ba Department of Child and Adolescent Psychiatry, Assistance Publique Hopitaux de Paris, Pierre and Marie Curie Faculty of Medicine, Institute for Intelligent Systems and Robotics, Paris, France
bb Blue Note Biosciences, Princeton, NJ, United States
bc Department of Genetics, University of North Carolina, Chapel Hill, NC, United States
bd Department of Psychological Medicine, Queen Mary University of London, London, United Kingdom
be Molecular Psychiatry Laboratory, Division of Psychiatry, University College London, London, United Kingdom
bf Sheba Medical Center, Tel Hashomer, Israel
bg Department of Genomics, Life and Brain Center, Bonn, Germany
bh Institute of Human Genetics, University of Bonn, Bonn, Germany
bi Applied Molecular Genomics Unit, VIB Department of Molecular Genetics, University of Antwerp, Antwerp, Belgium
bj Centre for Integrative Sequencing, ISEQ, Aarhus University, Aarhus C, Denmark
bk Department of Biomedicine, Aarhus University, Aarhus C, Denmark
bl First Department of Psychiatry, University of Athens Medical School, Athens, Greece
bm Department of Psychiatry, University College Cork, Co Cork, Ireland
bn Department of Medical Genetics, Oslo University Hospital, Oslo, Norway
bo Cognitive Genetics and Therapy Group, School of Psychology and Discipline of Biochemistry, National University of Ireland Galway, Co Galway, Ireland
bp Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, IL, United States
bq Department of Psychiatry and Behavioral Sciences, NorthShore University HealthSystem, Evanston, IL, United States
br Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, United Kingdom
bs Department of Child and Adolescent Psychiatry, University Clinic of Psychiatry, Skopje, Macedonia
bt Department of Psychiatry, University of Regensburg, Regensburg, Germany
bu Department of General Practice, Helsinki University Central Hospital, University of Helsinki, Po Box 20, Tukholmankatu 8 B, Helsinki, Finland
bv Folkhälsan Research Center, Biomedicum Helsinki 1, Haartmaninkatu 8, Helsinki, Finland
bw National Institute for Health and Welfare, PO Box 30, Helsinki, Finland
bx Translational Technologies and Bioinformatics, Pharma Research and Early Development, F Hoffman-La Roche, Basel, Switzerland
by Department of Psychiatry, Georgetown University School of Medicine, Washington, DC, United States
bz Department of Psychiatry, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
ca Department of Psychiatry, Virginia Commonwealth University School of Medicine, Richmond, VA, United States
cb Mental Health Service Line, Washington VA Medical Center, Washington, DC, United States
cc Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Mannheim, Germany
cd Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, Netherlands
ce Department of Psychiatry, University of Colorado Denver, Aurora, CO, United States
cf Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA, United States
cg Department of Psychiatry, University of Halle, Halle, Germany
ch Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, United States
ci Department of Psychiatry, University of Munich, Munich, Germany
cj Departments of Psychiatry and Human and Molecular Genetics, INSERM, Institut de Myologie, Hôpital de la Pitiè-Salpêtrière, Paris, France
ck Mental Health Research Centre, Russian Academy of Medical Sciences, Moscow, Russian Federation
cl Neuroscience Therapeutic Area, Janssen Research and Development, Raritan, NJ, United States
cm Academic Medical Centre University of Amsterdam, Department of Psychiatry, Amsterdam, Netherlands
cn Illumina, San Diego, CA, United States
co Institute of Biological Psychiatry, Mental Health Centre Sct Hans, Mental Health Services Copenhagen, Copenhagen, Denmark
cp Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States
cq J J Peters VA Medical Center, Bronx, New York, NY, United States
cr Priority Research Centre for Health Behaviour, University of Newcastle, Newcastle, NSW, Australia
cs School of Electrical Engineering and Computer Science, University of Newcastle, Newcastle, NSW, Australia
ct Division of Medical Genetics, Department of Biomedicine, University of Basel, Basel, Switzerland
cu Department of Genetics, Harvard Medical School, Boston, MA, United States
cv Section of Neonatal Screening and Hormones, Department of Clinical Biochemistry, Immunology and Genetics, Statens Serum Institut, Copenhagen, Denmark
cw Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Aichi, Japan
cx Regional Centre for Clinical Research in Psychosis, Department of Psychiatry, Stavanger University Hospital, Stavanger, Norway
cy Rheumatology Research Group, Vall d’Hebron Research Institute, Barcelona, Spain
cz Centre for Medical Research, University of Western Australia, Perth, WA, Australia
da Perkins Institute for Medical Research, University of Western Australia, Perth, WA, Australia
db Department of Medical Genetics, Medical University, Sofia, Bulgaria
dc Department of Psychology, University of Colorado Boulder, Boulder, CO, United States
dd Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada
de Department of Psychiatry, University of Toronto, Toronto, ON, Canada
df Institute of Medical Science, University of Toronto, Toronto, ON, Canada
dg Institute of Molecular Genetics, Russian Academy of Sciences, Moscow, Russian Federation
dh Latvian Biomedical Research and Study Centre, Riga, Latvia
di Department of Psychiatry and Zilkha Neurogenetics Institute, Keck School of Medicine at University of Southern California, Los Angeles, CA, United States
dj Faculty of Medicine, Vilnius University, Vilnius, Lithuania
dk Department of Biology and Medical Genetics, 2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic
dl Department of Child and Adolescent Psychiatry, Pierre and Marie Curie Faculty of Medicine, Paris, France
dm Duke-NUS Graduate Medical School, Singapore, Singapore
dn Department of Psychiatry, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
do Centre for Genomic Sciences, University of Hong Kong, Hong Kong, Hong Kong
dp Mental Health Centre and Psychiatric Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan, China
dq Department of Biostatistics, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, United States
dr Department of Psychiatry, Columbia University, New York, NY, United States
ds Priority Centre for Translational Neuroscience and Mental Health, University of Newcastle, Newcastle, NSW, Australia
dt Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University in Szczecin, Szczecin, Poland
du Department of Mental Health and Substance Abuse Services, National Institute for Health and Welfare, PO BOX30, Helsinki, Finland
dv Department of Mental Health, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, United States
dw Department of Psychiatry, University of Bonn, Bonn, Germany
dx Centre National de la Recherche Scientifique, Laboratoire de Génétique Moléculaire, Neurotransmission et des Processus Neurodégénératifs, Hôpital de la Pitié Salpêtrière, Paris, France
dy Department of Genomics Mathematics, University of Bonn, Bonn, Germany
dz Research Unit, Sørlandet Hospital, Kristiansand, Norway
ea Department of Psychiatry, Harvard Medical School, Boston, MA, United States
eb VA Boston Health Care System, Brockton, MA, United States
ec Department of Psychiatry, National University of Ireland Galway, Co Galway, Ireland
ed Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, United Kingdom
ee Division of Psychiatry, University of Edinburgh, Edinburgh, United Kingdom
ef Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway
eg Massachusetts Mental Health Center Public Psychiatry, Division of the Beth Israel Deaconess Medical Center, Boston, MA, United States
eh Estonian Genome Center, University of Tartu, Tartu, Estonia
ei School of Psychology, University of Newcastle, Newcastle, NSW, Australia
ej First Psychiatric Clinic, Medical University, Sofia, Bulgaria
ek Department P, Aarhus University Hospital, Risskov, Denmark
el Department of Psychiatry, Royal College of Surgeons in Ireland, Dublin 2, Ireland
em King’s College London, London, United Kingdom
en Maastricht University Medical Centre, South Limburg Mental Health Research and Teaching Network, EURON, Maastricht, Netherlands
eo Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom
ep Max Planck Institute of Psychiatry, Munich, Germany
eq Munich Cluster for SystemsNeurology (SyNergy), Munich, Germany
er Department of Psychiatry and Psychotherapy, Jena University Hospital, Jena, Germany
es Department of Psychiatry, Queensland Brain Institute and Queensland Centre for Mental Health Research, University of Queensland, St Lucia, QLD, Australia
et Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MA, United States
eu Department of Psychiatry, Trinity College Dublin, Dublin 2, Ireland
ev Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, United States
ew Department of Clinical Sciences, Psychiatry, Umeå University, Umeå, Sweden
ex DETECT Early Intervention Service for Psychosis, Blackrock, Co Dublin, Ireland
ey Centre for Public Health, Institute of Clinical Sciences, Queen’s University Belfast, Belfast, United Kingdom
ez Lawrence Berkeley National Laboratory, University of California at Berkeley, Berkeley, CA, United States
fa Institute of Psychiatry, Kings College London, London, United Kingdom
fb Melbourne Neuropsychiatry Centre, University of Melbourne and Melbourne Health, Melbourne, VIC, Australia
fc Department of Psychiatry, University of Helsinki, PO Box 590, HUS Helsinki, Finland
fd Public Health Genomics Unit, National Institute for Health and Welfare, PO BOX 30, Helsinki, Finland
fe Medical Faculty, University of Belgrade, Belgrade, Serbia
ff Department of Psychiatry, University of North Carolina, Chapel Hill, NC, United States
fg Institute for Molecular Medicine Finland, FIMM, University of Helsinki, PO Box 20, Helsinki, Finland
fh Department of Epidemiology, Harvard School of Public Health, Boston, MA, United States
fi Department of Psychiatry, University of Oxford, Oxford, United Kingdom
fj Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, United States
fk Institute for Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
fl PharmaTherapeutics Clinical Research, Pfizer Worldwide Research and Development, Cambridge, MA, United States
fm Department of Psychiatry and Psychotherapy, University of Gottingen, Göttingen, Germany
fn Psychiatry and Psychotherapy Clinic, University of Erlangen, Erlangen, Germany
fo Hunter New England Health Service, Newcastle, NSW, Australia
fp School of Biomedical Sciences, University of Newcastle, Newcastle, NSW, Australia
fq Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MA, United States
fr University of Iceland, Landspitali, National University Hospital, Reykjavik, Iceland
fs Department of Psychiatry and Drug Addiction, Tbilisi State Medical University (TSMU), Tbilisi, Georgia
ft Research and Development, Bronx Veterans Affairs Medical Center, New York, NY, United States
fu Wellcome Trust Centre for Human Genetics, Oxford, United Kingdom
fv DeCODE Genetics, Reykjavik, Iceland
fw Department of Clinical Neurology, Medical University of Vienna, Wien, Austria
fx Lieber Institute for Brain Development, Baltimore, MD, United States
fy Department of Medical Genetics, University Medical Centre Utrecht, Universiteitsweg 100, Utrecht, Netherlands
fz Berkshire Healthcare NHS Foundation Trust, Bracknell, United Kingdom
ga Section of Psychiatry, University of Verona, Verona, Italy
gb Department of Psychiatry, University of Oulu, PO Box 5000, Oulu, Finland
gc University Hospital of Oulu, PO Box 20, Oulu, Finland
gd Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin 2, Ireland
ge Health Research Board, Dublin 2, Ireland
gf School of Psychiatry and Clinical Neurosciences, University of Western Australia, Perth, WA, Australia
gg Computational Sciences CoE, Pfizer Worldwide Research and Development, Cambridge, MA, United States
gh Human Genetics, Genome Institute of Singapore, A STAR Singapore, Singapore, Singapore
gi University College London, London, United Kingdom
gj Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, United States
gk Institute of Neuroscience and Medicine (INM-1), Research Center Juelich, Juelich, Germany
gl Department of Genetics, Hebrew University of Jerusalem, Jerusalem, Israel
gm Neuroscience Discovery and Translational Area, Pharma Research and Early Development, F Hoffman-La Roche, Basel, Switzerland
gn Centre for Clinical Research in Neuropsychiatry, School of Psychiatry and Clinical Neurosciences, University of Western Australia, Medical Research Foundation Building, Perth, WA, Australia
go Virginia Institute for Psychiatric and Behavioral Genetics, Departments of Psychiatry and Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA, United States
gp Feinstein Institute for Medical Research, Manhasset, NY, United States
gq Hofstra NS-LIJ School of Medicine, Hempstead, NY, United States
gr Zucker Hillside Hospital, Glen Oaks, NY, United States
gs Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore
gt Queensland Centre for Mental Health Research, University of Queensland, Brisbane, QLD, Australia
gu Center for Human Genetic Research and Department of Psychiatry, Massachusetts General Hospital, Boston, MA, United States
gv Department of Child and Adolescent Psychiatry, Erasmus University Medical Centre, Rotterdam, Netherlands
gw Department of Complex Trait Genetics, Neuroscience Campus Amsterdam, VU University Medical Center Amsterdam, Amsterdam, Netherlands
gx Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University, Amsterdam, Netherlands
gy University of Aberdeen, Institute of Medical Sciences, Aberdeen, United Kingdom
gz Departments of Psychiatry, Neurology, Neuroscience, Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, MD, United States
ha Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark

Abstract
Previous studies have shown an increased risk for mental health problems in children born to both younger and older parents compared to children of average-aged parents. We previously used a novel design to reveal a latent mechanism of genetic association between schizophrenia and age at first birth in women (AFB). Here, we use independent data from the UK Biobank (N = 38,892) to replicate the finding of an association between predicted genetic risk of schizophrenia and AFB in women, and to estimate the genetic correlation between schizophrenia and AFB in women stratified into younger and older groups. We find evidence for an association between predicted genetic risk of schizophrenia and AFB in women (P-value = 1.12E-05), and we show genetic heterogeneity between younger and older AFB groups (P-value = 3.45E-03). The genetic correlation between schizophrenia and AFB in the younger AFB group is -0.16 (SE = 0.04) while that between schizophrenia and AFB in the older AFB group is 0.14 (SE = 0.08). Our results suggest that early, and perhaps also late, age at first birth in women is associated with increased genetic risk for schizophrenia in the UK Biobank sample. These findings contribute new insights into factors contributing to the complex bio-social risk architecture underpinning the association between parental age and offspring mental health. © 2018 The Author(s).

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

Estimates of age-related memory decline are inflated by unrecognized Alzheimer’s disease (2018) Neurobiology of Aging

Estimates of age-related memory decline are inflated by unrecognized Alzheimer’s disease
(2018) Neurobiology of Aging, 70, pp. 170-179. 

Harrington, K.D.a b , Schembri, A.c , Lim, Y.Y.a , Dang, C.d , Ames, D.e f , Hassenstab, J.g h i , Laws, S.M.b j k , Rainey-Smith, S.l m , Robertson, J.a , Rowe, C.C.n o , Sohrabi, H.R.l p , Salvado, O.q , Weinborn, M.l m r , Villemagne, V.L.a n o , Masters, C.L.a , Maruff, P.a c , AIBL Research Groups

a The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria, Australia
b Cooperative Research Centre for Mental Health, Carlton, Victoria, Australia
c CogState Ltd., Melbourne, Victoria, Australia
d Department of Obstetrics and Gynaecology, Melbourne Medical School, The University of Melbourne, Parkville, Victoria, Australia
e Department of Psychiatry, Academic Unit for Psychiatry of Old Age, The University of Melbourne, Parkville, Victoria, Australia
f National Ageing Research Institute, Parkville, Victoria, Australia
g Charles F. and Joanne Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, MO, United States
h Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
i Department of Psychological & Brain Sciences, Washington University, St. Louis, MO, United States
j Collaborative Genomics Group, Centre of Excellence for Alzheimer’s Disease Research and Care, School of Exercise, Biomedical and Health Sciences, Edith Cowan University, Perth, Western Australia, Australia
k School of Biomedical Sciences, Faculty of Health Sciences, Curtin Health Innovation Research Institute, Curtin UniversityWestern Australia, Australia
l Centre of Excellence for Alzheimer’s Disease Research and Care, School of Exercise, Biomedical and Health Sciences, Edith Cowan University, Perth, Western Australia, Australia
m Australian Alzheimer’s Disease Research Unit, Hollywood Private Hospital, Perth, Western Australia, Australia
n Department of Molecular Imaging & Therapy, Austin Health, Melbourne, Victoria, Australia
o Department of Medicine, Austin Health, The University of Melbourne, Melbourne, Victoria, Australia
p School of Psychiatry and Clinical Neurosciences, University of Western Australia, Nedlands, Western Australia, Australia
q CSIRO Health and Biosecurity, The Australian eHealth Research Centre, Brisbane, Queensland, Australia
r School of Psychological Science, University of Western Australia, Crawley, Western Australia, Australia

Abstract
Cognitive decline is considered an inevitable consequence of aging; however, estimates of cognitive aging may be influenced negatively by undetected preclinical Alzheimer’s disease (AD). This study aimed to determine the extent to which estimates of cognitive aging were biased by preclinical AD. Cognitively normal older adults (n = 494) with amyloid-β status determined from positron emission tomography neuroimaging underwent serial neuropsychological assessment at 18-month intervals over 72 months. Estimates of the effects of age on verbal memory, working memory, executive function, and processing speed were derived using linear mixed models. The presence of preclinical AD and clinical progression to mild cognitive impairment or dementia during the study were then added to these models as covariates. Initially, age was associated with decline across all 4 cognitive domains. With the effects of elevated amyloid-β and clinical progression controlled, age was no longer associated with decline in verbal or working memory. However, the magnitude of decline was reduced only slightly for executive function and was unchanged for processing speed. Thus, considered together, the results of the study indicate that undetected preclinical AD negatively biases estimates of age-related cognitive decline for verbal and working memory. © 2018 Elsevier Inc.

Author Keywords
Aging;  Alzheimer;  Amyloid-β;  Cognition;  Preclinical

Document Type: Article
Source: Scopus

Acid Sensing Ion Channel 1a (ASIC1a) Mediates Activity-induced Pain by Modulation of Heteromeric ASIC Channel Kinetics (2018) Neuroscience

Acid Sensing Ion Channel 1a (ASIC1a) Mediates Activity-induced Pain by Modulation of Heteromeric ASIC Channel Kinetics
(2018) Neuroscience, 386, pp. 166-174. 

Gregory, N.S.a b d f , Gautam, M.c d e , Benson, C.J.b c d e , Sluka, K.A.a b d

a Department of Physical Therapy and Rehabilitation Science, The University of Iowa, Iowa City, IA, United States
b Department of Neuroscience, The University of Iowa, Iowa City, IA, United States
c Department of Internal Medicine, The University of Iowa, Iowa City, IA, United States
d Pain Research Program, The University of Iowa, Iowa City, IA, United States
e Veterans Medical Center, Iowa City, IA, United States
f Washington University, Department of Anesthesia, St. Louis, MO, United States

Abstract
Chronic muscle pain is acutely worsened by exercise. Acid sensing ion channels (ASIC) are heteromeric channels expressed in muscle sensory neurons that detect decreases in pH. We have previously shown ASIC3 is important in activity-induced hyperalgesia. However, ASICs form heteromers with ASIC1a being a key component in sensory neurons. Therefore, we studied the role of ASIC1a in mice using behavioral pharmacology and genetic deletion in a model of activity-induced hyperalgesia. We found ASIC1a−/− mice developed mechanical hyperalgesia similar to wild-type mice, but antagonism of ASIC1a, with psalmotoxin, prevented development of mechanical hyperalgesia in wild-type mice, but not in ASIC1a−/− mice. To explain this discrepancy, we then performed electrophysiology studies of ASICs and examined the effects of psalmotoxin on ASIC heteromers. We expressed ASIC1a, 2 and 3 heteromers or ASIC1 and 3 heteromers in CHO cells, and examined the effects of psalmotoxin on pH sensitivity. Psalmotoxin significantly altered the properties of ASIC hetomeric channels. Specifically, in ASIC1a/2/3 heteromers, psalmotoxin slowed the kinetics of desensitization, slowed the recovery from desensitization, and inhibited pH-dependent steady-state desensitization, but had no effect on pH-evoked current amplitudes. We found a different pattern in ASIC1a/3 heteromers. There was a significant leftward shift in the pH dose response of steady-state desensitization and decrease in pH-evoked current amplitudes. These results suggest that blockade of ASIC1a modulates the kinetics of heteromeric ASICs to prevent development of activity-induced hyperalgesia. These data suggest ASIC1a is a key subunit in heteromeric ASICs and may be a pharmacological target for treatment of musculoskeletal pain. © 2018

Author Keywords
acid;  ASIC;  exercise;  fatigue;  hyperalgesia;  pain

Document Type: Article
Source: Scopus

Fractional anisotropy to quantify cervical spondylotic myelopathy severity (2018) Journal of Neurosurgical Sciences

Fractional anisotropy to quantify cervical spondylotic myelopathy severity
(2018) Journal of Neurosurgical Sciences, 62 (4), pp. 406-412. 

Murphy, R.K.a , Sun, P.b , Han, R.H.c , Griffin, K.J.b , Wagner, J.d , Yarbrough, C.K.a , Wright, N.M.a , Dorward, I.G.a , Riew, K.D.e , Kelly, M.P.f , Santiago, P.a , Zebala, L.P.f , Trinkaus, K.g , Ray, W.Z.a , Song, S.-K.b

a Department of Neurosurgery, Washington University, 660 South Euclid Ave, St. Louis, MO, United States
b Department of Radiology, Washington University, St. Louis, MO, United States
c Washington University School of Medicine, St. Louis, MO, United States
d Department of Physical Therapy and Athletic Training, Saint Louis University, St. Louis, MO, United States
e Department of Orthopedic Surgery, Columbia University, New York, NY, United States
f Department of Orthopedic Surgery, Washington University, St. Louis, MO, United States
g Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, United States

Abstract
BACKGROUND: A number of clinical tools exist for measuring the severity of cervical spondylotic myelopathy (CSM). Several studies have recently described the use of non-invasive imaging biomarkers to assess severity of disease. These imaging markers may provide an additional tool to measure disease progression and represent a surrogate marker of response to therapy. Correlating these imaging biomarkers with clinical quantitative measures is critical for accurate therapeutic stratification and quantification of axonal injury. METHODS: Fourteen patients and seven healthy control subjects were enrolled. Patients were classified as mildly (7) or moderately (7) impaired based on Modified Japanese Orthopedic Association Scale. All patients underwent diffusion tensor imaging (DTI) and diffusion basis spectrum imaging (DBSI) analyses. In addition to standard neurological examination, all participants underwent 30-m Walking Test, 9-hole Peg Test (9HPT), grip strength, key pinch, and vibration sensation thresholds in the index finger and great toe. Differences in assessment scores between controls, mild and moderate CSM patients were correlated with DTI and DBSI derived fractional anisotropy (FA). RESULTS: Clinically, 30-meter walking times were significantly longer in the moderately impaired group than in the control group. Maximum 9HPT times were significantly longer in both the mildly and moderately impaired groups as compared to normal controls. Scores on great toe vibration sensation thresholds were lower in the mildly impaired and moderately impaired groups as compared to controls. We found no clear evidence for any differences in minimum grip strength, minimum key pinch, or index finger vibration sensation thresholds. There were moderately strong associations between DTI and DBSI FA values and 30-meter walking times and 9HPT. CONCLUSIONS: The 30-m Walking Test and 9HPT were both moderately to strongly associated with DTI/DBSI FA values. FA may represent an additional measure to help differentiate and stratify patients with mild or moderate CSM. © 2016 EDIZIONI MINERVA MEDICA.

Author Keywords
Diffusion magnetic resonance imaging;  Spinal cord diseases;  Spondylosis

Document Type: Article
Source: Scopus

Molecular genetic overlap between migraine and major depressive disorder (2018) European Journal of Human Genetics

Molecular genetic overlap between migraine and major depressive disorder
(2018) European Journal of Human Genetics, pp. 1-15. Article in Press. 

Yang, Y.a b , Zhao, H.a c , Boomsma, D.I.d , Ligthart, L.d , Belin, A.C.e , Smith, G.D.f , Esko, T.g h i , Freilinger, T.M.j k , Hansen, T.F.l , Ikram, M.A.m , Kallela, M.n , Kubisch, C.o , Paraskevi, C.p , Strachan, D.P.q , Wessman, M.r s , Gormley, P.g v w x , Anttila, V.g w x , Winsvold, B.S.y z aa , Palta, P.r , Esko, T.g h i , Pers, T.H.g i ab ac , Farh, K.-H.g ad ae , Cuenca-Leon, E.g v w af , Muona, M.r s ag ah , Furlotte, N.A.ai , Kurth, T.aj ak , Ingason, A.al , McMahon, G.f , Ligthart, L.d , Terwindt, G.M.t , Kallela, M.am , Freilinger, T.M.j k , Ran, C.e , Gordon, S.G.an , Stam, A.H.t , Steinberg, S.al , Borck, G.ao , Koiranen, M.ap , Quaye, L.p , Adams, H.H.H.m aq , Lehtimäki, T.ar , Sarin, A.-P.r , Wedenoja, J.as , Hinds, D.A.ai , Buring, J.E.ak at , Schürks, M.au , Ridker, P.M.ak at , Hrafnsdottir, M.G.av , Stefansson, H.al , Ring, S.M.f , Hottenga, J.-J.d , Penninx, B.W.J.H.aw , Färkkilä, M.am , Artto, V.am , Kaunisto, M.r , Vepsäläinen, S.am , Malik, R.k , Heath, A.C.ax , Madden, P.A.F.ax , Martin, N.G.an , Montgomery, G.W.an , Kurki, M.I.g r v w ay , Kals, M.h , Mägi, R.h , Pärn, K.h , Hämäläinen, E.r , Huang, H.g w ad , Byrnes, A.E.g w ad , Franke, L.az , Huang, J.x , Stergiakouli, E.f , Lee, P.H.g v w , Sandor, C.ba , Webber, C.ba , Cader, Z.bb bc , Muller-Myhsok, B.u bd cg , Schreiber, S.be , Meitinger, T.bf bg , Eriksson, J.G.bh bi , Salomaa, V.bi , Heikkilä, K.bj , Loehrer, E.m bk , Uitterlinden, A.G.bl , Hofman, A.m , van Duijn, C.M.m , Cherkas, L.p , Pedersen, L.M.y , Stubhaug, A.bm bn , Nielsen, C.S.bm bo , Männikkö, M.ap , Mihailov, E.h , Milani, L.h , Göbel, H.bp , Esserlind, A.-L.bq , Christensen, A.F.bq , Hansen, T.F.br , Werge, T.bs bt bu , Kaprio, J.r as bv , Aromaa, A.J.bi , Raitakari, O.bw bx , Ikram, M.A.m aq by , Spector, T.p , Järvelin, M.-R.ap bz ca cb , Metspalu, A.h , Kubisch, C.o , Strachan, D.P.q , Ferrari, M.D.t , Belin, A.C.e , Dichgans, M.k cc , Wessman, M.r bb , van Den Maagdenberg, A.M.J.M.t u , Zwart, J.-A.y z aa , Boomsma, D.I.d , Smith, G.D.f , Stefansson, K.al cd , Eriksson, N.ai , Daly, M.J.g w ad , Neale, B.M.g w ad , Olesen, J.bq , Chasman, D.I.ak at , Nyholt, D.R.ce , Palotie, A.g r v w x ad cf , van Den Maagdenberg, A.M.J.M.t u , Terwindt, G.M.t , Nyholt, D.R.a , The International Headache Genetics Consortiumch

a Statistical and Genomic Epidemiology Laboratory, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, QLD, Australia
b Institute of Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia
c Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
d Department of Biological Psychology, Vrije Universiteit, Amsterdam, Netherlands
e Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden
f Medical Research Council (MRC) Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom
g Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, MA, United States
h Estonian Genome Center, University of Tartu, Tartu, Estonia
i Division of Endocrinology, Boston Children’s Hospital, Boston, MA, United States
j Department of Neurology and Epileptology, Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
k Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität München, Munich, Germany
l Danish Headache Center, Department of Neurology, Rigshospitalet, Glostrup Hospital, University of Copenhagen, Copenhagen, Denmark
m Department of Epidemiology, Erasmus University Medical Center, Rotterdam, Netherlands
n Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland
o Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
p Department of Twin Research and Genetic Epidemiology, King’s College London, London, United Kingdom
q Population Health Research Institute, St George’s, University of London, London, United Kingdom
r Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
s Folkhälsan Institute of Genetics, Helsinki, Finland
t Department of Neurology, Leiden University Medical Center, Leiden, Netherlands
u Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands
v Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
w Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, United States
x Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, United Kingdom
y FORMI, Oslo University Hospital, Oslo, Norway
z Department of Neurology, Oslo University Hospital, Oslo, Norway
aa Institute of Clinical Medicine, University of Oslo, Oslo, Norway
ab Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark
ac Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
ad Analytic and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
ae Illumina, San Diego, CA, United States
af Pediatric Neurology, Vall d’Hebron Research Institute, Barcelona, Spain
ag Neuroscience Center, University of Helsinki, Helsinki, Finland
ah Molecular Neurology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland
ai 23andMe, Inc., Mountain View, CA, United States
aj Institute of Public Health, Charité–Universitätsmedizin Berlin, Berlin, Germany
ak Division of Preventive Medicine, Brigham and Women’s Hospital, Boston, MA, United States
al deCODE Genetics, Reykjavik, Iceland
am Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland
an Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
ao Institute of Human Genetics, Ulm University, Ulm, Germany
ap Center for Life Course Epidemiology and Systems Medicine, University of Oulu, Oulu, Finland
aq Department of Radiology, Erasmus University Medical Center, Rotterdam, Netherlands
ar Department of Clinical Chemistry, Fimlab Laboratories, School of Medicine, University of Tampere, Tampere, Finland
as Department of Public Health, University of Helsinki, Helsinki, Finland
at Harvard Medical School, Boston, MA, United States
au Department of Neurology, University Duisburg–Essen, Essen, Germany
av Landspitali University Hospital, Reykjavik, Iceland
aw Department of Psychiatry, VU University Medical Center, Amsterdam, Netherlands
ax Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
ay Department of Neurosurgery, NeuroCenter, Kuopio University Hospital, Kuopio, Finland
az Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
ba MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, Oxford University, Oxford, United Kingdom
bb Nuffield Department of Clinical Neuroscience, University of Oxford, Oxford, United Kingdom
bc Oxford Headache Centre, John Radcliffe Hospital, Oxford, United Kingdom
bd Max Planck Institute of Psychiatry, Munich, Germany
be Institute of Clinical Molecular Biology, Christian Albrechts University, Kiel, Germany
bf Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany
bg Institute of Human Genetics, Technische Universität München, Munich, Germany
bh Department of General Practice and Primary Health Care, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
bi National Institute for Health and Welfare, Helsinki, Finland
bj Institute of Clinical Medicine, University of Helsinki, Helsinki, Finland
bk Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, United States
bl Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, Netherlands
bm Department of Pain Management and Research, Oslo University Hospital, Oslo, Norway
bn Medical Faculty, University of Oslo, Oslo, Norway
bo Department of Ageing and Health, Norwegian Institute of Public Health, Oslo, Norway
bp Kiel Pain and Headache Center, Kiel, Germany
bq Danish Headache Center, Department of Neurology, Rigshospitalet, Glostrup Hospital, University of Copenhagen, Copenhagen, Denmark
br Institute of Biological Psychiatry, Mental Health Center Sct. Hans, University of Copenhagen, Roskilde, Denmark
bs Institute of Biological Psychiatry, MHC Sct. Hans, Mental Health Services Copenhagen, Copenhagen, Denmark
bt Institute of Clinical Sciences, Faculty of Medicine and Health Sciences, University of Copenhagen, Copenhagen, Denmark
bu iPSYCH—The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Copenhagen, Denmark
bv Department of Health, National Institute for Health and Welfare, Helsinki, Finland
bw Research Center of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland
bx Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland
by Department of Neurology, Erasmus University Medical Center, Rotterdam, Netherlands
bz Department of Epidemiology and Biostatistics, MRC Health Protection Agency (HPE) Centre for Environment and Health, School of Public Health, Imperial College London, London, United Kingdom
ca Biocenter Oulu, University of Oulu, Oulu, Finland
cb Unit of Primary Care, Oulu University Hospital, Oulu, Finland
cc Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
cd Faculty of Medicine, University of Iceland, Reykjavik, Iceland
ce Statistical and Genomic Epidemiology Laboratory, Institute of Health and Biomedical Innovation, Queensland University of Technology, Kelvin Grove, Brisbane, QLD, Australia
cf Department of Neurology, Massachusetts General Hospital, Boston, MA, United States
cg Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom

Abstract
Migraine and major depressive disorder (MDD) are common brain disorders that frequently co-occur. Despite epidemiological evidence that migraine and MDD share a genetic basis, their overlap at the molecular genetic level has not been thoroughly investigated. Using single-nucleotide polymorphism (SNP) and gene-based analysis of genome-wide association study (GWAS) genotype data, we found significant genetic overlap across the two disorders. LD Score regression revealed a significant SNP-based heritability for both migraine (h2 = 12%) and MDD (h2 = 19%), and a significant cross-disorder genetic correlation (rG = 0.25; P = 0.04). Meta-analysis of results for 8,045,569 SNPs from a migraine GWAS (comprising 30,465 migraine cases and 143,147 control samples) and the top 10,000 SNPs from a MDD GWAS (comprising 75,607 MDD cases and 231,747 healthy controls), implicated three SNPs (rs146377178, rs672931, and rs11858956) with novel genome-wide significant association (PSNP ≤ 5 × 10−8) to migraine and MDD. Moreover, gene-based association analyses revealed significant enrichment of genes nominally associated (Pgene-based ≤ 0.05) with both migraine and MDD (Pbinomial-test = 0.001). Combining results across migraine and MDD, two genes, ANKDD1B and KCNK5, produced Fisher’s combined gene-based P values that surpassed the genome-wide significance threshold (PFisher’s-combined ≤ 3.6 × 10−6). Pathway analysis of genes with PFisher’s-combined ≤ 1 × 10−3 suggested several pathways, foremost neural-related pathways of signalling and ion channel regulation, to be involved in migraine and MDD aetiology. In conclusion, our study provides strong molecular genetic support for shared genetically determined biological mechanisms underlying migraine and MDD. © 2018 European Society of Human Genetics

Document Type: Article in Press
Source: Scopus

Anatomical and functional dichotomy of ocular itch and pain (2018) Nature Medicine

Anatomical and functional dichotomy of ocular itch and pain
(2018) Nature Medicine, pp. 1-9. Article in Press. 

Huang, C.-C.a g , Yang, W.a , Guo, C.a , Jiang, H.a , Li, F.a b , Xiao, M.a , Davidson, S.c , Yu, G.d , Duan, B.e h , Huang, T.e , Huang, A.J.W.f , Liu, Q.a f

a Department of Anesthesiology and Center for the Study of Itch, Washington University School of Medicine, St. Louis, MO, United States
b Department of Anesthesiology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
c Department of Anesthesiology and Pain Research Center, University of Cincinnati College of Medicine, Cincinnati, OH, United States
d School of Medicine and Life Sciences, Nanjing University of Chinese Medicine, Jiangsu, China
e Dana-Farber Cancer Institute and Department of Neurobiology, Harvard Medical School, Boston, MA, United States
f Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO, United States
g Merck Research Laboratories, South San Francisco, CA, United States
h Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, MI, United States

Abstract
Itch and pain are refractory symptoms of many ocular conditions. Ocular itch is generated mainly in the conjunctiva and is absent from the cornea. In contrast, most ocular pain arises from the cornea. However, the underlying mechanisms remain unknown. Using genetic axonal tracing approaches, we discover distinct sensory innervation patterns between the conjunctiva and cornea. Further genetic and functional analyses in rodent models show that a subset of conjunctival-selective sensory fibers marked by MrgprA3 expression, rather than corneal sensory fibers, mediates ocular itch. Importantly, the actions of both histamine and nonhistamine pruritogens converge onto this unique subset of conjunctiva sensory fibers and enable them to play a key role in mediating itch associated with allergic conjunctivitis. This is distinct from skin itch, in which discrete populations of sensory neurons cooperate to carry itch. Finally, we provide proof of concept that selective silencing of conjunctiva itch-sensing fibers by pruritogen-mediated entry of sodium channel blocker QX-314 is a feasible therapeutic strategy to treat ocular itch in mice. Itch-sensing fibers also innervate the human conjunctiva and allow pharmacological silencing using QX-314. Our results cast new light on the neural mechanisms of ocular itch and open a new avenue for developing therapeutic strategies. © 2018 The Author(s)

Document Type: Article in Press
Source: Scopus

The accessory olfactory system: Innately specialized or microcosm of mammalian circuitry? (2018) Annual Review of Neuroscience

The accessory olfactory system: Innately specialized or microcosm of mammalian circuitry?
(2018) Annual Review of Neuroscience, 41, pp. 501-525. 

Holy, T.E.

Department of Neuroscience, Washington University, St. Louis, MO, United States

Abstract
In mammals, the accessory olfactory system is a distinct circuit that has received attention for its role in detecting and responding to pheromones. While the neuroscientific investigation of this system is comparatively new, recent advances and its compact size have made it an attractive model for developing an end-to-end understanding of such questions as regulation of essential behaviors, plasticity, and individual recognition. Recent discoveries have indicated a need to reevaluate our conception of this system, suggesting that (a) physical principles – rather than biological necessity – play an underappreciated role in its raison d’être and that (b) the anatomy of downstream projections is not dominated by unique specializations but instead consists of an abbreviated cortical/basal ganglia motif reminiscent of other sensorimotor systems. These observations suggest that the accessory olfactory system distinguishes itself primarily by the physicochemical properties of its ligands, but its architecture is otherwise a microcosm of mammalian neurocircuitry. © 2018 by Annual Reviews. All rights reserved.

Author Keywords
hypothalamus;  innate behavior;  pallidum;  sensory processing;  striatum;  volatility

Document Type: Review
Source: Scopus

Voltage-gated sodium currents in cerebellar Purkinje neurons: functional and molecular diversity (2018) Cellular and Molecular Life Sciences

Voltage-gated sodium currents in cerebellar Purkinje neurons: functional and molecular diversity
(2018) Cellular and Molecular Life Sciences, pp. 1-11. Article in Press. 

Ransdell, J.L.a b , Nerbonne, J.M.a b

a Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, United States
b Department of Medicine, Washington University School of Medicine, 660 South Euclid Avenue, Box 8086, St. Louis, MO, United States

Abstract
Purkinje neurons, the sole output of the cerebellar cortex, deliver GABA-mediated inhibition to the deep cerebellar nuclei. To subserve this critical function, Purkinje neurons fire repetitively, and at high frequencies, features that have been linked to the unique properties of the voltage-gated sodium (Nav) channels expressed. In addition to the rapidly activating and inactivating, or transient, component of the Nav current (INaT) present in many types of central and peripheral neurons, Purkinje neurons, also expresses persistent (INaP) and resurgent (INaR) Nav currents. Considerable progress has been made in detailing the biophysical properties and identifying the molecular determinants of these discrete Nav current components, as well as defining their roles in the regulation of Purkinje neuron excitability. Here, we review this important work and highlight the remaining questions about the molecular mechanisms controlling the expression and the functioning of Nav currents in Purkinje neurons. We also discuss the impact of the dynamic regulation of Nav currents on the functioning of individual Purkinje neurons and cerebellar circuits. © 2018 Springer Nature Switzerland AG

Author Keywords
Accessory subunit;  Cerebellum;  Conductance;  Intrinsic excitability

Document Type: Article in Press
Source: Scopus

Event-related potential (ERP) correlates of face processing in verbal children with autism spectrum disorders (ASD) and their first-degree relatives: A family study (2018) Molecular Autism

Event-related potential (ERP) correlates of face processing in verbal children with autism spectrum disorders (ASD) and their first-degree relatives: A family study
(2018) Molecular Autism, 9 (1), art. no. 41, . 

Sysoeva, O.V.a b , Constantino, J.N.a , Anokhin, A.P.a

a Washington University, School of Medicine, Campus Box 8504, 660 South Euclid Avenue, Saint Louis, MO, United States
b Autism Research Laboratory, Moscow State University of Psychology and Education (MSUPE), 2A Shelepihinskaya Quay, Moscow, Russian Federation

Abstract
Background: Inherited abnormalities of perception, recognition, and attention to faces have been implicated in the etiology of autism spectrum disorders (ASD) including abnormal components of event-related brain potentials (ERP) elicited by faces. Methods: We examined familial aggregation of face processing ERP abnormalities previously implicated in ASD in 49 verbal individuals with ASD, 36 unaffected siblings (US), 18 unaffected fathers (UF), and 53 unrelated controls (UC). The ASD, US, and UC groups ranged in age from 12 to 21 years, the UF group ranged in age from 30 to 56 years. ERP responses to images of upright and inverted faces and houses were analyzed under disparate EEG reference schemes. Results: Face-sensitive features of N170 and P1 were readily observed in all groups. Differences between ASD and control groups depended upon the EEG reference scheme. Notably, the superiority of face over object for N170 latency was attenuated in ASD subjects, but not their relatives; this occurred exclusively with the average reference. The difference in N170 amplitude between inverted and upright faces was reduced in both ASD and US groups relative to UC, but this effect was significant only with the vertex reference. Furthermore, similar group differences were observed for both inverted faces and inverted houses, suggesting a lack of face specificity for the attenuation of the N170 inversion effect in ASD. Conclusion: The present findings refine understanding of face processing ERPs in ASD. These data provide only modest evidence for highly-selective ASD-sensitive ERP features, and underscore the sensitivity of these biomarkers to ERP reference scheme. These schemes have varied across published studies and must be accounted for in future studies of the relationship between these commonly acquired ERP characteristics, genotype, and ASD. © 2018 The Author(s).

Author Keywords
Autistic disorder;  Electrophysiology;  Endophenotype;  ERP;  N170

Document Type: Article
Source: Scopus

Motion onset really does capture attention (2018) Attention, Perception, and Psychophysics

Motion onset really does capture attention
(2018) Attention, Perception, and Psychophysics, pp. 1-10. Article in Press. 

Smith, K.C., Abrams, R.A.

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

Abstract
Several properties of visual stimuli have been shown to capture attention, one of which is the onset of motion. However, whether motion onset truly captures attention has been debated. It has been argued that motion onset only captured attention in previous studies because properties of the animated motion used in those experiments caused it to be “jerky” (i.e., there were gaps between successive images during animated motion). The present study sought to determine whether natural motion onset captures attention. Additionally, the present study further examined the circumstances under which animated motion onset, the only type of motion onset that can be produced on a computer display, does and does not capture attention. In Experiment 1, participants identified target letters in search arrays containing distinct animated motion types, either accompanied or unaccompanied by a new object. Animated motion onset captured attention, but not when the motion onset was accompanied by a new object, indicating that prior failures to replicate capture by animated motion onset were limited because a new object had always been included in the display. Experiment 2 employed natural motion rather than animated motion and found that participants were fastest at identifying motion-onset targets compared to other target types. These results provide further support for the claim that motion onset captures attention. © 2018 The Psychonomic Society, Inc.

Author Keywords
Attention;  Attentional capture;  Motion onset;  Motion perception

Document Type: Article in Press
Source: Scopus

Sex-specific genetic predictors of Alzheimer’s disease biomarkers (2018) Acta Neuropathologica

Sex-specific genetic predictors of Alzheimer’s disease biomarkers
(2018) Acta Neuropathologica, pp. 1-16. Article in Press. 

Deming, Y.a , Dumitrescu, L.b , Barnes, L.L.c , Thambisetty, M.d , Kunkle, B.e , Gifford, K.A.b , Bush, W.S.e , Chibnik, L.B.f g , Mukherjee, S.h , de Jager, P.L.i j , Kukull, W.k , Huentelman, M.l , Crane, P.K.h , Resnick, S.M.d , Keene, C.D.m , Montine, T.J.n , Schellenberg, G.D.o , Haines, J.L.e , Zetterberg, H.p q r s , Blennow, K.p q , Larson, E.B.h t , Johnson, S.C.u v , Albert, M.w , Moghekar, A.w , Del Aguila, J.L.a , Fernandez, M.V.a , Budde, J.a , Hassenstab, J.a , Fagan, A.M.x , Riemenschneider, M.y , Petersen, R.C.z , Minthon, L.aa , Chao, M.J.ab , van Deerlin, V.M.ac , Lee, V.M.-Y.ac , Shaw, L.M.ac , Trojanowski, J.Q.ac , Peskind, E.R.ad , Li, G.ad ae , Davis, L.K.af , Sealock, J.M.af , Cox, N.J.af , Weiner, M.W.ag , Petersen, R.ag , Aisen, P.ag , Jack, C.ag , Jagust, W.ag , Shaw, L.M.ag , Trojanowski, J.ag , Beckett, L.ag , Toga, A.ag , Saykin, A.ag , Morris, J.C.ag , Montine, T.ag , Green, R.ag , Abner, E.ag , Adams, P.ag , Albert, M.ag , Albin, R.ag , Apostolova, L.ag , Arnold, S.ag , Asthana, S.ag , Atwood, C.ag , Baldwin, C.ag , Barber, R.ag , Barnes, L.ag , Barral, S.ag , Beach, T.ag , Becker, J.ag , Beecham, G.ag , Beekly, D.ag , Bennett, D.ag , Bigio, E.ag , Bird, T.ag , Blacker, D.ag , Boeve, B.ag , Bowen, J.ag , Boxer, A.ag , Burke, J.ag , Burns, J.ag , Buxbaum, J.ag , Cairns, N.ag , Cantwell, L.ag , Cao, C.ag , Carlson, C.ag , Carlsson, C.ag , Carney, R.ag , Carrasquillo, M.ag , Chui, H.ag , Crane, P.ag , Cribbs, D.ag , Crocco, E.ag , Cruchaga, C.ag , de Jager, P.ag , DeCarli, C.ag , Dick, M.ag , Dickson, D.ag , Doody, R.ag , Duara, R.ag , Ertekin-Taner, N.ag , Evans, D.ag , Faber, K.ag , Fairchild, T.ag , Fallon, K.ag , Fardo, D.ag , Farlow, M.ag , Farrer, L.ag , Ferris, S.ag , Foroud, T.ag , Frosch, M.ag , Galasko, D.ag , Gearing, M.ag , Geschwind, D.ag , Ghetti, B.ag , Gilbert, J.ag , Goate, A.ag , Graff-Radford, N.ag , Green, R.ag , Growdon, J.ag , Haines, J.ag , Hakonarson, H.ag , Hamilton, R.ag , Hamilton-Nelson, K.ag , Hardy, J.ag , Harrell, L.ag , Honig, L.ag , Huebinger, R.ag , Huentelman, M.ag , Hulette, C.ag , Hyman, B.ag , Jarvik, G.ag , Jin, L.-W.ag , Jun, G.ag , Ilyas Kamboh, M.ag , Karydas, A.ag , Katz, M.ag , Kauwe, J.ag , Kaye, J.ag , Dirk Keene, C.ag , Kim, R.ag , Kowall, N.ag , Kramer, J.ag , Kukull, W.ag , Kunkle, B.ag , Kuzma, A.ag , LaFerla, F.ag , Lah, J.ag , Larson, E.ag , Leverenz, J.ag , Levey, A.ag , Li, G.ag , Lieberman, A.ag , Lipton, R.ag , Lopez, O.ag , Lunetta, K.ag , Lyketsos, C.ag , Malamon, J.ag , Marson, D.ag , Martin, E.ag , Martiniuk, F.ag , Mash, D.ag , Masliah, E.ag , Mayeux, R.ag , McCormick, W.ag , McCurry, S.ag , McDavid, A.ag , McDonough, S.ag , McKee, A.ag , Mesulam, M.ag , Miller, B.ag , Miller, C.ag , Miller, J.ag , Montine, T.ag , Morris, J.ag , Mukherjee, S.ag , Myers, A.ag , Naj, A.ag , O’Bryant, S.ag , Olichney, J.ag , Parisi, J.ag , Paulson, H.ag , Pericak-Vance, M.ag , Peskind, E.ag , Petersen, R.ag , Pierce, A.ag , Poon, W.ag , Potter, H.ag , Qu, L.ag , Quinn, J.ag , Raj, A.ag , Raskind, M.ag , Reiman, E.ag , Reisberg, B.ag , Reisch, J.ag , Reitz, C.ag , Ringman, J.ag , Roberson, E.ag , Rogaeva, E.ag , Rosen, H.ag , Rosenberg, R.ag , Royall, D.ag , Sager, M.ag , Sano, M.ag , Saykin, A.ag , Schellenberg, G.ag , Schneider, J.ag , Schneider, L.ag , Seeley, W.ag , Smith, A.ag , Sonnen, J.ag , Spina, S.ag , George-Hyslop, P.S.ag , Stern, R.ag , Swerdlow, R.ag , Tanzi, R.ag , Trojanowski, J.ag , Troncoso, J.ag , Tsuang, D.ag , Valladares, O.ag , van Deerlin, V.ag , van Eldik, L.ag , Vardarajan, B.ag , Vinters, H.ag , Vonsattel, J.P.ag , Wang, L.-S.ag , Weintraub, S.ag , Welsh-Bohmer, K.ag , Wilhelmsen, K.ag , Williamson, J.ag , Wingo, T.ag , Woltjer, R.ag , Wright, C.ag , Wu, C.-K.ag , Younkin, S.ag , Yu, C.-E.ag , Yu, L.ag , Zhao, Y.ag , Goate, A.M.ab , Bennett, D.A.c , Schneider, J.A.c , Jefferson, A.L.b , Cruchaga, C.a , Hohman, T.J.b , Alzheimer’S Disease Neuroimaging Initiative (Adni)ag , The Alzheimer Disease Genetics Consortium (Adgc)ag

a Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave. B8134, St. Louis, MO, United States
b Vanderbilt Memory and Alzheimer’s Center, Vanderbilt University Medical Center, Vanderbilt University School of Medicine, 1207 17th Avenue S, Nashville, TN, United States
c Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL, United States
d Unit of Clinical and Translational Neuroscience, Laboratory of Behavioral Neuroscience, National Institute on Aging, National Institutes of Health, Baltimore, MD, United States
e Department of Population and Quantitative Health Sciences, Institute for Computational Biology, Case Western Reserve University, Cleveland, OH, United States
f Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, United States
g Channing Division of Network Medicine, Brigham and Women’s Hospital, Boston, MA, United States
h Department of Medicine, University of Washington, Seattle, WA, United States
i Department of Neurology, Center for Translational and Computational Neuroimmunology, Columbia University Medical Center, New York, NY, United States
j Cell Circuits Program, Broad Institute, Cambridge, MA, United States
k Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA, United States
l Neurogenomics Division, Translational Genomics Research Institute, Phoenix, AZ, United States
m Department of Pathology, University of Washington, Seattle, WA, United States
n Department of Pathology, Stanford University, Stanford, CA, United States
o Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
p Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden
q Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
r Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London, United Kingdom
s UK Dementia Research Institute at UCL, London, United Kingdom
t Kaiser Permanente Washington Health Research Institute, Seattle, WA, United States
u Alzheimer’s Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
v Geriatric Research Education and Clinical Center of the Wm. S. Middleton Memorial VA Hospital, Madison, WI, United States
w Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD, United States
x Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
y Clinic of Psychiatry and Psychotherapy, Saarland University, Homburg/Saar, Germany
z Department of Neurology, Mayo Clinic, Rochester, MN, United States
aa Clinical Memory Research Unit, Department of Clinical Sciences, Lund University, Lund, Sweden
ab Ronald M Loeb Center for Alzheimer’s Disease, Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, United States
ac Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States
ad Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, United States
ae Geriatric Research, Education, and Clinical Center, VA Puget Sound Health Care System, Seattle, WA, United States
af Department of Medicine, Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, United States

Abstract
Cerebrospinal fluid (CSF) levels of amyloid-β 42 (Aβ42) and tau have been evaluated as endophenotypes in Alzheimer’s disease (AD) genetic studies. Although there are sex differences in AD risk, sex differences have not been evaluated in genetic studies of AD endophenotypes. We performed sex-stratified and sex interaction genetic analyses of CSF biomarkers to identify sex-specific associations. Data came from a previous genome-wide association study (GWAS) of CSF Aβ42 and tau (1527 males, 1509 females). We evaluated sex interactions at previous loci, performed sex-stratified GWAS to identify sex-specific associations, and evaluated sex interactions at sex-specific GWAS loci. We then evaluated sex-specific associations between prefrontal cortex (PFC) gene expression at relevant loci and autopsy measures of plaques and tangles using data from the Religious Orders Study and Rush Memory and Aging Project. In Aβ42, we observed sex interactions at one previous and one novel locus: rs316341 within SERPINB1 (p = 0.04) and rs13115400 near LINC00290 (p = 0.002). These loci showed stronger associations among females (β = − 0.03, p = 4.25 × 10−8; β = 0.03, p = 3.97 × 10−8) than males (β = − 0.02, p = 0.009; β = 0.01, p = 0.20). Higher levels of expression of SERPINB1, SERPINB6, and SERPINB9 in PFC was associated with higher levels of amyloidosis among females (corrected p values < 0.02) but not males (p > 0.38). In total tau, we observed a sex interaction at a previous locus, rs1393060 proximal to GMNC (p = 0.004), driven by a stronger association among females (β = 0.05, p = 4.57 × 10−10) compared to males (β = 0.02, p = 0.03). There was also a sex-specific association between rs1393060 and tangle density at autopsy (pfemale = 0.047; pmale = 0.96), and higher levels of expression of two genes within this locus were associated with lower tangle density among females (OSTN p = 0.006; CLDN16 p = 0.002) but not males (p ≥ 0.32). Results suggest a female-specific role for SERPINB1 in amyloidosis and for OSTN and CLDN16 in tau pathology. Sex-specific genetic analyses may improve understanding of AD’s genetic architecture. © 2018 Springer-Verlag GmbH Germany, part of Springer Nature

Author Keywords
Alzheimer disease;  Amyloid;  APOE;  Cerebrospinal fluid biomarkers;  Neuropathology;  Sex difference;  Tau

Document Type: Article in Press
Source: Scopus

Soluble amyloid-beta buffering by plaques in Alzheimer disease dementia versus high-pathology controls (2018) PLoS ONE

Soluble amyloid-beta buffering by plaques in Alzheimer disease dementia versus high-pathology controls
(2018) PLoS ONE, 13 (7), art. no. e0200251, . 

Esparza, T.J.a , Gangolli, M.b , Cairns, N.J.a c d , Brody, D.L.a b d

a Department of Neurology, Washington University, St. Louis, MO, United States
b Department of Biomedical Engineering, Washington University, St. Louis, MO, United States
c Knight Alzheimer Disease Research Center, Washington University, St. Louis, MO, United States
d Hope Center for Neurological Disorders, Washington University, St. Louis, MO, United States

Abstract
An unanswered question regarding Alzheimer disease dementia (ADD) is whether amyloid-beta (Aβ) plaques sequester toxic soluble Aβ species early during pathological progression. We previously reported that the concentration of soluble Aβ aggregates from patients with mild dementia was higher than soluble Aβ aggregates from patients with modest Aβ plaque burden but no dementia. The ratio of soluble Aβ aggregate concentration to Aβ plaque area fully distinguished these groups of patients. We hypothesized that initially plaques may serve as a reservoir or sink for toxic soluble Aβ aggregates, sequestering them from other targets in the extracellular space and thereby preventing their toxicity. To initially test a generalized version of this hypothesis, we have performed binding assessments using biotinylated synthetic Aβ1–42 peptide. Aβ1-42-biotin peptide was incubated on unfixed frozen sections from non-demented high plaque pathology controls and patients with ADD. The bound peptide was measured using ELISA and confocal microscopy. We observed no quantitative difference in Aβ binding between the groups using either method. Further testing of the buffering hypothesis using various forms of synthetic and human derived soluble Aβ aggregates will be required to definitively address the role of plaque buffering as it relates to ADD. © 2018 Esparza et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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

Emergency department time course for mild traumatic brain injury workup (2018) Western Journal of Emergency Medicine

Emergency department time course for mild traumatic brain injury workup
(2018) Western Journal of Emergency Medicine, 19 (4), pp. 635-640. 

Michelson, E.A.a , Huff, J.S.b , Loparo, M.c , Naunheim, R.S.d , Perron, A.e , Rahm, M.f , Smith, D.W.g , Stone, J.A.h , Berger, A.i

a Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, Department of Emergency Medicine, 4801 El Paso Drive, El Paso, TX, United States
b University of Virginia Health System, Department of Emergency Medicine, Charlottesville, VA, United States
c University Hospitals Cleveland Medical Center, Department of Emergency Medicine, Cleveland, OH, United States
d Washington University School of Medicine, Department of Emergency Medicine, St. Louis, MO, United States
e Maine Medical Center, Department of Emergency Medicine, Portland, ME, United States
f Barnes Jewish Hospital, Department of Emergency Medicine, St. Louis, MO, United States
g Integris Baptist Medical Center, Department of Emergency Medicine, Oklahoma City, OK, United States
h Brody School of Medicine, East Carolina School of Medicine, Department of Emergency Medicine, Greenville, NC, United States
i Evidera, Bethesda, MD, United States

Abstract
Introduction: Mild traumatic brain injury (mTBI) is a common cause for visits to the emergency department (ED). The actual time required for an ED workup of a patient with mTBI in the United States is not well known. National emergency medicine organizations have recommended reducing unnecessary testing, including head computed tomography (CT) for these patients.10 Methods: To examine this issue, we developed a care map that included each step of evaluation of mTBI (Glasgow Coma Scale Score 13-15) – from initial presentation to the ED to discharge. Time spent at each step was estimated by a panel of United States emergency physicians and nurses. We subsequently validated time estimates using retrospectively collected, real-time data at two EDs. Length of stay (LOS) time differences between admission and discharged patients were calculated for patients being evaluated for mTBI. Results: Evaluation for mTBI was estimated at 401 minutes (6.6 hours) in EDs. Time related to head CT comprised about one-half of the total LOS. Real-time data from two sites corroborated the estimate of median time difference between ED admission and discharge, at 6.3 hours for mTBI. Conclusion: Limiting use of head CT as part of the workup of mTBI to more serious cases may reduce time spent in the ED and potentially improve overall ED throughput. © 2018 Michelson et al.

Document Type: Article
Source: Scopus

Deficits in burrowing behaviors are associated with mouse models of neuropathic but not inflammatory pain or migraine (2018) Frontiers in Behavioral Neuroscience

Deficits in burrowing behaviors are associated with mouse models of neuropathic but not inflammatory pain or migraine
(2018) Frontiers in Behavioral Neuroscience, 12, art. no. 124, . 

Shepherd, A.J.a b , Cloud, M.E.a b , Cao, Y.-Q.a b , Mohapatra, D.P.a b

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

Abstract
Burrowing, or the removal of material from an enclosed tube, is emerging as a prominent means of testing changes in a voluntary behavior in rodent models of various pain states. Here, we report no significant differences between male and female mice in terms of burrowing performance, in a substantially shorter time frame than previous reports. We found that the color of the burrow tube affects the variability of burrowing performance when tested in a lit room, suggesting that light aversion is at least a partial driver of this behavior. Spared nerve injury (SNI; as a model of neuropathy) impairs burrowing performance and correlates with enhanced mechanical sensitivity as assessed by von Frey filaments, as well as being pharmacologically reversed by an analgesic, gabapentin. Loss of the SNI-induced burrowing deficit was observed with daily testing post-surgery, but not when the testing interval was increased to 5 days, suggesting a confounding effect of daily repeat testing in this paradigm. Intraplantar complete Freund’s adjuvant (as a model of inflammatory pain) and systemic nitroglycerin (as a model of migraine-like symptoms) administration did not induce any burrowing deficit, indicating that assessment of burrowing behavior may not be universally suitable for the detection of behavioral changes across all rodent pain models. © 2018 Shepherd, Cloud, Cao and Mohapatra.

Author Keywords
Burrowing;  Inflammatory pain;  Migraine;  Neuropathic pain;  Pain

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

Parental age and risk of genetic syndromes predisposing to nervous system tumors: Nested case–control study (2018) Clinical Epidemiology

Parental age and risk of genetic syndromes predisposing to nervous system tumors: Nested case–control study
(2018) Clinical Epidemiology, 10, pp. 729-738. 

Fahmideh, M.A.a , Tettamanti, G.a , Lavebratt, C.b , Talbäck, M.a , Mathiesen, T.c d , Lannering, B.e , Johnson, K.J.f g , Feychting, M.a

a Unit of Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
b Neurogenetics Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet, Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden
c Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
d University of Copenhagen, Copenhagen, Denmark
e Department of Pediatrics, University of Gothenburg, Gothenburg, Sweden
f Brown School, Washington University in St Louis, St Louis, MO, United States
g Department of Pediatrics, School of Medicine, Washington University in St Louis, St Louis, MO, United States

Abstract
Purpose: Phacomatoses are genetic syndromes that are associated with increased risk of developing nervous system tumors. Phacomatoses are usually inherited, but many develop de novo, with unknown etiology. In this population-based study, we investigated the effect of parental age on the risk of phacomatoses in offspring. Patients and methods: The study was a population-based nested case–control study. All individuals born and residing in Sweden between January 1960 and December 2010 were eligible for inclusion. Using the Patient Register, 4625 phacomatosis cases were identified and further classified as familial or nonfamilial. Ten matched controls per case were randomly selected from the eligible population. Data were analyzed using conditional logistic regression. Analyses were conducted for neurofibromatosis alone (n=2089) and other phacomatoses combined (n=2536). Results: Compared with offspring of fathers aged 25–29 years, increased risk estimates of nonfamilial neurofibromatosis were found for offspring of fathers aged 35–39 years (odds ratio [OR]=1.43 [95% CI 1.16–1.74]) and ≥40 years (OR =1.74 [95% CI 1.38–2.19]). For other nonfamilial phacomatoses, the risk estimate for offspring of fathers aged ≥40 years was OR =1.23 (95% CI 1.01–1.50). Paternal age was not associated with familial phacomatoses, and no consistent association was observed with maternal age. Conclusion: The findings show a consistent increase in risk of de novo occurrence of phacomatoses predisposing to nervous system tumors in offspring with increasing paternal age, most pronounced for neurofibromatosis, while maternal age did not seem to influence the risk. These findings suggest an increasing rate of new mutations in the NF1 and NF2 genes in spermatozoa of older fathers. © 2018 Adel Fahmideh et al.

Author Keywords
Nervous system tumor predisposition syndromes;  Neurofibromatosis;  Parental age;  Phacomatoses;  Registry

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

Functional characterization of biallelic RTTN variants identified in an infant with microcephaly, simplified gyral pattern, pontocerebellar hypoplasia, and seizures (2018) Pediatric Research

Functional characterization of biallelic RTTN variants identified in an infant with microcephaly, simplified gyral pattern, pontocerebellar hypoplasia, and seizures
(2018) Pediatric Research, pp. 1-7. Article in Press. 

Wambach, J.A.a , Wegner, D.J.a , Yang, P.a , Shinawi, M.a , Baldridge, D.a , Betleja, E.b , Shimony, J.S.c , Spencer, D.d , Hackett, B.P.a , Andrews, M.V.a , Ferkol, T.a , Dutcher, S.K.e , Mahjoub, M.R.b , Cole, F.S.a

a Edward Mallinckrodt Department of Pediatrics, Washington University School of Medicine and St. Louis Children’s Hospital, St. Louis, MO, United States
b John T. Milliken Department of Medicine, Washington University School of Medicine and St. Louis Children’s Hospital, St. Louis, MO, United States
c Mallinckrodt Institute of Radiology, Washington University School of Medicine and St. Louis Children’s Hospital, St. Louis, MO, United States
d McDonnell Genome Institute, Washington University School of Medicine and St. Louis Children’s Hospital, St. Louis, MO, United States
e Department of Genetics, Washington University School of Medicine and St. Louis Children’s Hospital, St. Louis, MO, United States

Abstract
Background: Biallelic deleterious variants in RTTN, which encodes rotatin, are associated with primary microcephaly, polymicrogyria, seizures, intellectual disability, and primordial dwarfism in human infants. Methods and results: We performed exome sequencing of an infant with primary microcephaly, pontocerebellar hypoplasia, and intractable seizures and his healthy, unrelated parents. We cultured the infant’s fibroblasts to determine primary ciliary phenotype. Results: We identified biallelic variants in RTTN in the affected infant: a novel missense variant and a rare, intronic variant that results in aberrant transcript splicing. Cultured fibroblasts from the infant demonstrated reduced length and number of primary cilia. Conclusion: Biallelic variants in RTTN cause primary microcephaly in infants. Functional characterization of primary cilia length and number can be used to determine pathogenicity of RTTN variants. © 2018 International Pediatric Research Foundation, Inc.

Document Type: Article in Press
Source: Scopus

Nerve and tendon transfer surgery in cervical spinal cord injury: Individualized choices to optimize function (2018) Topics in Spinal Cord Injury Rehabilitation

Nerve and tendon transfer surgery in cervical spinal cord injury: Individualized choices to optimize function
(2018) Topics in Spinal Cord Injury Rehabilitation, 24 (3), pp. 275-287. Cited 1 time.
Fox, I.K.a , Miller, A.K.b , Curtin, C.M.c

a Department of Surgery, Washington University, 660 South Euclid Avenue, St. Louis, MO, United States
b Department of Neurology, Washington University, St. Louis, MO, United States
c Department of Surgery, Veterans Affairs Healthcare System, Palo Alto, CA, United States

Abstract
Background: Recent adaption of nerve transfer surgery to improve upper extremity function in cervical spinal cord injury (SCI) is an exciting development. Tendon transfer procedures are well established, reliable, and can significantly improve function. Despite this, few eligible surgical candidates in the United States undergo these restorative surgeries. Evidence Acquisition: The literature on these procedures was reviewed. Results: Options to improve function include surgery to restore elbow extension, wrist extension, and hand opening and closing function. Tendon transfers are reliable and well tolerated but require weeks of immobilization and limits on extremity use. The role of nerve transfers is still being established. Early results indicate variable return of meaningful function with less immobilization but longer periods (up to years) required to gain appreciable function. Conclusion: Nerve and tendon transfer surgery sacrifice an expendable donor to restore a missing and more critical function. These procedures are well described in hand surgery; are reliable, well tolerated, and covered by insurance; and should be part of the SCI rehabilitation discussion. © 2018 Thomas Land Publishers, Inc.

Author Keywords
Nerve transfer;  Spinal cord injury;  Tendon transfer;  Tetraplegia;  Upper extremity

Document Type: Article
Source: Scopus

The immediate early gene Egr3 is required for hippocampal induction of Bdnf by electroconvulsive stimulation (2018) Frontiers in Behavioral Neuroscience

The immediate early gene Egr3 is required for hippocampal induction of Bdnf by electroconvulsive stimulation
(2018) Frontiers in Behavioral Neuroscience, 12, art. no. 92, . 

Meyers, K.T.a b , Marballi, K.K.a , Brunwasser, S.J.a c , Renda, B.d , Charbel, M.a e , Marrone, D.F.d f , Gallitano, A.L.a

a Department of Basic Medical Sciences, College of Medicine Phoenix, University of Arizona, Phoenix, AZ, United States
b Arizona State University, Tempe, AZ, United States
c School of Medicine, Washington University in St. Louis, St. Louis, MO, United States
d Department of Psychology, Wilfrid Laurier University, Waterloo, ON, Canada
e Barrett, The Honors college, Arizona State University, Tempe, AZ, United States
f Evelyn F. McKnight Brain Institute, The University of Arizona, Tucson, AZ, United States

Abstract
Early growth response 3 (Egr3) is an immediate early gene (IEG) that is regulated downstream of a cascade of genes associated with risk for psychiatric disorders, and dysfunction of Egr3 itself has been implicated in schizophrenia, bipolar disorder, and depression. As an activity-dependent transcription factor, EGR3 is poised to regulate the neuronal expression of target genes in response to environmental events. In the current study, we sought to identify a downstream target of EGR3 with the goal of further elucidating genes in this biological pathway relevant for psychiatric illness risk. We used electroconvulsive stimulation (ECS) to induce high-level expression of IEGs in the brain, and conducted expression microarray to identify genes differentially regulated in the hippocampus of Egr3-deficient (−/−) mice compared to their wildtype (WT) littermates. Our results replicated previous work showing that ECS induces high-level expression of the brain-derived neurotrophic factor (Bdnf) in the hippocampus of WT mice. However, we found that this induction is absent in Egr3−/− mice. Quantitative real-time PCR (qRT-PCR) validated the microarray results (performed in males) and replicated the findings in two separate cohorts of female mice. Follow-up studies of activity-dependent Bdnf exons demonstrated that ECS-induced expression of both exons IV and VI requires Egr3. In situ hybridization demonstrated high-level cellular expression of Bdnf in the hippocampal dentate gyrus following ECS in WT, but not Egr3−/−, mice. Bdnf promoter analysis revealed eight putative EGR3 binding sites in the Bdnf promoter, suggesting a mechanism through which EGR3 may directly regulate Bdnf gene expression. These findings do not appear to result from a defect in the development of hippocampal neurons in Egr3−/− mice, as cell counts in tissue sections stained with anti-NeuN antibodies, a neuron-specific marker, did not differ between Egr3−/− and WT mice. In addition, Sholl analysis and counts of dendritic spines in golgi-stained hippocampal sections revealed no difference in dendritic morphology or synaptic spine density in Egr3−/−, compared to WT, mice. These findings indicate that Egr3 is required for ECS-induced expression of Bdnf in the hippocampus and suggest that Bdnf may be a downstream gene in our previously identified biologically pathway for psychiatric illness susceptibility. © 2018 Meyers, Marballi, Brunwasser, Renda, Charbel, Marrone and Gallitano.

Author Keywords
Brain-derived neurotrophic factor;  Early growth response 3;  Electroconvulsive therapy;  Immediate early genes;  Psychosis treatment;  Schizophrenia

Document Type: Article
Source: Scopus

Effects of somatosensory impairment on participation after stroke (2018) American Journal of Occupational Therapy

Effects of somatosensory impairment on participation after stroke
(2018) American Journal of Occupational Therapy, 72 (3), art. no. 7203205100, . 

Carey, L.M.a b , Matyas, T.A.b c , Baum, C.d

a Department of Occupational Therapy, School of Allied Health, College of Science, Health, and Engineering, La Trobe University, Melbourne, VIC, Australia
b Neurorehabilitation and Recovery, Stroke Division, Florey Institute of Neuroscience and Mental Health, Heidelberg, VIC, Australia
c School of Allied Health, School of Psychology and Public Health, College of Science, Health, and Engineering, La Trobe University, Melbourne, VIC, Australia
d Program in Occupational Therapy, Washington University School of Medicine, St. Louis, MO, United States

Abstract
OBJECTIVE. Our objective was to determine the effect of loss of body sensation on activity participation in stroke survivors. METHOD. Participants (N 5 268) were assessed at hospital admission for somatosensory and motor impairment using the National Institutes of Health Stroke Scale. Participation was assessed using the Activity Card Sort (ACS) in the postacute phase. Between-group differences in activity participation were analyzed for participants with and without somatosensory impairment and with or without paresis. RESULTS. Somatosensory impairment was experienced in 33.6% of the sample and paresis in 42.9%. ACS profiles were obtained at a median of 222 days poststroke. Somatosensory loss alone (z 5 1.96, p 5 .048) and paresis in upper and lower limbs without sensory loss (z 5 4.62, p < .001) influenced activity participation. CONCLUSION. Somatosensory impairment is associated with reduced activity participation; however, paresis of upper and lower limbs can mask the contribution of sensory loss. © 2018 American Occupational Therapy Association, Inc. All rights reserved.

Document Type: Article
Source: Scopus

Loss of Local Tumor Control After Index Surgery for Spinal Metastases: A Prospective Cohort Study (2018) World Neurosurgery

Loss of Local Tumor Control After Index Surgery for Spinal Metastases: A Prospective Cohort Study
(2018) World Neurosurgery, . Article in Press. 

Depreitere, B.w , Ricciardi, F.b , Arts, M.c , Balabaud, L.d , Buchowski, J.M.e , Bunger, C.f , Chung, C.K.g , Coppes, M.H.h , Fehlings, M.G.i , Kawahara, N.j , Lee, C.-S.k , Leung, Y.l , Martin-Benlloch, J.A.m , Massicotte, E.M.i , Mazel, C.n , Meyer, B.o , Oner, F.C.p , Peul, W.q , Quraishi, N.r , Tokuhashi, Y.s , Tomita, K.t , Ulbricht, C.u , Verlaan, J.J.p , Wang, M.v , Crockard, H.A.a , Choi, D.a

a Department of Neurosurgery, National Hospital for Neurology and Neurosurgery, University College London, London, United Kingdom
b Department of Statistical Science, University College London, London, United Kingdom
c Department of Neurosurgery, Medical Center Haaglanden, Haaglanden, Netherlands
d Orthopaedics and Traumatology Centre, Clinique Mutualiste de la Porte de L’Orient, Lorient, France
e Department of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, Missouri, United States
f Department of Orthopedic Surgery, University Hospital of Aarhus, Aarhus, Denmark
g Department of Neurosurgery, Seoul National University Hospital, Seoul, South Korea
h Department of Neurosurgery, University Medical Centre Groningen, Groningen, Netherlands
i Division of Neurosurgery and Spinal Program, University of Toronto and Toronto Western Hospital, Toronto, Canada
j Department of Orthopedic Surgery, Kanazawa Medical University Hospital, Kanazawa, Japan
k Department of Orthopaedic Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
l Department of Orthopaedics, Musgrove Park Hospital, Taunton, United Kingdom
m Spinal Unit, Hospital Universitario Dr Peset, Valencia, Spain
n Department of Orthopedic Surgery, L’Institut Mutualiste Montsouris, Paris, France
o TUM School of Medicine, Technische Universitat Munchen, Munich, Germany
p Department of Orthopedic Surgery, University Medical Center Utrecht, Utrecht, Netherlands
q Department of Neurosurgery, Leiden University Medical Centre, Leiden, Netherlands
r Centre for Spine Studies and Surgery, Queens Medical Centre, Nottingham, United Kingdom
s Department of Orthopaedic Surgery, Nihon University School of Medicine, Tokyo, Japan
t Department of Orthopedic Surgery, Kanazawa University, Kanazawa, Japan
u Department of Neurosurgery, Charing Cross Hospital, London, United Kingdom
v Department of Neurosurgery, Jackson Memorial Hospital, University of Miami, Miami, United States
w Division of Neurosurgery, University Hospitals Leuven, Leuven, Belgium

Abstract
Background: As survival after treatment for symptomatic spinal metastases increases, the incidence of local tumor recurrence also may increase. However, data regarding incidence and timing of recurrence or duration of survival after second surgeries are not readily available and may help to inform clinicians when to perform second surgeries. Objective: To identify features associated with loss of local control (LLC) at a previously treated or new spinal level. Methods: Clinical and surgical data were collected from a prospective cohort of 1421 patients who had surgery for symptomatic spinal metastases. Patients undergoing repeat spinal surgery for symptomatic LLC at the same or a different level were identified and analyzed. Results: In total, 3.0% patients underwent repeat surgery for symptomatic LLC after a median interval of 184 days from the first surgery; median survival was 6.1 months after second surgery. Factors associated with second surgery for LLC were the primary tumor type, number of spinal levels, Tomita staging, Tokuhashi and Karnofsky scores, anterior surgical approach, more aggressive surgical resection, and postoperative radiotherapy. In total, 1.5% patients were admitted for surgery for a different spinal level than the index operation after median 338 days from the first operation. Conclusions: The likelihood for repeat surgery due to LLC cannot be accurately predicted at the time of initial presentation. Factors associated with second surgery for LLC relate to less aggressive tumor biology and better survival. Most patients had a reasonable duration of survival after second surgery. © 2018 Elsevier Inc.

Author Keywords
Metastases;  Recurrence;  Repeat surgery;  Spine;  Surgery;  Tumor

Document Type: Article in Press
Source: Scopus

Specific glycosaminoglycan chain length and sulfation patterns are required for cell uptake of tau versus -synuclein and -amyloid aggregates (2018) Journal of Biological Chemistry

Specific glycosaminoglycan chain length and sulfation patterns are required for cell uptake of tau versus -synuclein and -amyloid aggregates
(2018) Journal of Biological Chemistry, 293 (27), pp. 10826-10840. Cited 1 time.

Stopschinski, B.E.a e , Holmes, B.B.b e d e , Miller, G.M.c , Manon, V.A.e , Vaquer-Alicea, J.e , Prueitt, W.L.e , Hsieh-Wilson, L.C.c , Diamond, M.I.e

a Department of Neurology, RWTH University Aachen, Aachen, Germany
b Medical Scientist Training Program, Washington University School of Medicine, St. Louis, MO, United States
c Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA, United States
d University of California San Francisco, 505 Parnassus Ave., M798, Box 0114, San Francisco, CA, United States
e Center for Alzheimer’s and Neurodegenerative Diseases, University of Texas Southwestern Medical Center, 6000 Harry Hines Blvd., Dallas, TX, United States

Abstract
Transcellular propagation of protein aggregate “seeds” has been proposed to mediate the progression of neurodegenerative diseases in tauopathies and -synucleinopathies. We previously reported that tau and -synuclein aggregates bind heparan sulfate proteoglycans (HSPGs) on the cell surface, promoting cellular uptake and intracellular seeding. However, the specificity and binding mode of these protein aggregates to HSPGs remain unknown. Here, we measured direct interaction with modified heparins to determine the size and sulfation requirements for tau, -synuclein, and -amyloid (A) aggregate binding to glycosaminoglycans (GAGs). Varying the GAG length and sulfation patterns, we next conducted competition studies with heparin derivatives in cell-based assays. Tau aggregates required a precise GAG architecture with defined sulfate moieties in the N- and 6-O-positions, whereas the binding of -synuclein and A aggregates was less stringent. To determine the genes required for aggregate uptake, we used CRISPR/Cas9 to individually knock out the major genes of the HSPG synthesis pathway in HEK293T cells. Knockouts of the extension enzymes exostosin 1 (EXT1), exostosin 2 (EXT2), and exostosin-like 3 (EXTL3), as well as N-sulfotransferase (NDST1) or 6-O-sulfotransferase (HS6ST2) significantly reduced tau uptake, consistent with our biochemical findings, and knockouts of EXT1, EXT2, EXTL3, or NDST1, but not HS6ST2 reduced -synuclein uptake. In summary, tau aggregates display specific interactions with HSPGs that depend on GAG length and sulfate moiety position, whereas -synuclein and A aggregates exhibit more flexible interactions with HSPGs. These principles may inform the development of mechanism-based therapies to block transcel-lular propagation of amyloid protein–based pathologies. © 2018 by The American Society for Biochemistry and Molecular Biology, Inc.

Document Type: Article
Source: Scopus

Increased use of heroin as an initiating opioid of abuse: Further considerations and policy implications (2018) Addictive Behaviors

Increased use of heroin as an initiating opioid of abuse: Further considerations and policy implications
(2018) Addictive Behaviors, . Article in Press. 

Cicero, T.J., Kasper, Z.A., Ellis, M.S.

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

Abstract
Introduction: Previously, we reported a marked increase in the use of heroin as an initiating opioid in non-tolerant, first time opioid users. In the current paper, we sought to update and expand upon these results, with a discussion of the policy implications on the overall opioid epidemic. Methods: Opioid initiation data from the original study were updated to include surveys completed through 2017 (N = 8382) from a national sample of treatment-seeking opioid users. In addition, past month abuse of heroin and prescription were analyzed as raw numbers of treatment program entrant in the last five years (2013–2017), drawing from only those treatment centers that participated every year in that time frame. Results: The updated data confirm and extend the results of our original study: the use of heroin as an initiating opioid increased from 8.7% in 2005 to 31.6% in 2015, with increases in overall Ns per initiation year reflecting a narrowing of the “treatment gap” the time lag between opioid initiation from 2005 to 2015 and later treatment admission (up to 2017). Slight decreases were observed in treatment admissions, but this decline was totally confined to prescription opioid use, with heroin use continuing to increase in absolute numbers. Conclusions: Given that opioid novices have limited tolerance, the risk of fatal overdose for heroin initiates is elevated compared to prescription opioids, particularly given non-oral administration and often unknown purity/adulterants (i.e., fentanyl). Imprecision of titrating dose among opioid novices may explain observed increases opioid overdoses. Future policy decisions should note that prescription opioid-specific interventions may have little impact on a growing heroin epidemic. © 2018

Document Type: Article in Press
Source: Scopus

Short-term safety of mTOR inhibitors in infants and very young children with tuberous sclerosis complex (TSC): Multicentre clinical experience (2018) European Journal of Paediatric Neurology

Short-term safety of mTOR inhibitors in infants and very young children with tuberous sclerosis complex (TSC): Multicentre clinical experience
(2018) European Journal of Paediatric Neurology, . Article in Press. 

Krueger, D.A.a , Capal, J.K.a , Curatolo, P.b , Devinsky, O.c , Ess, K.d , Tzadok, M.e , Koenig, M.K.f , Narayanan, V.g , Ramos, F.h , Jozwiak, S.i , de Vries, P.j , Jansen, A.C.k , Wong, M.l , Mowat, D.m , Lawson, J.m , Bruns, S.a , Franz, D.N.a , TSCure Research Groupn

a Department of Neurology, University of Cincinnati, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
b Child Neurology and Psychiatry Unit, Systems Medicine Department, University Hospital Tor Vergata, Rome, Italy
c Langone Medical Center, New York University, New York, New York, United States
d Monroe Carell Jr Children’s Hospital, Vanderbilt University Medical Center, Nashville, TN, United States
e Pediatric Neurology Unit, Edmond and Lilly Safra Children Hospital, Chaim Sheba Medical Center, Sackler School of Medicine, Tel Aviv University, Tel HaShomer, Tel Aviv, Israel
f University of Texas at Houston, Houston, TX, United States
g Arizona Pediatric Neurology and Neurogenetics Associates, Phoenix, AZ, United States
h Department of Neurology, Sant Joan de Deu Hospital, Barcelona, Spain
i Department of Pediatric Neurology, Warsaw Medical University, Poland and Department of Neurology and Epileptology, The Children’s Memorial Health Institute, Warsaw, Poland
j Division of Child & Adolescent Psychiatry, University of Cape Town, Cape Town, South Africa
k Pediatric Neurology Unit, UZ Brussel, Brussels, Belgium
l Washington University St. Louis, St. Louis, MO, United States
m Sydney Children’s Hospital, Sydney, Australia

Abstract
Objective: To evaluate the safety of mTOR inhibitors (sirolimus or everolimus) in infants and very young children with tuberous sclerosis complex (TSC) under two years of age. Methods: Study design was retrospective to capture medical record data from 52 international TSC Centres who initiated treatment with sirolimus or everolimus in TSC children before the age of two years. Data collection included demographic and clinical information including reason(s) for initiating treatment with mTOR inhibitors, treatment duration, dosing, and corresponding serum trough levels, response to treatment, and adverse events (AE). Results: 19 of 52 (37%) TSC Centres reported treatment of at least one child with TSC under the age of two years with everolimus or sirolimus. Treatment-related data were provided for 45 patients meeting inclusion criteria. Everolimus was utilised 87% of the time, compared to 24% for sirolimus (5 subjects, 11%, were treated separately with both). Refractory epilepsy (45%) was the most common primary reason for initiating treatment and treatment was initiated on average at 11.6 ± 7.6 months of age. At least one AE, suspected or definitely treatment-related, occurred in 35 of 45 (78%) treated subjects. Most AEs were mild (Grade 1) or moderate (Grade 2) in severity and most commonly related to infections. Severe AE (Grade 3) was reported in 7 subjects (20%) and no life-threatening AE (Grade 4) or death/disability (Grade 5) was reported. Treatment was discontinued due to an AE in 9 of 45 (20%). Conclusions: Everolimus, and to a lesser extent sirolimus, are increasingly being used to treat TSC infants and very young children for multiple TSC-associated clinical indications. While AEs were common, most were not severe and did not prevent continued treatment in the majority of this younger population. © 2018 European Paediatric Neurology Society

Author Keywords
Everolimus;  Infant;  mTOR;  Safety;  Sirolimus;  Tuberous sclerosis complex

Document Type: Article in Press
Source: Scopus