WashU weekly Neuroscience publications

Effect of apolipoprotein E4 on clinical, neuroimaging, and biomarker measures in noncarrier participants in the Dominantly Inherited Alzheimer Network
(2019) Neurobiology of Aging, 75, pp. 42-50. 

Bussy, A.^{a b} , Snider, B.J.^{a b} , Coble, D.^{a c} , Xiong, C.^{a c} , Fagan, A.M.^{a b} , Cruchaga, C.^{a d} , Benzinger, T.L.S.^{a e} , Gordon, B.A.^{a e} , Hassenstab, J.^{a b} , Bateman, R.J.^{a b} , Morris, J.C.^{a b} , the Dominantly Inherited Alzheimer Network^f

^a Knight Alzheimer Disease Research Center, Washington University School of Medicine, Saint Louis, MO, United States
^b Department of Neurology, Washington University School of Medicine, Saint Louis, MO, United States
^c Division of Biostatistics, Washington University School of Medicine, Saint Louis, MO, United States
^d Department of Psychiatry, Washington University School of Medicine, Saint Louis, MO, United States
^e Department of Radiology, Washington University School of Medicine, Saint Louis, MO, United States

Abstract
The apolipoprotein E ε4 allele (APOE4) is the major genetic risk factor for sporadic Alzheimer’s disease (AD). APOE4 may have effects on cognition and brain atrophy years before the onset of symptomatic AD. We analyzed the effects of APOE4 in a unique cohort of young adults who had undergone comprehensive assessments as part of the Dominantly Inherited Alzheimer Network (DIAN), an international longitudinal study of individuals from families with autosomal dominant AD. We analyzed the effect of an APOE4 allele on cognitive measures, volumetric MRI, amyloid deposition, glucose metabolism, and on cerebrospinal fluid levels of AD biomarkers in 162 participants that did not carry the mutant gene (noncarriers). APOE4+ and APOE4− mutation noncarriers had similar performance on cognitive measures. Amyloid deposition began at an earlier age in APOE4+ participants, whereas hippocampal volume was similar between the groups. These preliminary findings are consistent with growing evidence that the APOE4 allele may exert effects in midlife years before symptom onset, promoting amyloid deposition before altering cognitive performance or brain structure. © 2018

Author Keywords
Alzheimer disease;  Amyloid precursor protein;  APOE;  Autosomal dominant;  Biomarkers;  Presenilin 1;  Presenilin 2

Document Type: Article
Publication Stage: Final
Source: Scopus

Analysis of GABAA receptor activation by combinations of agonists acting at the same or distinct binding sites
(2019) Molecular Pharmacology, 95 (1), pp. 70-81. 

Shin, D.J.^a , Germann, A.L.^a , Covey, D.F.^a , Steinbach, J.H.^a , Akk, G.^b

^a Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, St. Louis, MO, United States
^b Department of Anesthesiology, Washington University School of Medicine, 660 S. Euclid Ave, Campus Box 8054, St. Louis, MO 63110, United States

Abstract
Under both physiologic and clinical conditions GABAA receptors are exposed to multiple agonists, including the transmitter GABA, endogenous or exogenous neuroactive steroids, and various GABAergic anesthetic and sedative drugs. The functional output of the receptor reflects the interplay among all active agents. We have investigated the activation of the concatemeric a1b2g2L GABAA receptor by combinations of agonists. Simulations of receptor activity using the coagonist concerted transition model demonstrate that the response amplitude in the presence of agonist combinations is highly dependent on whether the paired agonists interact with the same or distinct sites. The experimental data for receptor activation by agonist combinations were in agreement with the established views of the overlap of binding sites for several pairs of orthosteric (GABA, b-alanine, and piperidine-4-sulfonic acid) and/or allosteric agents (propofol, pentobarbital, and several neuroactive steroids). Conversely, the degree of potentiation when two GABAergic agents are coapplied can be used to determine whether the compounds act by binding to the same or distinct sites. We show that common interaction sites mediate the actions of 5a- and 5b-reduced neuroactive steroids, and natural and enantiomeric steroids. Furthermore, the results indicate that the anesthetics propofol and pentobarbital interact with partially shared binding sites. We propose that the findings may be used to predict the efficacy of drug mixtures in combination therapy and thus have potential clinical relevance. Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.

Document Type: Article
Publication Stage: Final
Source: Scopus

Cognitive fusion and affective isolation: Blurred self-concept and empathy deficits in schizotypy
(2019) Psychiatry Research, 271, pp. 178-186. 

Kállai, J.^a , Rózsa, S.^b , Hupuczi, E.^a , Hargitai, R.^c , Birkás, B.^a , Hartung, I.^a , Martin, L.^d , Herold, R.^e , Simon, M.^e

^a Institute of Behavioral Sciences, Medical School, University of Pécs, Szigeti út 12, Pécs, 7625, Hungary
^b Department of Psychiatry, Washington University School of Medicine, St. Louis, United States
^c Department of Personality and Clinical Psychology, Pázmány Péter Catholic University, Budapest, Hungary
^d Department of Pedagogy and Psychology, Kaposvári University, Kaposvár, Hungary
^e Department of Psychiatry and Psychotherapy, Medical School, Universi of Pécs, Pécs, Hungary

Abstract
This is a cross-sectional nonclinical sample study to examine the different levels of the Ipsiety Disturbance Model (IDM) for schizophrenia spectrum disorders (introduced by Sass and Parnas, 2003). Three faces of schizotypy were studied: diminished self-presence, hyper-reflexivity, and distortion in experience of own self and another person’s self-discrimination. A sample of college students (N = 1312) was provided a questionnaire packet that contained the Schizotypy Personality Questionnaire Brief–Revisited (SPQ-BR), the Self-Concept Clarity Sale, the Tellegen Absorption Scale, and Interpersonal Reactivity Index measures. Results: higher absorption capabilities predict higher scores on both the SPQ-BR cognitive and SPQ-BR disorganization factors. High scores in cognitive empathy predicted a low score on both SPQ-BR cognitive and SPQ-BR interpersonal scores. In contrast, higher affective empathy predicted high scores on the SPQ-BR interpersonal factor. The deficiency in self-concept clarity predicted an elevated score on the SPQ-BR cognitive, interpersonal, and disorganization schizotypy symptoms. We argue that a lack of self-concept clarity manifested in both the hyperreflexivity level (measured by absorption) and the metallization level (measured by empathy). We argue that the IDM is a reliable way to interpret functioning with different levels of schizotypy. © 2018

Document Type: Article
Publication Stage: Final
Source: Scopus

KIAA1549-BRAF Expression Establishes a Permissive Tumor Microenvironment Through NFκB-Mediated CCL2 Production
(2019) Neoplasia (United States), 21 (1), pp. 52-60. 

Chen, R.^a , Keoni, C.^b , Waker, C.A.^c , Lober, R.M.^{b c d} , Gutmann, D.H.^a

^a Department of Neurology, Washington University, St. Louis, MO, United States
^b Department of Neurosurgery, Dayton Children’s Hospital, One Children’s Plaza, Dayton, OH, United States
^c Departments of Neuroscience, Cell Biology, and Physiology, Boonshoft School of Medicine, Wright State University, Dayton, OH, United States
^d Department of Pediatrics, Boonshoft School of Medicine, Wright State University, Dayton, OH, United States

Abstract
KIAA1549-BRAF is the most frequently identified genetic mutation in sporadic pilocytic astrocytoma (PA), creating a fusion BRAF (f-BRAF) protein with increased BRAF activity. Fusion-BRAF-expressing neural stem cells (NSCs) exhibit increased cell growth and can generate glioma-like lesions following injection into the cerebella of naïve mice. Increased Iba1+ monocyte (microglia) infiltration is associated with murine f-BRAF-expressing NSC-induced glioma-like lesion formation, suggesting that f-BRAF-expressing NSCs attract microglia to establish a microenvironment supportive of tumorigenesis. Herein, we identify Ccl2 as the chemokine produced by f-BRAF-expressing NSCs, which is critical for creating a permissive stroma for gliomagenesis. In addition, f-BRAF regulation of Ccl2 production operates in an ERK- and NFκB-dependent manner in cerebellar NSCs. Finally, Ccr2-mediated microglia recruitment is required for glioma-like lesion formation in vivo, as tumor do not form in Ccr2-deficient mice following f-BRAF-expressing NSC injection. Collectively, these results demonstrate that f-BRAF expression creates a supportive tumor microenvironment through NFκB-mediated Ccl2 production and microglia recruitment. © 2018 The Authors

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Applying the Monod-Wyman-Changeux allosteric activation model to pseudo–steady-state responses from GABAA receptors
(2019) Molecular Pharmacology, 95 (1), pp. 106-119. 

Steinbach, J.H.^{a b} , Akk, G.^{a b}

^a Department of Anesthesiology,, Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, St. Louis, MO, United States
^b Department of Anesthesiology, Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, St. Louis, MO, United States

Abstract
The Monod-Wyman-Changeux (MWC) cyclic model was described as a kinetic scheme to explain enzyme function and modulation more than 50 years ago and was proposed as a model for understanding the activation of transmitter-gated channels soon afterward. More recently, the MWC model has been used to describe the activation of the GABAA receptor by the transmitter, GABA, and drugs that bind to separate sites on the receptor. It is most interesting that the MWC formalism can also describe the interactions among drugs that activate the receptor. In this review, we describe properties of the MWC model that have been explored experimentally using the GABAA receptor, summarize analytical expressions for activation and interaction for drugs, and briefly review experimental results. Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics

Document Type: Article
Publication Stage: Final
Source: Scopus

Physical and Psychosocial Impact of a University-Based, Volunteer Student-Led Running Program for Children With Autism Spectrum Disorder
(2018) Journal of the American Academy of Child and Adolescent Psychiatry, 57 (12), pp. 974-977. 

Marggraff, A., Constantino, J.N.

Washington University in St. LouisMO, United States

Abstract
Children with autism spectrum disorder (ASD) are frequently excluded from group sports.1 This accentuates the social isolation inherent in their condition, perpetuates cycles of perceived incompetence in physical activity, and increases susceptibility to weight gain influenced by psychotropic medications.2 In a 2015 study of 376 children with ASD, 18.1% of children were overweight and 17% were obese.3 Scarcity of opportunity to participate on athletic teams can contribute to this liability and compound the social isolation inherent in the condition.4-6 Thus, programs that combine relationship building with physical conditioning present a double opportunity to offset significant hurdles for children with ASD. To address these needs locally, a group of volunteer college student-athletes (led by co-author Annie Marggraff) established a weekly Sunday afternoon program for athletic opportunity for children with ASD in the community. The program, Bear Cubs Running Team, was piloted over 5 successive semesters at Washington University in St. Louis, Missouri to empower children with ASD to set achievable physical conditioning goals, provide a forum to support their families, and increase college students’ awareness of barriers against and opportunities to meaningful improvements in health and quality of life. © 2018 American Academy of Child and Adolescent Psychiatry

Document Type: Letter
Publication Stage: Final
Source: Scopus

Genome-wide mega-analysis identifies 16 loci and highlights diverse biological mechanisms in the common epilepsies
(2018) Nature Communications, 9 (1), art. no. 5269, . 

Abou-Khalil, B.^a , Auce, P.^{b c} , Avbersek, A.^d , Bahlo, M.^{e f g} , Balding, D.J.^{h i} , Bast, T.^{j k} , Baum, L.^l , Becker, A.J.^m , Becker, F.^{n o} , Berghuis, B.^p , Berkovic, S.F.^q , Boysen, K.E.^q , Bradfield, J.P.^{r s} , Brody, L.C.^t , Buono, R.J.^{r u v} , Campbell, E.^w , Cascino, G.D.^x , Catarino, C.B.^d , Cavalleri, G.L.^{y z} , Cherny, S.S.^{aa ab} , Chinthapalli, K.^d , Coffey, A.J.^ac , Compston, A.^ad , Coppola, A.^{ae af} , Cossette, P.^ag , Craig, J.J.^ah , de Haan, G.-J.^ai , De Jonghe, P.^{aj ak} , de Kovel, C.G.F.^al , Delanty, N.^{y z am} , Depondt, C.^an , Devinsky, O.^ao , Dlugos, D.J.^ap , Doherty, C.P.^{z aq} , Elger, C.E.^ar , Eriksson, J.G.^as , Ferraro, T.N.^{u at} , Feucht, M.^au , Francis, B.^av , Franke, A.^aw , French, J.A.^ax , Freytag, S.^e , Gaus, V.^ay , Geller, E.B.^az , Gieger, C.^{ba bb} , Glauser, T.^bc , Glynn, S.^bd , Goldstein, D.B.^{be bf} , Gui, H.^aa , Guo, Y.^aa , Haas, K.F.^a , Hakonarson, H.^{r bg} , Hallmann, K.^{ar bh} , Haut, S.^bi , Heinzen, E.L.^{be bf} , Helbig, I.^{ap bj} , Hengsbach, C.ⁿ , Hjalgrim, H.^{bk bl} , Iacomino, M.^af , Ingason, A.^bm , Jamnadas-Khoda, J.^{d bn} , Johnson, M.R.^bo , Kälviäinen, R.^{bp bq} , Kantanen, A.-M.^bp , Kasperavičiūte, D.^d , Kasteleijn-Nolst Trenite, D.^al , Kirsch, H.E.^br , Knowlton, R.C.^bs , Koeleman, B.P.C.^al , Krause, R.^bt , Krenn, M.^bu , Kunz, W.S.^ar , Kuzniecky, R.^bv , Kwan, P.^{l bw bx} , Lal, D.^by , Lau, Y.-L.^bz , Lehesjoki, A.-E.^ca , Lerche, H.ⁿ , Leu, C.^{d by cb} , Lieb, W.^cc , Lindhout, D.^{ai al} , Lo, W.D.^cd , Lopes-Cendes, I.^{ce cf} , Lowenstein, D.H.^br , Malovini, A.^cg , Marson, A.G.^b , Mayer, T.^ch , McCormack, M.^y , Mills, J.L.^ci , Mirza, N.^b , Moerzinger, M.^au , Møller, R.S.^{bk bl cj} , Molloy, A.M.^ck , Muhle, H.^bj , Newton, M.^cl , Ng, P.-W.^cm , Nöthen, M.M.^cn , Nürnberg, P.^co , O’Brien, T.J.^{bw bx} , Oliver, K.L.^q , Palotie, A.^{cp cq} , Pangilinan, F.^t , Peter, S.^bt , Petrovski, S.^{bw cr} , Poduri, A.^cs , Privitera, M.^ct , Radtke, R.^cu , Rau, S.ⁿ , Reif, P.S.^{cv cw} , Reinthaler, E.M.^bu , Rosenow, F.^{cv cw} , Sander, J.W.^{d ai cx} , Sander, T.^{ay co} , Scattergood, T.^cy , Schachter, S.C.^cz , Schankin, C.J.^da , Scheffer, I.E.^{q db} , Schmitz, B.^ay , Schoch, S.^m , Sham, P.C.^aa , Shih, J.J.^dc , Sills, G.J.^b , Sisodiya, S.M.^{d cx} , Slattery, L.^dd , Smith, A.^by , Smith, D.F.^c , Smith, M.C.^de , Smith, P.E.^df , Sonsma, A.C.M.^al , Speed, D.^{h dg} , Sperling, M.R.^dh , Steinhoff, B.J.^j , Stephani, U.^bj , Stevelink, R.^al , Strauch, K.^{di dj} , Striano, P.^dk , Stroink, H.^dl , Surges, R.^ar , Tan, K.M.^bw , Thio, L.L.^dm , Thomas, G.N.^dn , Todaro, M.^bw , Tozzi, R.^do , Vari, M.S.^dk , Vining, E.P.G.^dp , Visscher, F.^dq , von Spiczak, S.^bj , Walley, N.M.^{be dr} , Weber, Y.G.ⁿ , Wei, Z.^ds , Weisenberg, J.^dm , Whelan, C.D.^y , Widdess-Walsh, P.^az , Wolff, M.^dt , Wolking, S.ⁿ , Yang, W.^bz , Zara, F.^af , Zimprich, F.^bu , The International League Against Epilepsy Consortium on Complex Epilepsies^q

^a Vanderbilt University Medical Center, Nashville, TN 37232, United States
^b Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, L69 3GL, United Kingdom
^c The Walton Centre NHS Foundation Trust, Liverpool, L9 7LJ, United Kingdom
^d Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, United Kingdom
^e Population Health and Immunity Divison, The Walter and Eliza Hall Institute of Medical Research, Parkville, 3052, Australia
^f Department of Biology, University of Melbourne, Parkville, 3010, Australia
^g School of Mathematics and Statistics, University of Melbourne, Parkville, 3010, Australia
^h UCL Genetics Institute, University College London, London, WC1E 6BT, United Kingdom
ⁱ Melbourne Integrative Genomics, University of Melbourne, Parkville, 3052, Australia
^j Epilepsy Center Kork, Kehl-Kork, 77694, Germany
^k Medical Faculty of the University of Freiburg, Freiburg, 79085, Germany
^l Centre for Genomic Sciences, The University of Hong Kong, Hong Kong, Hong Kong
^m Section for Translational Epilepsy Research, Department of Neuropathology, University of Bonn Medical Center, Bonn, 53105, Germany
ⁿ Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, 72076, Germany
^o Department of Neurology, University of Ulm, Ulm, 89081, Germany
^p Stichting Epilepsie Instellingen Nederland (SEIN), Zwolle, 8025 BV, Netherlands
^q Epilepsy Research Centre, University of Melbourne, Austin Health, Heidelberg, 3084, Australia
^r Center for Applied Genomics, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104, United States
^s Quantinuum Research LLC, San Diego, CA 92101, United States
^t National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, United States
^u Department of Biomedical Sciences, Cooper Medical School of Rowan University Camden, Camden, NJ 08103, United States
^v Department of Neurology, Thomas Jefferson University Hospital, Philadelphia, PA 19107, United States
^w Belfast Health and Social Care Trust, Belfast, BT9 7AB, United Kingdom
^x Division of Epilepsy, Department of Neurology, Mayo Clinic, Rochester, MN 55902, United States
^y Department of Molecular and Cellular Therapeutics, The Royal College of Surgeons in Ireland, Dublin 2, Ireland
^z The FutureNeuro Research Centre, Dublin 2, Ireland
^aa Department of Psychiatry, The University of Hong Kong, Hong Kong
^ab Department of Epidemiology and Preventive Medicine, School of Public Health, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, 6997801, Israel
^ac The Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA, United Kingdom
^ad Department of Clinical Neurosciences, Cambridge Biomedical Campus, Cambridge, CB2 0SL, United Kingdom
^ae Department of Neuroscience, Reproductive and Odontostomatological Sciences, University Federico II, Naples, 80138, Italy
^af Laboratory of Neurogenetics and Neurosciences, Institute G. Gaslini, Genova, 16148, Italy
^ag Department of Neurosciences, University of Montreal, Montreal, CA 26758, Canada
^ah Department of Neurology, Royal Victoria Hospital, Belfast Health and Social Care Trust, Grosvenor Road, Belfast, BT12 6BA, United Kingdom
^ai Stichting Epilepsie Instellingen Nederland (SEIN), Heemstede, 2103 SW, Netherlands
^aj Neurogenetics Group, Center for Molecular Neurology, VIB and Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, 2610, Belgium
^ak Department of Neurology, Antwerp University Hospital, Edegem, 2650, Belgium
^al Department of Genetics, University Medical Center Utrecht, Utrecht, 3584 CX, Netherlands
^am Division of Neurology, Beaumont Hospital, Dublin, D09 FT51, Ireland
^an Department of Neurology, Hôpital Erasme, Université Libre de Bruxelles, Brussels, 1070, Belgium
^ao Comprehensive Epilepsy Center, New York University School of Medicine, New York, NY 10016, United States
^ap Department of Neurology, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104, United States
^aq Neurology Department, St. James’s Hospital, Dublin, D03 VX82, Ireland
^ar Department of Epileptology, University of Bonn Medical Centre, Bonn, 53127, Germany
^as Department of General Practice and Primary Health Care, University of Helsinki and Helsinki University Hospital, Helsinki, 0014, Finland
^at Department of Pharmacology and Psychiatry, University of Pennsylvania Perlman School of Medicine, Philadelphia, PA 19104, United States
^au Department of Pediatrics and Neonatology, Medical University of Vienna, Vienna, 1090, Austria
^av Department of Biostatistics, University of Liverpool, Liverpool, L69 3GL, United Kingdom
^aw Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, University Hospital Schleswig Holstein, Kiel, 24105, Germany
^ax Department of Neurology, NYU School of Medicine, New York City, NY 10003, United States
^ay Department of Neurology, Charité Universitaetsmedizin Berlin, Campus Virchow-Clinic, Berlin, 13353, Germany
^az Institute of Neurology and Neurosurgery at St. Barnabas, Livingston, NJ 07039, United States
^ba Research Unit of Molecular Epidemiology, Helmholtz Zentrum München – German Research Center for Environmental Health, Neuherberg, D-85764, Germany
^bb Institute of Epidemiology, Helmholtz Zentrum München – German Research Center for Environmental Health, Neuherberg, D-85764, Germany
^bc Comprehensive Epilepsy Center, Division of Neurology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, United States
^bd Department of Neurology, University of Michigan, Ann Arbor, MI 48109, United States
^be Center for Human Genome Variation, Duke University School of Medicine, Durham, NC 27710, United States
^bf Institute for Genomic Medicine, Columbia University Medical Center, New York, NY 10032, United States
^bg Division of Human Genetics, Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States
^bh Life and Brain Center, University of Bonn Medical Center, Bonn, 53127, Germany
^bi Montefiore Medical Center, Bronx, NY 10467, United States
^bj Department of Neuropediatrics, University Medical Center Schleswig-Holstein (UKSH), Kiel, 24105, Germany
^bk Danish Epilepsy Centre, Dianalund, 4293, Denmark
^bl Institute of Regional Health Services Research, University of Southern Denmark, Odense, 5000, Denmark
^bm deCODE genetics, Inc., Reykjavik, IS-101, Iceland
^bn Department of Psychiatry and Applied Psychology, Institute of Mental Health University of Nottingham, Nottingham, NG7 2TU, United Kingdom
^bo Faculty of Medicine, Imperial College London, London, SW7 2AZ, United Kingdom
^bp Kuopio Epilepsy Center, Neurocenter, Kuopio University Hospital, Kuopio, 70029, Finland
^bq Institute of Clinical Medicine, University of Eastern Finland, Kuopio, 70029, Finland
^br Department of Neurology, University of California, San Francisco, CA 94143, United States
^bs University of Alabama Birmingham, Department of Neurology, Birmingham, AL 35233, United States
^bt Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, L-4362, Luxembourg
^bu Department of Neurology, Medical University of Vienna, Vienna, 1090, Austria
^bv Department of Neurology, Zucker-Hofstra Northwell School of Medicine, New York, NY 10075, United States
^bw Department of Medicine, University of Melbourne, Royal Melbourne Hospital, Parkville, VIC 3050, Australia
^bx Department of Neuroscience, Central Clinical School, Monash University, Melbourne, VIC 3004, Australia
^by Stanley Center for Psychiatric Research, Broad Institute of Harvard and M.I.T, Cambridge, MA 02142, United States
^bz Department of Paediatrics and Adolescent Medicine, The University of Hong Kong, Hong Kong
^ca Folkhälsan Research Center and Medical Faculty, University of Helsinki, Helsinki, 00290, Finland
^cb Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, United States
^cc Institut für Epidemiologie Christian-Albrechts-Universität zu Kiel, Kiel, 24105, Germany
^cd Department of Pediatrics and Neurology, Ohio State University and Nationwide Children’s Hospital, Columbus, OH 43205, United States
^ce Department of Medical Genetics, School of Medical Sciences, University of Campinas (UNICAMP), Campinas, SP 13083-887, Brazil
^cf Brazilian Institute of Neuroscience and Neurotechnology (BRAINN), Campinas, SP 13083-970, Brazil
^cg Istituti Clinici Scientifici Maugeri, Pavia, 27100, Italy
^ch Epilepsy Center Kleinwachau, Radeberg, 01454, Germany
^ci Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, United States
^cj Wilhelm Johannsen Centre for Functional Genome Research, Copenhagen, DK-2200, Denmark
^ck School of Medicine, Trinity College Dublin, Dublin 2, Ireland
^cl Department of Neurology, Austin Health, Heidelberg, VIC 3084, Australia
^cm United Christian Hospital, Hong Kong, Hong Kong
^cn Institute of Human Genetics, University of Bonn Medical Center, Bonn, 53127, Germany
^co Cologne Center for Genomics, University of Cologne, Cologne, 50931, Germany
^cp Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, 0014, Finland
^cq The Broad Institute of M.I.T. and Harvard, Cambridge, MA 02142, United States
^cr AstraZeneca Centre for Genomics Research, Precision Medicine and Genomics, IMED Biotech Unit, AstraZeneca, Cambridge, CB2 0AA, United Kingdom
^cs Department of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, United States
^ct Department of Neurology, Neuroscience Institute, University of Cincinnati Medical Center, Cincinnati, OH 45220, United States
^cu Department of Neurology, Duke University School of Medicine, Durham, NC 27710, United States
^cv Epilepsy-Center Hessen, Department of Neurology, University Medical Center Giessen and Marburg, Marburg, Germany and Philipps-University Marburg, Marburg, 35043, Germany
^cw Epilepsy Center Frankfurt Rhine-Main, Center of Neurology and Neurosurgery, Goethe University Frankfurt, Frankfurt, 60528, Germany
^cx Chalfont Centre for Epilepsy, Chalfont-St-Peter, Buckinghamshire, SL9 0RJ, United Kingdom
^cy Department of Endocrinology, Hospital of The University of Pennsylvania, Philadelphia, PA 19104, United States
^cz Departments of Neurology, Beth Israel Deaconess Medical Center, Massachusetts General Hospital, and Harvard Medical School, Boston, MA 02215, United States
^da Department of Neurology, Inselspital, Bern University Hospital, University of Bern, Bern, 3010, Switzerland
^db Department of Neurology, Royal Children’s Hospital, Parkville, VIC 3052, Australia
^dc Department of Neurosciences, University of California, San Diego, La Jolla, CA 92037, United States
^dd The Royal College of Surgeons in Ireland, Dublin, D02 YN77, Ireland
^de Rush University Medical Center, Chicago, IL 60612, United States
^df Department of Neurology, Alan Richens Epilepsy Unit, University Hospital of Wales, Cardiff, CF14 4XW, United Kingdom
^dg Aarhus Institute of Advanced Studies (AIAS), Aarhus University, Aarhus, 8000, Denmark
^dh Department of Neurology and Comprehensive Epilepsy Center, Thomas Jefferson University, Philadelphia, PA 19107, United States
^di Institute of Genetic Epidemiology, Helmholtz Zentrum München – German Research Center for Environmental Health, Neuherberg, Neuherberg, D-85764, Germany
^dj IBE, Faculty of Medicine, LMU Munich, Munich, 80539, Germany
^dk Pediatric Neurology and Muscular Diseases Unit, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, G. Gaslini Institute, University of Genoa, Genova, 16148, Italy
^dl CWZ Hospital, Nijmegen, 6532 SZ, Netherlands
^dm Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, United States
^dn Institute for Applied Health Research, University of Birmingham, Birmingham, B15 2TT, United Kingdom
^do C. Mondino National Neurological Institute, Pavia, 27100, Italy
^dp Departments of Neurology and Pediatrics, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, United States
^dq Department of Neurology, Admiraal De Ruyter Hospital, Goes, 4462, Netherlands
^dr Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, United States
^ds Department of Computer Science, New Jersey Institute of Technology, New Jersey, NJ 07102, United States
^dt Department of Pediatric Neurology and Developmental Medicine, University Children’s Hospital, Tübingen, 72076, Germany

Abstract
The epilepsies affect around 65 million people worldwide and have a substantial missing heritability component. We report a genome-wide mega-analysis involving 15,212 individuals with epilepsy and 29,677 controls, which reveals 16 genome-wide significant loci, of which 11 are novel. Using various prioritization criteria, we pinpoint the 21 most likely epilepsy genes at these loci, with the majority in genetic generalized epilepsies. These genes have diverse biological functions, including coding for ion-channel subunits, transcription factors and a vitamin-B6 metabolism enzyme. Converging evidence shows that the common variants associated with epilepsy play a role in epigenetic regulation of gene expression in the brain. The results show an enrichment for monogenic epilepsy genes as well as known targets of antiepileptic drugs. Using SNP-based heritability analyses we disentangle both the unique and overlapping genetic basis to seven different epilepsy subtypes. Together, these findings provide leads for epilepsy therapies based on underlying pathophysiology. © 2018, The Author(s).

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Sport-related concussion in children and adolescents
(2018) Pediatrics, 142 (6), art. no. e20183074, . 

Halstead, M.E.^a , Walter, K.D.^b , Moffatt, K.^c

^a Washington University, School of Medicine, St Louis, MO, United States
^b Department of Orthopaedic Surgery Pediatric Sports Medicine, Medical College of Wisconsin, Milwaukee, WI, United States
^c Creighton University, School of Medicine, Omaha, NE, United States

Abstract
Sport-related concussion is an important topic in nearly all sports and at all levels of sport for children and adolescents. Concussion knowledge and approaches to management have progressed since the American Academy of Pediatrics published its first clinical report on the subject in 2010. Concussion’s definition, signs, and symptoms must be understood to diagnose it and rule out more severe intracranial injury. Pediatric health care providers should have a good understanding of diagnostic evaluation and initial management strategies. Effective management can aid recovery and potentially reduce the risk of long-term symptoms and complications. Because concussion symptoms often interfere with school, social life, family relationships, and athletics, a concussion may affect the emotional well-being of the injured athlete. Because every concussion has its own unique spectrum and severity of symptoms, individualized management is appropriate. The reduction, not necessarily elimination, of physical and cognitive activity is the mainstay of treatment. A full return to activity and/ or sport is accomplished by using a stepwise program while evaluating for a return of symptoms. An understanding of prolonged symptoms and complications will help the pediatric health care provider know when to refer to a specialist. Additional research is needed in nearly all aspects of concussion in the young athlete. This report provides education on the current state of sport-related concussion knowledge, diagnosis, and management in children and adolescents. © 2018 by the American Academy of Pediatrics.

Document Type: Article
Publication Stage: Final
Source: Scopus

Imbalance of functional connectivity and temporal entropy in resting-state networks in autism spectrum disorder: A machine learning approach
(2018) Frontiers in Neuroscience, 12 (NOV), art. no. 00869, . 

Smith, R.X.^a , Jann, K.^b , Dapretto, M.^c , Wang, D.J.J.^b

^a NeuroImaging Laboratories (NIL), School of Medicine, Washington University in Saint Louis, Saint Louis, MO, United States
^b Keck School of Medicine of USC, University of Southern California, Los Angeles, CA, United States
^c Department of Psychiatry and Biobehavioral Sciences, University of California Los Angeles, Los Angeles, CA, United States

Abstract
Background: Two approaches to understanding the etiology of neurodevelopmental disorders such as Autism Spectrum Disorder (ASD) involve network level functional connectivity (FC) and the dynamics of neuronal signaling. The former approach has revealed both increased and decreased FC in individuals with ASD. The latter approach has found high frequency EEG oscillations and higher levels of epilepsy in children with ASD. Together, these findings have led to the hypothesis that atypical excitatory-inhibitory neural signaling may lead to imbalanced association pathways. However, simultaneously reconciling local temporal dynamics with network scale spatial connectivity remains a difficult task and thus empirical support for this hypothesis is lacking. Methods: We seek to fill this gap by combining two powerful resting-state functional MRI (rs-fMRI) methods-functional connectivity (FC) and wavelet-based regularity analysis. Wavelet-based regularity analysis is an entropy measure of the local rs-fMRI time series signal. We examined the relationship between the RSN entropy and integrity in individuals with ASD and controls from the Autism Brain Imaging Data Exchange (ABIDE) cohort using a putative set of 264 functional brain regions-of-interest (ROI). Results: We observed that an imbalance in intra- and inter-network FC across 11 RSNs in ASD individuals (p = 0.002) corresponds to a weakened relationship with RSN temporal entropy (p = 0.02). Further, we observed that an estimated RSN entropy model significantly distinguished ASD from controls (p = 0.01) and was associated with level of ASD symptom severity (p = 0.003). Conclusions: Imbalanced brain connectivity and dynamics at the network level coincides with their decoupling in ASD. The association with ASD symptom severity presents entropy as a potential biomarker. © 2007 – 2018 Frontiers Media S.A.

Author Keywords
Autism Spectrum Disorders;  Complexity;  Connectivity;  Dynamics;  FMRI;  Resting-state

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Mutations in Kinesin family member 6 reveal specific role in ependymal cell ciliogenesis and human neurological development
(2018) PLoS Genetics, 14 (11), art. no. e1007817, . 

Konjikusic, M.J.^{a b} , Yeetong, P.^{c d e} , Boswell, C.W.^{f g} , Lee, C.^b , Roberson, E.C.^b , Ittiwut, R.^{c d} , Suphapeetiporn, K.^{c d} , Ciruna, B.^{f g} , Gurnett, C.A.^h , Wallingford, J.B.^b , Shotelersuk, V.^{c d} , Gray, R.S.^a

^a Department of Pediatrics, Dell Pediatric Research Institute, The University of Texas at Austin, Dell Medical School, Austin, TX, United States
^b Department of Molecular Biosciences, Patterson Labs, The University of Texas at Austin, Austin, TX, United States
^c Center of Excellence for Medical Genetics, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
^d Excellence Center for Medical Genetics, King Chulalongkorn Memorial Hospital, the Thai Red Cross Society, Bangkok, Thailand
^e Division of Human Genetics, Department of Botany, Faculty of Science, Chulalongkorn University, Bangkok, Thailand
^f Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, ON, Canada
^g Department of Molecular Genetics, The University of Toronto, Toronto, ON, Canada
^h Department of Neurology, Division Pediatric Neurology, Washington University School of Medicine, St Louis, MO, United States

Abstract
Cerebrospinal fluid flow is crucial for neurodevelopment and homeostasis of the ventricular system of the brain, with localized flow being established by the polarized beating of the ependymal cell (EC) cilia. Here, we report a homozygous one base-pair deletion, c.1193delT (p.Leu398Glnfs*2), in the Kinesin Family Member 6 (KIF6) gene in a child displaying neurodevelopmental defects and intellectual disability. To test the pathogenicity of this novel human KIF6 mutation we engineered an analogous C-terminal truncating mutation in mouse. These mutant mice display severe, postnatal-onset hydrocephalus. We generated a Kif6-LacZ transgenic mouse strain and report expression specifically and uniquely within the ependymal cells (ECs) of the brain, without labeling other multiciliated mouse tissues. Analysis of Kif6 mutant mice with scanning electron microscopy (SEM) and immunofluorescence (IF) revealed specific defects in the formation of EC cilia, without obvious effect of cilia of other multiciliated tissues. Dilation of the ventricular system and defects in the formation of EC cilia were also observed in adult kif6 mutant zebrafish. Finally, we report Kif6-GFP localization at the axoneme and basal bodies of multi-ciliated cells (MCCs) of the mucociliary Xenopus epidermis. Overall, this work describes the first clinically-defined KIF6 homozygous null mutation in human and defines KIF6 as a conserved mediator of neurological development with a specific role for EC ciliogenesis in vertebrates. © 2018 Konjikusic et al. http://creativecommons.org/licenses/by/4.0/.

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Dose-dependent expression of claudin-5 is a modifying factor in schizophrenia
(2018) Molecular Psychiatry, 23 (11), pp. 2156-2166. Cited 2 times.

Greene, C.^a , Kealy, J.^a , Humphries, M.M.^a , Gong, Y.^b , Hou, J.^b , Hudson, N.^a , Cassidy, L.M.^a , Martiniano, R.^a , Shashi, V.^c , Hooper, S.R.^d , Grant, G.A.^e , Kenna, P.F.^a , Norris, K.^f , Callaghan, C.K.^{g h} , Islam, M.N.^{g h} , O’Mara, S.M.^{g h} , Najda, Z.^a , Campbell, S.G.^f , Pachter, J.S.ⁱ , Thomas, J.^j , Williams, N.M.^j , Humphries, P.^a , Murphy, K.C.^k , Campbell, M.^a

^a Department of Genetics, Smurfit Institute of Genetics, Lincoln Place Gate, Trinity College Dublin, Dublin, Ireland
^b Division of Renal Diseases, Department of Internal Medicine, Washington University School of Medicine, St Louis, MO, United States
^c Department of Pediatrics, Duke University Medical Center, Durham, NC, United States
^d Department of Allied Health Sciences, University of North Carolina School of Medicine, Chapel Hill, NC, United States
^e Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, United States
^f Biosciences Department, Faculty of Health and Wellbeing, Biosciences and Chemistry, Sheffield Hallam University, Sheffield, United Kingdom
^g Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland
^h School of Psychology, Trinity College Dublin, Dublin, Ireland
ⁱ Department of Cell Biology, University of Connecticut Health Center, Farmington, CT, United States
^j Department of Psychological Medicine and Neurology, MRC Centre in Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Cardiff, United Kingdom
^k Department of Psychiatry, Royal College of Surgeons in Ireland, Dublin, Ireland

Abstract
Schizophrenia is a neurodevelopmental disorder that affects up to 1% of the general population. Various genes show associations with schizophrenia and a very weak nominal association with the tight junction protein, claudin-5, has previously been identified. Claudin-5 is expressed in endothelial cells forming part of the blood-brain barrier (BBB). Furthermore, schizophrenia occurs in 30% of individuals with 22q11 deletion syndrome (22q11DS), a population who are haploinsufficient for the claudin-5 gene. Here, we show that a variant in the claudin-5 gene is weakly associated with schizophrenia in 22q11DS, leading to 75% less claudin-5 being expressed in endothelial cells. We also show that targeted adeno-associated virus-mediated suppression of claudin-5 in the mouse brain results in localized BBB disruption and behavioural changes. Using an inducible ‘knockdown’ mouse model, we further link claudin-5 suppression with psychosis through a distinct behavioural phenotype showing impairments in learning and memory, anxiety-like behaviour and sensorimotor gating. In addition, these animals develop seizures and die after 3–4 weeks of claudin-5 suppression, reinforcing the crucial role of claudin-5 in normal neurological function. Finally, we show that anti-psychotic medications dose-dependently increase claudin-5 expression in vitro and in vivo while aberrant, discontinuous expression of claudin−5 in the brains of schizophrenic patients post mortem was observed compared to age-matched controls. Together, these data suggest that BBB disruption may be a modifying factor in the development of schizophrenia and that drugs directly targeting the BBB may offer new therapeutic opportunities for treating this disorder. © 2018, Springer Nature Limited.

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Disordered Eating Attitudes and Behaviors in Youth with Overweight and Obesity: Implications for Treatment
(2018) Current obesity reports, 7 (3), pp. 235-246. Cited 1 time.

Hayes, J.F., Fitzsimmons-Craft, E.E., Karam, A.M., Jakubiak, J., Brown, M.L., Wilfley, D.E.

Psychiatry Department, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, MO 63110, United States

Abstract
PURPOSE OF THE REVIEW: Children with obesity experience disordered eating attitudes and behaviors at high rates, which increases their risk for adult obesity and eating disorder development. As such, it is imperative to screen for disordered eating symptoms and identify appropriate treatments. RECENT FINDINGS: Family-based multicomponent behavioral weight loss treatment (FBT) is effective at treating childhood obesity and demonstrates positive outcomes on psychosocial outcomes, including disordered eating. FBT utilizes a socio-ecological treatment approach that focuses on the development of individual and family healthy energy-balance behaviors as well as positive self- and body esteem, supportive family relationships, richer social networks, and the creation of a broader environment and community that facilitates overall physical and mental health. Existing literature suggests FBT is an effective treatment option for disordered eating and obesity in children. Future work is needed to confirm this conclusion and to examine the progression and interaction of obesity and disordered eating across development to identify the optimal time for intervention.

Author Keywords
Childhood obesity;  Disordered eating;  Obesity treatment;  Psychological comorbidities;  Risk factors

Document Type: Review
Publication Stage: Final
Source: Scopus

Dexamethasone and Dexamethasone Phosphate Entry into Perilymph Compared for Middle Ear Applications in Guinea Pigs
(2018) Audiology and Neurotology, pp. 245-258. Article in Press. 

Salt, A.N.^a , Hartsock, J.J.^a , Piu, F.^b , Hou, J.^b

^a Department of Otolaryngology, Washington University, School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, United States
^b Otonomy, Inc., San Diego, CA, United States

Abstract
Dexamethasone phosphate is widely used for intratympanic therapy in humans. We assessed the pharmacokinetics of dexamethasone entry into perilymph when administered as a dexamethasone phosphate solution or as a micronized dexamethasone suspension, with and without inclusion of poloxamer gel in the medium. After a 1-h application to guinea pigs, 10 independent samples of perilymph were collected from the lateral semicircular canal of each animal, allowing entry at the round window and stapes to be independently assessed. Both forms of dexamethasone entered the perilymph predominantly at the round window (73%), with a lower proportion entering at the stapes (22%). When normalized by applied concentration, dexamethasone phosphate was found to enter perilymph far more slowly than dexamethasone, in accordance with its calculated lipid solubility and polar surface area properties. Dexamethasone phosphate therefore has a problematic combination of kinetic properties when used for local therapy of the ear. It is relatively impermeable and enters perilymph only slowly from the middle ear. It is then metabolized in the ear to dexamethasone, which is more permeable through tissue boundaries and is rapidly lost from perilymph. Understanding the influence of molecular properties on the distribution of drugs in perilymph provides a new level of understanding which may help optimize drug therapies of the ear. © 2018 S. Karger AG, Basel.

Author Keywords
Dexamethasone;  Dexamethasone phosphate;  Elimination;  Intratympanic therapy;  Lipid solubility;  Perilymph;  Permeability;  Polar surface area;  Round window;  Stapes

Document Type: Article in Press
Publication Stage: Article in Press
Source: Scopus

Examining the Complicated Relationship between Depressive Symptoms and Cognitive Impairment in Preclinical Alzheimer Disease
(2018) Alzheimer Disease and Associated Disorders, . Article in Press. 

Javaherian, K.^a , Newman, B.M.^{c d} , Weng, H.^b , Hassenstab, J.^a , Xiong, C.^b , Coble, D.^b , Fagan, A.M.^a , Benzinger, T.^{e f} , Morris, J.C.^a

^a Department of Neurology, Washington University, School of Medicine, United States
^b Division of Biostatistics, United States
^c Department of Psychiatry and Behavioral Neuroscience, Saint Louis University, School of Medicine, United States
^d Department of Neurology, Knight Alzheimer’s Disease Research Center, United States
^e Division of Diagnostic Radiology, Mallinckrodt Institute of Radiology, Washington University, St. Louis, MO, United States
^f Evidera, Waltham, MA, United States

Abstract
Introduction: The relationships between Alzheimer disease (AD), cognitive performance, and depression are poorly understood. It is unclear whether depressive features are a prodrome of AD. In addition, some studies of aging exclude depressed individuals, which may inappropriately limit generalizability. The aim of the present study was to determine whether depressive symptoms affect cognitive function in the context of preclinical AD. Methods: Cross-sectional multivariate analysis of participants in a longitudinal study of aging (n=356) that evaluates the influence of depressive symptoms on cognitive function in cognitively normal adults. Results: There is no relationship between the presence of depressive symptoms and cognitive function in those with either no evidence of preclinical AD or biomarker evidence of early-stage preclinical AD. However, in later stages of preclinical AD, the presence of depressive symptoms demonstrated interactive effects, including in episodic memory (0.96; 95% confidence interval, 0.31-1.62) and global cognitive function (0.46; 95% confidence interval, 0.028-0.89). Conclusions: The presence of depressive symptoms may be a late prodrome of AD. In addition, studies investigating cognitive function in older adults may not need to exclude participants with depressive symptomology, but may still consider depressive symptoms as a potential confounder in the context of more extensive neuronal injury. © 2018 Wolters Kluwer Health, Inc. All rights reserved.

Author Keywords
Alzheimer disease;  biomarker;  cerebrospinal fluid;  clinical dementia rating;  cognitive impairment;  dementia;  depressive symptoms;  geriatric depression scale;  Pittsburgh compound B positron emission tomography;  preclinical AD

Document Type: Article in Press
Publication Stage: Article in Press
Source: Scopus

Whole brain imaging reveals distinct spatial patterns of amyloid beta deposition in three mouse models of Alzheimer’s disease
(2018) Journal of Comparative Neurology, . Article in Press. 

Whitesell, J.D.^a , Buckley, A.R.^b , Knox, J.E.^a , Kuan, L.^a , Graddis, N.^a , Pelos, A.^{a c} , Mukora, A.^a , Wakeman, W.^a , Bohn, P.^a , Ho, A.^a , Hirokawa, K.E.^a , Harris, J.A.^a

^a Allen Institute for Brain Science, Seattle, WA, United States
^b Washington University in St. Louis, United States
^c Department of Neuroscience, Pomona College, Claremont, CA, United States

Abstract
A variety of Alzheimer’s disease (AD) mouse models overexpress mutant forms of human amyloid precursor protein (APP), producing high levels of amyloid β (Aβ) and forming plaques. However, the degree to which these models mimic spatiotemporal patterns of Aβ deposition in brains of AD patients is unknown. Here, we mapped the spatial distribution of Aβ plaques across age in three APP-overexpression mouse lines (APP/PS1, Tg2576, and hAPP-J20) using in vivo labeling with methoxy-X04, high throughput whole brain imaging, and an automated informatics pipeline. Images were acquired with high resolution serial two-photon tomography and labeled plaques were detected using custom-built segmentation algorithms. Image series were registered to the Allen Mouse Brain Common Coordinate Framework, a 3D reference atlas, enabling automated brain-wide quantification of plaque density, number, and location. In both APP/PS1 and Tg2576 mice, plaques were identified first in isocortex, followed by olfactory, hippocampal, and cortical subplate areas. In hAPP-J20 mice, plaque density was highest in hippocampal areas, followed by isocortex, with little to no involvement of olfactory or cortical subplate areas. Within the major brain divisions, distinct regions were identified with high (or low) plaque accumulation; for example, the lateral visual area within the isocortex of APP/PS1 mice had relatively higher plaque density compared with other cortical areas, while in hAPP-J20 mice, plaques were densest in the ventral retrosplenial cortex. In summary, we show how whole brain imaging of amyloid pathology in mice reveals the extent to which a given model recapitulates the regional Aβ deposition patterns described in AD. © 2018 Wiley Periodicals, Inc.

Author Keywords
Alzheimer’s mouse model;  amyloid beta;  plaque deposition;  RRID: AB_1977025;  RRID: AB_2535766;  RRID:IMSR_TAC:1349;  RRID:MMRRC_034832-JAX;  RRID:MMRRC_034836-JAX;  whole brain imaging

Document Type: Article in Press
Publication Stage: Article in Press
Source: Scopus

Simultaneously evaluating the effect of baseline levels and longitudinal changes in disease biomarkers on cognition in dominantly inherited Alzheimer’s disease
(2018) Alzheimer’s and Dementia: Translational Research and Clinical Interventions, 4, pp. 669-676. 

Wang, G.^a , Xiong, C.^a , McDade, E.M.^b , Hassenstab, J.^b , Aschenbrenner, A.J.^b , Fagan, A.M.^b , Benzinger, T.L.S.^c , Gordon, B.A.^c , Morris, J.C.^b , Li, Y.^b , Bateman, R.J.^b , the Dominantly Inherited Alzheimer Network (DIAN)^d

^a Division of Biostatistics, Washington University School of Medicine, Saint Louis, MO, United States
^b Department of Neurology, Washington University School of Medicine, Saint Louis, MO, United States
^c Department of Radiology, Washington University School of Medicine, Saint Louis, MO, United States

Abstract
Introduction: As the role of biomarkers is increasing in Alzheimer’s disease (AD) clinical trials, it is critical to use a comprehensive temporal biomarker profile that reflects both baseline and longitudinal assessments to establish a more precise association between the change in biomarkers and change in cognition. Because age of onset of dementia symptoms is highly predictable, and there are relatively few age-related comorbidities, the Dominantly Inherited Alzheimer Network autosomal dominant AD population affords a unique opportunity to investigate these relationships in a well-characterized population. Methods: A novel joint statistical model was used to simultaneously evaluate how a comprehensive AD biomarker profile predicts change in cognition using amyloid positron emission tomography (PET), CSF Aβ42, CSF total tau and Ptau181, cortical metabolism using [F-18] fluorodeoxyglucose–PET, and hippocampal volume from participants enrolled in the Dominantly Inherited Alzheimer Network (n = 262) with mean (SD) duration of follow-up of 2.7 (1.2) years. Results: Baseline amyloid PET levels and CSF biomarkers were associated with change in cognition in contrast to the rate of change of brain metabolism and hippocampal volume, which predicted change in cognition. Conclusions: This study suggests that the baseline value of amyloid PET and CSF Aβ42 measures may be useful for screening participants for AD trials; however, brain hippocampus atrophy and hypometabolism are only useful as repeated longitudinal assessments for tracking cognition and disease progression. This suggests that measures of amyloid plaques predict future cognitive decline, but only longitudinal measures of neurodegeneration correlate with cognitive decline. The novel statistical model used in this study can be easily applied to any pair of outcomes and has potential to be widely used by the AD research community. © 2018 The Authors

Author Keywords
Biomarker;  Cognition;  Dominantly Inherited Alzheimer Network;  Joint model;  Two-stage method

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Clinical problem-solving: Fever and rapidly progressive weakness in an immunocompromised patient
(2018) Neurohospitalist, 8 (4), pp. 194-198. 

Albertson, A.J., Dietz, A.R., Younce, J.R., Varadhachary, A.S.

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

Abstract
Here we report the challenging case of a 41-year-old man with HIV complicated by AIDS and a history of prior neurologic injury from progressive multifocal leukoencephalopathy who presented with headache, fevers, lower extremity weakness, hyperreflexic upper extremities, and diminished lower extremity reflexes. We review the clinical decision-making and differential diagnosis for this presentation as the physical examination evolved and diagnostic testing changed over time. © The Author(s) 2018.

Author Keywords
HIV;  Spinal cord diseases;  West nile virus

Document Type: Article
Publication Stage: Final
Source: Scopus

Thalamic and ventricular volumes predict motor response to deep brain stimulation for Parkinson’s disease
(2018) Parkinsonism and Related Disorders, . Article in Press. 

Younce, J.R.^a , Campbell, M.C.^{a b} , Perlmutter, J.S.^{a b c d e} , Norris, S.A.^{a b}

^a Department of Neurology, Washington University in St Louis, 660 S Euclid Ave, Campus Box 8111, St Louis, MO 63110, United States
^b Department of Radiology, Washington University in St. Louis, 660 S. Euclid Ave, Campus Box 8225, St. Louis, MO 63110, United States
^c Department of Neuroscience, Washington University in St Louis, 660 S Euclid Ave, Campus Box 8108, St Louis, MO 63110, United States
^d Program in Physical Therapy, Washington University in St Louis, 4444 Forest Park Ave, Campus Box 8508, St Louis, MO 63108, United States
^e Program in Occupational Therapy, Washington University in St Louis, 4444 Forest Park Ave, Campus Box 8505, St Louis, MO 63108, United States

Abstract
Background: Brain atrophy frequently occurs with Parkinson’s disease (PD) and relates to increased motor symptoms of PD. The predictive value of neuroimaging-based measures of global and regional brain volume on motor outcomes in deep brain stimulation (DBS) remains unclear but potentially could improve patient selection and targeting. Objectives: To determine the predictive value of preoperative volumetric MRI measures of cortical and subcortical brain volume on motor outcomes of subthalamic nucleus (STN) DBS in PD. Methods: Preoperative T1 3D MP-RAGE structural brain MRI images were analyzed for each participant to determine subcortical, ventricular, and cortical volume and thickness. Change in Unified Parkinson’s Disease Rating Scale (UPDRS) scores for subsection 3, representing motor outcomes, was computed preoperatively and postoperatively following DBS programming in 86 participants. A multiple linear regression analysis was performed to investigate the relationship between volumetric data and the effect of DBS on UPDRS 3 scores. Results: Larger ventricular and smaller thalamic volumes predicted significantly less improvement of UPDRS 3 scores after STN DBS. Conclusions: Our findings demonstrate in PD that regional brain volumes, in particular thalamic and ventricular volumes, predict motor outcomes after DBS. Differences in regional brain volumes may alter electrode targeting, reflect a specific disease trait such as postoperative progression of subclinical dementia, or directly interfere with the action of DBS. © 2018 Elsevier Ltd

Author Keywords
Deep brain stimulation;  Magnetic resonance imaging;  Parkinson’s disease

Document Type: Article in Press
Publication Stage: Article in Press
Source: Scopus

Perspectives on ethnic and racial disparities in Alzheimer’s disease and related dementias: Update and areas of immediate need
(2018) Alzheimer’s and Dementia, . Article in Press. 

Babulal, G.M.^a , Quiroz, Y.T.^{b c} , Albensi, B.C.^{d e} , Arenaza-Urquijo, E.^f , Astell, A.J.^{g h} , Babiloni, C.^{i j} , Bahar-Fuchs, A.^k , Bell, J.^l , Bowman, G.L.^{m n} , Brickman, A.M.^o , Chételat, G.^p , Ciro, C.^q , Cohen, A.D.^r , Dilworth-Anderson, P.^s , Dodge, H.H.^t , Dreux, S.^u , Edland, S.^v , Esbensen, A.^w , Evered, L.^x , Ewers, M.^y , Fargo, K.N.^z , Fortea, J.^{aa ab} , Gonzalez, H.^ac , Gustafson, D.R.^ad , Head, E.^ae , Hendrix, J.A.^z , Hofer, S.M.^af , Johnson, L.A.^ag , Jutten, R.^ah , Kilborn, K.^ai , Lanctôt, K.L.^aj , Manly, J.J.^o , Martins, R.N.^ak , Mielke, M.M.^{al am} , Morris, M.C.^an , Murray, M.E.^ao , Oh, E.S.^ap , Parra, M.A.^{aq ar as} , Rissman, R.A.^at , Roe, C.M.^a , Santos, O.A.^au , Scarmeas, N.^{o av} , Schneider, L.S.^aw , Schupf, N.^ax , Sikkes, S.^ay , Snyder, H.M.^z , Sohrabi, H.R.^ak , Stern, Y.^{az ba} , Strydom, A.^bb , Tang, Y.^bc , Terrera, G.M.^bd , Teunissen, C.^be , Melo van Lent, D.^bf , Weinborn, M.^ak , Wesselman, L.^bg , Wilcock, D.M.^be , Zetterberg, H.^{bh bi bj bk} , O’Bryant, S.E.^ag , International Society to Advance Alzheimer’s Research and Treatment, Alzheimer’s Association^bl

^a Department of Neurology and Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, MO, United States
^b Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
^c Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
^d Division of Neurodegenerative Disorders, St. Boniface Hospital Albrechtsen Research Centre, Winnipeg, Manitoba, Canada
^e Department of Pharmacology & Therapeutics, University of Manitoba, Winnipeg, Manitoba, Canada
^f Department of Radiology, Mayo Clinic, Rochester, MN, United States
^g Department of Occupational Sciences & Occupational Therapy, University of TorontoCA, United States
^h School of Psychology and Clinical Language Sciences, University of Reading, United Kingdom
ⁱ Department of Physiology and Pharmacology “V. Erspamer”, Sapienza University of Rome, Rome, Italy
^j Department of Neuroscience, IRCCS-Hospital San Raffaele Pisana of Rome and Cassino, Rome and Cassino, Italy
^k Academic Unit for Psychiatry of Old Age, Department of Psychiatry, University of Melbourne, Australia
^l Syneos Health, Wilmington, NC, United States
^m Nutrition and Brain Health Laboratory, Nestlé Institute of Health Sciences, Lausanne, Switzerland
ⁿ Department of Neurology, Layton Aging & Alzheimer’s Disease Center, Oregon Health & Science University, Portland, OR, United States
^o Taub Institute for Research in Alzheimer’s Disease and the Aging Brain, The Gertrude H. Sergievsky Center, Department of Neurology, Columbia University, New York, NY, United States
^p Inserm, Inserm UMR-S U1237, Université de Caen-Normandie, GIP Cyceron, Caen, France
^q Department of Occupational Therapy Education, University of Kansas Medical Center, Kansas City, KS, United States
^r Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
^s Gillings School of Global Public Health, University of North Carolina Chapel HillNC, United States
^t Department of Neurology, Layton Aging and Alzheimer’s Disease Center, Oregon Health & Science University, Portland, OR, United States
^u Undergraduate Program of History and Science, Harvard College, Cambridge, MA, United States
^v Department of Family Medicine and Public Health, University of California, San Diego, CA, United States
^w Department of Pediatrics, University of Cincinnati College of Medicine & Division of Developmental and Behavioral Pediatrics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
^x Melbourne Medical School, University of Melbourne, Australia
^y Institute for Stroke and Dementia Research, Klinikum der Universität München, Munich, Germany
^z Medical & Scientific Relations, Alzheimer’s Association, Chicago, IL, United States
^aa Memory Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
^ab Barcelona Down Medical Center, Fundació Catalana de Síndrome de Down, Barcelona, Spain
^ac Department of Neurosciences and Shiley-Marcos Alzheimer’s Disease Research Center, University of San DiegoCA, United States
^ad Department of Neurology, Section for NeuroEpidemiology, State University of New York – Downstate Medical Center, Brooklyn, NY, United States
^ae Sanders Brown Center on Aging, University of Kentucky, Lexington, KY, United States
^af Adult Development and Aging, University of Victoria, British Columbia, CA, United States
^ag Department of Pharmacology & Neuroscience, University of North Texas Health Science Center, Fort Worth, TX, United States
^ah VU University Medical Center, Department of Neurology, Amsterdam Neuroscience, Amsterdam, Netherlands
^ai Department of Psychology, University of Glasgow, Glasgow, Scotland, United Kingdom
^aj Sunnybrook Research Institute of Psychiatry and Pharmacology, University of Toronto, Toronto, ON, Canada
^ak Aging and Alzheimer’s Disease, School of Medical and Health Sciences, Edith Cowan University, Joondalup, Australia
^al Department of Epidemiology, Mayo Clinic, Rochester, MN, United States
^am Department of Neurology, Mayo Clinic, Rochester, MN, United States
^an Department of Internal Medicine, Rush University, Chicago, IL, United States
^ao Department of Neuroscience, Mayo Clinic, Jacksonville, FL, United States
^ap Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States
^aq School of Social Sciences, Department of Psychology, Heriot-Watt University, United Kingdom
^ar Universidad Autónoma del Caribe, Barranquilla, Colombia
^as Neuroprogressive and Dementia Network, United Kingdom
^at Department of Neurosciences, University of California San Diego School of MedicineCA, United States
^au Department of Psychiatry and Psychology, Mayo Clinic, Jacksonville, FL, United States
^av Aiginition Hospital, 1st Neurology Clinic, Department of Social Medicine, Psychiatry and Neurology, National and Kapodistrian University of Athens, Athens, Greece
^aw Department of Psychiatry and The Behavioral Sciences, University of Southern CaliforniaCA, United States
^ax Department of Epidemiology, Mailman School of Public Health Columbia University, New York, NY, United States
^ay Massachusetts General Hospital, Department of Neurology, Boston, MA, United States
^az Department of Neurology, Columbia University, New York, NY, United States
^ba Department of Psychiatry, Columbia University, New York, NY, United States
^bb Department of Forensic and Neurodevelopmental Science, Institute of Psychiatry Psychology and Neuroscience, King’s College London, London, United Kingdom
^bc Department of Neurology, Xuan Wu Hospital, Capital Medical University, Beijing, China
^bd Centers for Clinical Brain Sciences and Dementia Prevention, University in Edinburgh, Scotland, United Kingdom
^be Neurochemistry Laboratory and Biobank, Department of Clinical Chemistry, Amsterdam Neuroscience, Vrije Universiteit University Medical Center, Amsterdam, Netherlands
^bf Department of Clinical Research, German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
^bg Vrije Universiteit Amsterdam, Amsterdam, Netherlands
^bh UK Dementia Research Institute at UCL, London, United Kingdom
^bi Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London, United Kingdom
^bj Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
^bk Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden

Abstract
Alzheimer’s disease and related dementias (ADRDs) are a global crisis facing the aging population and society as a whole. With the numbers of people with ADRDs predicted to rise dramatically across the world, the scientific community can no longer neglect the need for research focusing on ADRDs among underrepresented ethnoracial diverse groups. The Alzheimer’s Association International Society to Advance Alzheimer’s Research and Treatment (ISTAART; alz.org/ISTAART) comprises a number of professional interest areas (PIAs), each focusing on a major scientific area associated with ADRDs. We leverage the expertise of the existing international cadre of ISTAART scientists and experts to synthesize a cross-PIA white paper that provides both a concise “state-of-the-science” report of ethnoracial factors across PIA foci and updated recommendations to address immediate needs to advance ADRD science across ethnoracial populations. © 2018 The Authors

Author Keywords
Alzheimer’s disease;  Alzheimer’s related dementias;  Diversity;  Ethnicity;  Ethnoracial;  Translational;  Underserved

Document Type: Article in Press
Publication Stage: Article in Press
Source: Scopus
Access Type: Open Access