WashU weekly Neuroscience publications

The subcortical and neurochemical organization of the ventral and dorsal attention networks
(2022) Communications Biology, 5 (1), art. no. 1343, . 

Alves, P.N.^a b , Forkel, S.J.^c d e f , Corbetta, M.^g h i j , Thiebaut de Schotten, M.^c k

^a Laboratório de Estudos de Linguagem, Centro de Estudos Egas Moniz, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
^b Serviço de Neurologia, Departmento de Neurociências e Saúde Mental, Hospital de Santa Maria, CHULN, Lisboa, Portugal
^c Brain Connectivity and Behaviour Laboratory, Sorbonne University, Paris, France
^d Donders Institute for Brain Cognition Behaviour, Radboud University, Thomas van Aquinostraat 4, Nijmegen, 6525GD, Netherlands
^e Centre for Neuroimaging Sciences, Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom
^f Departments of Neurosurgery, Technical University of Munich School of Medicine, Munich, Germany
^g Clinica Neurologica, Department of Neuroscience, University of Padova, Padova, Italy
^h Padova Neuroscience Center (PNC), University of Padova, Padova, Italy
ⁱ Venetian Institute of Molecular Medicine, VIMM, Padova, Italy
^j Department of Neurology, Radiology, Neuroscience Washington University School of Medicine, St.Louis, MO, United States
^k Groupe d’Imagerie Neurofonctionnelle, Institut des Maladies Neurodégénératives-UMR 5293, CNRS, CEA, University of Bordeaux, Bordeaux, France

Abstract
Attention is a core cognitive function that filters and selects behaviourally relevant information in the environment. The cortical mapping of attentional systems identified two segregated networks that mediate stimulus-driven and goal-driven processes, the Ventral and the Dorsal Attention Networks (VAN, DAN). Deep brain electrophysiological recordings, behavioral data from phylogenetic distant species, and observations from human brain pathologies challenge purely corticocentric models. Here, we used advanced methods of functional alignment applied to resting-state functional connectivity analyses to map the subcortical architecture of the Ventral and Dorsal Attention Networks. Our investigations revealed the involvement of the pulvinar, the superior colliculi, the head of caudate nuclei, and a cluster of brainstem nuclei relevant to both networks. These nuclei are densely connected structural network hubs, as revealed by diffusion-weighted imaging tractography. Their projections establish interrelations with the acetylcholine nicotinic receptor as well as dopamine and serotonin transporters, as demonstrated in a spatial correlation analysis with a normative atlas of neurotransmitter systems. This convergence of functional, structural, and neurochemical evidence provides a comprehensive framework to understand the neural basis of attention across different species and brain diseases. © 2022, The Author(s).

Funding details
55403
CUP C94I20000420007
869505, H2020-SC5-2019-2
RF-2019-12369300
101028551, 2401512
MART_ECCELLENZA18_01
Fondazione Cassa di Risparmio di Padova e Rovigo
Horizon 2020 Framework ProgrammeH2020818521
European Research CouncilERC
Ministero della SaluteRF-2008 -12366899
Ministero dell’Istruzione, dell’Università e della RicercaMIUR
Fundação Bial361/18
Université de Bordeaux
Sociedade das Ciências Médicas de LisboaSCML

Document Type: Article
Publication Stage: Final
Source: Scopus

White matter abnormalities in the Hdc knockout mouse, a model of tic and OCD pathophysiology
(2022) Frontiers in Molecular Neuroscience, 15, art. no. 1037481, . 

Jindachomthong, K.^a h i , Yang, C.^b , Huang, Y.^c , Coman, D.^c , Rapanelli, M.^a , Hyder, F.^c d , Dougherty, J.^b , Frick, L.^a h i , Pittenger, C.^a e f g

^a Department of Psychiatry, Yale University School of Medicine, New Haven, CT, United States
^b Department of Genetics, Washington University in St. Louis, St. Louis, MO, United States
^c Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, CT, United States
^d Department of Biomedical Engineering, Yale University School of Medicine, New Haven, CT, United States
^e Yale Child Study Center, Yale University School of Medicine, New Haven, CT, United States
^f Interdepartmental Neuroscience Program, Yale University School of Medicine, New Haven, CT, United States
^g Center for Brain and Mind Health, Yale University School of Medicine, New Haven, CT, United States
^h Department of Ophthalmology, Ohio State University, Columbus, OH, United States
ⁱ Department of Neurology, Clinical and Translational Research Center, University at Buffalo, Buffalo, NY, United States

Abstract
Introduction: An inactivating mutation in the histidine decarboxylase gene (Hdc) has been identified as a rare but high-penetrance genetic cause of Tourette syndrome (TS). TS is a neurodevelopmental syndrome characterized by recurrent motor and vocal tics; it is accompanied by structural and functional abnormalities in the cortico-basal ganglia circuitry. Hdc, which is expressed both in the posterior hypothalamus and peripherally, encodes an enzyme required for the biosynthesis of histamine. Hdc knockout mice (Hdc-KO) functionally recapitulate this mutation and exhibit behavioral and neurochemical abnormalities that parallel those seen in patients with TS. Materials and methods: We performed exploratory RNA-seq to identify pathological alterations in several brain regions in Hdc-KO mice. Findings were corroborated with RNA and protein quantification, immunohistochemistry, and ex vivo brain imaging using MRI. Results: Exploratory RNA-Seq analysis revealed, unexpectedly, that genes associated with oligodendrocytes and with myelin production are upregulated in the dorsal striatum of these mice. This was confirmed by qPCR, immunostaining, and immunoblotting. These results suggest an abnormality in myelination in the striatum. To test this in an intact mouse brain, we performed whole-brain ex vivo diffusion tensor imaging (DTI), which revealed reduced fractional anisotropy (FA) in the dorsal striatum. Discussion: While the DTI literature in individuals with TS is sparse, these results are consistent with findings of disrupted descending cortical projections in patients with tics. The Hdc-KO model may represent a powerful system in which to examine the developmental mechanisms underlying this abnormality. Copyright © 2022 Jindachomthong, Yang, Huang, Coman, Rapanelli, Hyder, Dougherty, Frick and Pittenger.

Author Keywords
animal model;  histamine;  myelin;  striatum;  tourette syndrome

Funding details
National Institute of Mental HealthNIMHR01 MH091861, R01MH067528
National Institute of Neurological Disorders and StrokeNINDSP30NS052519
Brain and Behavior Research FoundationBBRF
National Alliance for Research on Schizophrenia and DepressionNARSAD
Allison Family Foundation

Document Type: Article
Publication Stage: Final
Source: Scopus

Genetic diversity fuels gene discovery for tobacco and alcohol use
(2022) Nature, . 

Saunders, G.R.B.^a , Wang, X.^b , Chen, F.^b , Jang, S.-K.^a , Liu, M.^a , Wang, C.^b , Gao, S.^b , Jiang, Y.^c , Khunsriraksakul, C.^b , Otto, J.M.^a , Addison, C.^d , Akiyama, M.^e f , Albert, C.M.^g h , Aliev, F.ⁱ , Alonso, A.^j , Arnett, D.K.^k , Ashley-Koch, A.E.^l m , Ashrani, A.A.ⁿ , Barnes, K.C.^o p , Barr, R.G.^q , Bartz, T.M.^r s , Becker, D.M.^t , Bielak, L.F.^u , Benjamin, E.J.^v w , Bis, J.C.^r , Bjornsdottir, G.^x , Blangero, J.^y , Bleecker, E.R.^z , Boardman, J.D.^aa , Boerwinkle, E.^ab , Boomsma, D.I.^ac , Boorgula, M.P.^o , Bowden, D.W.^ad , Brody, J.A.^r , Cade, B.E.^ae af ag , Chasman, D.I.^h , Chavan, S.^o , Chen, Y.-D.I.^ah , Chen, Z.^ai aj , Cheng, I.^ak al , Cho, M.H.^am an , Choquet, H.^ao , Cole, J.W.^ap aq , Cornelis, M.C.^ar , Cucca, F.^as , Curran, J.E.^y , de Andrade, M.^at , Dick, D.M.ⁱ , Docherty, A.R.^au av aw , Duggirala, R.^y , Eaton, C.B.^ax , Ehringer, M.A.^ay az , Esko, T.^ba , Faul, J.D.^bb , Silva, L.F.^bc , Fiorillo, E.^bd , Fornage, M.^ab be , Freedman, B.I.^bf , Gabrielsen, M.E.^bg , Garrett, M.E.^l m , Gharib, S.A.^r bh bi , Gieger, C.^bj , Gillespie, N.^av , Glahn, D.C.^bk , Gordon, S.D.^bl , Gu, C.C.^bm , Gu, D.^bn , Gudbjartsson, D.F.^x bo , Guo, X.^bp , Haessler, J.^bq , Hall, M.E.^br , Haller, T.^ba , Harris, K.M.^bs , He, J.^bt bu , Herd, P.^bv , Hewitt, J.K.^ay bw , Hickie, I.^bx , Hidalgo, B.^by , Hokanson, J.E.^bz , Hopfer, C.^ca , Hottenga, J.J.^ac , Hou, L.^ar , Huang, H.^cb cc , Hung, Y.-J.^cd , Hunter, D.J.^ce , Hveem, K.^bg cf cg , Hwang, S.-J.^ch , Hwu, C.-M.^ci , Iacono, W.^a , Irvin, M.R.^by , Jee, Y.H.^cb , Johnson, E.O.^cj ck , Joo, Y.Y.^ar cl , Jorgenson, E.^cm , Justice, A.E.^cn co , Kamatani, Y.^e cp , Kaplan, R.C.^bq cq , Kaprio, J.^cr , Kardia, S.L.R.^u , Keller, M.C.^ay bw , Kelly, T.N.^bt bu , Kooperberg, C.^s bq , Korhonen, T.^cr , Kraft, P.^cb cc , Krauter, K.^cs , Kuusisto, J.^ct cu , Laakso, M.^ct , Lasky-Su, J.^cv , Lee, W.-J.^cw , Lee, J.J.^a , Levy, D.^ch , Li, L.^cx , Li, K.^cy , Li, Y.^ak , Lin, K.^ai , Lind, P.A.^cz da db , Liu, C.^dc , Lloyd-Jones, D.M.^dd , Lutz, S.M.^de df , Ma, J.^ch dg , Mägi, R.^az , Manichaikul, A.^dh , Martin, N.G.^bl , Mathur, R.^cj , Matoba, N.^e di , McArdle, P.F.^dj , McGue, M.^a , McQueen, M.B.^dk , Medland, S.E.^cz , Metspalu, A.^ba , Meyers, D.A.^z , Millwood, I.Y.^ai aj , Mitchell, B.D.^dj dl , Mohlke, K.L.^dm , Moll, M.^am an , Montasser, M.E.^dj , Morrison, A.C.^ab , Mulas, A.^bd , Nielsen, J.B.^bg dn , North, K.E.^co , Oelsner, E.C.^q , Okada, Y.^{do dp dq dr} , Orrù, V.^bd , Palmer, N.D.^ad , Palviainen, T.^cr , Pandit, A.^cy , Park, S.L.^ds , Peters, U.^bq dt , Peters, A.^du dv dw , Peyser, P.A.^u , Polderman, T.J.C.^dx dy , Rafaels, N.^o , Redline, S.^ae af dz , Reed, R.M.^ea , Reiner, A.P.^bq dt , Rice, J.P.^eb , Rich, S.S.^dh , Richmond, N.E.^bz , Roan, C.^ec , Rotter, J.I.^bp , Rueschman, M.N.^ae , Runarsdottir, V.^ed , Saccone, N.L.^bm ee , Schwartz, D.A.^ef , Shadyab, A.H.^eg , Shi, J.^eh , Shringarpure, S.S.^eh , Sicinski, K.^ec , Skogholt, A.H.^bg , Smith, J.A.^u bb , Smith, N.L.^dt ei ej , Sotoodehnia, N.^r ek , Stallings, M.C.^ay bw , Stefansson, H.^x , Stefansson, K.^x el , Stitzel, J.A.^ay , Sun, X.^bt , Syed, M.^a , Tal-Singer, R.^em , Taylor, A.E.^en eo ep , Taylor, K.D.^bp , Telen, M.J.^l , Thai, K.K.^ao , Tiwari, H.^eq , Turman, C.^cb cc , Tyrfingsson, T.^ed , Wall, T.L.^er , Walters, R.G.^ai aj , Weir, D.R.^bb , Weiss, S.T.^cv , White, W.B.^es , Whitfield, J.B.^bl , Wiggins, K.L.^et , Willemsen, G.^ac , Willer, C.J.^eu ev ew , Winsvold, B.S.^bg ex ey , Xu, H.^dj , Yanek, L.R.^t , Yin, J.^ao , Young, K.L.^ez , Young, K.A.^bz , Yu, B.^ab , Zhao, W.^u , Zhou, W.^ew fa , Zöllner, S.^fb fc , Zuccolo, L.^en ep fd , Batini, C.^fe , Bergen, A.W.^ff fg , Bierut, L.J.^eb , David, S.P.^fh fi , Gagliano Taliun, S.A.^fj fk fl , Hancock, D.B.^cj , Jiang, B.^b , Munafò, M.R.^en eo fm , Thorgeirsson, T.E.^x , Liu, D.J.^b , Vrieze, S.^a , 23andMe Research Team^fn , The Biobank Japan Project^fo

^a Department of Psychology, University of Minnesota, Minneapolis, MN, United States
^b Department of Public Health Sciences, Penn State College of Medicine, Hershey, PA, United States
^c Department of Epidemiology & Population Health at Stanford University, Stanford, CA, United States
^d Jackson Heart Study (JHS) Graduate Training and Education Center (GTEC), Department of Epidemiology and Biostatistics, School of Public Health, Jackson State University, Jackson, MS, United States
^e Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
^f Department of Ocular Pathology and Imaging Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
^g Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States
^h Division of Preventive Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, United States
ⁱ Department of Psychiatry, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, United States
^j Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, United States
^k Dean’s Office and Department of Epidemiology, College of Public Health, University of Kentucky, Lexington, KY, United States
^l Department of Medicine and Duke Comprehensive Sickle Cell Center, Duke University School of Medicine, Durham, NC, United States
^m Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC, United States
ⁿ Division of Hematology, Department of Medicine, Mayo Clinic College of Medicine and Science, Rochester, MN, United States
^o Division of Biomedical Informatics & Personalized Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
^p Tempus, Chicago, IL, United States
^q Department of Medicine, Columbia University Medical Center, New York, NY, United States
^r Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, United States
^s Department of Biostatistics, University of Washington, Seattle, WA, United States
^t Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States
^u Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, United States
^v Department of Medicine, Boston Medical Center, Boston University School of Medicine, Boston, MA, United States
^w Department of Epidemiology, Boston University School of Public Health, Boston, MA, United States
^x deCODE Genetics/Amgen, Inc., Reykjavik, Iceland
^y Department of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX, United States
^z Department of Medicine, University of Arizona, Tucson, AZ, United States
^aa Institute of Behavioral Science, University of Colorado Boulder, Boulder, CO, United States
^ab Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, United States
^ac Netherlands Twin Register, Dept Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
^ad Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, United States
^ae Division of Sleep and Circadian Disorders, Brigham and Women’s Hospital, Boston, MA, United States
^af Division of Sleep Medicine, Harvard Medical School, Boston, MA, United States
^ag Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, United States
^ah Institute for Translational Genomics and Population Sciences, Department of Pediatrics, Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, United States
^ai Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom
^aj MRC Population Health Research Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom
^ak Department of Epidemiology & Biostatistics, University of California, San Francisco, CA, United States
^al UCSF Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, United States
^am Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston, MA, United States
^an Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston, MA, United States
^ao Kaiser Permanente Northern California (KPNC), Division of Research, Oakland, CA, United States
^ap Department of Neurology, Baltimore Veterans Affairs Medical Center, Baltimore, MD, United States
^aq Division of Vascular Neurology, Department of Neurology, University of Maryland School of Medicine, Baltimore, MD, United States
^ar Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
^as University of Sassari, Sassari SS, Italy
^at Division of Clinical Trials and Biostatistics, Department of Quantitative Health Sciences, Mayo Clinic College of Medicine and Science, Rochester, MN, United States
^au Department of Psychiatry, University of Utah School of Medicine, Salt Lake City, UT, United States
^av Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Virginia, United States
^aw Huntsman Mental Health Institute, Salt Lake City, UT, United States
^ax Department of Family Medicine, Brown University, Providence, RI, United States
^ay Institute for Behavioral Genetics, University of Colorado Boulder, Boulder, CO, United States
^az Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO, United States
^ba Institute of Genomics, University of Tartu, Tartu, Estonia
^bb Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, MI, United States
^bc Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, Kuopio, Finland
^bd Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche (CNR), Monserrato, Italy
^be Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, United States
^bf Department of Internal Medicine-Section on Nephrology, Wake Forest School of Medicine, Winston-Salem, NC, United States
^bg K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway
^bh Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, University of Washington, Seattle, WA, United States
^bi Center for Lung Biology, Department of Medicine, University of Washington, Seattle, WA, United States
^bj Research Unit Molecular Epidemiology, Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
^bk Department of Psychiatry & Behavioral Sciences, Boston Children’s Hospital & Harvard Medical School, Boston, MA, United States
^bl Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Brisbane, Australia
^bm Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, United States
^bn Department of Epidemiology and Key Laboratory of Cardiovascular Epidemiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
^bo School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland
^bp The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, United States
^bq Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States
^br Department of Medicine, University of Mississippi Medical Center, Jackson, MS, United States
^bs Department of Sociology and the Carolina Population Center, University of North Carolina, Chapel Hill, NC, United States
^bt Department of Epidemiology, Tulane University, New Orleans, LA, United States
^bu Translational Sciences Institute, Tulane University, New Orleans, LA, United States
^bv McCourt School of Public Policy, Georgetown University, Washington, DC, United States
^bw Department Of Psychology and Neuroscience, University of Colorado Boulder, Boulder, CO, United States
^bx Youth Mental Health & Technology Team, Brain and Mind Centre, University of Sydney, Sydney, Australia
^by Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, AL, United States
^bz Department of Epidemiology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
^ca Department of Psychiatry, University of Colorado Anschutz Medical Center, Denver, CO, United States
^cb Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, United States
^cc Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health, Boston, MA, United States
^cd Institute of Preventive Medicine, National Defense Medical Center, New Taipei City, Taiwan
^ce Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom
^cf HUNT Research Center, Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), Trondheim, Norway
^cg Department of Research, Innovation and Education, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway
^ch Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, United States
^ci Section of Endocrinology and Metabolism, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
^cj GenOmics, Bioinformatics, and Translational Research Center, RTI International, Research Triangle Park, NC, United States
^ck Fellow Program, RTI International, Research Triangle Park, NC, United States
^cl Institute of Data Science, Korea University, Seoul, South Korea
^cm Regeneron Genetics Center, Tarrytown, NY, United States
^cn Department of Population Health Sciences, Geisinger, Danville, PA, United States
^co Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
^cp Laboratory of Complex Trait Genomics, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan
^cq Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, United States
^cr Institute for Molecular Medicine Finland – FIMM, University of Helsinki, Helsinki, Finland
^cs Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, CO, United States
^ct Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland
^cu Center for Medicine and Clinical Research, Kuopio University Hospital, Kuopio, Finland
^cv Brigham and Women’s Hospital, Department of Medicine, Channing Division of Network Medicine, Boston, MA, United States
^cw Department of Medical Research, Taichung Veterans General Hospital, Taichung City, Taiwan
^cx Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Center, Beijing, China
^cy Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, MI, United States
^cz Psychiatric Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia
^da School of Biomedical Sciences, Faculty of Medicine, University of Queensland, Brisbane, Australia
^db School of Biomedical Sciences, Queensland University of Technology, Brisbane, Australia
^dc Department of Biostatistics, Boston University School of Public Health, Boston, MA, United States
^dd Departments of Preventive Medicine, Medicine, and Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
^de Department of Population Medicine, Harvard Pilgrim Health Care Institute, Boston, MA, United States
^df Department of Biostatics, Harvard T.H. Chan School of Public Health, Boston, MA, United States
^dg Division of Nutrition Epidemiology and Data Science, Friedman School of Nutrition Science and Policy, Tufts University, Boston, MA, United States
^dh Center for Public Health Genomics, Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, United States
^di Department of Genetics, UNC Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
^dj Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, United States
^dk Department of Integrative Physiology, University of Colorado, Boulder, CO, United States
^dl Geriatrics Research and Education Clinical Center, Baltimore Veterans Administration Medical Center, Baltimore, MD, United States
^dm Department of Genetics, University of North Carolina, Chapel Hill, NC, United States
^dn Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI, United States
^do Laboratory for Systems Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
^dp Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan
^dq Laboratory of Statistical Immunology, Immunology Frontier Research Center (WPI-IFReC), Osaka University, Suita, Japan
^dr Department of Genome Informatics, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan
^ds Population Sciences of the Pacific Program, University of Hawaii Cancer Center, Honolulu, HI, United States
^dt Department of Epidemiology, University of Washington, Seattle, WA, United States
^du Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
^dv Institute for Medical Information Processing, Biometry and Epidemiology, Ludwig Maximilians University Munich, Munich, Germany
^dw German Centre for Cardiovascular Research, DZHK, Partner Site Munich, Munich, Germany
^dx Department of Clinical Developmental Psychology, Vrije Universiteit, Amsterdam, Netherlands
^dy Department of Child and Adolescent Psychiatry, Amsterdam UMC, Amsterdam, Netherlands
^dz Division of Pulmonary, Critical Care, and Sleep Medicine, Beth Israel Deaconess Medical Center, Boston, MA, United States
^ea Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, United States
^eb Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^ec Center for Demography of Health and Aging, University of Wisconsin-Madison, Madison, WI, United States
^ed SAA-National Center of Addiction Medicine, Vogur Hospital, Reykjavik, Iceland
^ee Department of Genetics, Washington University School of Medicine, St. Louis, MO, United States
^ef Division of Pulmonary Sciences and Critical Care Medicine; Department of Medicine and Immunology, University of Colorado, Aurora, CO, United States
^eg Herbert Wertheim School of Public Health and Human Longevity Science, University of California, San Diego, La JollaCA, United States
^eh 23andMe, Inc, Sunnyvale, CA, United States
^ei Kaiser Permanente Washington Health Research Institute, Kaiser Permanente Washington, Seattle, WA, United States
^ej Seattle Epidemiologic Research and Information Center, Department of Veterans Affairs Office of Research and Development, Seattle, WA, United States
^ek Division of Cardiology, Department of Medicine, University of Washington, Seattle, WA, United States
^el Faculty of Medicine, University of Iceland, Reykjavik, Iceland
^em COPD Foundation, Washington, DC, United States
^en MRC Integrative Epidemiology Unit, Population Health Sciences, University of Bristol, Bristol, United Kingdom
^eo National Institute for Health Research Biomedical Research Centre at the University Hospitals Bristol NHS Foundation Trust and the University of Bristol, Bristol, United Kingdom
^ep Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
^eq Department of Biostatistics, School of Public Health, University of Alabama at Birmingham, Birmingham, AL, United States
^er Department of Psychiatry, University of California San Diego, San Diego, CA, United States
^es Jackson Heart Study Undergraduate Training and Education Center, Tougaloo College, Tougaloo, MS, United States
^et Department of Medicine, University of Washington, Seattle, WA, United States
^eu Department of Internal Medicine, Division of Cardiology, University of Michigan, Ann Arbor, MI, United States
^ev Department of Human Genetics, University of Michigan, Ann Arbor, MI, United States
^ew Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, United States
^ex Department of Research and Innovation, Division of Clinical Neuroscience, Oslo University Hospital, Oslo, Norway
^ey Department of Neurology, Oslo University Hospital, Oslo, Norway
^ez Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
^fa Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, United States
^fb Department of Biostatistics, University of Michigan, Ann Arbor, MI, United States
^fc Department of Psychiatry, University of Michigan, Ann Arbor, MI, United States
^fd Health Data Science Centre, Fondazione Human Technopole, Milan, Italy
^fe Department of Population Health Sciences, University of Leicester, Leicester, United Kingdom
^ff Oregon Research Institute, Springfield, OR, United States
^fg BioRealm, LLC, Walnut, CA, United States
^fh Outcomes Research Network & Department of Family Medicine, NorthShore University HealthSystem, Evanston, IL, United States
^fi Department of Family Medicine, University of Chicago, Chicago, IL, United States
^fj Department of Medicine, Université de Montréal, Montréal, QC, Canada
^fk Department of Neurosciences, Université de Montréal, Montréal, QC, Canada
^fl Research Centre, Montréal Heart Institute, Montréal, QC, Canada
^fm School of Psychological Science, University of Bristol, Bristol, United Kingdom

Abstract
Tobacco and alcohol use are heritable behaviours associated with 15% and 5.3% of worldwide deaths, respectively, due largely to broad increased risk for disease and injury1–4. These substances are used across the globe, yet genome-wide association studies have focused largely on individuals of European ancestries5. Here we leveraged global genetic diversity across 3.4 million individuals from four major clines of global ancestry (approximately 21% non-European) to power the discovery and fine-mapping of genomic loci associated with tobacco and alcohol use, to inform function of these loci via ancestry-aware transcriptome-wide association studies, and to evaluate the genetic architecture and predictive power of polygenic risk within and across populations. We found that increases in sample size and genetic diversity improved locus identification and fine-mapping resolution, and that a large majority of the 3,823 associated variants (from 2,143 loci) showed consistent effect sizes across ancestry dimensions. However, polygenic risk scores developed in one ancestry performed poorly in others, highlighting the continued need to increase sample sizes of diverse ancestries to realize any potential benefit of polygenic prediction. © 2022, The Author(s).

Funding details
National Institutes of HealthNIHR01DA042755, R01DA044283, R01GM126479, R01HG011035, R03OD032630, R56HG012358, T32DA050560, U01DA041120
Bayer
GlaxoSmithKlineGSK

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

Divalent 2-(4-Hydroxyphenyl)benzothiazole Bifunctional Chelators for 64Cu Positron Emission Tomography Imaging in Alzheimer’s Disease
(2022) Inorganic Chemistry, . 

Terpstra, K.^a , Wang, Y.^a , Huynh, T.T.^b c , Bandara, N.^b , Cho, H.-J.^a , Rogers, B.E.^b , Mirica, L.M.^a d

^a Department of Chemistry, University of Illinois at Urbana-Champaign, 600 S. Mathews Avenue, Urbana, IL 61801, United States
^b Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO 63108, United States
^c Department of Chemistry, Washington University, St. Louis, MO 63130, United States
^d Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
Herein, we report a new series of divalent 2-(4-hydroxyphenyl)benzothiazole bifunctional chelators (BFCs) with high affinity for amyloid β aggregates and favorable lipophilicity for blood-brain barrier penetration. The addition of an alkyl carboxylate ester pendant arm offers high binding affinity toward Cu(II). The novel BFCs form stable 64Cu-radiolabeled complexes and exhibit promising partition coefficient (logD) values of 1.05-1.85. Among the five compounds tested, the 64Cu-YW-15 complex exhibits significant staining of amyloid β plaques in ex vivo autoradiography studies. In addition, biodistribution studies show that 64Cu-YW-15-Me exhibits moderate brain uptake (0.69 ± 0.08 %ID/g) in wild type mice. © 2022 American Chemical Society.

Funding details
National Institutes of HealthNIHR01GM114588

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

Effects of nicotinamide mononucleotide on older patients with diabetes and impaired physical performance: A prospective, placebo-controlled, double-blind study
(2022) Geriatrics and Gerontology International, . 

Akasaka, H.^a , Nakagami, H.^b , Sugimoto, K.^c , Yasunobe, Y.^a , Minami, T.^a , Fujimoto, T.^a , Yamamoto, K.^a , Hara, C.^d , Shiraki, A.^d , Nishida, K.^d , Asano, K.^e , Kanou, M.^f g , Yamana, K.^g h , Imai, S.-I.ⁱ , Rakugi, H.^a

^a Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Suita, Japan
^b Department of Health Development and Medicine, Osaka University Graduate School of Medicine, Suita, Japan
^c Department of General and Geriatric Medicine, Kawasaki Medical University, Okayama, Japan
^d Department of Ophthalmology, Osaka University Graduate School of Medicine, Suita, Japan
^e Academic Clinical Research Center, Department of Medical Innovation, Osaka University Hospital, Suita, Japan
^f Nutraceutical Group, Division of New Business in Healthcare Business, Teijin Ltd, Chiyoda, Japan
^g NOMON Co., Ltd., Tokyo, Japan
^h Management Coordinator for the President Healthcare Business of Teijin Group, Chiyoda, Japan
ⁱ Department of Developmental Biology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Objective: Nicotinamide adenine dinucleotide regulates various biological processes. Nicotinamide mononucleotide (NMN) increases its intracellular levels and counteracts age-associated changes in animal models. We investigated the safety and efficacy of oral nicotinamide mononucleotide supplementation in older patients with diabetes and impaired physical performance. Method: We carried out a 24-week placebo-controlled, double-blinded study of male patients with diabetes aged ≥65 years with reduced grip strength (<26 kg) or walking speed (<1.0 m/s). The primary end-points were to determine the safety of NMN oral administration (250 mg/day), and changes in grip strength and walking speed. The secondary end-points were to determine the changes in various exploratory indicators. Results: We studied 14 participants aged 81.1 ± 6.4 years. NMN was tolerable without any severe adverse events. The changes in grip strength and walking speed showed no difference between the two groups: 1.25 kg (95% confidence interval −2.31 to 4.81) and 0.033 m/s (−0.021 to 0.087) in the NMN group, and −0.44 kg (−4.15 to 3.26) and 0.014 m/s (−0.16 to −0.13) in the placebo group, respectively. There were no significant differences in any exploratory indicators between the two groups. However, improved prevalence of frailty in the NMN group (P = 0.066) and different changes in central retinal thickness between the two groups (P = 0.051) was observed. Conclusion: In older male patients with diabetes and impaired physical performance, NMN supplementation for 24 weeks was safe, but did not improve grip strength and walking speed. Geriatr Gerontol Int 2022; ••: ••–••. © 2022 Japan Geriatrics Society.

Author Keywords
clinical medicine;  diabetes mellitus;  geriatric medicine;  musculoskeletal

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

Adverse driving behaviors increase over time as a function of preclinical Alzheimer’s disease biomarkers
(2022) Alzheimer’s and Dementia, . 

Doherty, J.M.^a , Murphy, S.A.^a , Bayat, S.^b c d , Wisch, J.K.^a , Johnson, A.M.^e , Walker, A.^a , Schindler, S.E.^a g h , Ances, B.M.^a f g h , Morris, J.C.^a f g h , Babulal, G.M.^{a h i j k}

^a Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
^b Department of Biomedical Engineering, University of Calgary, Calgary, AB, Canada
^c Department of Geomatics Engineering, University of Calgary, Calgary, AB, Canada
^d Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada
^e Center for Clinical Studies, Washington University in St. Louis, St. Louis, MO, United States
^f Department of Radiology, Washington University in St. Louis, St. Louis, MO, United States
^g Hope Center for Neurological Disorders, Washington University in St. Louis, St. Louis, MO, United States
^h Knight Alzheimer’s Disease Research Center, Washington University in St. Louis, St. Louis, MO, United States
ⁱ Institute of Public Health, Washington University in St. Louis, St. Louis, MO, United States
^j Department of Psychology, Faculty of Humanities, University of Johannesburg, Johannesburg, South Africa
^k Department of Clinical Research and Leadership, The George Washington University School of Medicine and Health Sciences, Washington, DC, United States

Abstract
Introduction: We investigated the relationship between preclinical Alzheimer’s disease (AD) biomarkers and adverse driving behaviors in a longitudinal analysis of naturalistic driving data. Methods: Naturalistic driving data collected using in-vehicle dataloggers from 137 community-dwelling older adults (65+) were used to model driving behavior over time. Cerebrospinal fluid (CSF) biomarkers were used to identify individuals with preclinical AD. Additionally, hippocampal volume and cognitive biomarkers for AD were investigated in exploratory analyses. Results: CSF biomarkers predicted the longitudinal trajectory of the incidence of adverse driving behavior. Abnormal amyloid beta (Aβ42/Aβ40) ratio was associated with an increase in adverse driving behaviors over time compared to ratios in the normal/lower range. Discussion: Preclinical AD is associated with increased adverse driving behavior over time that cannot be explained by cognitive changes. Driving behavior as a functional, neurobehavioral marker may serve as an early detection for decline in preclinical AD. Screening may also help prolong safe driving as older drivers age. © 2022 the Alzheimer’s Association.

Author Keywords
Alzheimer’s disease;  cerebrospinal fluid biomarkers;  driving;  older adults

Funding details
P01AG026276, P30 AG066444, R01AG057680, U19 AG024904, U19 AG032438
National Institutes of HealthNIH
National Institute on AgingNIAR01AG056466, R01AG067428, R01AG068183

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

Electrical stimulation or tacrolimus (FK506) alone enhances nerve regeneration and recovery after nerve surgery, while dual use reduces variance and combines strengths of each in promoting enhanced outcomes
(2022) Muscle and Nerve, . 

Marsh, E.B., Schellhardt, L., Hunter, D.A., Mackinnon, S.E., Snyder-Warwick, A.K., Wood, M.D.

Division of Plastic and Reconstructive Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Introduction/Aims: Repaired nerve injuries can fail to achieve functional recovery. Therapeutic options beyond surgery, such as systemic tacrolimus (FK506) and electrical stimulation (E-stim), can improve recovery. We tested whether dual administration of FK506 and E-stim enhances regeneration and recovery more than either therapeutic alone. Methods: Rats were randomized to four groups: E-stim, FK506, FK506 + E-stim, and repair alone. All groups underwent tibial nerve transection and repair. Two sets of animals were created to measure outcomes of early nerve regeneration using nerve histology (n = 36) and functional recovery (n = 42) (21- and 42-day endpoints, respectively). Functional recovery was measured by behavioral analyses (walking track and grid walk) and, at the endpoint, muscle mass and force. Results: Dual E-stim and FK506 administration produced histomorphometric measurements of nerve regeneration no different than either therapeutic alone. All treatments were superior to repair alone (FK506, P <.0001; E-stim, P <.05; FK506 + E-stim, P <.05). The E-stim and FK506 + E-stim groups had improved behavioral recovery compared with repair alone (at 6 weeks: E-stim, P <.05; FK506 + E-stim, P <.01). The FK506 group had improved recovery based on walking-track analysis (at 6 weeks: P <.001) and muscle force and mass (P <.05). The concurrent use of both therapies ensured earlier functional recovery and decreased variability in functional outcomes compared with either therapy alone, suggesting a moderate benefit. Discussion: Dual administration of FK506 and E-stim showed minimal additive effects to further improve regeneration or recovery compared with either therapy alone. The data suggest the combination of FK506 and E-stim appears to combine the relative strengths of each therapeutic. © 2022 Wiley Periodicals LLC.

Author Keywords
electrical stimulation;  FK506;  functional recovery;  peripheral nerve;  regeneration;  tacrolimus;  tibial nerve

Funding details
Washington University School of Medicine in St. Louis WUSM

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