WashU weekly Neuroscience publications | Office of Neuroscience Research

"Gait asymmetry, and bilateral coordination of gait during a six-minute walk test in persons with multiple sclerosis" (2020) Scientific Reports

Gait asymmetry, and bilateral coordination of gait during a six-minute walk test in persons with multiple sclerosis
(2020) Scientific Reports, 10 (1), art. no. 12382, .

Plotnik, M.^a ^b ^c , Wagner, J.M.^d , Adusumilli, G.^e , Gottlieb, A.^a , Naismith, R.T.^e

^a Center of Advanced Technologies in Rehabilitation, Sheba Medical Center, Ramat Gan, 5265601, Israel
^b Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel
^c Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel
^d Department of Physical Therapy and Athletic Training, Saint Louis University, St. Louis, United States
^e Department of Neurology, Washington University in St. Louis, St. Louis, United States

Abstract
Gait impairments in persons with multiple sclerosis (pwMS) leading to decreased ambulation and reduced walking endurance remain poorly understood. Our objective was to assess gait asymmetry (GA) and bilateral coordination of gait (BCG), among pwMS during the six-minute walk test (6MWT), and determine their association with disease severity. We recruited 92 pwMS (age: 46.6 ± 7.9; 83% females) with a range of clinical disability, who completed the 6MWT wearing gait analysis system. GA was assessed by comparing left and right swing times, and BCG was assessed by the phase coordination index (PCI). Several functional and subjective gait assessments were performed. Results show that gait is more asymmetric and less coordinated as the disease progresses (p < 0.0001). Participants with mild MS showed significantly better BCG as reflected by lower PCI values in comparison to the other two MS severity groups (severe: p = 0.001, moderate: p = 0.02). GA and PCI also deteriorated significantly each minute during the 6MWT (p < 0.0001). GA and PCI (i.e., BCG) show weaker associations with clinical MS status than associations observed between functional and subjective gait assessments and MS status. Similar to other neurological cohorts, GA and PCI may be important parameters to assess and target in interventions among pwMS. © 2020, The Author(s).

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

"Structural mechanism for gating of a eukaryotic mechanosensitive channel of small conductance" (2020) Nature Communications

Structural mechanism for gating of a eukaryotic mechanosensitive channel of small conductance
(2020) Nature Communications, 11 (1), art. no. 3690, .

Deng, Z.^a ^b , Maksaev, G.^a ^b , Schlegel, A.M.^c ^d , Zhang, J.^a ^b , Rau, M.^e , Fitzpatrick, J.A.J.^a ^e ^f ^g , Haswell, E.S.^c ^d , Yuan, P.^a ^b

^a Department of Cell Biology and Physiology, Washington University School of Medicine, Saint Louis, MO 63110, United States
^b Center for the Investigation of Membrane Excitability Diseases, Washington University School of Medicine, Saint Louis, MO 63110, United States
^c Department of Biology, Washington University in Saint Louis, Saint Louis, MO 63130, United States
^d NSF Center for Engineering Mechanobiology, Washington University in Saint Louis, Saint Louis, MO 63130, United States
^e Washington University Center for Cellular Imaging, Washington University School of Medicine, Saint Louis, MO 63110, United States
^f Department of Neuroscience, Washington University School of Medicine, Saint Louis, MO 63110, United States
^g Department of Biomedical Engineering, Washington University in Saint Louis, Saint Louis, MO 63130, United States

Abstract
Mechanosensitive ion channels transduce physical force into electrochemical signaling that underlies an array of fundamental physiological processes, including hearing, touch, proprioception, osmoregulation, and morphogenesis. The mechanosensitive channels of small conductance (MscS) constitute a remarkably diverse superfamily of channels critical for management of osmotic pressure. Here, we present cryo-electron microscopy structures of a MscS homolog from Arabidopsis thaliana, MSL1, presumably in both the closed and open states. The heptameric MSL1 channel contains an unusual bowl-shaped transmembrane region, which is reminiscent of the evolutionarily and architecturally unrelated mechanosensitive Piezo channels. Upon channel opening, the curved transmembrane domain of MSL1 flattens and expands. Our structures, in combination with functional analyses, delineate a structural mechanism by which mechanosensitive channels open under increased membrane tension. Further, the shared structural feature between unrelated channels suggests the possibility of a unified mechanical gating mechanism stemming from membrane deformation induced by a non-planar transmembrane domain. © 2020, The Author(s).

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

"Mendelian randomization implies no direct causal association between leukocyte telomere length and amyotrophic lateral sclerosis" (2020) Scientific Reports

Mendelian randomization implies no direct causal association between leukocyte telomere length and amyotrophic lateral sclerosis
(2020) Scientific Reports, 10 (1), art. no. 12184, .

Gao, Y.^a , Wang, T.^a , Yu, X.^a , Ferrari, R.^c , Hernandez, D.G.^d ^e , Nalls, M.A.^d , Rohrer, J.D.^e ^f , Ramasamy, A.^e ^g ^h , Kwok, J.B.J.ⁱ ^j , Dobson-Stone, C.ⁱ ^j , Brooks, W.S.ⁱ ^k , Schofield, P.R.ⁱ , Halliday, G.M.ⁱ , Hodges, J.R.ⁱ , Piguet, O.ⁱ , Bartley, L.ⁱ , Thompson, E.^l ^m , Haan, E.^l ^m , Hernández, I.ⁿ , Ruiz, A.ⁿ , Boada, M.ⁿ , Borroni, B.^o , Padovani, A.^o , Cruchaga, C.^p ^q , Cairns, N.J.^q ^r , Benussi, L.^s , Binetti, G.^t , Ghidoni, R.^s , Forloni, G.^u , Albani, D.^u , Galimberti, D.^v ^w , Fenoglio, C.^v ^w , Serpente, M.^v ^w , Scarpini, E.^v , Clarimón, J.^w ^x ^y , Lleó, A.^x ^y , Blesa, R.^x ^y , Waldö, M.L.^z , Nilsson, K.^z , Nilsson, C.^aa , Mackenzie, I.R.A.^ab , Hsiung, G.-Y.R.^ac , Mann, D.M.A.^ad , Grafman, J.^ae ^af , Morris, C.M.^ag ^ah , Attems, J.^ah , Griffiths, T.D.^ai , McKeith, I.G.^ah , Thomas, A.J.^ah , Pietrini, P.^aj , Huey, E.D.^ak , Wassermann, E.M.^al , Baborie, A.^am , Jaros, E.^an , Tierney, M.C.^al , Pastor, P.^y ^ao ^ap , Razquin, C.^ao , Ortega-Cubero, S.^y ^ao , Alonso, E.^ao , Perneczky, R.^aq ^ar , Diehl-Schmid, J.^as , Alexopoulos, P.^as , Kurz, A.^as , Rainero, I.^at ^au , Rubino, E.^at ^au , Pinessi, L.^at ^au , Rogaeva, E.^av , George-Hyslop, P.S.^av ^aw , Rossi, G.^ax , Tagliavini, F.^ax , Giaccone, G.^ax , Rowe, J.B.^ay ^az ^ba , Schlachetzki, J.C.M.^bb , Uphill, J.^bc , Collinge, J.^bc , Mead, S.^bc , Danek, A.^bd ^be , Van Deerlin, V.M.^bf , Grossman, M.^bg , Trojanowski, J.Q.^bf , van der Zee, J.^bh ^bi , Cruts, M.^bh ^bi , Van Broeckhoven, C.^bh ^bi , Cappa, S.F.^bj , Leber, I.^bk ^bl ^bm , Hannequin, D.^bo , Golfier, V.^bp , Vercelletto, M.^bq , Brice, A.^bk ^bl ^bm ^bn , Nacmias, B.^br , Sorbi, S.^bs , Bagnoli, S.^br , Piaceri, I.^br , Nielsen, J.E.^bt , Hjermind, L.E.^bt ^bu , Riemenschneider, M.^bv ^bw , Mayhaus, M.^bw , Ibach, B.^bx , Gasparoni, G.^bw , Pichler, S.^bw , Gu, W.^bw ^by , Rossor, M.N.^f , Fox, N.C.^f , Warren, J.D.^f , Spillantini, M.G.^bz , Morris, H.R.^c , Rizzu, P.^ca , Heutink, P.^ca , Snowden, J.S.^cb , Rollinson, S.^cb , Richardson, A.^cc , Gerhard, A.^cd , Bruni, A.C.^ce , Maletta, R.^ce , Frangipane, F.^ce , Cupidi, C.^ce , Bernardi, L.^ce , Anfossi, M.^ce , Gallo, M.^ce , Conidi, M.E.^ce , Smirne, N.^ce , Rademakers, R.^cf , Baker, M.^cf , Dickson, D.W.^cf , Graff-Radford, N.R.^cg , Petersen, R.C.^ch , Knopman, D.^ch , Josephs, K.A.^ch , Boeve, B.F.^ch , Parisi, J.E.^ci , Seeley, W.W.^cj , Miller, B.L.^ck , Karydas, A.M.^ck , Rosen, H.^ck , van Swieten, J.C.^cl ^cm , Dopper, E.G.P.^cl , Seelaar, H.^cl , Pijnenburg, Y.A.L.^cn , Scheltens, P.^cn , Logroscino, G.^co , Capozzo, R.^co , Novelli, V.^cp , Puca, A.A.^cq ^cr , Franceschi, M.^cs , Postiglione, A.^ct , Milan, G.^cu , Sorrentino, P.^cu , Kristiansen, M.^cv , Chiang, H.-H.^cw ^cx , Graff, C.^cw ^cx , Pasquier, F.^cy , Rollin, A.^cy , Deramecourt, V.^cy , Lebouvier, T.^cy , Kapogiannis, D.^cz , Ferrucci, L.^da , Pickering-Brown, S.^cb , Singleton, A.B.^d , Hardy, J.^c , Momeni, P.^db , Zhao, H.^a ^b , Zeng, P.^a ^b , International FTD-Genomics Consortium (IFGC)^dc

^a Department of Epidemiology and Biostatistics, School of Public Health, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China
^b Center for Medical Statistics and Data Analysis, School of Public Health, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China
^c Department of Molecular Neuroscience, UCL, Russell Square House, 9-12 Russell Square House, London, WC1B 5EH, United Kingdom
^d Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Building 35, Room 1A215, 35 Convent Drive, Bethesda, MD 20892, United States
^e Reta Lila Weston Research Laboratories, Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, United Kingdom
^f Department of Neurodegenerative Disease, Dementia Research Centre, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, United Kingdom
^g Department of Medical and Molecular Genetics, King’s College London Tower Wing, Guy’s Hospital, London, SE1 9RT, United Kingdom
^h The Jenner Institute, University of Oxford, Roosevelt Drive, Oxford, OX3 7BQ, United Kingdom
ⁱ Neuroscience Research Australia, Sydney, NSW 2031, Australia
^j School of Medical Sciences, University of New South Wales, Sydney, NSW 2052, Australia
^k Prince of Wales Clinical School, University of New South Wales, Sydney, NSW 2052, Australia
^l South Australian Clinical Genetics Service, SA Pathology (at Women’s and Children’s Hospital), North Adelaide, SA 5006, Australia
^m Department of Paediatrics, University of Adelaide, Adelaide, SA 5000, Australia
ⁿ Research Center and Memory Clinic of Fundació ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain
^o Neurology Clinic, University of Brescia, Brescia, Italy
^p Department of Psychiatry, Washington University, St. Louis, MO, United States
^q Hope Center, Washington University School of Medicine, St. Louis, MO, United States
^r Department of Pathology and Immunology, Washington University, St. Louis, MO, United States
^s Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy
^t MAC Memory Clinic, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy
^u Biology of Neurodegenerative Disorders, IRCCS Istituto di Ricerche Farmacologiche, “Mario Negri”, Milan, Italy
^v University of Milan, Milan, Italy
^w Fondazione Cà Granda, IRCCS Ospedale Maggiore Policlinico, via F. Sforza 35, Milan, 20122, Italy
^x Memory Unit, Neurology Department and Sant Pau Biomedical Research Institute, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
^y Center for Networker Biomedical Research in Neurodegenerative Diseases (CIBERNED), Madrid, Spain
^z Unit of Geriatric Psychiatry, Department of Clinical Sciences, Lund University, Lund, Sweden
^aa Clinical Memory Research Unit, Department of Clinical Sciences, Lund University, Lund, Sweden
^ab Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada
^ac Division of Neurology, University of British Columbia, Vancouver, Canada
^ad Institute of Brain, Behaviour and Mental Health, University of Manchester, Salford Royal Hospital, Stott Lane, Salford, M6 8HD, United Kingdom
^ae Departments of Physical Medicine and Rehabilitation, Psychiatry, and Cognitive Neurology and Alzheimer’s Disease Center, Rehabilitation Institute of Chicago, Feinberg School of Medicine, Northwestern University, Chicago, United States
^af Department of Psychology, Weinberg College of Arts and Sciences, Northwestern University, Chicago, United States
^ag Newcastle Brain Tissue Resource, Institute for Ageing, Newcastle University, Newcastle upon Tyne, NE4 5PL, United Kingdom
^ah Institute of Neuroscience and Institute for Ageing, Campus for Ageing and Vitality, Newcastle University, Newcastle upon Tyne, NE4 5PL, United Kingdom
^ai Institute of Neuroscience, Newcastle University Medical School, Framlington Place, Newcastle upon Tyne, NE2 4HH, United Kingdom
^aj IMT School for Advanced Studies, Lucca, Lucca, Italy
^ak Departments of Psychiatry and Neurology, Taub Institute, Columbia University, 630 West 168th Street, New York, NY 10032, United States
^al Behavioral Neurology Unit, National Insititute of Neurological Disorders and Stroke, National Insititutes of Health, 10 Center DR MSC 1440, Bethesda, MD 20892-1440, United States
^am Department of Laboratory Medicine and Pathology, Walter Mackenzie Health Sciences Centre, University of Alberta Edmonton, 8440 – 112 StAB T6G 2B7, Canada
^an Institute for Ageing and Health, Campus for Ageing and Vitality, Newcastle University, Newcastle upon Tyne, NE4 5PL, United Kingdom
^ao Neurogenetics Laboratory, Division of Neurosciences, Center for Applied Medical Research, Universidad de Navarra, Pamplona, Spain
^ap Department of Neurology, Clínica Universidad de Navarra, University of Navarra School of Medicine, Pamplona, Spain
^aq Neuroepidemiology and Ageing Research Unit, School of Public Health, Faculty of Medicine, The Imperial College of Science, Technology and Medicine, London, W6 8RP, United Kingdom
^ar West London Cognitive Disorders Treatment and Research Unit, West London Mental Health Trust, London, TW8 8 DS, United Kingdom
^as Department of Psychiatry and Psychotherapy, Technische Universität München, Munich, 81675, Germany
^at Neurology I, Department of Neuroscience, University of Torino, Turin, Italy
^au A.O. Città della Salute e della Scienza di Torino, Turin, Italy
^av Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, 60 Leonard Street, Toronto, ON M5T 2S8, Canada
^aw Department of Clinical Neurosciences, Cambridge Institute for Medical Research, University of Cambridge, Hills Road, Cambridge, CB2 0XY, United Kingdom
^ax Division of Neurology V and Neuropathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, 20133, Italy
^ay Department of Clinical Neurosciences, Cambridge University, Cambridge, CB2 0SZ, United Kingdom
^az MRC Cognition and Brain Sciences Unit, Cambridge, CB2 7EF, United Kingdom
^ba Behavioural and Clinical Neuroscience Institute, Cambridge, CB2 3EB, United Kingdom
^bb Department of Cellular and Molecular Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, United States
^bc MRC Prion Unit, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square House, Queen Square, London, WC1N 3BG, United Kingdom
^bd Neurologische Klinik und Poliklinik, Ludwig-Maximilians-Universität, Munich, Germany
^be German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
^bf Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States
^bg Department of Neurology and Penn Frontotemporal Degeneration Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States
^bh Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerp, Belgium
^bi Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
^bj Neurorehabilitation Unit, Department of Clinical Neuroscience, Vita-Salute University and San Raffaele Scientific Institute, Milan, Italy
^bk Inserm, UMR_S975, CRICM, Paris, 75013, France
^bl UPMC Univ Paris 06, UMR_S975, Paris, 75013, France
^bm CNRS UMR 7225, Paris, 75013, France
^bn Département de neurologie-centre de références des démences rares, AP-HP, Hôpital de la Salpêtrière, Paris, 75013, France
^bo Service de Neurologie, Inserm U1079, CNR-MAJ, Rouen University Hospital, Rouen, France
^bp Service de Neurologie, CH Saint Brieuc, Saint Brieuc, France
^bq Service de Neurologie, CHU Nantes, Nantes, France
^br Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Florence, Italy
^bs Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence and IRCCS “Don Carlo Gnocchi” Firenze, Florence, Italy
^bt Danish Dementia Research Centre, Neurogenetics Clinic, Department of Neurology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
^bu Department of Cellular and Molecular Medicine, Section of Neurogenetics, The Panum Institute, University of Copenhagen, Copenhagen, Denmark
^bv Department for Psychiatry and Psychotherapy, Saarland University Hospital, Kirrberger Str.1, Bld.90, Homburg/Saar, 66421, Germany
^bw Laboratory for Neurogenetics, Saarland University, Kirrberger Str.1, Bld.90, Homburg/Saar, 66421, Germany
^bx Department of Psychiatry, Psychotherapy and Psychosomatics, University Regensburg, Universitätsstr. 84, Regensburg, 93053, Germany
^by Luxembourg Centre For Systems Biomedicine (LCSB), University of Luxembourg, 7, Avenue des Hauts-Fourneaux, Esch-sur-Alzette, 4362, Luxembourg
^bz Department of Clinical Neurosciences, John Van Geest Brain Repair Centre, University of Cambridge, Forvie Site, Robinson Way, Cambridge, CB2 0PY, United Kingdom
^ca German Center for Neurodegenerative Diseases-Tübingen, Otfried Muellerstrasse 23, Tuebingen, 72076, Germany
^cb Faculty of Medical and Human Sciences, Institute of Brain, Behaviour and Mental Health, University of Manchester, Manchester, United Kingdom
^cc Salford Royal Foundation Trust, Faculty of Medical and Human Sciences, University of Manchester, Manchester, United Kingdom
^cd Institute of Brain, Behaviour and Mental Health, The University of Manchester, 27 Palatine Road, Withington, Manchester, M20 3LJ, United Kingdom
^ce Regional Neurogenetic Centre, ASPCZ, Lamezia Terme, Italy
^cf Department of Neuroscience, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL 32224, United States
^cg Department of Neurology, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL 32224, United States
^ch Department of Neurology, Mayo Clinic Rochester, 2001st Street SW, Rochester, MN 5905, United States
^ci Department of Pathology, Mayo Clinic Rochester, 2001st Street SW, Rochester, MN 5905, United States
^cj Department of Neurology, University of California, Box 1207, San Francisco, CA 94143, United States
^ck Department of Neurology, Memory and Aging Center, University of California, San Francisco, CA 94158, United States
^cl Department of Neurology, Erasmus Medical Centre, Rotterdam, Netherlands
^cm Department of Medical Genetics, VU University Medical Centre, Amsterdam, Netherlands
^cn Alzheimer Centre and Department of Neurology, VU University Medical Centre, Amsterdam, Netherlands
^co Department of Basic Medical Sciences, Neurosciences and Sense Organs of the “Aldo Moro” University of Bari, Bari, Italy
^cp Medical Genetics Unit, Fondazione Policlinico Universitario A. Gemelli, Rome, Italy
^cq Cardiovascular Research Unit, IRCCS Multimedica, Milan, Italy
^cr Department of Medicine and Surgery, University of Salerno, Baronissi, SA, Italy
^cs Neurology Department, IRCCS Multimedica, Milan, Italy
^ct Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
^cu Geriatric Center Frullone- ASL Napoli 1 Centro, Naples, Italy
^cv UCL Genomics, Institute of Child Health (ICH), UCL, London, United Kingdom
^cw Dept NVS, Alzheimer Research Center, Karolinska Institutet, Novum, Stockholm, 141 57, Sweden
^cx Department of Geriatric Medicine, Genetics Unit, M51, Karolinska University Hospital, Stockholm, 14186, Sweden
^cy Univ Lille, Inserm 1171, DISTALZ, CHU, Lille, 59000, France
^cz National Institute on Aging (NIA/NIH), 3001 S. Hanover St, NM 531, Baltimore, MD 21230, United States
^da Clinical Research Branch, National Institute on Aging, Baltimore, MD, United States
^db Laboratory of Neurogenetics, Department of Internal Medicine, Texas Tech University Health Science Center, 4th street, Lubbock, TX 79430, United States

Abstract
We employed Mendelian randomization (MR) to evaluate the causal relationship between leukocyte telomere length (LTL) and amyotrophic lateral sclerosis (ALS) with summary statistics from genome-wide association studies (n = ~ 38,000 for LTL and ~ 81,000 for ALS in the European population; n = ~ 23,000 for LTL and ~ 4,100 for ALS in the Asian population). We further evaluated mediation roles of lipids in the pathway from LTL to ALS. The odds ratio per standard deviation decrease of LTL on ALS was 1.10 (95% CI 0.93–1.31, p = 0.274) in the European population and 0.75 (95% CI 0.53–1.07, p = 0.116) in the Asian population. This null association was also detected between LTL and frontotemporal dementia in the European population. However, we found that an indirect effect of LTL on ALS might be mediated by low density lipoprotein (LDL) or total cholesterol (TC) in the European population. These results were robust against extensive sensitivity analyses. Overall, our MR study did not support the direct causal association between LTL and the ALS risk in neither population, but provided suggestive evidence for the mediation role of LDL or TC on the influence of LTL and ALS in the European population. © 2020, The Author(s).

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

"Applying dimensional psychopathology: transdiagnostic associations among regional homogeneity, leptin and depressive symptoms" (2020) Translational Psychiatry

Applying dimensional psychopathology: transdiagnostic associations among regional homogeneity, leptin and depressive symptoms
(2020) Translational Psychiatry, 10 (1), art. no. 248, .

Wei, Y.-G.^a ^b ^c , Duan, J.^a ^c , Womer, F.Y.^d , Zhu, Y.^a ^c , Yin, Z.^a ^c , Cui, L.^a ^e , Li, C.^a ^e , Liu, Z.^a ^f , Wei, S.^a ^e , Jiang, X.^a ^e , Zhang, Y.^g , Zhang, X.^h ⁱ , Tang, Y.^a ^c ^j , Wang, F.^a ^c ^e

^a Brain Function Research Section, the First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, China
^b Henan Key Laboratory of Immunology and Targeted Drugs, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, Henan 453003, China
^c Department of Psychiatry, the First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, China
^d Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63130, United States
^e Department of Radiology, the First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, China
^f School of Public Health, China Medical University, Shenyang, Liaoning 110001, China
^g Department of Psychiatry, College of Medicine University of Saskatchewan, Ellis Hall, Royal University Hospital, Saskatoon, SK S7N 0W8, Canada
^h Affiliated Nanjing Brain Hospital, Nanjing Medical University, Nanjing, Jiangsu 210029, China
ⁱ School of Biomedical Engineering and Informatics, Nanjing Medical University, Nanjing, Jiangsu 211166, China
^j Department of Geriatrics, the First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, China

Abstract
Dimensional psychopathology and its neurobiological underpinnings could provide important insights into major psychiatric disorders, including major depressive disorder, bipolar disorder and schizophrenia. In a dimensional transdiagnostic approach, we examined depressive symptoms and their relationships with regional homogeneity and leptin across major psychiatric disorders. A total of 728 participants (including 403 patients with major psychiatric disorders and 325 age–gender-matched healthy controls) underwent resting-state functional magnetic resonance imaging at a single site. We obtained plasma leptin levels and depressive symptom measures (Hamilton Depression Rating Scale (HAMD)) within 24 h of scanning and compared the regional homogeneity (ReHo), plasma leptin levels and HAMD total score and factor scores between patients and healthy controls. To reveal the potential relationships, we performed correlational and mediational analyses. Patients with major psychiatric disorders had significant lower ReHo in primary sensory and visual association cortices and higher ReHo in the frontal cortex and angular gyrus; plasma leptin levels were also elevated. Furthermore, ReHo alterations, leptin and HAMD factor scores had significant correlations. We also found that leptin mediated the transdiagnostic relationships among ReHo alterations in primary somatosensory and visual association cortices, core depressive symptoms and body mass index. The transdiagnostic associations we demonstrated support the common neuroanatomical substrates and neurobiological mechanisms. Moreover, leptin could be an important association among ReHo, core depressive symptoms and body mass index, suggesting a potential therapeutic target for dimensional depressive symptoms across major psychiatric disorders. © 2020, The Author(s).

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

"A telescope GWAS analysis strategy, based on SNPs-genes-pathways ensamble and on multivariate algorithms, to characterize late onset Alzheimer’s disease" (2020) Scientific Reports

A telescope GWAS analysis strategy, based on SNPs-genes-pathways ensamble and on multivariate algorithms, to characterize late onset Alzheimer’s disease
(2020) Scientific Reports, 10 (1), art. no. 12063, .

Squillario, M.^a , Abate, G.^b , Tomasi, F.^a , Tozzo, V.^a , Barla, A.^a , Uberti, D.^b , Weiner, M.W.^c , Aisen, P.^d , Petersen, R.^e , Clifford, J.R., Jr.^e , Jagust, W.^f , Trojanowki, J.Q.^g , Toga, A.W.^h , Beckett, L.ⁱ , Green, R.C.^j , Saykin, A.J.^k , Morris, J.^l , Shaw, L.M.^g , Khachaturian, Z.^m , Sorensen, G.ⁿ , Carrillo, M.^o , Kuller, L.^p , Raichle, M.^l , Paul, S.^q , Davies, P.^r , Fillit, H.^s , Hefti, F.^t , Holtzman, D.^l , Mesulam, M.M.^u , Potter, W.^v , Snyder, P.^w , Montine, T.^x , Thomas, R.G.^d , Donohue, M.^d , Walter, S.^d , Sather, T.^d , Jiminez, G.^d , Balasubramanian, A.B.^d , Mason, J.^d , Sim, I.^d , Harvey, D.ⁱ , Bernstein, M.^e , Fox, N.^y , Thompson, P.^z , Schuff, N.^c , DeCarli, C.ⁱ , Borowski, B.^e , Gunter, J.^e , Senjem, M.^e , Vemuri, P.^e , Jones, D.^e , Kantarci, K.^e , Ward, C.^e , Koeppe, R.A.^aa , Foster, N.^ab , Reiman, E.M.^ac , Chen, K.^ac , Mathis, C.^p , Landau, S.^f , Cairns, N.J.^l , Householder, E.^l , Taylor-Reinwald, L.^l , Lee, V.^z , Korecka, M.^z , Figurski, M.^z , Crawford, K.^h , Neu, S.^h , Foroud, T.M.^k , Potkin, S.^ad , Shen, L.^k , Faber, K.^k , Kim, S.^k , Tha, L.ⁿ , Frank, R.^af , Hsiao, J.^ag , Kaye, J.^ah , Quinn, J.^ah , Silbert, L.^ah , Lind, B.^ah , Carter, R.^ah , Dolen, S.^ah , Ances, B.^l , Carroll, M.^l , Creech, M.L.^l , Franklin, E.^l , Mintun, M.A.^l , Schneider, S.^l , Oliver, A.^l , Schneider, L.S.^l , Pawluczyk, S.^h , Beccera, M.^h , Teodoro, L.^h , Spann, B.M.^h , Brewer, J.^d , Vanderswag, H.^d , Fleisher, A.^d , Marson, D.^ai , Griffith, R.^ai , Clark, D.^ai , Geldmacher, D.^ai , Brockington, J.^ai , Roberson, E.^ai , Love, M.N.^ae , Heidebrink, J.L.^f , Lord, J.L.^f , Mason, S.S.^e , Albers, C.S.^e , Knopman, D.^e , Johnson, K.^e , Grossman, H.^af , Mitsis, E.^aj , Shah, R.C.^ak , de Toledo-Morrell, L.^ak , Doody, R.S.^al , Villanueva-Meyer, J.^al , Chowdhury, M.^al , Rountree, S.^al , Dang, M.^al , Duara, R.^am , Varon, D.^am , Greig, M.T.^am , Roberts, P.^am , Stern, Y.^an , Honig, L.S.^an , Bell, K.L.^an , Albert, M.^ae , Onyike, C.^ae , D’Agostino, D., II^ae , Kielb, S.^ae , Galvin, J.E.^ao , Cerbone, B.^ao , Michel, C.A.^ao , Pogorelec, D.M.^ao , Rusinek, H.^ao , de Leon, M.J.^ao , Glodzik, L.^ao , De Santi, S.^ao , Womack, K.^ap , Mathews, D.^ap , Quiceno, M.^ap , Doraiswamy, P.M.^aq , Petrella, J.R.^aq , Borges-Neto, S.^aq , Wong, T.Z.^aq , Coleman, E.^aq , Levey, A.I.^ar , Lah, J.J.^ar , Cella, J.S.^ar , Burns, J.M.^as , Swerdlow, R.H.^as , Brooks, W.M.^as , Arnold, S.E.^g , Karlawish, J.H.^g , Wolk, D.^g , Clark, C.M.^g , Apostolova, L.^z , Tingus, K.^z , Woo, E.^z , Silverman, D.H.S.^z , Lu, P.H.^z , Bartzokis, G.^z , Smith, C.D.^at , Jicha, G.^at , Hardy, P.^at , Sinha, P.^at , Oates, E.^at , Conrad, G.^at , Graff-Radford, N.R.^au , Parfitt, F.^au , Kendall, T.^au , Johnson, H.^au , Lopez, O.L.^p , Oakley, M.A.^p , Simpson, D.M.^p , Farlow, M.R.^k , Hake, A.M.^k , Matthews, B.R.^k , Brosch, J.R.^k , Herring, S.^k , Hunt, C.^k , Porsteinsson, A.P.^av , Goldstein, B.S.^av , Martin, K.^av , Makino, K.M.^av , Ismail, M.S.^av , Brand, C.^av , Mulnard, R.A.^av , Thai, G.^av , Mc-Adams-Ortiz, C.^av , van Dyck, C.H.^aw , Carson, R.E.^aw , MacAvoy, M.G.^aw , Varma, P.^aw , Chertkow, H.^ax , Bergman, H.^ax , Hosein, C.^ax , Black, S.^ay , Stefanovic, B.^ay , Caldwell, C.^ay , Hsiung, G.-Y.R.^az , Feldman, H.^az , Mudge, B.^az , Assaly, M.^az , Finger, E.^ba , Pasternack, S.^ba , Rachisky, I.^ba , Trost, D.^ba , Kertesz, A.^ba , Bernick, C.^bb , Munic, D.^bb , Lipowski, K.^u , Weintraub, M.^u , Bonakdarpour, B.^u , Kerwin, D.^u , Wu, C.-K.^u , Johnson, N.^u , Sadowsky, C.^bc , Villena, T.^bc , Turner, R.S.^bd , Johnson, K.^bd , Reynolds, B.^bd , Sperling, R.A.^j , Johnson, K.A.^j , Marshall, G.^j , Yesavage, J.^be , Taylor, J.L.^be , Lane, B.^be , Rosen, A.^be , Tinklenberg, J.^be , Sabbagh, M.N.^ac , Belden, C.M.^ac , Jacobson, S.A.^ac , Sirrel, S.A.^ac , Kowall, N.^bf , Killiany, R.^bf , Budson, A.E.^bf , Norbash, A.^bf , Johnson, P.L.^bf , Obisesan, T.O.^bg , Wolday, S.^bg , Allard, J.^bg , Lerner, A.^bh , Ogrocki, P.^bh , Tatsuoka, C.^bh , Fatica, P.^bh , Fletcher, E.ⁱ , Maillard, P.ⁱ , Olichney, J.ⁱ , Carmichael, O.ⁱ , Kittur, S.^bi , Borrie, M.^bj , Lee, T.-Y.^bj , Bartha, R.^bj , Johnson, S.^bj , Asthana, S.^bj , Carlsson, C.M.^bj , Preda, A.^ad , Nguyen, D.^ad , Tariot, P.^ac , Burke, A.^ac , Trncic, N.^ac , Fleisher, A.^ac , Reeder, S.^ac , Bates, V.^bk , Capote, H.^bk , Rainka, M.^bk , Scharre, D.W.^bl , Kataki, M.^bl , Adeli, A.^bl , Zimmerman, E.A.^bm , Celmins, D.^bm , Brown, A.D.^bm , Pearlson, G.D.^bn , Blank, K.^bn , Anderson, K.^bn , Flashman, L.A.^bo , Seltzer, M.^bo , Hynes, M.L.^bo , Santulli, R.B.^bo , Sink, K.M.^bp , Gordineer, L.^bp , Williamson, J.D.^bp , Garg, P.^bp , Watkins, F.^bp , Ott, B.R.^w , Querfurth, H.^w , Tremont, G.^w , Salloway, S.^w , Malloy, P.^w , Correia, S.^w , Rosen, H.J.^c , Miller, B.L.^c , Perry, D.^c , Mintzer, J.^bq , Spicer, K.^bq , Bachman, D.^bq , Finger, E.^ba , Pasternak, S.^ba , Rachinsky, I.^ba , Rogers, J.^bj , Drost, D.^bj , Pomara, N.^br , Hernando, R.^br , Sarrael, A.^br , Schultz, S.K.^bs , Ponto, L.L.B.^bs , Shim, H.^bs , Smith, K.E.^bs , Relkin, N.^q , Chaing, G.^q , Lin, M.^q , Ravdin, L.^q , Smith, A.^bt , Raj, B.A.^bt , Fargher, K.^bt , The Alzheimer’s Disease Neuroimaging Initiative^bu

^a DIBRIS, University of Genoa, Genoa, 16146, Italy
^b Department of Molecular and Translational Medicine, University of Brescia, Brescia, 25123, Italy
^c UC San Francisco, San Francisco, CA 94107, United States
^d UC San Diego, La Jolla, CA 92093, United States
^e Mayo Clinic, Rochester, MN, United States
^f UC Berkeley, Berkeley, San Francisco, United States
^g University of Pennsylvania, Philadelphia, PA 19104, United States
^h USC, Los Angeles, CA 90032, United States
ⁱ UC Davis, Sacramento, CA, United States
^j 10Brigham and Women’s Hospital/Harvard Medical School, Boston, MA 02215, United States
^k Indiana University, Bloomington, IN 47405, United States
^l Washington University St. Louis, St. Louis, MO 63110, United States
^m Prevent Alzheimer’s Disease 2020, Rockville, MD 20850, United States
ⁿ Siemens, Erlangen, Germany
^o Alzheimer’s Association, Chicago, IL 60631, United States
^p University of Pittsburg, Pittsburgh, PA 15213, United States
^q Cornell University, Ithaca, NY 14853, United States
^r Albert Einstein College of Medicine of Yeshiva University, Bronx, NY 10461, United States
^s AD Drug Discovery Foundation, New York, NY 10019, United States
^t Acumen Pharmaceuticals, Livermore, CA 94551, United States
^u Northwestern University, Chicago, IL 60611, United States
^v National Institute of Mental Health, Bethesda, MD 20892, United States
^w Brown University, Providence, RI 02912, United States
^x University of Washington, Seattle, WA 98195, United States
^y University of London, London, United Kingdom
^z UCLA, Torrance, CA 90509, United States
^aa University of Michigan, Ann Arbor, MI 48109-2800, United States
^ab University of Utah, Salt Lake City, UT 84112, United States
^ac Banner Alzheimer’s Institute, Phoenix, AZ 85006, United States
^ad UUC Irvine, Orange, CA 92868, United States
^ae Johns Hopkins University, Baltimore, MD 21205, United States
^af Richard Frank Consulting, Consulting, United States
^ag National Institute on Aging, Baltimore, MD, United States
^ah Oregon Health and Science University, Portland, OR 97239, United States
^ai University of Alabama, Birmingham, AL, United States
^aj Mount Sinai School of Medicine, New York, NY, United States
^ak Rush University Medical Center, Chicago, IL 60612, United States
^al Baylor College of Medicine, Houston, TX, United States
^am Wien Center, Miami Beach, FL 33140, United States
^an Columbia University Medical Center, New York, NY, United States
^ao New York University, New York, NY, United States
^ap University of Texas Southwestern Medical School, Galveston, TX 77555, United States
^aq Duke University Medical Center, Durham, NC, United States
^ar Emory University, Atlanta, GA 30307, United States
^as University of Kansas Medical Center, Kansas City, KS, United States
^at University of Kentucky, Lexington, KY, United States
^au Mayo Clinic, Jacksonville, FL, United States
^av University of Rochester Medical Center, Rochester, NY 14642, United States
^aw Yale University School of Medicine, New Haven, CT, United States
^ax McGill Univ. Montreal-Jewish General Hospital, Montreal, PQ H3A 2A7, Canada
^ay Sunnybrook Health Sciences, Toronto, ON, Canada
^az U.B.C. Clinic for AD & Related Disorders, Vancouver, BC, Canada
^ba Cognitive Neurology-St. Joseph’s, London, ON, Canada
^bb Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, NV 89106, United States
^bc Premiere Research Inst (Palm Beach Neurology), West Palm Beach, FL, United States
^bd Georgetown University Medical Center, Washington, DC 20007, United States
^be Stanford University, Stanford, CA 94305, United States
^bf Boston University, Boston, MA, United States
^bg Howard University, Washington, DC 20059, United States
^bh Case Western Reserve University, Cleveland, OH 44106, United States
^bi Neurological Care of CNY, Liverpool, NY 13088, United States
^bj St. Joseph’s Health Care, London, ON N6A 4H1, Canada
^bk Dent Neurologic Institute, Amherst, NY 14226, United States
^bl Ohio State University, Columbus, OH 43210, United States
^bm Albany Medical College, Albany, NY 12208, United States
^bn Hartford Hospital Olin Neuropsychiatry Research Center, Hartford, CT 06114, United States
^bo Dartmouth-Hitchcock Medical Center, Lebanon, NH, United States
^bp Wake Forest University Health Sciences, Winston-Salem, NC, United States
^bq Medical University South Carolina, Charleston, SC 29425, United States
^br Nathan Kline Institute, Orangeburg, NY, United States
^bs University of Iowa College of Medicine, Iowa City, IA 52242, United States
^bt University of South Florida: USF Health Byrd Alzheimer’s Institute, Tampa, FL 33613, United States

Abstract
Genome–wide association studies (GWAS) have revealed a plethora of putative susceptibility genes for Alzheimer’s disease (AD), with the sole exception of APOE gene unequivocally validated in independent study. Considering that the etiology of complex diseases like AD could depend on functional multiple genes interaction network, here we proposed an alternative GWAS analysis strategy based on (i) multivariate methods and on a (ii) telescope approach, in order to guarantee the identification of correlated variables, and reveal their connections at three biological connected levels. Specifically as multivariate methods, we employed two machine learning algorithms and a genetic association test and we considered SNPs, Genes and Pathways features in the analysis of two public GWAS dataset (ADNI-1 and ADNI-2). For each dataset and for each feature we addressed two binary classifications tasks: cases vs. controls and the low vs. high risk of developing AD considering the allelic status of APOEe4. This complex strategy allowed the identification of SNPs, genes and pathways lists statistically robust and meaningful from the biological viewpoint. Among the results, we confirm the involvement of TOMM40 gene in AD and we propose GRM7 as a novel gene significantly associated with AD. © 2020, The Author(s).

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

"Predicting dysfunctional age-related task activations from resting-state network alterations" (2020) NeuroImage

Predicting dysfunctional age-related task activations from resting-state network alterations
(2020) NeuroImage, 221, art. no. 117167, .

Mill, R.D.^a , Gordon, B.A.^b , Balota, D.A.^c , Cole, M.W.^a

^a Center for Molecular and Behavioral Neuroscience, Rutgers University, 197 University Avenue, Newark, NJ 07102, United States
^b Department of Radiology, Washington University in St Louis, St Louis, MO 63110, United States
^c Department of Psychological and Brain Sciences, Washington University in St Louis, St Louis, MO 63130, United States

Abstract
Alzheimer’s disease (AD) is linked to changes in fMRI task activations and fMRI resting-state functional connectivity (restFC), which can emerge early in the illness timecourse. These fMRI correlates of unhealthy aging have been studied in largely separate subfields. Taking inspiration from neural network simulations, we propose a unifying mechanism wherein restFC alterations associated with AD disrupt the flow of activations between brain regions, leading to aberrant task activations. We apply this activity flow model in a large sample of clinically normal older adults, which was segregated into healthy (low-risk) and at-risk subgroups based on established imaging (positron emission tomography amyloid) and genetic (apolipoprotein) AD risk factors. Modeling the flow of healthy activations over at-risk AD connectivity effectively transformed the healthy aged activations into unhealthy (at-risk) aged activations. This enabled reliable prediction of at-risk AD task activations, and these predicted activations were related to individual differences in task behavior. These results support activity flow over altered intrinsic functional connections as a mechanism underlying Alzheimer’s-related dysfunction, even in very early stages of the illness. Beyond these mechanistic insights, this approach raises clinical potential by enabling prediction of task activations and associated cognitive dysfunction in individuals without requiring them to perform in-scanner cognitive tasks. © 2020 The Author(s)

Author Keywords
Aging; Alzheimer’s; fMRI; Functional connectivity; Task activation

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

"Brain Function Differences in Children With Type 1 Diabetes: A Functional MRI Study of Working Memory" (2020) Diabetes

Brain Function Differences in Children With Type 1 Diabetes: A Functional MRI Study of Working Memory
(2020) Diabetes, 69 (8), pp. 1770-1778.

Foland-Ross, L.C.^a , Tong, G.^b , Mauras, N.^c , Cato, A.^d , Aye, T.^e , Tansey, M.^f , White, N.H.^g , Weinzimer, S.A.^h , Englert, K.^c , Shen, H.^b , Mazaika, P.K.^b , Reiss, A.L.ⁱ , Diabetes Research in Children Network (DirecNet)^j

^a Center for Interdisciplinary Brain Sciences Research, Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA lfolandross@stanford.edu
^b Center for Interdisciplinary Brain Sciences Research, Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA
^c Division of Endocrinology, Diabetes and Metabolism, Nemours Children’s Health System, FL, Jacksonville, United States
^d Division of Neurology, Nemours Children’s Health System, FL, Jacksonville, United States
^e Department of Pediatrics, Stanford University School of Medicine, Stanford, CA
^f Department of Pediatrics, University of Iowa, IA, Iowa City, United States
^g Department of Pediatrics, Washington University in St. Louis and the St. Louis Children’s Hospital, St. Louis, MO
^h Pediatric Endocrinology, Yale University, CT, New Haven, United States

Abstract
Glucose is a primary fuel source to the brain, yet the influence of dysglycemia on neurodevelopment in children with type 1 diabetes remains unclear. We examined brain activation using functional MRI in 80 children with type 1 diabetes (mean ± SD age 11.5 ± 1.8 years; 46% female) and 47 children without diabetes (control group) (age 11.8 ± 1.5 years; 51% female) as they performed a visuospatial working memory (N-back) task. Results indicated that in both groups, activation scaled positively with increasing working memory load across many areas, including the frontoparietal cortex, caudate, and cerebellum. Between groups, children with diabetes exhibited reduced performance on the N-back task relative to children in the control group, as well as greater modulation of activation (i.e., showed greater increase in activation with higher working memory load). Post hoc analyses indicated that greater modulation was associated in the diabetes group with better working memory function and with an earlier age of diagnosis. These findings suggest that increased modulation may occur as a compensatory mechanism, helping in part to preserve working memory ability, and further, that children with an earlier onset require additional compensation. Future studies that test whether these patterns change as a function of improved glycemic control are warranted. © 2020 by the American Diabetes Association.

Document Type: Article
Publication Stage: Final
Source: Scopus

"A Position Paper on Systematic and Meta-analysis Reviews" (2020) Otology & Neurotology : Official Publication of the American Otological Society, American Neurotology Society and European Academy of Otology and Neurotology

A Position Paper on Systematic and Meta-analysis Reviews
(2020) Otology & Neurotology : Official Publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology, 41 (7), pp. 879-882.

McRackan, T.R.^a , Kaylie, D.M.^b , Wick, C.C.^c , Bush, M.L.^d

^a Department of Otolaryngology-Head and Neck Surgery, Medical University of South Carolina, Charleston, SC, United States
^b Department of Otolaryngology-Head and Neck Surgery, Duke University, Durham, NC
^c Department of Otolaryngology-Head and Neck Surgery, Washington University, St. Louis, MO, United States
^d Department of Otolaryngology-Head and Neck Surgery, University of Kentucky, Lexington, KY, United States

Document Type: Article
Publication Stage: Final
Source: Scopus

"Painful Myoclonus Triggered by Lateral Antebrachial Cutaneous Nerve Entrapment at the Brachioradialis Muscle" (2020) American Journal of Physical Medicine & Rehabilitation

Painful Myoclonus Triggered by Lateral Antebrachial Cutaneous Nerve Entrapment at the Brachioradialis Muscle
(2020) American Journal of Physical Medicine & Rehabilitation, 99 (8), pp. e94-e96.

Aktas, A., Prather, H., Brogan, D., Colorado, D.

From the Department of Neurology, Washington University School of Medicine, St. Louis, Missouri (AA); Division of Physical Medicine and Rehabilitation, Department of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, Missouri (HP, DC); and Division of Hand Surgery, Department of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, Missouri (DB)

Abstract
Compression of the lateral antebrachial cutaneous nerve is a rare clinical entrapment syndrome often overlooked as an initial etiology of pain. We present a case of an episodic upper limb painful movement disorder (myoclonus) in a 16-yr-old adolescent girl with a remote history of a surgically stabilized supracondylar humeral fracture who was later found to have entrapment of the lateral antebrachial cutaneous nerve. The incidence of a painful myoclonus triggered by a peripheral nerve entrapment is unknown. Combining a history and physical examination, electromyography, nerve conduction studies, and ultrasound enabled us to make an accurate diagnosis that was confirmed by resolution of symptoms after surgical release. This study conforms to all CARE guidelines and reports the required information accordingly (see Supplemental Check list, Supplemental Digital Content 1, http://links.lww.com/PHM/A855).

Document Type: Article
Publication Stage: Final
Source: Scopus

"The Lymphatic Vasculature in the 21st Century: Novel Functional Roles in Homeostasis and Disease" (2020) Cell

The Lymphatic Vasculature in the 21st Century: Novel Functional Roles in Homeostasis and Disease
(2020) Cell, 182 (2), pp. 270-296.

Oliver, G.^a , Kipnis, J.^b ^c , Randolph, G.J.^d , Harvey, N.L.^e

^a Center for Vascular and Developmental Biology, Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, United States
^b Center for Brain Immunology and Glia (BIG), University of Virginia, Charlottesville, VA 22908, United States
^c Department of Neuroscience, University of Virginia, Charlottesville, VA 22908, United States
^d Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, United States
^e Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA, Australia

Abstract
Oliver et al. comprehensively review the anatomy, development, and functional roles of the lymphatic vasculature in health and disease. They highlight emerging evidence suggesting that the lymphatic system plays more diverse physiological roles that previously appreciated. © 2020 Elsevier Inc.

Mammals have two specialized vascular circulatory systems: the blood vasculature and the lymphatic vasculature. The lymphatic vasculature is a unidirectional conduit that returns filtered interstitial arterial fluid and tissue metabolites to the blood circulation. It also plays major roles in immune cell trafficking and lipid absorption. As we discuss in this review, the molecular characterization of lymphatic vascular development and our understanding of this vasculature’s role in pathophysiological conditions has greatly improved in recent years, changing conventional views about the roles of the lymphatic vasculature in health and disease. Morphological or functional defects in the lymphatic vasculature have now been uncovered in several pathological conditions. We propose that subtle asymptomatic alterations in lymphatic vascular function could underlie the variability seen in the body’s response to a wide range of human diseases. © 2020 Elsevier Inc.

Author Keywords
Alzheimer’s; cardiovascular; Crohn’s disease; glaucoma; immunity; inflammation; lymphatic function; lymphatic vasculature; Lymphatics; lymphedema; myocardial infarction; neurological disease; obesity; Parkinson’s; tumors

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

"When development is at stake: Fear the disease, not the vaccine" (2020) Neurology

When development is at stake: Fear the disease, not the vaccine
(2020) Neurology, 95 (3), pp. 103-104.

Joshi, C., Thio, L.L.

From the University of Colorado (C.J.), Children’s Hospital Colorado, Aurora; and Washington University at St. Louis (L.L.T.), MO

Document Type: Editorial
Publication Stage: Final
Source: Scopus

"Preterm intraventricular hemorrhage in vitro: Modeling the cytopathology of the ventricular zone" (2020) Fluids and Barriers of the CNS

Preterm intraventricular hemorrhage in vitro: Modeling the cytopathology of the ventricular zone
(2020) Fluids and Barriers of the CNS, 17 (1), art. no. 46, .

Castaneyra-Ruiz, L.^a , McAllister, J.P., II^a , Morales, D.M.^a , Brody, S.L.^b , Isaacs, A.M.^c , Limbrick, D.D., Jr.^a ^d

^a Department of Neurological Surgery, Washington University School of Medicine, St. Louis Children’s Hospital, 660 South Euclid Ave., St. Louis, MO 63110, United States
^b Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, United States
^c Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, United States
^d Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
Background: Severe intraventricular hemorrhage (IVH) is one of the most devastating neurological complications in preterm infants, with the majority suffering long-term neurological morbidity and up to 50% developing post-hemorrhagic hydrocephalus (PHH). Despite the importance of this disease, its cytopathological mechanisms are not well known. An in vitro model of IVH is required to investigate the effects of blood and its components on the developing ventricular zone (VZ) and its stem cell niche. To address this need, we developed a protocol from our accepted in vitro model to mimic the cytopathological conditions of IVH in the preterm infant. Methods: Maturing neuroepithelial cells from the VZ were harvested from the entire lateral ventricles of wild type C57BL/6 mice at 1-4 days of age and expanded in proliferation media for 3-5 days. At confluence, cells were re-plated onto 24-well plates in differentiation media to generate ependymal cells (EC). At approximately 3-5 days, which corresponded to the onset of EC differentiation based on the appearance of multiciliated cells, phosphate-buffered saline for controls or syngeneic whole blood for IVH was added to the EC surface. The cells were examined for the expression of EC markers of differentiation and maturation to qualitatively and quantitatively assess the effect of blood exposure on VZ transition from neuroepithelial cells to EC. Discussion: This protocol will allow investigators to test cytopathological mechanisms contributing to the pathology of IVH with high temporal resolution and query the impact of injury to the maturation of the VZ. This technique recapitulates features of normal maturation of the VZ in vitro, offering the capacity to investigate the developmental features of VZ biogenesis. © 2020 The Author(s).

Author Keywords
Cell culture; Ependyma; Intraventricular hemorrhage; Neonate; Neural stem cells; Post- hemorrhagic hydrocephalus; Premature; Preterm; Ventricular zone

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

"Characterization of a multicenter pediatric-hydrocephalus shunt biobank" (2020) Fluids and Barriers of the CNS

Characterization of a multicenter pediatric-hydrocephalus shunt biobank
(2020) Fluids and Barriers of the CNS, 17 (1), p. 45.

Gluski, J.^a , Zajciw, P.^b , Hariharan, P.^b , Morgan, A.^c , Morales, D.M.^c , Jea, A.^d , Whitehead, W.^e , Marupudi, N.^f , Ham, S.^f , Sood, S.^f , McAllister, J.P., 2nd^c , Limbrick, D.D., Jr^c , Harris, C.A.^b

^a Wayne State University School of Medicine, MI, 540 E. Canfield Avenue, Detroit, 48201, United States
^b Wayne State University Dept. of Chemical Engineering and Materials Science, Rm 1413, MI, 6135 Woodward Avenue, Detroit, 48202, United States
^c Washington University School of Medicine Dept. of Neurological Surgery, 660 S. Euclid Avenue, St. Louis, MO, 63110, USA
^d Riley Hospital for Children at IU Health, IN, 705 Riley Hospital Drive, Indianapolis, 46202, United States
^e Texas Children’s Hospital, Baylor College of Medicine, TX, 6701 Fannin Street, Houston, 77030, United States
^f Children’s Hospital of Michigan Dept. of Neurosurgery, MI, 3901 Beaubien Boulevard ,2nd Floor Carl’s Building, Detroit, 48201, United States

Abstract
BACKGROUND: Pediatric hydrocephalus is a devastating and costly disease. The mainstay of treatment is still surgical shunting of cerebrospinal fluid (CSF). These shunts fail at a high rate and impose a significant burden on patients, their families and society. The relationship between clinical decision making and shunt failure is poorly understood and multifaceted, but catheter occlusion remains the most frequent cause of shunt complications. In order to investigate factors that affect shunt failure, we have established the Wayne State University (WSU) shunt biobank. METHODS: To date, four hospital centers have contributed various components of failed shunts and CSF from patients diagnosed with hydrocephalus before adulthood. The hardware samples are transported in paraformaldehyde and transferred to phosphate-buffered saline with sodium azide upon deposit into the biobank. Once in the bank, they are then available for study. Informed consent is obtained by the local center before corresponding clinical data are entered into a REDCap database. Data such as hydrocephalus etiology and details of shunt revision history. All data are entered under a coded identifier. RESULTS: 293 shunt samples were collected from 228 pediatric patients starting from May 2015 to September 2019. We saw a significant difference in the number of revisions per patient between centers (Kruskal-Wallis H test, p value < 0.001). The leading etiology at all centers was post-hemorrhagic hydrocephalus, a fisher’s exact test showed there to be statistically significant differences in etiology between center (p = 0.01). Regression showed age (p < 0.01), race (p = 0.038) and hospital-center (p < 0.001) to explain significant variance in the number of revisions. Our model accounted for 31.9% of the variance in revisions. Generalized linear modeling showed hydrocephalus etiology (p < 0.001), age (p < 0.001), weight and physician (p < 0.001) to impact the number of ventricular obstructions. CONCLUSION: The retrospective analysis identified that differences exist between currently enrolled centers, although further work is needed before clinically actionable recommendations can be made. Moreover, the variables collected from this chart review explain a meaningful amount of variance in the number of revision surgeries. Future work will expand on the contribution of different site-specific and patient-specific factors to identify potential cause and effect relationships.

Author Keywords
Biobank; CSF = cerebrospinal fluid; Hydrocephalus; Improving surgical outcomes; Multicenter; Retrospective cohort; Shunt failure; Shunt obstruction; Translational; Ventriculoperitoneal shunt

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

"Disruptive Behavior in Siblings Discordant for Exposure to Maternal Smoking During Pregnancy: A Multi-rater Approach" (2020) Nicotine & Tobacco Research: Official Journal of the Society for Research on Nicotine and Tobacco

Disruptive Behavior in Siblings Discordant for Exposure to Maternal Smoking During Pregnancy: A Multi-rater Approach
(2020) Nicotine & Tobacco Research: Official Journal of the Society for Research on Nicotine and Tobacco, 22 (8), pp. 1330-1338.

Ekblad, M.O.^a ^b , Rolan, E.^a , Marceau, K.^a , Palmer, R.^c , Todorov, A.^d , Heath, A.C.^d , Knopik, V.S.^a

^a Department of Human Development and Family Studies, Purdue University, IN, West Lafayette, United States
^b Department of General Practice, Institute of Clinical Medicine, Turku University and Turku University Hospital, Turku, Finland
^c Department of Psychology, Emory University, Atlanta, United States
^d Department of Psychiatry, Midwest Alcoholism Research Center, Washington University School of Medicine, St Louis, MO

Abstract
INTRODUCTION: Maternal smoking during pregnancy (SDP) is associated with disruptive behavior. However, there is debate whether the SDP-disruptive behavior association is a potentially causal pathway or rather a spurious effect confounded by shared genetic and environmental factors. AIMS AND METHODS: The Missouri Mothers and Their Children Study is a sibling comparison study that includes families (n = 173) selected for sibling pairs (aged 7-16 years) discordant for SDP. Critically, the sibling comparison design is used to disentangle the effects of SDP from familial confounds on disruptive behavior. An SDP severity score was created for each child using a combination of SDP indicators (timing, duration, and amount of SDP). Multiple informants (parents and teachers) reported on disruptive behavior (i.e., DSM-IV semi-structured interview, the Child Behavior Checklist, and Teacher Report Form). RESULTS: The variability in disruptive behavior was primarily a function of within-family differences (66%-100%). Consistent with prior genetically informed approaches, the SDP-disruptive behavior association was primarily explained by familial confounds (genetic and environmental). However, when using a multi-rater approach (parents and teachers), results suggest a potentially causal effect of SDP on disruptive behavior (b = 0.09, SE = 0.04, p = 0.03). The potentially causal effect of SDP remained significant in sensitivity analyses. DISCUSSION: These findings suggest that familial confounding likely plays a complex role in the SDP-disruptive behavior association when examining both parent and teacher reports of behavior. Importantly, the current study highlights the importance of multiple raters, reflecting a more comprehensive measure of complex behaviors (e.g., disruptive behavior) to examine the teratogenic effects of SDP. IMPLICATIONS: Our study provides additional evidence that controlling for genetic and family factors is essential when examining the effect of SDP on later behavioral problems, as it explains a portion of the association between SDP and later behavioral problems. However, we found a significant association between SDP and disruptive behavior when using a multi-rater approach that capitalizes on both parent and teacher report, suggesting that parent and teacher ratings capture a unique perspective that is important to consider when examining SDP-behavior associations. © The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Document Type: Article
Publication Stage: Final
Source: Scopus

"Mitofusin 2 Dysfunction and Disease in Mice and Men" (2020) Frontiers in Physiology

Mitofusin 2 Dysfunction and Disease in Mice and Men
(2020) Frontiers in Physiology, 11, art. no. 782, .

Dorn, G.W., II

Center for Pharmacogenomics, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, United States

Abstract
A causal relationship between Mitofusin (MFN) 2 gene mutations and the hereditary axonal neuropathy Charcot-Marie-Tooth disease type 2A (CMT2A) was described over 15 years ago. During the intervening period much has been learned about MFN2 functioning in mitochondrial fusion, calcium signaling, and quality control, and the consequences of these MFN2 activities on cell metabolism, fitness, and development. Nevertheless, the challenge of defining the central underlying mechanism(s) linking mitochondrial abnormalities to progressive dying-back of peripheral arm and leg nerves in CMT2A is largely unmet. Here, a different perspective of why, in humans, MFN2 dysfunction preferentially impacts peripheral nerves is provided based on recent insights into its role in determining whether individual mitochondria will be fusion-competent and retained within the cell, or are fusion-impaired, sequestered, and eliminated by mitophagy. Evidence for and against a regulatory role of mitofusins in mitochondrial transport is reviewed, nagging questions defined, and implications on mitochondrial fusion, quality control, and neuronal degeneration discussed. Finally, in the context of recently described mitofusin activating peptides and small molecules, an overview is provided of potential therapeutic applications for pharmacological enhancement of mitochondrial fusion and motility in CMT2A and other neurodegenerative conditions. © Copyright © 2020 Dorn.

Author Keywords
Charcot-Marie-Tooth disease; mitochondrial fusion; mitochondrial transport; mitophagy; neurodegeneration

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

"Discovery of 6-Phenylhexanamide Derivatives as Potent Stereoselective Mitofusin Activators for the Treatment of Mitochondrial Diseases" (2020) Journal of Medicinal Chemistry

Discovery of 6-Phenylhexanamide Derivatives as Potent Stereoselective Mitofusin Activators for the Treatment of Mitochondrial Diseases
(2020) Journal of Medicinal Chemistry, 63 (13), pp. 7033-7051.

Dang, X.^a ^b , Zhang, L.^b , Franco, A.^b ^c , Li, J.^b , Rocha, A.G.^b , Devanathan, S.^c , Dolle, R.E.^c ^d , Bernstein, P.R.^e , Dorn, G.W., 2nd^b ^c

^a Department of Cardiology, First Affiliated Hospital of Xi’an Jiao Tong University, Xi’an, Shaanxi 710061, China
^b Center for Pharmacogenomics, Department of Internal Medicine, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110, United States
^c Inc. 4340 Duncan Avenue, St. Louis, MO 63110, United States
^d Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, 660 S. Euclid Ave. St. LouisMO 63110, United States
^e Harrington Discovery Institute at University Hospitals, Cleveland, OH 44106, United States

Abstract
Mutations in the mitochondrial fusion protein mitofusin (MFN) 2 cause the chronic neurodegenerative condition Charcot-Marie-Tooth disease type 2A (CMT2A), for which there is currently no treatment. Small-molecule activators of MFN1 and MFN2 enhance mitochondrial fusion and offer promise as therapy for this condition, but prototype compounds have poor pharmacokinetic properties. Herein, we describe a rational design of a series of 6-phenylhexanamide derivatives whose pharmacokinetic optimization yielded a 4-hydroxycyclohexyl analogue, 13, with the potency, selectivity, and oral bioavailability of a preclinical candidate. Studies of 13cis- and trans-4-hydroxycyclohexyl isostereomers unexpectedly revealed functionality and protein engagement exclusively for the trans form, 13B. Preclinical absorption, distribution, metabolism, and excretion (ADME) and in vivo target engagement studies of 13B support further development of 6-phenylhexanamide derivatives as therapeutic agents for human CMT2A.

Document Type: Article
Publication Stage: Final
Source: Scopus

"Interneuron Types as Attractors and Controllers" (2020) Annual Review of Neuroscience

Interneuron Types as Attractors and Controllers
(2020) Annual Review of Neuroscience, 43, pp. 1-30. Cited 4 times.

Fishell, G.^a ^b ^c , Kepecs, A.^d ^e

^a Department of Neurobiology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, United States
^b Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA 02142, United States
^c Center for Genomics and Systems Biology, New York University Abu Dhabi, Abu Dhabi, United Arab Emirates
^d Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, United States
^e Department of Neuroscience, Washington University in St. Louis, St. Louis, MO 63130, United States

Abstract
Cortical interneurons display striking differences in shape, physiology, and other attributes, challenging us to appropriately classify them. We previously suggested that interneuron types should be defined by their role in cortical processing. Here, we revisit the question of how to codify their diversity based upon their division of labor and function as controllers of cortical information flow. We suggest that developmental trajectories provide a guide for appreciating interneuron diversity and argue that subtype identity is generated using a configurational (rather than combinatorial) code of transcription factors that produce attractor states in the underlying gene regulatory network. We present our updated three-stage model for interneuron specification: An initial cardinal step, allocating interneurons into a few major classes, followed by definitive refinement, creating subclasses upon settling within the cortex, and lastly, state determination, reflecting the incorporation of interneurons into functional circuit ensembles. We close by discussing findings indicating that major interneuron classes are both evolutionarily ancient and conserved. We propose that the complexity of cortical circuits is generated by phylogenetically old interneuron types, complemented by an evolutionary increase in principal neuron diversity. This suggests that a natural neurobiological definition of interneuron types might be derived from a match between their developmental origin and computational function. © 2020 by Annual Reviews. All rights reserved.

Author Keywords
attractor network; cardinal specification; configurational code; gene regulatory network; interneuron development; transcription factors

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

"Elevated Lipase in an Infant with Altered Mental Status" (2020) Laboratory Medicine

Elevated Lipase in an Infant with Altered Mental Status
(2020) Laboratory Medicine, 51 (4), pp. e38-e41.

González, I., Roper, S.

Division of Laboratory and Genomic Medicine, Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, Missouri

Abstract
The pancreatic enzymes lipase and amylase serve important functions in digestion/absorption of fats and polysaccharides. Measurement of these enzymes is often used in the emergency department to rule out acute pancreatitis in patients with nonspecific abdominal pain. In acute pancreatitis, serial measurements of plasma lipase and amylase typically follow a predictable temporal pattern of rise-and-fall kinetics: lipase levels rise within 4 to 8 hours, crest at 2× to 50× the upper reference limit at 24 hours, and decline to normal concentrations in 7 to 14 days. In situations in which the duration and magnitude of pancreatic enzyme elevation are more transient, clinicians should consider alternative causes for enzyme elevation. In this case report, incidental discovery of elevated lipase in an African American baby girl who ingested oxycodone resulted in additional laboratory and radiological work-up. Stronger awareness of exogenous influences on gastrointestinal motility may have prevented the need for further testing in this patient. © American Society for Clinical Pathology 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Author Keywords
acute pancreatitis; amylase; lipase; opioids; Sphincter of Oddi; Sphincter of Oddi dysfunction

Document Type: Article
Publication Stage: Final
Source: Scopus

"Evaluating Circadian Dysfunction in Mouse Models of Alzheimer’s Disease: Where Do We Stand?" (2020) Frontiers in Neuroscience

Evaluating Circadian Dysfunction in Mouse Models of Alzheimer’s Disease: Where Do We Stand?
(2020) Frontiers in Neuroscience, 14, art. no. 703, .

Sheehan, P.W.^a , Musiek, E.S.^a ^b

^a Department of Neurology, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
^b Knight Alzheimer’s Disease Research Center, Washington University School of Medicine in St. Louis, St. Louis, MO, United States

Abstract
Circadian dysfunction has been described in patients with symptomatic Alzheimer’s disease (AD), as well as in presymptomatic phases of the disease. Modeling this circadian dysfunction in mouse models would provide an optimal platform for understanding mechanisms and developing therapies. While numerous studies have examined behavioral circadian function, and in some cases clock gene oscillation, in mouse models of AD, the results are variable and inconsistent across models, ages, and conditions. Ultimately, circadian changes observed in APP/PS1 models are inconsistent across studies and do not always replicate circadian phenotypes observed in human AD. Other models, including the 3xTG mouse, tau transgenic lines, and the accelerated aging SAMP8 line, show circadian phenotypes more consistent with human AD, although the literature is either inconsistent or minimal. We summarize these data and provide some recommendations to improve and standardize future studies of circadian function in AD mouse models. © Copyright © 2020 Sheehan and Musiek.

Author Keywords
Alzheimer’s disease; amyloid; circadian; clock; tau

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

"From Research to Clinical Practice: Ethical Issues with Neurotechnology and Industry Relationships" (2020) AJOB Neuroscience

From Research to Clinical Practice: Ethical Issues with Neurotechnology and Industry Relationships
(2020) AJOB Neuroscience, 11 (3), pp. 210-212.

McIntosh, T., DuBois, J.M.

Washington University School of Medicine, United States

Document Type: Note
Publication Stage: Final
Source: Scopus

"MRI signatures of brain age and disease over the lifespan based on a deep brain network and 14 468 individuals worldwide" (2020) Brain : A Journal of Neurology

MRI signatures of brain age and disease over the lifespan based on a deep brain network and 14 468 individuals worldwide
(2020) Brain : A Journal of Neurology, 143 (7), pp. 2312-2324.

Bashyam, V.M.^a , Erus, G.^a , Doshi, J.^a , Habes, M.^a ^b , Nasralah, I.^c , Truelove-Hill, M.^a , Srinivasan, D.^a , Mamourian, L.^a , Pomponio, R.^a , Fan, Y.^a , Launer, L.J.^d , Masters, C.L.^e , Maruff, P.^e , Zhuo, C.^f ^g , Völzke, H.^h ⁱ , Johnson, S.C.^j , Fripp, J.^k , Koutsouleris, N.^l , Satterthwaite, T.D.^a ^m , Wolf, D.^m , Gur, R.E.^c ^m , Gur, R.C.^c ^m , Morris, J.ⁿ , Albert, M.S.^o , Grabe, H.J.^p , Resnick, S.^q , Bryan, R.N.^r , Wolk, D.A.^b , Shou, H.^s , Davatzikos, C.^a

^a Center for Biomedical Image Computing and Analytics, Department of Radiology, University of Pennsylvania, Philadelphia, United States
^b Department of Neurology, University of Pennsylvania, Philadelphia, United States
^c Department of Radiology, University of Pennsylvania, Philadelphia, United States
^d Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Bethesda, United States
^e University of Melbourne, Florey Institute of Neuroscience and Mental Health, Melbourne, Australia
^f Tianjin Mental Health Center, Nankai University Affiliated Tianjin Anding HospitalTianjin, China
^g Department of Psychiatry, Tianjin Medical UniversityTianjin, China
^h Institute for Community Medicine, University of Greifswald, Germany
ⁱ German Centre for Cardiovascular Research, Partner Sit Greifswald, Germany
^j Wisconsin Alzheimer’s Institute, University of Wisconsin School of Medicine and Public Health, Madison, United States
^k CSIRO Health and Biosecurity, Australian e-Health Research Centre CSIRO, Melbourne, Australia
^l Department of Psychiatry and Psychotherapy, Ludwig Maximilian University of Munich, Munich, Germany
^m Department of Psychiatry, University of Pennsylvania, Philadelphia, United States
ⁿ Department of Neurology, Washington University in St. Louis, St Louis, United States
^o Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, United States
^p Department of Psychiatry and Psychotherapy, Ernst-Moritz-Arndt University, Greifswald, Mecklenburg-Vorpommern, Germany
^q Laboratory of Behavioral Neuroscience, National Institute on Aging, Bethesda, United States
^r Department of Diagnostic Medicine, University of Texas at Austin, Austin, United States
^s Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania, United States

Abstract
Deep learning has emerged as a powerful approach to constructing imaging signatures of normal brain ageing as well as of various neuropathological processes associated with brain diseases. In particular, MRI-derived brain age has been used as a comprehensive biomarker of brain health that can identify both advanced and resilient ageing individuals via deviations from typical brain ageing. Imaging signatures of various brain diseases, including schizophrenia and Alzheimer’s disease, have also been identified using machine learning. Prior efforts to derive these indices have been hampered by the need for sophisticated and not easily reproducible processing steps, by insufficiently powered or diversified samples from which typical brain ageing trajectories were derived, and by limited reproducibility across populations and MRI scanners. Herein, we develop and test a sophisticated deep brain network (DeepBrainNet) using a large (n = 11 729) set of MRI scans from a highly diversified cohort spanning different studies, scanners, ages and geographic locations around the world. Tests using both cross-validation and a separate replication cohort of 2739 individuals indicate that DeepBrainNet obtains robust brain-age estimates from these diverse datasets without the need for specialized image data preparation and processing. Furthermore, we show evidence that moderately fit brain ageing models may provide brain age estimates that are most discriminant of individuals with pathologies. This is not unexpected as tightly-fitting brain age models naturally produce brain-age estimates that offer little information beyond age, and loosely fitting models may contain a lot of noise. Our results offer some experimental evidence against commonly pursued tightly-fitting models. We show that the moderately fitting brain age models obtain significantly higher differentiation compared to tightly-fitting models in two of the four disease groups tested. Critically, we demonstrate that leveraging DeepBrainNet, along with transfer learning, allows us to construct more accurate classifiers of several brain diseases, compared to directly training classifiers on patient versus healthy control datasets or using common imaging databases such as ImageNet. We, therefore, derive a domain-specific deep network likely to reduce the need for application-specific adaptation and tuning of generic deep learning networks. We made the DeepBrainNet model freely available to the community for MRI-based evaluation of brain health in the general population and over the lifespan. © The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Author Keywords
brain age; deep learning; transfer learning

Document Type: Article
Publication Stage: Final
Source: Scopus

"Neurofilaments: neurobiological foundations for biomarker applications" (2020) Brain: A Journal of Neurology

Neurofilaments: neurobiological foundations for biomarker applications
(2020) Brain: A Journal of Neurology, 143 (7), pp. 1975-1998.

Gafson, A.R.^a , Barthélemy, N.R.^b , Bomont, P.^c , Carare, R.O.^d , Durham, H.D.^e , Julien, J.-P.^f ^g , Kuhle, J.^h , Leppert, D.^h , Nixon, R.A.ⁱ ^j ^k ^l , Weller, R.O.^d , Zetterberg, H.^m ⁿ ^o ^p , Matthews, P.M.^a ^q

^a Department of Brain Sciences, Imperial College, London, United Kingdom
^b Department of Neurology, Washington University School of Medicine, St Louis, MO, USA
^c ATIP-Avenir team, INM, INSERM, Montpellier University, Montpellier, France
^d Clinical Neurosciences, Faculty of Medicine, University of Southampton, Southampton General HospitalSouthampton, United Kingdom
^e Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Québec, Canada
^f Department of Psychiatry and Neuroscience, Laval UniversityQC, Canada
^g CERVO Brain Research Center, QC, 2601 Chemin de la CanardièreQuébec G1J 2G3, Canada
^h Neurologic Clinic and Policlinic, Departments of Medicine, Biomedicine and Clinical Research, University Hospital Basel, University of Basel, Basel, Switzerland
ⁱ Center for Dementia Research, Nathan Kline Institute, Orangeburg, NY, 10962, USA
^j Departments of Psychiatry, New York University School of Medicine, NY, NY 10016, United States
^k Neuroscience Institute, New York University School of Medicine, NY, NY 10016, United States
^l Department of Cell Biology, New York University School of Medicine, NY, NY 10016, United States
^m University College London Queen Square Institute of Neurology, London, United Kingdom
ⁿ UK Dementia Research Institute at University College London, London, United Kingdom
^o Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden
^p Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
^q UK Dementia Research Institute at Imperial College, London

Abstract
Interest in neurofilaments has risen sharply in recent years with recognition of their potential as biomarkers of brain injury or neurodegeneration in CSF and blood. This is in the context of a growing appreciation for the complexity of the neurobiology of neurofilaments, new recognition of specialized roles for neurofilaments in synapses and a developing understanding of mechanisms responsible for their turnover. Here we will review the neurobiology of neurofilament proteins, describing current understanding of their structure and function, including recently discovered evidence for their roles in synapses. We will explore emerging understanding of the mechanisms of neurofilament degradation and clearance and review new methods for future elucidation of the kinetics of their turnover in humans. Primary roles of neurofilaments in the pathogenesis of human diseases will be described. With this background, we then will review critically evidence supporting use of neurofilament concentration measures as biomarkers of neuronal injury or degeneration. Finally, we will reflect on major challenges for studies of the neurobiology of intermediate filaments with specific attention to identifying what needs to be learned for more precise use and confident interpretation of neurofilament measures as biomarkers of neurodegeneration. © The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Author Keywords
biomarkers; neurodegeneration; neurofilaments; neuroinflammation; traumatic brain injury

Document Type: Article
Publication Stage: Final
Source: Scopus

"Obex position is associated with syringomyelia and use of posterior fossa decompression among patients with Chiari I malformation" (2020) Journal of Neurosurgery: Pediatrics

Obex position is associated with syringomyelia and use of posterior fossa decompression among patients with Chiari I malformation
(2020) Journal of Neurosurgery: Pediatrics, 26 (1), pp. 45-52.

Haller, G.^a ^b , Sadler, B.^b , Kuensting, T.^b , Lakshman, N.^a , Greenberg, J.K.^a , Strahle, J.M.^a , Park, T.S.^a , Dobbs, M.B.^c ^e , Gurnett, C.A.^b ^c ^d , Limbrick, D.D., Jr^a

^a Departments of, Neurological Surgery, Washington University School of Medicine, United States
^b Departments of, Neurology, Washington University School of Medicine, United States
^c Departments of, Orthopaedic Surgery, Washington University School of Medicine, United States
^d Departments of, Pediatrics, Washington University School of Medicine, United States
^e Shriners Hospital for Children, St. Louis, MO, United States

Abstract
OBJECTIVE Chiari I malformation (CM-I) has traditionally been defined by measuring the position of the cerebellar tonsils relative to the foramen magnum. The relationships of tonsillar position to clinical presentation, syringomyelia, scoliosis, and the use of posterior fossa decompression (PFD) surgery have been studied extensively and yielded inconsistent results. Obex position has been proposed as a useful adjunctive descriptor for CM-I and may be associated with clinical disease severity. METHODS A retrospective chart review was performed of 442 CM-I patients with MRI who presented for clinical evaluation between 2003 and 2018. Clinical and radiological variables were measured for all patients, including presence/location of headaches, Chiari Severity Index (CSI) grade, tonsil position, obex position, clival canal angle, pB-C2 distance, occipitalization of the atlas, basilar invagination, syringomyelia, syrinx diameter, scoliosis, and use of PFD. Radiological measurements were then used to predict clinical characteristics using regression and survival analyses, with performing PFD, the presence of a syrinx, and scoliosis as outcome variables. RESULTS Among the radiological measurements, tonsil position, obex position, and syringomyelia were each independently associated with use of PFD. Together, obex position, tonsil position, and syringomyelia (area under the curve [AUC] 89%) or obex position and tonsil position (AUC 85.4%) were more strongly associated with use of PFD than tonsil position alone (AUC 76%) (Pdiff = 3.4 × 10−6 and 6 × 10−4, respectively) but were only slightly more associated than obex position alone (AUC 82%) (Pdiff = 0.01 and 0.18, respectively). Additionally, obex position was significantly associated with occipital headaches, CSI grade, syringomyelia, and scoliosis, independent of tonsil position. Tonsil position was associated with each of these traits when analyzed alone but did not remain significantly associated with use of PFD when included in multivariate analyses with obex position. CONCLUSIONS Compared with tonsil position alone, obex position is more strongly associated with symptomatic CM-I, as measured by presence of a syrinx, scoliosis, or use of PFD surgery. These results support the role of obex position as a useful radiological measurement to inform the evaluation and potentially the management of CM-I. ©AANS 2020

Author Keywords
Chiari I malformation; Headaches; Obex position; Posterior fossa decompression surgery; Scoliosis; Syringomyelia; Tonsil position

Document Type: Article
Publication Stage: Final
Source: Scopus

"Radiological and clinical associations with scoliosis outcomes after posterior fossa decompression in patients with Chiari malformation and syrinx from the Park-Reeves Syringomyelia Research Consortium" (2020) Journal of Neurosurgery: Pediatrics

Strahle, J.M.^a , Taiwo, R.^a , Averill, C.^a , Torner, J.^b , Gewirtz, J.I.^a , Shannon, C.N.^c , Bonfield, C.M.^c , Tuite, G.F.^d , Bethel-Anderson, T.^a , Anderson, R.C.E.^f , Kelly, M.P.^g , Shimony, J.S.^e , Dacey, R.G., Jr.^a , Smyth, M.D.^a , Park, T.S.^a , Limbrick, D.D., Jr.^a , for thePark-Reeves Syringomyelia Research Consortium^h

Radiological and clinical associations with scoliosis outcomes after posterior fossa decompression in patients with Chiari malformation and syrinx from the Park-Reeves Syringomyelia Research Consortium
(2020) Journal of Neurosurgery: Pediatrics, 26 (1), pp. 53-59.

^a Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, United States
^b Department of Epidemiology, University of Iowa, Iowa City, IA, United States
^c Department of Neurological Surgery, Vanderbilt University Medical Center, Nashville, TN, United States
^d Department of Neurosurgery, Neuroscience Institute, Johns Hopkins All Children’s Hospital, St. Petersburg, FL, United States
^e Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States
^f Department of Neurological Surgery, Columbia University College of Physicians and Surgeons, New York, NY, United States
^g Department of Orthopedic Surgery, Washington University School of Medicine, St. Louis, MO, United States

Abstract
OBJECTIVE In patients with Chiari malformation type I (CM-I) and a syrinx who also have scoliosis, clinical and radiological predictors of curve regression after posterior fossa decompression are not well known. Prior reports indicate that age younger than 10 years and a curve magnitude < 35° are favorable predictors of curve regression following surgery. The aim of this study was to determine baseline radiological factors, including craniocervical junction alignment, that might predict curve stability or improvement after posterior fossa decompression. METHODS A large multicenter retrospective and prospective registry of pediatric patients with CM-I (tonsils ≥ 5 mm below the foramen magnum) and a syrinx (≥ 3 mm in width) was reviewed for clinical and radiological characteristics of CM-I, syrinx, and scoliosis (coronal curve ≥ 10°) in patients who underwent posterior fossa decompression and who also had follow-up imaging. RESULTS Of 825 patients with CM-I and a syrinx, 251 (30.4%) were noted to have scoliosis present at the time of diagnosis. Forty-one (16.3%) of these patients underwent posterior fossa decompression and had follow-up imaging to assess for scoliosis. Twenty-three patients (56%) were female, the mean age at time of CM-I decompression was 10.0 years, and the mean follow-up duration was 1.3 years. Nine patients (22%) had stable curves, 16 (39%) showed improvement (> 5°), and 16 (39%) displayed curve progression (> 5°) during the follow-up period. Younger age at the time of decompression was associated with improvement in curve magnitude; for those with curves of ≤ 35°, 17% of patients younger than 10 years of age had curve progression compared with 64% of those 10 years of age or older (p = 0.008). There was no difference by age for those with curves > 35°. Tonsil position, baseline syrinx dimensions, and change in syrinx size were not associated with the change in curve magnitude. There was no difference in progression after surgery in patients who were also treated with a brace compared to those who were not treated with a brace for scoliosis. CONCLUSIONS In this cohort of patients with CM-I, a syrinx, and scoliosis, younger age at the time of decompression was associated with improvement in curve magnitude following surgery, especially in patients younger than 10 years of age with curves of ≤ 35°. Baseline tonsil position, syrinx dimensions, frontooccipital horn ratio, and craniocervical junction morphology were not associated with changes in curve magnitude after surgery. © AANS 2020.

Author Keywords
Chiari malformation; Posterior fossa decompression; Scoliosis; Spine; Syrinx

Document Type: Article
Publication Stage: Final
Source: Scopus

"Recruitment of African American and Non-Hispanic White Older Adults for Alzheimer Disease Research Via Traditional and Social Media: a Case Study" (2020) Journal of Cross-Cultural Gerontology

Recruitment of African American and Non-Hispanic White Older Adults for Alzheimer Disease Research Via Traditional and Social Media: a Case Study
(2020) Journal of Cross-Cultural Gerontology, .

Stout, S.H.^a ^b , Babulal, G.M.^a ^b , Johnson, A.M.^c , Williams, M.M.^d , Roe, C.M.^a ^b

^a Knight Alzheimer’s Disease Research Center, 4488 Forest Park Blvd, Saint Louis, MO 63108, United States
^b Department of Neurology, Saint Louis, MO, United States
^c Center for Clinical Studies, Washington University School of Medicine, Saint Louis, MO, United States
^d BJC Medical Group, Saint Louis, MO, United States

Abstract
The increasing prevalence of Alzheimer disease (AD), higher risk among certain ethnoracial groups, and lack of effective therapies highlights the need to recruit and enroll diverse populations in prospective, observational studies and clinical trials. However, there is little known about the effectiveness of traditional media vs. social media outreach on recruitment in aging study studies. This study retrospectively examined the effectiveness and differences in using both traditional and social media materials for the recruitment of African American (AA) versus non-Hispanic white (NHW) participants for a prospective, longitudinal study examining preclinical AD and driving outcomes. Participants needed to be at least 65 years old, drive at least an average of once weekly, own a vehicle that was manufactured in 1996 or later, and agree to cognitive testing, psychometric testing, brain magnetic resonance imaging (MRI), brain amyloid positron emission tomography (PET), and cerebrospinal fluid collection via lumbar puncture. A total of 546 individuals contacted the study coordinator by phone or email. Of those individuals, 97 enrolled and 192 were not contacted secondary to filling enrollment capacity. Sixteen participants (16.5%) were AA and the remainder were NHW. Of the 354 individuals whom the coordinator contacted back, approximately 73% declined or did not return calls. Social media was more effective with recruiting NHW participants, while traditional advertisement (newspaper) was more successful in recruiting AA participants in this urban setting. Prospective studies should balance participant burden and enrollment with a targeted, multi-tiered recruitment plan and sufficient budget to reach the population of interest. © 2020, Springer Science+Business Media, LLC, part of Springer Nature.

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

"Improvement in perioperative anesthesia documentation for fetal interventions" (2020) Paediatric Anaesthesia

Improvement in perioperative anesthesia documentation for fetal interventions
(2020) Paediatric Anaesthesia, .

Rico Mora, D.A.^a , Perez, K.M.^b , Parikh, J.M.^c , Chatterjee, D.^d , George, P.^e , O’Reilly-Shah, V.^a , Rollins, M.^f , Sinskey, J.L.^g , Patak, L.^a

^a Department of Anesthesiology and Pain Medicine, Seattle Children’s Hospital, University of Washington School of Medicine, Seattle, WA, United States
^b Department of Pediatrics, Division of Neonatology, Seattle Children’s Hospital, University of Washington School of Medicine, Seattle, WA, United States
^c Department of Anesthesia, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
^d Department of Anesthesiology, Children’s Hospital Colorado, University of Colorado School of Medicine, Aurora, CO, United States
^e Department of Anesthesiology and Pain Medicine, St. Louis Children’s Hospital, Washington University School of Medicine, St. Louis, MO, United States
^f Department of Anesthesiology, University of Utah School of Medicine, Salt Lake City, UT, United States
^g Department of Anesthesia and Perioperative Care, University of California, San Francisco, CA, United States

Author Keywords
anesthesia; anesthesiologists; anesthesiology; benchmarking; documentation; fetus; gestational age; infant; intensive care units; medical records; neonatal; neonate; neonatology; newborn; patient handoff; pregnancy

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

"Patient demographic and psychosocial characteristics associated with 30-day recall of self-reported lower urinary tract symptoms" (2020) Neurourology and Urodynamics

Patient demographic and psychosocial characteristics associated with 30-day recall of self-reported lower urinary tract symptoms
(2020) Neurourology and Urodynamics, .

Flynn, K.E.^a , Mansfield, S.A.^b , Smith, A.R.^b , Gillespie, B.W.^c , Bradley, C.S.^d , Cella, D.^e , Helmuth, M.E.^b , Lai, H.H.^f , Kirkali, Z.^g , Talaty, P.^h , Griffith, J.W.^e , Weinfurt, K.P.ⁱ

^a Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, United States
^b Arbor Research Collaborative for Health, Ann Arbor, MI, United States
^c Department of Biostatistics, University of Michigan, Ann Arbor, MI, United States
^d Department of Obstetrics and Gynecology, University of Iowa Carver College of Medicine, Iowa City, IA, United States
^e Department of Medical Social Sciences, Northwestern University, Chicago, IL, United States
^f Division of Urologic Surgery, Washington University in St Louis, St Louis, MO, United States
^g Division of Kidney, Urologic, and Hematologic Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, United States
^h NorthShore University Health System, Glenview, IL, United States
ⁱ Department of Population Health Sciences, Duke University Medical Center, Durham, NC, United States

Abstract
Aims: Measurement of self-reported lower urinary tract symptoms (LUTS) typically uses a recall period, for example, “In the past 30 days….” Compared to averaged daily reports, 30-day recall is generally unbiased, but recall bias varies by item. We examined the associations between personal characteristics (eg, age, symptom bother) and 30-day recall of LUTS using items from the Symptoms of Lower Urinary Tract Dysfunction Research Network Comprehensive Assessment of Self-reported Urinary Symptoms questionnaire. Methods: Participants (127 women and 127 men) were recruited from 6 US tertiary care sites. They completed daily assessments for 30 days and a 30-day recall assessment at the end of the study month. For each of the 18 tested items, representing 10 LUTS, the average of the participant’s daily responses was modeled as a function of their 30-day recall, the personal characteristic, and the interaction between the 30-day recall and the characteristic in separate general linear regression models, adjusted for sex. Results: Nine items representing 7 LUTS exhibited under- or overreporting (recall bias) for at least 25% of participants. Bias was associated with personal characteristics for six LUTS. Underreporting of incontinence was associated with older age, lower anxiety, and negative affect; overreporting of other LUTS was associated with, symptom bother, symptom variability, anxiety, and depression. Conclusions: We identified under- or overreporting that was associated with personal characteristics for six common LUTS. Some cues (eg, less bother and lower anxiety) were related to recall bias in an unexpected direction. Thus, providers should exercise caution when making judgments about the accuracy of a patient’s symptom recall based on patient demographic and psychosocial characteristics. © 2020 Wiley Periodicals LLC

Author Keywords
humans; lower urinary tract symptoms; measurement; mental recall; patient-reported outcomes; self-report; urination

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

"Global microRNA profiling identified miR-10b-5p as a regulator of neurofibromatosis 1 (NF1)-glioma migration" (2020) Neuropathology and Applied Neurobiology

Global microRNA profiling identified miR-10b-5p as a regulator of neurofibromatosis 1 (NF1)-glioma migration
(2020) Neuropathology and Applied Neurobiology, .

Nix, J.S.^a , Yuan, M.^a , Imada, E.L.^c , Ames, H.^d , Marchionni, L.^c , Gutmann, D.H.^e , Rodriguez, F.J.^a ^b ^c

^a Departments of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
^b Departments of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
^c Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, United States
^d Department of Pathology, University of Maryland, Baltimore, MD, United States
^e Department of Neurology, Washington University, St. Louis, MO, United States

Abstract
Aims: Neurofibromatosis 1 (NF1) is an autosomal-dominant cancer predisposition syndrome caused by loss of function alterations involving the NF1 locus on chromosome 17. The most common brain tumours encountered in affected patients are low-grade gliomas (pilocytic astrocytomas), although high-grade gliomas are also observed at increased frequency. While bi-allelic NF1 loss characterizes these tumours, previous studies have suggested noncoding RNA molecules (microRNA, miR) may have important roles in dictating glioma biology. Methods: To explore the contributions of miRs in NF1-associated gliomas, we analysed five high-grade gliomas (NF1-HGG) and five PAs (NF1-PA) using global microRNA profiling with NanoString-based microarrays followed by functional experiments with glioma cell lines. Results: miR-10b-5p, miR-135b-5p, miR-196a-5p, miR-196b-5p, miR-1247-5p and miR-320a (adjusted P < 0.05) were increased> 3-fold in NF1-HGG relative to NF1-PA tumours. In addition, miR-378b and miR-1305 were decreased 6.8- and 6-fold, respectively, whereas miR-451a was increased 2.7-fold (adjusted P < 0.05) in NF1-PAs compared to non-neoplastic NF1 patient brain specimens (n = 2). As miR-10b-5p was the microRNA overexpressed the most in NF1-high-grade glioma compared to NF1-low-grade glioma (5.76 fold), we examined its levels in glioma cell lines. miR-10b-5p levels were highest in adult glioma cell lines and lowest in paediatric low-grade glioma lines (P = 0.02). miR-10b-5p knockdown resulted in decreased invasion in NF1-deficient LN229 high-grade glioma line, whereas its overexpression in the NF1-PA derived line (JHH-NF1-PA1) led to increased invasion. There was no change in cell growth (viability and proliferation). Conclusions: These proof-of-concept experiments support a role for microRNA regulation in NF1-glioma biology. © 2020 British Neuropathological Society

Author Keywords
glioma; microRNA; miR-10b; neurofibromatosis; NF1

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