Amyloid PET scan diagnosis of Alzheimer’s disease in patients with multiple sclerosis: a scoping review study
(2023) Egyptian Journal of Radiology and Nuclear Medicine, 54 (1), art. no. 12, .
Khalafi, M.a , Rezaei Rashnoudi, A.b , Rahmani, F.c , Javanmardi, P.d , Panahi, P.e , Kiani Shahvandi, H.e , Tajik, M.b , Soleimantabar, H.f , Shirbandi, K.g
a School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
b Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
c Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, 510 South Kingshighway Boulevard, Campus Box 8131, St. Louis, MO 63110, United States
d Department of Radiologic Technology, Faculty of Paramedicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
e School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
f Department of Radiology, School of Medicine, Imam Hossein Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
g Research Center for Molecular and Cellular Imaging, Tehran University of Medical Sciences, Tehran, Iran
Abstract
Background: Multiple sclerosis (MS) is an autoimmune disease affecting the central nervous system. This study aimed to evaluate the advantages and disadvantages of a positron emission tomography (PET) scan method for diagnosing Alzheimer’s disease (AD) in MS patients with no clinical symptoms or early-onset AD. Main text: To identify potentially relevant documents, we systematically searched international databases from 2000 to 2021. We abstracted data on article characteristics, ID/country, study, design, population, type of tracer, and outcomes. The primary outcomes were mean amyloid tracer standardized uptake value relative (SUVr), AD diagnosis in MS patients, and the tracer’s uptake. Secondary outcomes were the megabecquerel amount of tracer and tracer side effects. Nine studies were finally entered into our research for review. Among the studies included, two studies used 18F-florbetaben, six of these used 11C-Pittsburgh compound B (11C-PiB), and in two studies (18)F‑florbetapir (18F-AV1451) was used for imaging. Data from 236 participants were included in this study (145 MS patients, 17 AD patients, 12 mild cognitive impairment patients, and 62 healthy controls). Conclusions: PET scan, especially florbetapir-based radio traces in helping to diagnose early AD, is imperative to use an age-specific cutoff in MS patients to support AD diagnosis. © 2023, The Author(s).
Author Keywords
Alzheimer’s disease; Amyloid PET scan; Amyloid tracer; Dementia; Multiple sclerosis; Neurodegenerative disease; Neuroimaging; Neuroinflammation
Document Type: Review
Publication Stage: Final
Source: Scopus
The impact of social isolation from COVID-19-related public health measures on cognitive function and mental health among older adults: A systematic review and meta-analysis
(2023) Ageing Research Reviews, 85, art. no. 101839, .
Prommas, P.a , Lwin, K.S.b , Chen, Y.C.b g , Hyakutake, M.c , Ghaznavi, C.a d , Sakamoto, H.b e f , Miyata, H.a e , Nomura, S.a b e
a Department of Health Policy and Management, Keio University School of Medicine, Tokyo, Japan
b Department of Global Health Policy, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
c Medical Education Center, Keio University School of Medicine, Tokyo, Japan
d Medical Education Program, Washington University School of Medicine in St Louis, Saint Louis, United States
e Tokyo Foundation for Policy Research, Tokyo, Japan
f Department of Hygiene and Public Health, Tokyo Women’s Medical University, Tokyo, Japan
g Division of Health Medical Intelligence, Human Genome Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
Abstract
We aimed to estimate the impact of social isolation on cognitive function and mental health among older adults during the two-year-and-a-half COVID-19 period. Pubmed Central, Medline, CINAHL Plus and PsychINFO were searched between March 1, 2020, and September 30, 2022. We included all studies that assessed proportions of older adults with the mean or the median with a minimum age above 60 reporting worsening cognitive function and mental health. Thirty-two studies from 18 countries met the eligibility criteria for meta-analyses. We found that the proportions of older adults with dementia who experienced worsening cognitive impairment and exacerbation or new onset of behavioral and psychological symptoms of dementia (BPSD) were approximately twice larger than that of older adults with HC experiencing SCD and worsening mental health. Stage of dementia, care options, and severity of mobility restriction measures did not yield significant differences in the number of older adults with dementia reporting worsening cognitive impairment and BPSD, while the length of isolation did for BPSD but not cognitive impairment. Our study highlights the impact of social isolation on cognitive function and mental health among older adults. Public health strategies should prioritize efforts to promote healthy lifestyles and proactive assessments. © 2023 The Authors
Author Keywords
Cognitive decline; Cognitive impairment; COVID-19; Dementia; Isolation; Mental health; Older adults
Document Type: Review
Publication Stage: Final
Source: Scopus
Amount of Pannexin 1 in Smooth Muscle Cells Regulates Sympathetic Nerve-Induced Vasoconstriction
(2023) Hypertension (Dallas, Tex. : 1979), 80 (2), pp. 416-425.
Dunaway, L.S.a , Billaud, M.b , Macal, E.a , Good, M.E.c , Medina, C.B.d e , Lorenz, U.e f , Ravichandran, K.f g , Koval, M.h i , Isakson, B.E.a j
a Robert M. Berne Cardiovascular Research Center (L.S.D., E.M., University of Virginia School of Medicine, Charlottesville, United States
b Department of Surgery, Division of Thoracic and Cardiac Surgery, Brigham and Women’s Hospital
c Molecular Cardiology Research Institute, Tufts Medical Center, Boston, United States
d Center for Cell Clearance (C.B.M.), University of Virginia School of Medicine, Charlottesville, United States
e Department of Microbiology, Immunology and Cancer Biology (C.B.M., University of Virginia School of Medicine, Charlottesville, United States
f Carter Immunology Center (U.L., University of Virginia School of Medicine, Charlottesville, United States
g Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States
h Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Medicine (M.K.), Emory University School of Medicine, Atlanta, GA, United States
i Department of Cell Biology (M.K.), Emory University School of Medicine, Atlanta, GA, United States
j Department of Molecular Physiology and Biophysics (B.E.I.), University of Virginia School of Medicine, Charlottesville, United States
Abstract
BACKGROUND: Panx1 (pannexin 1) forms high conductance channels that secrete ATP upon stimulation. The role of Panx1 in mediating constriction in response to direct sympathetic nerve stimulation is not known. Additionally, it is unknown how the expression level of Panx1 in smooth muscle cells (SMCs) influences α-adrenergic responses. We hypothesized that the amount of Panx1 in SMCs dictates the levels of sympathetic constriction and blood pressure. METHODS: To test this hypothesis, we used genetically modified mouse models enabling expression of Panx1 in vascular cells to be varied. Electrical field stimulation on isolated arteries and blood pressure were assessed. RESULTS: Genetic deletion of SMC Panx1 prevented constriction by electric field stimulation of sympathetic nerves. Conversely, overexpression of Panx1 in SMCs using a ROSA26 transgenic model increased sympathetic nerve-mediated constriction. Connexin 43 hemichannel inhibitors did not alter constriction. Next, we evaluated the effects of altered SMC Panx1 expression on blood pressure. To do this, we created mice combining a global Panx1 deletion, with ROSA26-Panx1 under the control of an inducible SMC specific Cre (Myh11). This resulted in mice that could express only human Panx1, only in SMCs. After tamoxifen, these mice had increased blood pressure that was acutely decreased by the Panx1 inhibitor spironolactone. Control mice genetically devoid of Panx1 did not respond to spironolactone. CONCLUSIONS: These data suggest Panx1 in SMCs could regulate the extent of sympathetic nerve constriction and blood pressure. The results also show the feasibility humanized Panx1-mouse models to test pharmacological candidates.
Author Keywords
blood pressure; pannexin; smooth muscle; spironolactone; sympathetic nerve
Document Type: Article
Publication Stage: Final
Source: Scopus
Polyphasic circadian neural circuits drive differential activities in multiple downstream rhythmic centers
(2023) Current Biology, 33 (2), pp. 351-363.e3.
Liang, X., Holy, T.E., Taghert, P.H.
Department of Neuroscience, Washington University in St. Louis, St. Louis, MO 63110, United States
Abstract
Circadian clocks align various behaviors such as locomotor activity, sleep/wake, feeding, and mating to times of day that are most adaptive. How rhythmic information in pacemaker circuits is translated to neuronal outputs is not well understood. Here, we used brain-wide, 24-h in vivo calcium imaging in the Drosophila brain and searched for circadian rhythmic activity among identified clusters of dopaminergic (DA) and peptidergic neurosecretory (NS) neurons. Such rhythms were widespread and imposed by the PERIOD-dependent clock activity within the ∼150-cell circadian pacemaker network. The rhythms displayed either a morning (M), evening (E), or mid-day (MD) phase. Different subgroups of circadian pacemakers imposed neural activity rhythms onto different downstream non-clock neurons. Outputs from the canonical M and E pacemakers converged to regulate DA-PPM3 and DA-PAL neurons. E pacemakers regulate the evening-active DA-PPL1 neurons. In addition to these canonical M and E oscillators, we present evidence for a third dedicated phase occurring at mid-day: the l-LNv pacemakers present the MD activity peak, and they regulate the MD-active DA-PPM1/2 neurons and three distinct NS cell types. Thus, the Drosophila circadian pacemaker network is a polyphasic rhythm generator. It presents dedicated M, E, and MD phases that are functionally transduced as neuronal outputs to organize diverse daily activity patterns in downstream circuits. © 2022 Elsevier Inc.
Author Keywords
calcium; circadian physiology; dopamine; Drosophila; GCaMP6; neuronal pacemakers; peptidergic
Funding details
National Institutes of HealthNIHR01 DP1 DA035081, R01 GM127508, R01 NS068409, R01 NS099332, R24 NS086741
Center for Cellular Imaging, Washington UniversityWUCCI
McDonnell Center for Cellular and Molecular Neurobiology, Washington University in St. Louis
Document Type: Article
Publication Stage: Final
Source: Scopus
TREM2-independent microgliosis promotes tau-mediated neurodegeneration in the presence of ApoE4
(2023) Neuron, 111 (2), pp. 202-219.e7. Cited 1 time.
Gratuze, M.a , Schlachetzki, J.C.M.b , D’Oliveira Albanus, R.c , Jain, N.a , Novotny, B.c , Brase, L.c , Rodriguez, L.a , Mansel, C.a , Kipnis, M.a , O’Brien, S.b , Pasillas, M.P.b , Lee, C.a , Manis, M.a , Colonna, M.d , Harari, O.c , Glass, C.K.b , Ulrich, J.D.a , Holtzman, D.M.a
a Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, MO 63110, United States
b Department of Cellular and Molecular Medicine, University of California, San Diego, San Diego, CA 92093, United States
c Department of Psychiatry, NeuroGenomics and Informatics Center, Hope Center for Neurological Disorders, Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, MO 63108, United States
d Department of Pathology and Immunology, Hope Center for Neurological Disorders, Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, MO 63110, United States
Abstract
In addition to tau and Aβ pathologies, inflammation plays an important role in Alzheimer’s disease (AD). Variants in APOE and TREM2 increase AD risk. ApoE4 exacerbates tau-linked neurodegeneration and inflammation in P301S tau mice and removal of microglia blocks tau-dependent neurodegeneration. Microglia adopt a heterogeneous population of transcriptomic states in response to pathology, at least some of which are dependent on TREM2. Previously, we reported that knockout (KO) of TREM2 attenuated neurodegeneration in P301S mice that express mouse Apoe. Because of the possible common pathway of ApoE and TREM2 in AD, we tested whether TREM2 KO (T2KO) would block neurodegeneration in P301S Tau mice expressing ApoE4 (TE4), similar to that observed with microglial depletion. Surprisingly, we observed exacerbated neurodegeneration and tau pathology in TE4-T2KO versus TE4 mice, despite decreased TREM2-dependent microgliosis. Our results suggest that tau pathology-dependent microgliosis, that is, TREM2-independent microgliosis, facilitates tau-mediated neurodegeneration in the presence of ApoE4. © 2022 Elsevier Inc.
Author Keywords
Alzheimer’s disease; ApoE4; microgliosis; tau pathology; tau-mediated neurodegeneration; TREM2
Funding details
4642, CDI-CORE-2015-505, CDI-CORE-2019-813, OD021629
National Institutes of HealthNIH1RF1 AG061060, R01 AG056511, RF1AG047644, RF1NS090934
National Institute on AgingNIAP01AG003991, P01AG026276, P30AG066444, P30AG10161, R01AG044546, R01AG057777, R01AG15819, R01AG17917, R01AG30146, R56AG067764, RF1AG053303, RF1AG57473, U01AD072464, U01AG072464, U01AG32984, U01AG61356
BrightFocus FoundationBFFA2020257F, S10 OD026929
JPB FoundationJPBF
Cure Alzheimer’s FundCAF
University of WashingtonUW
Alzheimer’s Disease Research Center, University of PittsburghADRC
Document Type: Article
Publication Stage: Final
Source: Scopus
Differential effects of anti-CD20 therapy on CD4 and CD8 T cells and implication of CD20-expressing CD8 T cells in MS disease activity
(2023) Proceedings of the National Academy of Sciences of the United States of America, 120 (3), pp. e2207291120.
Shinoda, K.a b , Li, R.a b , Rezk, A.a b , Mexhitaj, I.a b , Patterson, K.R.a b , Kakara, M.a b , Zuroff, L.a b , Bennett, J.L.c , von Büdingen, H.-C.d , Carruthers, R.e , Edwards, K.R.f , Fallis, R.g , Giacomini, P.S.h , Greenberg, B.M.i , Hafler, D.A.j , Ionete, C.k , Kaunzner, U.W.l , Lock, C.B.m , Longbrake, E.E.n , Pardo, G.o , Piehl, F.p q r , Weber, M.S.s t u , Ziemssen, T.v , Jacobs, D.a b , Gelfand, J.M.w x , Cross, A.H.y , Cameron, B.z , Musch, B.z , Winger, R.C.z , Jia, X.z , Harp, C.T.z , Herman, A.z , Bar-Or, A.a b aa
a Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States
b Center for Neuroinflammation and Experimental Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States
c Departments of Neurology and Ophthalmology, Programs in Neuroscience and Immunology, University of Colorado School of Medicine, Aurora, CO 80045, United States
d F. Hoffmann-La Roche, Basel, 4070, Switzerland
e Department of Medicine, University of British Columbia, Vancouver, Canada
f Multiple Sclerosis Center of Northeastern New York, Comprehensive MS Care Center Affiliated with the National MS Society, Latham, NY 12110
g Department of Neurology, Ohio State University Medical Center, Columbus, OH 43210, United States
h Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC H3A 2B4, Canada
i Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX 75390, United States
j Departments of Neurology and Immunobiology, Yale School of Medicine, CT 06510, New Haven, United States
k Department of Neurology, University of Massachusetts Medical School, Worcester, United Kingdom
l Judith Jaffe Multiple Sclerosis Center, Weill Cornell Medicine, NY, NY 10021, United States
m Department of Neurology and Neurological Sciences, Stanford University, Palo Alto, CA 94304
n Department of Neurology, Yale University, CT 06510, New Haven, United States
o Oklahoma Medical Research Foundation, Multiple Sclerosis Center of Excellence, Oklahoma City, OK 73104, United States
p Department of Clinical Neuroscience, Karolinska InstituteStockholm SE-171 76, Sweden
q Department of Neurology, Karolinska University HospitalStockholm SE-171 77, Sweden
r Neuroimmunology Unit, Center for Molecular Medicine, Karolinska University Hospital, Karolinska InstituteStockholm SE-171 77, Sweden
s Institute of Neuropathology, University Medical Center, 37075 Göttingen, Germany
t Department of Neurology, University Medical Center, 37075 Göttingen, Germany
u Fraunhofer-Institute for Translational Medicine and Pharmackology ITMP, 37075 Göttingen, Germany
v Department of Neurology, Center of Clinical Neuroscience, University Hospital Carl Gustav Carus, Technical University of Dresden, Dresden, 01307, Germany
w Weill Institute for Neurosciences, University of California, San Francisco, CA 94158
x Department of Neurology, University of California, San Francisco, CA 94158
y Department of Neurology, Washington University School of MedicineSaint Louis MO 63110, Seychelles
z Genentech, Inc., South San Francisco, CA 94080
aa Children’s Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA 19104, United States
Abstract
A small proportion of multiple sclerosis (MS) patients develop new disease activity soon after starting anti-CD20 therapy. This activity does not recur with further dosing, possibly reflecting deeper depletion of CD20-expressing cells with repeat infusions. We assessed cellular immune profiles and their association with transient disease activity following anti-CD20 initiation as a window into relapsing disease biology. Peripheral blood mononuclear cells from independent discovery and validation cohorts of MS patients initiating ocrelizumab were assessed for phenotypic and functional profiles using multiparametric flow cytometry. Pretreatment CD20-expressing T cells, especially CD20dimCD8+ T cells with a highly inflammatory and central nervous system (CNS)-homing phenotype, were significantly inversely correlated with pretreatment MRI gadolinium-lesion counts, and also predictive of early disease activity observed after anti-CD20 initiation. Direct removal of pretreatment proinflammatory CD20dimCD8+ T cells had a greater contribution to treatment-associated changes in the CD8+ T cell pool than was the case for CD4+ T cells. Early disease activity following anti-CD20 initiation was not associated with reconstituting CD20dimCD8+ T cells, which were less proinflammatory compared with pretreatment. Similarly, this disease activity did not correlate with early reconstituting B cells, which were predominantly transitional CD19+CD24highCD38high with a more anti-inflammatory profile. We provide insights into the mode-of-action of anti-CD20 and highlight a potential role for CD20dimCD8+ T cells in MS relapse biology; their strong inverse correlation with both pretreatment and early posttreatment disease activity suggests that CD20-expressing CD8+ T cells leaving the circulation (possibly to the CNS) play a particularly early role in the immune cascades involved in relapse development.
Author Keywords
anti-CD20 therapy; CD20-expressing T cells; CD20dim T cells; CD20dimCD8+ T cells; ocrelizumab
Document Type: Article
Publication Stage: Final
Source: Scopus
Thin-film optical-acoustic combiner enables high-speed wide-field multi-parametric photoacoustic microscopy in reflection mode
(2023) Optics Letters, 48 (2), pp. 195-198.
Zhong, F., Hu, S.
Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO 63130, United States
Abstract
Multi-parametric photoacoustic microscopy (PAM) is uniquely capable of simultaneous high-resolution mapping of blood oxygenation and flow in vivo. However, its speed has been limited by the dense sampling required for blood flow quantification. To overcome this limitation, we have developed a high-speed multi-parametric PAM system, which enables simultaneous acquisition of ∼500 densely sampled B-scans by superposing the rapid optical scanning across the line-shaped focus of a cylindrically focused ultrasonic transducer over the conventional mechanical scan of the optical-acoustic dual foci. A novel, to the best of our knowledge, optical-acoustic combiner (OAC) is designed and implemented to accommodate the short working distance of the transducer, enabling convenient confocal alignment of the dual foci in reflection mode. A resonant galvanometer (GM) provides stabilized high-speed large-angle scanning. This new system can continuously monitor microvascular blood oxygenation (sO2) and flow over a 4.5×3 mm2 area in the awake mouse brain with high spatial and temporal resolutions (6.9 μm and 0.3 Hz, respectively). c 2023 Optica Publishing Group. © 2023 Authors. All rights reserved.
Funding details
National Science FoundationNSF2023988
National Institute of Mental HealthNIMH099261, 120481
Document Type: Article
Publication Stage: Final
Source: Scopus
Retinopathy of prematurity: risk stratification by gestational age
(2023) Journal of Perinatology, .
Wu, T.a , Rao, R.b , Gu, H.c , Lee, A.d , Reynolds, M.d
a Division of Ophthalmology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
b Pediatrics, Washington University in St Louis, St. Louis, MO, United States
c Division of Biostatistics, Washington University in St Louis, St. Louis, MO, United States
d Department of Ophthalmology and Visual Sciences, Washington University in St Louis, St. Louis, MO, United States
Abstract
Objective: To identify gestational age (GA) specific risk factors for severe ROP (sROP). Study design: Single-center cohort stratified by GA into <24 weeks, 24–26 weeks and ≥27 weeks. Results: 132/1106 (11.9%) developed sROP. Time to full feeds was the only risk factor [HR 1.003 (1.001–1.006), p = 0.04] for infants<24 weeks GA. For infants 24–26 weeks GA, a higher GA was protective [HR 0.66 (0.51–0.85), p < 0.01], whereas steroids for bronchopulmonary dysplasia (BPD) [HR 2.21 (1.28–3.26), p < 0.01], patent ductus arteriosus (PDA) ligation [HR 1.99 (1.25–3.11), p < 0.01] and use of nitric oxide [HR 1.96 (1.11–3.30), p = 0.01] increased the hazard of sROP. Increasing birthweight was protective [HR 0.70 (0.54–0.89), p < 0.01] in infants ≥27 weeks GA. Cumulative hazard of sROP reached 1.0 by fifteen weeks for <24 weeks GA, 0.4 by twenty weeks for 24–26 weeks GA, and 0.05 by twenty weeks after birth for ≥27 weeks GA. Conclusions: Risk factors, cumulative hazard, and time to sROP vary by GA. © 2023, The Author(s), under exclusive licence to Springer Nature America, Inc.
Funding details
Research to Prevent BlindnessRPB
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Volume of subcortical brain regions in social anxiety disorder: mega-analytic results from 37 samples in the ENIGMA-Anxiety Working Group
(2023) Molecular Psychiatry, .
Groenewold, N.A.a b , Bas-Hoogendam, J.M.c d e , Amod, A.R.a , Laansma, M.A.f , Van Velzen, L.S.g , Aghajani, M.h , Hilbert, K.i , Oh, H.j , Salas, R.j k , Jackowski, A.P.l , Pan, P.M.l , Salum, G.A.m , Blair, J.R.n , Blair, K.S.o , Hirsch, J.p , Pantazatos, S.P.q r , Schneier, F.R.q r , Talati, A.q r , Roelofs, K.s , Volman, I.t , Blanco-Hinojo, L.u v , Cardoner, N.w x y , Pujol, J.u v , Beesdo-Baum, K.z , Ching, C.R.K.aa , Thomopoulos, S.I.aa , Jansen, A.ab , Kircher, T.ac , Krug, A.ac ad , Nenadić, I.ac , Stein, F.ac , Dannlowski, U.ae , Grotegerd, D.ae , Lemke, H.ae , Meinert, S.ae af , Winter, A.ae , Erb, M.ag , Kreifelts, B.ah , Gong, Q.ai aj , Lui, S.ai aj , Zhu, F.ai aj , Mwangi, B.ak , Soares, J.C.ak , Wu, M.-J.ak , Bayram, A.al , Canli, M.am , Tükel, R.an , Westenberg, P.M.d e , Heeren, A.ao , Cremers, H.R.ap , Hofmann, D.aq , Straube, T.aq , Doruyter, A.G.G.ar , Lochner, C.as , Peterburs, J.at , Van Tol, M.-J.au , Gur, R.E.av , Kaczkurkin, A.N.aw , Larsen, B.av , Satterthwaite, T.D.av , Filippi, C.A.ax , Gold, A.L.ay , Harrewijn, A.ax az , Zugman, A.ax , Bülow, R.ba , Grabe, H.J.bb bc , Völzke, H.bd , Wittfeld, K.bb bc , Böhnlein, J.ae , Dohm, K.ae , Kugel, H.be , Schrammen, E.ae , Zwanzger, P.bf bg , Leehr, E.J.ae , Sindermann, L.bh , Ball, T.M.bi , Fonzo, G.A.bj , Paulus, M.P.bk , Simmons, A.bl , Stein, M.B.bm , Klumpp, H.bn , Phan, K.L.bo , Furmark, T.bp , Månsson, K.N.T.bq , Manzouri, A.bq , Avery, S.N.br , Blackford, J.U.bs , Clauss, J.A.bt , Feola, B.br , Harper, J.C.bu , Sylvester, C.M.bu , Lueken, U.i , Veltman, D.J.bv , Winkler, A.M.ax , Jahanshad, N.aa , Pine, D.S.ax , Thompson, P.M.aa , Stein, D.J.a bw , Van der Wee, N.J.A.c e
a Neuroscience Institute, Department of Psychiatry and Mental Health, University of Cape Town, Cape Town, South Africa
b South African Medical Research Council (SA-MRC) Unit on Child and Adolescent Health, Department of Paediatrics and Child Health, Red Cross War Memorial Children’s Hospital, University of Cape Town, Cape Town, South Africa
c Department of Psychiatry, Leiden University Medical Center, Leiden, Netherlands
d Department of Developmental and Educational Psychology, Institute of Psychology, Leiden University, Leiden, Netherlands
e Leiden Institute for Brain and Cognition, Leiden, Netherlands
f Department of Anatomy & Neurosciences, Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
g Orygen & Centre for Youth Mental Health, The University of Melbourne, Melbourne, VIC, Australia
h Leiden University, Institute of Education & Child Studies, Section Forensic Family & Youth Care, Leiden, Netherlands
i Department of Psychology, Humboldt-Universität zu Berlin, Berlin, Germany
j Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, TX, United States
k Michael E DeBakey VA Medical Center, Center for Translational Research on Inflammatory Diseases, Houston, TX, United States
l LiNC, Department of Psychiatry, Federal University of São Paulo, SP, São Paulo, Brazil
m Section on Negative Affect and Social Processes, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, RS, Porto Alegre, Brazil
n Child and Adolescent Mental Health Centre, Mental Health Services, Capital Region of Denmark, Copenhagen, Denmark
o Center for Neurobehavioral Research, Boys Town National Research Hospital, Boys Town, NE, United States
p Departments of Psychiatry & Neurobiology, Yale School of Medicine, New Haven, CT, United States
q Department of Psychiatry, Columbia University Medical Center, New York, NY, United States
r New York State Psychiatric Institute, New York, NY, United States
s Donders Institute for Brain, Cognition and Behavior, Radboud University Behavioral Science Institute, Radboud University, Nijmegen, Netherlands
t Wellcome Centre for Integrative Neuroimaging Neuroimaging (WIN), Centre for Functional MRI of the Brain (FMRIB), Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, Oxford, United Kingdom
u MRI Research Unit, Department of Radiology, Hospital del Mar, Barcelona, Spain
v Centro Investigación Biomédica en Red de Salud Mental, Barcelona, CIBERSAM G21, Spain
w Department of Mental Health, University Hospital Parc Taulí-I3PT, Barcelona, Spain, Barcelona, Spain
x Department of Psychiatry and Forensic Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain
y Centro de Investigación Biomédica en Red de Salud Mental, Carlos III Health Institute, Madrid, Spain
z Behavioral Epidemiology, Institute of Clinical Psycholog and Psychotherapy, Technische Universität Dresden, Dresden, Germany
aa Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, Marina del Rey, CA, United States
ab Core-Facility Brainimaging, Faculty of Medicine, University of Marburg, Marburg, Germany
ac Department of Psychiatry, University of Marburg, Marburg, Germany
ad Department of Psychiatry, University Hospital of Bonn, Bonn, Germany
ae Institute for Translational Psychiatry, University of Münster, Münster, Germany
af Institute for Translational Neuroscience, University of Münster, Münster, Germany
ag Department of Biomedical Magnetic Resonance, University of Tübingen, Tübingen, Germany
ah Department of Psychiatry and Psychotherapy, Tübingen Center for Mental Health (TüCMH), University of Tübingen, Tübingen, Germany
ai Huaxi MR Research Center (HMRRC), Functional and Molecular Imaging Key Laboratory of Sichuan Province, Department of Radiology, West China Hospital of Sichuan University, Chengdu, China
aj Research Unit of Psychoradiology, Chinese Academy of Medical Sciences, Chengdu, China
ak Louis A. Faillace, MD, Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, TX, United States
al Department of Neuroscience, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Turkey
am Department of Physiology, Istanbul University, Istanbul, Turkey
an Department of Psychiatry, Istanbul University, Istanbul, Turkey
ao Psychological Science Research Institute, Université Catholique de Louvain, Louvain-la-Neuve, Belgium
ap Department of Clinical Psychology, University of Amsterdam, Amsterdam, Netherlands
aq Institute of Medical Psychology and Systems Neuroscience, University of Münster, Münster, Germany
ar Division of Nuclear Medicine, Stellenbosch University, Stellenbosch, South Africa
as SA-MRC Unit on Risk and Resilience in Mental Disorders, Stellenbosch University, Stellenbosch, South Africa
at Institute of Systems Medicine and Faculty of Human Medicine, MSH Medical School Hamburg, Hamburg, Germany
au Cognitive Neuroscience Center, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
av Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, United States
aw Department of Psychology, Vanderbilt University, Nashville, TN, United States
ax Emotion and Development Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, United States
ay Department of Psychiatry and Human Behavior, Brown University Warren Alpert Medical School, Providence, RI, United States
az Department of Psychology, Education and Child Studies, Erasmus University Rotterdam, Rotterdam, Netherlands
ba Institute for Diagnostic Radiology and Neuroradiology, University Medicine Greifswald, Greifswald, Germany
bb Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany
bc German Center for Neurodegenerative Diseases (DZNE), Site Rostock/Greifswald, Greifswald, Germany
bd Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany
be University Clinic for Radiology, University of Münster, Münster, Germany
bf KBO-Inn-Salzach-Klinikum, Munich, Germany
bg Department of Psychiatry and Psychotherapy, Ludwig Maximilians University of Munich, Munich, Germany
bh Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany
bi Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, United States
bj Department of Psychiatry and Behavioral Sciences, The University of Texas at Austin Dell Medical School, Austin, TX, United States
bk Laureate Institute for Brain Research, Tulsa, OK, United States
bl Department of Psychiatry, University of California, San Diego, La JollaCA, United States
bm Departments of Psychiatry & School of Public Health, University of California, San Diego, La JollaCA, United States
bn Departments of Psychology & Psychiatry, University of Illinois at Chicago, Chicago, IL, United States
bo Department of Psychiatry & Behavioral Health, the Ohio State University, Columbus, OH, United States
bp Department of Psychology, Uppsala University, Uppsala, Sweden
bq Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
br Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, TN, United States
bs Munroe-Meyer Institute, University of Nebraska Medical Center, Omaha, NE, United States
bt Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
bu Department of Psychiatry, Washington University, St. Louis, MO, United States
bv Department of Psychiatry, Amsterdam UMC location VUMC, Amsterdam, Netherlands
bw SA-MRC Unit on Risk & Resilience in Mental Disorders, University of Cape Town, Cape Town, South Africa
Abstract
There is limited convergence in neuroimaging investigations into volumes of subcortical brain regions in social anxiety disorder (SAD). The inconsistent findings may arise from variations in methodological approaches across studies, including sample selection based on age and clinical characteristics. The ENIGMA-Anxiety Working Group initiated a global mega-analysis to determine whether differences in subcortical volumes can be detected in adults and adolescents with SAD relative to healthy controls. Volumetric data from 37 international samples with 1115 SAD patients and 2775 controls were obtained from ENIGMA-standardized protocols for image segmentation and quality assurance. Linear mixed-effects analyses were adjusted for comparisons across seven subcortical regions in each hemisphere using family-wise error (FWE)-correction. Mixed-effects d effect sizes were calculated. In the full sample, SAD patients showed smaller bilateral putamen volume than controls (left: d = −0.077, pFWE = 0.037; right: d = −0.104, pFWE = 0.001), and a significant interaction between SAD and age was found for the left putamen (r = −0.034, pFWE = 0.045). Smaller bilateral putamen volumes (left: d = −0.141, pFWE < 0.001; right: d = −0.158, pFWE < 0.001) and larger bilateral pallidum volumes (left: d = 0.129, pFWE = 0.006; right: d = 0.099, pFWE = 0.046) were detected in adult SAD patients relative to controls, but no volumetric differences were apparent in adolescent SAD patients relative to controls. Comorbid anxiety disorders and age of SAD onset were additional determinants of SAD-related volumetric differences in subcortical regions. To conclude, subtle volumetric alterations in subcortical regions in SAD were detected. Heterogeneity in age and clinical characteristics may partly explain inconsistencies in previous findings. The association between alterations in subcortical volumes and SAD illness progression deserves further investigation, especially from adolescence into adulthood. © 2023, The Author(s), under exclusive licence to Springer Nature Limited.
Funding details
019.201SG.022
1.C.059.18 F
CX000994, CX001937
National Institutes of HealthNIHU54 EB020403
National Institute of Mental HealthNIMH5T32MH112485, K01MH083052, K23MH109983, K23MH114023, MH65413, R01MH117601, R01MH122389, T32MH018921, ZIA-MH-002781
Carnegie Corporation of New YorkCCNY
Brain and Behavior Research FoundationBBRF
Robert and Janice McNair Foundation
American Foundation for Suicide PreventionAFSPYIG-1-141-20
National Alliance for Research on Schizophrenia and DepressionNARSAD
Medical Research CouncilMRC
European Research CouncilERCERC_CoG-2017_772337
South African Medical Research CouncilSAMRC
Deutsche ForschungsgemeinschaftDFGBE 3809/8-1 – KBB, C06, DA1151/5-1, DA1151/5-2, FOR2107, FOR5187, HI 2189/4-1, JA 1890/7-1, JA 1890/7-2, KI588/14-1, KI588/14-2, KR 3822/7-1, KR 3822/7-2, KR 4398/5-1, LU 1509/10-1, LU 1509/11-1, LU 1509/9-1, NE2254/1-2, NE2254/3-1, NE2254/4-1
Universiteit Leiden
Rijksuniversiteit GroningenRUG
Fundação de Amparo à Pesquisa do Estado de São PauloFAPESP2014 / 50917-0
National Natural Science Foundation of ChinaNSFC81621003, 82120108014
ZonMw10-000-1002
Bundesministerium für Bildung und ForschungBMBF
Fonds De La Recherche Scientifique – FNRSFNRS
Conselho Nacional de Desenvolvimento Científico e TecnológicoCNPq465550/2014-2
Hjärnfonden
VetenskapsrådetVR
Riksbankens JubileumsfondRJ2018-06729
Harry Crossley Foundation
Medizinische Fakultät, Westfälische Wilhelms-Universität MünsterDan3/012/17
Leids Universitair Medisch CentrumLUMC
Interdisziplinäres Zentrum für Klinische Forschung, Universitätsklinikum WürzburgIZKF Würzburg
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
The Neurotoxin DSP-4 Dysregulates the Locus Coeruleus-Norepinephrine System and Recapitulates Molecular and Behavioral Aspects of Prodromal Neurodegenerative Disease
(2023) eNeuro, 10 (1), art. no. ENEURO.0483-22.2022, .
Iannitelli, A.F.a , Kelberman, M.A.a , Lustberg, D.J.a , Korukonda, A.a , McCann, K.E.a , Mulvey, B.b , Segal, A.a , Liles, L.C.a , Sloan, S.A.a , Dougherty, J.D.b c , Weinshenker, D.a
a Department of Human Genetics, Emory University, School of Medicine, Atlanta, GA 30322, United States
b Department of Genetics, Washington University, School of Medicine, St. Louis, MO 63110, United States
c Department of Psychiatry, Washington University, School of Medicine, St. Louis, MO 63110, United States
Abstract
The noradrenergic locus coeruleus (LC) is among the earliest sites of tau and alpha- synuclein pathology in Alzheimer’s disease (AD) and Parkinson’s disease (PD), respectively. The onset of these pathologies coincides with loss of noradrenergic fibers in LC target regions and the emergence of prodromal symptoms including sleep disturbances and anxiety. Paradoxically, these prodromal symptoms are indicative of a noradrenergic hyperactivity phenotype, rather than the predicted loss of norepinephrine (NE) transmission following LC damage, suggesting the engagement of complex compensatory mechanisms. Because current therapeutic efforts are targeting early disease, interest in the LC has grown, and it is critical to identify the links between pathology and dysfunction. We employed the LC-specific neurotoxin DSP-4, which preferentially damages LC axons, to model early changes in the LC-NE system pertinent to AD and PD in male and female mice. DSP-4 (2 doses of 50 mg/kg, 1 week apart) induced LC axon degeneration, triggered neuroinflammation and oxidative stress, and reduced tissue NE levels. There was no LC cell death or changes to LC firing, but transcriptomics revealed reduced expression of genes that define noradrenergic identity and other changes relevant to neurodegenerative disease. Despite the dramatic loss of LC fibers, NE turnover and signaling were elevated in terminal regions and were associated with anxiogenic phenotypes in multiple behavioral tests. These results represent a comprehensive analysis of how the LC-NE system responds to axon/terminal damage reminiscent of early AD and PD at the molecular, cellular, systems, and behavioral levels, and provides potential mechanisms underlying prodromal neuropsychiatric symptoms. © 2022 Iannitelli et al.
Author Keywords
Alzheimer’s disease; DSP-4; locus coeruleus; mice; norepinephrine; Parkinson’s disease
Funding details
National Institutes of HealthNIH
National Institute on AgingNIAAG061175, AG079199
National Institute of Neurological Disorders and StrokeNINDSNS129168
National Institute of Environmental Health SciencesNIEHSES12870
School of Medicine, Emory UniversityUL1TR002378
Document Type: Article
Publication Stage: Final
Source: Scopus
Cross-sectional and longitudinal comparisons of biomarkers and cognition among asymptomatic middle-aged individuals with a parental history of either autosomal dominant or late-onset Alzheimer’s disease
(2023) Alzheimer’s and Dementia, .
Xiong, C.a b c d , McCue, L.M.d , Buckles, V.a b c , Grant, E.d , Agboola, F.d , Coble, D.d , Bateman, R.J.a b c , Fagan, A.M.a b c , Benzinger, T.L.S.a b e f , Hassenstab, J.a b c g , Schindler, S.E.a b c , McDade, E.a b c , Moulder, K.a b c , Gordon, B.A.a b e g , Cruchaga, C.a h , Day, G.S.i , Ikeuchi, T.j , Suzuki, K.k , Allegri, R.F.l , Vöglein, J.m n , Levin, J.m n o , Morris, J.C.a b c p q r , and Dominantly Inherited Alzheimer Network (DIAN)s
a Knight Alzheimer Disease Research Center, Washington University, St. Louis, MO, United States
b The Dominantly Inherited Alzheimer Network, Washington University, St. Louis, MO, United States
c Department of Neurology, Washington University, St. Louis, MO, United States
d Division of Biostatistics, Washington University, St. Louis, MO, United States
e Department of Radiology, Washington University, St. Louis, MO, United States
f Department of Neurological Surgery, Washington University, St. Louis, MO, United States
g Department of Psychology, Washington University, St. Louis, MO, United States
h Department of Psychiatry, Washington University, St. Louis, MO, United States
i Department of Neurology, Mayo Clinic in Florida, Jacksonville, FL, United States
j Department of Molecular Genetics, Brain Research Institute, Niigata University, Niigata, Japan
k The University of Tokyo, Tokyo, Japan
l Institute for Neurological Research Fleni, Buenos Aires, Argentina
m Department of Neurology, Ludwig-Maximilians-Universität München, Munich, Germany
n German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
o Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
p Department of Pathology and Immunology, Washington University, St. Louis, MO, United States
q Department of Physical Therapy, Washington University, St. Louis, MO, United States
r Department of Occupational Therapy, Washington University, St. Louis, MO, United States
Abstract
Background: Comparisons of late-onset Alzheimer’s disease (LOAD) and autosomal dominant AD (ADAD) are confounded by age. Methods: We compared biomarkers from cerebrospinal fluid (CSF), magnetic resonance imaging, and amyloid imaging with Pittsburgh Compound-B (PiB) across four groups of 387 cognitively normal participants, 42 to 65 years of age, in the Dominantly Inherited Alzheimer Network (DIAN) and the Adult Children Study (ACS) of LOAD: DIAN mutation carriers (MCs) and non-carriers (NON-MCs), and ACS participants with a positive (FH+) and negative (FH–) family history of LOAD. Results: At baseline, MCs had the lowest age-adjusted level of CSF Aβ42 and the highest levels of total and phosphorylated tau-181, and PiB uptake. Longitudinally, MC had similar increase in PiB uptake to FH+, but drastically faster decline in hippocampal volume than others, and was the only group showing cognitive decline. Discussion: Preclinical ADAD and LOAD share many biomarker signatures, but cross-sectional and longitudinal differences may exist. © 2023 the Alzheimer’s Association.
Author Keywords
Alzheimer’s disease (AD); autosomal dominant Alzheimer’s disease (ADAD), cerebrospinal fluid (CSF); magnetic resonance imaging (MRI); Pittsburgh compound-B (PiB); positron emission tomography (PET)
Funding details
National Institutes of HealthNIH
National Institute on AgingNIAR01 AG053550, UF1AG032438
Biogen
Japan Agency for Medical Research and DevelopmentAMEDJP21dk0207049, K23AG064029
Deutsches Zentrum für Neurodegenerative ErkrankungenDZNE
Fleni
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Calcium-dependent modulation of BKCa channel activity induced by plasmonic gold nanoparticles in pulmonary artery smooth muscle cells and hippocampal neurons
(2023) Acta Physiologica, .
Soloviev, A.a , Ivanova, I.a , Sydorenko, V.a , Sukhanova, K.b , Melnyk, M.c d , Dryn, D.d , Zholos, A.c
a Department of Pharmacology of Cell Signaling Systems and Experimental Therapeutics, Institute of Pharmacology and Toxicology, National Academy of Medical Science of Ukraine, Kyiv, Ukraine
b McKelvey School of Engineering, Washington University in St. Louis, St. Louis, MO, United States
c Department of Biophysics and Medical Informatics, Educational and Scientific Centre “Institute of Biology and Medicine”, Taras Shevchenko National University of Kyiv, Kyiv, Ukraine
d Department of Cellular Membranology, A.A. Bogomoletz Institute of Physiology, Kyiv, Ukraine
Abstract
Aim: Gold nanoparticles are widely used for biomedical applications, but the precise molecular mechanism of their interaction with cellular structures is still unclear. Assuming that intracellular calcium fluctuations associated with surface plasmon-induced calcium entry could modulate the activity of potassium channels, we studied the effect of 5 nm gold nanoparticles on calcium-dependent potassium channels and associated calcium signaling in freshly isolated rat pulmonary artery smooth muscle cells and cultured hippocampal neurons. Methods: Outward potassium currents were recorded using patch-clamp techniques. Changes in intracellular calcium concentration were measured using the high affinity Ca2+ fluorescent indicator fluo-3 and laser confocal microscope. Results: In pulmonary artery smooth muscle cells, plasmonic gold nanoparticles increased the amplitude of currents via large-conductance Ca2+-activated potassium channels, which was potentiated by green laser irradiation near plasmon resonance wavelength (532 nm). Buffering of intracellular free calcium with ethylene glycol-bis-N,N,N′,N′-tetraacetic acid (EGTA) abolished these effects. Furthermore, using confocal laser microscopy it was found that application of gold nanoparticles caused oscillations of intracellular calcium concentration that were decreasing in amplitude with time. In cultured hippocampal neurons gold nanoparticles inhibited the effect of EGTA slowing down the decline of the BKCa current while partially restoring the amplitude of the slow after hyperpolarizing currents. Conclusion: We conclude that fluctuations in intracellular calcium can modulate plasmonic gold nanoparticles-induced gating of BKCa channels in smooth muscle cells and neurons through an indirect mechanism, probably involving the interaction of plasmon resonance with calcium-permeable ion channels, which leads to a change in intracellular calcium level. © 2023 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.
Author Keywords
afterhyperpolarization; BKCa potassium channels; gold nanoparticles; intracellular calcium; smooth muscle; surface plasmon resonance
Funding details
National Academy of Sciences of UkraineNASU0122U002126
Ministry of Education and Science of UkraineMESU0122U001535
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
The mediating effect of anxiety on the association between residual neurological impairment and post-stroke participation among persons with and without post-stroke depression
(2023) Neuropsychological Rehabilitation, .
Randolph, S.a , Lee, Y.a , Nicholas, M.L.b , Connor, L.T.c
a Program in Occupational Therapy, Washington University School of Medicine, St. Louis, MO, United States
b Department of Communication Sciences and Disorders, MGH Institute of Health Professions, Boston, MA, United States
c Program in Occupational Therapy and Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
Abstract
Previous research has reported that residual neurological impairment and emotional factors play a role in regaining successful participation post-stroke. The objective of this study was to investigate the mediating impact of anxiety on the association between residual neurological impairment and participation in survivors with and without post-stroke depressive symptoms. Participants (N = 79) were classified into 2 categories, those with post-stroke depressive symptoms (N = 40) and those without post-stroke depressive symptoms (N = 39). Variables measured in this study: residual neurological impairment (NIH Stroke Scale Score), participation (Reintegration to Normal Living Index), depressive symptoms (Patient Health Questionnaire-9), and trait anxiety (State-Trait Anxiety Inventory). A regression-based mediation analysis was conducted for each group of participants. The majority of participants had some level of anxiety. Residual neurological impairment predicted participation in stroke survivors both with (β = -.45, p =.003) and without (β = -.45, p =.004) post-stroke depressive symptoms. Anxiety mediated this relationship in participants with depressive symptoms (β = -.19, 95% CI = -.361 ∼ -.049), but not in participants without depressive symptoms (β = -.18, 95% CI = -.014 ∼.378). Depressive and anxious symptoms should both be addressed to best facilitate participation by stroke survivors. © 2023 Informa UK Limited, trading as Taylor & Francis Group.
Author Keywords
Anxiety; Depression; Mediation; Participation; Stroke
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Comprehensive multi-omic profiling of somatic mutations in malformations of cortical development
(2023) Nature Genetics, .
Chung, C.a b , Yang, X.a b , Bae, T.c , Vong, K.I.a b , Mittal, S.a b , Donkels, C.d , Westley Phillips, H.e , Li, Z.a b , Marsh, A.P.L.a b , Breuss, M.W.a b f , Ball, L.L.a b , Garcia, C.A.B.g , George, R.D.a b , Gu, J.a b , Xu, M.a b , Barrows, C.a b , James, K.N.a b , Stanley, V.a b , Nidhiry, A.S.a b , Khoury, S.a b , Howe, G.a b , Riley, E.a b , Xu, X.a b , Copeland, B.a b , Wang, Y.c , Kim, S.H.h , Kang, H.-C.i , Schulze-Bonhage, A.j , Haas, C.A.d j , Urbach, H.k , Prinz, M.j l m , Limbrick, D.D., Jr.n , Gurnett, C.A.n , Smyth, M.D.o , Sattar, S.p , Nespeca, M.p , Gonda, D.D.p , Imai, K.q , Takahashi, Y.q , Chen, H.-H.r , Tsai, J.-W.s , Conti, V.t , Guerrini, R.t , Devinsky, O.u , Silva, W.A., Jr.v , Machado, H.R.g , Mathern, G.W.e , Abyzov, A.c , Baldassari, S.w , Baulac, S.w , Gleeson, J.G.x , Jones, M.x , Masser-Frye, D.x , Sattar, S.x , Nespeca, M.x , Gonda, D.D.x , Imai, K.y , Takahashi, Y.y , Chen, H.-H.z , Tsai, J.-W.aa , Conti, V.ab , Guerrini, R.ac , Devinsky, O.ad , Machado, H.R.ae , Garcia, C.A.B.ae , Silva, W.A., Jr.ae , Kim, S.H.af , Kang, H.-C.af , Alanay, Y.ag , Kapoor, S.ah , Haas, C.A.ai , Ramantani, G.aj , Feuerstein, T.aj , Blumcke, I.ak , Busch, R.ak , Ying, Z.ak , Biloshytsky, V.al , Kostiuk, K.al , Pedachenko, E.al , Mathern, G.W.am , Gurnett, C.A.an , Smyth, M.D.an , Helbig, I.ao , Kennedy, B.C.ao , Liu, J.ap , Chan, F.ap , Krueger, D.aq , Frye, R.ab , Wilfong, A.ab , Adelson, D.ab , Gaillard, W.ar , Oluigbo, C.ar , Anderson, A.as , Lee, A.at , Huang, A.Y.at , D’Gama, A.at , Dias, C.at , Walsh, C.A.at , Maury, E.at , Ganz, J.at , Lodato, M.at , Miller, M.at , Li, P.at , Rodin, R.at , Borges-Monroy, R.at , Hill, R.at , Bizzotto, S.at , Khoshkhoo, S.at , Kim, S.at , Zhou, Z.at , Lee, A.au , Barton, A.au , Galor, A.au , Chu, C.au , Bohrson, C.au , Gulhan, D.au , Maury, E.au , Lim, E.au , Lim, E.au , Melloni, G.au , Cortes, I.au , Lee, J.au , Luquette, J.au , Yang, L.au , Sherman, M.au , Coulter, M.au , Kwon, M.au , Park, P.J.au , Borges-Monroy, R.au , Lee, S.au , Kim, S.au , Lee, S.au , Viswanadham, V.au , Dou, Y.au , Chess, A.J.av , Jones, A.av , Rosenbluh, C.av , Akbarian, S.av , Langmead, B.aw , Thorpe, J.aw , Cho, S.aw , Jaffe, A.ax , Paquola, A.ax , Weinberger, D.ax , Erwin, J.ax , Shin, J.ax , McConnell, M.ax , Straub, R.ax , Narurkar, R.ax , Abyzov, A.ay , Bae, T.ay , Jang, Y.ay , Wang, Y.ay , Addington, A.az , Senthil, G.az , Molitor, C.ba , Peters, M.ba , Gage, F.H.bb , Wang, M.bb , Reed, P.bb , Linker, S.bb , Urban, A.bc , Zhou, B.bc , Pattni, R.bc , Zhu, X.bc , Amero, A.S.bd , Juan, D.bd , Povolotskaya, I.bd , Lobon, I.bd , Moruno, M.S.bd , Perez, R.G.bd , Marques-Bonet, T.bd , Soriano, E.be , Mathern, G.bf , Antaki, D.bg , Averbuj, D.bg , Courchesne, E.bg , Gleeson, J.G.bg , Ball, L.L.bg , Breuss, M.W.bg , Roy, S.bg , Yang, X.bg , Chung, C.bg , Sun, C.bh , Flasch, D.A.bh , Trenton, T.J.F.bh , Kopera, H.C.bh , Kidd, J.M.bh , Moldovan, J.B.bh , Moran, J.V.bh , Kwan, K.Y.bh , Mills, R.E.bh , Emery, S.B.bh , Zhou, W.bh , Zhao, X.bh , Ratan, A.bi , Cherskov, A.bj , Jourdon, A.bj , Vaccarino, F.M.bj , Fasching, L.bj , Sestan, N.bj , Pochareddy, S.bj , Scuder, S.bj , Gleeson, J.G.a b , Focal Cortical Dysplasia Neurogenetics Consortiumbk , Brain Somatic Mosaicism Networkbk
a Department of Neurosciences, University of California San Diego, La JollaCA, United States
b Rady Children’s Institute for Genomic Medicine, San Diego, CA, United States
c Department of Quantitative Health Sciences, Center for Individualized Medicine, Mayo Clinic, Rochester, MN, United States
d Department of Neurosurgery, Experimental Epilepsy Research, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
e Department of Neurosurgery, University of California at Los Angeles, Los Angeles, CA, United States
f Department of Pediatrics, Section of Clinical Genetics and Metabolism, University of Colorado Aurora, Aurora, CO, United States
g Laboratory of Pediatric Neurosurgery and Developmental Neuropathology, Department of Surgery and Anatomy, University of São Paulo, Ribeirão Preto, Brazil
h Department of Pathology, Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea
i Division of Pediatric Neurology, Department of Pediatrics, Severance Children’s Hospital, Yonsei University College of Medicine, Seoul, South Korea
j Center for Basics in NeuroModulation, Faculty of Medicine, University of Freiburg, Freiburg, Germany
k Department of Neuroradiology, Medical Center-University of Freiburg, Faculty of Medicine, Freiburg, Germany
l Institute of Neuropathology, Medical Center-University of Freiburg, Faculty of Medicine, Freiburg, Germany
m Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany
n Department of Neurology, St. Louis Children’s Hospital, Washington University St Louis, Washington, MO, United States
o Department of Neurosurgery, St. Louis Children’s Hospital, Washington University St Louis, Washington, MO, United States
p Epilepsy Center, Rady Children’s Hospital, San Diego, CA, United States
q National Epilepsy Center, NHO Shizuoka Institute of Epilepsy and Neurological Disorders, Shizuoka, Japan
r Division of Pediatric Neurosurgery, The Neurological Institute, Taipei Veterans General Hospital, Taipei City, Taiwan
s Institute of Brain Science, Brain Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan
t Pediatric Neurology Unit and Laboratories, IRCCS Meyer Children’s Hospital University of Florence, Firenze, Italy
u Comprehensive Epilepsy Center, Department of Neurology, New York University Langone Health, New York, NY, United States
v Department of Genetics, Center for Cell-Based Therapy, Center for Integrative Systems Biology, University of São Paulo, Ribeirão Preto, Brazil
w Sorbonne Université, Institut du Cerveau – Paris Brain Institute – ICM, Inserm, CNRS, Hôpital de la Pitié Salpêtrière, Paris, France
x Rady Children’s Hospital, San Diego, CA, United States
y NHO Shizuoka Institute of Epilepsy and Neurological Disorders, Shizuoka, Japan
z Taipei Veterans General Hospital, Taipei City, Taiwan
aa National Yang Ming Chiao Tung University, Taipei City, Taiwan
ab Barrow Neurological Institute at Phoenix Children’s Hospital, University Arizona College of Medicine, Phoenix, AZ, United States
ac IRCCS Meyer Children’s Hospital, University of Florence, Firenze, Italy
ad New York University Langone Health, New York, NY, United States
ae University of São Paulo, Ribeirão Preto, Brazil
af Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea
ag Acibadem Hospital, Istanbul, Turkey
ah Lok Nayak Hospital & Maualana Azad Medical Center, New Delhi, India
ai University of Freiburg, Freiburg, Germany
aj Albert-Ludwigs University, Freiburg, Germany
ak University Hopsital Erlangen, Erlangen, Germany
al Romodanov Institute of Neurosurgery, Kyiv, Ukraine
am University of California at Los Angeles, Los Angeles, CA, United States
an St. Louis Children’s Hospital, Washington University St Louis, Washington, MO, United States
ao Children’s Hospital Philadelphia, Philadelphia, PA, United States
ap Brown University, Providence, RI, United States
aq Cincinnati Children’s Hospital, Cincinnati, OH, United States
ar Children’s National Hospital, Washington, DC, United States
as Baylor College of Medicine, Texas Children’s Hospital, Houston, TX, United States
at Boston Children’s Hospital, Boston, MA, United States
au Harvard University, Boston, MA, United States
av Icahn School of Medicine at Mount Sinai, New York, NY, United States
aw Kennedy Krieger Institute, Baltimore, MD, United States
ax Lieber Institute for Brain Development, Baltimore, MD, United States
ay Mayo Clinic, Rochester, MN, United States
az National Institute of Mental Health (NIMH), Bethesda, MD, United States
ba Sage Bionetworks Seattle, Seattle, WA, United States
bb Salk Institute for Biological Studies, La Jolla, CA, United States
bc Stanford University, CA, United States
bd Universitat Pompeu Fabra, Barcelona, Spain
be University of Barcelona, Barcelona, Spain
bf University of California, Los Angeles, CA, United States
bg University of California, San Diego, La Jolla, CA, United States
bh University of Michigan, Ann Arbor, MI, United States
bi University of Virginia, Charlottesville, VA, United States
bj Yale University, New Haven, CT, United States
Abstract
Malformations of cortical development (MCD) are neurological conditions involving focal disruptions of cortical architecture and cellular organization that arise during embryogenesis, largely from somatic mosaic mutations, and cause intractable epilepsy. Identifying the genetic causes of MCD has been a challenge, as mutations remain at low allelic fractions in brain tissue resected to treat condition-related epilepsy. Here we report a genetic landscape from 283 brain resections, identifying 69 mutated genes through intensive profiling of somatic mutations, combining whole-exome and targeted-amplicon sequencing with functional validation including in utero electroporation of mice and single-nucleus RNA sequencing. Genotype–phenotype correlation analysis elucidated specific MCD gene sets associated with distinct pathophysiological and clinical phenotypes. The unique single-cell level spatiotemporal expression patterns of mutated genes in control and patient brains indicate critical roles in excitatory neurogenic pools during brain development and in promoting neuronal hyperexcitability after birth. © 2023, The Author(s), under exclusive licence to Springer Nature America, Inc.
Funding details
National Institutes of HealthNIHS10OD026929
National Institute of Mental HealthNIMHR01MH124890, U01MH108898
National Institute on AgingNIAR21AG070462
National Cancer InstituteNCIP30CA23100
National Institute of Neurological Disorders and StrokeNINDSR01NS083823
Brain and Behavior Research FoundationBBRF30598
University of California, San DiegoUCSD
National Alliance for Research on Schizophrenia and DepressionNARSAD
Ente Cassa di Risparmio di Firenze
Regione Toscana
Document Type: Article
Publication Stage: Article in Press
Source: Scopus