Arts & Sciences Brown School McKelvey School of Engineering School of Medicine Weekly Publications

WashU weekly Neuroscience publications

β-amyloid PET harmonisation across longitudinal studies: Application to AIBL, ADNI and OASIS3” (2022) NeuroImage

β-amyloid PET harmonisation across longitudinal studies: Application to AIBL, ADNI and OASIS3
(2022) NeuroImage, 262, art. no. 119527, . 

Bourgeat, P.a , Doré, V.a b , Burnham, S.C.a , Benzinger, T.c , Tosun, D.d g , Li, S.a , Goyal, M.e , LaMontagne, P.e , Jin, L.f , Rowe, C.C.b f , Weiner, M.W.d g , Morris, J.C.h , Masters, C.L.f , Fripp, J.a , Villemagne, V.L.b i , Alzheimer’s Disease Neuroimaging Initiative, OASIS3, and the AIBL research groupj

a CSIRO Health and Biosecurity, Brisbane, Australia
b Department of Molecular Imaging & Therapy, Austin Health, Melbourne, Australia
c Knight Alzheimer Disease Research Center, St. Louis, MO, United States
d San Francisco Veterans Affairs Medical Center, San Francisco, CA, United States
e Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, United States
f The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Melbourne, Australia
g Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA, United States
h Washington University in St. Louis, St. Louis, MO, United States
i Department of Psychiatry, The University of Pittsburgh, Pittsburgh, PA, United States

Abstract
Introduction: The Centiloid scale was developed to harmonise the quantification of β-amyloid (Aβ) PET images across tracers, scanners, and processing pipelines. However, several groups have reported differences across tracers and scanners even after centiloid conversion. In this study, we aim to evaluate the impact of different pre and post-processing harmonisation steps on the robustness of longitudinal Centiloid data across three large international cohort studies. Methods: All Aβ PET data in AIBL (N = 3315), ADNI (N = 3442) and OASIS3 (N = 1398) were quantified using the MRI-based Centiloid standard SPM pipeline and the PET-only pipeline CapAIBL. SUVR were converted into Centiloids using each tracer’s respective transform. Global Aβ burden from pre-defined target cortical regions in Centiloid units were quantified for both raw PET scans and PET scans smoothed to a uniform 8 mm full width half maximum (FWHM) effective smoothness. For Florbetapir, we assessed the performance of using both the standard Whole Cerebellum (WCb) and a composite white matter (WM)+WCb reference region. Additionally, our recently proposed quantification based on Non-negative Matrix Factorisation (NMF) was applied to all spatially and SUVR normalised images. Correlation with clinical severity measured by the Mini-Mental State Examination (MMSE) and effect size, as well as tracer agreement in 11C-PiB-18F-Florbetapir pairs and longitudinal consistency were evaluated. Results: The smoothing to a uniform resolution partially reduced longitudinal variability, but did not improve inter-tracer agreement, effect size or correlation with MMSE. Using a Composite reference region for 18F-Florbetapir improved inter-tracer agreement, effect size, correlation with MMSE, and longitudinal consistency. The best results were however obtained when using the NMF method which outperformed all other quantification approaches in all metrics used. Conclusions: FWHM smoothing has limited impact on longitudinal consistency or outliers. A Composite reference region including subcortical WM should be used for computing both cross-sectional and longitudinal Florbetapir Centiloid. NMF improves Centiloid quantification on all metrics examined. © 2022

Author Keywords
Amyloid PET;  Centiloid;  Harmonisation

Funding details
National Institutes of HealthNIHP01 AG003991, P01AG026276, P30 AG066444, P30 NS09857781, P50 AG00561, R01 AG043434, R01 EB009352, R01-AG058676-01A1, U01 AG024904, U19 AG032438, UL1 TR000448
U.S. Department of DefenseDODW81XWH-12-2-0012
National Institute on AgingNIA
National Institute of Biomedical Imaging and BioengineeringNIBIB
International Business Machines CorporationIBM
Genentech
Johnson and JohnsonJ&J
Merck
Janssen Research and DevelopmentJRD
University of Southern CaliforniaUSC
GE Healthcare
Alzheimer’s Disease Neuroimaging InitiativeADNI
Northern California Institute for Research and EducationNCIRE
National Health and Medical Research CouncilNHMRCGA16788
Capital Medical UniversityCCMU
Fujirebio Europe
H. Lundbeck A/S
IXICO

Document Type: Article
Publication Stage: Final
Source: Scopus

Covariance-based vs. correlation-based functional connectivity dissociates healthy aging from Alzheimer disease“(2022) NeuroImage

Covariance-based vs. correlation-based functional connectivity dissociates healthy aging from Alzheimer disease
(2022) NeuroImage, 261, art. no. 119511, . 

Strain, J.F.a , Brier, M.R.a , Tanenbaum, A.a , Gordon, B.A.b c d , McCarthy, J.E.e , Dincer, A.b , Marcus, D.S.b c , Chhatwal, J.P.g , Graff-Radford, N.R.h , Day, G.S.h , la Fougère, C.i j , Perrin, R.J.a c f k , Salloway, S.l , Schofield, P.R.m n , Yakushev, I.o , Ikeuchi, T.p , Vöglein, J.q , Morris, J.C.a c , Benzinger, T.L.S.b c , Bateman, R.J.a c f , Ances, B.M.a b f , Snyder, A.Z.a b , Dominantly Inherited Alzheimer Networkr

a Department of Neurology, Washington University in Saint Louis, St. Louis, MO 63110, United States
b Department of Radiology, Washington University in Saint Louis, Box 8225, 660 South Euclid Ave, St. Louis, MO 63110, United States
c Knight Alzheimer Disease Research Center, Washington University in St. Louis, St. Louis, MO 63110, United States
d Department of Psychological & Brain Sciences, Washington University, St. Louis, MO, United States
e Department of Mathematics and Statistics, Washington University, St. Louis, MO 63130, United States
f Hope Center for Neurological Disorders, Washington University in St. Louis, St. Louis, MO 63110, United States
g Martinos Center, Massachusetts General Hospital, 149 13th St Room 2662, Charlestown, MA 02129, United States
h Mayo Clinic Florida, 4500 San Pablo Road, Jacksonville, FL 32224, United States
i Department of Nuclear Medicine and Clinical Molecular Imaging, Universityhospital Tübingen, Tübingen, Germany
j German Center for Neurodegenerative Diseases (DZNE) Tübingen, Germany
k Department of Pathology and Immunology, Washington University in St. Louis, St. Louis, MO 63110, United States
l Alpert Medical School of Brown University, 345 Blackstone Boulevard, Providence, RI 02906, United States
m Neuroscience Research Australia, Sydney, NSW 2131, Australia
n School of Medical Sciences, University of New South Wales, Sydney, NSW 2052, Australia
o Department of Nuclear Medicine, Klinikum Rechts der Isar, School of Medicine, Technical University of Munich, Ismaninger Str. 22, Munich, 81675, Germany
p Department of Molecular Genetics, Brain Research Institute, Niigata University, Japan
q Department of Neurology, Ludwig-Maximilians-Universität München, Germany

Abstract
Prior studies of aging and Alzheimer disease have evaluated resting state functional connectivity (FC) using either seed-based correlation (SBC) or independent component analysis (ICA), with a focus on particular functional systems. SBC and ICA both are insensitive to differences in signal amplitude. At the same time, accumulating evidence indicates that the amplitude of spontaneous BOLD signal fluctuations is physiologically meaningful. We systematically compared covariance-based FC, which is sensitive to amplitude, vs. correlation-based FC, which is not, in affected individuals and controls drawn from two cohorts of participants including autosomal dominant Alzheimer disease (ADAD), late onset Alzheimer disease (LOAD), and age-matched controls. Functional connectivity was computed over 222 regions of interest and group differences were evaluated in terms of components projected onto a space of lower dimension. Our principal observations are: (1) Aging is associated with global loss of resting state fMRI signal amplitude that is approximately uniform across resting state networks. (2) Thus, covariance FC measures decrease with age whereas correlation FC is relatively preserved in healthy aging. (3) In contrast, symptomatic ADAD and LOAD both lead to loss of spontaneous activity amplitude as well as severely degraded correlation structure. These results demonstrate a double dissociation between age vs. Alzheimer disease and the amplitude vs. correlation structure of resting state BOLD signals. Modeling results suggest that the AD-associated loss of correlation structure is attributable to a relative increase in the fraction of locally restricted as opposed to widely shared variance. © 2022 The Author(s)

Author Keywords
Aging;  Autosomal dominant Alzheimer disease;  Covariance;  Late onset Alzheimer disease;  Resting-state functional connectivity

Funding details
National Science FoundationNSF2054199
National Institutes of HealthNIHK01AG053474, P01AG026276, P01AG036694, P01AG03991, P30 AG066444, P30NS048056, P30NS098577, P50AG05681, R01AG04343404, R01AG052550, R01AG062667, R01EB009352, R01NR012657, R01NR012907, R01NR014449, R25NS090978-06, U01AG042791, UFAG032438, UL1TR000448
Foundation for the National Institutes of HealthFNIHR01AG046179, R01AG053267, R01AG068319, R56AG053267, U01AG059798
National Institute on AgingNIA
Alzheimer’s AssociationAA
Association for Frontotemporal DegenerationAFTD
Eli Lilly and Company
Biogen
BrightFocus FoundationBFF
F. Hoffmann-La Roche
Foundation for Barnes-Jewish HospitalFBJH
Cure Alzheimer’s FundCAF
Janssen Pharmaceuticals
Japan Agency for Medical Research and DevelopmentAMEDJP21dk0207049
Washington University School of Medicine in St. LouisWUSM
Hope Center for Neurological Disorders
GHR FoundationGHR
Centene Corporation
Medical Research CouncilMRCMR/009076/1, MR/L023784/1
National Institute for Health and Care ResearchNIHR
Eisai
Deutsches Zentrum für Neurodegenerative ErkrankungenDZNE

Document Type: Article
Publication Stage: Final
Source: Scopus

Persistence of Chemotherapy-Induced Peripheral Neuropathy Despite Vincristine Reduction in Childhood B-Acute Lymphoblastic Leukemia” (2022) Journal of the National Cancer Institute

Persistence of Chemotherapy-Induced Peripheral Neuropathy Despite Vincristine Reduction in Childhood B-Acute Lymphoblastic Leukemia
(2022) Journal of the National Cancer Institute, 114 (8), pp. 1167-1175. 

Rodwin, R.L.a , Kairalla, J.A.b , Hibbitts, E.b , Devidas, M.c , Whitley, M.K.a , Mohrmann, C.E.d , Schore, R.J.e f , Raetz, E.g , Winick, N.J.h , Hunger, S.P.i , Loh, M.L.j , Hockenberry, M.J.k l , Angiolillo, A.L.e f , Ness, K.K.m , Kadan-Lottick, N.S.n

a Department of Pediatrics, Yale University School of Medicine, New Haven, CT, United States
b Department of Biostatistics, Colleges of Medicine and Public Health & Health Professions, University of Florida, Gainesville, FL, United States
c Department of Global Pediatric Medicine, St. Jude Children’s Research Hospital, Memphis, TN, United States
d Department of Pediatrics, Washington University School of Medicine, St. Louis Children’s Hospital, St. Louis, MO, United States
e Division of Oncology, Center for Cancer and Blood Disorders, Children’s National Medical CenterWA, United States
f Cancer Biology Research Program, George Washington University School of Medicine and Health SciencesWA, United States
g Department of Pediatrics, NYU Langone Medical Center, New York, NY, USA
h Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, United States
i Department of Pediatrics, Children’s Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States
j Department of Pediatrics, Benioff Children’s Hospital, the Helen Diller Family Comprehensive Cancer Institute, University of California, San Francisco, CA, United States
k Department of Pediatrics, Baylor College of Medicine, Houston, TX, United States
l School of Nursing, Duke University, Durham, NC, United States
m Department of Epidemiology and Cancer Control, St. Jude Children’s Research Hospital, Memphis, TN, United States
n Cancer Prevention and Control, Georgetown Lombardi Comprehensive Cancer CenterWA, United States

Abstract
BACKGROUND: Children with B-acute lymphoblastic leukemia (B-ALL) are at risk for chemotherapy-induced peripheral neuropathy (CIPN). Children’s Oncology Group AALL0932 randomized reduction in vincristine and dexamethasone (every 4 weeks vs 12 weeks during maintenance in the average-risk subset of National Cancer Institute standard-B-ALL (SR AR B-ALL). We longitudinally measured CIPN, overall and by treatment group. METHODS: AALL0932 standard-B-ALL patients aged 3 years and older were evaluated at T1-T4 (end consolidation, maintenance month 1, maintenance month 18, 12 months posttherapy). Physical and occupational therapists (PT/OT) measured motor CIPN (hand and ankle strength, dorsiflexion and plantarflexion range of motion), sensory CIPN (finger and toe vibration and touch), function (dexterity [Purdue Pegboard], and walking efficiency [Six-Minute Walk]). Proxy-reported function (Pediatric Outcome Data Collection Instrument) and quality of life (Pediatric Quality of Life Inventory) were assessed. Age- and sex-matched z scores and proportion impaired were measured longitudinally and compared between groups. RESULTS: Consent and data were obtained from 150 participants (mean age = 5.1 years [SD = 1.7], 48.7% female). Among participants with completed evaluations, 81.8% had CIPN at T1 (74.5% motor, 34.1% sensory). When examining severity of PT/OT outcomes, only handgrip strength (P < .001) and walking efficiency (P = .02) improved from T1-T4, and only dorsiflexion range of motion (46.7% vs 14.7%; P = .008) and handgrip strength (22.2% vs 37.1%; P = .03) differed in vincristine and dexamethasone every 4 weeks vs vincristine and dexamethasone 12 weeks at T4. Proxy-reported outcomes improved from T1 to T4 (P < .001), and most did not differ between groups. CONCLUSIONS: CIPN is prevalent early in B-ALL therapy and persists at least 12 months posttherapy. Most outcomes did not differ between treatment groups despite reduction in vincristine frequency. Children with B-ALL should be monitored for CIPN, even with reduced vincristine frequency. © The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Document Type: Article
Publication Stage: Final
Source: Scopus

Developmental Pathways Are Epigenetically Reprogrammed during Lung Cancer Brain Metastasis” (2022) Cancer Research

Developmental Pathways Are Epigenetically Reprogrammed during Lung Cancer Brain Metastasis
(2022) Cancer Research, 82 (15), pp. 2692-2703. 

Karlow, J.A.a b , Devarakonda, S.c , Xing, X.a b , Jang, H.S.a b d , Govindan, R.c , Watson, M.d , Wang, T.a b e

a Department of Genetics, Washington University School of Medicine, St. Louis, MO, United States
b Edison Family Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO, United States
c Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States
d Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States
e McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Non-small cell lung cancer (NSCLC) is one of the most commonly diagnosed and deadliest cancers worldwide, with roughly half of all patients initially presenting with both primary and metastatic disease. While the major events in the metastatic cascade have been identified, a mechanistic understanding of how NSCLC routinely and successfully colonizes the brain is largely unknown. Recent studies have begun demonstrating the role of epigenetic misregulation during tumorigenesis and metastasis, including widespread changes in DNA methylation and histone modifications. To better understand the role of altered DNA methylation in NSCLC metastasis to the brain, we measured DNA methylation during disease progression for 12 patients, globally profiling the methylation status of normal lung, primary lung tumor, and brain metastasis samples. The variation in methylation was similar during metastatic spread and primary tumorigenesis but less coordinated across genomic features during metastasis. The greatest recurrent changes during metastatic progression were methylation gains in DNA methylation valleys (DMV) harboring the constitutive heterochromatin mark H3K9me3 as well as bivalent marks H3K27me3 and H3K4me1. In a lymph node-derived cancer cell line, EZH2 binding within DMVs was lost, accompanied by an increase in DNA methylation, exemplifying epigenetic switching. The vast majority of the differentially methylated region-associated DMVs harbored developmental genes, suggesting that altered epigenetic regulation of developmentally important genes may confer a selective advantage during metastatic progression. The characterization of epigenetic changes during NSCLC brain metastasis identified recurrent methylation patterns that may be prognostic biomarkers and contributors to disease progression. SIGNIFICANCE: Altered DNA methylation in lung cancer brain metastases corresponds with loss of EZH2 occupancy at developmental genes, which could promote stem-like phenotypes permissive of dissemination and survival in different microenvironments. ©2022 American Association for Cancer Research.

Document Type: Article
Publication Stage: Final
Source: Scopus

Infant Visual Brain Development and Inherited Genetic Liability in Autism” (2022) The American Journal of Psychiatry

Infant Visual Brain Development and Inherited Genetic Liability in Autism
(2022) The American Journal of Psychiatry, 179 (8), pp. 573-585. 

Girault, J.B.a , Donovan, K.b , Hawks, Z.b , Talovic, M.b , Forsen, E.b , Elison, J.T.b , Shen, M.D.b , Swanson, M.R.b , Wolff, J.J.b , Kim, S.H.b , Nishino, T.b , Davis, S.b , Snyder, A.Z.b , Botteron, K.N.b , Estes, A.M.b , Dager, S.R.b , Hazlett, H.C.b , Gerig, G.b , McKinstry, R.b , Pandey, J.b , Schultz, R.T.b , St John, T.b , Zwaigenbaum, L.b , Todorov, A.b , Truong, Y.b , Styner, M.b , Pruett, J.R., Jrb , Constantino, J.N.b , Piven, J.b , IBIS Networkb

a Carolina Institute for Developmental Disabilities (Girault, Forsen, Shen, Hazlett, Piven), Department of Psychiatry (Girault, Shen, Kim, Hazlett, Styner, Piven), Department of Biostatistics (Donovan, Truong), and ; Department of Psychological and Brain Sciences (Hawks) and Department of Psychiatry (Talovic, Nishino, Davis, Botteron, Todorov, Pruett, Constantino), Washington University School of Medicine in St. Louis; Institute of Child Development (Elison) and Department of Educational Psychology (Wolff), University of Minnesota, Minneapolis;Department of Psychology, School of Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, Tex. (Swanson); Department of Radiology, Washington University in St. Louis (Snyder, McKinstry); Department of Speech and Hearing Science, University of Washington, Seattle (Estes, St. John); Department of Radiology, University of Washington Medical Center, Seattle (Dager); Tandon School of Engineering, New York University, New York (Gerig); Center for Autism Research, Children’s Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia (Pandey, Schultz); Department of Pediatrics, University of Alberta, Edmonton, Canada (Zwaigenbaum)
b Carolina Institute for Developmental Disabilities (Girault, Forsen, Shen, Hazlett, Piven), Department of Psychiatry (Girault, Shen, Kim, Hazlett, Styner, Piven), Department of Biostatistics (Donovan, Truong), and ; Department of Psychological and Brain Sciences (Hawks) and Department of Psychiatry (Talovic, Nishino, Davis, Botteron, Todorov, Pruett, Constantino), Washington University School of Medicine in St. Louis; Institute of Child Development (Elison) and Department of Psychology, School of Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, Tex. (Swanson); Department of Radiology, Washington University in St. Louis (Snyder, McKinstry); Department of Speech and Hearing Science, University of Washington, Seattle (Estes, St. John); Department of Radiology, University of Washington Medical Center, Seattle (Dager); Tandon School of Engineering, New York University, New York (Gerig); Center for Autism Research, Children’s Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia (Pandey, Schultz); Department of Pediatrics, University of Alberta, Edmonton, Canada (Zwaigenbaum)

Abstract
OBJECTIVE: Autism spectrum disorder (ASD) is heritable, and younger siblings of ASD probands are at higher likelihood of developing ASD themselves. Prospective MRI studies of siblings report that atypical brain development precedes ASD diagnosis, although the link between brain maturation and genetic factors is unclear. Given that familial recurrence of ASD is predicted by higher levels of ASD traits in the proband, the authors investigated associations between proband ASD traits and brain development among younger siblings. METHODS: In a sample of 384 proband-sibling pairs (89 pairs concordant for ASD), the authors examined associations between proband ASD traits and sibling brain development at 6, 12, and 24 months in key MRI phenotypes: total cerebral volume, cortical surface area, extra-axial cerebrospinal fluid, occipital cortical surface area, and splenium white matter microstructure. Results from primary analyses led the authors to implement a data-driven approach using functional connectivity MRI at 6 months. RESULTS: Greater levels of proband ASD traits were associated with larger total cerebral volume and surface area and larger surface area and reduced white matter integrity in components of the visual system in siblings who developed ASD. This aligned with weaker functional connectivity between several networks and the visual system among all siblings during infancy. CONCLUSIONS: The findings provide evidence that specific early brain MRI phenotypes of ASD reflect quantitative variation in familial ASD traits. Multimodal anatomical and functional convergence on cortical regions, fiber pathways, and functional networks involved in visual processing suggest that inherited liability has a role in shaping the prodromal development of visual circuitry in ASD.

Author Keywords
Autism Spectrum Disorder;  Development;  Neurodevelopmental Disorders;  Neuroimaging

Document Type: Article
Publication Stage: Final
Source: Scopus

Relative Brain Volume of Carnivorans Has Evolved in Correlation with Environmental and Dietary Variables Differentially among Clades” (2022) Brain, Behavior and Evolution

Relative Brain Volume of Carnivorans Has Evolved in Correlation with Environmental and Dietary Variables Differentially among Clades
(2022) Brain, Behavior and Evolution, 97 (5), pp. 284-297. 

Lynch, L.M.a b , Allen, K.L.a

a Washington University School of Medicine in St. Louis, St. Louis, MO, United States
b Midwestern University, Glendale, AZ, United States

Abstract
Carnivorans possess relatively large brains compared to most other mammalian clades. Factors like environmental complexity (Cognitive Buffer Hypothesis) and diet quality (Expensive-Tissue Hypothesis) have been proposed as mechanisms for encephalization in other large-brained clades. We examine whether the Cognitive Buffer and Expensive-Tissue Hypotheses account for brain size variation within Carnivora. Under these hypotheses, we predict a positive correlation between brain size and environmental complexity or protein consumption. Relative endocranial volume (phylogenetic generalized least-squares residual from species’ mean body mass) and 9 environmental and dietary variables were collected from the literature for 148 species of terrestrial and marine carnivorans. We found that the correlation between relative brain volume and environment and diet differed among clades, a trend consistent with other larger brained vertebrates (i.e., Primates, Aves). Mustelidae and Procyonidae demonstrate larger brains in species with higher-quality diets, consistent with the Expensive-Tissue Hypothesis, while in Herpestidae, correlations between relative brain size and environment are consistent with the Cognitive Buffer Hypothesis. Our results indicate that carnivorans may have evolved relatively larger brains under similar selective pressures as primates despite the considerable differences in life history and behavior between these two clades. © 2022 S. Karger AG, Basel.

Author Keywords
Carnivora;  Cognitive Buffer Hypothesis;  Diet quality;  Environmental complexity;  Expensive-Tissue Hypothesis

Funding details
Midwestern UniversityMWU

Document Type: Article
Publication Stage: Final
Source: Scopus

Multi-Ancestry GWAS reveals excitotoxicity associated with outcome after ischaemic stroke” (2022) Brain

Multi-Ancestry GWAS reveals excitotoxicity associated with outcome after ischaemic stroke
(2022) Brain, 145 (7), pp. 2394-2406. Cited 1 time.

Ibanez, L.a b , Heitsch, L.c d , Carrera, C.e , Farias, F.H.G.a b , Del Aguila, J.L.a b , Dhar, R.c , Budde, J.a b , Bergmann, K.a b , Bradley, J.a b , Harari, O.a b f g , Phuah, C.-L.c , Lemmens, R.h , Souza, A.A.V.O.i j , Moniche, F.k , Cabezas-Juan, A.k l , Arenillas, J.F.m , Krupinksi, J.n o , Cullell, N.o p , Torres-Aguila, N.o p , Muiño, E.p , Cárcel-Márquez, J.p , Marti-Fabregas, J.p , Delgado-Mederos, R.p , Marin-Bueno, R.p , Hornick, A.q , Vives-Bauza, C.r , Navarro, R.D.s , Tur, S.s , Jimenez, C.s , Obach, V.t , Segura, T.u , Serrano-Heras, G.u , Chung, J.-W.v , Roquer, J.w , Soriano-Tarraga, C.a b w , Giralt-Steinhauer, E.w , Mola-Caminal, M.w x , Pera, J.y , Lapicka-Bodzioch, K.y , Derbisz, J.y , Davalos, A.z , Lopez-Cancio, E.aa , Muñoz, L.z , Tatlisumak, T.ab ac , Molina, C.e , Ribo, M.e , Bustamante, A.z , Sobrino, T.ad , Castillo-Sanchez, J.ad , Campos, F.ad , Rodriguez-Castro, E.ad , Arias-Rivas, S.ad , Rodríguez-Yáñez, M.ad , Herbosa, C.c , Ford, A.L.c f ae , Gutierrez-Romero, A.af , Uribe-Pacheco, R.af , Arauz, A.af , Lopes-Cendes, I.i j , Lowenkopf, T.ag , Barboza, M.A.ah , Amini, H.ai , Stamova, B.ai , Ander, B.P.ai , Sharp, F.R.ai , Moon Kim, G.v , Bang, O.Y.v , Jimenez-Conde, J.w , Slowik, A.y , Stribian, D.aj , Tsai, E.A.ak , Burkly, L.C.al , Montaner, J.e k l , Fernandez-Cadenas, I.e p , Lee, J.-M.c f ae am an , Cruchaga, C.a b c f g ao

a Department of Psychiatry, School of Medicine, Washington University, Saint Louis, MO 63110, United States
b NeuroGenomics and Informatics, School of Medicine, Washington University, Saint Louis, MO 63110, United States
c Department of Neurology, School of Medicine, Washington University, Saint Louis, 63110, United States
d Department of Emergency Medicine, School of Medicine, Washington University, Saint Louis, MO 63110, United States
e Stroke Unit, Vall d’Hebron University Hospital, Universitat de Barcelona, Barcelona, 08035, Spain
f Hope Center for Neurological Disorders, School of Medicine, Washington University, Saint Louis, MO 63110, United States
g The Charles F. and Joanne Knight Alzheimer Disease Research Center, School of Medicine, Washington University, Saint Louis, MO 63110, United States
h Department of Neuroscience, Katholieke Universiteit Leuven, Campus Gasthuisberg OandN2, Leuven, BE-3000, Belgium
i Department of Neurology, School of Medical Sciences, University of Campinas (UNICAMP), Cidade Universitaria, Campinas, 13083-887, Brazil
j Brazilian Institute of Neuroscience and Neurotechnology (BRAINN), R. Tessalia Viera de Camargo, Campinas, 13083-887, Brazil
k Department of Neurology, Hospital Virgen Del Rocio, University of Seville, Seville, 41013, Spain
l Hospital Virgen de la Macarena, University of Seville, Seville, 41009, Spain
m Department of Neurology, Hospital Clinico Universitario Valladolid, Valladolid University, Valladolid, 47003, Spain
n Department of Neurology, Mutua Terrassa University Hospital, Universitat de Barcelona, Terrassa, 08221, Spain
o Fundacio Docencia i Recerca Mutua Terrassa, Universitat de Barcelona, Terrassa, 08221, Spain
p Department of Neurology, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona, 08041, Spain
q Department of Neurology, Southern Illinois Healthcare Memorial Hospital of Carbondale, Carbondale, IL 62901, United States
r Department of Biology, Universitat de les Illes Balears, Palma, 07122, Spain
t Department of Neurology, Hospital Universitari Son Espases, Universitat de les Illes Balears, Palma, 07120, Spain
u Research Unit, Complejo Hospitalario Universitario de Albacete, Albacete, 02008, Spain
v Department of Neurology, Samsung Medical Center, Seoul, South Korea
w Neurovascular Research Group, Institut Hospital Del Mar de Investigacions Mediques, Barcelona, 08003, Spain
x Department of Surgical Sciences, Orthopedics Uppsala University, Uppsala, 75185, Sweden
y Department of Neurology, Jagiellonian University, Krakow, 31-007, Poland
z Department of Neurology, Hospital Germans Trias i Pujol, Universitat Autonoma de Barcelona, Badalona, 08916, Spain
aa Department of Neurology, Hospital Universitario Central de Asturias, Oviedo, Spain
ab Department of Neurology, Sahlgrenska University Hospital, University of Gothenburg, Gothenburg, 413 45, Sweden
ac Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
ad Clinical Neurosciences Research Laboratory, Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, 15706, Spain
ae Department of Radiology, School of Medicine, Washington University, Saint Louis, MO 63110, United States
af Instituto Nacional de Neurologia y Neurocirurgia de Mexico, Ciudad de Mexico, 14269, Mexico
ag Department of Neurology, Providence St. Vincent Medical Center, Portland, OR 97225, United States
ah Neurosciences Department, Hospital Rafael A. Calderon Guardia, Aranjuez, Costa Rica
ai Department of Neurology and MIND Institute, University of California at Davis, Sacramento, CA 95817, United States
aj Department of Neurology, Helsinki University Hospital, Helsinki, 00290, Finland
ak Translational Biology, Biogen, Inc, Cambridge, MA 02142, United States
al Genetics and Neurodevelopmental Disease Research Unit, Biogen, Inc, Cambridge, MA 02142, United States
am Department of Biomedical Engineering, School of Medicine, Washington University, Saint Louis, MO 63110, United States
an Stroke and Cerebrovascular Center, School of Medicine, Washington University, Saint Louis, MO 63110, United States
ao Department of Genetics, School of Medicine, Washington University, Saint Louis, MO 63110, United States

Abstract
During the first hours after stroke onset, neurological deficits can be highly unstable: some patients rapidly improve, while others deteriorate. This early neurological instability has a major impact on long-Term outcome. Here, we aimed to determine the genetic architecture of early neurological instability measured by the difference between the National Institutes of Health Stroke Scale (NIHSS) within 6h of stroke onset and NIHSS at 24h. A total of 5876 individuals from seven countries (Spain, Finland, Poland, USA, Costa Rica, Mexico and Korea) were studied using a multi-Ancestry meta-Analyses. We found that 8.7% of NIHSS at 24h of variance was explained by common genetic variations, and also that early neurological instability has a different genetic architecture from that of stroke risk. Eight loci (1p21.1, 1q42.2, 2p25.1, 2q31.2, 2q33.3, 5q33.2, 7p21.2 and 13q31.1) were genome-wide significant and explained 1.8% of the variability suggesting that additional variants influence early change in neurological deficits. We used functional genomics and bioinformatic annotation to identify the genes driving the association from each locus. Expression quantitative trait loci mapping and summary data-based Mendelian randomization indicate that ADAM23 (log Bayes factor = 5.41) was driving the association for 2q33.3. Gene-based analyses suggested that GRIA1 (log Bayes factor = 5.19), which is predominantly expressed in the brain, is the gene driving the association for the 5q33.2 locus. These analyses also nominated GNPAT (log Bayes factor = 7.64) ABCB5 (log Bayes factor = 5.97) for the 1p21.1 and 7p21.1 loci. Human brain single-nuclei RNA-sequencing indicates that the gene expression of ADAM23 and GRIA1 is enriched in neurons. ADAM23, a presynaptic protein and GRIA1, a protein subunit of the AMPA receptor, are part of a synaptic protein complex that modulates neuronal excitability. These data provide the first genetic evidence in humans that excitotoxicity may contribute to early neurological instability after acute ischaemic stroke. © 2022 The Author(s). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.

Author Keywords
genetics;  ischaemic stroke;  neuroprotection;  NIHSS

Document Type: Article
Publication Stage: Final
Source: Scopus

Causal links among amyloid, tau, and neurodegeneration” (2022) Brain Communications

Causal links among amyloid, tau, and neurodegeneration
(2022) Brain Communications, 4 (4), art. no. fcac193, . 

Bilgel, M.a , Wong, D.F.b , Moghekar, A.R.c , Ferrucci, L.d , Resnick, S.M.a , The Alzheimer’s Disease Neuroimaging Initiativee

a Brain Aging and Behavior Section, Laboratory of Behavioral Neuroscience, National Institute on Aging, Baltimore, MD 21224, United States
b Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO 63110, United States
c Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21224, United States
d Longitudinal Studies Section, Translational Gerontology Branch, National Institute on Aging, Baltimore, MD 21224, United States

Abstract
Amyloid-β pathology is associated with greater tau pathology and facilitates tau propagation from the medial temporal lobe to the neocortex, where tau is closely associated with local neurodegeneration. The degree of the involvement of amyloid-β versus existing tau pathology in tau propagation and neurodegeneration has not been fully elucidated in human studies. Careful quantification of these effects can inform the development and timing of therapeutic interventions. We conducted causal mediation analyses to investigate the relative contributions of amyloid-β and existing tau to tau propagation and neurodegeneration in two longitudinal studies of individuals without dementia: the Baltimore Longitudinal Study of Aging (N = 103, age range 57-96) and the Alzheimer’s Disease Neuroimaging Initiative (N = 122, age range 56-92). As proxies of neurodegeneration, we investigated cerebral blood flow, glucose metabolism, and regional volume. We first confirmed that amyloid-β moderates the association between tau in the entorhinal cortex and in the inferior temporal gyrus, a neocortical region exhibiting early tau pathology (amyloid group × entorhinal tau interaction term β = 0.488, standard error [SE] = 0.126, P < 0.001 in the Baltimore Longitudinal Study of Aging; β = 0.619, SE = 0.145, P < 0.001 in the Alzheimer’s Disease Neuroimaging Initiative). In causal mediation analyses accounting for this facilitating effect of amyloid, amyloid positivity had a statistically significant direct effect on inferior temporal tau as well as an indirect effect via entorhinal tau (average direct effect =0.47, P < 0.001 and average causal mediation effect =0.44, P = 0.0028 in Baltimore Longitudinal Study of Aging; average direct effect =0.43, P = 0.004 and average causal mediation effect =0.267, P = 0.0088 in Alzheimer’s Disease Neuroimaging Initiative). Entorhinal tau mediated up to 48% of the total effect of amyloid on inferior temporal tau. Higher inferior temporal tau was associated with lower colocalized cerebral blood flow, glucose metabolism, and regional volume, whereas amyloid had only an indirect effect on these measures via tau, implying tau as the primary driver of neurodegeneration (amyloid-cerebral blood flow average causal mediation effect =-0.28, P = 0.021 in Baltimore Longitudinal Study of Aging; amyloid-volume average causal mediation effect =-0.24, P < 0.001 in Alzheimer’s Disease Neuroimaging Initiative). Our findings suggest targeting amyloid or medial temporal lobe tau might slow down neocortical spread of tau and subsequent neurodegeneration, but a combination therapy may yield better outcomes. © 2022 Published by Oxford University Press on behalf of the Guarantors of Brain.

Author Keywords
amyloid;  causal mediation;  longitudinal;  neurodegeneration;  tau

Document Type: Article
Publication Stage: Final
Source: Scopus

Genotype-phenotype correlations in valosin-containing protein disease: A retrospective muticentre study” (2022) Journal of Neurology, Neurosurgery and Psychiatry

Genotype-phenotype correlations in valosin-containing protein disease: A retrospective muticentre study
(2022) Journal of Neurology, Neurosurgery and Psychiatry, art. no. 328921, . 

Schiava, M.a , Ikenaga, C.b , Villar-Quiles, R.N.c , Caballero-Ávila, M.d , Topf, A.e , Nishino, I.f , Kimonis, V.g , Udd, B.h i , Schoser, B.j , Zanoteli, E.k , Souza, P.V.S.l , Tasca, G.m , Lloyd, T.b , Lopez-De Munain, A.n , Paradas, C.o p q , Pegoraro, E.r , Nadaj-Pakleza, A.s , De Bleecker, J.t , Badrising, U.u , Alonso-Jiménez, A.v , Kostera-Pruszczyk, A.w , Miralles, F.x , Shin, J.-H.y , Bevilacqua, J.A.z aa , Olivé, M.ab ac ad , Vorgerd, M.ae , Kley, R.af , Brady, S.ag , Williams, T.ah , Domínguez-González, C.ai aj , Papadimas, G.K.ak , Warman, J.al , Claeys, K.G.am an , De Visser, M.ao , Muelas, N.ai ap aq , Laforet, P.ar , Malfatti, E.as , Alfano, L.N.at au , Nair, S.S.av , Manousakis, G.aw , Kushlaf, H.A.ax , Harms, M.B.ay , Nance, C.az , Ramos-Fransi, A.ba , Rodolico, C.bb , Hewamadduma, C.bc , Cetin, H.bd , García-García, J.be , Pál, E.bf , Farrugia, M.E.bg , Lamont, P.J.bh , Quinn, C.bi , Nedkova-Hristova, V.bj , Peric, S.bk , Luo, S.bl bm , Oldfors, A.bn , Taylor, K.bo , Ralston, S.bp , Stojkovic, T.c , Weihl, C.bq , Diaz-Manera, J.a br

a John Walton Muscular Dystrophy Research Centre, Newcastle University, Newcastle Hospitals Nhs Foundation Trusts, Newcastle Upon Tyne, United Kingdom
b Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
c Aphp, Centre de Référence des Maladies Neuromusculaires, Institut de Myologie, Sorbonne Université, Aphp, Hôpital Pitié-Salpêtrière, Paris, France
d Neuromuscular Disorders Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
e Newcastle University and Newcastle Hospitals Nhs Foundation Trusts, Newcastle University, Newcastle upon Tyne, United Kingdom
f Department of Neuromuscular Research, National Institute of Neuroscience National Center of Neurology and Psychiatry (NCNP), Tokyo, Japan
g Department of Pediatrics Division of Genetics and Genomic Medicine, University of California-Irvine Medical Center Children’s Hospital of Orange County, Orange, CA, United States
h Tampere Neuromuscular Center, Tampere University Hospital, Tampere, Finland
i Folkhalsan Genetic Institute, Helsinki University, Helsinki, Finland
j Department of Neurology, Friedrich-Baur-Institute Ludwig Maximilian University Clinics, Munich, Germany
k Department of Neurology, School of Medicine, Universidade de São Paulo (FMUSP), São Paulo, Brazil
l Disciplina de Neurologia, Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil
m Unità Operativa Complessa di Neurologia, Fondazione Policlinico Universitario A Gemelli, Irccs, Rome, Italy
n Biodonostia Neurosci. Area Grp. of Neuromuscular Dis. Biodonostia-Osakidetza Basque Health Service, San Sebastian, Spain
o Neurology Department, Neuromuscular Disorders Unit, Hospital Universitario Virgen Del Rocío, Sevilla, Spain
p Instituto de Biomedicina de Sevilla, Sevilla, Spain
q Center for Biomedical Network Research on Neurodegenerative Disorders (CIBERNED), Instituto de Salud Carlos Iii, Madrid, Spain
r Department of Neurosciences, University of Padova, Padova, Italy
s Department of Neurology, Centre de Reference des Maldies Neuromusculaires Nord-Est-Ile de France, University Hospital of Strasbourg, Strasbourg, France
t Department of Neurology and Neuromuscular Reference Center, Ghent University Hospital, Ghent, Belgium
u Department of Neurology, Leiden University Medical Centre, Leiden, Netherlands
v Department of Neurology, Neuromuscular Reference Centre, Antwerp University Hospital, Universiteit Antwerpen, Instituut Born Bunge, Antwerpen, Belgium
w Department of Neurology, Medical University of Warsaw, European Reference Network ERN-NMD, Warsaw, Poland
x Department of Neurology, Unitat de Patologia Neuromuscular i Gabinet d’Electrodiagnòstic, Hospital Universitari Son Espases, Palma de Mallorca, Spain
y Laboratory of Molecular Neurology, Pusan National University Yangsan Hospital, Yangsan, South Korea
z Unidad Neuromuscular, Departamento de Neurología y Neurocirugía, Hospital Clínico Universidad de Chile, Santiago de Chile, Chile
aa Departamento de Neurología y Neurocirugía Clínica, Clínica Dávila, Santiago, Chile
ab Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain
ac Deaprtment of Neurology, Neuromuscular Disorders Unit, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
ad Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain
ae Heimer Institut for Muscle Research, Klinikum Bergmannsheil, Ruhr University, Bochum, Germany
af Department of Neurology and Clinical Neurophysiology, St Marien-Hospital Borken, Borken, Germany
ag Neurology Department, John Radcliffe Hospital, Oxford, United Kingdom
ah Newcastle Motor Neurone Disease Care Centre, Royal Victoria Infirmary, Newcastle, United Kingdom
ai Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER), Madrid, Spain
aj Neurology Service, Hospital Universitario 12 de Octubre, Madrid, Spain
ak First Department of Neurology, Medical School, Eginition Hospital and National, Kapodistrian University of Athens, Athens, Greece
al Department of Medicine, Ottawa Neuromuscular Centre, Ottawa Hospital, Ottawa, ON, Canada
am Department of Neurology, University Hospitals Leuven, Leuven, Belgium
an Ku Leuven Laboratory for Muscle Diseases and Neuropathies, Leuven, Belgium
ao Department of Neurology, Academic Medical Center, Amsterdam, Netherlands
ap Neuromuscular Unit, Department of Neurology, Hospital Universitari i Politècnic la Fe, Valencia, Spain
aq Neuromuscular and Ataxias Research Group, Instituto de Investigación Sanitaria la Fe, Valencia, Spain
ar Neurology Department, Raymond-Poincaré Hospital, Aphp, Uvsq, Paris-Saclay University, Paris, France
as Aphp, Neuromuscular Reference Center Nord-Est-Ile-de-France, Henri Mondor Hospital, Université Paris Est, U955, Inserm, Créteil, Imrb, Paris, France
at Center for Gene Therapy, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, United States
au Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH, United States
av Department of Neurology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Kerala, Thiruvananthapuram, India
aw Department of Neurology, University of Minnesota Hospital, Minneapolis, MN, United States
ax Department of Neurology and Rehabilitation Medicine, University of Cincinnati, Cincinnati, OH, United States
ay NewYork Presbyterian Columbia University Irving Medical Centre, New York, NY, United States
az Department of Neurology, Carver College of Medicine, The University of Iowa, IowaIA, United States
ba Neuromuscular Unit, Neurology Department, Hospital Germas Trias i Pujol, Badalona, Spain
bb Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy
bc Sheffield Institute for Translational Neurosciences (SITRAN), Neuroscience Institute, University of Sheffield, Sheffield, United Kingdom
bd Department of Neurology, Medical University of Vienna, Vienna, Austria
be Neurology Department, Complejo Hospitalario Universitario de Albacete, Albacete, Spain
bf Department of Neurology, University of Pécs, Pécs, Hungary
bg Institute of Neurological Sciences, Queen Elizabeth University Hospital, Glasgow, United Kingdom
bh Department of Neurology, Royal Perth Hospital, Perth, WA, Australia
bi Neuromuscular Division, Neurology Department, University of Pennsylvania, Philadelphia, PA, United States
bj Neurology Department, Bellvitge University Hospital, Spain
bk Neurology Clinic, Clinical Centre of Serbia, Faculty of Medicine, University of Belgrade, Belgrade, Serbia
bl Department of Neurology, Huashan Hospital Fudan University, Shanghai, China
bm National Center for Neurological Disorders, Shanghai, China
bn Department of Laboratory Medicine, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden
bo Southern General Hospital, Glasgow, United Kingdom
bp Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom
bq Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
br Institut de Recerca de l’Hospital de la Santa Creu i Sant Pau, Barcelona, Spain

Abstract
Background: Valosin-containing protein (VCP) disease, caused by mutations in the VCP gene, results in myopathy, Paget’s disease of bone (PBD) and frontotemporal dementia (FTD). Natural history and genotype-phenotype correlation data are limited. This study characterises patients with mutations in VCP gene and investigates genotype-phenotype correlations. Methods: Descriptive retrospective international study collecting clinical and genetic data of patients with mutations in the VCP gene. Results: Two hundred and fifty-five patients (70.0% males) were included in the study. Mean age was 56.8±9.6 years and mean age of onset 45.6±9.3 years. Mean diagnostic delay was 7.7±6 years. Symmetric lower limb weakness was reported in 50% at onset progressing to generalised muscle weakness. Other common symptoms were ventilatory insufficiency 40.3%, PDB 28.2%, dysautonomia 21.4% and FTD 14.3%. Fifty-seven genetic variants were identified, 18 of these no previously reported. c.464G>A (p.Arg155His) was the most frequent variant, identified in the 28%. Full time wheelchair users accounted for 19.1% with a median time from disease onset to been wheelchair user of 8.5 years. Variant c.463C>T (p.Arg155Cys) showed an earlier onset (37.8±7.6 year) and a higher frequency of axial and upper limb weakness, scapular winging and cognitive impairment. Forced vital capacity (FVC) below 50% was as risk factor for being full-time wheelchair user, while FVC <70% and being a full-time wheelchair user were associated with death. Conclusion: This study expands the knowledge on the phenotypic presentation, natural history, genotype-phenotype correlations and risk factors for disease progression of VCP disease and is useful to improve the care provided to patient with this complex disease. © Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.

Author Keywords
FRONTOTEMPORAL DEMENTIA;  GENETICS;  INCL BODY MYOSITIS;  MUSCLE DISEASE;  MYOPATHY

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