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, 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, 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, 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, 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, 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, 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, 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, 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
Identification of activity-induced Egr3-dependent genes reveals genes associated with DNA damage response and schizophrenia
(2022) Translational Psychiatry, 12 (1), art. no. 320, .
Marballi, K.K.a b , Alganem, K.c , Brunwasser, S.J.d , Barkatullah, A.a e , Meyers, K.T.a e f , Campbell, J.M.a , Ozols, A.B.a , Mccullumsmith, R.E.c g , Gallitano, A.L.a
a Department of Basic Medical Sciences, University of Arizona College of Medicine – Phoenix, Phoenix, AZ 85004, United States
b Northeastern University, Toronto, ON M5X 1E2, Canada
c Department of Neurosciences, University of Toledo College of Medicine and Life Sciences, Toledo, OH, United States
d Washington University, Washington University School of Medicine, St. Louis, MO 63110, United States
e School of Life Sciences, Arizona State University, Tempe, AZ 85287, United States
f Department of Neurobiology, Barrow Neurological Institute, Phoenix, AZ 85013, United States
g Neurosciences Institute, ProMedica, Toledo, OH, United States
Abstract
Bioinformatics and network studies have identified the immediate early gene transcription factor early growth response 3 (EGR3) as a master regulator of genes differentially expressed in the brains of patients with neuropsychiatric illnesses ranging from schizophrenia and bipolar disorder to Alzheimer’s disease. However, few studies have identified and validated Egr3-dependent genes in the mammalian brain. We have previously shown that Egr3 is required for stress-responsive behavior, memory, and hippocampal long-term depression in mice. To identify Egr3-dependent genes that may regulate these processes, we conducted an expression microarray on hippocampi from wildtype (WT) and Egr3−/− mice following electroconvulsive seizure (ECS), a stimulus that induces maximal expression of immediate early genes including Egr3. We identified 69 genes that were differentially expressed between WT and Egr3−/− mice one hour following ECS. Bioinformatic analyses showed that many of these are altered in, or associated with, schizophrenia, including Mef2c and Calb2. Enrichr pathway analysis revealed the GADD45 (growth arrest and DNA-damage-inducible) family (Gadd45b, Gadd45g) as a leading group of differentially expressed genes. Together with differentially expressed genes in the AP-1 transcription factor family genes (Fos, Fosb), and the centromere organization protein Cenpa, these results revealed that Egr3 is required for activity-dependent expression of genes involved in the DNA damage response. Our findings show that EGR3 is critical for the expression of genes that are mis-expressed in schizophrenia and reveal a novel requirement for EGR3 in the expression of genes involved in activity-induced DNA damage response. © 2022, The Author(s).
Funding details
National Institutes of HealthNIHR01MH097803, R01MH107487, R01MH121102, R21MH113154
National Institute of Mental HealthNIMH
National Institute on AgingNIAR01AG057598
Document Type: Article
Publication Stage: Final
Source: Scopus
Structural covariance of the ventral visual stream predicts posttraumatic intrusion and nightmare symptoms: a multivariate data fusion analysis
(2022) Translational Psychiatry, 12 (1), art. no. 321, .
Harnett, N.G.a b , Finegold, K.E.a , Lebois, L.A.M.a b , van Rooij, S.J.H.c , Ely, T.D.c , Murty, V.P.d , Jovanovic, T.e , Bruce, S.E.f , House, S.L.g , Beaudoin, F.L.h , An, X.i , Zeng, D.j , Neylan, T.C.k , Clifford, G.D.l m , Linnstaedt, S.D.i , Germine, L.T.b n o , Bollen, K.A.p , Rauch, S.L.b n q , Haran, J.P.r , Storrow, A.B.s , Lewandowski, C.t , Musey, P.I.u , Hendry, P.L.v , Sheikh, S.v , Jones, C.W.w , Punches, B.E.x y , Kurz, M.C.z aa ab , Swor, R.A.ac , Hudak, L.A.ad , Pascual, J.L.ae af , Seamon, M.J.af ag , Harris, E.ah , Chang, A.M.ai , Pearson, C.aj , Peak, D.A.ak , Domeier, R.M.al , Rathlev, N.K.am , O’Neil, B.J.an , Sergot, P.ao , Sanchez, L.D.ap aq , Miller, M.W.ar as , Pietrzak, R.H.at au , Joormann, J.av , Barch, D.M.aw , Pizzagalli, D.A.a b , Sheridan, J.F.ax ay , Harte, S.E.az ba , Elliott, J.M.bb bc bd , Kessler, R.C.be , Koenen, K.C.bf , McLean, S.A.bg bh , Nickerson, L.D.b bi , Ressler, K.J.a b , Stevens, J.S.c
a Division of Depression and Anxiety, McLean Hospital, Belmont, MA, United States
b Department of Psychiatry, Harvard Medical School, Boston, MA, United States
c Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, United States
d Department of Psychology, Temple University, Philadelphia, PA, United States
e Department of Psychiatry and Behavioral Neurosciences, Wayne State University, Detroit, MI, United States
f Department of Psychological Sciences, University of Missouri – St. Louis, St. Louis, MO, United States
g Department of Emergency Medicine, Washington University School of Medicine, St. Louis, MO, United States
h Department of Emergency Medicine & Department of Health Services, Policy, and Practice, The Alpert Medical School of Brown University, Rhode Island Hospital and The Miriam Hospital, Providence, RI, United States
i Institute for Trauma Recovery, Department of Anesthesiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
j Department of Biostatistics, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, United States
k Departments of Psychiatry and Neurology, University of California San Francisco, San Francisco, CA, United States
l Department of Biomedical Informatics, Emory University School of Medicine, Atlanta, GA, United States
m Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, United States
n Institute for Technology in Psychiatry, McLean Hospital, Belmont, MA, United States
o The Many Brains Project, Belmont, MA, United States
p Department of Psychology and Neuroscience & Department of Sociology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
q Department of Psychiatry, McLean Hospital, Belmont, MA, United States
r Department of Emergency Medicine, University of Massachusetts Chan Medical School, Worcester, MA, United States
s Department of Emergency Medicine, Vanderbilt University Medical Center, Nashville, TN, United States
t Department of Emergency Medicine, Henry Ford Health System, Detroit, MI, United States
u Department of Emergency Medicine, Indiana University School of Medicine, Indianapolis, IN, United States
v Department of Emergency Medicine, University of Florida College of Medicine-Jacksonville, Jacksonville, FL, United States
w Department of Emergency Medicine, Cooper Medical School of Rowan University, Camden, NJ, United States
x Department of Emergency Medicine, Ohio State University College of Medicine, Columbus, OH, United States
y Ohio State University College of Nursing, Columbus, OH, United States
z Department of Emergency Medicine, University of Alabama School of Medicine, Birmingham, AL, United States
aa Department of Surgery, Division of Acute Care Surgery, University of Alabama School of Medicine, Birmingham, AL, United States
ab Center for Injury Science, University of Alabama at Birmingham, Birmingham, AL, United States
ac Department of Emergency Medicine, Oakland University William Beaumont School of Medicine, Rochester, MI, United States
ad Department of Emergency Medicine, Emory University School of Medicine, Atlanta, GA, United States
ae Department of Surgery, Department of Neurosurgery, University of Pennsylvania, Philadelphia, PA, United States
af Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
ag Department of Surgery, Division of Traumatology, Surgical Critical Care and Emergency Surgery, University of Pennsylvania, Philadelphia, PA, United States
ah Einstein Medical Center, Philadelphia, PA, United States
ai Department of Emergency Medicine, Jefferson University Hospitals, Philadelphia, PA, United States
aj Department of Emergency Medicine, Wayne State University, Ascension St. John Hospital, Detroit, MI, United States
ak Department of Emergency Medicine, Massachusetts General Hospital, Boston, MA, United States
al Department of Emergency Medicine, Saint Joseph Mercy Hospital, Ypsilanti, MI, United States
am Department of Emergency Medicine, University of Massachusetts Medical School-Baystate, Springfield, MA, United States
an Department of Emergency Medicine, Wayne State University, Detroit Receiving Hospital, Detroit, MI, United States
ao Department of Emergency Medicine, McGovern Medical School, University of Texas Health, Houston, TX, United States
ap Department of Emergency Medicine, Brigham and Women’s Hospital, Boston, MA, United States
aq Department of Emergency Medicine, Harvard Medical School, Boston, MA, United States
ar National Center for PTSD, Behavioral Science Division, VA Boston Healthcare System, Boston, MA, United States
as Department of Psychiatry, Boston University School of Medicine, Boston, MA, United States
at National Center for PTSD, Clinical Neurosciences Division, VA Connecticut Healthcare System, West Haven, CT, United States
au Department of Psychiatry, Yale School of Medicine, New Haven, CT, United States
av Department of Psychology, Yale University, New Haven, CT, United States
aw Department of Psychological & Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States
ax Division of Biosciences, Ohio State University College of Dentistry, Columbus, OH, United States
ay Institute for Behavioral Medicine Research, OSU Wexner Medical Center, Columbus, OH, United States
az Department of Anesthesiology, University of Michigan Medical School, Ann Arbor, MI, United States
ba Department of Internal Medicine-Rheumatology, University of Michigan Medical School, Ann Arbor, MI, United States
bb Kolling Institute, University of Sydney, St Leonards, NSW, Australia
bc Faculty of Medicine and Health, University of Sydney, Northern Sydney Local Health DistrictNSW, Australia
bd Physical Therapy & Human Movement Sciences, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
be Department of Health Care Policy, Harvard Medical School, Boston, MA, United States
bf Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, United States
bg Department of Emergency Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
bh Institute for Trauma Recovery, Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
bi McLean Imaging Center, McLean Hospital, Belmont, MA, United States
Abstract
Visual components of trauma memories are often vividly re-experienced by survivors with deleterious consequences for normal function. Neuroimaging research on trauma has primarily focused on threat-processing circuitry as core to trauma-related dysfunction. Conversely, limited attention has been given to visual circuitry which may be particularly relevant to posttraumatic stress disorder (PTSD). Prior work suggests that the ventral visual stream is directly related to the cognitive and affective disturbances observed in PTSD and may be predictive of later symptom expression. The present study used multimodal magnetic resonance imaging data (n = 278) collected two weeks after trauma exposure from the AURORA study, a longitudinal, multisite investigation of adverse posttraumatic neuropsychiatric sequelae. Indices of gray and white matter were combined using data fusion to identify a structural covariance network (SCN) of the ventral visual stream 2 weeks after trauma. Participant’s loadings on the SCN were positively associated with both intrusion symptoms and intensity of nightmares. Further, SCN loadings moderated connectivity between a previously observed amygdala-hippocampal functional covariance network and the inferior temporal gyrus. Follow-up MRI data at 6 months showed an inverse relationship between SCN loadings and negative alterations in cognition in mood. Further, individuals who showed decreased strength of the SCN between 2 weeks and 6 months had generally higher PTSD symptom severity over time. The present findings highlight a role for structural integrity of the ventral visual stream in the development of PTSD. The ventral visual stream may be particularly important for the consolidation or retrieval of trauma memories and may contribute to efficient reactivation of visual components of the trauma memory, thereby exacerbating PTSD symptoms. Potentially chronic engagement of the network may lead to reduced structural integrity which becomes a risk factor for lasting PTSD symptoms. © 2022, The Author(s).
Funding details
R33AG05654
National Science FoundationNSF
National Institutes of HealthNIHR01HD079076, R03HD094577
U.S. Department of Health and Human ServicesHHS
National Institute of Mental HealthNIMHK00MH119603, K01MH118467, U01MH110925
Centers for Disease Control and PreventionCDC
Substance Abuse and Mental Health Services AdministrationSAMHSA1H79TI083101-01
Medical Research and Materiel CommandMRMC
Bill and Melinda Gates FoundationBMGF
Brain and Behavior Research FoundationBBRF
Gordon and Betty Moore FoundationGBMF
Dana FoundationDF
Blue Cross and Blue Shield of Florida Foundation
Allergan Foundation
Microsoft ResearchMSR
eNeura Therapeutics
Vanderbilt UniversityVU
Google
University of North CarolinaUNC
National Center for Medical Rehabilitation ResearchNCMRR
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHD
Jazz Pharmaceuticals
International Society for the Study of Trauma and DissociationISSTD
ACADIA PharmaceuticalsACADIA
MathWorks
Rainwater Charitable FoundationRCF
NSW Ministry of Health
Document Type: Article
Publication Stage: Final
Source: Scopus
Corpora amylacea are associated with tau burden and cognitive status in Alzheimer’s disease
(2022) Acta Neuropathologica Communications, 10 (1), art. no. 110, .
Wander, C.M.a b , Tsujimoto, T.H.M.c , Ervin, J.F.d , Wang, C.e , Maranto, S.M.a , Bhat, V.a , Dallmeier, J.D.f , Wang, S.-H.J.d g , Lin, F.-C.c , Scott, W.K.f h i , Holtzman, D.M.e , Cohen, T.J.a j
a Department of Neurology, UNC Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
b Department of Pharmacology, University of North Carolina, Chapel Hill, NC, United States
c Department of Biostatistics, University of North Carolina, Chapel Hill, NC, United States
d Bryan Brain Bank, Department of Neurology, Duke University School of Medicine, Durham, NC, United States
e Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, MO, United States
f Brain Endowment Bank, Department of Neurology, University of Miami Miller School of Medicine, Miami, FL, United States
g Department of Pathology, Duke University School of Medicine, Durham, NC, United States
h John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, United States
i Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL, United States
j Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC, United States
Abstract
Corpora amylacea (CA) and their murine analogs, periodic acid Schiff (PAS) granules, are age-related, carbohydrate-rich structures that serve as waste repositories for aggregated proteins, damaged cellular organelles, and other cellular debris. The structure, morphology, and suspected functions of CA in the brain imply disease relevance. Despite this, the link between CA and age-related neurodegenerative diseases, particularly Alzheimer’s disease (AD), remains poorly defined. We performed a neuropathological analysis of mouse PAS granules and human CA and correlated these findings with AD progression. Increased PAS granule density was observed in symptomatic tau transgenic mice and APOE knock-in mice. Using a cohort of postmortem AD brain samples, we examined CA in cognitively normal and dementia patients across Braak stages with varying APOE status. We identified a Braak-stage dependent bimodal distribution of CA in the dentate gyrus, with CA accumulating and peaking by Braak stages II–III, then steadily declining with increasing tau burden. Refined analysis revealed an association of CA levels with both cognition and APOE status. Finally, tau was detected in whole CA present in human patient cerebrospinal fluid, highlighting CA-tau as a plausible prodromal AD biomarker. Our study connects hallmarks of the aging brain with the emergence of AD pathology and suggests that CA may act as a compensatory factor that becomes depleted with advancing tau burden. © 2022, The Author(s).
Funding details
U54HD079124
National Institutes of HealthNIHR01AG061188, R01AG066871
National Center for Advancing Translational SciencesNCATSP30AG072958, UL1TR001111
University of North CarolinaUNCP30NS045892
JPB FoundationJPBFRF1AG047644, RF1NS090934
Cure Alzheimer’s FundCAF
Document Type: Article
Publication Stage: Final
Source: Scopus
Discovery and validation of dominantly inherited Alzheimer’s disease mutations in populations from Latin America
(2022) Alzheimer’s Research and Therapy, 14 (1), art. no. 108, .
Takada, L.T.a , Aláez-Verson, C.b , Burgute, B.D.c , Nitrini, R.a , Sosa, A.L.d , Castilhos, R.M.e , Chaves, M.F.e f , Longoria, E.-M.d , Carrillo-Sánchez, K.b , Brucki, S.M.D.a , Flores-Lagunes, L.L.b , Molina, C.b , Olivares, M.J.b , Ziegemeier, E.g , Petranek, J.g , Goate, A.M.h , Cruchaga, C.c , Renton, A.E.h , Fernández, M.V.c , Day, G.S.i , McDade, E.g , Bateman, R.J.g , Karch, C.M.c , Llibre-Guerra, J.J.g , for the Dominantly Inherited Alzheimer Networkj
a Department of Neurology, Hospital das Clinicas, University of São Paulo Medical School, São Paulo, Brazil
b Laboratorio de Diagnóstico Genómico, Instituto Nacional de Medicina Genómica, Ciudad de México, Mexico
c Department of Psychiatry, Washington University School of Medicine, St Louis, MO, United States
d Instituto Nacional de Neurología y Neurocirugía, Ciudad de Mexico, Mexico
e Neurology Service, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
f Department of Internal Medicine, Faculty of Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
g Department of Neurology, Washington University School of Medicine, St Louis, MO, United States
h Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, United States
i Department of Neurology, Mayo Clinic Florida, Jacksonville, FL, United States
Abstract
Background: In fewer than 1% of patients, AD is caused by autosomal dominant mutations in either the presenilin 1 (PSEN1), presenilin 2 (PSEN2), or amyloid precursor protein (APP) genes. The full extent of familial AD and frequency of these variants remains understudied in Latin American (LatAm) countries. Due to the rare nature of these variants, determining the pathogenicity of a novel variant in these genes can be challenging. Here, we use a systematic approach to assign the likelihood of pathogenicity in variants from densely affected families in Latin American populations. Methods: Clinical data was collected from LatAm families at risk for DIAD. Symptomatic family members were identified and assessed by local clinicians and referred for genetic counseling and testing. To determine the likelihood of pathogenicity among variants of unknown significance from LatAm populations, we report pedigree information, frequency in control populations, in silico predictions, and cell-based models of amyloid-beta ratios. Results: We identified five novel variants in the presenilin1 (PSEN1) gene from Brazilian and Mexican families. The mean age at onset in newly identified families was 43.5 years (range 36–54). PSEN1 p.Val103_Ser104delinsGly, p.Lys395Ile, p.Pro264Se, p.Ala275Thr, and p.Ile414Thr variants have not been reported in PubMed, ClinVar, and have not been reported in dominantly inherited AD (DIAD) families. We found that PSEN1 p.Val103_Ser104delinsGly, p.Lys395Ile, p.Pro264Se, and p.Ala275Thr produce Aβ profiles consistent with known AD pathogenic mutations. PSEN1 p.Ile414Thr did not alter Aβ in a manner consistent with a known pathogenic mutation. Conclusions: Our study provides further insights into the genetics of AD in LatAm. Based on our findings, including clinical presentation, imaging, genetic, segregations studies, and cell-based analysis, we propose that PSEN1 p.Val103_Ser104delinsGly, p.Lys395Ile, p.Pro264Se, and p.Ala275Thr are likely pathogenic variants resulting in DIAD, whereas PSEN1 p.Ile414Thr is likely a risk factor. This report is a step forward to improving the inclusion/engagement of LatAm families in research. Family discovery is of great relevance for the region, as new initiatives are underway to extend clinical trials and observational studies to families living with DIAD. © 2022, The Author(s).
Author Keywords
Dominantly inherited Alzheimer disease; Early-onset Alzheimer disease; Latin America; Presenilin 1
Funding details
National Institute on AgingNIA
Alzheimer’s AssociationAASG-20-690363
Foundation for Barnes-Jewish HospitalFBJH
Japan Agency for Medical Research and DevelopmentAMED
Consejo Nacional de Investigaciones Científicas y TécnicasCONICETPICT 2015/2110
Korea Health Industry Development InstituteKHIDI
Deutsches Zentrum für Neurodegenerative ErkrankungenDZNE
Fleni
Document Type: Article
Publication Stage: Final
Source: Scopus
Infants’ selective imitation of a transitive agent and an intransitive agent
(2022) Journal of Experimental Child Psychology, 224, art. no. 105517, .
Luo, Y.a , Pattanakul, D.a , Weng, Q.a , Markson, L.b
a University of Missouri, Columbia, MO 65211, United States
b Washington University at St. Louis, St. Louis, MO 63130, United States
Abstract
This study examined how the reliability (i.e., transitivity) of an agent’s object choices affects 16-month-old infants’ (N = 48) imitation of her unconventional way of turning on a touch light box with her head when her hands were available. When the agent made transitive choices (i.e., she chose Object A over Object B, Object B over Object C, and then A over C), infants imitated her head touch actions. When the agent made intransitive choices (i.e., after choosing A over B and B over C, she chose C over A), infants were more likely to use only their hands to touch the light box. In addition, when it was presumably difficult for infants to judge the transitivity of the agent’s choices (i.e., she chose B over C, A over B, and then A over C), they used their hands more. These results demonstrate that infants’ understanding informs their decisions to selectively imitate others’ specific ways to act on novel artifacts, consistent with young children’s selective trust in information provided by other people based on their epistemic reliability. © 2022 Elsevier Inc.
Author Keywords
Cognitive development; Epistemic trust; Imitation; Infancy; Social cognition; Transitivity
Funding details
National Science FoundationNSF2123485, 2123494
University of MissouriMU
Document Type: Article
Publication Stage: Final
Source: Scopus
Gonadal sex patterns p21-induced cellular senescence in mouse and human glioblastoma
(2022) Communications Biology, 5 (1), art. no. 781, .
Broestl, L.a , Warrington, N.M.a , Grandison, L.a , Abou-Antoun, T.a , Tung, O.a , Shenoy, S.b , Tallman, M.M.c d , Rhee, G.a , Yang, W.e , Sponagel, J.a , Yang, L.a , Kfoury-Beaumont, N.a f , Hill, C.M.a , Qanni, S.A.a , Mao, D.D.g h i , Kim, A.H.g h i , Stewart, S.A.i j k l , Venere, M.c , Luo, J.m , Rubin, J.B.a h
a Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
b Brown School, Washington University in St. Louis, St. Louis, MO, United States
c Department of Radiation Oncology, James Cancer Hospital and Comprehensive Cancer Center, The Ohio State University Wexner School of Medicine, Columbus, OH, United States
d Biomedical Sciences Graduate Program, The Ohio State University, Columbus, OH, United States
e Department of Genetics, Washington University School of Medicine, St. Louis, MO, United States
f Department of Neurological Surgery, University of California San Diego, La Jolla, CA, United States
g Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO, United States
h Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, United States
i Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, United States
j Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO, United States
k Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States
l ICCE Institute, Washington University School of Medicine, St. Louis, MO, United States
m Department of Surgery, Washington University School of Medicine, St. Louis, MO, United States
Abstract
Males exhibit higher incidence and worse prognosis for the majority of cancers, including glioblastoma (GBM). Disparate survival may be related to sex-biased responses to treatment, including radiation. Using a mouse model of GBM, we show that female cells are more sensitive to radiation, and that senescence represents a major component of the radiation therapeutic response in both sexes. Correlation analyses revealed that the CDK inhibitor p21 and irradiation induced senescence were differentially regulated between male and female cells. Indeed, female cellular senescence was more sensitive to changes in p21 levels, a finding that was observed in wildtype and transformed murine astrocytes, as well as patient-derived GBM cell lines. Using a novel Four Core Genotypes model of GBM, we further show that sex differences in p21-induced senescence are patterned during early development by gonadal sex. These data provide a rationale for the further study of sex differences in radiation response and how senescence might be enhanced for radiation sensitization. The determination that p21 and gonadal sex are required for sex differences in radiation response will serve as a foundation for these future mechanistic studies. © 2022, The Author(s).
Funding details
R01 NS094670, R01 NS106612, R03 CA227206, RSG-18-066-01-TBG
National Institutes of HealthNIHR01 CA174737-06, R21 NS098210, T32GM068412-11A1
American Cancer SocietyACS
National Cancer InstituteNCIP30 CA091842
National Institute of General Medical SciencesNIGMS
Washington University in St. LouisWUSTLT34 GM083914
Alvin J. Siteman Cancer Center
Document Type: Article
Publication Stage: Final
Source: Scopus
Excessive screen time behaviors and cognitive difficulties among adolescents in the United States: Results from the 2017 and 2019 national youth risk behavior survey
(2022) Psychiatry Research, 316, art. no. 114740, .
Onyeaka, H.K.a b c , Muoghalu, C.d e , Baiden, P.f , Okine, L.g , Szlyk, H.S.h , Peoples, J.E.i , Kasson, E.h , Cavazos-Rehg, M.S.W.P.h , Firth, J.j , Torous, J.a k
a Harvard Medical School, Department of Psychiatry, Boston, MA 02115, United States
b Massachusetts General Hospital, Department of Psychiatry, Boston, MA 02115, United States
c McLean Hospital, Department of Psychiatry, Boston, MA 02478, United States
d Plains Regional Medical Center, Clovis, NM 88101, United States
e Duke University School of MedicineNC 27710, United States
f The University of Texas at Arlington, School of Social Work, 211 S. Cooper St., Box 19129, Arlington, TX 76019, United States
g University of Southern California, USC Suzanne Dworak-Peck School of Social Work, 669 W 34th St. Los AngelesCA 90089, United States
h Department of Psychiatry, Washington University School of Medicine, 660 South Euclid Avenue, Box 8134, St. Louis, MO 63110, United States
i The Brown School at Washington University in St. Louis, St. Louis, MO 63130, United States
j Division of Psychology and Mental Health, The University of ManchesterManchester, United Kingdom
k Department of Psychiatry, Beth Israel Deaconess Medical Center, Boston, MA, United States
Abstract
Background: The widespread use of digital media by young people has generated speculations that their excessive use may have deleterious cognitive effects. Previous studies examining the association between screen time and cognitive deficits in youth have yielded mixed conclusions. We study this association using a nationally representative sample of school going adolescents in the United States. Methods: We queried data from the 2017 and 2019 Youth Risk Behavior Survey. An analytic sample of 17,076 adolescents was analyzed using binary logistic regression. Outcome variable was cognitive difficulties (difficulty in concentrating, remembering, or making decisions), and the explanatory variable was excessive screen-time behaviors. Results: Of the 17,076 adolescents, about one in three (34.1%) had cognitive difficulties, and 45% of adolescents engaged in excessive screen-time behaviors on an average school day. After adjusting for covariates, the odds were 1.28 times higher for adolescents who engaged in excessive screen-time behaviors to report serious cognitive difficulties compared to adolescents who did not engage in excessive screen-time behaviors (AOR = 1.28, p <.001, 95% CI = 1.18–1.40). Conclusion: Study results support the association between excessive screen behaviors and cognitive difficulties in adolescence. Findings of this study are discussed with implications for practice and research. © 2022
Author Keywords
Cognitive; Mental health; Screen time; Youth
Funding details
MR/T021780/1
American Psychiatric AssociationAPA
American Psychiatric Association FoundationAPAF
University of ManchesterP123958
Document Type: Article
Publication Stage: Final
Source: Scopus
Monitoring condensate dynamics in S. cerevisiae using fluorescence recovery after photobleaching
(2022) STAR protocols, 3 (3), p. 101592.
Sprunger, M.L., Jackrel, M.E.
Department of Chemistry, Washington University, St. Louis, MO 63130, USA
Abstract
This protocol describes the use of fluorescence recovery after photobleaching (FRAP) to investigate the dynamics of Matrin-3 (MATR3) condensates in live budding yeast. We detail how to generate yeast strains containing MATR3 with an enhanced green fluorescent protein (eGFP) tag and induce MATR3-eGFP expression. We provide steps to prepare slides of immobilized yeast cells and perform FRAP imaging and data analysis. This protocol can be broadly applied to study condensate dynamics of a range of proteins in different model systems. For complete details on the use and execution of this protocol, please refer to Sprunger et al. (2022). © 2022 The Author(s).
Author Keywords
Biophysics; Cell Biology; Microscopy; Model Organisms; Protein Biochemistry
Document Type: Article
Publication Stage: Final
Source: Scopus
Cognability: An Ecological Theory of neighborhoods and cognitive aging
(2022) Social Science and Medicine, 309, art. no. 115220, .
Finlay, J.a b , Esposito, M.c , Langa, K.M.d , Judd, S.e , Clarke, P.a b
a Social Environment and Health Program, Institute for Social Research, University of Michigan, 426 Thompson Street, Ann Arbor, MI 48104, United States
b Center for Social Epidemiology and Population Health, Department of Epidemiology, School of Public Health, University of Michigan, 1415 Washington Heights, Ann Arbor, MI 48109, United States
c Department of Sociology, Washington University in St. Louis, St. Louis, MO 63130, United States
d Department of Internal Medicine, Division of General Medicine, 2800 Plymouth Road, Ann Arbor, MI 48109, United States
e School of Public Health, University of Alabama at Birmingham, 1665 University Blvd, Birmingham, AL 35233, United States
Abstract
While a growing body of evidence points to potentially modifiable individual risk factors for dementia, the built and social environments in which people develop and navigate cognitive decline are largely overlooked. This paper proposes a new theoretical concept, Cognability, to conceptualize how supportive an area is to cognitive health among aging residents. Cognability incorporates a constellation of both positive and negative neighborhood features related to physical activity, social interaction and cognitive stimulation in later life. We analyzed data from the REasons for Geographic And Racial Differences in Stroke Study, a national sample of older Black and white adults in the United States (n = 21,151; mean age at assessment = 67; data collected 2006–2017). Generalized additive multilevel models examined how cognitive function varied by neighborhood features. Access to civic and social organizations, recreation centers, fast-food and coffee establishments, arts centers, museums, and highways were significantly associated with cognitive function. Race-, gender-, and education-specific models did not yield substantial improvements to the full-model. Our results suggest that the unequal distribution of amenities and hazards across neighborhoods may help account for considerable inequities observed in cognitive health among older adults. Cognability advances ecological theories of aging through an innovative “whole neighborhood” approach. It aims to identify which specific neighborhood features are most protective of cognitive health among aging adults to inform upstream public health initiatives, community interventions, and policy. © 2022 Elsevier Ltd
Author Keywords
Aging in place; Built environment; Cognitive function; Dementia risk; Disparities; Health behaviors; Urban amenities
Funding details
F32 AG064815-01, UL1 TR002240-02
National Institutes of HealthNIH
U.S. Department of Health and Human ServicesHHS1RF1AG057540-01
National Institute on AgingNIA
National Institute of Neurological Disorders and StrokeNINDS
Document Type: Article
Publication Stage: Final
Source: Scopus
The intersectionality of life course socioeconomic status, race, and cognitive decline: An 18-year follow-up
(2022) International Journal of Geriatric Psychiatry, 37 (8), .
Zeng, Y.a , Lum, T.Y.S.a , Chen, Y.-C.a b
a Department of Social Work and Social Administration, The University of Hong Kong, Hong Kong
b Social Policy Institute, Washington University in St. Louis, St. Louis, MO, United States
Abstract
Objectives: Studies have documented the impact of childhood socioeconomic status (SES) on cognition. However, research that simultaneously considers SES in varied life stages, the multidimensional mechanisms, and racial differences is relatively understudied. This study examines the intersectionality across age, SES, and race and its impact on cognitive trajectories. Methods: Using 8376 respondents aged 65+ from the 1998–2016 Health and Retirement Study, we used latent growth curve modeling to examine the effects of four life course models (latency, pathway, accumulation, and mobility) on 18-year trajectories of mental status and episodic memory. We further tested for differences in the links between SES and cognitive trajectories between black and white respondents. Results: Cognitive function declines with age and is interrelated with SES and race. Adulthood has a stronger effect on cognitive performance than childhood. However, linked positive childhood and adulthood SES contributes to positive cognition. Accumulated SES disadvantages were associated with lower cognition. Older adults with downward mobility and low SES throughout their lifespans had the lowest cognition scores. Life course models operated differently on trajectories of cognitive decline, yet the effects were particularly evident among older black respondents. Overall, those with socioeconomic advantages tended to have a slower decline in cognition, while a faster decline occurred for those with accrued disadvantages. Conclusions: Cognitive performance is a complex, longitudinal process intertwined with socioeconomic conditions and population heterogeneity shaped by life course contexts. Policies that facilitate healthy cognitive performance and address SES inequality could equalize health opportunities and address racial cognitive disparities later in life. © 2022 John Wiley & Sons Ltd.
Author Keywords
cognitive decline; health and retirement study; race; socioeconomic status; trajectory
Funding details
Heart Rhythm SocietyHRS
Washington University in St. LouisWUSTL
Document Type: Article
Publication Stage: Final
Source: Scopus
Brain Imaging Features Associated with 20-Year Cognitive Decline in a Community-Based Multiethnic Cohort without Dementia
(2022) Neuroepidemiology, 56 (3), pp. 183-191.
Orlando, A.a , Sharrett, A.R.a , Schneider, A.L.C.b , Gottesman, R.F.c , Knopman, D.S.d , Rawlings, A.a , Mosley, T.H.e , Jack, C.R.f , Wong, D.g , Pike, J.R.h , Coresh, J.a
a Department of Epidemiology, Johns Hopkins University Bloomberg, School of Public Health, Baltimore, MD, United States
b Department of Neurology, Johns Hopkins University, School of Medicine, Baltimore, MD, United States
c National Institute of Neurological Disorders and Stroke Intramural Research Program, Nih, Bethesda, MD, United States
d Department of Neurology, Mayo Clinic Alix School of Medicine, Rochester, MN, United States
e Department of Neurology, University of Mississippi Medical Center, Jackson, MS, United States
f Department of Radiology, Mayo Clinic Alix School of Medicine, Rochester, MN, United States
g Department of Radiology, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
h Collaborative Studies Coordinating Center, University of North Carolina Gillings, School of Public Health, Chapel Hill, NC, United States
Abstract
Introduction: This study aimed to characterize the association of cognitive decline starting in midlife with brain pathology in late life in the absence of dementia. Methods: Nondemented Atherosclerosis Risk in Communities participants with brain imaging, all cognitive factor scores (CFSs), and nonmissing covariates were included. CFSs were collected at three visits across 21 years (1990-2013) (short-term cognitive change [1990-1996], long-term cognitive change [1990-2013]), and brain magnetic resonance imaging and florbetapir positron emission tomography (PET) imaging were collected in 2011-13 (PET subset n = 327). Outcomes of interest were total and regional brain volumes (cm3), log2 (white matter hyperintensity volume), white matter integrity (fractional anisotropy, mean diffusivity), ≥1 lacunar infarct (3-20 mm), and elevated brain β-amyloid (SUVR >1.2). Multivariable linear/logistic regression related outcomes to CFS slopes after adjusting for demographics and total intracranial volume. Results: At baseline, the 1,734 participants had a mean (SD) age of 55 (5.2) years, and were 60% female and 26% Black. After adjustment, a 1-SD larger long-term decline in CFS was associated with a smaller relative total brain volume by 1.2% (95% CI: 1.0, 1.5), a smaller relative temporal lobe meta region volume by 1.9% (1.5, 2.3), a 13% (9, 17) larger volume of white matter hyperintensities, a 1.3-fold (1.2, 1.4) higher odds of having ≥1 lacune, and 1.7-fold (1.3, 2.2) higher odds of elevated brain β-amyloid deposition and worse white matter integrity. Some long-term associations were also found for midlife short-term declines in CFS. Conclusions: This study provides evidence that starting in midlife, short-term and long-term declines in cognition are associated with multiple deleterious late-life differences in nondemented brains. © 2022 S. Karger AG, Basel.
Author Keywords
Brain; Cognitive decline; Cohort; Imaging; Longitudinal design
Funding details
National Institutes of HealthNIH
U.S. Department of Health and Human ServicesHHS75N92022D00001, 75N92022D00002, 75N92022D00003, 75N92022D00004, 75N92022D00005, U01HL096812, U01HL096814, U01HL096899, U01HL096902, U01HL096917
National Institute on AgingNIAR01AG040282
National Heart, Lung, and Blood InstituteNHLBI
National Institute on Deafness and Other Communication DisordersNIDCDR01HL70825
National Institute of Neurological Disorders and StrokeNINDS
Israel National Road Safety AuthorityNRSA
Document Type: Article
Publication Stage: Final
Source: Scopus
Ascertaining Design and Implementation Requirements for a Perioperative Neurocognitive Training Intervention for the Prevention of Persistent Pain After Surgery
(2022) Pain Medicine (Malden, Mass.), 23 (8), pp. 1355-1365.
Holzer, K.J.a , Haroutounian, S.a , Meng, A.a , Wilson, E.A.a , Steinberg, A.a , Avidan, M.S.a , Kozower, B.D.b , Abraham, J.a c
a Department of Anesthesiology
b Department of Surgery
c Institute for Informatics, Washington University School of Medicine, St. Louis, MO, United States
Abstract
BACKGROUND: Persistent postsurgical pain (PPSP) is a common complication that impacts quality of life, often necessitating long-term opioid treatment. Certain neurocognitive factors, including reduced performance on cognitive flexibility tasks, are associated with increased risk of PPSP. We examine the perceptions of surgical patients and clinicians with regard to perioperative pain management activities and needs; patient acceptance and use of a perioperative neurocognitive training intervention; and implementation feasibility. METHODS: We conducted both individual and focus group interviews with patients undergoing thoracic surgery and clinicians in an academic medical center. The Consolidated Framework for Intervention Research guided the development of interview questions related to the adoption and implementation of a neurocognitive intervention to mitigate PPSP. A thematic analysis was used to analyze the responses. RESULTS: Forty patients and 15 clinicians participated. Interviews revealed that there is minimal discussion between clinicians and patients about PPSP. Most participants were receptive to a neurocognitive intervention to prevent PPSP, if evidence demonstrating its effectiveness were available. Potential barriers to neurocognitive training program adoption included fatigue, cognitive overload, lack of familiarity with the technology used for delivering the intervention, and immediate postoperative pain and stress. Implementation facilitators would include patient education about the intervention, incentives for its use, and daily reminders. CONCLUSION: The study identified several guiding principles for addressing patients’ and clinicians’ barriers to effectively implementing a neurocognitive training intervention to mitigate PPSP after surgery. To ensure the sustainability of neurocognitive interventions for preventing PPSP, such interventions would need to be adapted to meet patients’ and clinicians’ needs within the perioperative context. © The Author(s) 2021. Published by Oxford University Press on behalf of the American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
Author Keywords
Anesthesia; Cognitive Training; Implementation; Pain; Qualitative Methods; Thoracic Surgery
Document Type: Article
Publication Stage: Final
Source: Scopus
Risk factors for treatment-refractory and relapsed optic pathway glioma in children with neurofibromatosis type 1
(2022) Neuro-Oncology, 24 (8), pp. 1377-1386. Cited 1 time.
Kotch, C.a , Avery, R.b , Getz, K.D.a , Bouffet, E.c , De Blank, P.a , Listernick, R.d , Gutmann, D.H.e , Bornhorst, M.a , Campen, C.f , Liu, G.T.g , Aplenc, R.h , Li, Y.i j , Fisher, M.J.a
a Division of Oncology, Department of Pediatrics, Children’s Hospital of Philadelphia, 3615 Civic Center Blvd, Philadelphia, PA 19104, United States
b Division of Ophthalmology, Department of Surgery, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
c Department of Biostatistics, University of Pennsylvania, Philadelphia, PA, United States
d University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States
e Division of Haematology/Oncology, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada
f Division of Oncology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
g Division of Advanced General Pediatrics, Department of Pediatrics, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, United States
h Department of Neurology, Washington University School of Medicine, St Louis, MO, United States
i Department of Pediatric Hematology-Oncology, Children’s National Hospital, Washington, DC, United States
j Department of Neurology, Stanford University, Palo Alto, CA, United States
Abstract
Background: Nearly one-third of patients with neurofibromatosis type 1-associated optic pathway glioma (NF1-OPG) fail frontline chemotherapy; however, little is known about risk factors for treatment failure. Methods: We performed a retrospective multi-institutional cohort study to identify baseline risk factors for treatment-refractory/relapsed disease and poor visual outcome in children with NF1-OPG. Refractory/relapsed NF1-OPG was defined as a requirement of two or more treatment regimens due to progression or relapse. Results: Of 111 subjects eligible for inclusion, adequate clinical and visual data were available for 103 subjects from 7 institutions. Median follow-up from the initiation of first chemotherapy regimen was 95 months (range 13-185). Eighty-four (82%) subjects received carboplatin-based frontline chemotherapy. Forty-five subjects (44%) experienced refractory/relapsed disease, with a median time of 21.5 months (range 2-149) from the initiation of first treatment to the start of second treatment. The proportion of patients without refractory/relapsed disease at 2 and 5 years was 78% and 60%. In multivariable analyses, age less than 24 months at initial treatment, posterior tumor location, and familial inheritance were associated with refractory/relapsed NF1-OPG by 2 years. Both age less than 24 months and posterior tumor location were associated with refractory/relapsed NF1-OPG by 5 years. Subjects with moderate to severe vision loss at last follow-up were more likely to have posterior tumor location, optic disc abnormalities, or abnormal visual acuity at initial treatment. Conclusion: Young age, posterior tumor location, and optic disc abnormalities may identify patients with the greatest likelihood of refractory/relapsed NF1-OPG and poor visual outcomes, and who may benefit from newer treatment strategies. © 2022 The Author(s). Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved.
Author Keywords
cancer epidemiology; neurofibromatosis type 1; optic pathway glioma; refractory; relapsed
Document Type: Article
Publication Stage: Final
Source: Scopus
Impaired mitophagy in Sanfilippo a mice causes hypertriglyceridemia and brown adipose tissue activation
(2022) Journal of Biological Chemistry, 298 (8), art. no. 102159, .
Tillo, M.a , Lamanna, W.C.b , Dwyer, C.A.b , Sandoval, D.R.b c , Pessentheiner, A.R.a , Al-Azzam, N.a , Sarrazin, S.b , Gonzales, J.C.b c , Kan, S.-H.d e , Andreyev, A.Y.f , Schultheis, N.g , Thacker, B.E.h , Glass, C.A.h , Dickson, P.I.f i , Wang, R.Y.j k , Selleck, S.B.g , Esko, J.D.b l , Gordts, P.L.S.M.a b l
a Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA, United States
b Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, United States
c Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla, CA, United States
d The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, United States
e CHOC Children’s Hospital Orange County, Orange, CA, United States
f Department of Pharmacology, University of California, San Diego, La Jolla, CA, United States
g Department of Biochemistry & Molecular Biology, The Pennsylvania State University, University ParkPA, United States
h TEGA Therapeutics Inc, San Diego, CA, United States
i Department of Pediatrics, Washington University in St Louis, St Louis, MO, United States
j Division of Metabolic Disorders, Orange, CA, United States
k Department of Pediatrics, University of California-Irvine School of Medicine, Irvine, CA, United States
l Glycobiology Research and Training Center, University of California, San Diego, La Jolla, CA, United States
Abstract
Lysosomal storage diseases result in various developmental and physiological complications, including cachexia. To study the causes for the negative energy balance associated with cachexia, we assessed the impact of sulfamidase deficiency and heparan sulfate storage on energy homeostasis and metabolism in a mouse model of type IIIa mucopolysaccharidosis (MPS IIIa, Sanfilippo A syndrome). At 12-weeks of age, MPS IIIa mice exhibited fasting and postprandial hypertriglyceridemia compared with wildtype mice, with a reduction of white and brown adipose tissues. Partitioning of dietary [3H]triolein showed a marked increase in intestinal uptake and secretion, whereas hepatic production and clearance of triglyceride-rich lipoproteins did not differ from wildtype controls. Uptake of dietary triolein was also elevated in brown adipose tissue (BAT), and notable increases in beige adipose tissue occurred, resulting in hyperthermia, hyperphagia, hyperdipsia, and increased energy expenditure. Furthermore, fasted MPS IIIa mice remained hyperthermic when subjected to low temperature but became cachexic and profoundly hypothermic when treated with a lipolytic inhibitor. We demonstrated that the reliance on increased lipid fueling of BAT was driven by a reduced ability to generate energy from stored lipids within the depot. These alterations arose from impaired autophagosome–lysosome fusion, resulting in increased mitochondria content in beige and BAT. Finally, we show that increased mitochondria content in BAT and postprandial dyslipidemia was partially reversed upon 5-week treatment with recombinant sulfamidase. We hypothesize that increased BAT activity and persistent increases in energy demand in MPS IIIa mice contribute to the negative energy balance observed in patients with MPS IIIa. © 2022 The Authors
Author Keywords
autophagy; dyslipidemia; hyperthermia; mitochondria; mucopolysaccharidoses; sulfamidase
Funding details
GM008243
National Institutes of HealthNIHGM33063, P01 HL107150
Israel National Road Safety AuthorityNRSADK085905, F31HL977212
Seventh Framework ProgrammeFP7P30 DK063491, PIOF-GA-2010-273994
Document Type: Article
Publication Stage: Final
Source: Scopus
Opioid exposure during therapeutic hypothermia and short-term outcomes in neonatal encephalopathy
(2022) Journal of Perinatology, 42 (8), pp. 1017-1025.
Natarajan, G.a , Hamrick, S.E.b , Zaniletti, I.c , Lee, K.-S.d , Mietzsch, U.e , DiGeronimo, R.e , Dizon, M.L.V.f , Peeples, E.S.g , Yanowitz, T.D.h , Wu, T.-W.i , Flibotte, J.j , Joe, P.k , Massaro, A.N.l , Rao, R.m , Children’s Hospitals Neonatal Database Hypoxic-Ischemic Encephalopathy Focus groupn
a Pediatrics, Central Michigan University, Children’s Hospital of Michigan, Detroit, MI, United States
b Pediatrics, Emory University, Atlanta, GA, United States
c Children’s Hospital Association, Lenexa, KS, United States
d Pediatrics, Hospital for Sick Children, Toronto, ON, Canada
e Pediatrics/Neonatology, Seattle Children’s Hospital/University of Washington, Seattle, WA, United States
f Pediatrics, Ann & Robert H. Lurie Children’s Hospital of Chicago and Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
g Pediatrics, University of Nebraska Medical Center, Omaha, NE, United States
h Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
i Neonatology, Children’s Hospital Los Angeles, Los Angeles, CA, United States
j Pediatrics/ Neonatology, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
k Neonatology, UCSF Benioff Children’s Hospital Oakland, Oakland, CA, United States
l Neonatology, Children’s National Health Systems, Washington, DC, United States
m Pediatrics, Washington University in St. Louis, St. Louis, MO, United States
Abstract
Objective: To assess the association between opioid exposure during therapeutic hypothermia (TH) for perinatal hypoxic-ischemic encephalopathy (HIE) and in-hospital outcomes. Study design: In this retrospective cohort study, linked data were accessed on infants ≥36 weeks gestation, who underwent TH for HIE, born from 2010–2016 in 23 Neonatal Intensive Care Units participating in Children’s Hospitals Neonatal Consortium and Pediatric Health Information Systems. We excluded infants who received opioids for >5 days. Results: The cohort (n = 1484) was categorized as No opioid [240(16.2%)], Low opioid (1–2 days) [574 (38.7%)] and High opioid group (HOG, 3–5 days) [670 (45.2%)]. After adjusting for HIE severity, opioids were not associated with abnormal MRI, but were associated with decreased likelihood of complete oral feeds at discharge. HOG had increased likelihood of prolonged hospital stay and ventilation. Conclusion: Opioid exposure during TH was not associated with abnormal MRI; its association with adverse short-term outcomes suggests need for cautious empiric use. © 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.
Document Type: Article
Publication Stage: Final
Source: Scopus
Elevated cerebrospinal fluid iron and ferritin associated with early severe ventriculomegaly in preterm posthemorrhagic hydrocephalus
(2022) Journal of Neurosurgery: Pediatrics, 30 (2), pp. 169-176.
Mahaney, K.B.a , Buddhala, C.b , Paturu, M.b , Morales, D.M.b , Smyser, C.D.c d e , Limbrick, D.D., Jr.b , Gummidipundi, S.E.f , Han, S.S.a f , Strahle, J.M.b
a Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, United States
b Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, United States
c Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
d Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
e Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States
f Quantitative Sciences Unit, Stanford Center for Biomedical Informatics Research (BMIR), Stanford University, Stanford, CA, United States
Abstract
OBJECTIVE Posthemorrhagic hydrocephalus (PHH) following preterm intraventricular hemorrhage (IVH) is among the most severe sequelae of extreme prematurity and a significant contributor to preterm morbidity and mortality. The authors have previously shown hemoglobin and ferritin to be elevated in the lumbar puncture cerebrospinal fluid (CSF) of neonates with PHH. Herein, they evaluated CSF from serial ventricular taps to determine whether neonates with PHH following severe initial ventriculomegaly had higher initial levels and prolonged clearance of CSF hemoglobin and hemoglobin degradation products compared to those in neonates with PHH following moderate initial ventriculomegaly. METHODS In this observational cohort study, CSF samples were obtained from serial ventricular taps in premature neonates with severe IVH and subsequent PHH. CSF hemoglobin, ferritin, total iron, total bilirubin, and total protein were quantified using ELISA. Ventriculomegaly on cranial imaging was assessed using the frontal occipital horn ratio (FOHR) and was categorized as severe (FOHR > 0.6) or moderate (FOHR ≤ 0.6). RESULTS Ventricular tap CSF hemoglobin (mean) and ferritin (initial and mean) were higher in neonates with severe versus moderate initial ventriculomegaly. CSF hemoglobin, ferritin, total iron, total bilirubin, and total protein decreased in a nonlinear fashion over the weeks following severe IVH. Significantly higher levels of CSF ferritin and total iron were observed in the early weeks following IVH in neonates with severe initial ventriculomegaly than in those with initial moderate ventriculomegaly. CONCLUSIONS Among preterm neonates with PHH following severe IVH, elevated CSF hemoglobin, ferritin, and iron were associated with more severe early ventricular enlargement (FOHR > 0.6 vs ≤ 0.6 at first ventricular tap). © AANS 2022.
Author Keywords
cerebrospinal fluid; ferritin; intraventricular hemorrhage; iron; posthemorrhagic hydrocephalus
Funding details
National Institutes of HealthNIHNS110793
Doris Duke Charitable FoundationDDCFKL2TR003143
Hydrocephalus AssociationHA
Document Type: Article
Publication Stage: Final
Source: Scopus
Automated intraoperative central sulcus localization and somatotopic mapping using median nerve stimulation
(2022) Journal of Neural Engineering, 19 (4), art. no. 046020, .
Xie, T.a b c , Wu, Z.d , Schalk, G.c d e , Tong, Y.d , Vato, A.c f , Raviv, N.c g , Guo, Q.d , Ye, H.b , Sheng, X.b , Zhu, X.b , Brunner, P.a c h , Chen, L.d
a Department of Neurosurgery, Washington University, School of Medicine, St. Louis, MO, United States
b State Key Laboratory of Mechanical System and Vibration, Shanghai Jiao Tong University, Shanghai, China
c National Center for Adaptive Neurotechnologies, Albany, NY, United States
d Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China
e Frontier Lab for Applied Neurotechnology, Tianqiao and Chrissy Chen Institute, Shanghai, China
f Istituto Italiano di Tecnologia, Genova, Italy
g Department of Neurosurgery, Albany Medical College, Albany, NY, United States
h Department of Neurology, Albany Medical College, Albany, NY, United States
Abstract
Objective. Accurate identification of functional cortical regions is essential in neurological resection. The central sulcus (CS) is an important landmark that delineates functional cortical regions. Median nerve stimulation (MNS) is a standard procedure to identify the position of the CS intraoperatively. In this paper, we introduce an automated procedure that uses MNS to rapidly localize the CS and create functional somatotopic maps. Approach. We recorded electrocorticographic signals from 13 patients who underwent MNS in the course of an awake craniotomy. We analyzed these signals to develop an automated procedure that determines the location of the CS and that also produces functional somatotopic maps. Main results. The comparison between our automated method and visual inspection performed by the neurosurgeon shows that our procedure has a high sensitivity (89%) in identifying the CS. Further, we found substantial concordance between the functional somatotopic maps generated by our method and passive functional mapping (92% sensitivity). Significance. Our automated MNS-based method can rapidly localize the CS and create functional somatotopic maps without imposing additional burden on the clinical procedure. With additional development and validation, our method may lead to a diagnostic tool that guides neurosurgeons and reduces postoperative morbidity in patients undergoing resective brain surgery. © 2022 The Author(s). Published by IOP Publishing Ltd.
Author Keywords
central sulcus (CS); electrocorticography (ECoG); functional mapping; median nerve stimulation (MNS); phase reversal technique (PRT); somatotopy
Funding details
18YF1403300
National Institutes of HealthNIH
National Institute of Mental HealthNIMHP50-MH109429
National Institute of Neurological Disorders and StrokeNINDSU01-NS108916, U24-NS109103
National Institute of Biomedical Imaging and BioengineeringNIBIBP41-EB018783, R01-EB026439
National Natural Science Foundation of ChinaNSFC51620105002
Science and Technology Commission of Shanghai MunicipalitySTCSM18JC1410400, 2018SHZDZX01
Document Type: Article
Publication Stage: Final
Source: Scopus
Can Electrocochleography Help Preserve Hearing after Cochlear Implantation with Full Electrode Insertion?
(2022) Otology and Neurotology, 43 (7), pp. 789-796.
Harris, M.S.a , Koka, K.b , Riggs, W.J.c , Saleh, S.d , Holder, J.T.e , Dwyer, R.T.e , Prentiss, S.f , Lefler, S.g , Kozlowski, K.a , Hiss, M.M.c , Ortmann, A.J.g , Nelson-Bakkum, E.b , Büchner, A.h , Salcher, R.h , Harvey, S.A.a , Hoffer, M.E.f , Bohorquez, J.E.i , Alzhrani, F.d , Alshihri, R.d , Fida, A.d , Danner, C.J.j , Friedland, D.R.a , Seidman, M.D.k , Lenarz, T.h , Telischi, F.F.f , Labadie, R.F.e , Buchman, C.A.g , Adunka, O.F.c
a Department of Otolaryngology and Communication Sciences, Medical College of Wisconsin, Milwaukee, WI, United States
b Advanced Bionics, Valencia, CA, United States
c Department of Otolaryngology-Head and Neck Surgery, Wexner Medical Center, The Ohio State University, Columbus, OH, United States
d King Saud University, College of Medicine, King Abdullah Ear Specialist Center (KAESC), Riyadh, Saudi Arabia
e Department of Otolaryngology-Head and Neck Surgery, Vanderbilt University Medical Center, Nashville, TN, United States
f Department of Otolaryngology-Head and Neck Surgery, Miller School of Medicine, University of Miami, Miami, FL, United States
g Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine, St. Louis, MO, United States
h Medizinische Hochschule Hannover, Hannover, Germany
i Department of Biomedical Engineering, University of Miami, Miami, United States
j Tampa Bay General Hospital Tampa Bay, United States
k AdventHealth, University of Central Florida, Orlando, FL, United States
Abstract
Objectives To evaluate the utility of intracochlear electrocochleography (ECochG) monitoring during cochlear implant (CI) surgery on postoperative hearing preservation. Study Design Prospective, randomized clinical trial. Setting Ten high-volume, tertiary care CI centers. Patients Adult patients with sensorineural hearing loss meeting the CI criteria who selected an Advanced Bionics CI. Methods Patients were randomized to CI surgery either with audible ECochG monitoring available to the surgeon during electrode insertion or without ECochG monitoring. Hearing preservation was determined by comparing preoperative unaided low-frequency (125-, 250-, and 500-Hz) pure-tone average (LF-PTA) to postoperative LF-PTA at CI activation. Pre- and post-CI computed tomography was used to determine electrode scalar location and electrode translocation. Results Eighty-five adult CI candidates were enrolled. The mean (standard deviation [SD]) unaided preoperative LF-PTA across the sample was 54 (17) dB HL. For the whole sample, hearing preservation was “good”(i.e., LF-PTA change 0-15 dB) in 34.5%, “fair”(i.e., LF-PTA change >15-29 dB) in 22.5%, and “poor”(i.e., LF-PTA change ≥30 dB) in 43%. For patients randomized to ECochG “on,”mean (SD) LF-PTA change was 27 (20) dB compared with 27 (23) dB for patients randomized to ECochG “off”(p = 0.89). Seven percent of patients, all of whom were randomized to ECochG off, showed electrode translocation from the scala tympani into the scala vestibuli. Conclusions Although intracochlear ECochG during CI surgery has important prognostic utility, our data did not show significantly better hearing preservation in patients randomized to ECochG “on”compared with ECochG “off.” © Wolters Kluwer Health, Inc. All rights reserved.
Author Keywords
Clinical trial; Cochlear implantation; Electrocochleography monitoring; Electrode translocation; Hearing preservation
Document Type: Article
Publication Stage: Final
Source: Scopus
International Prevalence and Mechanisms of SARS-CoV-2 in Childhood Arterial Ischemic Stroke during the COVID-19 Pandemic
(2022) Stroke, 53 (8), pp. 2497-2503.
Beslow, L.A.a , Agner, S.C.b , Santoro, J.D.c , Ram, D.d , Wilson, J.L.e , Harrar, D.f , Appavu, B.g , Fraser, S.M.h , Rossor, T.i , Torres, M.D.j , Kossorotoff, M.k , Zuñiga Zambrano, Y.C.l , Hernández-Chávez, M.m , Hassanein, S.M.A.n , Zafeiriou, D.o , Dowling, M.M.p , Kopyta, I.q , Stence, N.V.r , Bernard, T.J.s , Dlamini, N.t
a Division of Neurology, Children’s Hospital of Philadelphia, Departments of Neurology and Pediatrics, Perelman School of Medicine, The University of Pennsylvania, United States
b Division of Pediatric and Developmental Neurology, St. Louis Children’s Hospital, Washington University, School of MedicineMO, United States
c Division of Neurology, Children’s Hospital Los Angeles, Department of Neurology, Keck School of Medicine at USCCA, United States
d Department of Paediatric Neurology, Royal Manchester Children’s Hospital, England, United Kingdom
e Department of Pediatrics, Division of Pediatric Neurology, Oregon Health & Science University, Portland, United States
f Division of Neurology, Children’s National Medical Center, Washington, DC, United States
g Divison of Neurology, Phoenix Children’s Hospital, University of Arizona, College of Medicine, Phoenix, United States
h Division of Neurology, Children’s Memorial Hermann Hospital, Houston, TX, United States
i Evelina London Children’s Hospital, England, United Kingdom
j Division of Hematology, Cook Children’s Medical Center, Fort Worth, TX, United States
k French Center for Pediatric Stroke, Pediatric Neurology Department, APHP University Hospital Necker-Enfants Maladies, Paris, France
l Unit of Pediatric Neurology, HOMI Fundación Hospital Pediátrico la Misericordia, Bogotá, Colombia
m Unit of Pediatric Neurology, Division of Pediatrics, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
n Department of Pediatrics, Faculty of Medicine, Ain Shams University, Cairo, Egypt
o Department of Pediatrics, Hippokratio General Hospital, Aristotle University, Thessaloniki, Greece
p Departments of Pediatrics and Neurology, University of Texas, Southwestern Medical Center, Dallas, United States
q Department of Child Neurology, Medical University of Silesia in Katowice, Poland
r Section of Pediatric Radiology, Children’s Hospital Colorado, Department of Radiology, University of Colorado, School of Medicine, Aurora, United States
s Section of Child Neurology, Children’s Hospital Colorado, Departments of Pediatrics and Neurology, Hemophilia and Thrombosis Center, University of Colorado, School of Medicine, Aurora, United States
t Division of Neurology, Department of Pediatrics, The Hospital for Sick Children, Child Health Evaluative Sciences Program, University of TorontoON, Canada
Abstract
Background: Data from the early pandemic revealed that 0.62% of children hospitalized with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) had an acute arterial ischemic stroke (AIS). In a larger cohort from June 2020 to December 2020, we sought to determine whether our initial point estimate was stable as the pandemic continued and to understand radiographic and laboratory data that may clarify mechanisms of pediatric AIS in the setting of SARS-CoV-2. Methods: We surveyed international sites with pediatric stroke expertise to determine numbers of hospitalized SARS-CoV-2 patients <18 years, numbers of incident AIS cases among children (29 days to <18 years), frequency of SARS-CoV-2 testing for children with AIS, and numbers of childhood AIS cases positive for SARS-CoV-2 June 1 to December 31, 2020. Two stroke neurologists with 1 neuroradiologist determined whether SARS-CoV-2 was the main stroke risk factor, contributory, or incidental. Results: Sixty-one centers from 21 countries provided AIS data. Forty-eight centers (78.7%) provided SARS-CoV-2 hospitalization data. SARS-CoV-2 testing was performed in 335/373 acute AIS cases (89.8%) compared with 99/166 (59.6%) in March to May 2020, P<0.0001. Twenty-three of 335 AIS cases tested (6.9%) were positive for SARS-CoV-2 compared with 6/99 tested (6.1%) in March to May 2020, P=0.78. Of the 22 of 23 AIS cases with SARS-CoV-2 in whom we could collect additional data, SARS-CoV-2 was the main stroke risk factor in 6 (3 with arteritis/vasculitis, 3 with focal cerebral arteriopathy), a contributory factor in 13, and incidental in 3. Elevated inflammatory markers were common, occurring in 17 (77.3%). From centers with SARS-CoV-2 hospitalization data, of 7231 pediatric patients hospitalized with SARS-CoV-2, 23 had AIS (0.32%) compared with 6/971 (0.62%) from March to May 2020, P=0.14. Conclusions: The risk of AIS among children hospitalized with SARS-CoV-2 appeared stable compared with our earlier estimate. Among children in whom SARS-CoV-2 was considered the main stroke risk factor, inflammatory arteriopathies were the stroke mechanism. © 2022 Lippincott Williams and Wilkins. All rights reserved.
Author Keywords
arteriopathy; child; hospitalization; ischemic stroke; risk factors
Funding details
National Institutes of HealthNIH
National Institute of Neurological Disorders and StrokeNINDS
Maternal and Child Health BureauMCHB
Document Type: Article
Publication Stage: Final
Source: Scopus
Ito, N.a b , Takatsu, A.a b , Ito, H.a b , Koike, Y.a b , Yoshioka, K.c d , Kamei, Y.d , Imai, S.-I.a b e
Slc12a8 in the lateral hypothalamus maintains energy metabolism and skeletal muscle functions during aging
(2022) Cell Reports, 40 (4), art. no. 111131, .
a AMED Frailty Research Laboratory (Teijin), AMED Cyclic Innovation for Clinical Empowerment (CiCLE), Osaka, Japan
b Laboratory of Molecular Life Science, Institute of Biomedical Research and Innovation (IBRI), Foundation for Biomedical Research and Innovation (FBRI), Kobe, Japan
c Institute for Research on Productive Aging (IRPA), Tokyo, Japan
d Laboratory of Molecular Nutrition, Graduate School of Life and Environmental Sciences, Kyoto Prefectural University, Kyoto, Japan
e Department of Developmental Biology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States
Abstract
Sarcopenia and frailty are urgent socio-economic problems worldwide. Here we demonstrate a functional connection between the lateral hypothalamus (LH) and skeletal muscle through Slc12a8, a recently identified nicotinamide mononucleotide transporter, and its relationship to sarcopenia and frailty. Slc12a8-expressing cells are mainly localized in the LH. LH-specific knockdown of Slc12a8 in young mice decreases activity-dependent energy and carbohydrate expenditure and skeletal muscle functions, including muscle mass, muscle force, intramuscular glycolysis, and protein synthesis. LH-specific Slc12a8 knockdown also decreases sympathetic nerve signals at neuromuscular junctions and β2-adrenergic receptors in skeletal muscle, indicating the importance of the LH-sympathetic nerve-β2-adrenergic receptor axis. LH-specific overexpression of Slc12a8 in aged mice significantly ameliorates age-associated decreases in energy expenditure and skeletal muscle functions. Our results highlight an important role of Slc12a8 in the LH for regulation of whole-body metabolism and skeletal muscle functions and provide insights into the pathogenesis of sarcopenia and frailty during aging. © 2022 The Authors
Author Keywords
aging; CP: Metabolism; CP: Neuroscience; frailty; lateral hypothalamus; NAD+; NMN transporter; PDK4; sarcopenia; skeletal muscle; Slc12a8; β2-adrenergic receptor
Funding details
Japan Agency for Medical Research and DevelopmentAMED
National Center for Geriatrics and GerontologyNCGGJP18pc0101021
Shinshu UniversityShindai
Document Type: Article
Publication Stage: Final
Source: Scopus
Is Characteristic Frequency Limiting Real-Time Electrocochleography During Cochlear Implantation?
(2022) Frontiers in Neuroscience, 16, art. no. 915302, .
Walia, A., Shew, M.A., Lefler, S.M., Kallogjeri, D., Wick, C.C., Holden, T.A., Durakovic, N., Ortmann, A.J., Herzog, J.A., Buchman, C.A.
Department of Otolaryngology—Head and Neck Surgery, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
Abstract
Objectives: Electrocochleography (ECochG) recordings during cochlear implantation have shown promise in estimating the impact on residual hearing. The purpose of the study was (1) to determine whether a 250-Hz stimulus is superior to 500-Hz in detecting residual hearing decrement and if so; (2) to evaluate whether crossing the 500-Hz tonotopic, characteristic frequency (CF) place partly explains the problems experienced using 500-Hz. Design: Multifrequency ECochG comprising an alternating, interleaved acoustic complex of 250- and 500-Hz stimuli was used to elicit cochlear microphonics (CMs) during insertion. The largest ECochG drops (≥30% reduction in CM) were identified. After insertion, ECochG responses were measured using the individual electrodes along the array for both 250- and 500-Hz stimuli. Univariate regression was used to predict whether 250- or 500-Hz CM drops explained low-frequency pure tone average (LFPTA; 125-, 250-, and 500-Hz) shift at 1-month post-activation. Postoperative CT scans were performed to evaluate cochlear size and angular insertion depth. Results: For perimodiolar insertions (N = 34), there was a stronger linear correlation between the largest ECochG drop using 250-Hz stimulus and LFPTA shift (r = 0.58), compared to 500-Hz (r = 0.31). The 250- and 500-Hz CM insertion tracings showed an amplitude peak at two different locations, with the 500-Hz peak occurring earlier in most cases than the 250-Hz peak, consistent with tonotopicity. When using the entire array for recordings after insertion, a maximum 500-Hz response was observed 2–6 electrodes basal to the most-apical electrode in 20 cases (58.9%). For insertions where the apical insertion angle is >350 degrees and the cochlear diameter is <9.5 mm, the maximum 500-Hz ECochG response may occur at the non-apical most electrode. For lateral wall insertions (N = 14), the maximum 250- and 500-Hz CM response occurred at the most-apical electrode in all but one case. Conclusion: Using 250-Hz stimulus for ECochG feedback during implantation is more predictive of hearing preservation than 500-Hz. This is due to the electrode passing the 500-Hz CF during insertion which may be misidentified as intracochlear trauma; this is particularly important in subjects with smaller cochlear diameters and deeper insertions. Multifrequency ECochG can be used to differentiate between trauma and advancement of the apical electrode beyond the CF. Copyright © 2022 Walia, Shew, Lefler, Kallogjeri, Wick, Holden, Durakovic, Ortmann, Herzog and Buchman.
Author Keywords
250 Hz vs. 500 Hz; acoustic stimulus; characteristic frequency; cochlear implantation; electrocochleography; hearing preservation; multifrequency electrocochleography
Funding details
National Institutes of HealthNIH
National Institute on Deafness and Other Communication DisordersNIDCDT32DC000022
American Neurotology SocietyANS
Document Type: Article
Publication Stage: Final
Source: Scopus
Monosynaptic targets of utricular afferents in the larval zebrafish
(2022) Frontiers in Neurology, 13, art. no. 937054, .
Jia, Y., Bagnall, M.W.
Department of Neuroscience, Washington University, St. Louis, MO, United States
Abstract
The larval zebrafish acquires a repertoire of vestibular-driven behaviors that aid survival early in development. These behaviors rely mostly on the utricular otolith, which senses inertial (tilt and translational) head movements. We previously characterized the known central brainstem targets of utricular afferents using serial-section electron microscopy of a larval zebrafish brain. Here we describe the rest of the central targets of utricular afferents, focusing on the neurons whose identities are less certain in our dataset. We find that central neurons with commissural projections have a wide range of predicted directional tuning, just as in other vertebrates. In addition, somata of central neurons with inferred responses to contralateral tilt are located more laterally than those with inferred responses to ipsilateral tilt. Many dorsally located central utricular neurons are unipolar, with an ipsilateral dendritic ramification and commissurally projecting axon emerging from a shared process. Ventrally located central utricular neurons tended to receive otolith afferent synaptic input at a shorter distance from the soma than in dorsally located neurons. Finally, we observe an unexpected synaptic target of utricular afferents: afferents from the medial (horizontal) semicircular canal. Collectively, these data provide a better picture of the gravity-sensing circuit. Furthermore, we suggest that vestibular circuits important for survival behaviors develop first, followed by the circuits that refine these behaviors. Copyright © 2022 Jia and Bagnall.
Author Keywords
balance; electron microscopy; utricle; vestibular; zebrafish
Funding details
National Institutes of HealthNIHR56 DC016413
Document Type: Article
Publication Stage: Final
Source: Scopus
Population-Based Screening of Newborns: Findings From the NBS Expansion Study (Part One)
(2022) Frontiers in Genetics, 13, art. no. 867337, .
Brower, A.a , Chan, K.a , Williams, M.b , Berry, S.c , Currier, R.d , Rinaldo, P.e , Caggana, M.f , Gaviglio, A.g , Wilcox, W.h , Steiner, R.i , Holm, I.A.j , Taylor, J.a , Orsini, J.J.f , Brunelli, L.k , Adelberg, J.l , Bodamer, O.j , Viall, S.m , Scharfe, C.n , Wasserstein, M.o , Chen, J.Y.p , Escolar, M.q , Goldenberg, A.r , Swoboda, K.s , Ficicioglu, C.t , Matern, D.u , Lee, R.v , Watson, M.w
a American College of Medical Genetics and Genomics (ACMG), Bethesda, MD, United States
b Geisinger Health System, Danville, PA, United States
c Division of Genetics and Metabolism, Department of Pediatrics, University of Minnesota Twin Cities, Minneapolis, MN, United States
d School of Medicine, University of California, San Francisco, San Francisco, CA, United States
e Mayo College, Ajmer, India
f Wadsworth Center, New York State Department of Health, Albany, NY, United States
g Connectics Consulting, Atlanta, GA, United States
h Department of Human Genetics, Division of Medical Genetics, Emory University, Atlanta, GA, United States
i Department of Pediatrics, University of Wisconsin-Madison, Madison, WI, United States
j Boston Children’s Hospital, Harvard Medical School, Boston, MA, United States
k Division of Neonatology, The University of Utah, Salt Lake City, UT, United States
l MedStar Heart and Vascular Institute, Fairfax, VA, United States
m Departments of Molecular Medical Genetics and Pediatrics, Oregon Health and Science University, Portland, OR, United States
n Department of Pediatrics, Yale University, New Haven, CT, United States
o Albert Einstein College of Medicine, New York, NY, United States
p Center for Genomic Medicine, Harvard University, Cambridge, MA, United States
q Department of Pediatrics, Children’s Hospital of Pittsburgh, Pittsburgh, PA, United States
r Department of Bioethics and Medical Humanities, Case Western Reserve University, Cleveland, OH, United States
s Massachusetts General Hospital Cancer Center, Boston, MA, United States
t Children’s Hospital of Philadelphia, Philadelphia, PA, United States
u Mayo Clinic, Rochester, MN, United States
v Texas Department of State Health Services, Austin, TX, United States
w Washington University School of Medicine (Adjunct), St. Louis, MO, United States
Abstract
Each year, through population-based newborn screening (NBS), 1 in 294 newborns is identified with a condition leading to early treatment and, in some cases, life-saving interventions. Rapid advancements in genomic technologies to screen, diagnose, and treat newborns promise to significantly expand the number of diseases and individuals impacted by NBS. However, expansion of NBS occurs slowly in the United States (US) and almost always occurs condition by condition and state by state with the goal of screening for all conditions on a federally recommended uniform panel. The Newborn Screening Translational Research Network (NBSTRN) conducted the NBS Expansion Study to describe current practices, identify expansion challenges, outline areas for improvement in NBS, and suggest how models could be used to evaluate changes and improvements. The NBS Expansion Study included a workshop of experts, a survey of clinicians, an analysis of data from online repositories of state NBS programs, reports and publications of completed pilots, federal committee reports, and proceedings, and the development of models to address the study findings. This manuscript (Part One) reports on the design, execution, and results of the NBS Expansion Study. The Study found that the capacity to expand NBS is variable across the US and that nationwide adoption of a new condition averages 9.5 years. Four factors that delay and/or complicate NBS expansion were identified. A companion paper (Part Two) presents a use case for each of the four factors and highlights how modeling could address these challenges to NBS expansion. Copyright © 2022 Brower, Chan, Williams, Berry, Currier, Rinaldo, Caggana, Gaviglio, Wilcox, Steiner, Holm, Taylor, Orsini, Brunelli, Adelberg, Bodamer, Viall, Scharfe, Wasserstein, Chen, Escolar, Goldenberg, Swoboda, Ficicioglu, Matern, Lee and Watson.
Author Keywords
ACMG; genomics; NBSTRN; newborn screening; research
Funding details
National Institutes of HealthNIH
U.S. Department of Health and Human ServicesHHSHHSN275201800005C
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHD
Document Type: Article
Publication Stage: Final
Source: Scopus
In vivo near-infrared fluorescent fibrin highlights growth of nerve during regeneration across a nerve gap
(2022) Journal of Biomedical Optics, 27 (7), art. no. 070502, .
Luzhansky, I.D.a , Anisman, E.a b , Patel, D.a , Syed, N.a , Wood, M.D.c , Berezin, M.Y.a b
a Washington University in St. Louis, School of Medicine, Department of Radiology, St. Louis, MO, United States
b Washington University in St. Louis, Institute of Materials Science and Engineering, St. Louis, MO, United States
c Washington University in St. Louis, School of Medicine, Department of Surgery, St. Louis, MO, United States
Abstract
Significance: Exogenous extracellular matrix (ECM) proteins, such as fibrinogen and the thrombin-polymerized scaffold fibrin, are used in surgical repair of severe nerve injuries to supplement ECM produced via the injury response. Monitoring the dynamic changes of fibrin during nerve regeneration may shed light on the frequent failure of grafts in the repair of long nerve gaps. Aim: We explored whether monitoring of fibrin dynamics can be carried out using nerve guidance conduits (NGCs) containing fibrin tagged with covalently bound fluorophores. Approach: Fibrinogen was conjugated to a near-infrared (NIR) fluorescent dye. NGCs consisting of silicone tubes filled with the fluorescent fibrin were used to repair a 5-mm gap injury in rat sciatic nerve (n = 6). Results: Axonal regeneration in fluorescent fibrin-filled NGCs was confirmed at 14 days after implantation. Intraoperative fluorescence imaging after implantation showed that the exogenous fibrin was embedded in the early stage regenerative tissue. The fluorescent signal temporarily highlighted a cable-like structure within the conduit and gradually degraded over two weeks. Conclusions: This study, for the first time, visualized in vivo intraneural fibrin degradation, potentially a useful prospective indicator of regeneration success, and showed that fluorescent ECM, in this case fibrin, can facilitate imaging of regeneration in peripheral nerve conduits without significantly affecting the regeneration process. © The Authors. Published by SPIE under a Creative Commons Attribution 4.0 International License. Distribution or reproduction of this work in whole or in part requires full attribution of the original publication, including its DOI.
Author Keywords
fibrin sealant; fluorescent extracellular matrix; nerve guidance conduit; nerve regeneration imaging; nerve repair; nerve tissue engineering
Funding details
T32EB014855-10
National Institutes of HealthNIHR01 NS115960
National Cancer InstituteNCIR01 CA208623
National Institute of Neurological Disorders and StrokeNINDS
Washington University in St. LouisWUSTL
Document Type: Article
Publication Stage: Final
Source: Scopus
Surgery for Pituitary Tumor Apoplexy Is Associated with Rapid Headache and Cranial Nerve Improvement
(2022) Current Oncology, 29 (7), pp. 4914-4922.
Cross, K.A.a , Desai, R.a , Vellimana, A.a b , Liu, Y.a , Rich, K.a b , Zipfel, G.a b , Dacey, R.a , Chicoine, M.a b , Klatt-Cromwell, C.c , McJunkin, J.c , Pipkorn, P.c , Schneider, J.S.c , Silverstein, J.d , Kim, A.H.a b
a Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO 63110, United States
b The Brain Tumor Center, Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, United States
c Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine, St. Louis, MO 63110, United States
d Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, St. Louis, MO 63110, United States
Abstract
Pituitary tumor apoplexy (PTA) classically comprises sudden-onset headache, loss of vision, ophthalmoparesis, and decreased consciousness. It typically results from hemorrhage and/or infarction within a pituitary adenoma. Presentation is heterologous, and optimal management is debated. The time course of recovery of cranial nerve deficits (CNDs) and headaches is not well established. In this study, a retrospective series of consecutive patients with PTA managed at a single academic institution over a 22-year period is presented. Headaches at the time of surgery were more severe in the early and subacute surgical cohort and improved significantly within 72 h postoperatively (p < 0.01). At one year, 90% of CNDs affecting cranial nerves (CNs) 3, 4, and 6 had recovered, with no differences between early (<4 d), subacute (4–14 d), and delayed (>14 d) time-to-surgery cohorts. Remarkably, half recovered within three days. In total, 56% of CN2 deficits recovered, with the early surgery cohort including more severe deficits and recovering at a lower rate (p = 0.01). No correlation of time-to-surgery and rapidity of recovery of CNDs was observed (p = 0.65, 0.72). Surgery for PTA is associated with rapid recovery of CNDs in the early, subacute, and delayed time frames, and with rapid headache improvement in the early and subacute time frames in 50% or more of patients. © 2022 by the authors.
Author Keywords
headache; ophthalmoplegia; pituitary apoplexy; pituitary tumor apoplexy; recovery
Funding details
UL1 TR000448
National Cancer InstituteNCIP30 CA091842
Alvin J. Siteman Cancer Center
Head for the Cure FoundationHFTC
Document Type: Article
Publication Stage: Final
Source: Scopus
Regulation of rod photoreceptor function by farnesylated G-protein γ-subunits
(2022) PloS One, 17 (8), p. e0272506.
Kolesnikov, A.V.a b , Lobysheva, E.c , Gnana-Prakasam, J.P.c d , Kefalov, V.J.a b e , Kisselev, O.G.c d
a Department of Ophthalmology, Gavin Herbert Eye Institute, University of California, Irvine, CA, United States
b Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO, United States
c Department of Ophthalmology, Saint Louis University School of Medicine, Saint Louis, Missouri, United States of America
d Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, Saint Louis, Missouri, United States of America
e Department of Physiology and Biophysics, University of California, Irvine, CA, United States
Abstract
Heterotrimeric G-protein transducin, Gt, is a key signal transducer and amplifier in retinal rod and cone photoreceptor cells. Despite similar subunit composition, close amino acid identity, and identical posttranslational farnesylation of their Gγ subunits, rods and cones rely on unique Gγ1 (Gngt1) and Gγc (Gngt2) isoforms, respectively. The only other farnesylated G-protein γ-subunit, Gγ11 (Gng11), is expressed in multiple tissues but not retina. To determine whether Gγ1 regulates uniquely rod phototransduction, we generated transgenic rods expressing Gγ1, Gγc, or Gγ11 in Gγ1-deficient mice and analyzed their properties. Immunohistochemistry and Western blotting demonstrated the robust expression of each transgenic Gγ in rod cells and restoration of Gαt1 expression, which is greatly reduced in Gγ1-deficient rods. Electroretinography showed restoration of visual function in all three transgenic Gγ1-deficient lines. Recordings from individual transgenic rods showed that photosensitivity impaired in Gγ1-deficient rods was also fully restored. In all dark-adapted transgenic lines, Gαt1 was targeted to the outer segments, reversing its diffuse localization found in Gγ1-deficient rods. Bright illumination triggered Gαt1 translocation from the rod outer to inner segments in all three transgenic strains. However, Gαt1 translocation in Gγ11 transgenic mice occurred at significantly dimmer background light. Consistent with this, transretinal ERG recordings revealed gradual response recovery in moderate background illumination in Gγ11 transgenic mice but not in Gγ1 controls. Thus, while farnesylated Gγ subunits are functionally active and largely interchangeable in supporting rod phototransduction, replacement of retina-specific Gγ isoforms by the ubiquitous Gγ11 affects the ability of rods to adapt to background light.
Document Type: Article
Publication Stage: Final
Source: Scopus
The Utility of the Carpal Tunnel Syndrome-6 for Predicting the Outcomes of Carpal Tunnel Release
(2022) Journal of Hand Surgery, .
Aversano, F.J., Goldfarb, C.A., Gelberman, R.H., Calfee, R.P.
Department of Orthopedic Surgery, Washington University in St. Louis, School of Medicine, St. Louis, MO
Abstract
Purpose: Considering the cost of, discomfort with, and time required for nerve conduction testing, the Carpal Tunnel Syndrome-6 (CTS-6) is often used to determine the likelihood of the presence of carpal tunnel syndrome. We sought to determine whether the CTS-6, designed as a diagnostic instrument, could serve a dual purpose and predict the outcome of carpal tunnel release (CTR) based on postoperative changes in the Boston Carpal Tunnel Questionnaire (BCTQ) score. Methods: This prospective observational study enrolled 118 adults before they underwent open CTR at a tertiary center. A primary regression analysis was used to determine the association between preoperative CTS-6 scores and changes in the BCTQ score at ≥6 months after surgery. Additional demographic, social, electrodiagnostic, and mental health variables were assessed for associations with changes in the BCTQ score. The secondary outcomes included single questions rating satisfaction with the result of CTR as well as symptom changes and the Decision Regret Scale. Noneffective CTR was defined as a BCTQ score change of <1.0 point or reported dissatisfaction. Results: Postoperatively, the BCTQ score improvement averaged 1.38 ± 0.77. Although 102 of 109 patients (94%) noted symptom improvement, 94 of 109 (86%) were satisfied with the result of CTR, and 78 of 109 patients (72%) demonstrated a meaningful change in the BCTQ score. Preoperative CTS-6 scores were not correlated with changes in BCTQ scores. CTS-6 scores were not associated with Decision Regret Scale scores, reported satisfaction, or the single-question assessment of symptom changes. Satisfaction, decision regret, and the single symptom change question were correlated with changes in the BCTQ score and each other. Dissatisfied patients were distinguished by a differential improvement in the BCTQ score (1.5 vs 0.7), but no preoperative variable consistently predicted noneffective CTR. Conclusions: The CTS-6 score does not predict changes in BCTQ scores after CTR. Patient satisfaction with surgical results is associated with postoperative changes in carpal tunnel symptoms but is not predictable using preoperative information. A single question of symptom change may offer an efficient assessment of CTR outcomes. Type of study/level of evidence: Prognostic II. © 2022 American Society for Surgery of the Hand
Author Keywords
Carpal tunnel; CTS-6; outcomes; predict; release
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Using Alzheimer’s disease blood tests to accelerate clinical trial enrollment
(2022) Alzheimer’s and Dementia, .
Schindler, S.E.a b , Li, Y.a b , Li, M.a , Despotis, A.c , Park, E.a , Vittert, L.c , Hamilton, B.H.c , Womack, K.B.a b , Saef, B.a , Holtzman, D.M.a b d , Morris, J.C.a b , Bateman, R.J.a b d , Gupta, M.R.c
a Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
b Knight Alzheimer Disease Research Center, St. Louis, MO, United States
c Olin Business School, Washington University, St. Louis, MO, United States
d Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, United States
Abstract
Introduction: Screening potential participants in Alzheimer’s disease (AD) clinical trials with amyloid positron emission tomography (PET) is often time consuming and expensive. Methods: A web-based application was developed to model the time and financial cost of screening for AD clinical trials. Four screening approaches were compared; three approaches included an AD blood test at different stages of the screening process. Results: The traditional screening approach using only amyloid PET was the most time consuming and expensive. Incorporating an AD blood test at any point in the screening process decreased both the time and financial cost of trial enrollment. Improvements in AD blood test accuracy over currently available tests only marginally increased savings. Use of a high specificity cut-off may improve the feasibility of screening with only an AD blood test. Discussion: Incorporating AD blood tests into screening for AD clinical trials may reduce the time and financial cost of enrollment. HIGHLIGHTS: The time and cost of enrolling participants in Alzheimer’s disease (AD) clinical trials were modeled. A web-based application was developed to enable evaluation of key parameters. AD blood tests may decrease the time and financial cost of clinical trial enrollment. Improvements in AD blood test accuracy only marginally increased savings. Use of a high specificity cut-off may enable screening with only an AD blood test. © 2022 The Authors. Alzheimer’s & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer’s Association.
Author Keywords
amyloid positron emission tomography; blood tests; blood-based biomarkers; clinical trials; cost; economics; false negative; false positive; modeling; screening; screening approaches; Shiny app; time of enrollment
Funding details
National Institutes of HealthNIHP01AG003991, P01AG026276, P30AG066444, R01AG070941, R56AG061900, U19AG024904, U19AG032438
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Spontaneous Motor Recovery after Cervical Spinal Cord Injury: Issues for Nerve Transfer Surgery Decision Making
(2022) Spinal Cord, .
Dengler, J.a b , Steeves, J.D.c , Curt, A.d , Mehra, M.e , Novak, C.B.b , Curtin, C.h , Kennedy, C.f , Ota, D.h , Stenson, K.C.g i , Maier, D.j , Abel, R.k , Weidner, N.l , Rupp, R.l , Vidal, J.m , Benito, J.m , Kalke, Y.-B.n , Fox, I.K.f g , DOD consortiumo , EMSCI consortiumo
a Division of Plastic and Reconstructive Surgery, Tory Trauma Program, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada
b University of Toronto, Division of Plastic & Reconstructive Surgery, Toronto, ON, Canada
c ICORD, University of British Columbia, Vancouver, BC, Canada
d Spinal Cord Injury Center, Balgrist University Hospital, Zurich, Switzerland
e Tigermed-BDM Inc, Gaithersburg, MD, United States
f Division of Plastic and Reconstructive Surgery, Department of Surgery, Washington University School of Medicine, St Louis, MO, United States
g VA St. Louis Healthcare System, St Louis, MO, United States
h Palo Alto Veterans Healthcare System, Palo Alto, CA, United States
i Division of Physical Medicine and Rehabilitation, Washington University School of Medicine, St. Louis, MO, United States
j BG-Trauma Center, Murnau, Germany
k Hohe Warte Bayreuth, Bayreuth, Germany
l Spinal Cord Injury Center, Heidelberg University Hospital, Heidelberg, Germany
m Institute Guttmann, Neurorehabilitation Hospital, Barcelona, Spain
n RKU Universitäts- und Rehabilitationskliniken Ulm, Ulm, Germany
Abstract
Study design: Retrospective cohort study. Objectives: To quantify spontaneous upper extremity motor recovery between 6 and 12 months after spinal cord injury (SCI) to help guide timing of nerve transfer surgery to improve upper limb function in cervical SCI. Setting: Nineteen European SCI rehabilitation centers. Methods: Data was extracted from the European Multicenter Study of SCI database for individuals with mid-level cervical SCI (N = 268). Muscle function grades at 6 and 12 months post-SCI were categorized for analysis. Results: From 6 to 12 months after SCI, spontaneous surgically-relevant recovery was limited. Of all limbs (N = 263) with grade 0–2 elbow extension at 6 months, 4% regained grade 4–5 and 11% regained grade 3 muscle function at 12 months. Of all limbs (N = 380) with grade 0–2 finger flexion at 6 months, 3% regained grade 4–5 and 5% regained grade 3 muscle function at 12 months. Conclusion: This information supports early (6 month) post-injury surgical consultation and evaluation. With this information, individuals with SCI can more fully engage in preference-based decision-making about surgical intervention versus continued rehabilitation and spontaneous recovery to gain elbow extension and/or hand opening and closing. © 2022, The Author(s), under exclusive licence to International Spinal Cord Society.
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Psychiatry training in autism spectrum disorder and intellectual disability: Ongoing gaps and emerging opportunities
(2022) Autism, .
Marrus, N.a , Koth, K.A.b , Hellings, J.A.c , McDonald, R.d , Gwynette, M.F.e , Muhle, R.f , Lohr, W.D.g , Vasa, R.A.d
a Washington University School of Medicine, St. Louis, United States
b Medical College of Wisconsin, United States
c University of Missouri–Kansas City School of Medicine, United States
d Johns Hopkins University School of Medicine, United States
e Medical University of South Carolina, United States
f Columbia University, United States
g University of Louisville School of Medicine, United States
Abstract
Autism spectrum disorder and intellectual disability are associated with psychiatric comorbidities, yet a 2009 study of US child and adolescent psychiatry program directors indicated that psychiatry residents receive insufficient training in autism spectrum disorder/intellectual disability. This follow-up study surveyed child and adolescent psychiatry and general psychiatry program directors to assess (1) the current extent of residency training in autism spectrum disorder/intellectual disability, (2) program director perceptions of educational topics and resident competency in autism spectrum disorder/intellectual disability, and (3) preferred resources to strengthen autism spectrum disorder/intellectual disability training. As in 2009, many child and adolescent psychiatry program directors reported few lecture hours, although current child and adolescent psychiatry residents saw slightly more patients with autism spectrum disorder but not intellectual disability. General psychiatry program directors reported fewer lecture hours in autism spectrum disorder/intellectual disability and fewer patients with autism spectrum disorder than child and adolescent psychiatry program directors. Both child and adolescent psychiatry and general psychiatry program directors recognized the importance of a range of educational topics in autism spectrum disorder/intellectual disability. Child and adolescent psychiatry program directors reported higher resident competency, and lecture hours and patients seen moderately correlated with resident competency. Program directors indicated that online videos and other resources would help improve autism spectrum disorder/intellectual disability training in their programs. Collectively, these findings suggest minimal improvements in autism spectrum disorder/intellectual disability training over the past decade and highlight the urgent need to advance psychiatry training in this field through dissemination of resources. Lay abstract: Children, adolescents, and adults with autism spectrum disorder and intellectual disability experience high rates of co-occurring psychiatric conditions throughout their lifetime. However, there is a shortage of psychiatrists to treat these populations. We evaluated how much education psychiatrists-in-training receive on how to care for individuals with autism spectrum disorder/intellectual disability. We found that in many psychiatry programs, residents receive limited training experiences in autism spectrum disorder/intellectual disability involving lectures and patient contact and that psychiatry program directors would benefit from more resources to strengthen education in autism spectrum disorder/intellectual disability. © The Author(s) 2022.
Author Keywords
autism spectrum disorder; education; intellectual disability; psychiatry; residency training
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Does Macbeth See a Dagger? An Empirical Argument for the Existence-Neutrality of Seeing
(2022) Erkenntnis, .
Sant’Anna, A.a , Dranseika, V.b c
a Department of Philosophy and Philosophy-Neuroscience-Psychology Program, Washington University in St. Louis, 1 Brookings Drive, St. Louis, MO 63130, United States
b Interdisciplinary Centre for Ethics and Institute of Philosophy, Jagiellonian University, Grodzka 52, Kraków, 31-044, Poland
c Institute of Philosophy, Vilnius University, 3 Universiteto St., Vilnius, 01513, Lithuania
Abstract
In a recent paper, Justin D’Ambrosio (2020) has offered an empirical argument in support of a negative solution to the puzzle of Macbeth’s dagger—namely, the question of whether, in the famous scene from Shakespeare’s play, Macbeth sees a dagger in front of him. D’Ambrosio’s strategy consists in showing that “seeing” is not an existence-neutral verb; that is, that the way it is used in ordinary language is not neutral with respect to whether its complement exists. In this paper, we offer an empirical argument in favor of an existence-neutral reading of “seeing”. In particular, we argue that existence-neutral readings are readily available to language users. We thus call into question D’Ambrosio’s argument for the claim that Macbeth does not see a dagger. According to our positive solution, Macbeth sees a dagger, even though there is not a dagger in front of him. © 2022, The Author(s), under exclusive licence to Springer Nature B.V.
Author Keywords
Existence-neutrality; Experimental philosophy; Hallucinating; Macbeth’s dagger; Seeing
Funding details
MND190721457781, UID120812
South African Medical Research CouncilSAMRC
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Putting participants and study partners FIRST when clinical trials end early
(2022) Alzheimer’s and Dementia, .
Largent, E.A.a , Walter, S.b , Childs, N.c , Dacks, P.A.d , Dodge, S.d , Florian, H.e , Jackson, J.f , Llibre Guerra, J.J.g , Iturriaga, E.h , Miller, D.S.i , Moreno, M.j , Nosheny, R.L.k , Obisesan, T.O.l , Portacolone, E.m , Siddiqi, B.n , Silverberg, N.o , Warren, R.C.p , Welsh-Bohmer, K.A.q , Edelmayer, R.M.j , the Participant FIRST Work Groupr
a Department of Medical Ethics and Health Policy, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States
b Alzheimer’s Therapeutic Research Institute, University of Southern California, San Diego, CA, United States
c Care Partner, Philadelphia, PA, United States
d The Association for Frontotemporal Degeneration, King of Prussia, PA, United States
e AbbVie Neuroscience Clinical Development, North Chicago, IL, United States
f Department of Neurology, Harvard Medical School, Massachusetts General Hospital, Boston, MA, United States
g Department of Neurology, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
h National Institutes of Health, National Heart, Lung, and Blood Institute, Bethesda, MD, United States
i Signant Health, Blue Bell, PA, United States
j Alzheimer’s Association, Chicago, IL, United States
k Department of Psychiatry and Behavioral Sciences, VA Advanced Imaging Research Center, San Francisco Veterans Administration Medical Center, University of California San Francisco, San Fancisco, CA, United States
l Division of Geriatrics, Department of Medicine, Howard University and Hospital, Washington, DC, United States
m Institute for Health & Aging, Philip Lee Institute for Health Policy Studies, University of California San Francisco, San Francisco, CA, United States
n The Michael J. Fox Foundation for Parkinson’s Research, New York, NY, United States
o National Institutes of Health, National Institute on Aging, Bethesda, MD, United States
p National Center for Bioethics in Research and Health Care, Tuskegee University, Tuskegee, AL, United States
q Department of Psychiatry, Duke University School of Medicine, Durham, NC, United States
Abstract
Between 2018 and 2019, multiple clinical trials ended earlier than planned, resulting in calls to improve communication with and support for participants and their study partners (“dyads”). The multidisciplinary Participant Follow-Up Improvement in Research Studies and Trials (Participant FIRST) Work Group met throughout 2021. Its goals were to identify best practices for communicating with and supporting dyads affected by early trial stoppage. The Participant FIRST Work Group identified 17 key recommendations spanning the pre-trial, mid-trial, and post-trial periods. These focus on prospectively allocating sufficient resources for orderly closeout; developing dyad-centered communication plans; helping dyads build and maintain support networks; and, if a trial stops, informing dyads rapidly. Participants and study partners invest time, effort, and hope in their research participation. The research community should take intentional steps toward better communicating with and supporting participants when clinical trials end early. The Participant FIRST recommendations are a practical guide for embarking on that journey. © 2022 The Authors. Alzheimer’s & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer’s Association.
Funding details
National Institutes of HealthNIH
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Structural Connectivity and Emotion Recognition Impairment in Children and Adolescents with Chromosome 22q11.2 Deletion Syndrome
(2022) Journal of Autism and Developmental Disorders, .
Sanders, A.F.P.a b , Hobbs, D.A.a c , Knaus, T.A.a , Beaton, E.A.a
a Department of Psychology, University of New Orleans, 2000 Lakeshore Drive, New Orleans, LA 70148, United States
b Department of Psychiatry, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
c Department of Radiology, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
Abstract
Children with chromosome 22q11.2 deletion syndrome (22q11.2DS) exhibit impaired ability to process and understand emotions in others. We measured structural connectivity in children and adolescents with 22q11.2DS (n = 28) and healthy controls (n = 29). Compared to controls, those with 22q11.2DS had poorer social skills and more difficulty recognizing facial emotions. Children with 22q11.2DS also had higher fractional anisotropic diffusion in right amygdala to fusiform gyrus white matter pathways. Right amygdala to fusiform gyrus fractional anisotropy values partially mediated the relationship between 22q11.2DS and social skills, as well as the relationship between 22q11.2DS and emotion recognition accuracy. These findings provide insight into the neural origins of social skills deficits seen in 22q11.2DS and may serve as a biomarker for risk of future psychiatric problems. © 2022, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
Author Keywords
Brain imaging; DiGeorge syndrome; Emotion processing; Face processing; Genetic deletion; Velocardiofacial syndrome
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Association of Elevated Amyloid and Tau Positron Emission Tomography Signal with Near-Term Development of Alzheimer Disease Symptoms in Older Adults Without Cognitive Impairment
(2022) JAMA Neurology, .
Strikwerda-Brown, C.a b , Hobbs, D.A.c , Gonneaud, J.a b d , St-Onge, F.a b , Binette, A.P.a b e , Ozlen, H.b , Provost, K.f , Soucy, J.-P.g , Buckley, R.F.h i j , Benzinger, T.L.S.c , Morris, J.C.c , Villemagne, V.L.k , Doré, V.l , Sperling, R.A.h i , Johnson, K.A.h i , Rowe, C.C.l , Gordon, B.A.c , Poirier, J.a b , Breitner, J.C.S.a b , Villeneuve, S.a b g
a Department of Psychiatry, Faculty of Medicine, McGill University, Montreal, QC, Canada
b Douglas Mental Health University Institute, 6875 Blvd LaSalle, Perry Pavilion, Montreal, QC H4H 1R3, Canada
c Washington University School of Medicine, St Louis, MO, United States
d Inserm, Inserm UMR-S U1237, Université de Caen-Normandie, GIP Cyceron, Caen, France
e Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Lund, Sweden
f Centre Hospitalier, Université de Montréal, Montreal, QC, Canada
g McConnell Brain Imaging Centre, Montreal Neurological Institute, Montreal, QC, Canada
h Department of Neurology, Massachusetts General Hospital, Boston, United States
i Center for Alzheimer Research and Treatment, Brigham and Women’s Hospital, Boston, MA, United States
j Melbourne School of Psychological Sciences, University of Melbourne, Melbourne, VIC, Australia
k Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, United States
l Department of Molecular Imaging & Therapy, Austin Health, Melbourne, VIC, Australia
Abstract
Importance: National Institute on Aging-Alzheimer’s Association (NIA-AA) workgroups have proposed biological research criteria intended to identify individuals with preclinical Alzheimer disease (AD). Objective: To assess the clinical value of these biological criteria to identify older individuals without cognitive impairment who are at near-term risk of developing symptomatic AD. Design, Setting, and Participants: This longitudinal cohort study used data from 4 independent population-based cohorts (PREVENT-AD, HABS, AIBL, and Knight ADRC) collected between 2003 and 2021. Participants were older adults without cognitive impairment with 1 year or more of clinical observation after amyloid β and tau positron emission tomography (PET). Median clinical follow-up after PET ranged from 1.94 to 3.66 years. Exposures: Based on binary assessment of global amyloid burden (A) and a composite temporal region of tau PET uptake (T), participants were stratified into 4 groups (A+T+, A+T-, A-T+, A-T-). Presence (+) or absence (-) of neurodegeneration (N) was assessed using temporal cortical thickness. Main Outcomes and Measures: Each cohort was analyzed separately. Primary outcome was clinical progression to mild cognitive impairment (MCI), identified by a Clinical Dementia Rating score of 0.5 or greater in Knight ADRC and by consensus committee review in the other cohorts. Clinical raters were blind to imaging, genetic, and fluid biomarker data. A secondary outcome was cognitive decline, based on a slope greater than 1.5 SD below the mean of an independent subsample of individuals without cognitive impairment. Outcomes were compared across the biomarker groups. Results: Among 580 participants (PREVENT-AD, 128; HABS, 153; AIBL, 48; Knight ADRC, 251), mean (SD) age ranged from 67 (5) to 76 (6) years across cohorts, with between 55% (137/251) and 74% (95/128) female participants. Across cohorts, 33% to 83% of A+T+ participants progressed to MCI during follow-up (mean progression time, 2-2.72 years), compared with less than 20% of participants in other biomarker groups. Progression further increased to 43% to 100% when restricted to A+T+(N+) individuals. Cox proportional hazard ratios for progression to MCI in the A+T+ group vs other biomarker groups were all 5 or greater. Many A+T+ nonprogressors also showed longitudinal cognitive decline, while cognitive trajectories in other groups remained predominantly stable. Conclusions and Relevance: The clinical prognostic value of NIA-AA research criteria was confirmed in 4 independent cohorts, with most A+T+(N+) older individuals without cognitive impairment developing AD symptoms within 2 to 3 years.. © 2022 American Medical Association. All rights reserved.
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Associations of Vascular Risk and Amyloid Burden with Subsequent Dementia
(2022) Annals of Neurology, .
Gottesman, R.F.a , Wu, A.b , Coresh, J.b , Knopman, D.S.c , Jack, C.R., Jr.c , Rahmim, A.d , Sharrett, A.R.b , Spira, A.P.e , Wong, D.F.f , Wagenknecht, L.E.g , Hughes, T.M.h , Walker, K.A.i , Mosley, T.H.j
a National Institute of Neurological Disorders and Stroke Intramural Program, National Institutes of Health, Bethesda, MD, United States
b Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States
c Mayo Clinic, Rochester, MN, United States
d Departments of Radiology and Physics, University of British Columbia, Vancouver, BC, Canada
e Department of Mental Health and Center on Aging and Health, Johns Hopkins Bloomberg School of Public Health, and Department of Psychiatry and Behavioral Science, Johns Hopkins School of Medicine, Baltimore, MD, United States
f Department of Radiology, Washington University, St Louis, MO, United States
g Division of Public Health Sciences, Wake Forest University Health Sciences, Winston-Salem, NC, United States
h Department of Gerontology and Geriatric Medicine, Wake Forest School of Medicine, Winston-Salem, NC, United States
i National Institute on Aging Intramural Program, National Institutes of Health, Bethesda, MD, United States
j Department of Medicine, University of Mississippi Medical Center, Jackson, MS, United States
Abstract
Objective: Midlife vascular risk factors (MVRFs) are associated with incident dementia, as are amyloid β (Aβ) deposition and neurodegeneration. Whether vascular and Alzheimer disease-associated factors contribute to dementia independently or interact synergistically to reduce cognition is poorly understood. Methods: Participants in the Atherosclerosis Risk in Communities–Positron Emission Tomography study were followed from 1987–1989 (45–64 years old) through 2016–2017 (74–94 years old), with repeat cognitive assessment and dementia adjudication. In 2011–2013, dementia-free participants underwent brain magnetic resonance imaging (with white matter hyperintensity [WMH] and brain volume measurement) and florbetapir (Aβ) positron emission tomography. The relative contributions of vascular risk and injury (MVRFs, WMH volume), elevated Aβ standardized uptake value ratio (SUVR), and neurodegeneration (smaller temporoparietal brain regions) to incident dementia were evaluated with adjusted Cox models. Results: In 298 individuals, 36 developed dementia (median follow-up = 4.9 years). Midlife hypertension and Aβ each independently predicted dementia risk (hypertension: hazard ratio [HR] = 2.57, 95% confidence interval [CI] = 1.16–5.67; Aβ SUVR [per standard deviation (SD)]: HR = 2.57, 95% CI = 1.72–3.84), but did not interact significantly, whereas late life diabetes (HR = 2.50, 95% CI = 1.18–5.28) and Aβ independently predicted dementia risk. WMHs (per SD: HR = 1.51, 95% CI = 1.03–2.20) and Aβ SUVR (HR = 2.52, 95% CI = 1.83–3.47) independently contributed to incident dementia, but WMHs lost significance when MVRFs were included. Smaller temporoparietal brain regions were associated with incident dementia, independent of Aβ and MVRFs (HR = 2.18, 95% CI = 1.18–4.01). Interpretation: Midlife hypertension and late life Aβ are independently associated with dementia risk, without evidence for synergy on a multiplicative scale. Given the independent contributions of vascular and amyloid mechanisms, multiple pathways should be considered when evaluating interventions to reduce the burden of dementia. ANN NEUROL 2022. © 2022 American Neurological Association. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.
Funding details
National Institutes of HealthNIH
National Institute on AgingNIA
National Heart, Lung, and Blood InstituteNHLBI2U01HL096814, 2U01HL096899, 2U01HL096902, 2U01HL096917, HHSN268201700005I, U01 2U01HL096812
National Institute on Deafness and Other Communication DisordersNIDCDR01AG040282, R01‐HL70825
National Institute of Neurological Disorders and StrokeNINDS
Mayo Clinic
GHR FoundationGHR
Document Type: Article
Publication Stage: Article in Press
Source: Scopus