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
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
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
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
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
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
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
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
Slc12a8 in the lateral hypothalamus maintains energy metabolism and skeletal muscle functions during aging
(2022) Cell Reports, 40 (4), art. no. 111131, .
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
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
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
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
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
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