Publications

Hope Center member publications

List of publications for the week of May 25, 2021

Network dysfunction in cognitively normal APOE ε4 carriers is related to subclinical tau” (2021) Alzheimer’s and Dementia

Network dysfunction in cognitively normal APOE ε4 carriers is related to subclinical tau
(2021) Alzheimer’s and Dementia, . 

Butt, O.H.a , Meeker, K.L.a , Wisch, J.K.a , Schindler, S.E.a , Fagan, A.M.a b c , Benzinger, T.L.S.d , Cruchaga, C.b c e , Holtzman, D.M.a b c , Morris, J.C.a b c , Ances, B.M.a b c d

a Department of Neurology, Washington University in Saint Louis, Saint Louis, MO, United States
b Knight Alzheimer Disease Research Center, Washington University in Saint Louis, St. Louis, MO, United States
c Hope Center for Neurological Disorders, Washington University in Saint Louis, St. Louis, MO, United States
d Department of Radiology, Washington University in Saint Louis, Saint Louis, MO, United States
e Department of Psychiatry, Washington University in Saint Louis, Saint Louis, MO, United States

Abstract
Introduction: Apolipoprotein E (APOE) ε4 allele status is associated with amyloid and tau-related pathological changes related to Alzheimer’s disease (AD). However, it is unknown whether brain network changes are related to amyloid beta (Aβ) and/or tau-related pathology in cognitively normal APOE ε4 carriers with subthreshold Aβ accumulation. Methods: Resting state functional connectivity measures of network integrity were evaluated in cognitively normal individuals (n = 121, mean age 76.6 ± 7.8 years, 15% APOE ε4 carriers, 65% female) with minimal Aβ per cerebrospinal fluid (CSF) or amyloid positron emission tomography. Results: APOE ε4 carriers had increased lateralized connections relative to callosal connections within the default-mode, memory, and salience networks (P =.02), with significant weighting on linear regression toward CSF total tau (P =.03) and CSF phosphorylated tau at codon 181 (P =.03), but not CSF Aβ42. Discussion: Cognitively normal APOE ε4 carriers with subthreshold amyloid accumulation may have network reorganization associated with tau. © 2021 the Alzheimer’s Association

Author Keywords
apolipoprotein E;  functional connectivity;  preclinical Alzheimer’s disease;  resting state;  tau

Funding details
Hope Center for Neurological Disorders
National Institute on AgingNIAP01 AG026276

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

T-box transcription factor 21 is expressed in terminal Schwann cells at the neuromuscular junction” (2021) Muscle and Nerve

T-box transcription factor 21 is expressed in terminal Schwann cells at the neuromuscular junction
(2021) Muscle and Nerve, . 

Jablonka-Shariff, A., Broberg, C., Rios, R., Snyder-Warwick, A.K.

Division of Plastic Surgery, Department of Surgery, Washington University School of Medicine, Saint Louis, MO, United States

Abstract
Introduction/Aims: Terminal Schwann cells (tSCs) are nonmyelinating Schwann cells present at the neuromuscular junction (NMJ) with multiple integral roles throughout their lifespan. There is no known gene differentiating tSCs from myelinating Schwann cells, making their isolation and investigation challenging. In this work we investigated genes expressed within tSCs. Methods: A novel dissection technique was utilized to isolate the tSC-containing NMJ band from the sternomastoid muscles of S100-GFP mice. RNA was isolated from samples containing: (a) NMJ bands (tSCs with nerve and muscle), (b) nerve, and (c) muscle, and microarray genetic expression analysis was conducted. Data were validated by quantitative real-time polymerase chain reaction (qRT-PCR) and immunofluorescent staining. To identify genes specific to tSCs compared with other NMJ components, analysis of variance and rank-order analysis were performed using the Partek Genomic Suite. Results: Microarray analysis of the tSC-enriched NMJ band revealed upregulation (by 4- to 12-fold) of several genes unique to the NMJ compared with muscle or nerve parts alone (P <.05). Among these genes, Tbx21 (or T-bet) was identified, which showed a 12-fold higher expression at the NMJ compared with sciatic nerve (P <.002). qRT-PCR analysis showed Tbx21 mRNA expression was over ninefold higher (P <.05) in the NMJ relative to muscle and nerve. Tbx21 protein colocalized with tSCs and was not noted in myelinating SCs from sciatic nerve. Discussion: We found TBX21 to be expressed in tSCs. Additional studies will be performed to determine the functional significance of TBX21 in tSCs. These studies may enhance the investigative tools available to modulate tSCs to improve motor recovery after nerve injury. © 2021 Wiley Periodicals LLC.

Author Keywords
nerve injury;  neuromuscular junction;  reinnervation;  T-BET;  TBX21;  terminal Schwann cell

Funding details
National Institutes of HealthNIHK08NS096232
National Institute of Neurological Disorders and StrokeNINDS
Plastic Surgery FoundationPSF

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

Brain Biomarkers: Follow-Up of RNA Expression Discovery Approach: CSF Assays for Neurogranin, SNAP-25, and VILIP-1” (2021) Neuromethods

Brain Biomarkers: Follow-Up of RNA Expression Discovery Approach: CSF Assays for Neurogranin, SNAP-25, and VILIP-1
(2021) Neuromethods, 168, pp. 181-221. 

Herries, E.M.a , Brada, N.b , Sutphen, C.L.c , Fagan, A.M.c , Ladenson, J.H.b

a Departments of Neurology and of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO, United States
b Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO, United States
c Department of Neurology, Knight Alzheimer’s Disease Research Center, Hope Center for Neurological Disorders, Washington University School of Medicine, Saint Louis, MO, United States

Abstract
Here, we describe our methods for identifying biomarkers of neurological disease that have the potential to evaluate patients with probable Alzheimer’s disease (AD) and efficacy of novel therapeutics. We report a follow-up to our RNA expression discovery approach in mice to identify potential brain biomarkers. The gene expression approach identified 26 genes as having reasonable abundance and specificity and with human homologs known at the time. This chapter describes our follow-up in developing and evaluating the assays for the proteins expressed by these genes. We then present validated working assays for three analytes: VILIP-1 (visinin-like protein 1), a robust marker of neurodegeneration; synaptosomal-associated protein-25 (SNAP-25) and two different assays for neurogranin (Ng), as biomarkers of synaptic pathology, that we have utilized for studying AD, and which have demonstrated diagnostic utility. © 2021, Springer Science+Business Media, LLC, part of Springer Nature.

Author Keywords
Alzheimer’s disease;  Biomarker;  Cerebrospinal fluid;  Neurogranin;  Single Molecule Counting™ immunoassays;  SNAP-25;  VILIP-1

Document Type: Book Chapter
Publication Stage: Final
Source: Scopus

International stroke genetics consortium recommendations for studies of genetics of stroke outcome and recovery” (2021) International Journal of Stroke

Lindgren, A.G.a b , Braun, R.G.c , Juhl Majersik, J.d , Clatworthy, P.e , Mainali, S.f , Derdeyn, C.P.g , Maguire, J.h , Jern, C.i j , Rosand, J.k , Cole, J.W.l m , Lee, J.-M.n , Khatri, P.o , Nyquist, P.p , Debette, S.q r , Keat Wei, L.s , Rundek, T.t , Leifer, D.u , Thijs, V.v , Lemmens, R.w x , Heitsch, L.n , Prasad, K.y , Jimenez Conde, J.z aa , Dichgans, M.ab , Rost, N.S.k , Cramer, S.C.ac ad , Bernhardt, J.v , Worrall, B.B.ae , Fernandez-Cadenas, I.af , International Stroke Genetics Consortiumag

International stroke genetics consortium recommendations for studies of genetics of stroke outcome and recovery
(2021) International Journal of Stroke, . 

a Department of Clinical Sciences Lund, Neurology, –SPiCloseGreaterLund University, Lund, Sweden
b Department of Neurology, Skåne University Hospital, Lund, Sweden
c Department of Neurology, University of Maryland, Baltimore, MD, United States
d Department of Neurology, University of Utah, Salt Lake Cit, UT, United States
e Department of Neurology, North Bristol NHS Trust, Bristol, United Kingdom
f Department of Neurology, -SPiCloseGreaterThe Ohio State University, Columbus, OH, United States
g Department of Radiology, University of Iowa, Iowa City, IA, United States
h Faculty of Health, University of Technology Sydney, Ultimo, NSW, Australia
i Department of Laboratory Medicine, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden
j Department of Clinical Genetics and Genomics, Sahlgrenska University Hospital, Gothenburg, Sweden
k Department of Neurology, Massachusetts General Hospital, Boston, MA, United States
l Neurology Service, Baltimore Veterans Affairs Medical Center, Baltimore, MD, United States
m Department of Neurology, -SPiCloseGreaterUniversity of Maryland School of Medicine, Baltimore, MD, United States
n Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
o Department of Neurology and Rehabilitation Sciences, University of Cincinnati, Cincinnati, OH, United States
p Anesthesiology/Critical Care Medicine, Neurosurgery, and General Internal Medicine, -SPiCloseGreaterJohns Hopkins School of Medicine, Baltimore, MD, United States
q Bordeaux Population Health, Inserm U1219, University of Bordeaux, Bordeaux, France
r Neurology Department, Bordeaux University Hospital, Bordeaux, France
s Department of Biological Science, Faculty of Science, Universiti Tunku Abdul Rahman, Perak, Malaysia
t Department of Neurology, -SPiCloseGreaterUniversity of Miami Miller School of Medicine, Miami, FL, United States
u Department of Neurology, Weill Cornell Medicine, New York, NY, United States
v Stroke Theme, Florey Institute of Neuroscience and Mental Health, Melbourne, Vic, Australia
w Department of Neuroscience, University of Leuven, Leuven, Belgium
x Department of Neurology, University Hospitals Leuven, Leuven, Belgium
y Rajendra Institute of Medical Sciences, Ranchi, Jharkhand, India
z Neurology Department, Neurovascular Research Group, Institut Hospital del Mar d’Investigació Mèdica, Barcelona, Spain
aa Universitat Autònoma de Barcelona, Barcelona, Spain
ab Institute for Stroke and Dementia Research, University Hospital, LMU, Munich, Germany
ac Department of Neurology, UCLA, Los Angeles, CA, United States
ad California Rehabilitation Institute, Los Angeles, CA, United States
ae Department of Neurology, University of Virginia, Charlottesville, VA, United States
af Stroke Pharmacogenomics and Genetics Group, Sant Pau Biomedical Research Institute, Barcelona, Spain

Abstract
Numerous biological mechanisms contribute to outcome after stroke, including brain injury, inflammation, and repair mechanisms. Clinical genetic studies have the potential to discover biological mechanisms affecting stroke recovery in humans and identify intervention targets. Large sample sizes are needed to detect commonly occurring genetic variations related to stroke brain injury and recovery. However, this usually requires combining data from multiple studies where consistent terminology, methodology, and data collection timelines are essential. Our group of expert stroke and rehabilitation clinicians and researchers with knowledge in genetics of stroke recovery here present recommendations for harmonizing phenotype data with focus on measures suitable for multicenter genetic studies of ischemic stroke brain injury and recovery. Our recommendations have been endorsed by the International Stroke Genetics Consortium. © 2021 World Stroke Organization.

Author Keywords
Data collection;  genetics;  ischemic stroke;  outcome;  phenotype;  recovery;  standardization

Funding details
VetenskapsrådetVR2018–02543, 2019–01757
1841918N
Department of Biotechnology, Ministry of Science and Technology, IndiaDBT
Instituto de Salud Carlos IIIISCIII
National Institute of Child Health and Human DevelopmentNICHDK12HD093427
Sparbanksstiftelsen Färs and Frosta
European Regional Development FundERDF
National Institutes of HealthNIHKL2TR003016, R01-NS105150, R21-NS106480, R01-NS114045, U24-NS107237, R01-NS085419, U24-NS107230, R01-NS100178, U24-NS107222
Region Skåne
Lunds Universitet
Skånes universitetssjukhusSUS
U.S. Department of Veterans AffairsVA
American Heart AssociationAHA15GPSG23770000, 17IBDG3300328
National Institute of Neurological Disorders and StrokeNINDSR01-NS082285, K23NS099487-01, U19-NS115388, 5U10NS086606, R01-NS086905

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

Genome-wide survival study identifies a novel synaptic locus and polygenic score for cognitive progression in Parkinson’s disease” (2021) Nature Genetics

Genome-wide survival study identifies a novel synaptic locus and polygenic score for cognitive progression in Parkinson’s disease
(2021) Nature Genetics, . 

Liu, G.a b c , Peng, J.a b d , Liao, Z.a b , Locascio, J.J.a b e , Corvol, J.-C.f , Zhu, F.a b , Dong, X.a b , Maple-Grødem, J.g h , Campbell, M.C.i , Elbaz, A.j , Lesage, S.f , Brice, A.f , Mangone, G.f , Growdon, J.H.e , Hung, A.Y.e , Schwarzschild, M.A.e , Hayes, M.T.a k , Wills, A.-M.e , Herrington, T.M.e , Ravina, B.l , Shoulson, I.m , Taba, P.n , Kõks, S.o p , Beach, T.G.q , Cormier-Dequaire, F.f , Alves, G.g h r , Tysnes, O.-B.s t , Perlmutter, J.S.i u v , Heutink, P.w , Amr, S.S.x , van Hilten, J.J.y , Kasten, M.z aa , Mollenhauer, B.ab ac , Trenkwalder, C.ac ad , Klein, C.ae , Barker, R.A.af ag , Williams-Gray, C.H.af , Marinus, J.y , van Hilten, J.J.y , Scherzer, C.R.a b e k , International Genetics of Parkinson Disease Progression (IGPP) Consortiumah

a Center for Advanced Parkinson Research, Harvard Medical School, Brigham and Women’s Hospital, Boston, MA, United States
b Precision Neurology Program of Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
c School of Medicine, Sun Yat-sen University, Shenzhen, Guangdong, China
d School of Computer Science, Northwestern Polytechnical University, Xi’an, Shaanxi, China
e Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
f Sorbonne Université, Paris Brain Institute – Institut du Cerveau – ICM, Institut National de Santé et en Recherche Médicale, Centre National de Recherche Scientifique, Assistance Publique Hôpitaux de Paris, Département de Neurologie et de Génétique, Centre d’Investigation Clinique Neurosciences, Hôpital Pitié-Salpêtrière, Paris, France
g The Norwegian Centre for Movement Disorders, Stavanger University Hospital, Stavanger, Norway
h Department of Chemistry, Bioscience and Environmental Engineering, University of Stavanger, Stavanger, Norway
i Departments of Neurology and Radiology, Washington University School of Medicine, St. Louis, MO, United States
j Paris-Saclay University, Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Inserm, Gustave Roussy, ‘Exposome and heredity’ team, Centre de researche en épidémiologie et santé des populations (CESP), Villejuif, France
k Department of Neurology, Brigham and Women’s Hospital, Boston, MA, United States
l Praxis Precision Medicines, Cambridge, MA, United States
m Department of Neurology, Center for Health + Technology, University of Rochester, Rochester, NY, United States
n Department of Neurology and Neurosurgery, University of Tartu, Tartu, Estonia
o Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Perth, WA, Australia
p Perron Institute for Neurological and Translational Science, Perth, WA, Australia
q Banner Sun Health Research Institute, Sun City, AZ, United States
r Department of Neurology, Stavanger University Hospital, Stavanger, Norway
s Department of Neurology, Haukeland University Hospital, Bergen, Norway
t Department of Clinical Medicine, University of Bergen, Bergen, Norway
u Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, United States
v Program of Physical Therapy and Program of Occupational Therapy, Washington University School of Medicine, St. Louis, MO, United States
w German Center for Neurodegenerative diseases (DZNE), Tübingen, Germany
x Translational Genomics Core of Partners HealthCare Personalized Medicine, Cambridge, MA, United States
y Department of Neurology, Leiden University Medical Center, Leiden, Netherlands
z Institute of Neurogenetics, University of Lübeck, University Hospital of Schleswig-Holstein, Lübeck, Germany
aa Department of Psychiatry and Psychotherapy, University of Lübeck, Lübeck, Germany
ab Department of Neurology, University Medical Center Göttingen, Göttingen, Germany
ac Paracelsus-Elena-Klinik, Kassel, Germany
ad Department of Neurosurgery, University Medical Center Göttingen, Göttingen, Germany
ae Institute of Neurogenetics, University of Lübeck, University Hospital of Schleswig-Holstein, Lübeck, Germany
af John Van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom
ag Wellcome – MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom

Abstract
A key driver of patients’ well-being and clinical trials for Parkinson’s disease (PD) is the course that the disease takes over time (progression and prognosis). To assess how genetic variation influences the progression of PD over time to dementia, a major determinant for quality of life, we performed a longitudinal genome-wide survival study of 11.2 million variants in 3,821 patients with PD over 31,053 visits. We discover RIMS2 as a progression locus and confirm this in a replicate population (hazard ratio (HR) = 4.77, P = 2.78 × 10−11), identify suggestive evidence for TMEM108 (HR = 2.86, P = 2.09 × 10−8) and WWOX (HR = 2.12, P = 2.37 × 10−8) as progression loci, and confirm associations for GBA (HR = 1.93, P = 0.0002) and APOE (HR = 1.48, P = 0.001). Polygenic progression scores exhibit a substantial aggregate association with dementia risk, while polygenic susceptibility scores are not predictive. This study identifies a novel synaptic locus and polygenic score for cognitive disease progression in PD and proposes diverging genetic architectures of progression and susceptibility. © 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.

Funding details
2019QN01Y139
National Institutes of HealthNIHU01NS100603, U01NS095736
National Institute on AgingNIAR01NS115144
Fundamental Research Funds for the Central Universities19ykpy146
National Institute of Neurological Disorders and StrokeNINDS
Shenzhen Fundamental Research ProgramJCYJ20190807161601692
K23NS099380
National Natural Science Foundation of ChinaNSFC31900475
Evelyn Trust
ZonMw
NIHR Cambridge Biomedical Research Centre146281
Bristol-Myers SquibbBMS
Wellcome TrustWT203151/Z/16/Z
H. Lundbeck A/S
Cure Parkinson’s TrustCPT
Parkinson’s UK
Rosetrees TrustA1519 M654
Deutsche Parkinson VereinigungDPV
American Parkinson Disease AssociationAPDA
Deutsche ForschungsgemeinschaftDFG
Medical Research CouncilMRC
Amyotrophic Lateral Sclerosis AssociationALSA
Michael J. Fox Foundation for Parkinson’s ResearchMJFF
MR/R007446/1
AbbVie
Sanofi Genzyme
Pfizer
National Institutes of HealthNIH
Center for Protein Therapeutics, University at BuffaloCPT
European CommissionEC
Biogen
Novo Nordisk
Perron Institute for Neurological and Translational Science
U.S. Department of DefenseDOD
Medical Research CouncilMRC

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