CYP1B1-RMDN2 Alzheimer’s disease endophenotype locus identified for cerebral tau PET
(2024) Nature Communications, 15 (1), art. no. 8251, .
Nho, K.a b c d , Risacher, S.L.a c , Apostolova, L.G.a c e f , Bice, P.J.a c , Brosch, J.R.c e , Deardorff, R.c e , Faber, K.f g , Farlow, M.R.c e , Foroud, T.c f g , Gao, S.c h , Rosewood, T.a b c , Kim, J.P.a b c , Nudelman, K.c f g , Yu, M.a c , Aisen, P.i , Sperling, R.j , Hooli, B.k , Shcherbinin, S.k , Svaldi, D.k , Jack, C.R., Jr.l , Jagust, W.J.m , Landau, S.m , Vasanthakumar, A.n , Waring, J.F.n , Doré, V.o p , Laws, S.M.q , Masters, C.L.r , Porter, T.q , Rowe, C.C.p r , Villemagne, V.L.p s , Dumitrescu, L.t u , Hohman, T.J.t u , Libby, J.B.t , Mormino, E.v , Buckley, R.F.j , Johnson, K.j w , Yang, H.-S.j x , Petersen, R.C.y , Ramanan, V.K.y , Ertekin-Taner, N.z aa , Vemuri, P.l , Cohen, A.D.s , Fan, K.-H.ab , Kamboh, M.I.ab , Lopez, O.L.s ac , Bennett, D.A.ad , Ali, M.ae , Benzinger, T.af , Cruchaga, C.ae ag , Hobbs, D.af , De Jager, P.L.ah , Fujita, M.ah , Jadhav, V.f ai , Lamb, B.T.c f ai , Tsai, A.P.v ai aj , Castanho, I.ak al , Mill, J.ak , Weiner, M.W.am an , Saykin, A.J.a b c e f , for the Alzheimer’s Disease Neuroimaging Initiative (ADNI)ao , the Department of Defense Alzheimer’s Disease Neuroimaging Initiative (DoD-ADNI)ao , the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Study (A4 Study) and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN)ao , the Australian Imaging, Biomarker & Lifestyle Study (AIBL)ao
a Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, United States
b Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, United States
c Indiana Alzheimer’s Disease Research Center, Indiana University School of Medicine, Indianapolis, United States
d Department of BioHealth Informatics, Indiana University, Indianapolis, United States
e Department of Neurology, Indiana University School of Medicine, Indianapolis, United States
f Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, United States
g National Centralized Repository for Alzheimer’s Disease and Related Dementias, Indiana University School of Medicine, Indianapolis, United States
h Department of Biostatistics, Indiana University School of Medicine, Indianapolis, United States
i Department of Neurology, Keck School of Medicine, University of Southern California, San Diego, United States
j Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, United States
k Eli Lilly and Company, Indianapolis, United States
l Department of Radiology, Mayo Clinic, Rochester, United States
m UC Berkeley Helen Wills Neuroscience Institute, University of California – Berkeley, Berkeley, United States
n Genomics Research Center, AbbVie, North Chicago, United States
o CSIRO Health and Biosecurity, Melbourne, Australia
p Department of Molecular Imaging & amp; Therapy, Austin Health, Heidelberg, Australia
q Centre for Precision Health, School of Medical and Health Sciences, Edith Cowan University, Joondalup, Australia
r Florey Institute of Neuroscience and Mental Health and The University of Melbourne, Parkville, Australia
s Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, United States
t Vanderbilt Memory & amp; Alzheimer’s Center, Vanderbilt University Medical Center, Nashville, United States
u Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, United States
v Department of Neurology & amp; Neurological Sciences, Stanford University, Stanford, United States
w Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, United States
x Center for Alzheimer’s Research and Treatment, Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States
y Department of Neurology, Mayo Clinic, Rochester, United States
z Department of Neurology, Mayo Clinic, Jacksonville, United States
aa Department of Neuroscience, Mayo Clinic, Jacksonville, United States
ab Department of Human Genetics, University of Pittsburgh, Pittsburgh, United States
ac Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, United States
ad Department of Neurological Sciences, Rush Medical College, Rush University, Chicago, United States
ae Department of Psychiatry, Washington University, St. Louis, United States
af Department of Radiology, Washington University School of Medicine, St. Louis, United States
ag NeuroGenomics and Informatics Center, Washington University School of Medicine, St. Louis, United States
ah Center for Translational and Computational Neuroimmunology, Department of Neurology and Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University Irving Medical CenterNY, United States
ai Stark Neuroscience Research Institute, Indiana University School of Medicine, Indianapolis, United States
aj Wu Tsai Neurosciences Institute, Stanford University School of Medicine, Stanford, United States
ak Department for Clinical and Biomedical Sciences, University of Exeter Medical School, University of Exeter, Exeter, United Kingdom
al Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States
am Departments of Radiology, Medicine, and Psychiatry, University of California-San Francisco, San Francisco, United States
an Department of Veterans Affairs Medical Center, San Francisco, United States
Abstract
Determining the genetic architecture of Alzheimer’s disease pathologies can enhance mechanistic understanding and inform precision medicine strategies. Here, we perform a genome-wide association study of cortical tau quantified by positron emission tomography in 3046 participants from 12 independent studies. The CYP1B1-RMDN2 locus is associated with tau deposition. The most significant signal is at rs2113389, explaining 4.3% of the variation in cortical tau, while APOE4 rs429358 accounts for 3.6%. rs2113389 is associated with higher tau and faster cognitive decline. Additive effects, but no interactions, are observed between rs2113389 and diagnosis, APOE4, and amyloid beta positivity. CYP1B1 expression is upregulated in AD. rs2113389 is associated with higher CYP1B1 expression and methylation levels. Mouse model studies provide additional functional evidence for a relationship between CYP1B1 and tau deposition but not amyloid beta. These results provide insight into the genetic basis of cerebral tau deposition and support novel pathways for therapeutic development in AD. © The Author(s) 2024.
Document Type: Article
Publication Stage: Final
Source: Scopus
Elevated VCP ATPase Activity Correlates With Disease Onset in Multisystem Proteinopathy-1
(2024) Neurology: Genetics, 10 (5), art. no. e200191, .
Robinson, S.E.a , Findlay, A.R.a , Li, S.b , Wang, F.b , Schiava, M.b , Daw, J.a b , Diaz-Manera, J.b , Chou, T.-F.c , Weihl, C.C.a
a Department of Neurology, Washington University, St. Louis, MO, United States
b John Walton Muscular Dystrophy Research Centre, Newcastle University, Newcastle Hospitals NHS Foundation Trusts, United Kingdom
c Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States
Abstract
Objectives Multisystem proteinopathy-1 (MSP1) is a late onset disease with >50 pathogenic variants in p97/VCP. MSP1 patients have multiple phenotypes that include inclusion body myopathy, Paget disease of the bone, amyotrophic lateral sclerosis, and frontotemporal dementia. There have been no clear genotype-phenotype correlations. We sought to identify genotype-phenotype correlations and associate these with VCP intrinsic ATPase activity. Methods Patients with MSP1 were identified from the literature and the Cure VCP patient registry. Age at onset and at loss of ambulation were collated. VCP intrinsic ATPase activity was evaluated from recombinant purified protein. Results Among the 5 most common pathogenic VCP variants in MSP1 patients, R155C patients had the earliest average age at onset (38.15 ± 9.78). This correlated with higher ATPase activity. Evaluation of 5 variants confirmed an inverse correlation between age at onset and ATPase activity (r = −0.94, p = 0.01). Discussion Previous studies have reported that VCP pathogenic variants are “hyperactive.” Whether this elevation in VCP ATPase activity is relevant to disease is unclear. Our study supports that in vitro VCP activity correlates with disease onset and may guide the prognosis of patients with rare or unreported variants. Moreover, it suggests that inhibition of VCP ATPase activity in MSP1 may be therapeutic. Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
Funding details
National Institutes of HealthNIHR01 AG031867, K24 AR073317
National Institutes of HealthNIH
Document Type: Article
Publication Stage: Final
Source: Scopus
Structure-function coupling in highly sampled individual brains
(2024) Cerebral Cortex, 34 (9), art. no. bhae361, .
Rajesh, A.a , Seider, N.A.b , Newbold, D.J.c , Adeyemo, B.d , Marek, S.b , Greene, D.J.e , Snyder, A.Z.a c , Shimony, J.S.a c , Laumann, T.O.b , Dosenbach, N.U.F.a b d f g , Gordon, E.M.a
a Department of Radiology, Washington University School of Medicine, 4525 Scott Avenue, St. Louis, MO 63110, United States
b Department of Psychiatry, Washington University School of Medicine, 660 S Euclid Ave, St. Louis, MO 63110, United States
c Department of Neurology, New York Langone Medical Center, 550 First Avenue, New York, NY 10016, United States
d Department of Neurology, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110, United States
e Department of Cognitive Science, University of California San Diego, 9500 Gilman Dr La JollaCA 92037, United States
f Department of Biomedical Engineering, Washington University, 1 Brookings Drive, St. Louis, MO 63130, United States
g Program in Occupational Therapy, Washington University, 4444 Forest Park Ave, St. Louis, MO 63108, United States
Abstract
Structural connectivity (SC) between distant regions of the brain support synchronized function known as functional connectivity (FC) and give rise to the large-scale brain networks that enable cognition and behavior. Understanding how SC enables FC is important to understand how injuries to SC may alter brain function and cognition. Previous work evaluating whole-brain SC-FC relationships showed that SC explained FC well in unimodal visual and motor areas, but only weakly in association areas, suggesting a unimodal-heteromodal gradient organization of SC-FC coupling. However, this work was conducted in group-Averaged SC/FC data. Thus, it could not account for inter-individual variability in the locations of cortical areas and white matter tracts. We evaluated the correspondence of SC and FC within three highly sampled healthy participants. For each participant, we collected 78 min of diffusion-weighted MRI for SC and 360 min of resting state fMRI for FC. We found that FC was best explained by SC in visual and motor systems, as well as in anterior and posterior cingulate regions. A unimodal-To-heteromodal gradient could not fully explain SC-FC coupling. We conclude that the SC-FC coupling of the anterior-posterior cingulate circuit is more similar to unimodal areas than to heteromodal areas. © 2024 The Author(s). Published by Oxford University Press. All rights reserved.
Author Keywords
dense sampling; diffusion imaging; functional imaging; individual; structure-function coupling
Funding details
Intellectual and Developmental Disabilities Research CenterIDDRC
Hope Center for Neurological Disorders, Washington University in St. Louis
Dysphonia InternationalNSDA
Mallinckrodt Institute of Radiology, School of Medicine, Washington University in St. LouisMIR
MH122066, NS088590, NS129521, MH124567, MH121276
National Institutes of HealthNIHMH096773, MH100019, NS110332, MH129616
National Institutes of HealthNIH
Document Type: Article
Publication Stage: Final
Source: Scopus
Survey of the Landscape of Society Practice Guidelines for Genetic Testing of Neurodevelopmental Disorders
(2024) Annals of Neurology, .
Srivastava, S.a , Cole, J.J.b , Cohen, J.S.c d , Chopra, M.a , Smith, H.S.e , Deardorff, M.A.f , Pedapati, E.g , Corner, B.h , Anixt, J.S.g , Jeste, S.i , Sahin, M.a , Gurnett, C.A.j , Campbell, C.A.k , the Intellectual and Developmental Disabilities Research Center (IDDRC) Workgroup on Advocating for Access to Genomic Testingl
a Department of Neurology, Rosamund Stone Zander Translational Neuroscience Center, Boston Children’s Hospital, Harvard Medical School, Boston, MA, United States
b Department of Pediatrics, University of Colorado, Children’s Hospital Colorado, Aurora, CO, United States
c Department of Neurology and Developmental Medicine, Kennedy Krieger Institute, Baltimore, MD, United States
d Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, United States
e Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, MA, United States
f Departments of Pathology and Pediatrics, Keck School of Medicine of USC, Children’s Hospital Los Angeles, Los Angeles, CA, United States
g Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati Children’s Hospital, Cincinnati, OH, United States
h Department of Pediatrics and Genetics, Vanderbilt University Medical Center, Nashville, TN, United States
i Department of Neurology, Keck School of Medicine of USC, Children’s Hospital Los Angeles, Los Angeles, CA, United States
j Department of Neurology, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
k Department of Internal Medicine, University of Iowa, Carver College of Medicine, Iowa City, IA, United States
Abstract
Genetic testing of patients with neurodevelopmental disabilities (NDDs) is critical for diagnosis, medical management, and access to precision therapies. Because genetic testing approaches evolve rapidly, professional society practice guidelines serve an essential role in guiding clinical care; however, several challenges exist regarding the creation and equitable implementation of these guidelines. In this scoping review, we assessed the current state of United States professional societies’ guidelines pertaining to genetic testing for unexplained global developmental delay, intellectual disability, autism spectrum disorder, and cerebral palsy. We describe several identified shortcomings and argue the need for a unified, frequently updated, and easily-accessible cross-specialty society guideline. ANN NEUROL 2024. © 2024 The Author(s). Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.
Document Type: Review
Publication Stage: Article in Press
Source: Scopus
A modular chemigenetic calcium indicator for multiplexed in vivo functional imaging
(2024) Nature Methods, .
Farrants, H.a , Shuai, Y.a , Lemon, W.C.a , Monroy Hernandez, C.b , Zhang, D.a , Yang, S.a , Patel, R.a , Qiao, G.c , Frei, M.S.d e , Plutkis, S.E.a , Grimm, J.B.a , Hanson, T.L.a , Tomaska, F.a f , Turner, G.C.a , Stringer, C.a , Keller, P.J.a , Beyene, A.G.a , Chen, Y.b , Liang, Y.c , Lavis, L.D.a , Schreiter, E.R.a
a Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA, United States
b Department of Neuroscience, Washington University in St. Louis, St. Louis, MO, United States
c Department of Diagnostic Radiology and Nuclear Medicine, University of Maryland School of Medicine, Baltimore, MD, United States
d Department of Chemical Biology, Max Planck Institute for Medical Research, Heidelberg, Germany
e Department of Pharmacology, University of California San Diego, La Jolla, CA, United States
f Department of Electrical and Computer Engineering, Center for BioEngineering, Neuroscience Research Institute, University of California, Santa Barbara, Santa Barbara, CA, United States
Abstract
Genetically encoded fluorescent calcium indicators allow cellular-resolution recording of physiology. However, bright, genetically targetable indicators that can be multiplexed with existing tools in vivo are needed for simultaneous imaging of multiple signals. Here we describe WHaloCaMP, a modular chemigenetic calcium indicator built from bright dye-ligands and protein sensor domains. Fluorescence change in WHaloCaMP results from reversible quenching of the bound dye via a strategically placed tryptophan. WHaloCaMP is compatible with rhodamine dye-ligands that fluoresce from green to near-infrared, including several that efficiently label the brain in animals. When bound to a near-infrared dye-ligand, WHaloCaMP shows a 7× increase in fluorescence intensity and a 2.1-ns increase in fluorescence lifetime upon calcium binding. We use WHaloCaMP1a to image Ca2+ responses in vivo in flies and mice, to perform three-color multiplexed functional imaging of hundreds of neurons and astrocytes in zebrafish larvae and to quantify Ca2+ concentration using fluorescence lifetime imaging microscopy (FLIM). © The Author(s) 2024.
Document Type: Article
Publication Stage: Article in Press
Source: Scopus