@article{9cd7191ff16a4984a97b38f5f37b53ec,
title = "Resting-State Functional Connectivity Disruption as a Pathological Biomarker in Autosomal Dominant Alzheimer Disease",
abstract = "Aim: Identify a global resting-state functional connectivity (gFC) signature in mutation carriers (MC) from the Dominantly Inherited Alzheimer Network (DIAN). Assess the gFC with regard to amyloid (A), tau (T), and neurodegeneration (N) biomarkers, and estimated years to symptom onset (EYO). Introduction: Cross-sectional measures were assessed in MC (n = 171) and mutation noncarrier (NC) (n = 70) participants. A functional connectivity (FC) matrix that encompassed multiple resting-state networks was computed for each participant. Methods: A global FC was compiled as a single index indicating FC strength. The gFC signature was modeled as a nonlinear function of EYO. The gFC was linearly associated with other biomarkers used for assessing the AT(N) framework, including cerebrospinal fluid (CSF), positron emission tomography (PET) molecular biomarkers, and structural magnetic resonance imaging. Results: The gFC was reduced in MC compared with NC participants. When MC participants were differentiated by clinical dementia rating (CDR), the gFC was significantly decreased in MC CDR >0 (demented) compared with either MC CDR 0 (cognitively normal) or NC participants. The gFC varied nonlinearly with EYO and initially decreased at EYO =-24 years, followed by a stable period followed by a further decline near EYO = 0 years. Irrespective of EYO, a lower gFC associated with values of amyloid PET, CSF Aβ1-42, CSF p-tau, CSF t-tau, 18F-fluorodeoxyglucose, and hippocampal volume. Conclusions: The gFC correlated with biomarkers used for defining the AT(N) framework. A biphasic change in the gFC suggested early changes associated with CSF amyloid and later changes associated with hippocampal volume.",
keywords = "18F-fluorodeoxyglucose (FDG), amyloid, autosomal dominant Alzheimer disease, cerebrospinal fluid (CSF), estimated years to onset (EYO), hippocampus, positron emission tomography (PET), resting-state functional connectivity, tau",
author = "Smith, {Robert X.} and Strain, {Jeremy F.} and Aaron Tanenbaum and Fagan, {Anne M.} and Jason Hassenstab and Eric McDade and Schindler, {Suzanne E.} and Gordon, {Brian A.} and Chengjie Xiong and Jasmeer Chhatwal and Clifford Jack and Celeste Karch and Sarah Berman and Brosch, {Jared R.} and Lah, {James J.} and Brickman, {Adam M.} and Cash, {David M.} and Fox, {Nick C.} and Graff-Radford, {Neill R.} and Johannes Levin and James Noble and Holtzman, {David M.} and Masters, {Colin L.} and Farlow, {Martin R.} and Christoph Laske and Schofield, {Peter R.} and Marcus, {Daniel S.} and Morris, {John C.} and Benzinger, {Tammie L.S.} and Bateman, {Randall J.} and Ances, {Beau M.}",
note = "Funding Information: R.X.S., J.F.S., A.T., A.M.F., J.H., S.E.S., C.X., J.C., C.K., S.B., J.J.L., A.B., D.M.C., J.L., J.N., C.L.M., C.L., and P.R.S.: Report no disclosures. E.M.: Research support: NIA, Eli Lilly, Roche, Janssen, GHR Foundation; Advisory Board: Eli Lilly; DSMB: Eli Lilly. B.A.G.: Involved in a clinical trial sponsored by Avid. C.J. Jr.: Consults for Eli Lilly, and serves on an independent data monitoring board for Roche but receives no personal compensation from and commercial entity. He receives research support from NIH/NIA and the Alexander Family Professor of Alzheimer{\textquoteright}s Disease Research, Mayo Clinic. J.R.B.: Research support includes AbbVie, Avanir, Biogen, Eisai, Eli Lilly, Genetech, Novartis, Roche, Suven Life Sciences Ltd. N.C.F.: Is on the scientific advisory board for Roche and Biogen. N.R.G.-R.: Research support includes AbbVie, Novartis, Biogen and Lilly. D.M.H.: Cofounded and is on the scientific advisory board of C2N diagnostics, LLC. Is on the scientific advisory board of Denali and consults for Genetech and AbbVie. M.R.F.: Research support includes AbbVie, Accera, ADCS, Posiphen, Biogen, Eisai, Eli Lilly, Genentech, Novartis, Suven Life Sciences, Ltd. He is on the advisory boards for Accera, Allergan, Avanir, AZTherapies, Cognition Therapeutics, Cortexyme, Eli Lilly & Company, Longeveron, Green Valley, MedAvante, Merck and Co. Inc., Otsuka Pharmaceutical, Proclara, Neurotrope Bioscience, Regenera, Samumed, Takeda, vTv Therapeutics, Zhejiang Hisun Pharmaceuticals. D.S.M.: Funding support from Radiologics, Inc., and White-Rabbat.ai. J.C.M.: He is currently participating in clinical trials of antidementia drugs developed by Eli Lilly and Company, Biogen and Janssen. Dr. Morris serves as a consultant for Lilly USA. Research support from Eli Lilly/Avid Radiopharmaceuticals. T.L.S.B.: Involved in a clinical trial sponsored by Avid. R.J.B.: He is on the scientific advisory board for C2N Diagnostics. Research support from AbbVie, Biogen, Eisai, Eli Lilly, and Co/Avid Radiopharmaceuticals, Roche, Janssen, and United Neuroscience. B.M.A.: Involved in a clinical trial sponsored by Avid. Funding Information: Data collection and sharing for this project were supported by the Dominantly Inherited Alzheimer{\textquoteright}s Network (DIAN, UF1AG032438) funded by the National Institute on Aging (NIA), the German Center for Neurodegenerative Diseases (DZNE), Raul Carrea Institute for Neurological Research (FLENI), partial support by the Research and Development, AMED, and the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI). Further support for this study was funded by NIH grants R01NR012907, R01NR012657, R01NR014449, P50AG05681, P01AG003991, P01AG026276, P30NS048056, UL1TR000448, R01AG04343404, R01AG052550, R01AG057680, K01AG053474, BrightFocus Foundation A2018817F, and NSF grant DMS1300280. Funding was also provided by the Charles F. and Joanne Knight Alzheimer{\textquoteright}s Research Initiative, the Hope Center for Neurological Disorders, and generous support from the Fred Simmons and Olga Mohan Fund, the Paula and Rodger O. Riney Fund, and the Daniel J Brennan MD Fund. Publisher Copyright: {\textcopyright} Copyright 2021, Mary Ann Liebert, Inc.",
year = "2021",
month = apr,
doi = "10.1089/brain.2020.0808",
language = "English (US)",
volume = "11",
pages = "239--249",
journal = "Brain Connectivity",
issn = "2158-0014",
publisher = "Mary Ann Liebert Inc.",
number = "3",
}