Covariance-based vs. correlation-based functional connectivity dissociates healthy aging from Alzheimer disease.

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.

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Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of Competing Interest Randall J. Bateman Randall Bateman (RJB), Professor of Neurology at Washington University's School of Medicine (WUSM) receives lab research funding from the National Institutes of Health, Alzheimer's Association, BrightFocus Foundation, Rainwater Foundation Tau Consortium, Association for Frontotemporal Degeneration, the Cure Alzheimer's Fund, Centene Corporation, Tau SILK Consortium (AbbVie, Biogen, and Eli Lilly and Company), and an anonymous organization. RJB has received honoraria as a speaker/consultant/advisory board member from Amgen, AC Immune, Eisai, F. Hoffman-LaRoche, and Janssen; and reimbursement of travel expenses from AC Immune, F. Hoffman-La Roche and Janssen. Unrelated to this article, RJB serves as principal investigator of the DIAN-TU, which is supported by the Alzheimer's Association, GHR Foundation, an anonymous organization and the DIAN-TU Pharma Consortium (Active: Eli Lilly and Company/Avid Radiopharmaceuticals, F. Hoffman-La Roche/Genentech, Biogen, Eisai, Janssen, and United Neuroscience. Previous: Abbvie, Amgen, AstraZeneca, Forum, Mithridion, Novartis, Pfizer, Sanofi). The DIAN-TU-001 Clinical Trial is supported by Pharmaceutical Partners Eli Lilly and Company, F. Hoffman-La Roche and Janssen, the Alzheimer's Association, NIH U01AG042791, NIH U01AG42791-S1 (FNIH and Accelerating Medicines Partnership), NIH R01AG046179, NIH R56AG053267, NIH R01AG053267, NIH U01AG059798, NIH R01AG068319, Avid Radiopharmaceuticals, GHR Foundation, and an anonymous organization. In-kind support has been received from CogState and Bracket. Washington University, Randall Bateman, and David Holtzman have equity ownership interest in C2N Diagnostics and receive royalty income based on technology (stable isotope labeling kinetics and blood plasma assay) licensed by Washington University to C2N Diagnostics. RJB receives income from C2N Diagnostics for serving on the scientific advisory board. Washington University, with RJB as co-inventor, has submitted the US nonprovisional patent application “Methods for Measuring the Metabolism of CNS Derived Biomolecules In Vivo” and provisional patent application “Plasma Based Methods for Detecting CNS Amyloid Deposition”. Tammie L.S. Benzinger Dr. Benzinger reports grants and non-financial support from Avid Radiopharmaceuticals/ Eli Lilly, during the conduct of the study; grants and non-financial support from Avid Radiopharmaceuticals/ Eli Lilly, other from Eli Lilly, Biogen, Eisai, Jaansen, personal fees from Biogen, non-financial support from Eisai, non-financial support from Siemens, outside the submitted work. Matthew R. Brier Dr. Brier reports grants from NIH, during the conduct of the study. Gregory S. Day Dr. Day reports grants from NIH, during the conduct of the study; personal fees from Parabon Nanolabs, Inc, personal fees from DynaMed (EBSCO Health), outside the submitted work. Brian A. Gordon Dr. Gordon reports participation in clinical trials of therapies to alter the course of Alzheimer Disease. Neill Graff-Radford Dr. Graff-Radford reports grants from NIH, during the conduct of the study; grants from Biogen, grants from AbbVie, grants from Lilly, outside the submitted work. Taleshi Ikeuchi Dr. Ikeuchi reports grants from AMED (Japan Agency for Medical Research and Development), during the conduct of the study. Daniel S. Marcus Dr. Marcus reports other from Radiologics, Inc, outside the submitted work. John C. Morris Dr. Morris reports grants from NIH grant P30 AG066444, grants from NIH grant P01AG003991, grants from NIH grant P01AG026276, grants from NIH grant UF1AG032438, during the conduct of the study. Richard J. Perrin Dr. Perrin reports grants from NIH during the conduct of the study. Stephen Salloway Dr. Salloway reports grants and personal fees from Biogen, grants and personal fees from Eisai, grants and personal fees from Avid, grants and personal fees from Lilly, personal fees from Genentech, personal fees from Novartis, grants and personal fees from Roche, outside the submitted work. Peter Schofield Dr. Schofield reports grants from NIH, grants from Anonymous Foundation, grants from Roth Charitable Foundation, during the conduct of the study. Abraham Z. Snyder Dr. Snyder is a consultant for Sora Neuroimaging, LLC.