Rostral-Caudal Hippocampal Functional Convergence Is Reduced Across the Alzheimer’s Disease Spectrum
Beginning in the early stages of Alzheimer’s disease (AD), the hippocampus reduces its functional connections to other cortical regions due to synaptic depletion. However, little is known regarding connectivity abnormalities within the hippocampus. Here, we describe rostral-caudal hippocampal convergence (rcHC), a metric of the overlap between the rostral and caudal hippocampal functional networks, across the clinical spectrum of AD. We predicted a decline in rostral-caudal hippocampal convergence in the early stages of the disease. Using fMRI, we generated resting-state hippocampal functional networks across 56 controls, 48 early MCI (EMCI), 35 late MCI (LMCI), and 31 AD patients from the Alzheimer’s Disease Neuroimaging Initiative cohort. For each diagnostic group, we performed a conjunction analysis and compared the rostral and caudal hippocampal network changes using a mixed effects linear model to estimate the convergence and differences between these networks, respectively. The conjunction analysis showed a reduction of rostral-caudal hippocampal convergence strength from early MCI to AD, independent of hippocampal atrophy. Our results demonstrate a parallel between the functional convergence within the hippocampus and disease stage, which is independent of brain atrophy. These findings support the concept that network convergence might contribute as a biomarker for connectivity dysfunction in early stages of AD.
KeywordsAlzheimer’s disease Brain network Functional connectivity Hippocampus Mild cognitive impairment
This work was supported by the Canadian Institutes of Health Research (CIHR) (MOP-11-51-31); the Alan Tiffin Foundation; the Alzheimer’s Association (NIRG-08-92090); and the Fonds de recherche du Québec—Santé (chercheur boursier); the CAPES Foundation (0327/13-1), and a fellowship from the Stop-AD Centre, provided by McGill University and the Douglas Hospital Research Centre Institutional Funding. Data collection and sharing for this project was funded by the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen Idec Inc.; Bristol-Myers Squibb Company; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd., and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Medpace, Inc.; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Synarc Inc.; and Takeda Pharmaceutical Company. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California.
Compliance with Ethical Standards
In this section, we outline our manuscript’s compliance with all relevant ethical standards.
Conflict of Interest
Therriault J, Wang S, Mathotaarachchi S, Pascoal TA, Parent M, Beaudry T, Shin M, Benedet AL, Kang MS, Ng KP, Dansereau C, Park MTM, Fonov V, Carbonell F, Zimmer E, Chakravarty M, Bellec P, and Rosa-Neto P have no conflicts of interest to disclose. S. Gauthier has received honoraria for serving on the scientific advisory boards of Alzheon, Axovant, Lilly, Lundbeck, Novartis, Schwabe, and TauRx and on the Data Safety Monitoring Board of a study sponsored by Eisai and studies run by the Alzheimer’s Disease Cooperative Study and by the Alzheimer’s Therapeutic Research Institute.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
The ADNI study was approved by the Institutional Review Boards of all of the participating institutions. Informed written consent was obtained from all participants in the study.
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