Abstract
Major depressive disorder (MDD) is associated with an increased risk of developing dementia. The present study aimed to better understand this risk by comparing resting state functional connectivity (rsFC) in the executive control network (ECN) and the default mode network (DMN) in older adults with MDD or mild cognitive impairment (MCI). Additionally, we examined the association between rsFC in the ECN or DMN and cognitive impairment transdiagnostically. We assessed rsFC alterations in ECN and DMN in 383 participants from five groups at-risk for dementia—remitted MDD with normal cognition (MDD-NC), non-amnestic mild cognitive impairment (naMCI), remitted MDD + naMCI, amnestic MCI (aMCI), and remitted MDD + aMCI—and from healthy controls (HC) or individuals with Alzheimer’s dementia (AD). Subject-specific whole-brain functional connectivity maps were generated for each network and group differences in rsFC were calculated. We hypothesized that alteration of rsFC in the ECN and DMN would be progressively larger among our seven groups, ranked from low to high according to their risk for dementia as HC, MDD-NC, naMCI, MDD + naMCI, aMCI, MDD + aMCI, and AD. We also regressed scores of six cognitive domains (executive functioning, processing speed, language, visuospatial memory, verbal memory, and working memory) on the ECN and DMN connectivity maps. We found a significant alteration in the rsFC of the ECN, with post hoc testing showing differences between the AD group and the HC, MDD-NC, or naMCI groups, but no significant alterations in rsFC of the DMN. Alterations in rsFC of the ECN and DMN were significantly associated with several cognitive domain scores transdiagnostically. Our findings suggest that a diagnosis of remitted MDD may not confer functional brain risk for dementia. However, given the association of rs-FC with cognitive performance (i.e., transdiagnostically), rs-FC may help in stratifying this risk among people with MDD and varying degrees of cognitive impairment.
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This Project has been made possible by Brain Canada through the Canada Brain Research Fund, with the financial support of Health Canada and the Chagnon Family.
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NRR: substantial contributions to the conception or design of the work and the acquisition, analysis, or interpretation of data for the work; drafting the work or revising it critically for important intellectual content; final approval of the version to be published; and agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. TKR, CH and BGP: substantial contributions to the conception or design of the work; the acquisition, analysis, or interpretation of data for the work; and final approval of the version to be published. SK and NH: substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; and final approval of the version to be published. LM, AJF, CEF, MAB, EWD, CRB and MS: substantial contributions to the acquisition, analysis, or interpretation of data for the work; and final approval of the version to be published. BHM and ANV: substantial contributions to the conception or design of the work; the acquisition, analysis, or interpretation of data for the work; drafting the work or revising it critically for important intellectual content; final approval of the version to be published; and agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
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NRR has received funding by the Alzheimer Society of Canada Research Program (ASRP) Doctoral Fellowship. ANV has received grant support from the Canadian Institutes of Health Research (CIHR), National Institute of Mental Health (NIMH), the Brain and Behavior Research Foundation (BBRF), Canada Foundation for Innovation (CFI), the CAMH Foundation, and University of Toronto. AJF has received grant support from the US National Institutes of Health, the Patient-Centered Outcomes Research Institute, the Canadian Institutes of Health Research, Brain Canada, the Ontario Brain Institute, and the Alzheimer’s Association. BHM holds and receives support from the Labatt Family Chair in Biology of Depression in Late-Life Adults at the University of Toronto. He currently receives research support from Brain Canada, the Canadian Institutes of Health Research, the CAMH Foundation, the Patient-Centered Outcomes Research Institute (PCORI), the US National Institute of Health (NIH), Capital Solution Design LLC (software used in a study founded by CAMH Foundation), and HAPPYneuron (software used in a study founded by Brain Canada). Within the past 5 years, he has also received research support from Eli Lilly (medications for a NIH-funded clinical trial) and Pfizer (medications for a NIH-funded clinical trial). He has been an unpaid consultant to Myriad Neuroscience. BGP receives research support from the Peter & Shelagh Godsoe Endowed Chair in Late-Life Mental Health, CAMH Foundation and Discovery Fund, National Institute of Aging, Brain Canada, the Canadian Institutes of Health Research, the Alzheimer’s Drug Discovery Foundation, the Ontario Brain Institute, the Centre for Aging and Brain Health Innovation, the Bright Focus Foundation, the Alzheimer’s Society of Canada, the W. Garfield Weston Foundation, the Weston Brain Institute, the Canadian Consortium on Neurodegeneration in Aging and Genome Canada. BGP receives honoraria from the American Geriatrics Society and holds United States Provisional Patent Nos. 16/490,680, 17/396,030 and Canadian Provisional Patent No. 3,054,093 for a cell-based assay and kits for assessing serum anticholinergic activity. CEF receives grant funding from the following sources: CCNA/CIHR, Vielight Inc, Hoffman La Roche, NIH, Brian Canada, St. Michaels Hospital Foundation Heather and Eric Donnelly Endowment. EWD has received funding from BBRF, NIMH, CHIR and CAMH Foundation. CH has received funding from Canadian Institutes of Health Research (CIHR), National Institute of Mental Health (NIMH), and the CAMH foundation. SK has received grant support from Brain Canada, NIH, BBRF, BrightFocus Foundation, Weston Brain Institute, Canadian Centre for Ageing and Brain Health Innovation, CAMH foundation, and University of Toronto, and in-kind equipment support from Soterix Medical Inc. TKR has received research support from Brain Canada, Brain and Behavior Research Foundation, BrightFocus Foundation, Canada Foundation for Innovation, Canada Research Chair, Canadian Institutes of Health Research, Centre for Aging and Brain Health Innovation, National Institutes of Health, Ontario Ministry of Health and Long-Term Care, Ontario Ministry of Research and Innovation, and the Weston Brain Institute. TKR also received in-kind equipment support for an investigator-initiated study from Magstim, and in-kind research accounts from Scientific Brain Training Pro, and participated in 2021 in one advisory board meeting for Biogen Canada Inc. TKR is also an inventor on the United States Provisional Patent No. 17/396,030 that describes cell-based assays and kits for assessing serum cholinergic receptor activity. CRB receives in-kind research support from Scientific Brain Training Pro. He has had grant support from Lundbeck, Pfizer, and Takeda. LM, NH, MAB, and MS have no potential conflicts of interest to declare.
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Rashidi-Ranjbar, N., Rajji, T.K., Hawco, C. et al. Association of functional connectivity of the executive control network or default mode network with cognitive impairment in older adults with remitted major depressive disorder or mild cognitive impairment. Neuropsychopharmacol. 48, 468–477 (2023). https://doi.org/10.1038/s41386-022-01308-2
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DOI: https://doi.org/10.1038/s41386-022-01308-2
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