PMID- 29440553 OWN - NLM STAT- MEDLINE DCOM- 20190705 LR - 20200514 IS - 1529-2401 (Electronic) IS - 0270-6474 (Print) IS - 0270-6474 (Linking) VI - 38 IP - 11 DP - 2018 Mar 14 TI - The Longitudinal Trajectory of Default Mode Network Connectivity in Healthy Older Adults Varies As a Function of Age and Is Associated with Changes in Episodic Memory and Processing Speed. PG - 2809-2817 LID - 10.1523/JNEUROSCI.3067-17.2018 [doi] AB - The default mode network (DMN) supports memory functioning and may be sensitive to preclinical Alzheimer's pathology. Little is known, however, about the longitudinal trajectory of this network's intrinsic functional connectivity (FC). In this study, we evaluated longitudinal FC in 111 cognitively normal older human adults (ages 49-87, 46 women/65 men), 92 of whom had at least three task-free fMRI scans (n = 353 total scans). Whole-brain FC and three DMN subnetworks were assessed: (1) within-DMN, (2) between anterior and posterior DMN, and (3) between medial temporal lobe network and posterior DMN. Linear mixed-effects models demonstrated significant baseline age x time interactions, indicating a nonlinear trajectory. There was a trend toward increasing FC between ages 50-66 and significantly accelerating declines after age 74. A similar interaction was observed for whole-brain FC. APOE status did not predict baseline connectivity or change in connectivity. After adjusting for network volume, changes in within-DMN connectivity were specifically associated with changes in episodic memory and processing speed but not working memory or executive functions. The relationship with processing speed was attenuated after covarying for white matter hyperintensities (WMH) and whole-brain FC, whereas within-DMN connectivity remained associated with memory above and beyond WMH and whole-brain FC. Whole-brain and DMN FC exhibit a nonlinear trajectory, with more rapid declines in older age and possibly increases in connectivity early in the aging process. Within-DMN connectivity is a marker of episodic memory performance even among cognitively healthy older adults.SIGNIFICANCE STATEMENT Default mode network and whole-brain connectivity, measured using task-free fMRI, changed nonlinearly as a function of age, with some suggestion of early increases in connectivity. For the first time, longitudinal changes in DMN connectivity were shown to correlate with changes in episodic memory, whereas volume changes in relevant brain regions did not. This relationship was not accounted for by white matter hyperintensities or mean whole-brain connectivity. Functional connectivity may be an early biomarker of changes in aging but should be used with caution given its nonmonotonic nature, which could complicate interpretation. Future studies investigating longitudinal network changes should consider whole-brain changes in connectivity. CI - Copyright (c) 2018 the authors 0270-6474/18/382810-09$15.00/0. FAU - Staffaroni, Adam M AU - Staffaroni AM AUID- ORCID: 0000-0002-3903-9805 AD - Memory and Aging Center, Departments of Neurology, Adam.Staffaroni@ucsf.edu. FAU - Brown, Jesse A AU - Brown JA AD - Memory and Aging Center, Departments of Neurology. FAU - Casaletto, Kaitlin B AU - Casaletto KB AD - Memory and Aging Center, Departments of Neurology. FAU - Elahi, Fanny M AU - Elahi FM AD - Memory and Aging Center, Departments of Neurology. FAU - Deng, Jersey AU - Deng J AD - Memory and Aging Center, Departments of Neurology. FAU - Neuhaus, John AU - Neuhaus J AD - Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California 94143, and. FAU - Cobigo, Yann AU - Cobigo Y AD - Memory and Aging Center, Departments of Neurology. FAU - Mumford, Paige S AU - Mumford PS AUID- ORCID: 0000-0003-0163-0760 AD - Memory and Aging Center, Departments of Neurology. FAU - Walters, Samantha AU - Walters S AD - Memory and Aging Center, Departments of Neurology. FAU - Saloner, Rowan AU - Saloner R AUID- ORCID: 0000-0002-1351-6183 AD - Memory and Aging Center, Departments of Neurology. FAU - Karydas, Anna AU - Karydas A AD - Memory and Aging Center, Departments of Neurology. FAU - Coppola, Giovanni AU - Coppola G AUID- ORCID: 0000-0003-2105-1061 AD - Departments of Psychiatry and Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California 90095. FAU - Rosen, Howie J AU - Rosen HJ AD - Memory and Aging Center, Departments of Neurology. FAU - Miller, Bruce L AU - Miller BL AD - Memory and Aging Center, Departments of Neurology. FAU - Seeley, William W AU - Seeley WW AD - Memory and Aging Center, Departments of Neurology. AD - Pathology. FAU - Kramer, Joel H AU - Kramer JH AD - Memory and Aging Center, Departments of Neurology. LA - eng GR - P50 AG023501/AG/NIA NIH HHS/United States GR - U24 AG021886/AG/NIA NIH HHS/United States GR - R01 AG048234/AG/NIA NIH HHS/United States GR - P01 AG019724/AG/NIA NIH HHS/United States GR - K01 AG055698/AG/NIA NIH HHS/United States GR - R01 AG032289/AG/NIA NIH HHS/United States GR - P30 AG010129/AG/NIA NIH HHS/United States GR - UH3 NS100608/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20180213 PL - United States TA - J Neurosci JT - The Journal of neuroscience : the official journal of the Society for Neuroscience JID - 8102140 RN - 0 (Apolipoproteins E) SB - IM MH - Aged MH - Aged, 80 and over MH - Aging/*physiology/*psychology MH - Apolipoproteins E/genetics MH - Female MH - Humans MH - Magnetic Resonance Imaging MH - Male MH - *Memory, Episodic MH - Middle Aged MH - Nerve Net/diagnostic imaging/*physiology MH - Neuropsychological Tests MH - Psychomotor Performance/physiology MH - *Reaction Time MH - Temporal Lobe/diagnostic imaging/growth & development/physiology PMC - PMC5852659 OTO - NOTNLM OT - aging OT - cognition OT - default mode network OT - episodic memory OT - functional MRI OT - neuroimaging EDAT- 2018/02/15 06:00 MHDA- 2019/07/06 06:00 PMCR- 2018/09/14 CRDT- 2018/02/15 06:00 PHST- 2017/10/18 00:00 [received] PHST- 2018/02/01 00:00 [revised] PHST- 2018/02/02 00:00 [accepted] PHST- 2018/02/15 06:00 [pubmed] PHST- 2019/07/06 06:00 [medline] PHST- 2018/02/15 06:00 [entrez] PHST- 2018/09/14 00:00 [pmc-release] AID - JNEUROSCI.3067-17.2018 [pii] AID - 3067-17 [pii] AID - 10.1523/JNEUROSCI.3067-17.2018 [doi] PST - ppublish SO - J Neurosci. 2018 Mar 14;38(11):2809-2817. doi: 10.1523/JNEUROSCI.3067-17.2018. Epub 2018 Feb 13.