Emma M. Tinney, Aaron E. L. Warren, Amanda O'Brien, Hannah Odom, Meishan Ai, Bradley P. Sutton, Shivangi Jain, Chaeryon Kang, Haiqing Huang, Lu Wan, Lauren E. Oberlin, George Grove, John M. Jakicic, Audrey M. Collins, Kelsey R. Sewell, Jeffrey M. Burns, Eric D. Vidoni, Edward McAuley, Arthur F. Kramer, Kirk I. Erickson, Charles H. Hillman
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Previous magnetic resonance imaging (MRI) studies have suggested that CRF-related changes in white matter microstructure might prevent or slow age-related cognitive decline, but have been limited by small sample sizes and methodological limitations. Specifically, most prior studies used tensor-based diffusion-weighted MRI metrics, which are insensitive to complex white matter architectures, including crossing fibers.</p>\n </section>\n \n <section>\n \n <h3> METHODS</h3>\n \n <p>Here, we leveraged a novel analysis framework capable of resolving individual fiber populations at the within-voxel level—fixel-based analysis (FBA)—to analyze three metrics of white matter organization from diffusion-weighted MRI scans: fiber density (FD), fiber cross-section (FC), and their combined measure (FDC). Using a cross-sectional sample of 636 cognitively unimpaired older adults aged 65 to 80 years (mean age = 69.8 years; 71% female), we hypothesized that FBA metrics would be associated with CRF and that this variation in FBA metrics would mediate associations between CRF and cognitive performance.</p>\n </section>\n \n <section>\n \n <h3> RESULTS</h3>\n \n <p>In whole-brain analyses, higher CRF was associated with greater FD, FC, and FDC. Furthermore, these FBA-derived metrics statistically mediated the relationship between CRF and cognitive performance in the domains of visuospatial abilities, processing speed, working memory, and executive function/attentional control, but not episodic memory.</p>\n </section>\n \n <section>\n \n <h3> DISCUSSION</h3>\n \n <p>These findings highlight the potential for CRF in the preservation of multiple aspects of cognition as a function of white matter micro- and macro-structural properties. Our results provide novel insights into the neurobiological mechanisms of fitness-related cognitive resilience.</p>\n </section>\n \n <section>\n \n <h3> Highlights</h3>\n \n <div>\n <ul>\n \n <li>Higher cardiorespiratory fitness (CRF) is linked to better white matter integrity in older adults.</li>\n \n <li>Fixel-based analysis reveals CRF associations with fiber density and cross-section.</li>\n \n <li>White matter properties mediate CRF effects on cognition, excluding episodic memory.</li>\n \n <li>Findings suggest CRF supports cognitive resilience via white matter organization.</li>\n </ul>\n </div>\n </section>\n </div>","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"11 3","pages":""},"PeriodicalIF":4.9000,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/trc2.70125","citationCount":"0","resultStr":"{\"title\":\"White matter microstructure mediates the association between cardiorespiratory fitness and cognitive performance in older adults\",\"authors\":\"Emma M. 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White matter microstructure mediates the association between cardiorespiratory fitness and cognitive performance in older adults
INTRODUCTION
Age-related cognitive decline occurs, in part, due to diminishing white matter integrity. Higher cardiorespiratory fitness (CRF) is associated with better cognitive performance, but the neurobiological mechanisms underlying this association remain uncertain. Previous magnetic resonance imaging (MRI) studies have suggested that CRF-related changes in white matter microstructure might prevent or slow age-related cognitive decline, but have been limited by small sample sizes and methodological limitations. Specifically, most prior studies used tensor-based diffusion-weighted MRI metrics, which are insensitive to complex white matter architectures, including crossing fibers.
METHODS
Here, we leveraged a novel analysis framework capable of resolving individual fiber populations at the within-voxel level—fixel-based analysis (FBA)—to analyze three metrics of white matter organization from diffusion-weighted MRI scans: fiber density (FD), fiber cross-section (FC), and their combined measure (FDC). Using a cross-sectional sample of 636 cognitively unimpaired older adults aged 65 to 80 years (mean age = 69.8 years; 71% female), we hypothesized that FBA metrics would be associated with CRF and that this variation in FBA metrics would mediate associations between CRF and cognitive performance.
RESULTS
In whole-brain analyses, higher CRF was associated with greater FD, FC, and FDC. Furthermore, these FBA-derived metrics statistically mediated the relationship between CRF and cognitive performance in the domains of visuospatial abilities, processing speed, working memory, and executive function/attentional control, but not episodic memory.
DISCUSSION
These findings highlight the potential for CRF in the preservation of multiple aspects of cognition as a function of white matter micro- and macro-structural properties. Our results provide novel insights into the neurobiological mechanisms of fitness-related cognitive resilience.
Highlights
Higher cardiorespiratory fitness (CRF) is linked to better white matter integrity in older adults.
Fixel-based analysis reveals CRF associations with fiber density and cross-section.
White matter properties mediate CRF effects on cognition, excluding episodic memory.
Findings suggest CRF supports cognitive resilience via white matter organization.
期刊介绍：
Alzheimer''s & Dementia: Translational Research & Clinical Interventions (TRCI) is a peer-reviewed, open access,journal from the Alzheimer''s Association®. The journal seeks to bridge the full scope of explorations between basic research on drug discovery and clinical studies, validating putative therapies for aging-related chronic brain conditions that affect cognition, motor functions, and other behavioral or clinical symptoms associated with all forms dementia and Alzheimer''s disease. The journal will publish findings from diverse domains of research and disciplines to accelerate the conversion of abstract facts into practical knowledge: specifically, to translate what is learned at the bench into bedside applications. The journal seeks to publish articles that go beyond a singular emphasis on either basic drug discovery research or clinical research. Rather, an important theme of articles will be the linkages between and among the various discrete steps in the complex continuum of therapy development. For rapid communication among a multidisciplinary research audience involving the range of therapeutic interventions, TRCI will consider only original contributions that include feature length research articles, systematic reviews, meta-analyses, brief reports, narrative reviews, commentaries, letters, perspectives, and research news that would advance wide range of interventions to ameliorate symptoms or alter the progression of chronic neurocognitive disorders such as dementia and Alzheimer''s disease. The journal will publish on topics related to medicine, geriatrics, neuroscience, neurophysiology, neurology, psychiatry, clinical psychology, bioinformatics, pharmaco-genetics, regulatory issues, health economics, pharmacoeconomics, and public health policy as these apply to preclinical and clinical research on therapeutics.
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