Emilie T Reas1, Donald J Hagler2, Joshua M Kuperman2, Christina E Wierenga3,4, Douglas Galasko1, Nathan S White2, Anders M Dale1,2, Sarah J Banks1, Linda K McEvoy2,5, James B Brewer1,2. 1. Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA. 2. Department of Radiology, University of California, San Diego, La Jolla, CA, USA. 3. Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA. 4. Department of Veterans Affairs, San Diego Healthcare System, La Jolla, CA, USA. 5. Department of Family Medicine and Public Health, University of California, San Diego, La Jolla, CA, USA.
Abstract
BACKGROUND: Although amyloid-β (Aβ) and microstructural brain changes are both effective biomarkers of Alzheimer's disease, their independent or synergistic effects on cognitive decline are unclear. OBJECTIVE: To examine associations of Aβ and brain microstructure with cognitive decline in amnestic mild cognitive impairment and dementia. METHODS: Restriction spectrum imaging, cerebrospinal fluid Aβ, and longitudinal cognitive data were collected on 23 healthy controls and 13 individuals with mild cognitive impairment or mild to moderate Alzheimer's disease. Neurite density (ND) and isotropic free water diffusion (IF) were computed in fiber tracts and cortical regions of interest. We examined associations of Aβ with regional and whole-brain microstructure, and assessed whether microstructure mediates effects of Aβ on cognitive decline. RESULTS: Lower ND in limbic and association fibers and higher medial temporal lobe IF predicted baseline impairment and longitudinal decline across multiple cognitive domains. ND and IF predicted cognitive outcomes after adjustment for Aβ or whole-brain microstructure. Correlations between microstructure and cognition were present for both amyloid-positive and amyloid-negative individuals. Aβ correlated with whole-brain, rather than regional, ND and IF. CONCLUSION: Aβ correlates with widespread microstructural brain changes, whereas regional microstructure correlates with cognitive decline. Microstructural abnormalities predict cognitive decline regardless of amyloid, and may inform about neural injury leading to cognitive decline beyond that attributable to amyloid.
BACKGROUND: Although amyloid-β (Aβ) and microstructural brain changes are both effective biomarkers of Alzheimer's disease, their independent or synergistic effects on cognitive decline are unclear. OBJECTIVE: To examine associations of Aβ and brain microstructure with cognitive decline in amnestic mild cognitive impairment and dementia. METHODS: Restriction spectrum imaging, cerebrospinal fluid Aβ, and longitudinal cognitive data were collected on 23 healthy controls and 13 individuals with mild cognitive impairment or mild to moderate Alzheimer's disease. Neurite density (ND) and isotropic free water diffusion (IF) were computed in fiber tracts and cortical regions of interest. We examined associations of Aβ with regional and whole-brain microstructure, and assessed whether microstructure mediates effects of Aβ on cognitive decline. RESULTS: Lower ND in limbic and association fibers and higher medial temporal lobe IF predicted baseline impairment and longitudinal decline across multiple cognitive domains. ND and IF predicted cognitive outcomes after adjustment for Aβ or whole-brain microstructure. Correlations between microstructure and cognition were present for both amyloid-positive and amyloid-negative individuals. Aβ correlated with whole-brain, rather than regional, ND and IF. CONCLUSION: Aβ correlates with widespread microstructural brain changes, whereas regional microstructure correlates with cognitive decline. Microstructural abnormalities predict cognitive decline regardless of amyloid, and may inform about neural injury leading to cognitive decline beyond that attributable to amyloid.
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