Jennifer S Rabin1,2,3,4, Jeremy Pruzin5,6, Matthew Scott5, Hyun-Sik Yang5,7, Olivia Hampton5, Stephanie Hsieh5, Aaron P Schultz5,8, Rachel F Buckley5,9,10, Trey Hedden11, Dorene Rentz5,7, Keith A Johnson5,7,8,12, Reisa A Sperling5,7,8, Jasmeer P Chhatwal13,7. 1. Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School. 2. Division of Neurology, Department of Medicine, Sunnybrook Health Sciences Centre, University of Toronto. 3. Harquail Centre for Neuromodulation, Hurvitz Brain Sciences Program, Sunnybrook Research Institute. 4. Rehabilitation Sciences Institute, University of Toronto. 5. Department of Neurology, Massachusetts General Hospital, Harvard Medical School. 6. Banner Alzheimer's Institute. 7. Center for Alzheimer Research and Treatment, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School. 8. Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School. 9. Florey Institute, University of Melbourne. 10. Melbourne School of Psychological Sciences, University of Melbourne. 11. Department of Neurology, Icahn School of Medicine at Mount Sinai. 12. Department of Radiology, Massachusetts General Hospital, Harvard Medical School. 13. Department of Neurology, Massachusetts General Hospital, Harvard Medical School chhatwal.jasmeer@mgh.harvard.edu.
Abstract
BACKGROUND AND OBJECTIVES: Vascular risk factors and elevated β-amyloid (Aβ) are commonly observed together among older adults. Here, we examined the interactive versus independent effects of systemic vascular risk and Aβ burden on longitudinal gray matter atrophy, and how their co-occurrence may be related to cognitive decline in a cohort of clinically normal adults. A secondary goal was to examine whether vascular risk influences gray matter atrophy independently from markers of white matter injury. METHODS: Participants were 196 adults (age=73.8±6.1 years) from the Harvard Aging Brain Study. Baseline Aβ burden was quantified with Pittsburgh Compound-B PET. Baseline vascular risk was measured with the Framingham Heart Study cardiovascular disease risk score. Brain atrophy was quantified longitudinally with structural magnetic resonance imaging over a median of 4.50 (±1.26) years. Cognition was assessed yearly with the Preclinical Alzheimer Cognitive Composite over a median of 6.25 (±1.40) years. Linear mixed-effects models examined vascular risk and Aβ burden as interactive versus independent predictors of gray matter atrophy, adjusting for age, sex, years of education, APOE ε4 status, intracranial volume (where appropriate), and their interactions with time. In subsequent models we adjusted for markers of white matter injury to determine whether vascular risk accelerates brain atrophy independently from diffusion- and FLAIR-based markers. Mediation analyses examined whether brain atrophy mediated the interactive association of vascular risk and Aβ burden on cognitive decline. RESULTS: Higher vascular risk and elevated Aβ burden interacted to predict more severe atrophy within frontal and temporal lobes, thalamus, and striatum. Higher Aβ burden, but not vascular risk, was associated with more severe atrophy in parietal and occipital lobes, as well as the hippocampus. Adjusting for diffusion- and FLAIR-based markers of white matter injury had little impact on the above associations. Gray matter atrophy mediated the association between vascular risk and cognitive decline at higher levels of Aβ burden. DISCUSSION: We observed an interaction between elevated vascular risk and higher Aβ burden with longitudinal brain atrophy, which in turn influenced cognitive decline. These results support vascular risk factor management as a potential intervention to slow neurodegeneration and cognitive decline in preclinical Alzheimer's disease.
BACKGROUND AND OBJECTIVES: Vascular risk factors and elevated β-amyloid (Aβ) are commonly observed together among older adults. Here, we examined the interactive versus independent effects of systemic vascular risk and Aβ burden on longitudinal gray matter atrophy, and how their co-occurrence may be related to cognitive decline in a cohort of clinically normal adults. A secondary goal was to examine whether vascular risk influences gray matter atrophy independently from markers of white matter injury. METHODS: Participants were 196 adults (age=73.8±6.1 years) from the Harvard Aging Brain Study. Baseline Aβ burden was quantified with Pittsburgh Compound-B PET. Baseline vascular risk was measured with the Framingham Heart Study cardiovascular disease risk score. Brain atrophy was quantified longitudinally with structural magnetic resonance imaging over a median of 4.50 (±1.26) years. Cognition was assessed yearly with the Preclinical Alzheimer Cognitive Composite over a median of 6.25 (±1.40) years. Linear mixed-effects models examined vascular risk and Aβ burden as interactive versus independent predictors of gray matter atrophy, adjusting for age, sex, years of education, APOE ε4 status, intracranial volume (where appropriate), and their interactions with time. In subsequent models we adjusted for markers of white matter injury to determine whether vascular risk accelerates brain atrophy independently from diffusion- and FLAIR-based markers. Mediation analyses examined whether brain atrophy mediated the interactive association of vascular risk and Aβ burden on cognitive decline. RESULTS: Higher vascular risk and elevated Aβ burden interacted to predict more severe atrophy within frontal and temporal lobes, thalamus, and striatum. Higher Aβ burden, but not vascular risk, was associated with more severe atrophy in parietal and occipital lobes, as well as the hippocampus. Adjusting for diffusion- and FLAIR-based markers of white matter injury had little impact on the above associations. Gray matter atrophy mediated the association between vascular risk and cognitive decline at higher levels of Aβ burden. DISCUSSION: We observed an interaction between elevated vascular risk and higher Aβ burden with longitudinal brain atrophy, which in turn influenced cognitive decline. These results support vascular risk factor management as a potential intervention to slow neurodegeneration and cognitive decline in preclinical Alzheimer's disease.
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