Resumen de Longitudinal interplay between subclinical atherosclerosis, cardiovascular risk factors and cerebral glucose metabolism in middle-aged asymptomatic individuals
Atherosclerosis, the main cause of cardiovascular disease (CVD), often co-exists at advanced stages with Alzheimer’s disease (AD), the most common form of dementia. Indeed, controlling cardiovascular risk factors in midlife may reduce the risk of developing dementia later in life. However, the impact of cardiovascular risk factors on brain health in midlife remains unexplored. Longitudinal studies examining their interplay with cerebral glucose metabolism, a predictor of cognitive decline, are scarce. Thus, this thesis sought to determine the cross-sectional and longitudinal associations between cerebral glucose metabolism, subclinical atherosclerosis and cardiovascular risk factors in middle-aged asymptomatic individuals. The Progression of Early Subclinical Atherosclerosis (PESA) is a longitudinal observational cohort study that recruited 4184 asymptomatic individuals aged 40-54. Participants with subclinical atherosclerosis in at least one vascular territory underwent longitudinal cerebral [18F]fluoro-2-deoxyglucose (FDG) positron emission tomography. Cardiovascular risk was assessed with standard CVD risk equations; and subclinical atherosclerosis in the carotid and femoral arteries was measured by 3D vascular ultrasound. Additionally, plasma biomarkers of neuropathology including neurofilament light chain (NfL), glial fibrillary acidic protein, amyloid-β42/40 and phosphorylated tau 181, were quantified. The cross-sectional study included 547 participants and the longitudinal study 370 participants with two sets of cerebral FDG-PET scans (mean [SD] age at baseline 49.0 ± 4.2 years, 84% males, follow-up time 4.7 ± 0.6 years). At baseline, higher burden of cardiovascular risk factors, particularly hypertension, and subclinical carotid atherosclerosis were associated with lower FDG uptake in regions typically affected in AD. Longitudinally, the sustained high risk of CVD over time was associated with an accelerated decline of cerebral FDG uptake, with plasma NfL mediating this association by 20%. Moreover, progression of subclinical carotid atherosclerosis was associated with a greater decline in FDG uptake in the hypometabolic signature of AD, with an effect that was additive to that of cardiovascular risk. Sustained high cardiovascular risk in midlife is associated with a decline in cerebral glucose consumption, partially attributable to irreversible neurodegeneration. The presence and progression of subclinical carotid atherosclerosis was linked to an additional metabolic decline in brain regions vulnerable to AD, revealing effects that escape traditional cardiovascular risk models. Our results suggest that maintaining cardiovascular health during midlife may be key to reducing neurodegenerative disease burden later in life and support the screening for subclinical atherosclerosis in middle-age as a primary prevention strategy of dementia
