DTI-ALPS as a Biomarker of Small Vessel Disease Progression and Amyloid-β in Normal Aging: A 3-Year Longitudinal Study.

Cerebral small vessel disease (SVD) is a leading cause of stroke, vascular cognitive impairment, and functional decline in older adults. Emerging experimental and translational data implicate glymphatic dysfunction in SVD pathogenesis and in vascular amyloid accumulation. The analysis along the perivascular space (ALPS) index, derived from diffusion tensor imaging (DTI), noninvasively estimates water diffusivity along perivascular pathways and has been proposed as an indirect imaging marker related to glymphatic function. In this study, we aim to determine whether the baseline DTI-ALPS index is associated with baseline SVD burden and subsequent longitudinal changes in SVD markers and amyloid-β deposition in cognitively normal aging. We analyzed 204 cognitively normal participants from the Harvard Aging Brain Study with baseline and follow-up visits separated by 3 years. Primary MRI SVD outcomes were intracranial-volume-normalized white matter hyperintensities (WMH/ICV), and visual SVD ratings (Fazekas, ARWMC, perivascular space, and BOMBS [microbleed scale]). Secondary outcomes included cortical amyloid PET burden (PIB_FS_DVR_FLR). We tested the effects of time, baseline ALPS (z-scored), and the time-ALPS interaction using Bayesian mixed-effects models with subject-specific random intercepts adjusted for baseline age, sex, and education; amyloid models were additionally adjusted for APOE4 status. Continuous outcomes were modeled with Gaussian mixed-effects models, binary outcomes with Bernoulli mixed-effects models, and ordinal outcomes with Bayesian cumulative mixed-effects models. In a sensitivity analysis, ALPS was recalculated after excluding voxels with λ