Plasma inflammatory markers and brain white matter microstructure in late middle-aged and older adults

Chronic inflammation is a common feature of aging and is observed across various age-related neurodegenerative diseases, including Alzheimer's disease (AD). Diffusion magnetic resonance imaging (dMRI) metrics of white matter microstructure are hypothesized to be sensitive to inflammation, though few studies have assessed this relationship in non-clinical populations. This cross-sectional study of 457 dementia-free older adults (M_age=63.82) examined associations of plasma markers related to inflammation with white matter microstructure metrics from multi-shell dMRI Neurite Orientation Dispersion and Density Imaging (NODDI) and conventional, single-shell dMRI metrics. Plasma inflammatory markers included high-sensitivity C-reactive protein (CRP), a composite of pro-inflammatory cytokines, and glial fibrillary acidic protein (GFAP), a measure of astrocytic activation. Higher cytokine composite levels were associated with higher cerebral free water fraction (FWF) and higher cerebellar peduncle orientation dispersion index (ODI). Higher CRP was associated with higher cerebral and cerebellar ODI, which was non-significant after adjusting for additional demographics and vascular risk factors. Higher GFAP was associated with lower cerebral FWF and lower cerebral and cerebellar neurite density index (NDI). The only significant association with conventional DTI metrics was between higher cytokine composite levels and higher cerebral mean diffusivity (MD). Results were consistent after accounting for plasma AD biomarkers. Thus, higher levels of peripheral pro-inflammatory markers are associated with white matter microstructure (FWF, ODI, NDI, and MD), supporting the sensitivity of these dMRI-based metrics to inflammatory processes. Additionally, the sensitivity of dMRI-based measures to inflammation may differ by inflammatory marker types, with multi-shell approaches like NODDI providing information beyond conventional, single-shell dMRI.