Periventricular gradient of normal-appearing white matter in normal aging and multiple neurological diseases

INTRODUCTION: A potential inflammation-associated periventricular gradient of normal-appearing white matter (NAWM) abnormalities has been identified in multiple sclerosis, but its presence in normal aging and other neurological diseases remains unclear. OBJECTIVES: We aimed to determine whether a periventricular gradient of NAWM abnormalities occurs in normal aging and other neurological diseases. METHODS: A total of 290 Alzheimer's disease, 262 Parkinson's disease, 154 cerebral small vessel disease, 212 multiple sclerosis, as well as 344 younger healthy controls (HCs), 344 middle-aged HCs, and 398 older HCs with available MR diffusion images were included in this study. The periventricular gradient (the slope of regression model) in NAWM of normalized neurite density (NDI) and orientation dispersion indices (ODI), derived from diffusion MRI, was calculated using linear mixed models. Its associations with other MRI measures, clinical variables, and brain-wide gene expression were analyzed. Additional sensitivity and replication analyses were conducted. RESULTS: The periventricular gradients of both normalized NDI and ODI were observed in older HCs and all neurological disease groups. Such periventricular gradients play mediating roles between choroid plexus volume (a marker of neuroinflammation) and NAWM NDI or ODI, white matter hyperintensity volume, white and gray matter volumes, especially in neurological diseases. They exhibited both direct and indirect associations with cognitive and physical performance in normal aging and multiple neurological diseases. We observed correlations between periventricular gradients and underlying inflammatory, endothelial and synaptic gene expression. Sensitivity and replication analyses confirmed the main findings. CONCLUSION: Clinically relevant periventricular gradients in tissue diffusion characteristics occur in normal aging and multiple neurological diseases, and share some underlying pathological mechanisms.