Cerebrospinal fluid YKL-40 relates to white matter hyperintensity progression in females but not males over a 6-year period.

INTRODUCTION: Neuroinflammation may have sex-specific effects on white matter injury and impact the development of dementia. METHODS: Human chitinase-3-like protein-1 (YKL-40) concentrations at baseline were related to white matter hyperintensity (WMH) volume, free water (FW), and FW-corrected fractional anisotropy using linear effects models (for cross-sectional outcomes) and linear mixed-effects models (for longitudinal outcomes), adjusting for demographic and medical risk factors. Models were repeated with a sex-interaction term and then stratified by sex. RESULTS: In stratified analyses, greater baseline YKL-40 concentrations were associated with increased WMHs in females but not males in the parietal (females p = 0.04; males p = .34) and temporal lobes (females p = 0.005; males = p = 0.71) longitudinally. YKL-40 associations with FW and FW-corrected fractional anisotropy were null. DISCUSSION: Results suggest that neuroinflammation is a sex-specific driver of WMHs (but not FW) in females. Differential sequelae of neuroinflammation may be one reason that females have a greater burden of WMHs. HIGHLIGHTS: ·Cerebrospinal fluid YKL-40 is associated with white matter hyperintensities in females but not males cross-sectionally and longitudinally.·Longitudinally, cerebrospinal fluid YKL-40 is associated with white matter hyperintensities in the parietal and temporal lobes, regions that exhibit early pathological changes in Alzheimer's disease .·Cerebrospinal fluid YKL-40 is not associated with white matter microstructural measures.