Sex-dependent associations among peripheral inflammation, glymphatic system-related imaging markers, and cognitive and motor manifestations in Parkinson’s disease

Peripheral inflammation and glymphatic system-related imaging abnormalities have been implicated in Parkinson’s disease (PD), but whether their associations with cognitive and motor manifestations differ by sex remains unclear. Using the Parkinson’s Progression Markers Initiative (PPMI) cohort, we analyzed 335 patients with PD cross-sectionally and 293 longitudinally over 5 years, and further evaluated the findings in an independent self-collected validation cohort of 159 patients with PD. Multivariable regression and linear mixed-effects models were performed, with sex-stratified and interaction analyses. In the PPMI cohort, cross-sectional analyses showed that ALPS was associated with the systemic immune-inflammation index, whereas a higher neutrophil-to-lymphocyte ratio was associated with lower delayed verbal memory performance. In females, ALPS was associated with multiple inflammatory markers, whereas in males ALPS was associated with motor severity; a significant FWF × sex interaction was observed for visuospatial performance. Longitudinally, lower baseline ALPS was associated with worse motor severity across follow-up, while baseline NLR, FWF, and ALPS were associated with domain-specific cognitive trajectories. Sex-stratified longitudinal analyses showed that NLR-related visuospatial decline was more evident in males, whereas FWF-related decline in processing speed was more evident in females. In the validation cohort, the overall associations of ALPS with UPDRS-III and of FWF with MoCA were reproduced, and broader inflammation-linked imaging and clinical associations were again observed in females. These findings support sex-dependent associations among peripheral inflammation, glymphatic system-related imaging markers, and cognitive and motor manifestations in PD, and highlight sex as an important modifier of biomarker-clinical relationships.