Investigating how biological markers relate to clinical symptoms in Parkinson’s disease, a study has identified sex-dependent associations connecting peripheral inflammation, glymphatic system-related imaging markers, and both cognitive and motor manifestations. Although peripheral inflammation and imaging abnormalities related to the glymphatic system have previously been implicated in Parkinson’s disease, whether the associations linking these markers to cognitive and motor symptoms differ between male and female patients had remained unclear.
To examine these relationships, the researchers utilized patient data from the Parkinson’s Progression Markers Initiative cohort alongside an independent replication group. Within the Parkinson’s Progression Markers Initiative cohort, the investigators evaluated 335 patients diagnosed with Parkinson’s disease in a cross-sectional framework and followed 293 patients longitudinally over a period of five years. To further test the validity and reproducibility of the observations, the authors analyzed an independent, self-collected validation cohort consisting of 159 patients with Parkinson’s disease.
The investigators evaluated the data using multivariable regression and linear mixed-effects models, carrying out both sex-stratified assessments and interaction analyses. In the cross-sectional evaluation of the Parkinson’s Progression Markers Initiative cohort, ALPS was associated with the systemic immune-inflammation index. In the same cross-sectional cohort analysis, a higher neutrophil-to-lymphocyte ratio was associated with lower performance in delayed verbal memory.
The cross-sectional analyses revealed distinct divergence between female and male participants within the Parkinson’s Progression Markers Initiative cohort. Among female patients, ALPS showed associations with multiple inflammatory markers. In contrast, among male patients, ALPS was associated with motor severity. Additionally, statistical testing identified a significant interaction between FWF and sex with respect to visuospatial performance.
Longitudinal assessments tracking patients across the five-year follow-up period in the Parkinson’s Progression Markers Initiative cohort showed that lower baseline ALPS was associated with worse motor severity over time. Furthermore, baseline measurements of the neutrophil-to-lymphocyte ratio, FWF, and ALPS were each associated with domain-specific cognitive trajectories. Sex-stratified analyses of these longitudinal cognitive trajectories indicated that visuospatial decline associated with the neutrophil-to-lymphocyte ratio was more evident in males, whereas decline in processing speed related to FWF was more evident in females.
In the independent self-collected validation cohort of 159 patients, the primary relationships between imaging markers and clinical scores were reproduced, specifically confirming the overall association of ALPS with UPDRS-III and the association of FWF with MoCA. Broader associations linking inflammation, imaging markers, and clinical measures were again observed specifically among females. Based on these cross-sectional and longitudinal outcomes, the researchers concluded that the findings support sex-dependent associations among peripheral inflammation, glymphatic system-related imaging markers, and cognitive and motor manifestations in Parkinson’s disease, highlighting sex as an important modifier of biomarker-clinical relationships.
Subject of Research: Sex-dependent associations among peripheral inflammation, glymphatic imaging markers, and Parkinson's disease manifestations
Article Title: Sex-dependent associations among peripheral inflammation, glymphatic system-related imaging markers, and cognitive and motor manifestations in Parkinson’s disease
Article References: Ruan, X., Huang, X., Zhou, Q., Gong, J., Li, Y., Guo, R., Wang, M., Wang, T., Li, M., & Wei, X. (2026). Sex-dependent associations among peripheral inflammation, glymphatic system-related imaging markers, and cognitive and motor manifestations in Parkinson’s disease. npj Parkinson's Disease. https://doi.org/10.1038/s41531-026-01617-z
Image Credits: AI Generated
DOI: 10.1038/s41531-026-01617-z
Keywords: Parkinson's disease, glymphatic system, peripheral inflammation, ALPS, FWF, neutrophil-to-lymphocyte ratio, biomarkers, sex differences, Sex-dependent, associations, peripheral, inflammation
News Source: Diana Fleming. (November 6, 2026). Sex Influences Inflammation and Glymphatic Marker Associations in Parkinson’s Disease. Scienmag.
