Glymphatic system dysfunction as a biomarker of disease progression in Parkinson's disease: neuroimaging evidence from longitudinal cohort studies.

Background and objective: The brain glymphatic system is involved in the clearance of misfolded α-synuclein, and the impaired glymphatic system may contribute to the progression of Parkinson's disease (PD). This study aimed to investigate the association between glymphatic function, as assessed by the diffusion tensor image analysis along the perivascular space (DTI-ALPS) index, and disease progression in PD.

Methods: One hundred thirty nine PD patients and 62 healthy controls (HCs) were enrolled in this prospective cohort study and followed up for 4 years. At baseline and 1-, 2-, and 4-year follow-ups, the enrolled population was examined with DTI scans, and the ALPS index was calculated. Unified Parkinson's Disease Rating Scale (UPDRS)-III and Montreal Cognitive Assessment (MoCA) were used to assess the motor and cognitive functions of the patients, respectively.

Result: The ALPS index was significantly lower in PD patients compared with HCs. Receiver operating characteristic curve analysis demonstrated that the ALPS index had a great diagnostic ability on PD, both at baseline and subsequent follow-ups (AUC_baseline: 0.729; AUC_1-year: 0.653; AUC_2-year: 0.714; AUC_4-year: 0.728). The adjusted linear mixed-effects models showed that the ALPS index was significantly associated with UPDRS-III scores (β: - 5.173, 95%CI: - 8.850 to - 1.497, p = 0.006), but this association was lost for MoCA. A lower baseline ALPS index was associated with a faster increase in UPDRS-III, but not for MoCA.

Conclusion: The ALPS index could be used as an early potential imaging marker not only to differentiate PD patients from HCs but also to predict longitudinal motor function progression in PD.