Perivascular space fluid diffusivity predicts clinical deterioration in prodromal and early-stage Parkinson's disease

Abstract

The glymphatic system is essential for clearing toxic proteins from the brain, and understanding its dysfunction in the early stages of Parkinson's disease (PD) may facilitate the development of disease-modifying therapies. This study aimed to evaluate alterations in glymphatic function and its correlation with disease progression in prodromal and early clinical stages of PD. Participants were categorized into three groups: prodromal PD (pPD), de novo PD (dnPD), and healthy controls (HCs), further divided by age. Glymphatic function was assessed using the ALPS index derived from diffusion tensor imaging. Results indicated that the ALPS index was significantly lower in older pPD and dnPD patients, correlating with various clinical symptoms. Longitudinal analysis revealed a decrease in the ALPS index over time in pPD patients who progressed to clinical PD, while it remained stable in non-converters. Additionally, the baseline ALPS index was predictive of the progression of both motor and non-motor symptoms in pPD patients. In dnPD patients, a lower baseline ALPS index predicted the progression of motor symptoms in the older subgroup. Overall, the ALPS index is reduced in the early stages of PD and may serve as a predictor for disease progression.

Fig. 1. Association of the ALPS index with age and diagnostic status.

A Correlations of the ALPS index and age in the 3 groups. B The changing trend of the ALPS index in three groups of patients in different age groups. Significant main effects were observed for age subgroup (F = 15.743, p < 0.001) and diagnostic status (F = 8.453, p < 0.001) on the ALPS index. Additionally, a significant interaction effect between age subgroup and diagnostic status was found (F = 5.081, p = 0.007).

Fig. 2. Results of inter-group comparison of the ALPS index.

A The ALPS index among the 3 groups. B The ALPS index among the 3 subgroups aged less than 65 years old. C The ALPS index among the 3 subgroups aged 65 years or older. ANCOVA was used to examine group differences, controlling for age, sex, and education level. *P < 0.05, **P < 0.01, and ***P < 0.001. ALPS, diffusion tensor image analysis along the perivascular space; HC healthy controls, dnPD de novo Parkinson’s disease, pPD prodromal Parkinson’s disease.

Fig. 3. Longitudinal study of pPD cohort.

A Correlations of the baseline ALPS index with ΔUPDRS-III score in entire pPD cohort. B Correlations of the baseline ALPS index with ΔPDNMS score in entire pPD cohort. C Longitudinal ALPS index in converted pPD subgroup. ΔUPDRS-III and ΔPDNMS are defined as the value at the end of follow-up minus the baseline value. Controlling for age, sex, education level, and baseline UPDRS-III or PDNMS scores.

Fig. 4. Longitudinal study of dnPD cohort.

A Correlations of the baseline ALPS index with ΔUPDRS-III score in entire dnPD cohort. B Correlations of the baseline ALPS index with ΔUPDRS-III score in the longitudinal cohort of dnPD individuals aged 65 or older. ΔUPDRS-III was defined as the value at the end of follow-up minus the baseline value. Controlling for age, sex, education level, baseline disease duration, follow-up time, LED and baseline UPDRS-III score.