Glymphatic Dysfunction in Non‐Manifesting Carriers of LRRK2 and GBA Pathogenic Variants

BACKGROUND: Non-manifesting carriers of LRRK2 and GBA pathogenic variants represent a unique cohort for investigating neuroprotective interventions at the prodromal stage of Parkinson's disease (PD). A critical challenge is identifying effective markers to predict non-manifesting carriers at high risk of developing PD. OBJECTIVES: Our goal was to investigate whether glymphatic function is impaired in non-manifesting carriers and to evaluate the potential of glymphatic dysfunction as a marker for identifying individuals at high risk of PD. METHODS: We used diffusion-tensor imaging analysis along the perivascular space (ALPS) method to assess glymphatic function in participants from the Parkinson's Progression Markers Initiative (PPMI) dataset. Cross-sectional and longitudinal changes in the ALPS index were evaluated, and baseline predictors of clinical progression were identified. The association between ALPS index and the risk of phenoconversion was examined using Kaplan-Meier survival analysis and Cox proportional hazards regression. RESULTS: Eighty non-manifesting carriers of LRRK2 and GBA pathogenic variants were included. ALPS index values were reduced cross-sectionally and longitudinally, and were correlated with cognitive function and daytime sleepiness scores. Baseline ALPS index values predicted a decline in Hopkins Verbal Learning Test-immediate recall scores over a 3-year follow-up period. During follow-up, 17 non-manifesting carriers converted to clinically defined PD. Increasing ALPS index values were associated with a decreased risk of phenoconversion (hazard ratio [95% confidence interval] = 0.128 [0.029-0.565], P = 0.0013). CONCLUSIONS: Glymphatic function is impaired in non-manifesting carriers. Glymphatic dysfunction is associated with an increased risk of phenoconversion. The ALPS index has the potential as a marker for identifying individuals at high risk of developing PD. © 2025 International Parkinson and Movement Disorder Society.