Glymphatic system dysfunction and risk of clinical milestones in patients with Parkinson disease

Abstract Background and purpose Glymphatic dysfunction may play a significant role in the development of neurodegenerative diseases. We aimed to evaluate the association between glymphatic dysfunction and the risk of malignant event/clinical milestones in Parkinson disease (PD). Methods This study included 236 patients from August 2014 to December 2020. Diffusion tensor imaging analysis along the perivascular space (DTI‐ALPS) index was calculated as an approximate measure of glymphatic function. The primary outcomes were four clinical milestones including recurrent falls, wheelchair dependence, dementia, and placement in residential or nursing home care. The associations of DTI‐ALPS with the risk of clinical milestones were examined using multivariate Cox proportional hazards regression models. Then, logistic regression was repeated using clinical variables and DTI‐ALPS index individually and in combination of the two to explore the ability to distinguish patients who reached clinical milestones within a 5‐year period. Results A total of 175 PD patients with baseline DTI‐ALPS index and follow‐up clinical assessments were included. A lower DTI‐ALPS was independently associated with increased risk of recurrent falls, wheelchair dependence, and dementia. Additionally, in 103 patients monitored over 5 years, a logistic regression model combining clinical variables and DTI‐ALPS index showed better performance for predicting wheelchair dependence within 5 years than a model using clinical variables or DTI‐ALPS index alone. Conclusions Glymphatic dysfunction, as measured by the DTI‐ALPS index, was associated with increased risk of clinical milestones in patients with PD. This finding implies that therapy targeting the glymphatic system may serve as a viable strategy for slowing down the progression of PD.