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We aimed to evaluate the association between glymphatic dysfunction and the risk of malignant event\/clinical milestones in Parkinson disease (PD).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>This study included 236 patients from August 2014 to December 2020. Diffusion tensor imaging analysis along the perivascular space (DTI\u2010ALPS) 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\u2010ALPS 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\u2010ALPS index individually and in combination of the two to explore the ability to distinguish patients who reached clinical milestones within a 5\u2010year period.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>A total of 175 PD patients with baseline DTI\u2010ALPS index and follow\u2010up clinical assessments were included. A lower DTI\u2010ALPS was independently associated with increased risk of recurrent falls, wheelchair dependence, and dementia. Additionally, in 103 patients monitored over 5\u2009years, a logistic regression model combining clinical variables and DTI\u2010ALPS index showed better performance for predicting wheelchair dependence within 5\u2009years than a model using clinical variables or DTI\u2010ALPS index alone.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Glymphatic dysfunction, as measured by the DTI\u2010ALPS 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.<\/jats:p><\/jats:sec>","DOI":"10.1111\/ene.16521","type":"journal-article","created":{"date-parts":[[2024,10,19]],"date-time":"2024-10-19T05:15:16Z","timestamp":1729314916000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":40,"title":["Glymphatic system dysfunction and risk of clinical milestones in patients with Parkinson disease"],"prefix":"10.1111","volume":"31","author":[{"given":"Cheng","family":"Zhou","sequence":"first","affiliation":[{"name":"Department of Radiology, Second Affiliated Hospital Zhejiang University School of Medicine  Hangzhou China"},{"name":"Joint Laboratory of Clinical Radiology, Second Affiliated Hospital Zhejiang University School of Medicine  Hangzhou 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