GCase activity and long‐term risk of dementia in Parkinson’s disease

Abstract

AbstractBackgroundClinically, patients with Parkinson disease (PD) carrying a mutation in the glucocerebrosidase (GCase) gene (GBA) are at higher risk of dementia, suggesting that GCase dysfunction may contribute to a more severe disease course, although evidence is lacking. We aimed to discover if cerebrospinal fluid (CSF) GCase activity is altered in newly diagnosed PD patients and if GCase activity at diagnosis predicts the future development of dementia.MethodWe measured CSF GCase activity in 117 PD patients from the Norwegian ParkWest study, a population‐based study of incident PD with 10 years of biannual, prospective follow up, and 50 control subjects without neurological disease. PD dementia diagnosis was set according to established clinical criteria. Parametric accelerated failure time models were applied to analyze the association of GCase activity at the time of PD diagnosis with dementia free survival.ResultGCase activity was reduced in PD patients with (0.92±0.40 mU/mg) or without GBA mutations (1.00±0.37 mU/mg) compared to controls (1.20±0.35 mU/mg). GCase activity at the time of diagnosis was lower in PD patients who developed dementia within 10 years (n=41, 35%) than in those who remained free of dementia (p = 0.001). Further, patients in the lowest tertile of GCase activity at PD diagnosis were at 3‐fold increased risk of developing dementia in the next ten years (HR 3.10; 95% 0.72 to 4.68; P= .014; Figure), a finding that was also independent of GBA carrier status.ConclusionThis is the first study to show both that GCase dysfunction is evident in idiopathic PD at the time of diagnosis and that low GCase activity is associated with greater risk of developing dementia over the next ten years. GCase‐targeting compounds are among the most promising strategies towards disease‐modifying treatments in PD, and evidence for the association of CSF GCase activity with disease progression, independent of GBA mutation status, will have important implications for clinical trial design and patient management.