Assessment of Plasma Glucosylceramides and Ceramides as Biomarkers of Cognitive Impairment in Parkinson's Disease

Objective/Rationale:
Metabolism of the lipids glucosylceramide and ceramide is altered in Parkinson’s disease (PD). GBA mutations in this pathway, causing a build-up of glucosylceramide, increase the risk of PD, and PD patients with GBA mutations are more likely to develop cognitive deficits and dementia. This pathway may also be affected in PD patients without GBA mutations. This study aims to determine whether plasma ceramide and glucosylceramide levels are associated with cognitive impairment in PD patients, with and without GBA mutations, and predict rate of cognitive decline.

Project Description:
Researchers will use blood and data already collected from 500 PD patients (325 cognitively normal, 100 mild cognitive impairment, 75 dementia) enrolled in the Dempark/Landscape study. At baseline and at 12 and 24 months, participants completed medical and depression questions, a neurological exam, cognitive tests and a blood draw. Plasma ceramides and glucosylceramides will be measured by mass spectrometry. All GBA coding exons will be Sanger-sequenced, and a series of 37 other genetic variants will be genotyped. Researchers expect 35 PD patients will have GBA mutations. They will examine the plasma lipid levels by cognitive status and GBA mutation status at baseline, and determine whether high levels of these plasma lipids predict rate of cognitive decline. They will also examine behavioral and motor outcomes.

Relevance to Diagnosis/Treatment of Parkinson’s Disease:
There are currently no biomarkers to predict which PD patients will develop cognitive impairment and when. A blood-based biomarker would be less costly and invasive than neuroimaging or cerebrospinal fluid measures. This study will determine whether plasma ceramides and glucosylceramides can be used as diagnostic and/or predictive biomarkers of cognitive impairment in PD. This information will be important for PD clinical trials, patient care and therapeutic research targeting this pathway.

Anticipated Outcome:
Investigators predict that PD patients with cognitive impairment or dementia will have higher plasma glucosylceramides than cognitively normal patients. Further, high glycosylceramide levels will be associated with a greater risk of developing cognitive impairment and a faster rate of decline. This project will clarify the relationship between plasma ceramide and glucosylceramides and cognition in PD patients with and without GBA mutations.