Objective: To determine whether plasma ceramides, glucosylceramides, and their ratios predict cognitive decline among cognitively normal Parkinson’s disease (PD) patients.

Background: There are no biomarkers to predict which PD patients will develop progressive cognitive decline. Mutations in the gene coding for glucocerebrosidase (GBA), which metabolizes glucosylceramide into glucose and ceramide, is the most common genetic risk factor for sporadic PD. GBA mutation carriers are more likely to develop cognitive impairment and dementia. We reported that higher plasma ceramide and glucosylceramide levels were cross-sectionally associated with cognitive impairment in PD non-GBA mutations carriers. These plasma lipids have not been examined as predictors of cognitive decline.

Methods: We included 110 cognitively normal sporadic PD patients who were enrolled in the DEMPARK/LANDSCAPE study, had a 12 month follow-up visit, and did not have pathogenic mutations including GBA. At each visit, an extensive neuropsychological battery was administered. Plasma ceramides and glucosylceramides were determined by LC/ESI/MS/MS. Linear mixed models were used to assess the association between baseline plasma ceramides and glucosylceramides, their ratios, and 12-month change in cognitive performance adjusting for age, sex, education, and disease duration.

Results: The mean age was 67.2 (SD 8.3) years and the mean disease duration was 4.9 (SD 3.7) years. Many of the ceramides and glucosylceramides were associated with greater cognitive decline in tests of attention and psychomotor speed, but the ratios were most predictive. For example, each log unit increase in the ceramide to glucosylceramide C18:0 ratio was associated with greater decline in all tests including Trail Making Test, Part A z-score (b=-1.08, p = 0.008), CERAD Semantic (b=-1.29; p=0.001) and Phonemic Fluency (b=-1.22, 0.005) z-scores; Stroop Word reading (b=-3.21, p=0.008) and Color Naming (b=-2.81, p=0.021) t-scores, and MMSE total score (b=-1.35, p=0.002). Excluding 18 individuals with non-pathogenic GBA mutations did not affect the results.

Conclusions: Our results suggest that a higher plasma ceramide to glucosylceramide C18:0 ratio is predictive of greater rates of cognitive decline in cognitively normal PD patients and may be a potential blood-based prognostic cognitive biomarker.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/plasma-ceramides-and-glucosylceramides-predict-cognitive-decline-among-cognitively-normal-parkinsons-disease-patients/