Impaired synaptic function is linked to cognition in Parkinson's disease.

Objective: Cognitive impairment is frequent in Parkinson's disease, but the underlying mechanisms are insufficiently understood. Because cortical metabolism is reduced in Parkinson's disease and closely associated with cognitive impairment, and CSF amyloid-beta species are reduced and correlate with neuropsychological performance in Parkinson's disease, and amyloid-beta release to interstitial fluid may be related to synaptic activity; we hypothesize that synapse dysfunction links cortical hypometabolism, reduced CSF amyloid-beta, and presynaptic deposits of alpha-synuclein. We expect a correlation between hypometabolism, CSF amyloid-beta, and the synapse related-markers CSF neurogranin and asynuclein. Methods: Thirty patients with mild-to-moderate Parkinson's disease and 26 healthy controls underwent a clinical assessment, lumbar puncture, MRI, 18 F-fludeoxyglucose-PET, and a neuropsychological test battery (repeated for the patients after 2 years). Results: All subjects had CSF amyloid-b 1-42 within normal range. In Parkinson's disease, we found strong significant correlations between cortical glucose metabolism, CSF Ab, alpha-synuclein, and neurogranin. All PET CSF biomarker-based cortical clusters correlated strongly with cognitive parameters. CSF neurogranin levels were significantly lower in mildto-moderate Parkinson's disease compared to controls, correlated with amyloidb and alpha-synuclein, and with motor stage. There was little change in cognition after 2 years, but the cognitive tests that were significantly different, were also significantly associated with cortical metabolism. No such correlations were found in the control group. Interpretation: CSF Ab, alpha-synuclein, and neurogranin concentrations are related to cortical metabolism and cognitive decline. Synaptic dysfunction due to Ab and alpha-synuclein dysmetabolism may be central in the evolution of cognitive impairment in Parkinson's disease.