Abstract
Recent findings of morphological and functional changes in Parkinson’s disease brains have shown altered synapse formation, but their role in cognitive decline is still an area under exploration. Here we measured the concentration of three key synaptic proteins, Rab3A, SNAP25 and neurogranin by enzyme-linked immunosorbent assay, in cerebrospinal fluid from a total of 139 participants (87 controls and 52 Parkinson’s disease patients out of which 30 were drug-naïve) and explored their associations with motor and cognitive symptoms. Associations with motor disease stage (assessed by Hoehn and Yahr scale) and cognitive performance (assessed by the Montreal Cognitive Assessment scores) were explored. An overall increase in the concentration of SNAP25 was found in Parkinson’s disease patients (p = 0.032). Increased neurogranin levels were found in the drug naïve patients subgroup (p = 0.023). Significant associations were observed between increased concentration of neurogranin and cognitive impairment in total Parkinson’s disease group (p = 0.017), as well as in the drug naïve (p = 0.021) and with motor disease stage (p = 0.041). There were no significant disease-driven changes observed in the concentration of Rab3a. Concentrations SNAP25 and neurogranin were increased in cerebrospinal fluid of Parkinson’s disease patients in a disease specific manner and related to cognitive and motor symptom severity. Future longitudinal studies should explore whether cerebrospinal fluid synaptic proteins can predict cognitive decline in Parkinson’s disease.
Highlights
We found that cerebrospinal fluid (CSF) concentrations of SNAP25 and neurogranin are increased in Parkinson’s disease (PD) in a disease stage specific manner, whereas no differences were found for the synaptic vesicle protein Rab3A
The increase in the concentration of postsynaptic neurogranin was associated with reduced cognition and higher motor disease stage in PD; their limited diagnostic and prognostic value places them on hold in the rapidly roaring biomarker field
Other studies have found that α-synuclein levels are increased in later stages of PD, and that increased levels are associated with cognitive decline
Summary
Synaptic dysfunction is an early change in both Alzheimer's disease (AD)[5] and PD6, that is, more robustly correlated with cognitive decline than neuropathological hallmarks in AD.[7,8] Of note, α-synuclein and other synaptic proteins have been shown to be differentially expressed in various neurodegenerative diseases compared to non-demented controls and may have potential as biomarkers.[9,10,11,12] α-synuclein seems to be deeply implicated in the synaptic vesicle trafficking as previous findings reported increased binding of α-synuclein aggregates to the synaptic vesicle protein Rab3A in synucleinopathies, proposing that decreased Rab3A levels are likely to directly affect the reserve synaptic vesicle pool but α-synuclein pathology as well.[13] Accumulating evidences suggest that synaptic dysfunction is predominantly present in mutations of PARK-7, PINK1, as well as in gene mutations of LRRK2.14–17. SNAP25 is known to provide the driving force for vesicle fusion and docking,[23] while the protein Rab3A reflects the recycling pool of synaptic vesicles.[24]
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