Plasma alpha-synuclein predicts cognitive impairment in Parkinson's disease: a systematic review and meta-analysis

Alpha-synuclein (ɑ-syn) plays a key role in Parkinson's disease (PD) pathogenesis, but existing studies have found mixed results regarding the associations between plasma ɑ-syn and the development of cognitive impairment. We aim to clarify the potentially important relationship between ɑ-syn level in plasma and development of cognitive impairment in PD through systematic review and meta-analysis.

A systematic search was conducted in the PubMed, Embase and Web of Science databases for studies reporting plasma ɑ-syn concentrations and cognitive impairment in PD. Effect directions were plotted to investigate methodological factors, and a meta-analysis was performed comparing PD patients with dementia (PDD) to PD patients with normal cognition (PDNC).

Twenty-five studies were identified for the systematic review, involving 1,888 PD patients. Studies using the clinical diagnostic Movement Disorder Society (MDS) criteria for PD with mild cognitive impairment and PDD found consistently positive associations with plasma ɑ-syn level. This was further supported by a meta-analysis which found a significant standardised mean difference (g = 1.770, 95% CI: 0.749-2.790, p < 0.001) between PDD and PDNC patients in 10 studies. Furthermore, studies using emerging immunomagnetic reduction or single-molecule array techniques to quantify ɑ-syn reported strong positive associations. In contrast, studies using enzyme-linked immunoassay and cognitive screening tests alone found mixed results.

There is an overall positive effect between plasma ɑ-syn levels and cognitive impairment in PD. As methodological factors can significantly affect associations, future studies should carefully select ɑ-syn immunoassays and utilise the MDS diagnostic criteria for cognitive impairment in PD.