Objective: The aim was to investigate the role of both well-established and novel protein biomarkers of cognitive impairment in Parkinson’s disease (PD) and multiple system atrophy (MSA) using the NULISA immunoassay platform in blood and cerebrospinal fluid (CSF).

Background: Cognitive impairment is a common non-motor manifestation of alpha synucleinopathies, and can severely affect quality of life. Establishing biomarkers for its early detection has important clinical implications, as well as facilitating targeted recruitment for disease-modifying trials.

Method: We analysed data from the Exenatide PD3 and Exenatide MSA trials (ClinicalTrials.gov: NCT04232969 & NCT04431713). Plasma and CSF samples were taken at baseline and 2-years for PD participants. Serum and CSF samples were taken at baseline and 1-year for MSA participants. Based on previous literature, the following proteins were studied: apolipoprotein E, phosphorylated tau (pTau) at amino acids 181, 217 and 231, neurofilament light chain (NfL), amyloid-β isoforms Aβ40 and Aβ42, and neurogranin. We also explored the Aβ42/Aβ40 and Aβ42/neurogranin ratios. Cognition was measured using the Montreal Cognitive Assessment (MoCA) and all participants were considered cognitively normal at baseline.

Results: We studied 161 participants with PD and 43 participants with MSA who had longitudinal data. Blood samples were available from all participants, while CSF samples were available in 51 PD cases and 23 MSA cases. In the MSA cohort, there were no significant associations between: (1) the change in MoCA score after 1-year and the quantified levels of each protein or ratio at baseline; and (2) the change in MoCA score and the change in levels of each protein or ratio after 1-year in either serum or CSF. In the PD cohort however, univariate linear regression models revealed a significant negative association between the change in MoCA scores after 2-years and baseline pTau-217 (p = 0.022) and NfL (p = 0.048) plasma levels.  Age, gender and disease duration were not significant predictors of cognitive change in PD. There was no significant relationship between CSF pTau-217 (nor in any of the other proteins) and subsequent cognitive decline.

Conclusion: Plasma pTau-217 is a potential non-invasive biomarker of Alzheimer’s disease co-pathology, and levels may predict future cognitive decline in PD. Further study with larger cohorts and a longer follow-up period is needed.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/blood-and-csf-biomarkers-of-cognitive-impairment-in-alpha-synucleinopathies/