Can Blood Biomarkers Be Predictive of Cognitive Decline in Parkinson's Disease? An Exploratory Study.

Parkinson's Disease (PD) is a multifaceted neurodegenerative pathology that shows heterogeneity in its phenotypic manifestation across patients, spanning from strictly motor to cognitive symptoms of various type. This research project aims to explore the role of blood biomarkers, which are mainly proteins detectable in the human body, in the clinical understanding and management of PD, to help diagnosis, prognosis and treatment practices. Neurofilament light chain protein (NfL) is a biomarker of neurodegeneration, and high values may predict later development of mild cognitive impairment (MCI) or dementia even in subjects with baseline normal cognitive (NC) status. The combined role of glial fibrillary acidic protein (GFAP) and phosphorylated tau at residue 181 (pTau181) measures in Parkinson’s disease (PD) is not fully explored. We measured serum NfL, GFAP and pTau181 in PD patients with and without cognitive deficits with the objective to detect those who may be at risk of worse cognitive and motor progression. The biomarkers were measured in 92 PD patients as well as in 20 age, education and sex-matched healthy controls (HC). A subgroup of PD patients (n=65) underwent a comprehensive neuropsychological assessment, 44 were classified as PD-NC and 21 as PD-MCI. NfL, GFAP and pTau181 concentrations were measured using the commercially available SiMoa kits. Normality distribution assumption was tested with Shapiro-Wilk tests, the Spearman’s correlations and non-parametric ANOVA model (Kruskal-Wallis) were run for between group comparisons. Results showed that each serum NfL, GFAP and pTau181 values were more elevated in PD overall compared to HC. NfL levels positively correlated with PD disease duration (r2=0.29, p=0.011), while NfL and GFAP negatively correlated with MoCA (r2=–0.30, p=0.010 and r2=–0.27, p=0.026, respectively). Further analyses, focused on PD-subgroups, highlighted that NfL and GFAP levels were higher in PD-MCI compared to PD-NC (p=0.005 and p=0.025, respectively), while there was no difference in the pTau181. In addition, NfL concentration negatively correlated with the attentive domain (compound z score) (r2=–0.38, pFDR=0.040), but not with other cognitive domains. Our findings support the hypothesis that neurodegeneration biomarkers are higher in PD vs. HC. Serum NfL and GFAP have a potential value for distinguishing PD patients with MCI, and higher NfL levels were associated with worse performance in the attentive domain. These results indicate these biomarkers may help detecting PD at greater risk of cognitive and motor deterioration. The role of pTau181 in PD and its relationship with cognition needs further elucidation.