Objective: To analyze the contribution of serum NfL and p-tau181 levels to cognitive impairment and mild cognitive impairment (PD-MCI) in non-demented PD patients.

Background: Autopsy studies of Parkinson’s disease (PD) patients with cognitive impairment have disclosed a combination of pathological markers with synergistic effects on neuronal degeneration. Inclusions of alpha-synuclein, hyperphosphorylated Tau and amyloid pathology are present in the brains of PD patients with dementia, but their relative contribution on cognitive impairment in non-demented PD patients is less clear.
Neurofilament light chain (NfL) blood levels are an accepted marker of neuroaxonal damage shown to act as a non-specific marker of progressive neurodegeneration severity and progression¹. Plasma levels of phospho-tau181 (p-tau181) increase with Alzheimer’s disease clinical severity and are associated with tau- and amyloid-positron emission tomography².

Method: Cross-sectional study of 110 non-demented PD patients (41 PD-MCI, 69 PD-NC), and 37 HC. Plasma NfL and p-tau181 were measured on the Simoa Human NF-light Advantage kit and the Simoa HD-X instrument (Quanterix, Billerica, MA, USA) using the Single Molecule Array technology, following previously published protocols. Global cognitive function was measured using the Parkinson’s Disease–Cognitive Rating Scale (PD-CRS), and diagnosis of PD-MCI was based on a total PD-CRS score ≤83. Partial correlations included age, education and disease duration as covariates.

Results: Serum NfL (p = 0.004) and p-tau181 (p = 0.003) levels were significantly increased in PD patients compared with HC. However, in the comparison between PD-MCI and PD-NC patients only serum NfL showed significantly higher levels in the PD-MCI group (19.9 ± 7 vs. 14.1 ± 5; p <0.04), while p-tau181 levels did not differentiate both groups (1.2 ± 0.6 vs.1.6 ± 0.7; p <0.06).
Higher NfL levels correlated significantly with measures of global cognitive function (PD-CRS; r=-0.39, p=0.002) and visuospatial abilities (JLOT; r=-0.28, p=0.03). Phospo-tau181 levels did not correlate with total PD-CRS scores (r=-0.21, p=0.09).

Conclusion: The dissociable contribution of NfL and p-tau181 levels to cognitive impairment in non-demented PD patients suggests that alpha-synuclein deposition has a more important role than amyloid and Tau pathology in the development of cognitive dysfunction at pre-dementia stages.

References: 1. Cedarbaum, S. J. Hutten, C. Trenkwalder and D. Graham. Validation of Serum Neurofilament Light Chain as a Biomarker of Parkinson’s Disease Progression. Mov Disord. 2020; 35: 1999-2008. 2. Mielke, M. M. et al. Plasma phospho-tau181 increases with Alzheimer’s disease clinical severity and is associated with tau- and amyloid-positron emission tomography. Alzheimers Dement. 2018; 14: 989–997.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/dissociable-contribution-of-serum-nfl-and-p-tau181-to-cognitive-impairment-and-mild-cognitive-impairment-in-parkinsons-disease/