Cerebrospinal Fluid Neurofilament Dynamic Profiles Predict Cognitive Progression in Individuals with Parkinson's Disease

Background: Neurofilament light chain protein (NfL) in cerebrospinal fluid (CSF) reflects the severity of neurodegeneration, with its altered concentrations discovered in Parkinson's disease (PD) and Parkinson's disease dementia (PD-D).

Objective: To determine whether CSF NfL, a promising biomarker of neuronal/axonal damage, can be used to monitor cognitive progression in Parkinson's disease and predict future cognitive decline.

Methods: A total of 259 people were recruited in this study, including 85 healthy controls (HC) and 174 neonatal PD patients from the Parkinson's Progression Markers Initiative (PPMI). Multiple linear regression and linear mixed effects models were used to examine the associations of baseline/longitudinal CSF NfL with cognitive decline and other CSF biomarkers. Kaplan-Meier analysis and log-rank test were used to compare the cumulative probability risk of cognition progression during the follow-up. Multivariate cox regression was used to detect cognitive progression in PD.

Results: We found PD patients with mild cognitive impairment (PD-MCI) was higher than with normal cognition (PD-NC) in terms of CSF NfL baseline levels ( = 0.003) and longitudinal increase rate ( = 0.034). Both baseline CSF NfL and its rate of change predicted measurable cognitive decline in PD (MoCA,  = -0.010,  = 0.011;  = -0.0002,  < 0.001, respectively). The predictive effects in PD patients aged >65, male, ill-educated (<13 years) and without carrying Apolipoprotein E () seemed to be more obvious and reflected in more domains investigated. We also observed that CSF NfL levels predicted progression in PD patients with different cognitive diagnosis and amyloid status. After an average follow-up of 6.66 ± 2.54 years, higher concentration above the median of baseline CSF NfL was associated with a future high risk of PD with dementia (adjusted HR 2.82, 95% CI: 1.11-7.20,  = 0.030).

Conclusion: Our results indicated that CSF NfL is a promising prognostic predictor of PD, and its concentration and dynamics can monitor the severity and progression of cognitive decline in PD patients.