Serum Neurofilament Light Chain as a Marker of Progression in Parkinson's Disease: Long-Term Observation and Implications of Clinical Subtypes

Abstract

Background: Biochemical and clinical biomarkers correlate with progression rate and disease severity in Parkinson's disease (PD) but are not sufficiently studied in late PD.

Objective: To examine how serum neurofilament light chain (S-NfL) alone or combined with clinical classifications predicts PD outcome in later disease stages.

Methods: Eighty-five patients with 7.9±5.1 years of PD duration were included in an observational cohort. Clinical scores were obtained at two separate examinations 8.2±2.0 years apart. S-NfL levels were determined with single molecule array (SiMoA). Five predefined disease progression milestones were assessed. After affirming combination potential of S-NfL and either of two clinical classifications, three combined models were constructed based on these factors and age at onset in different combinations.

Results: S-NfL levels showed significant hazard ratios for four out of five disease progression milestones: walking-aid usage (HR 3.5; 95% CI 1.4-8.5), nursing home living (5.1; 2.1-12.5), motor end-stage (6.2; 2.1-17.8), and death (4.1; 1.7-9.7). Higher S-NfL levels were associated with lower ability in activities of daily living and poorer cognition at baseline and/or at follow-up. Combined models showed significantly improved area under receiver operating characteristic curves (0.77-0.91) compared to S-NfL levels alone (0.68-0.71) for predicting the five disease milestones.

Conclusion: S-NfL levels stratified patients according to their likelihood to reach clinically relevant progression milestones during this long-term observational study. S-NfL alone reflected motor and social outcomes in later stages of PD. Combining S-NfL with clinical factors was possible and exploratory combined models improved prognostic accuracy.

Keywords: Parkinson’s disease; biomarkers; dementia; mortality; neurofilament proteins; prognosis.

Fig. 1

Flow chart. Flow chart of patient inclusion and exclusion into the study at baseline and re-examination. Number of blood samples readily analyzed for serum neurofilament light chain levels in parenthesis. Adapted from [24].

Fig. 2

Survival curves for studied milestones of disease progression. Survival curves of Kaplan-Meier estimates for individuals below or above cohort median of serum neurofilament light chain levels. Graphs show time from the baseline examination to: A) walking-aid usage, B) nursing-home residency, C) Hoehn and Yahr stage 5, D) dementia development, E) death. Log rank test results in the lower left part of the corresponding graph. Number of individuals remaining to be observed at each 2-year step showed below each graph. S-NfL, serum neurofilament light chain.

Fig. 3

ROC-curves for S-NfL. Receiver operator characteristics (ROC) curves for having reached the five different milestones of disease progression at any point during the study period. A) walking-aid usage, B) nursing-home residency, C) Hoehn and Yahr stage 5, D) dementia development, E) death. S-NfL, serum neurofilament light chain levels (pg/ml); S-NfL + AaO, combined model based on tertiles of age at onset and S-NfL levels; S-NfL + SCS + AaO combined model based on simplified clinical subtype combined with tertiles of age at onset and S-NfL levels; S-NfL + PIGD score + AaO, combined model based on tertiles of postural instability and gait disorder score, age at onset and S-NfL levels.