NfL as a biomarker for neurodegeneration and survival in Parkinson disease

Abstract

Objective: To determine whether neurofilament light chain protein in CSF (cNfL), a sensitive biomarker of neuroaxonal damage, reflects disease severity or can predict survival in Parkinson disease (PD).

Methods: We investigated whether disease severity, phenotype, or survival in patients with new-onset PD correlates with cNfL concentrations around the time of diagnosis in the population-based New Parkinsonism in Umeå (NYPUM) study cohort (n = 99). A second, larger new-onset PD cohort (n = 194) was used for independent validation. Association of brain pathology with the cNfL concentration was examined with striatal dopamine transporter imaging and repeated diffusion tensor imaging at baseline and 1 and 3 years.

Results: Higher cNfL in the early phase of PD was associated with greater severity of all cardinal motor symptoms except tremor in both cohorts and with shorter survival and impaired olfaction. cNfL concentrations above the median of 903 ng/L conferred an overall 5.8 times increased hazard of death during follow-up. After adjustment for age and sex, higher cNfL correlated with striatal dopamine transporter uptake deficits and lower fractional anisotropy in diffusion tensor imaging of several axonal tracts.

Conclusions: cNfL shows usefulness as a biomarker of disease severity and to predict survival in PD. The present results indicate that the cNfL concentration reflects the intensity of the neurodegenerative process, which could be important in future clinical trials.

Classification of evidence: This study provides Class II evidence that in patients with PD, cNfL concentrations are associated with more severe disease and shorter survival.

Figure 1. Survival in PD in relation to baseline cNfL concentration

(A) Box plots of baseline neurofilament light chain protein in CSF (cNfL) levels in Parkinson disease (PD). Cumulative survival for patients with a baseline cNfL below the median concentration of 903 ng/L (blue line) compared with those with cNfL above 903 ng/L (red line) in the (B) New Parkinsonism in Umeå (NYPUM) cohort and (C) validation cohort. (D) Cumulative survival in the combined, pooled cohort for patients (n = 293) with baseline cNfL levels in the lowest (<660 ng/L; blue line) and highest (>1,255 ng/L; green line) quartiles and those with concentrations between these levels (red line).

Figure 2. Imaging of impaired diffusion associated with cNfL elevations in PD

Brain diffusion tensor imaging of patients in the New Parkinsonism in Umeå (NYPUM) cohort. Imaging was performed in 45, 20, and 14 patients with Parkinson disease (PD) at baseline (left) and the 1-year (middle) and 3-year (right) follow-ups, respectively. For all contiguous diffusion tensor imaging clusters, the fractional anisotropy value in all individual voxels significantly correlated with the neurofilament light chain protein in CSF (cNfL) level after adjustment for age and sex. A more yellow color denotes a larger cluster.