Association of Cerebrospinal Fluid Neurofilament Heavy Protein Levels With Clinical Progression in Patients With Parkinson Disease

IMPORTANCE: Neurofilament light in biofluids has been associated with progression of Parkinson disease (PD), but the association between neurofilament heavy (NfH) and progression of PD has not been investigated. OBJECTIVE: To evaluate the associations of cerebrospinal fluid (CSF) NfH (cNfH) levels and motor and cognitive progression in PD. DESIGN, SETTING, AND PARTICIPANTS: This cohort study used data from the Parkinson Progression Marker Initiative ranging from June 2010 to November 2018. Participants were recruited from 24 participating sites worldwide (United States, Europe, and Australia). Data were analyzed from October 20 to December 18, 2021. EXPOSURES: Concentrations of NfH in CSF. MAIN OUTCOMES AND MEASURES: The primary outcomes were Movement Disorder Society–sponsored revisions of the Unified Parkinson Disease Rating Scale (MDS-UPDRS) Part III; scores range from 0 to 132, with higher scores indicating worse motor function, and Montreal Cognitive Assessment (MoCA); scores range from 0 to 30, with higher scores indicating better cognitive function. The associations of cNfH levels and longitudinal change in MDS-UPDRS-Part-III and MoCA were examined using linear mixed-effects models with PD duration as the time scale. Partial correlation analysis was conducted to examine the associations of cNfH levels and α-synuclein, amyloid-β 1-42 (Aβ(42)), phosphorylated tau at threonine 181 position (P-tau), and total tau (T-tau) levels in CSF. RESULTS: A total of 404 patients with PD (mean [SD] age, 61.7 [9.7] years; 263 were men [65.1%]; within 2 years of diagnosis; Hoehn and Yahr <3) were included. Higher baseline cNfH levels were associated with greater increases in MDS-UPDRS Part-III (β = 0.39; 95% CI, 0.12-0.66; P = .003) and faster decreases in MoCA (β = −0.18; CI, −0.24 to −0.11; P < .001). Levels of cNfH were correlated with CSF levels of α-synuclein (Spearman r = 0.25; 95% CI, 0.15-0.34; P < .001), Aβ(42) (Spearman r = 0.18; 95% CI, 0.08-0.27; P < .001), P-tau (Spearman r = 0.25; 95% CI, 0.15-0.35; P < .001), and T-tau (Spearman r = 0.31; 95% CI, 0.21-0.40; P < .001) at baseline. CONCLUSIONS AND RELEVANCE: Higher baseline cNfH levels were associated with faster motor and cognitive progression. This finding suggests that cNfH may be of some value for stratifying patients with PD who have different progression rates.