Greater Cerebrospinal Fluid Protein Levels May Accelerate Progression of Parkinson Disease

Faster motor and cognitive progression of Parkinson disease was found in patients with higher baseline cerebrospinal fluid neurofilament heavy levels.

Higher cerebrospinal fluid (CSF) neurofilament heavy (cNfH) levels were associated with more rapid progression of motor and cognitive symptoms in Parkinson disease (PD), according to study findings published Tuesday in JAMA Network Open.

As major cytoskeletal components of myelinated axons, neurofilaments are released into the extracellular fluid, CSF, and peripheral blood during axonal degeneration, which is an early pathologic process in PD. These neurofilament proteins are heteropolymers composed of a family of 5 intermediate filaments, note researchers, with the largest being NfH, followed by the medium chain (NfM), the light chain (NfL), α-internexin, and peripherin.

“NfL in biofluids has been associated with progression of PD, but the association between NfH and progression of PD has not been investigated,” the study authors said.

They conducted a post hoc cohort study of data derived from the Parkinson Progression Marker Initiative (PPMI) to assess the associations of cNfH levels and motor and cognitive progression in PD. Patient data from 24 PPMI participating sites worldwide (United States, Europe, and Australia) were collected from June 2010 to November 2018, with data analyzed from October 20 to December 18, 2021.

Primary outcomes evaluated were Movement Disorder Society–sponsored revisions of the Unified Parkinson Disease Rating Scale (MDS-UPDRS) Part III (score range, 0 to 132), in which higher scores indicated worse motor function, and the Montreal Cognitive Assessment (MoCA) (score range, 0 to 30), with higher scores representing 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 (Aβ42), phosphorylated tau at threonine 181 position (P-tau), and total tau (T-tau) levels in CSF,” explained researchers.

The study included 404 patients with PD (mean [SD] age, 61.7 [9.7] years; 65.1% male; Hoehn and Yahr stage less than 3) who had been newly diagnosed (within 2 years of diagnosis) and were drug naive, as well as 183 healthy controls. Participants were tracked for a median (SD) follow-up time of 5.26 (1.34) years (range, 0.11-7.99 years).

Among the study cohort, mean (SD) levels of cNfH were shown to be significantly higher in patients with PD compared with the controls (control, 9.2 [0.72] log2 relative fluorescence units [RFU]; PD, 9.3 [0.60] log2 RFU; P = .04).

After controlling for potential confounders, findings of the linear mixed-effect models showed that 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; 95% CI, −0.24 to −0.11; P < .001).

Furthermore, levels of cNfH were positvely correlated with CSF levels of α-synuclein (Spearman r = 0.25; 95% CI, 0.15-0.34; P < .001), Aβ42 (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.

“Our findings suggest that cNfH level measurements might assist clinicians in identifying patients with PD at risk of fast clinical progression,” concluded the study authors. “Further study is warranted to assess the associations of NfH levels in blood and clinical progression in PD.”


Wang L, Zhang W, Liu F, et al. Association of cerebrospinal fluid neurofilament heavy protein levels with clinical progression in  patients with Parkinson disease. JAMA Netw Open. 2022 Jul 1;5(7):e2223821. doi:10.1001/jamanetworkopen.2022.23821