Validation of Serum Neurofilament Light Chain as a Biomarker of Parkinson’s Disease Progression

Abstract

Background: Alterations in neurofilament light chain (NfL), reflecting axonal damage, have been proposed as a biomarker for neurological disorders including Parkinson's disease (PD). Methods:We measured NfL concentrations by immunoassay in (1) a set of longitudinal CSF samples from 82 PD, 14 other neurodegenerative disorders (OND), and 53 healthy controls (HC);(2) A cross-sectional cohort with paired CSF and serum samples from subjects with 151 PD, 344 OND, and 20 HC, and (3a) a large longitudinal validation cohort with serum samples from 375 PD, 178 HC, and 57 prodromal Lewy Body disorder with hyposmia or isolated REM sleep behaviour disorder (iRBD), (3b) 216 symptomatic and 298 asymptomatic LRRK2, GBA, and SNCA mutation carriers in the Parkinson's Progression Markers Initiative (PPMI). Mean differences in serum NfL levels between diagnostic groups, and correlation with motor signs, cognitive measures and dopamine transporter imaging, were assessed. Linear mixed effects models were used to assess longitudinal changes in log10 (NfL) in relation to demographic, clinical, and imaging variables. Findings:In the longitudinal cohort (1) NfL in CSF increased over time and was significantly positively correlated with MDS-UPDRS III motor and total scores in the PD group (p=0·0231 and 0·0081). In the cross-sectional cohort (2) the paired CSF and serum NfL samples were highly correlated (Spearman's rank ߩ ො ൌ 0 7 3 ; p<10^-6). In the large validation cohort (3a) mean baseline serum NfL was higher in PD (13 ±7·2pg/ml), hyposmics (15±15·1pg/ml), and iRBD (17±8pg/ml) compared with HC (12±6·7pg/ml) but was highest in the seven OND cases (18±7pg/ml). In the genetic cohort (3b), serum NfL levels were lower in asymptomatic than in symptomatic mutation carriers. There was a significant (age-adjusted) longitudinal increase in serum NfL in PD compared with HC. Serum NfL values were significantly positively associated with longitudinal MDS-UPDRS motor and total scores, as well as age. Interpretation: We identified NfL as the first blood-based PD progression biomarker. NfL levels in serum samples are increased in PD compared to HC, increase significantly over time in PD, and correlate with a clinical measure of disease severity. Although the specificity of NfL in PD is low and additional, more specific biomarkers are needed, serum NfL is the first blood-based biomarker candidate that could support disease stratification (PD vs. OND), track clinical progression, and might be used to assess responsiveness to neuroprotective treatments. M o l l e n h a u e r 5Neurofilaments are highly phosphorylated neuronal cytoskeleton components composed of three subunits of differing molecular weight maintaining neuronal structure and determining axonal calibre. The 68 kDa neurofilament light chain (NfL) is essential for the assembly of the complex as it forms its backbone and is released into extracellular fluids in response to axonal damage. 6,7 Several studies have shown elevated levels of NfL in the CSF of patients suffering from neurodegenerativ...

CLU rs11136000 Promotes Early Cognitive Decline in Parkinson's Disease

“…As expected, PD patients showed motor and cognitive compromise with respect to controls and also had alterations in common biomarkers of neural damage . High‐risk CLU patients showed both a quantitative (lower MoCA scores) and qualitative (higher prevalence of clinically diagnosed PD‐MCI or PDD) cognitive decline at follow‐up.…”

“…16,17 As expected, PD patients showed motor and cognitive compromise with respect to controls and also had alterations in common biomarkers of neural damage. 18,19 High-risk CLU patients showed both a quantitative (lower MoCA scores) and qualitative (higher prevalence of clinically diagnosed PD-MCI or PDD) cognitive decline at follow-up. Further characterization of this cognitive compromise revealed both frontal and posterior-cortical relative deficits with respect to the low-risk CLU group.…”

Utility of plasma Neurofilament light as a diagnostic and prognostic biomarker of the postural instability gait disorder motor subtype in early Parkinson’s disease

“…Out of the neurofilament proteins, neurofilament light (NfL) chain has been recognized as a possible marker of axonal injury in various neurological disorders [1], including multiple sclerosis [2], motor neurone disease [3,4], frontotemporal dementia spectrum disorders [5,6], traumatic brain injury [7], and cerebrovascular disease [8]. In Parkinson's disease (PD), blood NfL has been reported to be higher in cases vs controls [9,10], and shown to be able to distinguish PD from atypical PD (APD) [11,12]. NfL has also been found to associate with longer disease duration, more aggravated motor symptoms [11], and correlate with motor and/or cognitive decline [13] in PD.…”

Plasma Neurofilament Light Chain predicts cognitive progression in prodromal and clinical dementia with Lewy Bodies

“…Neurofilament light chain (NfL), a highly expressed protein in large caliber myelinated axons, has been recently proposed as general marker of neuronal degeneration and damage in different neurological disorders [7,8]. In fact, CSF and plasma NfL levels are significantly altered in Alzheimer’s disease (AD), prion diseases, amyotrophic lateral sclerosis, frontotemporal dementia, whereas findings in Parkinson’s disease (PD) and early DLB were contradictory [9].…”

“…In fact, CSF and plasma NfL levels are significantly altered in Alzheimer’s disease (AD), prion diseases, amyotrophic lateral sclerosis, frontotemporal dementia, whereas findings in Parkinson’s disease (PD) and early DLB were contradictory [9]. In addition to that, it has been reported that plasma and CSF NfL levels correlated with disease severity and progression in PD [8,10,11] and Alzheimer’s disease [12]. Very few studies have focused on DLB patients and, to the best of our knowledge, no prospective longitudinal studies evaluated plasma NfL as potential early diagnostic and prognostic marker in DLB.…”