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

Abstract

Background: The main motor subtypes of Parkinson's disease (PD) include tremor-dominant (TD) and postural instability gait disorder (PIGD), with varying disease course that warrant the development of biomarkers capable of predicting progression according to motor subtype. The PIGD subtype is associated with a poorer prognosis, hence identification of a biomarker associated with PIGD is clinically relevant. Neurofilament light (NfL) chain is a potential biomarker of disease severity in neurological disorders including PD. However, no study has investigated NfL and PD motor subtypes. Here, we aimed to investigate the diagnostic and prognostic utility of plasma NfL for PD motor subtypes in early Parkinson's disease. Given the higher risk for cognitive and motor decline in PIGD, we hypothesized that plasma NfL is a potential biomarker for PIGD.

Methods: Plasma NfL was measured in 199 participants (149 PD and 50 healthy controls, HC) using an ultrasensitive single molecule array. Patients were classified into TD or PIGD based on MDS-UPDRS components. After 2 years, 115 patients were reassessed. Association between NfL and clinical measures in PIGD and TD at baseline and at 2-year follow-up were analysed.

Results: At baseline, plasma NfL levels were higher in PD than HC (8.8 ± 3.4 vs 16.2 ± 7.6 pg/ml, p < 0.0001), and differentiated PD from HC with a good diagnostic accuracy (AUC = 0.833, p < 0.001). At 2 years, NfL was higher in PIGD than TD (18.4 ± 14.5 vs 12.6 ± 4.4 pg/ml, p = 0.039). Within the PIGD group, higher NfL associated significantly with worse global cognition and UPDRS motor scores at baseline, and was able to predict motor and cognitive decline at a mean follow-up duration of 1.9 years, controlled for age, sex and disease duration.

Conclusions: In this longitudinal study, we demonstrated for the first time the potential utility of plasma NfL as a diagnostic and prognostic biomarker in PIGD even at early stages of PD. These important novel findings will require further confirmation in larger, longitudinal PD cohorts.

Keywords: Biomarkers; Cognition; Motor subtype; Neurofilament light chain; PIGD; Parkinson’s disease.

Fig. 1

Plasma NfL in healthy controls and patients with Parkinson’s disease. a At baseline, plasma NfL was significantly increased in PD compared to HC, adjusting for age and sex; b but not between TD and PIGD, adjusting for age, sex and disease duration. c At year 2, plasma NfL was significantly increased in PIGD compared to TD, adjusting for age, sex and disease duration. Abbreviations: BL, Baseline; PD, Parkinson’s Disease; HC, Healthy Control; NfL, Neurofilament light chain protein; TD, Tremor-Dominant; PIGD, Postural Instability Gait Disorder; Y2, Year 2

Fig. 2

Baseline plasma NfL discriminates PD from healthy controls. a Receiver operating characteristic curve analysis in PD vs HC b Contour plot showing predicted probability of clinical diagnosis of PD at different NfL levels and age group. The darker shade of red indicates higher risk and darker blue indicates lower risk of PD. The solid line depicts the risk of PD using multivariable logistic regression model adjusted NfL x age interaction term. Abbreviations: PD, Parkinson’s Disease; HC, Healthy Control; NfL, Neurofilament light chain protein