Neurofilament light levels predict clinical progression and death in multiple system atrophy
Authors: Chelban Viorica , Nikram Elham , Perez-Soriano Alexandra , Wilke Carlo , Foubert-Samier Alexandra , Vijiaratnam Nirosen , Guo Tong , Jabbari Edwin , Olufodun Simisola , Gonzalez Mariel , Senkevich Konstantin , Laurens Brice , Péran Patrice , Rascol Olivier , Le Traon Anne Pavy , Todd Emily G , Costantini Alyssa A , Alikhwan Sondos , Tariq Ambreen , Ng Bai Lin , Muñoz Esteban , Painous Celia , Compta Yaroslau , Junque Carme , Segura Barbara , Zhelcheska Kristina , Wellington Henny , Schöls Ludger , Jaunmuktane Zane , Kobylecki Christopher , Church Alistair , Hu Michele T M , Rowe James B , Leigh P Nigel , Massey Luke , Burn David J , Pavese Nicola , Foltynie Tom , Pchelina Sofya , Wood Nicholas , Heslegrave Amanda J , Zetterberg Henrik , Bocchetta Martina , Rohrer Jonathan D , Marti Maria J , Synofzik Matthis , Morris Huw R , Meissner Wassilios G , Houlden Henry 
Published: July 2022

Disease-modifying treatments are currently being trialled in multiple system atrophy. Approaches based solely on clinical measures are challenged by heterogeneity of phenotype and pathogenic complexity. Neurofilament light chain protein has been explored as a reliable biomarker in several neurodegenerative disorders but data on multiple system atrophy have been limited. Therefore, neurofilament light chain is not yet routinely used as an outcome measure in multiple system atrophy. We aimed to comprehensively investigate the role and dynamics of neurofilament light chain in multiple system atrophy combined with cross-sectional and longitudinal clinical and imaging scales and for subject trial selection.

In this cohort study, we recruited cross-sectional and longitudinal cases in a multicentre European set-up. Plasma and CSF neurofilament light chain concentrations were measured at baseline from 212 multiple system atrophy cases, annually for a mean period of 2 years in 44 multiple system atrophy patients in conjunction with clinical, neuropsychological and MRI brain assessments. Baseline neurofilament light chain characteristics were compared between groups. Cox regression was used to assess survival; receiver operating characteristic analysis to assess the ability of neurofilament light chain to distinguish between multiple system atrophy patients and healthy controls. Multivariate linear mixed-effects models were used to analyse longitudinal neurofilament light chain changes and correlated with clinical and imaging parameters. Polynomial models were used to determine the differential trajectories of neurofilament light chain in multiple system atrophy. We estimated sample sizes for trials aiming to decrease neurofilament light chain levels.

We show that in multiple system atrophy, baseline plasma neurofilament light chain levels were better predictors of clinical progression, survival and degree of brain atrophy than the neurofilament light chain rate of change. Comparative analysis of multiple system atrophy progression over the course of disease, using plasma neurofilament light chain and clinical rating scales, indicated that neurofilament light chain levels rise as the motor symptoms progress, followed by deceleration in advanced stages. Sample size prediction suggested that significantly lower trial participant numbers would be needed to demonstrate treatment effects when incorporating plasma neurofilament light chain values into multiple system atrophy clinical trials in comparison to clinical measures alone.

In conclusion, neurofilament light chain correlates with clinical disease severity, progression and prognosis in multiple system atrophy. Combined with clinical and imaging analysis, neurofilament light chain can inform patient stratification and serve as a reliable biomarker of treatment response in future multiple system atrophy trials of putative disease-modifying agents.