Neurofilament light levels predict clinical progression and death in multiple system atrophy

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

doi:10.1093/brain/awac253

Neurofilament light levels predict clinical progression and death in multiple system atrophy

Brain. 2022 Dec 19;145(12):4398-4408. doi: 10.1093/brain/awac253.

Authors

Viorica Chelban^{1

2}, Elham Nikram³, Alexandra Perez-Soriano^{4

5

6}, Carlo Wilke^{7

8}, Alexandra Foubert-Samier^{9

10

11

12}, Nirosen Vijiaratnam¹³, Tong Guo¹³, Edwin Jabbari¹³, Simisola Olufodun¹, Mariel Gonzalez¹, Konstantin Senkevich^{14

15

16

17}, Brice Laurens^{9

10}, Patrice Péran¹⁸, Olivier Rascol^{19

20

21}, Anne Pavy Le Traon^{19

22}, Emily G Todd²³, Alyssa A Costantini¹³, Sondos Alikhwan¹, Ambreen Tariq¹, Bai Lin Ng²⁴, Esteban Muñoz^{4

5

6}, Celia Painous^{4

5

6}, Yaroslau Compta^{4

5

6}, Carme Junque^{5

6

25}, Barbara Segura^{5

6

25}, Kristina Zhelcheska¹, Henny Wellington²⁶, Ludger Schöls^{7

8}, Zane Jaunmuktane²⁷, Christopher Kobylecki^{28

29}, Alistair Church³⁰, Michele T M Hu³¹, James B Rowe^{32

33

34}, P Nigel Leigh³⁵, Luke Massey³⁶, David J Burn³⁷, Nicola Pavese³⁸, Tom Foltynie¹³, Sofya Pchelina^{16

17}, Nicholas Wood¹³, Amanda J Heslegrave²⁶, Henrik Zetterberg^{26

38

39

40

41}, Martina Bocchetta²³, Jonathan D Rohrer²³, Maria J Marti^{4

5

6}, Matthis Synofzik^{7

8}, Huw R Morris¹³, Wassilios G Meissner^{9

10

42

43}, Henry Houlden¹

Affiliations

¹ Department of Neuromuscular Diseases, Queen Square Institute of Neurology, University College London, London WC1N 3BG, UK.
² Neurobiology and Medical Genetics Laboratory, "Nicolae Testemitanu" State University of Medicine and Pharmacy, MD 2004 Chisinau, Republic of Moldova.
³ Peninsula Technology Assessment Group (PenTAG), University of Exeter, Exeter EX 2LU, UK.
⁴ Movement Disorders Unit, Neurology Service, Hospital Clínic de Barcelona, Barcelona 08036, Spain.
⁵ Parkinson's Disease and Movement Disorders Unit, Neurology Department, Institute of Biomedical Research August Pi i Sunyer (IDIBAPS), Barcelona 08036, Spain.
⁶ Parkinson's Disease and Movement Disorders Unit, Neurology Department, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Madrid 28029, Spain.
⁷ Division Translational Genomics of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen, 72074 Tübingen, Germany.
⁸ German Center for Neurodegenerative Diseases (DZNE), 72074 Tübingen, Germany.
⁹ CRMR AMS, Service de Neurologie - Maladies Neurodégénératives, CHU de Bordeaux, F-33000 Bordeaux, France.
¹⁰ Université de Bordeaux, CNRS, IMN, UMR 5293, F-33000 Bordeaux, France.
¹¹ Université de Bordeaux, INSERM, BPH, U1219, F-33000 Bordeaux, France.
¹² Inserm, CIC 1401 Bordeaux, Clinical Epidemiology Unit, F-33000 Bordeaux, France.
¹³ Department Clinical and Movement Neuroscience, UCL Queen Square Institute of Neurology, University College London, London WC1N 3BG, UK.
¹⁴ Neurogenomics and Precision Medicine (NAP-Med) Laboratory, The Neuro (Montreal Neurological Institute-Hospital), Montreal, QC H3A 2B4, Canada.
¹⁵ Department of Neurology & Neurosurgery, McGill University, Montreal, QC H3A 2B4, Canada.
¹⁶ Laboratory of Human Genetics, Petersburg Nuclear Physics Institute named by B.P. Konstantinov of National Research Centre 'Kurchatov Institute', Gatchina 188300, Russia.
¹⁷ Laboratory of Medical Genetics, Pavlov First Saint-Petersburg State Medical University, St. Petersburg 197022, Russia.
¹⁸ ToNIC, Toulouse NeuroImaging Center, UMR 1214, Université de Toulouse, 31024 Toulouse, France.
¹⁹ CRMR AMS, CHU de Toulouse, 31300 Toulouse, France.
²⁰ Clinical Investigation Center CIC 1436, NS-Park/F-CRIN Network and NeuroToul COEN Center; Inserm, University of Toulouse 3 and CHU of Toulouse, F-31000 Toulouse, France.
²¹ Departments of Neurosciences and Clinical Pharmacology, CHU Toulouse and University of Toulouse 3, F-31000 Toulouse, France.
²² Institut des Maladies Métaboliques et Cardiovasculaires, Inserm U 1297, Toulouse University, F-31000 Toulouse, France.
²³ Dementia Research Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, WC1N 3BG London, UK.
²⁴ Department of Economics, University College London, London WC1N 3BG, UK.
²⁵ Medical Psychology Unit, Department of Medicine, Institute of Neuroscience, University of Barcelona, 08035 Barcelona, Spain.
²⁶ Biomarkers Factory Laboratory, UK Dementia Research Institute, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK.
²⁷ Queen Square Brain Bank for Neurological Disorders, UCL Queen Square Institute of Neurology, WC1N 3BG London, UK.
²⁸ Department of Neurology, Manchester Academic Health Science Centre, Northern Care Alliance NHS Foundation Trust, Stott Lane, Salford M6 8HD, UK.
²⁹ Division of Neuroscience and Experimental Psychology, School of Biological Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
³⁰ Department of Neurology, Royal Gwent Hospital, Newport NP20 2UB, UK.
³¹ Division of Neurology, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, UK.
³² Department of Clinical Neurosciences, Cambridge University, Cambridge CB3 0SZ, UK.
³³ MRC Cognition and Brain Sciences Unit, University of Cambridge, CB3 0SZ Cambridge, UK.
³⁴ Neurology Department, Cambridge University Hospitals NHS Trust, Cambridge CB2 0QQ, UK.
³⁵ Department of Neuroscience, Brighton and Sussex Medical School, Brighton BN1 9PX, UK.
³⁶ Neurology Department, University Hospitals Dorset, Poole BH15 2JB, UK.
³⁷ Faculty of Medical Sciences, Clinical Ageing Research Unit, Newcastle University, NE4 5PL Newcastle, UK.
³⁸ Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, WC1N 3BG London, UK.
³⁹ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, 405 30 Mölndal, Sweden.
⁴⁰ Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, 405 30 Mölndal, Sweden.
⁴¹ Hong Kong Center for Neurodegenerative Diseases, Clear Water Bay, Hong Kong 1512-1518, China.
⁴² Department of Medicine, University of Otago, Christchurch 8140, New Zealand.
⁴³ New Zealand Brain Research Institute, Christchurch 8011, New Zealand.

Abstract

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.

Keywords: MSA; NfL; multiple system atrophy.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Biomarkers
Cohort Studies
Cross-Sectional Studies
Disease Progression
Humans
Intermediate Filaments
Multiple System Atrophy*
Neurofilament Proteins

Substances

Neurofilament Proteins
Biomarkers

Abstract

Publication types

MeSH terms

Substances

Grants and funding