Neurofilament light levels predict clinical progression and death in multiple system atrophy-Reference-Cited by-同舟云学术

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

Published:2022-07-29 Issue:12 Volume:145 Page:4398-4408
ISSN:0006-8950
Container-title:Brain
language:en
Short-container-title:

Author:

Chelban Viorica¹²^ORCID,Nikram Elham³,Perez-Soriano Alexandra⁴⁵⁶,Wilke Carlo⁷⁸^ORCID,Foubert-Samier Alexandra⁹¹⁰¹¹¹²,Vijiaratnam Nirosen¹³^ORCID,Guo Tong¹³,Jabbari Edwin¹³^ORCID,Olufodun Simisola¹,Gonzalez Mariel¹,Senkevich Konstantin¹⁴¹⁵¹⁶¹⁷,Laurens Brice⁹¹⁰,Péran Patrice¹⁸^ORCID,Rascol Olivier¹⁹²⁰²¹,Le Traon Anne Pavy¹⁹²²,Todd Emily G²³^ORCID,Costantini Alyssa A¹³,Alikhwan Sondos¹,Tariq Ambreen¹,Ng Bai Lin²⁴,Muñoz Esteban⁴⁵⁶,Painous Celia⁴⁵⁶,Compta Yaroslau⁴⁵⁶,Junque Carme⁵⁶²⁵,Segura Barbara⁵⁶²⁵,Zhelcheska Kristina¹,Wellington Henny²⁶,Schöls Ludger⁷⁸,Jaunmuktane Zane²⁷,Kobylecki Christopher²⁸²⁹,Church Alistair³⁰,Hu Michele T M³¹,Rowe James B³²³³³⁴,Leigh P Nigel³⁵,Massey Luke³⁶,Burn David J³⁷,Pavese Nicola³⁸^ORCID,Foltynie Tom¹³^ORCID,Pchelina Sofya¹⁶¹⁷,Wood Nicholas¹³,Heslegrave Amanda J²⁶,Zetterberg Henrik²⁶³⁸³⁹⁴⁰⁴¹,Bocchetta Martina²³^ORCID,Rohrer Jonathan D²³,Marti Maria J⁴⁵⁶,Synofzik Matthis⁷⁸^ORCID,Morris Huw R¹³^ORCID,Meissner Wassilios G⁹¹⁰⁴²⁴³,Houlden Henry¹^ORCID

Affiliation:

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

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.

Funder

MSA Coalition

Medical Research Council

Wellcome Trust equipment and strategic awards

French Clinical Research Programme

PSP Association

Horizon 2020 research and innovation programme

Publisher

Oxford University Press (OUP)

Subject

Neurology (clinical)

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