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

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Neurofilament light levels predict clinical progression and death in multiple system atrophy
Brain ( IF 10.6 ) Pub Date : 2022-07-29 , DOI: 10.1093/brain/awac253
Viorica Chelban _{1,

2} , Elham Nikram ₃ , Alexandra Perez-Soriano _{4,

5,

6} , Carlo Wilke _{7,

8} , Alexandra Foubert-Samier _{9,

10,

11,

12} , Nirosen Vijiaratnam ₁₃ , Tong Guo ₁₃ , Edwin Jabbari ₁₃ , Simisola Olufodun ₁ , Mariel Gonzalez ₁ , Konstantin Senkevich _{14,

15,

16,

17} , Brice Laurens _{9,

10} , Patrice Péran ₁₈ , Olivier Rascol _{19,

20,

21} , Anne Pavy Le Traon _{19,

22} , Emily G Todd ₂₃ , Alyssa A Costantini ₁₃ , Sondos Alikhwan ₁ , Ambreen Tariq ₁ , Bai Lin Ng ₂₄ , 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 Zhelcheska ₁ , Henny Wellington ₂₆ , Ludger Schöls _{7,

8} , Zane Jaunmuktane ₂₇ , Christopher Kobylecki _{28,

29} , Alistair Church ₃₀ , Michele T M Hu ₃₁ , James B Rowe _{32,

33,

34} , P Nigel Leigh ₃₅ , Luke Massey ₃₆ , David J Burn ₃₇ , Nicola Pavese ₃₈ , Tom Foltynie ₁₃ , Sofya Pchelina _{16,

17} , Nicholas Wood ₁₃ , Amanda J Heslegrave ₂₆ , Henrik Zetterberg _{26,

38,

39,

40,

41} , Martina Bocchetta ₂₃ , Jonathan D Rohrer ₂₃ , Maria J Marti _{4,

5,

6} , Matthis Synofzik _{7,

8} , Huw R Morris ₁₃ , Wassilios G Meissner _{9,

10,

42,

43} , Henry Houlden ₁

Affiliation

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

Disease-modifying treatments are currently being trialed in multiple system atrophy (MSA). 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 in multiple system atrophy have been limited. Therefore, neurofilament light chain is not yet routinely used as an outcome measure in MSA. 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 multicentre European set-up. Plasma and cerebrospinal fluid 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; ROC 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 NfL 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 NfL 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.

中文翻译：

神经丝光水平预测多系统萎缩的临床进展和死亡

目前正在多系统萎缩症 (MSA) 中试用疾病改善疗法。仅基于临床措施的方法受到表型异质性和致病复杂性的挑战。神经丝轻链蛋白已被探索为多种神经退行性疾病的可靠生物标志物，但多系统萎缩的数据有限。因此，神经丝轻链尚未常规用作 MSA 的结果测量。我们的目的是综合研究神经丝轻链在多系统萎缩中的作用和动力学，结合横断面和纵向临床和影像学量表，并用于受试者试验选择。在这项队列研究中，我们在多中心欧洲机构中招募了横断面和纵向病例。结合临床、神经心理学和 MRI 大脑评估，对 212 名多系统萎缩患者的血浆和脑脊液神经丝轻链浓度进行了基线测量，平均每年对 44 名多系统萎缩患者进行为期 2 年的测量。比较各组的基线神经丝轻链特征。Cox回归用于评估生存；ROC 分析评估神经丝轻链区分多系统萎缩患者和健康对照的能力。多元线性混合效应模型用于分析纵向神经丝轻链变化并与临床和成像参数相关联。多项式模型用于确定多系统萎缩中神经丝轻链的差异轨迹。我们估计了旨在降低 NfL 水平的试验的样本量。我们表明，在多系统萎缩中，基线血浆神经丝轻链水平比 NfL 变化率更能预测临床进展、生存和脑萎缩程度。使用血浆神经丝轻链和临床评定量表对病程中多系统萎缩进展的比较分析表明，神经丝轻链水平随着运动症状的进展而升高，随后在晚期阶段减速。样本量预测表明，与单独的临床措施相比，将血浆神经丝轻链值纳入多系统萎缩临床试验时，需要显着减少试验参与者数量来证明治疗效果。综上所述，神经丝轻链与多系统萎缩的临床疾病严重程度、进展和预后相关。结合临床和影像学分析，神经丝轻链可以为患者分层提供信息，并在未来推定的疾病改善剂的多系统萎缩试验中作为治疗反应的可靠生物标志物。

更新日期：2022-07-29

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