Increased Disability Progression in rs10191329AA Carriers with Multiple Sclerosis Is Preceded by Neurofilament Light Chain Elevations.

IF 8.1 1区 医学 Q1 CLINICAL NEUROLOGY
Maria Protopapa, Falk Steffen, Muriel Schraad, Tobias Ruck, Menekse Öztürk, Nicholas Hanuscheck, Josef Shin, Tobias Brummer, Katrin Pape, Timo Uphaus, Sven G Meuth, Vinzenz Fleischer, Charlotte E Teunissen, Philip L De Jager, Felix Luessi, Stefan Bittner, Frauke Zipp
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Abstract

Objective: We examined the impact of the rs10191329 genetic risk variant on neuroaxonal damage as measured by serum neurofilament light chain (sNfL) levels, and disability progression in people with multiple sclerosis (pwMS).

Methods: In a cohort of pwMS (n = 740), 658 participants were prospectively monitored every 2 years for less than a decade while 82 of 740 pwMS were monitored retrospectively for up to 40 years. We investigated associations between rs10191329 variants and clinical outcome, including Expanded Disability Status Scale (EDSS), disability accrual (defined by EDSS-increase of at least 1.5 for patients starting at EDSS 0, at least 1.0 EDSS-points for patients with an initial EDSS between 1 and 4.5 and at least 0.5 points for patients starting with an EDSS equal or greater than 5) and progression to secondary progressive MS (SPMS). Clinical outcomes were analyzed using Kaplan-Meier and Cox proportional hazards analyses. Disability accumulation over time was depicted using a generalized mixed-effect model. Single-molecule array was used to assess sNfL levels.

Results: Homozygous, heterozygous, and non-carriers of the rs10191329 risk variant displayed comparable sNfL levels indicating similar neuroaxonal damage at the time of diagnosis. Importantly, in homozygous carriers we found highest sNfL levels in follow-up visits preceding elevated disease progression later in the disease course, a steeper increase in overall disability measures and higher probability of SPMS development.

Interpretation: These findings highlight how genetic variants may serve as new biomarkers for disease progression and can be used for personalized medicine and risk assessment in MS. ANN NEUROL 2024.

多发性硬化症 rs10191329AA 携带者的残疾进展先于神经丝蛋白轻链升高。
研究目的我们研究了rs10191329基因风险变异对多发性硬化症患者(pwMS)神经轴索损伤(以血清神经丝蛋白轻链(sNfL)水平衡量)和残疾进展的影响:在一个多发性硬化症患者队列(n = 740)中,658 名参与者每两年接受一次前瞻性监测,监测时间不到十年,而 740 名多发性硬化症患者中有 82 名接受了长达 40 年的回顾性监测。我们研究了rs10191329变异与临床结果之间的关系,包括扩展残疾状况量表(EDSS)、残疾累积(定义为起始EDSS为0的患者EDSS至少增加1.5分,起始EDSS在1到4.5之间的患者EDSS至少增加1.0分,起始EDSS等于或大于5的患者EDSS至少增加0.5分)和进展为继发性进展性多发性硬化症(SPMS)。临床结果采用 Kaplan-Meier 和 Cox 比例危险度分析法进行分析。采用广义混合效应模型对残疾随时间的累积进行描述。单分子阵列用于评估sNfL水平:结果:rs10191329风险变异的同卵、杂合子和非携带者显示出相似的sNfL水平,表明诊断时神经轴损害相似。重要的是,在同卵携带者中,我们发现随访中的 sNfL 水平最高,而在疾病后期,疾病进展加剧,总体残疾程度陡增,SPMS 的发病概率也更高:这些发现凸显了基因变异可作为疾病进展的新生物标志物,并可用于多发性硬化症的个性化医疗和风险评估。ann neurol 2024.
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来源期刊
Annals of Neurology
Annals of Neurology 医学-临床神经学
CiteScore
18.00
自引率
1.80%
发文量
270
审稿时长
3-8 weeks
期刊介绍: Annals of Neurology publishes original articles with potential for high impact in understanding the pathogenesis, clinical and laboratory features, diagnosis, treatment, outcomes and science underlying diseases of the human nervous system. Articles should ideally be of broad interest to the academic neurological community rather than solely to subspecialists in a particular field. Studies involving experimental model system, including those in cell and organ cultures and animals, of direct translational relevance to the understanding of neurological disease are also encouraged.
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