Progression of biological markers in spinocerebellar ataxia type 3: longitudinal analysis of prospective data from the ESMI cohort

IF 13.6 Q1 HEALTH CARE SCIENCES & SERVICES

Lancet Regional Health-Europe Pub Date : 2025-07-03 DOI:10.1016/j.lanepe.2025.101339

Moritz Berger , Hector Garcia-Moreno , Mónica Ferreira , Jeannette Hubener-Schmid , Tamara Schaprian , Philipp Wegner , Tim Elter , Kennet M. Teichmann , Magda M. Santana , Marcus Grobe-Einsler , Demet Oender , Berkan S.C. Koyak , Sarah Bernsen , Luís Pereira de Almeida , Patrick Silva , Joana Afonso Ribeiro , Inês Cunha , Cristina Gonzalez-Robles , Shamsher Khan , Amanda Heslegrave , Jennifer Faber

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Abstract

Background

Spinocerebellar ataxia type 3 (SCA3) is an autosomal dominantly inherited adult-onset disease. We aimed to describe longitudinal changes in clinical and biological findings and to identify predictors for clinical progression.

Methods

We used data from participants enrolled in the ESMI cohort collected between Nov 09, 2016 and July 18, 2023. The data freeze included data from 14 sites in five European countries and the United States. We assessed ataxia with the Scale for the Assessment and Rating of Ataxia (SARA). We measured disease-specific mutant ataxin-3 protein (ATXN3) and neurofilament light chain (NfL) in plasma and performed MRIs. Data were analysed by regression modelling on a timescale defined by onset. The onset of abnormality of a marker was defined as the time at which its value, as determined by modelling, exceeded the mean ± 2 SD of healthy controls. To study responsiveness of markers, we determined the sensitivity to change ratios (SCSs).

Findings

Data from 291 SCA3 mutation carriers before and after clinical onset and 121 healthy controls were included. NfL levels became abnormal in SCA3 mutation carriers more than 20 years (−21.5 years [95% CI n.d.–9.5]) before onset. The earliest MRI abnormality was volume loss of medulla oblongata (−4.7 years [95% CI n.d.–3.3]). The responsiveness of markers depended on the disease stage. Across all stages, pons volume had the highest responsiveness with an SCS of 1.35 [95% CI 1.11–1.78] exceeding that of SARA (0.99 [95% CI 0.88–1.11]). In SCA3, lower age (p = 0.0459 [95% CI of slope change −0.0018 to 0.0000]) and lower medulla oblongata volume (p < 0.0001 [95% CI of slope change −0.0298 to −0.0115]) were predictors of SARA progression.

Interpretation

Our study provides quantitative information on the progression of biological markers in SCA3 mutation carriers before and after onset of ataxia, and allowed the identification of predictors for clinical progression. Our data could prove useful for the design of future clinical trials.

Funding

HEU Joint Programme – Neurodegenerative Disease Research (JPND) (Federal Ministry of Education and Research, Germany; The Netherlands Organisation for Health Research and Development; Foundation for Science and Technology, Portugal; Medical Research Council, Regional Fund for Science and Technology, Azores), and Servier. At the US sites this work was in part supported by the National Ataxia Foundation and the National Institute of Neurological Disorders and Stroke (NINDS) grant R01NS080816.

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脊髓小脑性共济失调3型生物标志物的进展：ESMI队列前瞻性数据的纵向分析

背景脊髓小脑性共济失调3型（SCA3）是一种常染色体显性遗传的成人发病疾病。我们的目的是描述临床和生物学发现的纵向变化，并确定临床进展的预测因素。方法：我们使用了2016年11月9日至2023年7月18日ESMI队列参与者的数据。数据冻结包括来自五个欧洲国家和美国的14个站点的数据。我们用共济失调评定量表（SARA）来评估共济失调。我们测量了血浆中疾病特异性突变ataxin-3蛋白（ATXN3）和神经丝轻链（NfL），并进行了mri。通过回归模型对发病定义的时间尺度进行数据分析。标记物异常的开始被定义为通过建模确定其值超过健康对照的平均值±2 SD的时间。为了研究标记物的反应性，我们测定了对变化比率的敏感性（sensitivity To change ratio, scs）。研究结果包括291名SCA3突变携带者临床发病前后和121名健康对照者的数据。在SCA3突变携带者发病前20多年（- 21.5年[95% CI n.d.-9.5]）， NfL水平出现异常。最早的MRI异常为延髓体积损失（- 4.7年[95% CI n.d.-3.3]）。标志物的反应性取决于疾病分期。在所有分期中，脑桥体积的反应性最高，SCS为1.35 [95% CI 1.11-1.78]，超过SARA （0.99 [95% CI 0.88-1.11]）。SCA3患者年龄较低（p = 0.0459[斜率变化的95% CI为- 0.0018 ~ 0.0000]），延髓体积较低(p <；0.0001[斜率变化的95% CI为- 0.0298 ~ - 0.0115])是SARA进展的预测因子。我们的研究提供了SCA3突变携带者在共济失调发病前后生物标志物进展的定量信息，并允许识别临床进展的预测因子。我们的数据可能对未来临床试验的设计有用。资助heu联合计划-神经退行性疾病研究（JPND）(德国联邦教育和研究部；荷兰卫生研究与发展组织；葡萄牙科学技术基金会；医学研究理事会、区域科学和技术基金、亚速尔群岛)和施维雅。在美国，这项工作部分得到了国家共济失调基金会和国家神经疾病和中风研究所（NINDS）的资助R01NS080816。

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来源期刊

Lancet Regional Health-Europe Multiple-

CiteScore

19.90

自引率

1.40%

发文量

260

审稿时长

9 weeks

期刊介绍： The Lancet Regional Health – Europe, a gold open access journal, is part of The Lancet's global effort to promote healthcare quality and accessibility worldwide. It focuses on advancing clinical practice and health policy in the European region to enhance health outcomes. The journal publishes high-quality original research advocating changes in clinical practice and health policy. It also includes reviews, commentaries, and opinion pieces on regional health topics, such as infection and disease prevention, healthy aging, and reducing health disparities.