Multimodal, Longitudinal Profiling of SCA1 Identifies Predictors of Disease Severity and Progression

IF 8.1 1区医学 Q1 CLINICAL NEUROLOGY Annals of Neurology Pub Date : 2024-08-03 DOI:10.1002/ana.27032

Teije H. van Prooije MD, Kirsten C.J. Kapteijns, Jack J.A. van Asten, Joanna IntHout, Marcel M. Verbeek PhD, Tom W.J. Scheenen PhD, Bart P. van de Warrenburg MD, PhD

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Abstract

Objectives

Spinocerebellar ataxia type 1 (SCA1) is a rare autosomal dominant neurodegenerative disease. Objective surrogate markers sensitive to detect changes in disease severity are needed to reduce sample sizes in interventional trials and identification of predictors of faster disease progression would facilitate patient selection, enrichment, or stratification in such trials.

Methods

We performed a prospective 1-year longitudinal, multimodal study in 34 ataxic SCA1 individuals and 21 healthy controls. We collected clinical, patient-reported outcomes, biochemical and magnetic resonance (MR) biomarkers at baseline and after 1 year. We determined 1-year progression and evaluated the potential predictive value of several baseline markers on 1-year disease progression.

Results

At baseline, multiple structural and spectroscopic MR markers in pons and cerebellum differentiated SCA1 from healthy controls and correlated with disease severity. Plasma and cerebrospinal fluid (CSF) neurofilament light (NfL) chain and CSF glial fibrillary acidic protein (GFAP) were elevated in SCA1. In longitudinal analysis, total brainstem and pontine volume change, inventory of non-ataxia signs (INAS) count, and SCA functional index (SCAFI) showed larger responsiveness compared to the Scale for Assessment and Rating of Ataxia (SARA).

Longer disease duration, longer non-expanded CAG repeat length, and higher disease burden were associated with faster SARA increase after 1-year in the SCA1 group. Similarly, lower baseline brainstem, pontine, and cerebellar volumes, as well as lower levels of N-acetylaspartate and glutamate in the cerebellar white matter, were also associated with faster SARA increase.

Interpretation

Our results guide the selection of the most sensitive measures of disease progression in SCA1 and have identified features associated with accelerated progression that could inform the design of clinical trials. ANN NEUROL 2024;96:774–787

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对 SCA1 进行多模态、纵向剖析，发现疾病严重程度和进展的预测因素。

目的：脊髓小脑共济失调 1 型（SCA1）是一种罕见的常染色体显性神经退行性疾病。需要能检测疾病严重程度变化的客观替代标记物来减少干预性试验的样本量，而确定疾病进展更快的预测因子将有助于在此类试验中对患者进行选择、富集或分层：我们对 34 名共济失调型 SCA1 患者和 21 名健康对照者进行了为期 1 年的前瞻性多模态纵向研究。我们收集了基线和一年后的临床、患者报告结果、生化和磁共振（MR）生物标志物。我们确定了1年的病情进展，并评估了几个基线标志物对1年病情进展的潜在预测价值：基线时，脑桥和小脑中的多种结构和光谱磁共振标记物将 SCA1 与健康对照组区分开来，并与疾病严重程度相关。SCA1患者血浆和脑脊液（CSF）中神经丝轻链（NfL）和脑脊液胶质纤维酸性蛋白（GFAP）升高。在纵向分析中，与共济失调评估和评级量表（SARA）相比，脑干和桥脑总体积变化、非共济失调体征（INAS）计数和SCA功能指数（SCAFI）显示出更大的反应性。在SCA1组中，病程越长、非扩展CAG重复长度越长、疾病负担越重，1年后SARA的上升速度越快。同样，较低的基线脑干、桥脑和小脑体积以及小脑白质中较低的N-乙酰天冬氨酸和谷氨酸水平也与SARA的快速增长有关：我们的研究结果为选择最灵敏的SCA1疾病进展测量指标提供了指导，并发现了与疾病进展加速相关的特征，这些特征可为临床试验的设计提供参考。ann neurol 2024.

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来源期刊

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.