Department of Neurology, Donders Institute for Brain, Cognition, and Behavior, Radboud University Medical Center, Nijmegen, Netherlands.
Department of Medical Imaging, Radboud University Medical Center, Nijmegen, Netherlands.
Ann Neurol. 2024 Oct;96(4):774-787. doi: 10.1002/ana.27032. Epub 2024 Aug 3.
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.
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.
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.
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.
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。需要客观替代标志物来敏感地检测疾病严重程度的变化，以减少干预性试验中的样本量，并确定疾病进展更快的预测因素，这将有助于在这些试验中选择、富集或分层患者。
我们对 34 名共济失调 SCA1 患者和 21 名健康对照者进行了前瞻性为期 1 年的纵向多模态研究。我们在基线和 1 年后收集了临床、患者报告的结果、生化和磁共振（MR）生物标志物。我们确定了 1 年的进展，并评估了几种基线标志物对 1 年疾病进展的潜在预测价值。
在基线时，桥脑和小脑的多种结构和波谱磁共振标志物可将 SCA1 与健康对照组区分开来，并与疾病严重程度相关。SCA1 患者的血浆和脑脊液（CSF）神经丝轻链（NfL）和 CSF 胶质纤维酸性蛋白（GFAP）升高。在纵向分析中，总脑干和桥脑体积变化、非共济失调体征量表（INAS）计数和 SCA 功能指数（SCAFI）的反应性大于共济失调量表（SARA）。在 SCA1 组中，更长的疾病持续时间、更长的非扩展 CAG 重复长度和更高的疾病负担与 1 年后 SARA 的增加更快相关。同样，较低的基线脑干、桥脑和小脑体积，以及小脑白质中 N-乙酰天冬氨酸和谷氨酸水平较低，也与 SARA 的更快增加相关。
我们的结果指导了 SCA1 中疾病进展最敏感测量方法的选择，并确定了与加速进展相关的特征，这可以为临床试验的设计提供信息。ANN NEUROL 2024；96：774-787。
