Arpin David J, Subramony S H, Vaillancourt David E, Ashizawa Tetsuo, Durr Alexandra, Mareci Thomas, Klockgether Thomas, Faber Jennifer, Paulson Henry L, Öz Gülin, Burns Matthew R
Department of Applied Physiology & Kinesiology, University of Florida, Gainesville, Florida, USA.
Department of Neurology, University of Florida, Gainesville, Florida, USA.
Ann Clin Transl Neurol. 2025 Jul 15. doi: 10.1002/acn3.70116.
Spinocerebellar ataxias (SCAs) are a group of genetically heterogeneous neurodegenerative diseases causing progressive deterioration and reduced quality of life. Therapeutic advances have been limited by a lack of sensitive anatomic, functional, or diffusion imaging-based biomarkers. This study aimed to identify white matter differences in the brains of preataxic and early-stage SCA1 and SCA3 mutation carriers using diffusion magnetic resonance imaging data from a multisite trial setting.
Fixel-based analysis was used to estimate microscopic fiber density, macroscopic fiber-bundle cross-section, and a combined fiber density and fiber-bundle cross-section measure within 45 cerebral and cerebellar tracts. Multivariate ANOVAs compared controls (n = 16), pre-ataxic (n = 10 SCA1, n = 24 SCA3), and ataxic patients (n = 14 SCA1, n = 36 SCA3). Clinical variables were correlated with fixel metrics and receiver operating characteristic analyses identified white matter tracts sensitive to distinguishing controls from pre-ataxic SCA1 and SCA3.
We found widespread white matter deficits in pre-ataxic and ataxic patients compared to controls with regard to fiber density, fiber-bundle cross-section, and combined measures, all of which were associated with clinical measures of ataxia severity. We also found the combined fiber density and fiber-bundle cross-section measure from cerebellar tracts distinguished controls from pre-ataxia with high sensitivity and specificity for both SCA1 (receiver operating characteristic area under the curve = 0.96) and SCA3 (area under the curve = 0.97). The receiver operating characteristic analyses revealed that cerebellar tracts resulted in greater area under the curve than cortico-spinal and transcallosal tracts.
These results demonstrate that fixel metrics offer sensitive disease-specific measures of early SCA disease state that correlate with standard clinical measures.
Clinical Trial Readiness for SCA1 and SCA3 (READISCA), NCT03487367. https://clinicaltrials.gov/ct2/show/NCT03487367.
脊髓小脑共济失调（SCA）是一组具有遗传异质性的神经退行性疾病，会导致病情逐渐恶化并降低生活质量。由于缺乏基于敏感的解剖学、功能或扩散成像的生物标志物，治疗进展一直受到限制。本研究旨在利用来自多中心试验的扩散磁共振成像数据，确定未出现共济失调症状的以及处于SCA1和SCA3早期阶段的突变携带者大脑中的白质差异。
基于固定点的分析用于估计45条大脑和小脑神经束内的微观纤维密度、宏观纤维束横截面积以及纤维密度与纤维束横截面积的综合测量值。多变量方差分析比较了对照组（n = 16）、未出现共济失调症状的患者（n = 10例SCA1，n = 24例SCA3）和共济失调患者（n = 14例SCA1，n = 36例SCA3）。临床变量与固定点指标相关，受试者工作特征分析确定了对白质束敏感的指标，这些指标可用于区分对照组与未出现共济失调症状的SCA1和SCA3患者。
与对照组相比，我们发现未出现共济失调症状的患者和共济失调患者在纤维密度、纤维束横截面积以及综合测量值方面均存在广泛的白质缺陷，所有这些都与共济失调严重程度的临床指标相关。我们还发现，小脑神经束的纤维密度与纤维束横截面积综合测量值能够以高敏感性和特异性区分对照组与未出现共济失调症状的患者，对于SCA1（受试者工作特征曲线下面积 = 0.96）和SCA3（曲线下面积 = 0.97）均如此。受试者工作特征分析显示，小脑神经束的曲线下面积大于皮质脊髓束和胼胝体束。
这些结果表明，固定点指标为早期SCA疾病状态提供了敏感的疾病特异性测量方法，且与标准临床测量方法相关。
SCA1和SCA3的临床试验准备（READISCA），NCT03487367。https://clinicaltrials.gov/ct2/show/NCT03487367 。
