由于脊髓小脑共济失调(SCA)患者可能很快会出现基于基因的疗法,有一个关键的需要,以确定生物标志物的疾病进展的影响大小大于临床评分,能够以较小的样本量进行试验。
我们招募了一组独特的SCA1患者(n=15),SCA2(n=12),SCA3(n=20)和SCA7(n=10)以及24名年龄相似的健康对照,性别和体重指数。我们在基线和随访(平均间隔24个月)收集纵向临床和影像学数据。我们进行了手动和自动体积分析。扩散张量成像(DTI)和一种新颖的纤维束成像方法,称为基于fixel的分析(FBA),在后续评估。计算临床评分和成像参数的效应大小。
临床评分随着萎缩随时间增加而恶化(p<0.05)。然而,与临床评分(<0.8)相比,小脑和脑桥的萎缩显示出非常大的效应大小(>1.2)。FBA,第一次申请SCA,对传统DTI指标没有捕捉到的微观结构横截面差异敏感,特别是在研究较少的SCA7组中。FBA还显示出比DTI度量更大的效应大小。
这项研究表明,在SCA1、SCA2、SCA3和SCA7中,容量测量优于临床评分。因此,我们主张在常染色体显性遗传共济失调的治疗试验中使用体积生物标志物.此外,FBA显示出比DTI更大的效应大小,以检测患者相对于对照组的横截面微观结构改变。
As gene-based therapies may soon arise for patients with spinocerebellar ataxia (SCA), there is a critical need to identify biomarkers of disease progression with effect sizes greater than clinical scores, enabling trials with smaller sample sizes.
We enrolled a unique cohort of patients with SCA1 (n = 15), SCA2 (n = 12), SCA3 (n = 20) and SCA7 (n = 10) and 24 healthy controls of similar age, sex and body mass index. We collected longitudinal clinical and imaging data at baseline and follow-up (mean interval of 24 months). We performed both manual and automated volumetric analyses. Diffusion tensor imaging (DTI) and a novel tractography method, called fixel-based analysis (FBA), were assessed at follow-up. Effect sizes were calculated for clinical scores and imaging parameters.
Clinical scores worsened as atrophy increased over time (p < 0.05). However, atrophy of cerebellum and pons showed very large effect sizes (>1.2) compared to clinical scores (<0.8). FBA, applied for the first time to SCA, was sensitive to microstructural cross-sectional differences that were not captured by conventional DTI metrics, especially in the less studied SCA7 group. FBA also showed larger effect sizes than DTI metrics.
This study showed that volumetry outperformed clinical scores to measure disease progression in SCA1, SCA2, SCA3 and SCA7. Therefore, we advocate the use of volumetric biomarkers in therapeutic trials of autosomal dominant ataxias. In addition, FBA showed larger effect size than DTI to detect cross-sectional microstructural alterations in patients relative to controls.