目的:在多谷氨酰胺脊髓小脑共济失调发病前的横断面研究中主要观察到脑MRI异常和神经丝轻链(NfL)增加。我们的研究旨在确定生物学的纵向变化,临床,和/或在脊髓小脑共济失调(SCA)2和SCA7携带者中成像生物标志物超过1年。
方法:我们在巴黎脑研究所研究了SCA2和SCA7携带者和对照(扩增阴性亲属)。纳入标准包括共济失调评估量表(SARA)评分在0和15之间。基线评估,6个月,12个月包括神经系统,生活质量,口面运动,神经心理学,和眼科检查,以及步态和动眼记录,脑部MRI,CSF,和血液采样。主要结果是这些评估在1年内的纵向变化。
结果:我们包括15个SCA2运营商,15个SCA7运营商,以及2020年5月至2021年4月之间的10个控制措施。在基线,年龄相似(SCA2为41[37,46],SCA7为38[28.5,39.8],对照组为39.5[31,54.5],p=0.78),性别(p=0.61);SARA得分低但不同(SCA2中的4[1.25,6.5],SCA7中的2[0,11.5]和对照组中的0,p<0.01)。SCAs中的脑桥和髓质体积较小(p<0.05),仅SCA2中的小脑体积较小(p=0.01)。SCA参与者的血浆NfL水平较高(SCA2:14.2pg/mL[11.52,15.89],SCA7:15.53[13.27,23.23])比对照组(4.88[3.56,6.17],p<0.001)。经过1年的随访,在SCA2中,脑桥(-144±60mm3)和小脑(-1,508±580mm3)体积明显减少,步态评估恶化;在SCA7中,SARA评分显着增加(1.3±0.4),视网膜外层厚度减少(-15.4±1.6μm);对于两个SCA组,口面运动评估明显恶化。对于共济失调前和共济失调早期携带者,结局指标中最显著的纵向恶化是SCA2的口面部运动和SCA7的视网膜厚度.
结论:尽管样本量小,我们在脑MRI成像中检测到共济失调前和共济失调早期SCA个体的年度变化,临床评分,步态参数,和视网膜厚度。这些参数可以作为共济失调前期未来治疗试验的潜在终点。
■ClinicalTrials.govNCT04288128。
OBJECTIVE: Brain MRI abnormalities and increases in neurofilament light chain (NfL) have mostly been observed in cross-sectional studies before ataxia onset in polyglutamine spinocerebellar ataxias. Our study aimed to identify longitudinal changes in biological, clinical, and/or imaging biomarkers in spinocerebellar ataxia (SCA) 2 and SCA7 carriers over 1 year.
METHODS: We studied SCA2 and SCA7 carriers and controls (expansion-negative relatives) at the Paris Brain Institute. Inclusion criteria included Scale for the Assessment and Rating of Ataxia (SARA) scores between 0 and 15. Assessments at baseline, 6 months, and 12 months comprised neurologic, quality of life, orofacial motor, neuropsychological, and ophthalmologic examinations, along with gait and oculomotor recordings, brain MRI, CSF, and blood sampling. The primary outcome was the longitudinal change in these assessments over 1 year.
RESULTS: We included 15 SCA2 carriers, 15 SCA7 carriers, and 10 controls between May 2020 and April 2021. At baseline, the ages were similar (41 [37, 46] for SCA2, 38 [28.5, 39.8] for SCA7, and 39.5 [31, 54.5] for controls, p = 0.78), as well the sex (p = 0.61); SARA scores were low but different (4 [1.25, 6.5] in SCA2, 2 [0, 11.5] in SCA7, and 0 in controls, p < 0.01). Pons and medulla volumes were smaller in SCAs (p < 0.05) and cerebellum volume only in SCA2 (p = 0.01). Plasma NfL levels were higher in SCA participants (SCA2: 14.2 pg/mL [11.52, 15.89], SCA7: 15.53 [13.27, 23.23]) than in controls (4.88 [3.56, 6.17], p < 0.001). After 1-year follow-up, in SCA2, there was significant pons (-144 ± 60 mm3) and cerebellum (-1,508 ± 580 mm3) volume loss and a worsening of gait assessment; in SCA7, SARA score significantly increased (+1.3 ± 0.4) and outer retinal nuclear layer thickness decreased (-15.4 ± 1.6 μm); for both SCA groups, the orofacial motor assessment significantly worsened. For preataxic and early ataxic carriers, the strongest longitudinal deterioration on outcome measures was orofacial motility in SCA2 and retinal thickness in SCA7.
CONCLUSIONS: Despite the limitation of the small sample size, we detected annual changes in preataxic and early ataxic SCA individuals across brain MRI imaging, clinical scores, gait parameters, and retinal thickness. These parameters could serve as potential end points for future therapeutic trials in the preataxic phase.
UNASSIGNED: ClinicalTrials.gov NCT04288128.