BACKGROUND Spinocerebellar ataxia type 3 (SCA3) is the most common subtype of autosomal dominantly inherited spinocerebellar ataxias (SCAs). No validated blood biomarker is available to assess either disease progression or therapeutic response. Neurofilament light chain (NfL) was recently proposed as a serum biomarker for many neurodegenerative disorders. The present study investigated whether NfL was a promising serum biomarker for SCA3. METHODS Seventeen SCA3 patients and 9 controls were enrolled in cohort A, and 116 SCA3 individuals (preclinical and patients) and 91 controls were recruited as cohort B. We assessed whether serum NfL correlated with cerebrospinal fluid (CSF) NfL in cohort A and correlations between serum NfL levels and clinical features and brain volumes were determined in cohort B. The single-molecule array method was used to measure serum NfL levels. Disease severity was determined using the scale for the assessment and rating of ataxia (SARA) and the international cooperative ataxia rating scale (ICARS). Cerebellar and brainstem volumes were assessed using MRI neuroimaging measurements. RESULTS Serum/CSF NfL levels in cohort A were elevated in SCA3 patients, and serum and CSF NfL exhibited a significant positive correlation (r = 0.9179, p < 0.0001). Levels of serum NfL in cohort B were significantly higher in preclinical SCA3 (15.03 ± 7.49 vs 6.88 ± 2.72 pg/ mL, p < 0.0001) and manifest SCA3 subjects (37.56 ± 13.47 vs 9.07 ± 6.02 pg/ mL, p < 0.0001) compared to those in controls. Serum NfL concentrations increased from early disease stage to the next stage. Levels of serum NfL in ATXN3 mutation carriers were positively associated with SARA (r = 0.5458, p < 0.0001) and ICARS scores (r = 0.5522, p < 0.0001). Significant negative associations with cerebellar volumes (r = - 0.4217, p = 0.0003) and brainstem volumes (r = - 0.4263, p = 0.0003) were observed. All changes remained significant after adjustment for age and CAG repeat. CONCLUSIONS Levels of serum NfL were significantly elevated in SCA3 individuals and correlated with disease severity. Serum NfL is a promising serum biomarker of disease onset and progression, and a potential candidate biomarker of treatment response in SCA3.

中文翻译：

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神经丝轻链是3型脊髓小脑共济失调中有希望的血清生物标志物。

背景技术3型小脑共济失调（SCA3）是常染色体显性遗传的小脑共济失调（SCAs）最常见的亚型。没有经过验证的血液生物标志物可用于评估疾病进展或治疗反应。神经丝轻链（NfL）最近被提议作为许多神经退行性疾病的血清生物标志物。本研究调查了NfL是否是SCA3的有希望的血清生物标志物。方法A队列17例SCA3患者和9例对照，B队列116例SCA3患者（临床前和患者）和91例对照。我们评估了A队列中血清NfL是否与脑脊液（CSF）NfL相关，以及之间的相关性。在队列B中确定血清NfL水平，临床特征和脑容量 单分子阵列法用于测量血清NfL水平。使用共济失调评估和评定量表（SARA）和国际合作性共济失调评定量表（ICARS）确定疾病的严重程度。小脑和脑干的体积使用MRI神经影像测量技术进行评估。结果SCA3患者队列A的血清/ CSF NfL水平升高，血清和CSF NfL呈显着正相关（r = 0.9179，p <0.0001）。在临床前SCA3中，队列B中的血清NfL水平显着更高（15.03±7.49 vs 6.88±2.72 pg / mL，p <0.0001）和明显的SCA3受试者（37.56±13.47 vs 9.07±6.02 pg / mL，p <0.0001）给那些在控制中的人。从疾病早期到下一阶段，血清NfL浓度增加。ATXN3突变携带者的血清NfL水平与SARA（r = 0.5458，p <0.0001）和ICARS评分（r = 0.5522，p <0.0001）呈正相关。观察到与小脑体积（r =-0.4217，p = 0.0003）和脑干体积（r =-0.4263，p = 0.0003）的显着负相关。在调整年龄和CAG重复后，所有变化仍然很明显。结论SCA3个体的血清NfL水平显着升高，并与疾病的严重程度相关。血清NfL是疾病发作和进展的有希望的血清生物标志物，也是SCA3中治疗反应的潜在候选生物标志物。观察到4263，p ＝ 0.0003）。在调整年龄和CAG重复后，所有变化仍然很明显。结论SCA3个体的血清NfL水平显着升高，并与疾病的严重程度相关。血清NfL是疾病发作和进展的有希望的血清生物标志物，也是SCA3中治疗反应的潜在候选生物标志物。观察到4263，p ＝ 0.0003）。在调整年龄和CAG重复后，所有变化仍然很明显。结论SCA3个体的血清NfL水平显着升高，并与疾病的严重程度相关。血清NfL是疾病发作和进展的有希望的血清生物标志物，也是SCA3中治疗反应的潜在候选生物标志物。