Shen Xue-Ning, Wu Kai-Min, Huang Yu-Yuan, Guo Yu, Huang Shu-Yi, Zhang Ya-Ru, Chen Shu-Fen, Wang Hui-Fu, Zhang Wei, Cheng Wei, Cui Mei, Dong Qiang, Yu Jin-Tai
Department of Neurology and National Center for Neurological Disorders, Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai, China.
Department of Neurology, Qingdao Municipal Hospital, Qingdao University, China.
Neurobiol Dis. 2023 Jun 1;181:106112. doi: 10.1016/j.nbd.2023.106112. Epub 2023 Mar 30.
Plasma neurofilament light (NfL), glial fibrillary acidic protein (GFAP), phosphorylated-tau (p-tau), and β-amyloid (Aβ) have emerged as promising markers in several neurodegenerative disorders, but whether they can be used as biomarkers in spinocerebellar ataxias (SCA) is yet to be determined. This study aimed to identify sensitive plasma markers for SCA and investigate their effectiveness in tracking ataxia severity, cognition, non-motor symptoms, and brain atrophy.
This observational study recruited consecutive participants from Huashan Hospital and the CABLE study from November 2019. Patients with SCA were genetically diagnosed, grouped according to the ataxia severity, and compared with healthy older individuals and patients with multiple system atrophy type C (MSA-C). Plasma NfL, GFAP, p-tau, and Aβ levels were measured by Simoa in all participants. Analysis of covariance, Spearman correlation, and multivariable regression were used to explore candidate markers in SCA.
A total of 190 participants (60 SCA, 56 MSA-C, and 74 healthy controls) were enrolled. Plasma NfL level increased early in the pre-ataxic stage of SCA (32.23 ± 3.07 vs. 11.41 ± 6.62 pg/mL in controls), was positively associated with the ataxia severity (r = 0.45, P = 0.005) and CAG repeat length (r = 0.51, P = 0.001), varied among the different SCA subtypes (39.57 ± 13.50 pg/mL in SCA3, which was higher than 28.17 ± 8.02 pg/mL in SCA2, 17.08 ± 6.78 pg/mL in SCA8, and 24.44 ± 18.97 pg/mL in rare SCAs; P < 0.05), and was associated with brainstem atrophy. NfL alone (area under the curve [AUC] 0.867) or combined with p-tau181 and Aβ (AUC 0.929), showed excellent performance in discriminating SCA patients from controls. Plasma GFAP distinguished SCA from MSA-C with moderate accuracy (AUC > 0.700) and correlated with cognitive performance and cortical atrophy. Changes in levels of p-tau181 and Aβ were observed in SCA patients compared to controls. They were both correlated with cognition, while Aβ was also associated with non-motor symptoms, such as anxiety and depression.
Plasma NfL may serve as a sensitive biomarker for SCA, and its level is elevated in the pre-ataxic stage. The different performance of NfL and GFAP indicates differences in the underlying neuropathology of SCA and MSA-C. Moreover, amyloid markers may be useful for detecting memory dysfunction and other non-motor symptoms in SCA.
血浆神经丝轻链（NfL）、胶质纤维酸性蛋白（GFAP）、磷酸化tau蛋白（p-tau）和β-淀粉样蛋白（Aβ）已成为多种神经退行性疾病中有前景的标志物，但它们是否可作为脊髓小脑共济失调（SCA）的生物标志物尚待确定。本研究旨在识别SCA敏感的血浆标志物，并研究其在追踪共济失调严重程度、认知、非运动症状和脑萎缩方面的有效性。
本观察性研究于2019年11月从华山医院和CABLE研究中连续招募参与者。对SCA患者进行基因诊断，根据共济失调严重程度分组，并与健康老年人和多系统萎缩C型（MSA-C）患者进行比较。所有参与者均采用单分子阵列免疫检测技术（Simoa）测定血浆NfL、GFAP、p-tau和Aβ水平。采用协方差分析、Spearman相关性分析和多变量回归分析来探索SCA中的候选标志物。
共纳入190名参与者（60名SCA患者、56名MSA-C患者和74名健康对照）。SCA共济失调前期血浆NfL水平即升高（对照组为11.41±6.62 pg/mL，SCA患者为32.23±3.07 pg/mL），与共济失调严重程度呈正相关（r = 0.45，P = 0.005），与CAG重复长度呈正相关（r = 0.51，P = 0.001），在不同SCA亚型中有所差异（SCA3为39.57±13.50 pg/mL，高于SCA2的28.17±8.02 pg/mL、SCA8的17.08±6.78 pg/mL和罕见SCA的24.44±18.97 pg/mL；P < 0.05），且与脑干萎缩相关。单独的NfL（曲线下面积[AUC]为0.867）或与p-tau181和Aβ联合使用（AUC为0.929），在区分SCA患者与对照组方面表现出色。血浆GFAP区分SCA与MSA-C具有中等准确性（AUC > 0.700），并与认知表现和皮质萎缩相关。与对照组相比，SCA患者中观察到p-tau181和Aβ水平的变化。它们均与认知相关，而Aβ还与焦虑和抑郁等非运动症状相关。
血浆NfL可能作为SCA的敏感生物标志物，其水平在共济失调前期即升高。NfL和GFAP的不同表现表明SCA和MSA-C潜在神经病理学存在差异。此外，淀粉样蛋白标志物可能有助于检测SCA中的记忆功能障碍和其他非运动症状。
