From the Division Translational Genomics of Neurodegenerative Diseases (C.W., D.M., M.S.) and Department of Neurodegenerative Diseases (L.S., H.H., R.S.), Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen; German Center for Neurodegenerative Diseases (DZNE) (C.W., D.M., L.S., H.H., R.S., M.S.), Tübingen, Germany; First Department of Neurology (M.R.), Institute of Psychiatry and Neurology, Warsaw, Poland; Department of Neurology (T.K.), University Hospital Bonn; German Center for Neurodegenerative Diseases (DZNE) (T.K., H.J.), Bonn, Germany; Sorbonne Université (A.D.), Paris Brain Institute, APHP, INSERM, CNRS, France; Department of Neuroscience and Reproductive and Odontostomatological Sciences (A.F.), Federico II University Naples, Italy; Department of Medical Genetics and Szentagothai Research Center (B.M.), University of Pécs Medical School, Hungary; Department of Neurology (K.R.), RWTH Aachen University; JARA-BRAIN Institute Molecular Neuroscience and Neuroimaging (K.R.), Forschungszentrum Jülich, RWTH Aachen; and Department of Neurology (H.J.), University Hospital of Heidelberg, Germany.
Neurology. 2022 May 17;98(20):e1985-e1996. doi: 10.1212/WNL.0000000000200257. Epub 2022 Mar 9.
Neurofilament light (NfL) appears to be a promising fluid biomarker in repeat-expansion spinocerebellar ataxias (SCAs), with piloting studies in mixed SCA cohorts suggesting that NfL might be increased at the ataxic stage of SCA type 1 (SCA1). We here hypothesized that NfL is increased not only at the ataxic stage of SCA1, but also at its (likely most treatment-relevant) preataxic stage.
We assessed serum NfL (sNfL) and CSF NfL (cNfL) levels in both preataxic and ataxic SCA1, leveraging a multicentric cohort recruited at 6 European university centers, and clinical follow-up data, including actually observed (rather than only predicted) conversion to the ataxic stage. Levels of sNfL and cNfL were assessed by single-molecule array and ELISA technique, respectively.
Forty individuals with SCA1 (23 preataxic, 17 ataxic) and 89 controls were enrolled, including 11 preataxic individuals converting to the ataxic stage. sNfL levels were increased at the preataxic (median 15.5 pg/mL [interquartile range 10.5-21.1 pg/mL]) and ataxic stage (31.6 pg/mL [26.2-37.7 pg/mL]) compared to controls (6.0 pg/mL [4.7-8.6 pg/mL]), yielding high age-corrected effect sizes (preataxic: = 0.62, ataxic: = 0.63). sNfL increases were paralleled by increases of cNfL at both the preataxic and ataxic stage. In preataxic individuals, sNfL levels increased with proximity to predicted ataxia onset, with significant sNfL elevations already 5 years before onset, and confirmed in preataxic individuals with actually observed ataxia onset. sNfL increases were detected already in preataxic individuals with SCA1 without volumetric atrophy of cerebellum or pons, suggesting that sNfL might be more sensitive to early preataxic neurodegeneration than the currently known most change-sensitive regions in volumetric MRI. Using longitudinal sNfL measurements, we estimated sample sizes for clinical trials with the reduction of sNfL as the endpoint.
sNfL levels might provide easily accessible peripheral biomarkers in both preataxic and ataxic SCA1, allowing stratification of preataxic individuals regarding proximity to onset, early detection of neurodegeneration even before volumetric MRI alterations, and potentially capture of treatment response in clinical trials.
ClinicalTrials.gov Identifier: NCT01037777.
This study provides Class III evidence that NfL levels are increased in both ataxic and preataxic SCA1 and are associated with ataxia onset.
神经丝轻链（NfL）似乎是一种很有前途的重复扩展脊髓小脑共济失调（SCA）的液体生物标志物，初步研究表明 NfL 在 SCA 1 型（SCA1）的共济失调阶段可能会升高。我们假设 NfL 不仅在 SCA1 的共济失调阶段升高，而且在其（可能是最相关的治疗）前期阶段也升高。
我们评估了 SCA1 的前期和共济失调期的血清 NfL（sNfL）和脑脊液 NfL（cNfL）水平，利用来自 6 个欧洲大学中心的多中心队列和临床随访数据，包括实际观察到的（而不是仅预测到的）向共济失调阶段的转化。sNfL 和 cNfL 的水平分别通过单分子阵列和 ELISA 技术进行评估。
共纳入 40 名 SCA1 患者（23 名前期，17 名共济失调）和 89 名对照组，包括 11 名从前期发展为共济失调的患者。sNfL 水平在前期（中位数 15.5pg/ml [四分位距 10.5-21.1pg/ml]）和共济失调阶段（31.6pg/ml [26.2-37.7pg/ml]）均高于对照组（6.0pg/ml [4.7-8.6pg/ml]），校正年龄后的效应大小较大（前期： = 0.62，共济失调： = 0.63）。在前期和共济失调阶段，cNfL 也随之增加。在前期患者中，sNfL 水平随着预测的共济失调发作的临近而升高，在发病前 5 年就已经出现显著的 sNfL 升高，并在实际观察到的共济失调发作的前期患者中得到证实。甚至在小脑或脑桥没有体积萎缩的 SCA1 前期患者中也检测到 sNfL 升高，这表明 sNfL 可能比目前已知的体积 MRI 中最敏感的区域更能早期检测到前期的神经退行性变。使用纵向 sNfL 测量值，我们估计了以 sNfL 减少为终点的临床试验的样本量。
sNfL 水平可能为 SCA1 的前期和共济失调阶段提供易于获得的外周生物标志物，允许根据接近发作的情况对前期患者进行分层，即使在体积 MRI 改变之前也能早期检测神经退行性变，并且有可能在临床试验中捕捉到治疗反应。
ClinicalTrials.gov 标识符：NCT01037777。
本研究提供了 III 级证据，表明 NfL 水平在 SCA1 的共济失调和前期阶段升高，并与共济失调发作相关。
