Dreger Marie, Steinbach Robert, Gaur Nayana, Metzner Klara, Stubendorff Beatrice, Witte Otto W, Grosskreutz Julian
Hans Berger Department of Neurology, Jena University Hospital, Jena, Germany.
Center for Healthy Ageing, Jena University Hospital, Jena, Germany.
Front Neurosci. 2021 Apr 6;15:651651. doi: 10.3389/fnins.2021.651651. eCollection 2021.
Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive neurodegenerative disorder. As previous therapeutic trials in ALS have been severely hampered by patients' heterogeneity, the identification of biomarkers that reliably reflect disease progression represents a priority in ALS research. Here, we used the D50 disease progression model to investigate correlations between cerebrospinal fluid (CSF) neurofilament light chain (NfL) levels and disease aggressiveness. The D50 model quantifies individual disease trajectories for each ALS patient. The value D50 provides a unified measure of a patient's overall disease aggressiveness (defined as time taken in months to lose 50% of functionality). The relative D50 (rD50) reflects the individual disease covered and can be calculated for any time point in the disease course. We analyzed clinical data from a well-defined cohort of 156 patients with ALS. The concentration of NfL in CSF samples was measured at two different laboratories using the same procedure. Based on patients' individual D50 values, we defined subgroups with high (<20), intermediate (20-40), or low (>40) disease aggressiveness. NfL levels were compared between these subgroups via analysis of covariance, using an array of confounding factors: age, gender, clinical phenotype, frontotemporal dementia, rD50-derived disease phase, and analyzing laboratory. We found highly significant differences in NfL concentrations between all three D50 subgroups ( < 0.001), representing an increase of NfL levels with increasing disease aggressiveness. The conducted analysis of covariance showed that this correlation was independent of gender, disease phenotype, and phase; however, age, analyzing laboratory, and dementia significantly influenced NfL concentration. We could show that CSF NfL is independent of patients' disease covered at the time of sampling. The present study provides strong evidence for the potential of NfL to reflect disease aggressiveness in ALS and in addition proofed to remain at stable levels throughout the disease course. Implementation of CSF NfL as a potential read-out for future therapeutic trials in ALS is currently constrained by its demonstrated susceptibility to (pre-)analytical variations. Here we show that the D50 model enables the discovery of correlations between clinical characteristics and CSF analytes and can be recommended for future studies evaluating potential biomarkers.
肌萎缩侧索硬化症（ALS）是一种 relentlessly progressive neurodegenerative disorder。由于先前在 ALS 中的治疗试验受到患者异质性的严重阻碍，因此识别能够可靠反映疾病进展的生物标志物是 ALS 研究的首要任务。在此，我们使用 D50 疾病进展模型来研究脑脊液（CSF）神经丝轻链（NfL）水平与疾病侵袭性之间的相关性。D50 模型量化了每位 ALS 患者的个体疾病轨迹。D50 值提供了对患者整体疾病侵袭性的统一衡量标准（定义为以月为单位失去 50%功能所需的时间）。相对 D50（rD50）反映了个体所经历的疾病情况，并且可以在疾病过程中的任何时间点进行计算。我们分析了来自 156 名明确诊断的 ALS 患者队列的临床数据。使用相同程序在两个不同实验室测量了脑脊液样本中 NfL 的浓度。根据患者的个体 D50 值，我们定义了疾病侵袭性高（<20）、中（20 - 40）或低（>40）的亚组。通过协方差分析比较了这些亚组之间的 NfL 水平，使用了一系列混杂因素：年龄、性别、临床表型、额颞叶痴呆、rD50 衍生的疾病阶段以及分析实验室。我们发现所有三个 D50 亚组之间的 NfL 浓度存在高度显著差异（<0.001），这表明随着疾病侵袭性的增加，NfL 水平升高。进行的协方差分析表明，这种相关性与性别、疾病表型和阶段无关；然而，年龄、分析实验室和痴呆症显著影响 NfL 浓度。我们可以证明脑脊液 NfL 与采样时患者所经历的疾病情况无关。本研究为 NfL 在反映 ALS 疾病侵袭性方面的潜力提供了有力证据，此外还证明其在整个疾病过程中保持稳定水平。脑脊液 NfL 作为 ALS 未来治疗试验的潜在读数，目前受到其对（预）分析变异敏感性的限制。在此我们表明，D50 模型能够发现临床特征与脑脊液分析物之间的相关性，并且可以推荐用于未来评估潜在生物标志物的研究。
