Nuffield Department of Clinical Neurosciences, University of Oxford, United Kingdom.
Target Discovery Institute, University of Oxford, Oxford, United Kingdom.
Ann Neurol. 2018 Feb;83(2):258-268. doi: 10.1002/ana.25143. Epub 2018 Feb 9.
The neurodegenerative disease, amyotrophic lateral sclerosis (ALS), is a heterogeneous clinical syndrome involving multiple molecular pathways. The development of biomarkers for use in therapeutic trials is a priority. We sought to use a high-throughput proteomic method to identify novel biomarkers in individual cerebrospinal fluid (CSF) samples.
Liquid chromatography/tandem mass spectrometry with label-free quantification was used to identify CSF proteins using samples from a well-characterized longitudinal cohort comprising patients with ALS (n = 43), the upper motor neuron variant, primary lateral sclerosis (PLS; n = 6), and cross-sectional healthy (n = 20) and disease controls (Parkinsons' disease, n = 20; ALS mimic disorders, n = 12).
Three macrophage-derived chitinases showed increased abundance in ALS: chitotriosidase (CHIT1), chitinase-3-like protein 1 (CHI3L1), and chitinase-3-like protein 2 (CHI3L2). Elevated CHI3L1 was common to ALS and PLS, whereas CHIT1 and CHI3L2 levels differed. Chitinase levels correlated with disease progression rate (CHIT1, r = 0.56, p < 0.001; CHI3L1, r = 0.31; p = 0.028; CHI3L2, r = 0.29, p = 0.044). CHIT1, CHI3L1, and CHI3L2 levels correlated with phosphorylated neurofilament heavy chain (pNFH; r = 0.62, p < 0.001; r = 0.49, p < 0.001; r = 0.41, p < 0.001). CHI3L1 levels, but not CHIT1 or CHI3L2, increased over time in those with low initial levels (gradient = 0.005 log abundance units/month, p = 0.001). High CHIT1 was associated with shortened survival (hazard ratio [HR] 2.84; p = 0.009). Inclusion of pNFH in survival models left only an association of pNFH and survival (HR 1.26; p = 0.019).
Neuroinflammatory mechanisms have been consistently implicated through various experimental paradigms. These results support a key role for macrophage activity in ALS pathogenesis, offering novel target engagement and pharmacodynamic biomarkers for neuroinflammation-focused ALS therapy. Ann Neurol 2018;83:258-268.
神经退行性疾病肌萎缩侧索硬化症（ALS）是一种涉及多种分子途径的异质性临床综合征。开发用于治疗试验的生物标志物是当务之急。我们试图使用高通量蛋白质组学方法来鉴定个体脑脊液（CSF）样本中的新型生物标志物。
使用经过充分特征描述的纵向队列中的样本，使用无标记定量的液相色谱/串联质谱法鉴定 CSF 蛋白，该队列包括肌萎缩侧索硬化症（ALS）患者（n = 43）、上运动神经元变异型原发性侧索硬化症（PLS；n = 6）和横断面健康对照（帕金森病，n = 20；ALS 模拟疾病，n = 12）。
三种巨噬细胞衍生的壳聚糖酶在 ALS 中显示出增加的丰度：壳三糖苷酶（CHIT1）、几丁质酶 3 样蛋白 1（CHI3L1）和几丁质酶 3 样蛋白 2（CHI3L2）。CHI3L1 在 ALS 和 PLS 中均升高，而 CHIT1 和 CHI3L2 水平则不同。壳聚糖酶水平与疾病进展速度相关（CHIT1，r = 0.56，p < 0.001；CHI3L1，r = 0.31；p = 0.028；CHI3L2，r = 0.29，p = 0.044）。CHIT1、CHI3L1 和 CHI3L2 水平与磷酸化神经丝重链（pNFH；r = 0.62，p < 0.001；r = 0.49，p < 0.001；r = 0.41，p < 0.001）相关。在初始水平较低的患者中，CHI3L1 水平（梯度= 0.005 对数丰度单位/月，p = 0.001）随时间增加。高 CHIT1 与缩短的生存时间相关（风险比[HR]2.84；p = 0.009）。在生存模型中纳入 pNFH 后，只有 pNFH 和生存时间之间存在关联（HR 1.26；p = 0.019）。
神经炎症机制通过各种实验范式得到了一致的证实。这些结果支持巨噬细胞活性在 ALS 发病机制中的关键作用，为针对神经炎症的 ALS 治疗提供了新的靶点和药效学生物标志物。神经病学年鉴 2018；83：258-268。
