Association of Cerebrospinal Fluid Levels of Lateral Olfactory Tract Usher Substance (LOTUS) With Disease Activity in Multiple Sclerosis
Association of Cerebrospinal Fluid Levels of Lateral Olfactory Tract Usher Substance (LOTUS) With Disease Activity in Multiple Sclerosis
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DOI：
10.1001/jamaneurol.2014.3613
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发表时间：
2015-02-01
期刊：
影响因子：
29
通讯作者：
Takei, Kohtaro
中科院分区：
文献类型：
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作者：
Takahashi, Keita;Kurihara, Yuji;Takei, Kohtaro
重要性 尽管多发性硬化症 (MS) 通常被认为是中枢神经系统的自身免疫性脱髓鞘疾病，但 Nogo 受体 1 信号传导导致的轴突变性最近被认为是一种重要的病理特征。我们之前鉴定出侧嗅束引导物质 (LOTUS)，一种内源性 Nogo 受体 1 拮抗剂，促使我们分析脑脊液中 LOTUS 水平与 MS 临床病程之间的关系，以评估 LOTUS 是否可以成为 MS 的有用生物标志物。 目的 根据 MS 患者的临床病程，检查其脑脊液中 LOTUS 浓度的变化。 设计、设置和参与者回顾性采集 2008 年 1 月 1 日至 2014 年 1 月 1 日期间正常对照 (NC；n = 27) 和 MS 患者 (n = 40)、肌萎缩侧索硬化症 (n = 22) 和多系统萎缩 (n = 10) 患者的脑脊液样本。 MS 患者分为复发缓解型 MS (RRMS；n = 30) 和继发进展型 MS (n = 30)。 = 10）。 RRMS患者进一步分为复发组和缓解组。 主要观察指标和指标 采用特异性LOTUS抗体，通过免疫印迹法定量检测脑脊液中LOTUS浓度，并根据患者临床病程，如RRMS缓解组和复发组以及继发进展型MS进行比较。 结果 RRMS复发组脑脊液中LOTUS浓度的平均值（SD）为9.3 [3.6] μ g/dL) 低于 NC 的水平 (19.2 [4.7] μ g/dL; P < .001)，而 RRMS 缓解组的水平 (19.6 [5.8] μ g/dL) 与 NC 相似。 SPMS 中的 LOTUS 浓度（6.7 [1.4] μ g/dL；P < .001）低于 NC 和 RRMS 缓解组。其他神经退行性疾病（例如肌萎缩侧索硬化症和多系统萎缩症）中的 LOTUS 水平正常。 结论和相关性 LOTUS 浓度的变化与 MS 中的疾病活动度相关。因此，LOTUS 浓度可作为 MS 的可能生物标志物。低 LOTUS 浓度可能参与 Nogo 受体 1 信号传导，这可能在 RRMS 复发期和继发进展性 MS 中诱导轴突变性。
IMPORTANCE Although multiple sclerosis (MS) is generally considered an autoimmune demyelinating disorder of the central nervous system, axonal degeneration through Nogo receptor-1 signaling was recently recognized as an important pathological feature. Our previous identification of lateral olfactory tract usher substance (LOTUS), an endogenous Nogo receptor-1 antagonist, prompted us to analyze the relationship between LOTUS levels of cerebrospinal fluid and the clinical course of MS to evaluate whether LOTUS could be a useful biomarker for MS.OBJECTIVE To examine variations in LOTUS concentrations in the cerebrospinal fluid of patients with MS in accordance with their clinical course.DESIGN, SETTING, AND PARTICIPANTS Cerebrospinal fluid samples were obtained retrospectively from normal controls (NCs; n = 27) and patients with MS (n = 40), amyotrophic lateral sclerosis (n = 22), and multiple system atrophy (n = 10) between January 1, 2008, and January 1, 2014. Patients with MS were divided into relapsing-remitting MS (RRMS; n = 30) and secondary progressive MS (n = 10). Patients with RRMS were further divided into relapse and remission groups.MAIN OUTCOMES AND MEASURES The LOTUS concentration in cerebropsinal fluid was quantitatively detected by immunoblotting using a specific LOTUS antibody and the concentrations compared in accordance with the patients' clinical course, such as remission and relapse groups in RRMS and secondary progressive MS.RESULTS The mean (SD) cerebrospinal fluid LOTUS concentration in the relapse group of RRMS (9.3 [3.6] mu g/dL) was lower than that of NCs (19.2 [4.7] mu g/dL; P < .001) whereas the level in the remission group of RRMS (19.6 [5.8] mu g/dL) was similar to that of NCs. The LOTUS concentration in SPMS (6.7 [1.4] mu g/dL; P < .001) was lower than that of NCs and the remission group of RRMS. The LOTUS levels in other neurodegenerative diseases, such as amyotrophic lateral sclerosis and multiple system atrophy, were normal.CONCLUSIONS AND RELEVANCE Variations in LOTUS concentrations were correlated with disease activity in MS. Therefore, LOTUS concentration may be useful as a possible biomarker for MS. Low LOTUS concentrations may be possibly involved in Nogo receptor-1 signaling, which may induce axonal degeneration in the relapse phase of RRMS and secondary progressive MS.