Diagnostic and Natural History Markers in ALS

肌萎缩侧索硬化症(ALS)是最具破坏性的神经系统疾病之一。它影响上下运动神经元(UMN和LMN)。病因在很大程度上尚不清楚，因此还没有有效的治疗方法。到目前为止，“还没有客观和定量的UMN或LMN标记物”-ALS最严重的缺陷之一。因此，对UMN和LMN受累的发病机制的了解是有限的，并且没有可靠的早期诊断和有效的替代标记物。因此，我们建议(1)研究几种新技术以建立准确的UMN和LMN标记物，(2)调查这些标记物是否提供早期诊断和具有临床意义的自然病史数据，这些数据以高灵敏度指示随时间的变化，(3)确定这些标记物是否可以预测ALS残疾和生存，以及(4)从组织学上验证技术识别的标记物所观察到的变化。首先，将在两个医院校园使用新兴的神经成像技术在健康对照组中建立重测效度和正常数据。对于疑似/可能的ALS或可能/确诊的ALS患者，我们将调查以下定量证据：(1)单体素磁共振波谱(MRS)显示运动区UMN受累，多体素MRS更准确地显示初级运动皮质UMN受累；(2)MR弥散张量成像显示UMN下行纤维束的纤维束完整性；(3)经颅磁刺激技术检测皮质脊髓束的生理完整性。LMN标记将通过使用多点刺激技术的运动单位数量估计来研究。肌萎缩侧索硬化症的状态将通过经过充分验证的量化临床评估来衡量。患者将每3个月随访一次，为期15个月。技术识别的标记用作临床试验终点的替代标记的潜在价值将通过统计建模进行分析。功能性残疾和存活率也将与这些标记物相关。当尸检被允许时，技术识别的标记将被组织学验证。据我们所知，这个项目将是第一个全面的方法来研究如何发展ALS的可靠和早期诊断，在临床试验中开发替代标记物，并改善ALS的预后。从这个项目中获得的知识不仅将扩大对肌萎缩侧索硬化症中UMN和LMN参与的发病机制的了解，还将在不久的将来允许进行更有效的新药临床试验，并改善这种疾病患者的诊断和治疗。

Amyotrophic lateral sclerosis (ALS) is one of the most devastating neurological diseases. It affects upper and lower motor neurons (UMN and LMN). The cause is largely unknown, so no effective treatments are available. To date, "no objective and quantitative UMN or LMN markers" are available---one of most serious deficiencies in ALS. Thus, "understanding of the pathogenesis of UMN and LMN involvement" is limited, and no reliable early diagnosis and effective surrogate markers are available. Therefore, we propose (1) to investigate several novel technologies to establish accurate UMN and LMN markers, (2) to investigate whether these markers provide early diagnosis and clinically meaningful natural history data that indicate changes over time with high sensitivity, (3) to identify whether these markers prognosticate ALS disability and survival, and (4) to validate histologically the changes observed with technology- identified markers. First, test-retest validity and normal data will be established in healthy controls using emerging neuroimaging technologies at two hospital campuses. In patients with suspected/possible ALS or probable/definite ALS, we will investigate quantitative evidence for (1) UMN involvement at the motor cortex area by single-voxel magnetic resonance spectroscopy (MRS) and more accurately at the primary motor cortex by multiple-voxel MRS; (2) fiber tract integrity of descending UMN fiber tracts by MR diffusion tensor imaging; and (3) physiological integrity of the corticospinal tracts using transcranial magnetic stimulation technology. An LMN marker will be studied by motor unit number estimation using multiple point stimulation technology. ALS status will be measured by well- validated quantitative clinical assessments. The patients will be followed every 3 months for 15 months. The potential value of the technology-identified markers for use as surrogate markers as endpoints in clinical trials will be analyzed by statistical modeling. Functional disability and survival also will be correlated with these markers. When autopsy is permitted, technology-identified markers will be validated histologically. To our knowledge, this project will be the first comprehensive approach to investigate ways to develop a reliable and early diagnosis of ALS, to develop surrogate markers in clinical trials, and to improve prognostication in ALS. The knowledge gained from this project not only will expand understanding of the pathogenesis of UMN and LMN involvement in ALS, but also will permit more effective clinical trials of new drugs in the near future and improve diagnosis and treatment for patients with this disease.