Diagnostic and Natural History Markers in ALS

肌萎缩侧索硬化症（Amyotrophic lateral sclerosis，ALS）是一种严重的神经系统疾病。 它影响上下运动神经元（UMN和LMN）。 原因在很大程度上是未知的，因此没有有效的治疗方法。 迄今为止，“没有客观和定量的UMN或LMN标记物”是可用的-ALS最严重的缺陷之一。 因此，“对UMN和LMN受累的发病机制的理解”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）研究几种新技术来建立准确的UMN和LMN标志物，（2）研究这些标志物是否提供早期诊断和具有临床意义的自然病史数据，这些数据表明随着时间的推移发生了高灵敏度的变化，（3）确定这些标志物是否能准确地预测ALS的残疾和生存，以及（4）在组织学上验证用技术鉴定的标记物观察到的变化。 首先，将在两个医院使用新兴的神经影像技术建立健康对照组的重测有效性和正常数据。 在疑似/可能的ALS或可能/确定的ALS患者中，我们将调查以下定量证据：（1）通过单体素磁共振波谱（MRS）在运动皮层区域的UMN受累，以及通过多体素MRS更准确地在初级运动皮层的UMN受累;（2）通过MR扩散张量成像的下行UMN纤维束的纤维束完整性;和（3）使用经颅磁刺激技术的皮质脊髓束的生理完整性。 将通过使用多点刺激技术的运动单位数量估计来研究LMN标记。 ALS状态将通过充分验证的定量临床评估来测量。 患者将每3个月随访一次，持续15个月。 将通过统计建模分析技术确定的标志物用作临床试验终点的替代标志物的潜在价值。 功能障碍和生存率也将与这些标志物相关。 当允许尸检时，将对技术识别的标记物进行组织学验证。据我们所知，该项目将是第一个全面的方法来研究如何开发可靠的ALS早期诊断，在临床试验中开发替代标志物，并改善ALS的诊断。 从该项目中获得的知识不仅将扩大对ALS中UMN和LMN参与的发病机制的理解，而且将在不久的将来允许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.