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”，这是ALS最严重的缺陷之一。因此，“对UMN和LMN累及的发病机制的了解”是有限的，并且没有可靠的早期诊断和有效的替代标志物。因此，我们建议(1)研究几种新技术来建立准确的UMN和LMN标记，(2)研究这些标记是否提供早期诊断和临床有意义的自然历史数据，这些数据可以高灵敏度地指示随时间的变化，(3)确定这些标记是否可以预测ALS的残疾和生存，以及(4)从组织学上验证技术识别标记所观察到的变化。首先，使用新兴的神经成像技术在两个医院校区的健康对照中建立重测效度和正常数据。对于疑似/可能的ALS或可能/确定的ALS患者，我们将通过单体素磁共振波谱（MRS）和多体素磁共振波谱（MRS）更准确地研究UMN累及运动皮层区域的定量证据；(2)磁共振扩散张量成像下行UMN纤维束完整性；(3)经颅磁刺激技术对皮质脊髓束生理完整性的影响。利用多点刺激技术估计运动单元数，研究LMN标记。ALS状态将通过有效的定量临床评估来衡量。每3个月随访一次，随访15个月。技术鉴定标记物作为替代标记物作为临床试验终点的潜在价值将通过统计建模进行分析。功能性残疾和生存也将与这些标志物相关。当允许尸检时，技术识别标记将在组织学上进行验证。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记物，并改善ALS的预后。从该项目中获得的知识不仅将扩大对UMN和LMN参与ALS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，提高对该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.