CSF Indicators for Diagnosis and Disease Progression of ALS

描述（由申请人提供）：在美国，大约有30,000人患有肌萎缩性侧索硬化症（ALS），每年有5000个新病例被诊断出来。肌萎缩性侧索硬化症是最衰弱的神经退行性疾病之一，发病年龄为成人（30-70岁）。它的临床特征是语言和吞咽困难、肌肉无力、消瘦、脓疡和痉挛，这是由皮质和脊髓运动神经元选择性变性引起的。呼吸衰竭导致的死亡通常发生在诊断后3-5年内。目前还没有一种治疗方法可以显著改善或延缓疾病的进展。此外，对这种疾病的潜在病理生理过程几乎没有了解。零星的ALS病例占总病例的95%，没有特定的实验室检查可以确诊。金标准仍然是由实验室测试支持的临床检查，以排除可能模仿ALS的条件，但由于疾病的高度可变表现，这变得复杂。由于疾病进展是临床表现的重要组成部分，并且早期ALS病例难以诊断，因此延迟了对ALS的治疗。狼疮、副肿瘤综合征和重症肌无力等疾病的特异性生物标志物直接反映了这些疾病的病因，是首选的诊断方法。这一建议概述了实验，以确定是否类似的生物标志物可以识别在ALS患者。我们的初步数据表明，在ALS患者脑脊液（CSF）中，中枢神经系统（CNS）中存在针对特定蛋白质的抗体。到目前为止，10个患者样本中有8个含有这些抗体。这些抗体在健康或神经控制样本中不存在。ALS的自身免疫问题仍有争议；然而，针对ALS患者的特定蛋白质的抗体将具有临床和科学价值。本实验利用独特的临床资源，旨在进一步研究ALS患者中是否存在针对特定中枢神经系统蛋白的抗体。如果是这样的话，这些抗体可能会提供一种临床测试方法，从而更快地诊断出这种疾病。此外，如果发现这样的抗体，鉴定这些抗体所指向的蛋白质可能为至少散发性ALS患者的亚群提供疾病病理学的见解。这将有助于指导未来的研究，以确定有效的治疗方法。公共卫生相关性：本提案中的实验利用独特的临床资源，旨在进一步研究ALS患者中是否存在针对特定中枢神经系统蛋白的抗体。如果是这样的话，这些抗体可能会提供一种临床测试方法，从而更快地诊断出这种疾病。此外，如果发现这样的抗体，鉴定这些抗体所指向的蛋白质可能为至少散发性ALS患者的亚群提供疾病病理学的见解。这将有助于指导未来的研究，以确定有效的治疗方法。

DESCRIPTION (provided by applicant): In the United States, approximately 30,000 individuals have amyotrophic lateral sclerosis (ALS), with 5000 new cases being diagnosed each year. ALS is one of the most debilitating neurodegenerative diseases with an adult onset (30-70 years of age). It is clinically characterized by difficulties with speech and swallowing, muscle weakness, wasting, fesiculations and spasticity resulting from selective degeneration of cortical and spinal motorneurons. Death resulting from respiratory failure typically occurs within 3-5 years from diagnosis. Currently there is no treatment that significantly ameliorates or delays the progression of the disease. Furthermore, there is little to no understanding of the underlying pathophysiological processes of this disorder. Sporadic cases of ALS make up ~95% of the total cases and there is no specific lab test that can confirm the diagnosis. The gold standard continues to be clinical examination supported by lab testing that rules out conditions that may mimic ALS, but this is complicated by the highly variable presentation of the disease. Treatment of ALS is delayed because progression of disease is an important part of the clinical presentation and early cases of ALS are difficult to diagnose. Specific biologic markers for diseases such as lupus, paraneoplastic syndromes, and myasthenia gravis directly reflect the cause of these diseases and are the preferred diagnostic methods. This proposal outlines experiments to determine if similar biologic markers can be identified in ALS patients. Our preliminary data indicate that in ALS patient cerebral spinal fluid (CSF) there are antibodies to specific proteins in the central nervous system (CNS). Eight of ten patient samples examined so far had these antibodies. The antibodies were not present in healthy or neurological control samples tested. The question of autoimmunity in ALS remains controversial; however, antibodies to specific proteins in ALS patients would be of clinical and scientific value. The experiments in this proposal take advantage of unique clinical resources and are designed to further investigate if there are antibodies to specific CNS proteins present in ALS patients. If so, these antibodies may provide a clinical test that would allow for a more rapid diagnosis of the disease. Furthermore, if such antibodies are found, identification of the proteins to which these antibodies are directed may provide insight into disease pathology for at least a sub-population of sporadic ALS patients. This would help direct future research to identify effective therapeutic approaches. PUBLIC HEALTH RELEVANCE: The experiments in this proposal take advantage of unique clinical resources and are designed to further investigate if there are antibodies to specific CNS proteins present in ALS patients. If so, these antibodies may provide a clinical test that would allow for a more rapid diagnosis of the disease. Furthermore, if such antibodies are found, identification of the proteins to which these antibodies are directed may provide insight into disease pathology for at least a sub-population of sporadic ALS patients. This would help direct future research to identify effective therapeutic approaches.