CSF Indicators for Diagnosis and Disease Progression of ALS

描述(申请人提供)：在美国，大约有30,000人患有肌萎缩侧索硬化症(ALS)，每年新增5000例确诊病例。肌萎缩侧索硬化症是最衰弱的神经退行性疾病之一，起病于成人(30-70岁)。它的临床特征是说话和吞咽困难，肌肉无力，消瘦，发炎和痉挛，原因是皮质和脊髓运动神经元的选择性变性。呼吸衰竭导致的死亡通常发生在确诊后的3-5年内。目前还没有明显改善或延缓疾病进展的治疗方法。此外，对这种疾病的潜在病理生理过程几乎没有或根本没有了解。散发的ALS病例占总病例的95%，目前还没有特异性的实验室检测来确认诊断。黄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的情况，但由于疾病的高度可变表现，这一点变得复杂。ALS的治疗被推迟，因为疾病的进展是临床表现的重要部分，而且ALS的早期病例很难诊断。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。这项建议概述了确定是否可以在ALS患者中识别类似生物标志物的实验。我们的初步数据表明，在ALS患者的脑脊液(CSF)中，中枢神经系统(CNS)中存在针对特定蛋白的抗体。到目前为止，接受检查的10个患者样本中有8个具有这些抗体。在测试的健康或神经对照样本中不存在这些抗体。ALS的自身免疫问题仍然存在争议；然而，ALS患者中针对特定蛋白的抗体将具有临床和科学价值。该方案中的实验利用了独特的临床资源，旨在进一步调查ALS患者中是否存在针对特定CNS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，从而能够更快地诊断这种疾病。此外，如果发现了这种抗体，鉴定这些抗体所针对的蛋白质可能会为至少一群散发性ALS患者提供对疾病病理的洞察。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：这项建议中的实验利用了独特的临床资源，旨在进一步调查ALS患者中是否存在针对特定CNS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，从而能够更快地诊断这种疾病。此外，如果发现了这种抗体，鉴定这些抗体所针对的蛋白质可能会为至少一群散发性ALS患者提供对疾病病理的洞察。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.