JPND: Stratification of presymptomatic amyotrophic lateral sclerosis: the development of novel imaging biomarkers

肌萎缩侧索硬化症（Amyotrophic lateral sclerosis，ALS）是一种进行性神经退行性疾病，目前尚无有效的治疗方法。根据目前的诊断标准，全球范围内症状发作和诊断之间的延迟约为12个月，这使得无法及时将疑似患者纳入临床试验。当患者被招募进行成像和药理学研究时，已经发生了显著的病理变化。虽然绝大多数现有的ALS研究是“后症状”，疾病的症状前阶段是一个独特的机会，以评估疾病传播的机制，解剖扩散的模式，验证分期系统和评估新兴的成像方式的比较敏感性。尽管脊髓影像学研究有可能发现ALS的下运动神经元和上运动神经元成分，但目前对ALS的脊髓影像学研究很少。该联盟建议开展一项大型的，前瞻性的，多中心的，纵向研究的无症状和有症状的c9orf72六核苷酸载体使用目的设计的脊髓和脑成像协议和全面的临床，遗传，电生理和神经心理学分析。除了已建立的脊髓和脑成像技术外，还将实施新开发的成像技术，如脊髓NODDI、脊髓fMRI、定量胸髓成像。无症状六核苷酸突变携带者目前没有准确的预后指标来预测他们是否会发展为ALS或FTD以及何时可能出现症状。除了表征症状前传播模式的学术相关性之外，该研究还具有许多实用的可交付成果，例如开发个性化的预后指标，敏感的基于成像的诊断方案和新的监测工具，这些工具对于未来生物标志物支持的临床试验设计是不可或缺的。该提案致力于利用最新的技术进步，开发用于学术应用、临床试验、患者和疑似患者的临床护理以及支持无症状亲属的精确成像工具。该应用的最终愿望是优化新型成像方案，其将可转移到其他运动神经元疾病、痴呆综合征，并有意义地促进新型疾病修饰疗法的开发。

Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive neurodegenerative disorder with no effective disease-modifying therapies at present. The delay between symptom onset and diagnosis by current diagnostic criteria is approximately 12 months worldwide which precludes the timely inclusion of suspected patients into clinical trials. By the time patients are recruited into imaging and pharmacological studies significant pathological changes have already taken place. While the vast majority of existing ALS studies are 'post-symptomatic', the presymptomatic phase of the disease represents a unique opportunity to evaluate mechanisms of disease propagation, characterise patterns of anatomical spread, validate staging systems and appraise the comparative sensitivity profile of emerging imaging modalities. Very few spinal cord imaging studies currently exist in ALS despite their potential to characterise both the lower and upper motor neuron components of the disease. This consortium proposes to embark on a large, prospective, multicentre, longitudinal study of asymptomatic and symptomatic c9orf72 hexanucleotide carriers using a purpose-designed spinal and brain imaging protocol and comprehensive clinical, genetic, electrophysiological and neuropsychological profiling. Newly developed imaging techniques such as spinal cord NODDI, spinal fMRI, quantitative thoracic cord imaging will be implemented in addition to established spinal cord and brain imaging techniques. No accurate prognostic indicators currently exist in asymptomatic hexanucleotide mutation carriers to foretell if they will develop ALS or FTD and when symptoms are likely to manifest. Beyond the academic relevance of characterising presymptomatic propagation patterns, the study has a number of pragmatic deliverables such as the development of individualised prognostic indicators, sensitive imaging-based diagnostic protocols and novel monitoring tools which are indispensable for future biomarker-supported clinical trial designs. This proposal endeavours to capitalise on recent technological advances to develop precision imaging tools for academic applications, clinical trials, the clinical care of patients and suspected patients and the support asymptomatic relatives. The ultimate aspiration of this application is the optimisation of novel imaging protocols which will be transferable to other motor neuron diseases, dementia syndromes, and meaningfully contribute to the development of novel disease-modifying therapies.