Natural history and biomarker discovery in C9orf72 Amyotrophic lateral sclerosis and frontotemporal dementia

肌萎缩侧索硬化症(ALS)和额颞叶痴呆(FTD)是成人起病的神经退行性疾病，多达三分之一的患者具有重叠的临床和病理特征。2011年，在C9ORF72基因上发现了一个大的六核苷酸重复扩增，导致了ALS和FTD。利用储存的DNA样本确定携带C9orf72突变的患者的回顾性研究报告称，C9orf72突变是家族性ALS和家族性FTD的最常见原因，也是相当数量的散发性ALS病例的原因。尽管通过检测储存的样本确定了大量患者，但人们对C9ORF72相关疾病的自然历史知之甚少：运动无力和认知功能障碍的进展速度有多快，临床表现是否影响生存，以及在出现明确症状之前是否可以检测到轻微的运动或认知异常。因此，该项目的第一个目标是通过对一组携带C9ORF72重复扩增的症状个体和作为受影响患者亲属的症状前携带者进行为期3年的前瞻性纵向研究来填补这一知识空白。这项研究的第二个目的是探索疾病进展的候选生物标志物。能够在临床明显恶化之前发出疾病活动改善或下降信号的生物标志物将对加快临床试验的周期具有价值。将在纵向访问中收集生理、影像和生物流体生物标记物，以检查它们与临床进展测量的相关性。这是一项高度合作的研究。生物流体标志物的探索性研究正在由国家老龄研究所的合作研究员布莱恩·特雷诺博士协调。所有参与者都同意分享已查明身份的数据和标本。 这项研究的组织、IRB批准、聘请一名研究协调员和数据库建设在2013-2014财年完成，第一名参与者在2014财年登记。参与者在注册时和在NIH的后续访问中接受一系列有组织的临床评级、神经心理测试和运动测量，以评估疾病的严重性。参与者通常住在当地的酒店里，进行为期2到3天的访问。在这些访问中收集的候选生物标记物包括：经颅磁刺激、电阻抗肌图；用于静息状态功能MRI的脑MRI、扩散张量成像和高分辨率T1；血浆、血清和脑脊液。皮肤活组织检查是对校外协作者一次访问获得的。在2015财年结束时，将完成25名参与者的基线访问，18名参与者进行6个月的跟踪访问，4名参与者进行18个月的跟踪访问。已完成前20次基线检查的数据库质量检查，目前正在分析这些检查的经颅磁刺激数据以及扩散和体积成像。约翰·霍普金斯大学和梅奥诊所的研究人员已经分享了脑脊液样本，探索重复相关二肽作为疾病活动性的标志。

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are adult-onset neurodegenerative disorders in which up to one-third of patients have overlapping clinical and pathological features. In 2011 a large hexanucleotide repeat expansion in the C9ORF72 gene was discovered that caused both ALS and FTD. Retrospective studies using stored DNA samples that identified patients carrying the C9orf72 mutation reported that it is the commonest cause of familial ALS and familial FTD and also accounts for a significant number of sporadic ALS cases. Despite the large number of patients identified from testing of stored samples, relatively little is known about the natural history of C9ORF72-related disease: how quickly the motor weakness and cognitive dysfunction progress, whether clinical presentation influences survival, and whether subtle motor or cognitive abnormalities are detectable prior to the onset of definite symptoms. Therefore, the first aim of this project is designed to fill this knowledge gap through a 3-year prospective longitudinal study of a cohort of symptomatic individuals carrying the C9ORF72 repeat expansion and pre-symptomatic carriers who are relatives of affected patients. The second aim of the study is to explore candidate biomarkers of disease progression. Biomarkers that can signal improvement or decline in disease activity before clinically evident deterioration would be valuable to speed the cycle of clinical trials. Physiological, imaging, and biofluid biomarkers will be collected at longitudinal visits, to examine their correlation with clinical measures of progression. This is a highly collaborative study. Exploratory studies of biofluid markers are being coordinated by a collaborative investigator, Dr. Bryan Traynor, in the National Institute of Aging. All participants consent to sharing of de-identified data and specimens. The organization of the study, IRB approval, hiring of a study coordinator, and database construction were completed in FY13-4, and the first participant was enrolled in FY14. Participants undergo a structured battery of clinical ratings, neuropsychological tests, and motor measurements at enrollment and at follow-up visits to NIH to assess disease severity. Participants are typically housed at a local hotel for the 2 or 3-day visit. At these visits candidate biomarkers collected include: transcranial magnetic stimulation, electroimpedance myography; brain MRI for resting-state functional MRI, diffusion tensor imaging, and high resolution T1; plasma, serum, and CSF. Skin biopsies are obtained at one visit for extramural collaborators. At end FY15, baseline visits will be complete for 25 participants, 18 participants with 6-month follow-ups, and 4 participants with 18-month follow-up visits. Database quality checks have been completed for the first 20 baseline visits, and analysis of transcranial magnetic stimulation data and diffusion and volumetric imaging from those visits is underway. CSF specimens have been shared with investigators at Johns Hopkins and Mayo Clinic exploring repeat-associated dipeptide as a marker of disease activity.