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。C9ORF72扩增突变是美国家族性ALS和家族性FTD最常见的原因，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无症状携带者进行为期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。这是一项高度合作的研究。美国国家老龄研究所的合作研究员布莱恩·特雷诺博士负责协调对生物标本的研究。所有参与者都同意分享已查明身份的数据和标本。 参与者在NIH注册2-4天后接受一系列有组织的临床评级、神经心理测试和运动测量，并进行随访，以评估疾病的严重性和进展。获得生理、成像和生物流体生物标记物，以检查它们与临床进展措施的相关性。皮肤活检是为研究疾病机制的外部合作者一次访问获得的。第一位参与者是在2014财年注册的。截至2016财年结束，已有34名C9ORF72突变携带者入选，并进行了91次访问。到目前为止，经颅磁刺激研究发现了表现出较低运动神经元体征的患者皮质过度兴奋的证据。对纵向生理和成像数据的分析正在进行中。脑脊液和血浆样本已经与约翰·霍普金斯大学、梅奥诊所杰克逊维尔的研究人员和制药公司共享，以探索疾病活动的标志和疾病机制。

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. The C9ORF72 expansion mutation is the commonest cause of familial ALS and familial FTD in the US 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 asymptomatic 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. This is a highly collaborative study. Studies of biospecimens are coordinated by Dr. Bryan Traynor, a collaborative investigator in the National Institute of Aging. All participants consent to sharing of de-identified data and specimens. Participants undergo a structured battery of clinical ratings, neuropsychological tests, and motor measurements over a 2-4 day visit at NIH at enrollment and follow-up to assess disease severity and progression. Physiological, imaging, and biofluid biomarkers are obtained to examine their correlations with the clinical measures of progression. Skin biopsies are obtained at one visit for extramural collaborators studying disease mechanisms. The first participant was enrolled in FY14. As FY16 ends, 34 C9ORF72 mutation carriers have been enrolled and 91 visits have been carried out. To date, transcranial magnetic stimulation studies found evidence of cortical hyperexcitability in patients exhibiting lower motor neuron signs. Analysis of longitudinal physiological and imaging data is underway. CSF and plasma specimens have been shared with investigators at Johns Hopkins University, the Mayo Clinic Jacksonville, and pharmaceutical companies for exploring markers of disease activity and mechanisms of disease.