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。C9orf72基因的重复扩增突变是美国家族性ALS和家族性FTD最常见的原因，也是散发性ALS病例的5%-8%的原因。2013年，我们开始了一项针对C9orf72突变携带者的前瞻性纵向研究，其中包括无症状携带者、ALS患者和FTD患者。第一个目标是了解C9orf72相关疾病的自然历史：虚弱和认知功能障碍进展的速度有多快，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。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。临床试验需要在临床明显恶化之前发出疾病活跃度改善或下降的信号的生物标志物。在三年的四次访问中，每次都要收集成像、生理学和生物液。获得的生物样品正在与NIH内外的合作者共享，以促进翻译研究。 截至17财年末，已有45名C9orf72突变携带者参加了自然史研究。我们已经公布了前半部分受试者的临床、影像和生理学结果，并对其进行了18个月的随访。为了记录临床进展，需要对运动、认知和行为功能进行测量。影像显示有认知功能障碍的C9orf72携带者的运动外区域有更广泛的体积损失。脑室扩大和脑白质弥漫性改变可在6个月内被检测到。与学术机构和制药公司的合作者分享了生物谱系，他们在纵向标本中发现了重复扩张产生的稳定水平的二肽，支持将其用作药效标记物。其他脊髓液蛋白也被发现与疾病活动有关。这些措施显示出作为生物标记物的前景，这将对临床试验有用。 为了更好地了解导致扩散成像变化的脑组织变化，在17财年，我们完成了一项扩散张量成像的分析，并发表了一项关于ALS患者尸检大脑的扩散张量成像的研究，其中包括C9orf72突变，并将分数各向异性测量与组织学相关联。分数各向异性丢失背后的组织变化包括轴突丢失，但更引人注目的是小胶质细胞的渗透，这在C9orf72 ALS患者中更为明显。

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. A repeat expansion mutation in the C9orf72 gene is the commonest cause of familial ALS and familial FTD in the US and also accounts for a 5-8% of ALS cases thought to be sporadic. In 2013, we began a prospective longitudinal study of persons who carry the C9orf72 mutation that includes asymptomatic carriers, patients with ALS, and patients with FTD. The first goal is to understand the natural history of C9orf72-related disease: how quickly 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. The second aim of the study is to explore candidate biomarkers of disease progression. Biomarkers that signal improvement or decline in disease activity before clinically evident deterioration are need for clinical trials. Imaging, physiology, and biofluids are being collected at each of 4 visits over 3 years. Biospecimens obtained are being shared with collaborators within and outside NIH, to facilitate translational research. As of the end of FY 17, 45 C9orf72 mutation carriers have been enrolled in the natural history study. We have published clinical, imaging, and physiological findings from the first half of the enrolled participants followed through 18 months. To capture clinical progression, measures of motor, cognitive and behavioral function were needed. Imaging shows more extensive volume loss of extramotor areas in C9orf72 carriers with cognitive dysfunction. Ventricular enlargement and spread of white matter diffusion alterations could be detected over a 6-month period. Biospecimens were shared with collaborators at academic institutions and pharmaceutical companies, who found stable levels of the dipeptide made by the repeat expansion in longitudinal specimens, supporting its use as a pharmacodynamic markers. Other spinal fluid proteins were found to be associated with disease activity. These measures show promise as biomarkers that will be useful for clinical trials. To better understand changes in brain tissue that produce the alterations in diffusion imaging, in FY17 we completed analysis and published a study of diffusion tensor imaging in autopsy brains of patients with ALS with or without the C9orf72 mutation, and correlated fractional anistropy measures with histology. Tissue changes underlying loss of fractional anisotropy included axonal loss, but more striking was the microglial infiltration, which was more pronounced in C9orf72 ALS patients.