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

C9orf72 肌萎缩侧索硬化症和额颞叶痴呆的自然史和生物标志物发现

• 批准号: 9157579
• 负责人: Mary Kay Floeter
• 金额: $ 39.61万
• 依托单位: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9157579
• 关键词: Accounting; Adult; Affect; Aging; Amyotrophic Lateral Sclerosis; Biological Markers; Biopsy; Brain; C9ORF72; Clinic; Clinical; Clinical Trials; Cognitive; Consent; DNA; Data; Databases; Deterioration; Diffusion; Diffusion Magnetic Resonance Imaging; Dipeptides; Disease; Disease Marker; Disease Progression; Enrollment; Extramural Activities; Familial Amyotrophic Lateral Sclerosis; Frontotemporal Dementia; Functional Magnetic Resonance Imaging; Genes; Housing; Image; Impaired cognition; Individual; Institutes; Institutional Review Boards; Knowledge; Longitudinal Studies; Magnetic Resonance Imaging; Measurement; Measures; Motor; Mutation; Myography; Natural History; Neurodegenerative Disorders; Neuropsychological Tests; Participant; Patients; Physiological; Plasma; Relative (related person); Reporting; Research Personnel; Resolution; Rest; Retrospective Studies; Sampling; Severity of illness; Signal Transduction; Skin; Specimen; Speed; Structure; Symptoms; Testing; Transcranial magnetic stimulation; United States National Institutes of Health; Visit; cohort; design; follow-up; prospective

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.

肌萎缩侧索硬化症 (ALS) 和额颞叶痴呆 (FTD) 是成人发病的神经退行性疾病，其中多达三分之一的患者具有重叠的临床和病理特征。 2011 年，人们发现 C9ORF72 基因中存在大量六核苷酸重复扩增，从而导致 ALS 和 FTD。使用储存的 DNA 样本进行的回顾性研究发现携带 C9orf72 突变的患者报告称，这是家族性 ALS 和家族性 FTD 的最常见原因，也是大量散发性 ALS 病例的原因。尽管通过储存样本的检测识别出大量患者，但人们对 C9ORF72 相关疾病的自然史知之甚少：运动无力和认知功能障碍进展的速度、临床表现是否影响生存，以及在明确症状出现之前是否可以检测到细微的运动或认知异常。因此，该项目的首要目标是通过对一组携带 C9ORF72 重复扩增的有症状个体和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。该研究的第二个目的是探索疾病进展的候选生物标志物。在临床明显恶化之前可以发出疾病活动改善或下降信号的生物标志物对于加快临床试验周期很有价值。将在纵向访视时收集生理学、影像学和生物流体生物标志物，以检查它们与临床进展指标的相关性。这是一项高度合作的研究。国家衰老研究所的合作研究员 Bryan Traynor 博士正在协调生物流体标记物的探索性研究。所有参与者都同意共享去识别化的数据和样本。 研究的组织、IRB 批准、研究协调员的聘用以及数据库建设均于 2013-4 财年完成，第一个参与者于 2014 财年入组。参与者在入组和 NIH 随访时接受一系列结构化的临床评级、神经心理学测试和运动测量，以评估疾病严重程度。参与者通常会入住当地酒店进行为期 2 或 3 天的访问。在这些访问中收集的候选生物标志物包括：经颅磁刺激、电阻抗肌描记法；脑部 MRI，用于静息态功能 MRI、弥散张量成像和高分辨率 T1；血浆、血清和脑脊液。校外合作者一次就诊即可获得皮肤活检。 2015 财年末，将完成 25 名参与者的基线访视、18 名参与者进行 6 个月的随访、4 名参与者进行 18 个月的随访。前 20 次基线访问的数据库质量检查已经完成，对这些访问的经颅磁刺激数据以及扩散和体积成像的分析正在进行中。约翰·霍普金斯大学和梅奥诊所的研究人员已与脑脊液标本共享，探索重复相关二肽作为疾病活动的标志物。