Frontotemporal degeneration: a basis for clinical trials

描述(由申请者提供)：为了在紧张症患者中测试药物，额颞叶痴呆(FTLD)的自然病史知识必须以适合设计临床试验的术语来表达。如果没有对6个月或12个月变化的有效估计，就无法确定适用于试验的工具和试验的样本量。我们建议对FTLD患者进行一项为期4年的多点纵向研究，在该研究中，我们将使用标准化标准招募受试者。该项目的具体目标是1)确定认知、行为和功能仪器的变化与变异之间的比率，以便在未来的临床试验中估计每种仪器检测治疗效果的能力；2)进行系列磁共振成像，以确定全球和区域性额叶或颞叶脑体积的变化幅度及其方差，以便在未来的临床试验中估计对脑容量的治疗影响；3)开发一种针对FTLD亚型的复合认知仪器，用于临床试验；以及4)确定ApoE基因和tau单倍型是否与FTLD的认知、行为、功能或成像的进展率有关。 我们建议让3个阿尔茨海默病中心(梅奥·罗切斯特/杰克逊维尔、加州大学洛杉矶分校和亚利桑那州)以及加州大学旧金山分校招募120名FTLD患者。我们将招募额颞叶痴呆的行为执行障碍综合征患者、语义性痴呆患者和进行性非流利性失语患者。这三种综合征的操作标准已经制定，将符合适用于临床试验招募的严格标准。受试者将在基线和12个月时接受认知、行为、功能评估以及磁共振成像检查。关键结果将包括对磁共振成像一年内变化及其变异性的估计，认知任务(包括复合任务)的变化，以及功能和行为测量的变化。虽然这项研究还将发展关于FTLD认知、行为和大脑结构之间关系的丰富新知识，但这项研究的基本成果将是FTLD药物试验基本设计的基本原则。

DESCRIPTION (provided by applicant): In order to test drugs in patients with tauopathies, knowledge of the natural history of the frontotemporal lobar dementias (FTLD) must be expressed in terms suitable for designing clinical trials. Without valid estimates of change over 6 or 12 months, instruments appropriate for trials and sample sizes for the trials simply cannot be determined. We are proposing a 4 year, multi-site, longitudinal study of patients with FTLD in which we will recruit subjects using standardized criteria. The specific aims of this project are 1) determine the ratio between change and variance in cognitive, behavioral and functional instruments in order to estimate power to detect treatment effects with each instrument in future clinical trials; 2) perform serial MR imaging to determine the magnitude of change and its variance in global and regional frontal or temporal brain volume in order to estimate power to detect treatment effects on brain volume in future clinical trials; 3) develop a composite FTLD-subtype-specific cognitive instrument for use in clinical trials; and 4) determine whether ApoE genotype and tau haplotype are associated with rate of progression on cognitive, behavioral, functional or imaging in FTLD. We propose to involve 3 Alzheimer Disease Centers (Mayo Rochester/Jacksonville, UCLA and Arizona) plus the University of California- San Francisco to recruit 120 patients with FTLD. We shall recruit patients with the behavioral-dysexecutive syndrome of fronto-temporal dementia, patients with semantic dementia, and patients with progressive nonfluent aphasia. Operational criteria for these 3 syndromes have been developed that will meet rigorous standards suitable for clinical trial recruitment. Subjects will be examined with cognitive, behavioral, functional assessments as well as MR imaging at baseline and 12 months. Key outcomes will include estimates of change and its variability over 1 year on MR imaging, change on cognitive tasks including the composite task, and change on functional and behavioral measures. While the study will also develop a wealth of new knowledge about the relationships between cognition, behavior and brain structure in FTLD, the essential product of this study will be the principles underlying a rationale design for trials of drugs for FTLD.