Frontotemporal degeneration: a basis for clinical trials

描述（由申请人提供）：为了在牛头病变患者中测试药物，必须以适合设计临床试验的术语表达额颞叶痴呆（FTLD）的自然史知识。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、多地点的纵向研究，我们将使用标准化标准招募受试者。该项目的具体目的是：1)确定认知、行为和功能工具的变化和方差之比，以估计在未来的临床试验中使用每种工具检测治疗效果的能力；2)进行连续磁共振成像，以确定整体和区域额叶或颞叶脑容量的变化幅度及其方差，以便估计在未来临床试验中检测治疗对脑容量影响的能力；3)开发用于临床试验的复合ftld亚型特异性认知工具；4)确定ApoE基因型和tau单倍型是否与FTLD的认知、行为、功能或影像学进展速度相关。

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.