Project 2

摘要- ARTFL LEFFTDS纵向FTLD：项目2 对FTLD生物学理解的提高，以及药物治疗的革命性进展 开发，已经创造了新的化合物，可以改变基本的生物机制，造成 FTLD。FTLD通常与潜在的tau（FTLD-tau）或TAR DNA结合蛋白相关 43（FTLD-TDP）脑神经病理学和许多新的治疗方法，现在正在进入临床试验的目标之一 或者其他的分子病理学。这给临床试验设计带来了一个重大挑战：如何 测量这些新的分子靶向治疗在临床异质性，症状， FTLD人群。该项目的第一个目标是开发新的临床工具和替代终点， 在异质性FTLD临床人群中测量疾病进展。第二个目标是发展 在临床试验入组时对患者进行分层的方法， 变化率或对特定治疗策略的反应。我们将开发优化的临床，成像 症状性FTLD临床试验的生物标志物终点，可能包括多种临床和遗传学研究。 具有单一分子病理学的变体（称为篮式试验设计）或可在患者中展开 具有共同表型（标准平行设计），以提高检测治疗效果的功效。纵向 将在多中心临床试验就绪人群中收集临床、成像和液体生物标志物数据 代表FTLD的完整临床谱，包括散发性FTLD（n=600）和症状性f-FTLD （n=167）来自ARTFL LEFFTDS纵向额颞叶变性（ALLFTD）联盟， 这构成了中心的核心小组，将支持北卡罗来纳州FTLD临床试验的招募。 美国参考我们还将研究在试验中使用每种方法开发个性化结果的影响。 患者的基线特征，以预测哪些指标将随着时间的推移而下降，特别强调 最大限度地发挥对患者的临床意义。具体目标是：（1）确定最佳 临床和基于MRI的终点，用于测量入组患者的“篮子设计”临床试验的疗效 根据预测的潜在蛋白质病理学，（2）开发试验富集策略，其联合收割机 多个基线特征来预测FTLD的临床变化，和（3）研究炎症作为一种 症状性FTLD的潜在晚期治疗靶点。

ABSTRACT – ARTFL LEFFTDS Longitudinal FTLD: Project 2 Improvements in understanding the biology of FTLD, combined with revolutionary advancements in drug development, have created new compounds that can alter the fundamental biological mechanisms that cause FTLD. FTLD is most commonly associated with either underlying tau (FTLD-tau) or TAR DNA binding protein 43 (FTLD-TDP) brain neuropathology and many new treatments that are now entering clinical trials target one or the other of these molecular pathologies. This creates a major challenge for designing clinical trials: how to measure the effects of these new molecularly-targeted therapies in clinically heterogeneous, symptomatic FTLD populations. The first goal of this project is to develop new clinical tools and surrogate endpoints that can measure disease progression in heterogeneous FTLD clinical populations. The second goal is to develop methods to stratify patients at the time of clinical trial enrollment to define populations with more predictable rates of change or responses to specific therapeutic strategies. We will develop optimized clinical, imaging and biomarker endpoints for symptomatic FTLD clinical trials that could include multiple clinical and genetic variants with a single molecular pathology (referred to as a basket trial design) or could be deployed in patients with a common phenotype (standard parallel design) to improve power to detect treatment effects. Longitudinal clinical, imaging and fluid biomarker data will be collected in a multicenter clinical trial-ready population representing the full clinical spectrum of FTLD, including both sporadic FTLD (n=600) and symptomatic f-FTLD (n=167) from the ARTFL LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) consortium, which constitutes the core group of centers that will support recruitment for FTLD clinical trials in North America. We will also examine the impact of developing personalized outcomes in a trial by using each patient's baseline characteristics to predict which measures will decline over time, with a particular emphasis on maximizing what is most clinically meaningful to that patient. The specific aims are to: (1) identify the best clinical and MRI-based endpoints to measure efficacy in “basket design” clinical trials that enroll patients according to predicted underlying protein pathology, (2) develop trial enrichment strategies that combine multiple baseline characteristics to predict clinical change in FTLD, and (3) investigate inflammation as a potential late stage therapeutic target in symptomatic FTLD.