Project 2

摘要-ARTFL LEFFTDS纵向FTLD：项目2 对FTLD生物学认识的进步，结合药物方面的革命性进展 发展，创造了新的化合物，可以改变导致 FTLD。FTLD最常与潜在的tau(FTLD-tau)或TAR DNA结合蛋白有关 43(FTLD-TDP)脑神经病理学和许多正在进入临床试验的新疗法针对的是一个 或者这些分子病理中的另一种。这给设计临床试验带来了一个重大挑战：如何 测量这些新的分子靶向疗法对临床异质性、症状性 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端，这些终端可以 测量不同FTLD临床人群的疾病进展。第二个目标是发展 方法在临床试验登记时对患者进行分层，以确定更具预测性的人群 对特定治疗策略的改变率或应答率。我们将开发优化的临床、成像 和生物标志物终点，用于可能包括多个临床和遗传学的症状FTLD临床试验 具有单分子病理的变体(称为篮子试验设计)或可在患者中部署 具有共同表型(标准平行设计)，以提高检测治疗效果的能力。纵向 临床、影像和液体生物标记物数据将在多中心临床试验准备人群中收集 代表FTLD的全部临床范围，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， 它构成了支持北方FTLD临床试验招募的核心中心群 美国。我们还将检查在试验中开发个性化结果的影响 患者的基线特征，以预测哪些措施将随着时间的推移而下降，并特别强调 最大化对患者最有临床意义的东西。具体目标是：(1)找出最好的 临床和基于MRI的终点在招募患者的“篮子设计”临床试验中衡量疗效 根据预测的潜在蛋白质病理学，(2)开发试验浓缩策略，结合 预测FTLD临床变化的多个基线特征，以及(3)调查炎症作为 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.