Validating remote digital assessments for familial frontotemporal dementia

项目摘要/摘要 额颞叶痴呆(FTD)是一种致命的神经退行性疾病，表现为行为、认知和 或运动功能障碍，没有有效的治疗方法。大约20%-30%的病例是家族性的(FFTD)，由 常染色体显性突变。越来越多针对这些基因异常的新疗法 正在进入临床试验阶段。Fftd治疗发展的一个主要障碍是缺乏有临床意义的 易于收集并对早期治疗效果敏感的结果衡量标准 疾病。由于fFTD很少见，参与者分散在不同的地理位置，旅行是另一种招募 面对面临床试验的障碍。为了促进更具包容性的临床试验，ARTFL/的研究人员 LEFFTDS纵向FTD(ALLFTD)财团与Datacued Health合作开发一种新的 智能手机应用程序，支持远程测试执行和运动功能，早期受影响的领域 在fFTD中。该提案的目标是验证这些创新的远程智能手机评估 FFTD症状的检测、纵向监测和预测。为了实现这一目标，该项目将 招募两个独立但相关的队列。第一个是1,000人认知和横截面队列 通过与NIH资助的大脑合作登记的不同寿命的成年人的功能完好无损 健康登记处(BHR)。BHR参与者将进行智能手机测试和在线BHR临床测量。这个 BHR队列将用于开发心理测量学稳健的综合分数，并将用于验证 在健康的老龄化队列中得分。第二组是由400名参与者组成的纵向临床验证队列 来自将通过ALLFTD联盟招募的具有已知致病fFTD突变的亲属， 包括100名症状携带者和150名症状前fFTD突变携带者和150名非携带者家系对照。 该队列的参与者将在三年内每六个月完成一次数字应用程序评估， 通过家长ALLFTD研究进行全面的年度面对面访问。目标1将 用关联测验考察APP综合得分的横断面结构效度 神经心理功能、疾病严重性和生物标记物的黄金标准测量 神经退行性变。目标1还将测试该复合材料是否可以检测出早期的横断面缺陷 症状前fFTD。目标2将研究这些智能手机措施对纵向跟踪的效用 FFTD疾病进展，目标3调查这些测量是否预测未来的临床进展。 如果成功，该项目将产生一个可扩展的数字评估工具，用于早期发现、预测和 疾病监测可能导致更具包容性和更强大的fFTD试验。此外，随着 执行和运动功能在神经科和老年人群中随处可见，这款应用程序具有广泛的适用性 研究认知老化及其相关疾病，如阿尔茨海默病和相关痴呆症。

PROJECT SUMMARY/ABSTRACT Frontotemporal Dementia (FTD) is a fatal neurodegenerative disease that presents with behavioral, cognitive, or motor dysfunction and has no effective treatments. About 20-30% of cases are familial (fFTD), caused by autosomal dominant mutations. Increasing numbers of novel therapeutics targeting these genetic abnormalities are entering clinical trials. A major barrier to fFTD therapeutic development is the lack of clinically meaningful outcome measures that can be easily collected and are sensitive to treatment effects at early stages of disease. Because fFTD is rare, participants are geographically dispersed and travel is another recruitment barrier for in-person clinical trials. To facilitate more inclusive clinical trials, investigators from the ARTFL/ LEFFTDS Longitudinal FTD (ALLFTD) consortium partnered with Datacubed Health to develop a novel smartphone application that enables remote testing of executive and motor functioning, domains affected early in fFTD. The goal of this proposal is to validate these innovative remote smartphone assessments for early detection, longitudinal monitoring, and prognostication of fFTD symptoms. To achieve this goal, the project will recruit two separate but related cohorts. The first is a cross-sectional cohort of 1,000 cognitively and functionally intact adults from across the lifespan enrolled through a collaboration with the NIH-funded Brain Health Registry (BHR). BHR participants will take the smartphone tests and online BHR clinical measures. The BHR cohort will be used to develop psychometrically robust composite scores and will be used to validate the scores in a healthy aging cohort. The second arm is a longitudinal clinical validation cohort of 400 participants from kindreds with known pathogenic fFTD mutations who will be recruited through the ALLFTD consortium, including 100 symptomatic and 150 presymptomatic fFTD mutation carriers and 150 noncarrier family controls. Participants in this cohort will complete the digital app assessments every six months for three years, along with comprehensive, annual in-person visits conducted through the parent ALLFTD study. Aim 1 will investigate the cross-sectional construct validity of the app composite scores by testing for associations with gold-standard measures of neuropsychological functioning, disease severity, and biomarkers of neurodegeneration. Aim 1 will also test whether the composites can detect early cross-sectional deficits in presymptomatic fFTD. Aim 2 will study the utility of these smartphone measures for longitudinal tracking of fFTD disease progression, and Aim 3 investigates whether these measures predict future clinical progression. If successful, this project will yield a scalable digital assessment tool for early detection, prognosis, and disease monitoring that could lead to more inclusive and powerful fFTD trials. Furthermore, as changes in executive and motor function are ubiquitous in neurological and aging cohorts, this app has broad applicability to study cognitive aging and associated conditions such as Alzheimer’s disease and related dementias.