Decision-Making in Genetic FTD

项目摘要/摘要 额颞性痴呆(FTD)的特点是决策能力严重受损；不幸的是，FTD 通常只有在患者在判断上犯了重大错误后才能诊断。临床上，诊断的延误 反映缺乏客观的临床测试以供决策，并错失了预防的机会 严重的伤害。从科学上讲，延迟诊断限制了我们研究决策缺陷的能力， 确诊为FTD的患者往往有更严重的缺陷，可能不能反映早期的变化，而且通常 不能容忍更复杂的行为模式。这一临床和科学上的差距将通过 家族性FTD家系症状前突变携带者决策的神经经济学分析 美国国立卫生研究院资助的横跨美国和加拿大的两个大型多中心网络。中心假设是，早期 FTD突变携带者的行为和生理变化将揭示FTD突变的初步征兆和机制 FTD的判断受损，潜在地也阐明了其他患者决策受损的神经机制 神经精神障碍。其中110名症状前携带者和110名非携带者家庭成员 将招募多中心网络在安全的网络平台上进行决策测试，该平台 支持从北美各地的参与者那里快速、灵活地收集数据。以强劲的前期工作为指导 数据，中心假说将通过追求三个具体目标来检验：1)应用 确定症状前bvFTD突变携带者判断的细微变化的决策；2) 确定bvFTD决策改变的结构和功能(静息状态)MRI预测因子 突变携带者；以及3)阐明潜在的行为变化的神经和生理机制。 突变携带者。在前两个目标下，这个支持网络的平台将分析神经经济学参数 例如损失厌恶、框定效应和人际决策；这些问题将在 与已经按照协议收集的认知和神经成像测量的丰富数据集相结合 跨网络站点。在目标3下，将使用网络平台上的行为表现来选择 突变携带者和非携带者的子集，用于更详细的面对面生理和基于任务的功能磁共振 测试。这种基于网络的方法是创新的，因为当其他研究人员已经开始使用在线 方法来管理大量家庭参与者的任务，该策略允许评估 涉及神经成像和标准化测量的假设不能在网上进行。这 将传统现场评估的优势与较新的现场评估的灵活性和扩展优势相结合 在线方法。因此，拟议的工作将通过应用新的方法和 在大样本症状前基因携带者中进行更精确的神经经济学决策， 解决了对FTD一些最早和最具破坏性的症状进行研究的主要限制。

PROJECT SUMMARY/ABSTRACT Frontotemporal dementia (FTD) is marked by profound impairments in decision-making; unfortunately, FTD is typically only diagnosed after patients have made significant errors in judgment. Clinically, delays in diagnosis reflect the absence of objective clinical tests for decision-making, and are missed opportunities to prevent serious harms. Scientifically, delayed diagnosis limits our ability to study decision-making deficits, as research patients with confirmed FTD tend to have more profound deficits that may not reflect early changes, and often cannot tolerate more sophisticated behavioral paradigms. This clinical and scientific gap will be addressed with neuroeconomic analyses of decision-making in presymptomatic mutation carriers from familial FTD kindreds in two large NIH-funded multicenter networks spanning the US and Canada. The central hypothesis is that early behavioral and physiological changes in FTD mutation carriers will reveal initial signs and mechanisms of impaired judgment in FTD, potentially also elucidating neural mechanisms of impaired decision-making in other neuropsychiatric disorders. 110 presymptomatic carriers and 110 noncarrier family members from these multicenter networks will be recruited for tests of decision-making on a secure web-enabled platform that enables rapid and flexible data collection from participants across North America. Guided by strong preliminary data, the central hypothesis will be tested by pursuing three specific aims: 1) Apply neuroeconomic models of decision-making to define subtle alterations in judgment in presymptomatic bvFTD mutation carriers; 2) Determine structural and functional (resting-state) MRI predictors of altered decision- making in bvFTD mutation carriers; and 3) Elucidate neural and physiological mechanisms underlying behavioral change in mutation carriers. Under the first two aims, the web-enabled platform will assay neuroeconomic parameters such as loss aversion, framing effects, and interpersonal decision-making; which will then be analyzed in conjunction with a rich dataset of cognitive and neuroimaging measures already being collected per protocol across network sites. Under Aim 3, behavioral performance on the web-enabled platform will be used to select a subset of mutation carriers and noncarriers for more detailed in-person physiological and task-based fMRI testing. This web-enabled approach is innovative, because while other researchers have begun to use online methods to administer tasks to large numbers of participants at home, this strategy allows the evaluation of hypotheses involving neuroimaging and standardized measures that cannot be performed online. This combines the strengths of traditional on-site evaluation with the flexibility and scaling advantages of newer online methods. The proposed work will thus make a significant contribution by applying novel methods and more precise neuroeconomic measures of decision-making in a large sample of presymptomatic gene carriers, addressing a major limitation to research on some of the earliest and most damaging symptoms of FTD.