Decision-Making in Genetic FTD

项目总结/摘要 额颞叶痴呆症（FTD）的特点是决策能力严重受损;不幸的是，FTD 通常只有在病人在判断上犯了重大错误后才能诊断出来。临床上，诊断延迟 反映了缺乏客观的临床测试决策，并错过了机会，以防止 危害严重。科学上，延迟诊断限制了我们研究决策缺陷的能力， 确诊的FTD患者往往有更严重的缺陷，可能无法反映早期变化， 无法容忍更复杂的行为模式。这一临床和科学差距将得到解决， 家族性FTD激酶基因突变携带者决策的神经经济学分析 两个大型NIH资助的多中心网络，横跨美国和加拿大。核心假设是， FTD突变携带者的行为和生理变化将揭示 FTD的判断力受损，也可能阐明其他神经系统疾病中决策受损的神经机制。 神经精神障碍110名前驱携带者和110名非携带者家庭成员， 将招募多中心网络，在一个安全的网络平台上进行决策测试， 能够从北美的参与者那里快速、灵活地收集数据。以强有力的初步指导 数据，中心假设将通过追求三个具体目标进行测试：1）应用神经经济学模型， 决策以确定症状前bvFTD突变携带者判断的细微变化; 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;和3）阐明行为改变的神经和生理机制， 变异携带者在前两个目标下，网络平台将分析神经经济学参数 如损失厌恶，框架效应和人际决策;然后将在 结合已按照方案收集的丰富的认知和神经成像测量数据集 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 一个突变携带者和非携带者的子集，用于更详细的生理和基于任务的fMRI 试验.这种网络化的方法是创新的，因为当其他研究人员已经开始使用在线 方法来管理任务，以大量的参与者在家里，这一战略允许评估 涉及神经成像和标准化测量的假设不能在线执行。这 结合了传统现场评估的优势和新技术的灵活性和扩展优势， 在线方法。因此，拟议的工作将通过应用新的方法作出重大贡献， 在症状前基因携带者的大样本中进行更精确的决策神经经济学测量， 解决了对FTD的一些最早和最具破坏性症状的研究的主要限制。

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.