Determinants of neurodegenerative decline in the aphasic variant of Alzheimer's disease

项目摘要/摘要： 原发性进行性失语(PPA)是一种由神经退行性脑病引起的临床痴呆综合征， 以语言障碍为主要特征。PPA与两种主要的潜在神经病理学有关： 阿尔茨海默病(AD)神经病理学和额颞叶变性(FTLD)神经病理学。研究 在过去的几年里，由于FTLD，对痴呆症的进步、知识和兴趣蓬勃发展，使得新的 专用资源(例如，促进额颞部退行性疾病的研究和治疗[ARTFL])， 为促进我们对这种疾病的了解和开发治疗方法提供了令人振奋的新机会。 不幸的是，由于AD导致的PPA患者在这一过程中大部分是孤儿；未能满足病理 FTLD研究的纳入标准，以及未能满足AD临床试验的临床标准，这往往集中在 具有更典型的遗忘症表型的个体。这是不幸的，因为由于AD而患有PPA的人 占所有PPA病例的45%，这些人可能是AD相关疗法的可行候选者。 拟议的研究将纵向和定量地描述临床、认知、功能和 具有与AD一致的生物标志物的PPA患者的神经解剖学和分子特征 (本项目称为PPA-ADBio+)。目标1a将定量描述形态测量中的纵向变化 (使用结构MRI)、功能连接性(使用静息状态MRI)、tau蓄积(使用[18F]-AV-1451 Tau- PET)和临床资料(使用详细的神经心理测试)，50名PPA-ADBio+参与者连续3次 每年一次的访问。目标1b将描述目标1a中测量的变量之间的时间关系。这个项目 是使用相对较新的tau对纵向航道进行的首批前瞻性多维研究之一。 生物标记物[18F]-AV-1451在PPA-ADBio+个体中的表达。除了他们的理论兴趣之外，这项研究的结果还包括 与定义疾病类型和进展的客观生物标志物有关，这将为治疗提供信息 针对这一相对服务不足的痴呆症人群的战略。

PROJECT SUMMARY/ABSTRACT: Primary progressive aphasia (PPA) is a clinical dementia syndrome caused by neurodegenerative brain disease, with language impairment as the primary feature. PPA is associated with two main classes of underlying neuropathology: Alzheimer’s disease (AD) neuropathology and frontotemporal lobar degeneration (FTLD) neuropathology. Research advances, knowledge and interest in dementias due to FTLD have flourished over the past few years allowing for new dedicated resources (e.g., Advancing Research and Treatment for Frontotemporal Degeneration [ARTFL]), which promise exciting new opportunities for advancing our understanding the disease and for developing therapeutics. Unfortunately, individuals with PPA due to AD have been largely orphaned during this process; failing to meet pathologic inclusion criteria for FTLD studies and failing to meet clinical criteria for AD clinical trials, which tend to focus on individuals with the more typical amnestic phenotype. This is unfortunate because individuals with PPA due to AD represent up to 45% of all PPA cases and these individuals are potentially viable candidates for AD-related therapeutics. The proposed study will longitudinally and quantitatively characterize the clinical, cognitive, functional, neuroanatomic and molecular features of individuals with PPA who have biomarker findings consistent with AD (termed PPA-ADbio+ for this project). Aim 1a will quantitatively characterize longitudinal changes in morphometry (using structural MRI), functional connectivity (using resting state MRI), tau accumulation (with [18F]-AV-1451 Tau- PET) and clinical profiles (using detailed neuropsychological testing) of 50 PPA-ADbio+ participants at 3 consecutive annual visits. Aim 1b will characterize the temporal relationship among the variables measured in Aim 1a. This project represents one of the first prospective multidimensional studies of longitudinal course using the relatively new tau biomarker [18F]-AV-1451 in PPA-ADbio+ individuals. In addition to their theoretical interest, the results from this study are relevant for defining objective biomarkers of disease type and progression, which will inform therapeutic treatment strategies for this relatively underserved dementia population.