Identification of Endophenotypes in the Behavioral-Variant of Frontotemporal Deme

描述(由申请人提供)：前额颞叶痴呆行为变异型末端表型的鉴定这项建议的目的是发展必要的专业知识，以建立一个独立的实验室，研究年轻起病的神经退行性疾病的末端表型。行为变异型额颞叶痴呆(BvFTD)是前额叶变性(FTLD)谱系障碍中最常见的临床表型。临床上，bvFTD包括与两类主要神经病理相关的社会行为和执行功能的进行性下降：由微管结合蛋白tau组成的包涵体(即FTLD-tau)和由RNA结合蛋白TDP-43组成的包涵体(即FTLD-TDP)。目前的药物开发工作集中在防止Tau或TDP-43在大脑中的病理性聚集。尽管20%的病例有致病突变导致FTLD-tau或FTLD-TDP，但大多数病例是散发性的，目前还没有可靠的方法来检测活着患者的潜在分子病因学，这给这些新兴疗法的临床试验带来了巨大的挑战。这一建议的科学目标是将bvFTD细分为具有生物学相关性的筛查表型(即末端表型)，假设bvFTD中tau和TDP聚集体在神经元到神经元之间的不同扩散模式与可以在死前检测到的独特的临床和遗传特征有关。目的#1将使用一种新的方法来量化前额颞叶网络内神经病理区域扩散的差异，以比较FTLD-tau和FTLD-TDP对bvFTD的影响。目的#2将检验先前病例对照FTLD全基因组关联研究中确定的危险等位基因在尸检散发性bvFTD中的诊断价值，并评估它们与QRP MAP病理负担的关系。AIM 3将在AIM#1和AIM#2中整合临床和遗传标记，在患者分类中使用先进的统计技术来识别终端表型。这些项目的成功完成将对bvFTD的疾病修正疗法的临床实践和试验设计产生立竿见影的作用。通过这些具体目标的工作，结构化的职业发展计划将扩大应聘者的培训范围，在该领域国际公认的领导者的指导下，包括数字量化神经病理学、社会认知、神经发生和患者分类的先进统计方法的新方法。拟议的工作将作为未来R01提案的基础，研究这些末端表型的前瞻性多模式生物标记物变化。

DESCRIPTION (provided by applicant): Identification of end phenotypes in the behavioral-variant of front temporal dementia the purpose of this proposal is to develop the expertise necessary to establish an independent lab investigating end phenotypes in young-onset neurodegenerative conditions. The behavioral-variant of fronto temporal dementia (bvFTD) is the most common clinical phenotype in front temporal lobar degeneration (FTLD) spectrum disorders. Clinically, bvFTD includes progressive decline in social conduct and executive function associated with two major classes of underlying neuropathology: inclusions composed of the microtubule-binding protein, tau (i.e. FTLD-tau), and inclusions of the RNA-binding protein, TDP-43 (i.e. FTLD- TDP). Current drug development efforts are focused on prevention of pathological tau or TDP-43 aggregation in the brain. Although 20% of cases have a pathogenic mutation resulting in FTLD-tau or FTLD-TDP, most cases are sporadic and there is currently no reliable way to detect the underlying molecular etiology in living patients, posing a significant challenge for clinical trials of these emerging therapies. The scientific goal of thi proposal is to subdivide bvFTD into screening phenotypes with biological relevance (i.e. end phenotypes) with the hypothesis that differing patterns of neuron-to-neuron spread of tau and TDP aggregations in bvFTD are associated with unique clinical and genetic features that can be detected ante mortem. Aim#1 will use a novel approach to quantify differences in regional spread of neuropathology within front temporal networks for comparative study in bvFTD with FTLD-tau vs. FTLD-TDP. Aim#2 will examine the diagnostic value of risk alleles identified in previous case-control FTLD genome-wide association studies in autopsied sporadic bvFTD, and assess their relationship to QRP map pathology burden. Aim 3 will integrate clinical and genetic markers in Aims #1 and 2 using advanced statistical techniques in patient classification to identify end phenotypes. Successful completion of these projects will have immediate utility for clinical practice and trial design for disease-modifying therapies in bvFTD. Through work on these specific aims, the structured career development plan will expand the candidate's training to include novel approaches to digital quantitative neuropathology, social cognition, neurogenesis and advanced statistical methods of patient classification under guidance from internationally-recognized leaders in the field. The proposed work will serve as the basis for a future R01 proposal studying prospective multimodal biomarker changes in these end phenotypes.