Identification of Endophenotypes in the Behavioral-Variant of Frontotemporal Deme

描述（由申请人提供）：前颞叶痴呆行为变异体中终末表型的鉴定 该提案的目的是发展必要的专业知识，以建立一个独立的实验室，研究慢性神经退行性疾病的终末表型。额颞叶痴呆（bvFTD）的行为变体是前颞叶变性（FTLD）谱系疾病中最常见的临床表型。在临床上，bvFTD包括与两大类基础神经病理学相关的社会行为和执行功能进行性下降：由微管结合蛋白tau（即FTLD-tau）组成的包涵体和RNA结合蛋白TDP-43（即FTLD-TDP）的包涵体。目前的药物开发工作集中在预防脑中病理性tau或TDP-43聚集。尽管20%的病例具有导致FTLD-tau或FTLD-TDP的致病性突变，但大多数病例是散发性的，并且目前没有可靠的方法来检测活体患者的潜在分子病因，这对这些新兴疗法的临床试验构成了重大挑战。 本提案的科学目标是将bvFTD细分为具有生物学相关性的筛选表型（即终末表型），假设bvFTD中tau和TDP聚集体的神经元间扩散的不同模式与可在尸检前检测到的独特临床和遗传特征相关。目标1将使用一种新方法量化前颞叶网络内神经病理学区域扩散的差异，用于bvFTD与FTLD-tau vs. FTLD-TDP的比较研究。目标2将检查既往病例对照FTLD全基因组关联研究中在尸检散发性bvFTD中确定的风险等位基因的诊断价值，并评估其与QRP图谱病理学负荷的关系。目标3将在患者分类中使用先进的统计技术整合目标1和2中的临床和遗传标记，以识别最终表型。这些项目的成功完成将直接用于bvFTD疾病改善治疗的临床实践和试验设计。通过这些具体目标的工作，结构化的职业发展计划将扩大候选人的培训，包括数字定量神经病理学，社会认知，神经发生和先进的患者分类统计方法的新方法，并在该领域国际公认的领导者的指导下。拟议的工作将作为未来R 01提案的基础，研究这些最终表型中的前瞻性多模态生物标志物变化。

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.