Selective Vulnerability in Frontotemporal Dementia

描述（由申请人提供）：本项目将研究额颞叶痴呆（FTD）和阿尔茨海默病（AD）的选择性脆弱性。阿尔茨海默症始于记忆障碍，而早期的FTD则导致社交情绪处理缺陷。一些FTD患者发展为运动神经元疾病（MND），这缩短了病程，并为早期FTD解剖缺陷提供了一个窗口。在FTD的行为变异（bvFTD）中，早期萎缩和代谢功能障碍局部影响前扣带（ACC）和额岛（FI）皮质，特别是在右半球。最近的研究表明，一种独特的大型投射神经元——von Economo神经元（VENs）具有选择性脆弱性，这种神经元仅在ACC和FI中发现，在灵长类动物中仅限于人类和类人猿。提出的研究将进一步检验VENs是早期bvFTD解剖损伤模式的核心特征这一假设。我们的目标是：(1)确定在bvFTD与AD和非神经对照（NNC）中，FI - VENs是否具有选择性易感性，并探索侧边效应；(2)检查VEN细胞死亡的组织病理学相关性和前因；(3)探索bvFTD中VEN易感性与特定神经发育信号蛋白改变有关的假设。我们将研究15名NNC、15名AD、20名bvFTD- mnd和30名bvFTD受试者的脑解剖材料，使用定量神经解剖学和免疫组织化学方法评估神经元数量和形态、疾病蛋白包涵体形成、突触丢失、星形胶质增生和神经发育/可塑性信号。所获得的知识可以通过确定早期疾病的特定解剖底物和围绕这种靶向损伤的病理生理事件，帮助创建更全面的bvFTD发病机制模型。公共卫生相关性：该项目将研究额颞叶痴呆患者退化的特定大脑区域和神经元，额颞叶痴呆是一种导致人格和行为改变的神经系统疾病。这项研究的目的是澄清这种疾病在大脑的哪个部位发作，以及什么生物学特性使特定的脑细胞易受伤害。这一信息可能为该疾病新的潜在治疗方法提供线索。

DESCRIPTION (provided by applicant): This project will investigate selective vulnerability in frontotemporal dementia (FTD) and Alzheimer's disease (AD). Whereas AD begins with memory impairment, early FTD leads to social-emotional processing deficits. Some patients with FTD develop motor neuron disease (MND), which shortens the disease course and provides a window into early FTD anatomical deficits. In the behavioral variant of FTD (bvFTD), early atrophy and metabolic dysfunction focally affects the anterior cingulate (ACC) and frontoinsular (FI) cortices, especially in the right hemisphere. Recent work suggests selective vulnerability of a unique class of large projection neurons, von Economo neurons (VENs), found only in ACC and FI and restricted, among primates, to humans and great apes. The proposed studies will further examine the hypothesis that VENs are a central feature of the early bvFTD anatomic injury pattern. Our aims are to (1) Determine whether FI VENs are selectively vulnerable in bvFTD vs. AD and non-neurological controls (NNC) and explore laterality effects, (2) Examine histopathological correlates and antecedents of VEN cell death, and (3) explore the hypothesis that VEN vulnerability in bvFTD relates to specific neurodevelopmental signaling proteins alterations. We will study brain autopsy materials from 15 NNC, 15 AD, 20 bvFTD-MND, and 30 bvFTD subjects using quantitative neuroanatomical and immunohistochemical methods to assess neuron number and morphology, disease protein inclusion formation, synapse loss, astrogliosis, and neurodevelopmental/plasticity signals. The knowledge gained could help create a more comprehensive bvFTD pathogenesis model by determining the specific anatomical substrates of early disease and pathophysiological events that surround this targeted injury. PUBLIC HEALTH RELEVANCE: This project will investigate the specific brain regions and neurons that degenerate in frontemporal dementia, a neurological disease that causes changes in personality and behavior. The goal of the research is to clarify where in the brain the disease strikes and what biological properties render specific brain cells vulnerable. This information may provide clues regarding new potential treatments for the disorder.