Selective Vulnerability in Frontotemporal Dementia

描述（由申请人提供）：本项目将调查额颞叶痴呆（FTD）和阿尔茨海默病（AD）的选择性脆弱性。而AD开始于记忆障碍，早期FTD导致社交情绪处理缺陷。一些FTD患者发生运动神经元病（MND），缩短了病程，并为早期FTD解剖缺陷提供了一个窗口。在FTD的行为变体（bvFTD）中，早期萎缩和代谢功能障碍局灶性影响前扣带回（ACC）和额岛（FI）皮质，尤其是右半球。最近的工作表明，选择性的脆弱性，一类独特的大型投射神经元，von Economo神经元（VENs），发现只有在ACC和FI和限制，在灵长类动物中，人类和类人猿。拟定的研究将进一步检查VEN是早期bvFTD解剖损伤模式的中心特征的假设。我们的目的是（1）确定在bvFTD与AD和非神经系统对照（NNC）中是否存在选择性VEN易损性，并探索偏侧效应，（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易损性与特定神经发育信号蛋白改变相关的假设。我们将使用定量神经解剖学和免疫组织化学方法研究15例NNC、15例AD、20例bvFTD-MND和30例bvFTD受试者的脑尸检材料，以评估神经元数量和形态、疾病蛋白包涵体形成、突触丢失、星形胶质细胞增生和神经发育/可塑性信号。所获得的知识可以通过确定围绕该靶向损伤的早期疾病和病理生理学事件的特定解剖学底物，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症中退化的特定大脑区域和神经元，这是一种导致个性和行为变化的神经系统疾病。这项研究的目的是阐明这种疾病在大脑中的哪个部位发作，以及哪些生物学特性使特定的脑细胞变得脆弱。这些信息可能会为这种疾病的新的潜在治疗提供线索。

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.