Selective Vulnerability in Frontotemporal Dementia

描述(由申请者提供)：该项目将调查额颞部痴呆(FTD)和阿尔茨海默病(AD)的选择性脆弱性。虽然阿尔茨海默病始于记忆障碍，但早期的FTD会导致社交-情绪处理缺陷。一些FTD患者发展为运动神经元病(MND)，这缩短了病程，并提供了了解早期FTD解剖缺陷的窗口。在FTD的行为变异型(BvFTD)中，早期萎缩和代谢功能障碍局灶性影响前扣带回(ACC)和额岛皮质(FI)，尤其是在右半球。最近的研究表明，一类独特的大型投射神经元--von Economo神经元(VENS)具有选择性脆弱性，这种神经元只在ACC和FI中发现，在灵长类动物中仅限于人类和类人猿。拟议的研究将进一步检验Vens是早期bvFTD解剖损伤模式的中心特征的假设。我们的目标是(1)确定bvFTD与AD和非神经对照(NNC)相比是否选择性地易受FN的影响，并探索偏侧效应；(2)检验VEN细胞死亡的组织病理学相关性和先兆因素；(3)探索bvFTD中VEN易损性与特定神经发育信号蛋白改变有关的假设。我们将使用定量神经解剖学和免疫组织化学方法研究15名NNC、15名AD、20名bvFTD-MND和30名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早期疾病的特定解剖基础和围绕这种靶向损伤的病理生理事件来帮助创建更全面的bvFTD发病机制模型。

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.