Selective Vulnerability in Frontotemporal Dementia

额颞叶痴呆的选择性脆弱性

• 批准号: 8431393
• 负责人: WILLIAM W SEELEY
• 金额: $ 48.34万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-15 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8431393
• 关键词: Adult; Affect; Age; Alzheimer' s Disease; Anatomy; Animal Model; Anterior; Atrophic; Autopsy; Behavior; Behavioral; Biological; Brain; Brain Diseases; Brain region; Cell Death; Cells; Cessation of life; Clinical; Cognitive; Complex; Cues; Data; Dementia; Development; Diagnosis; Disease; Emotional; Empathy; Employee Strikes; Event; Faculty; Frontotemporal Dementia; Frontotemporal Lobar Degenerations; Functional disorder; Gliosis; Goals; Handedness; Health; Histopathology; Human; Injury; Insula of Reil; Knowledge; Laboratories; Left; Lesion; Mammals; Memory impairment; Metabolic; Methods; Modeling; Molecular; Molecular Genetics; Morals; Morphology; Motor; Motor Neuron Disease; Neurodegenerative Disorders; Neuronal Dysfunction; Neurons; Pathogenesis; Pathology; Patients; Pattern; Personality; Pongidae; Population; Predisposition; Prevalence; Primates; Process; Property; Proteins; Relative (related person); Research; Right-On; Self Perception; Signal Transduction; Signaling Protein; Site; Social Functioning; Staging; Structure; Synapses; Syndrome; System; Testing; Ubiquitin; Variant; Vertebral column; Work; astrogliosis; axon guidance; brain cell; cell type; cingulate cortex; density; immunoreactivity; improved; nervous system disorder; neuron loss; novel therapeutics; protein TDP-43; protein aggregation; receptor; social; synaptogenesis; tau Proteins; tau-1

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.

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。

项目成果

Functional network disruption in the degenerative dementias.

• DOI: 10.1016/s1474-4422(11)70158-2
• 发表时间: 2011-09
• 期刊: LANCET NEUROLOGY
• 影响因子: 48
• 作者: Pievani, Michela;de Haan, Willem;Wu, Tao;Seeley, William W.;Frisoni, Giovanni B.
• 通讯作者: Frisoni, Giovanni B.