Vulnerability Profiles of Comorbid Alzheimer and TDP-43 Proteinopathies in Amnestic Dementia

遗忘性痴呆中共病阿尔茨海默病和 TDP-43 蛋白病的脆弱性概况

• 批准号: 10901010
• 负责人: Tamar D Gefen
• 金额: $ 60.3万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10901010
• 关键词: Address; Affect; Alzheimer like pathology; Alzheimer' s Disease; Amygdaloid structure; Anatomy; Autopsy; Axon; Basal Nucleus of Meynert; Behavior; Bilateral; Biological; Biology; Biometry; Brain; Brain region; Cell Count; Cell Nucleus; Cessation of life; Clinical; Cognition; Cognitive; Complex; DNA-Binding Proteins; Data; Dementia; Development; Disease; Dissociation; Early identification; Elderly; Encephalopathies; Fingerprint; Frontotemporal Lobar Degenerations; Future; Glean; Goals; Hippocampus; Histocytochemistry; Histopathology; Impairment; Individual; Intervention; Invaded; Label; Lead; Life; Limbic System; Link; Memory; Memory impairment; Methods; Microglia; Moods; Nerve Degeneration; Network-based; Neurobiology; Neurofibrillary Tangles; Neuroglia; Neurons; Neuropsychological Tests; Neuropsychology; Nomenclature; Outcome; Participant; Pathogenesis; Pathologic; Pathology; Pattern; Performance; Persons; Phenotype; Play; Population; Predisposition; Productivity; Psychometrics; Public Health; Regional Anatomy; Research Personnel; Resources; Role; Senile Plaques; Site; Specimen; Symptoms; Synapses; Syndrome; System; Trees; Vertebral column; Visual Cortex; Work; age related; aging population; clinical diagnostics; comorbidity; dentate gyrus; design; diagnostic criteria; digital; functional decline; granule cell; gray matter; insight; mossy fiber; neural circuit; neurofibrillary tangle formation; neuropathology; novel; protein TDP-43; psychiatric symptom; public health relevance; response; targeted treatment; tau Proteins; therapeutic target; white matter

ABSTRACT. Comorbid pathologies are extremely common in the aging population. In recent years, inclusions containing the hyperphosphorylated form of transactive response DNA-binding protein 43 (TDP-43) have been found in a vast proportion of elderly with common amnestic dementia and pathologically confirmed Alzheimer’s disease (AD; characterized by amyloid plaques and tau-containing tangles). These cooccurring diseases, referred here to as “AD/TDP”, impact cognition, functioning, and brain integrity, and target older adults—a population that continues to rise globally. Despite this, the clinical and biologic features of AD/TDP remain undefined. The major goal of this study is to identify the clinical, cellular, and pathologic signatures of AD/TDP using brain specimens from participants who were characterized by rigorous neuropsychological tests during life and neuropathologically after death. This project is carefully designed to focus on affected neurons in the corticolimbic system that play a critical role in memory, cognition, and mood/behavior. It is anchored to neuronal groups in anatomic regions that typically show early susceptibility to 1) AD but not TDP-43 (Ch4 cells of the nucleus basalis); 2) TDP-43 but not AD (e.g., dentate gyrus); 3) both (e.g., amygdala); and 4) neither (e.g., visual cortex). It is based on longitudinal data acquired over decades, along with unbiased stereological quantification in corticolimbic regions from AD/TDP, AD, cognitively-healthy controls, and persons found to show TDP-43 of the FTLD-type. Clinicopathologic information on AD/TDP will help characterize its syndromic phenotype, clarify the link between clinical syndrome and neuropathology, and can address critical questions about the determinants of selective vulnerability and disease spread in dementia. Through longitudinal psychometric analysis, Aim 1 will identify the shared versus distinct clinical, neuropsychological, and psychiatric features of AD/TDP , with a focus on initial symptom onset and patterns of decline. Aim 2 will determine the cellular features and distribution of TDP-43 and AD-related pathology in amnestic dementia. The design confined to neuronal groups that show early susceptibility to either AD, TDP-43, both, or neither, will allow us to glean novel insights into the substrates of neurodegeneration. Stereological and digital analysis of pathology in white & grey matter microglia, cell number/size, dendritic trees & spines, and synapses will be performed in hemispheric regions. Aim 3 will investigate the well-known trans-synaptic circuitry of the memory-related hippocampus as a putative anatomic mechanism for spread and memory dysfunction in AD/TDP. Relationships between antemortem (Aim 1) and postmortem findings (Aims 2 & 3) will establish clinicopathologic concordance between the unique phenotype and anatomic vulnerability profile of AD/TDP. The study will leverage the resources of the Northwestern ADRC and will be carried out by a team of investigators with expertise in anatomy, neuropsychology, pathology, and biostatistics. This study will address a major public health challenge by contributing to clinical diagnostic criteria and ultimately guiding interventions targeted at TDP-43 in the elderly.

抽象的。合并症在衰老人群中非常普遍。近年来，夹杂物 含有超磷酸化形式的交易反应DNA结合蛋白43（TDP-43）已是 在很大一部分的情况下发现了普通的炎症性痴呆症和病理确认的阿尔茨海默氏症 疾病（AD；以淀粉样蛋白斑块和含TAU的缠结为特征）。这些疾病， 在此称为“ AD/TDP”，影响认知，功能和大脑完整性以及目标老年人 全球持续增长的人口。尽管如此，AD/TDP的临床和生物学特征 保持 不明确的。这项研究的主要目的是确定AD/TDP的临床，细胞和病理特征 使用来自生活中严格神经心理学特征的参与者的脑标本 并在死亡后神经病理学。该项目经过精心设计，专注于受影响的神经元 在记忆，认知和情绪/行为中起着至关重要的角色的Corticolimbic系统。它固定在神经元上 解剖区域的组通常显示出早期对1）AD但不显示TDP-43的敏感性（CH4细胞 巴萨利斯核）; 2）TDP-43但没有AD（例如，齿状回）； 3）两个（例如，杏仁核）; 4）既不（例如，视觉 皮质）。它基于数十年来获得的纵向数据，以及公正的立体定量 在AD/TDP的Corticolimbic区域中 FTLD类型。有关AD/TDP的临床病理学信息将有助于表征其综合征表型，Clariify 临床综合征与神经病理学之间的联系，可以解决有关 选择性脆弱性和疾病的决定因素在痴呆中扩散。通过纵向心理测量学 分析，AIM 1将确定共享与独特的临床，神经心理学和精神病学特征 AD/TDP，重点是初始症状发作和下降模式。 AIM 2将确定细胞特征 TDP-43和AD相关的病理学分布在芳香痴呆症中。限于神经元的设计 表现出对AD（TDP-43）早期敏感性的群体，或者都不是，都将使我们能够收集新颖的见解 进入神经变性的底物。白物和灰质中病理学的立体和数字分析 小胶质细胞，细胞数/大小，树突树和刺以及突触将在半球区域进行。 AIM 3将研究与记忆相关海马的众所周知的跨突触电路 AD/TDP中传播和记忆功能障碍的解剖机制。触角之间的关系（目标 1）和验尸发现（AIM 2和3）将在独特之间建立临床病理一致性 AD/TDP的表型和解剖脆弱性概况。该研究将利用 西北ADRC，将由一组具有解剖学专业知识的调查员进行， 神经心理学，病理学和生物统计学。这项研究将解决由 促进了临床诊断标准，并最终导致针对TDP-43的指导干预措施。