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.

摘要。合并症在老年人群中极为常见。近年来，包括 含有反式反应DNA结合蛋白43（TDP-43）的过度磷酸化形式， 在大多数患有普通遗忘性痴呆和病理证实的阿尔茨海默氏症的老年人中发现 疾病（AD;特征在于淀粉样蛋白斑块和含tau蛋白的缠结）。这些并发的疾病， 在此称为“AD/TDP”，影响认知、功能和大脑完整性，并针对老年人-a 全球人口持续增长。尽管如此，AD/TDP的临床和生物学特征 保持 未定义。本研究的主要目标是识别AD/TDP的临床、细胞和病理特征 使用的大脑样本来自参与者，这些参与者在生活中接受了严格的神经心理学测试。 以及死后的神经病理学这个项目是精心设计的，专注于受影响的神经元， 在记忆、认知和情绪/行为中起关键作用的皮质边缘系统。它锚定在神经元上， 在解剖区域中的组通常显示对1）AD而不是TDP-43的早期易感性（ 基底核）; 2）TDP-43但不是AD（例如，齿状回）; 3）两者（例如，杏仁核）;和4）两者都没有（例如，视觉 皮质）。它是基于几十年来获得的纵向数据，沿着无偏体视学量化 在来自AD/TDP、AD、认知健康对照和被发现显示TDP-43的人的皮质边缘区域中， FTLD类型。AD/TDP的临床病理信息将有助于描述其综合征表型，阐明 临床综合征和神经病理学之间的联系，并可以解决关键问题， 痴呆症中选择性脆弱性和疾病传播的决定因素。通过纵向心理测量 分析，目标1将确定共同与不同的临床，神经心理学和精神病学特征， AD/TDP，重点关注初始症状发作和下降模式。目标2将确定细胞特征 TDP-43和AD相关病理在遗忘性痴呆中的分布。设计局限于神经元 对AD、TDP-43、两者或两者都没有表现出早期易感性的群体，将使我们能够收集新的见解， 神经退化的基质白色和灰质病理的体视学和数字化分析 小胶质细胞、细胞数量/大小、树突树和棘以及突触将在半球区域中进行。 目的3将探讨众所周知的跨突触回路的记忆相关的海马作为一个假定的 AD/TDP中扩散和记忆功能障碍的解剖学机制。死前（Aim） 1)和尸检结果（目的2和3）将建立独特的临床病理学一致性之间的一致性， AD/TDP的表型和解剖易损性特征。这项研究将利用 西北ADRC将由一个具有解剖学专业知识的调查小组进行， 神经心理学、病理学和生物统计学。这项研究将解决一个重大的公共卫生挑战， 有助于临床诊断标准，并最终指导针对老年人TDP-43的干预措施。