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：近年来，合并症在老龄化人群中极为常见。 含有过度磷酸化形式的反式反应 DNA 结合蛋白 43 (TDP-43) 在患有常见遗忘性痴呆和病理证实的阿尔茨海默氏症的大部分老年人中发现 疾病（AD；以淀粉样斑块和含 tau 蛋白缠结为特征）这些同时发生的疾病， 这里称为“AD/TDP”，影响认知、功能和大脑完整性，并针对老年人—— 尽管如此，AD/TDP 的临床和生物学特征仍在全球范围内持续增长。 保持 本研究的主要目标是确定 AD/TDP 的临床、细胞和病理特征。 使用生前经过严格神经心理学测试的大脑样本 该项目经过精心设计，专注于研究死后受影响的神经元。 皮质边缘系统在记忆、认知和情绪/行为中起着关键作用，它锚定于神经元。 解剖区域中的群体通常表现出对 1) AD 的早期易感性，但对 TDP-43（Ch4 细胞）不敏感 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）两者都不是（例如，视觉） 它基于几十年来获得的纵向数据以及无偏见的体视量化。 AD/TDP、AD、认知健康对照以及被发现显示 TDP-43 的人的皮质边缘区域 AD/TDP 的 FTLD 型临床病理信息将有助于表征其综合征表型，阐明其症状。 临床综合征和神经病理学之间的联系，并可以解决有关 通过纵向心理测量研究痴呆症选择性脆弱性和疾病传播的决定因素。 分析，目标 1 将确定以下人群的共同与不同的临床、神经心理学和精神病学特征： AD/TDP，重点关注衰退的初始症状发作模式，将确定细胞特征。 遗忘性痴呆中 TDP-43 的分布和 AD 相关病理学的设计仅限于神经元。 对 AD、TDP-43、两者或两者都表现出早期易感性的群体将使我们能够收集新的见解 研究白质和灰质病理学的体视学和数字分析。 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进行。 目标 3 将研究众所周知的与记忆相关的海马体的跨突触回路，作为假定的 AD/TDP 中传播和记忆功能障碍的解剖学机制（目的） 1）和尸检结果（目标 2 和 3）将建立独特的临床病理学一致性 该研究将利用 AD/TDP 的表型和解剖学脆弱性概况。 西北 ADRC 将由具有解剖学专业知识的研究人员团队进行， 这项研究将通过神经心理学、病理学和生物统计学来解决重大的公共卫生挑战。 有助于制定临床诊断标准并最终指导针对老年人的 TDP-43 干预措施。