Histopathologic interrogation of laminar microcircuits underlying cognition in frontotemporal dementia

额颞叶痴呆认知层状微电路的组织病理学研究

• 批准号: 10643786
• 负责人: Daniel Timothy Ohm
• 金额: $ 12.73万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10643786
• 关键词: Address; Anatomy; Antibodies; Architecture; Area; Autopsy; Axon; Bioinformatics; Biological; Biological Markers; Brain; Brain region; Cessation of life; Classification; Clinical; Cluster Analysis; Cognition; Cognitive; Comparative Study; Data; Dementia; Development; Diagnosis; Diagnostic; Disease; Disinhibition; Disparate; Distant; Frontotemporal Dementia; Frontotemporal Lobar Degenerations; Genetic; Goals; Heterogeneity; Human; Impaired cognition; Impairment; Interneurons; Knowledge; Language; Life; Link; Machine Learning; Measures; Mediating; Mentors; Methods; Microscopic; Modeling; Myelin; Neocortex; Nerve Degeneration; Neural Pathways; Neurocognitive; Neurodegenerative Disorders; Neurons; Pathologic; Pathology; Pathway interactions; Patients; Pattern; Population; Property; Proteins; Regional Anatomy; Research; Resolution; Resources; Stains; Stratum Granulosum; Subgroup; Symptoms; Synaptic Transmission; Syndrome; Tauopathies; Techniques; Testing; Therapeutic; Therapeutic Studies; Training; Translational Research; Visualization; brain behavior; clinically relevant; cohort; comparative; connectome; demographics; diagnostic biomarker; digital; executive function; high dimensionality; improved; in vivo; innovation; neural; neuroimaging; neuron loss; neuronal cell body; neuroprotection; novel; preservation; prospective; protein TDP-43; segmentation algorithm; social cognition; tau Proteins; therapeutic target; translational impact; white matter

The neural determinants of cognition are not well understood in the human brain and particularly elusive in patients diagnosed with frontotemporal dementia (FTD). FTD is a heterogeneous spectrum of clinical disorders often associated with impairments in social cognition, executive function, or language. FTD is typically caused by frontotemporal lobar degeneration proteinopathies including tau or TDP-43 pathology not yet diagnosable during life. Thus, identification of the neurons that selectively degenerate in FTD with tau (FTD-tau) and FTD with TDP-43 (FTD-TDP) may be informative to the development of anatomically-grounded diagnostics and neuroprotective therapeutics lacking in FTD. However, the clinical relevance of neuron loss remains unclear due in part to clinicopathologic heterogeneity within the FTD spectrum. Another limiting factor is that traditional, low- throughput methods preclude large-scale postmortem studies of FTD and rarely examine the cyto- or myeloarchitectonic subdivisions of brain regions (e.g. cortical layers) where distinct neurons reside and microcircuits connect local and distant regions. My recent comparative study of cortical layer pathology found that tau and TDP-43 pathology accumulate distinct laminar distributions in clinically similar FTD patients. However, the layer-specific neurons that accrue pathology and the axonal pathways by which pathology may spread are understudied in FTD syndromes, despite the compelling experimental evidence for trans-synaptic transmission of pathologic proteins in diverse networks. To address these gaps in knowledge, the current project plans to examine laminar architecture to leverage the unique cellular organization and connectivity of cortical layers to identify differential loss of laminar microcircuits embedded in large-scale frontotemporal networks involved in FTD. I propose to develop a new high-throughput approach to quantify laminar neuronal features comprising short and long-range microcircuits with inhibitory or excitatory properties. Based on my preliminary data, I hypothesize that tau and TDP-43 pathology will be related to the loss of partly distinct laminar microcircuits in regional networks vulnerable to FTD, suggesting that different neural microcircuits may contribute to similar cognitive impairments across the FTD spectrum. My cortical layer framework is a unique approach to interrogate changes to laminar microcircuits, facilitating the discovery of new disease-specific patterns of neurodegeneration within gross anatomical regions to identify the neural substrates of pathologic subgroups and clinical symptoms of FTD. The differential loss of laminar microcircuits in FTD is a conceptual paradigm for advancing the study of selective vulnerability at the mesoscale, thereby serving as a critical bridge between emerging microscopic genetic expression data and macroscopic network/connectome studies. Completing this project will require I obtain interdisciplinary training in machine learning and segmentation methods, bioinformatics, and social cognition, all areas that will directly benefit my transition to becoming an independent neuroscientist conducting translational research for dementia syndromes.

认知的神经决定因素在人脑中还没有得到很好的理解，特别是在大脑中， 额颞叶痴呆（FTD）患者。FTD是一种异质性临床疾病谱 通常与社会认知、执行功能或语言障碍有关。FTD通常是由 额颞叶变性蛋白病，包括tau或TDP-43病理学尚未诊断 在生活中。因此，鉴别FTD中选择性退化的神经元与tau（FTD-tau）和FTD 与TDP-43（FTD-TDP）的结合可能对解剖学基础诊断的发展提供信息， 缺乏FTD的神经保护疗法。然而，神经元丢失的临床相关性仍然不清楚， 部分原因是FTD谱内的临床病理异质性。另一个限制因素是传统的、低- 通量方法排除了FTD的大规模尸检研究，很少检查细胞或 不同神经元所在的脑区域（例如皮质层）的脊髓结构细分， 微电路连接本地和远程区域。 我最近对皮质层病理学的比较研究发现，tau蛋白和TDP-43病理学的积累明显不同于 临床相似FTD患者的层状分布。然而，层特异性神经元， 病理学传播的轴突途径在FTD综合征中研究不足，尽管 令人信服的实验证据跨突触传递的病理蛋白质在不同的网络。到 为了解决这些知识差距，当前项目计划检查分层架构，以利用 独特的细胞组织和皮质层的连通性，以识别层状微电路的差异性损失 嵌入在大规模的额颞叶网络涉及FTD。我建议开发一种新的高通量 一种量化层状神经元特征的方法，包括具有抑制性或抑制性的短程和长程微电路， 兴奋性根据我的初步数据，我假设tau蛋白和TDP-43病理学相关， 在容易受到FTD影响的区域网络中，部分不同的层状微电路的损失，表明不同的 神经微电路可能导致FTD范围内的类似认知障碍。 我的皮质层框架是一种独特的方法来询问层状微电路的变化， 在大体解剖区域内发现新的疾病特异性神经变性模式， 病理亚组的神经基质和FTD的临床症状。层流的微分损失 FTD中的微电路是推进中尺度选择性脆弱性研究的概念范例， 从而充当新兴的微观遗传表达数据和宏观遗传表达数据之间的关键桥梁。 网络/连接体研究。完成这个项目将需要我获得跨学科的培训，在机器 学习和分割方法，生物信息学和社会认知，所有这些领域都将直接使我受益。 过渡到成为一个独立的神经科学家进行痴呆综合征的转化研究。