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

基本信息

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
项目类别：
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

项目摘要

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.

人类大脑中认知的神经决定因素还没有被很好地理解，在人类大脑中尤其难以捉摸。被诊断患有额颞叶痴呆（FTD）的患者。 FTD 是一系列异质性临床疾病通常与社会认知、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 病理学尚未诊断一生中。因此，用 tau (FTD-tau) 和 FTD 鉴定在 FTD 中选择性退化的神经元与 TDP-43 (FTD-TDP) 的结合可能对基于解剖学的诊断和治疗的发展提供信息 FTD 缺乏神经保护疗法。然而，神经元丢失的临床相关性仍不清楚，因为部分原因是 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 的大规模死后研究，并且很少检查细胞或不同神经元所在的大脑区域（例如皮质层）的骨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 和 TDP-43 病理学积累截然不同临床相似的 FTD 患者的层流分布。然而，产生病理学的层特异性神经元尽管 FTD 综合征中病理可能传播的轴突途径尚未得到充分研究病理蛋白在不同网络中跨突触传递的令人信服的实验证据。到为了解决这些知识差距，当前的项目计划研究层状结构以利用独特的细胞组织和皮质层连接性，可识别层状微电路的差异损耗嵌入 FTD 涉及的大规模额颞叶网络中。我建议开发一种新的高通量量化层状神经元特征的方法，包括具有抑制或抑制作用的短程和长程微电路兴奋特性。根据我的初步数据，我假设 tau 和 TDP-43 病理学相关易受 FTD 影响的区域网络中部分不同层状微电路的丢失，表明不同的层状微电路神经微电路可能会导致 FTD 谱系中类似的认知障碍。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，促进在大体解剖区域内发现新的疾病特异性神经变性模式，以确定 FTD 病理亚组的神经基质和临床症状。层流的差分损耗 FTD 中的微电路是推进中尺度选择性脆弱性研究的概念范式，从而成为新兴的微观基因表达数据和宏观基因表达数据之间的重要桥梁。网络/连接组研究。完成这个项目需要我获得机器方面的跨学科培训学习和分割方法、生物信息学和社会认知，所有这些领域都将直接使我受益转型成为一名独立的神经科学家，从事痴呆症综合征的转化研究。