Understanding the dynamic interactions between tau pathology and microgliamediated inflammation in Alzheimer's Disease

了解阿尔茨海默病中 tau 蛋白病理学与小胶质细胞介导的炎症之间的动态相互作用

• 批准号: 10622513
• 负责人: Ajay Gupta
• 金额: $ 120.31万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10622513
• 关键词: Address; Affinity; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer’s disease biomarker; Amyloid; Anti-Inflammatory Agents; Atrophic; Biological; Biological Markers; Biological Models; Brain; Cerebrospinal Fluid; Clinical; Cognition; Cognitive; Computer Models; Dementia; Diagnosis; Diagnostic; Diffusion; Disease; Disease Progression; Disease model; Education; Elderly; Etiology; Foundations; Functional disorder; Future; Generations; Glucose; Goals; Human; Image; Inflammation; Inflammatory; Investigation; Kinetics; Laboratories; Ligands; Linear Models; Longitudinal cohort; Machine Learning; Magnetic Resonance Imaging; Measures; Mediating; Mediation; Microglia; Modeling; Modernization; Nerve Degeneration; Neurofibrillary Tangles; Pathogenesis; Pathologic; Pathology; Patients; Pattern; Positron-Emission Tomography; Property; Protocols documentation; Public Health; Race; Research; Role; Science; Senile Plaques; Series; Serum; Signal Transduction; Specificity; Speed; Statistical Models; TREM2 gene; Testing; Time; Visit; animal data; brain magnetic resonance imaging; clinical application; clinical heterogeneity; density; disease phenotype; follow-up; genetic risk factor; glial activation; imaging study; in vivo; inflammatory marker; insight; longitudinal, prospective study; mathematical model; model design; neuroinflammation; neuron loss; neurotransmission; novel; predictive modeling; predictive test; prognostication; sex; spatiotemporal; systemic inflammatory response; tau Proteins; tau aggregation; tau interaction; tau mutation; tractography; transmission process

Project Summary/Abstract The etiology, mechanism and progression of Alzheimer’s Disease (AD), and the relationship of AD pathology to clinical manifestations, are not fully understood. Emerging studies suggest that inflammation and microglial activation is an important contributor to AD pathogenesis and progression. The association between tau and microglia is especially critical, since tau is most closely associated with AD. The conventionally accepted sequence of this interaction is that misfolded tau, which is pro-inflammatory, causes microglial activation, leading to dendritic pruning and eventually neuronal cell death. However, it is recently emerging that microglial activation can itself cause tau aggregation and subsequent propagation. Therefore the causality of these interactions is controversial, and requires much needed elucidation in humans in vivo. The goal of this proposal is to understand the interaction and causal sequencing between tau, neurodegeneration, microglia and systemic inflammation in governing the etiology and progression of human AD. This proposal involves a series of principled statistical and mathematical model-based tests that will uncover these relationships, for the first time, directly in patients. This proposal involves a new prospective longitudinal study of 100 AD spectrum patients acquiring brain MRI and PET imaging of activated microglia using a new generation TSPO ligand called DPA-713 and tau-PET imaging using a relatively novel ligand, MK6240. The same imaging protocol (MRI, DPA-713 and MK6240 PET) will be repeated at 18- and 36-month follow up time points. All subjects will have amyloid neuritic plaque density measured at baseline using florbetaben PET. Next this proposal involves developing and testing a model of microglial inflammation-tau interaction via mathematical models to determine whether regional microglia-mediated neuroinflammation measured by DPA-PET is higher in AD spectrum patients or in cognitively normal older adults; and whether regional microglial activation is predictable directly from tau and/or amyloid. Finally, this proposed research includes testing a network spread model of tau and microglia. Mounting animal data implicate a trans-neuronal transmission mechanism of tau through brain networks. Using a network diffusion model of disease spread, this proposal will further investigate the role of microglia in tau progression directly in humans. Since tau and microglia provide complementary signal about evolving pathology, this proposal will determine whether combining imaging studies that measure both biomarkers will result in a uniquely powerful and predictive test of AD progression. Given the rapidly evolving understanding of the role of microglia and systemic inflammation in dementias, the current proposal is timely, topical and necessary for advancing human dementia research. If successful, it will give the first validated spatiotemporal model of the causal interactions between pathology and neuroinflammation in AD, catalyzing future advances in prognostication and targeted anti-inflammatory therapies.

项目摘要/摘要 阿尔茨海默氏病（AD）的病因，机制和进展以及AD病理学的关系 对于临床表现，尚不完全了解。新兴研究表明炎症和小胶质细胞 激活是导致AD发病机理和进展的重要原因。 tau和 小胶质细胞尤其重要，因为tau与AD最密切相关。传统上接受 这种相互作用的序列是促炎性的错误折叠tau导致小胶质激活， 导致树突状修剪，并最终导致神经元细胞死亡。但是，最近出现了小胶质的 激活本身会导致tau聚集和随后的传播。因此，这些的偶然性 相互作用是有争议的，需要在体内人类中急需阐明。该提议的目标 是要了解tau，神经变性，小胶质细胞和 管理人类AD的病因和进展中的系统性炎症。该建议涉及一个系列 主要的统计和基于数学模型的测试，这些测试将发现这些关系，第一个 时间，直接在患者中。该提案涉及100个AD光谱的新的前瞻性纵向研究 使用新一代TSPO配体获得活化小胶质细胞的脑MRI和PET成像的患者 使用相对新型配体MK6240称为DPA-713和Tau-Pet成像。相同的成像协议 （MRI，DPA-713和MK6240 PET）将在18个月和36个月的随访时间点重复。所有受试者都会 使用Florbetaben PET在基线时测量的淀粉样神经质斑块密度。接下来，该提议涉及 开发和测试通过数学模型的小胶质注射tau相互作用的模型 确定AD中DPA-PET测量的区域小胶质细胞介导的神经炎症是否更高 频谱患者或认知正常的老年人；以及区域小胶质细胞激活是否可预测 直接来自tau和/或淀粉样蛋白。最后，这项拟议的研究包括测试TAU的网络传播模型 和小胶质细胞。安装动物数据暗示了tau通过大脑的跨神经传输机制 网络。使用网络扩散模型的疾病扩散模型，该提案将进一步研究 tau进展的小胶质细胞直接在人类中。由于tau和小胶质细胞提供了有关的完整信号 不断发展的病理学，该提案将决定是否结合了测量既测量的成像研究 生物标志物将对AD进展进行独特的强大和预测性测试。鉴于快速发展的 了解小胶质细胞和全身注射在痴呆症中的作用，当前的建议是及时的， 局部且需要推进人类痴呆症研究所必需的。如果成功，它将提供第一个经过验证的 AD中病理与神经炎症之间的因果相互作用的时空模型，催化 未来提示和靶向抗炎疗法的进展。

项目成果

Modeling seeding and neuroanatomic spread of pathology in amyotrophic lateral sclerosis.

• DOI: 10.1016/j.neuroimage.2022.118968
• 发表时间: 2022-05-01
• 期刊: NEUROIMAGE
• 影响因子: 5.7
• 作者: Pandya, Sneha;Maia, Pedro D.;Freeze, Benjamin;Menke, Ricarda A. L.;Talbot, Kevin;Turner, Martin R.;Raj, Ashish
• 通讯作者: Raj, Ashish

Emergence of directional bias in tau deposition from axonal transport dynamics.

• DOI: 10.1371/journal.pcbi.1009258
• 发表时间: 2021-07
• 期刊: PLoS computational biology
• 影响因子: 4.3
• 作者: Torok J;Maia PD;Verma P;Mezias C;Raj A
• 通讯作者: Raj A

Predicting Functional Connectivity From Observed and Latent Structural Connectivity via Eigenvalue Mapping.

• DOI: 10.3389/fnins.2022.810111
• 发表时间: 2022
• 期刊: Frontiers in neuroscience
• 影响因子: 4.3
• 作者: Cummings JA;Sipes B;Mathalon DH;Raj A
• 通讯作者: Raj A

Structure-function models of temporal, spatial, and spectral characteristics of non-invasive whole brain functional imaging.

• DOI: 10.3389/fnins.2022.959557
• 发表时间: 2022
• 期刊: FRONTIERS IN NEUROSCIENCE
• 影响因子: 4.3
• 作者: Raj, Ashish;Verma, Parul;Nagarajan, Srikantan
• 通讯作者: Nagarajan, Srikantan

The effects of microglia on tauopathy progression can be quantified using Nexopathy in silico (Nexis) models.

• DOI: 10.1038/s41598-022-25131-3
• 发表时间: 2022-12-07
• 期刊: SCIENTIFIC REPORTS
• 影响因子: 4.6
• 作者: Anand, Chaitali;Maia, Pedro D.;Torok, Justin;Mezias, Christopher;Raj, Ashish
• 通讯作者: Raj, Ashish