Development of an Innovative Vervet (Chlorocebus aethiops sabaeous) Model of Early Alzheimer’s-like Neuropathology and Symptomatology

开发早期阿尔茨海默病样神经病理学和症状学的创新黑长尾猴（Chlorocebus aethiops sabaeous）模型

• 批准号: 10845821
• 负责人: SUZANNE CRAFT
• 金额: $ 38.74万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10845821
• 关键词: Abeta clearance; Acceleration; African Green Monkey; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease risk; Alzheimer’s disease biomarker; Amyloid; Amyloid deposition; Animal Model; Behavioral; Biological Markers; Blood; Brain; Brain imaging; Brain region; Cercopithecus tantalus; Collection; Data; Development; Diabetic mouse; Functional disorder; Funding; Glycoproteins; Hippocampus; Human; Image; Imaging technology; Impairment; Liquid substance; Magnetic Resonance Imaging; Measures; Meningeal lymphatic system; Methods; Modeling; Neurocognitive; Neurocognitive Deficit; Non-Insulin-Dependent Diabetes Mellitus; Pathologic; Phase; Phenotype; Pontine structure; Positron-Emission Tomography; Prediabetes syndrome; Predisposition; Prefrontal Cortex; Presynaptic Terminals; Primates; R24; Reporting; Research; Research Personnel; Resources; Role; Route; Specimen; Subarachnoid Space; Synapses; Synaptic Vesicles; Temporal Lobe; Testing; Type 2 diabetic; Vascular Diseases; Vesicle; Work; abeta accumulation; abeta deposition; age related; arachnoid villi; cerebrospinal fluid flow; cingulate gyrus; cisterna magna; cohort; comparison control; comparison group; density; diabetic; end of life; frontal lobe; glymphatic dysfunction; glymphatic function; glymphatic system; gray matter; imaging facilities; innovation; lymphatic vessel; mouse model; neuropathology; normal aging; parent grant; radiotracer; symptomatology; synaptic function; tau Proteins; uptake; vervet

This application is a Supplement to R24 AG073199 Development of a Vervet Model of Early AD-like Neuropathology & Symptomatology. The purpose of this supplement is to: A) exploit an unexpected opportunity that fits within the approved scope of work, the collection and analysis of specimens from a unique resource of type 2 diabetic vervets, which would be significantly delayed through the competitive supplement route; and B) take advantage of new brain imaging technology which has become available since the application was submitted that will facilitate the completion of the R24 specific aims: PET imaging of synaptic function and MRI imaging of CSF flow. Type 2 diabetes (T2D) increases with age and significantly increases Alzheimer's disease (AD) risk. Amyloid-β accumulates in the brains of human T2Ds and may involve impaired CSF clearance. Synaptic loss has been observed in a T2D mouse model. Vervet monkeys, an established model of early AD-like neuropathology, are also susceptible to T2D. We propose to add 8 T2Ds, to our aging vervet cohort and compare all phenotypes from the parent grant (behavioral, fluid biomarkers, imaging) in normal aging vervets with the T2Ds. We have recently developed two new methods to assess brain function that are particularly well-suited to neuropathologic changes with T2D: synaptic function with PET, and cerebrospinal fluid flow with MRI. Synapse loss is an early pathological change in AD. Neuropathological studies have reported lower synaptic densities in AD compared to controls. Synaptic vesicle glycoprotein 2A (SV2A) is expressed in all synapses. Changes in synaptic density in animal models and AD patients are currently studied using the SV2A-based PET radiotracer [18F]UCBH which we have recently characterized and optimized for vervets. We propose to assess the 15 older vervets in our R24 imaging cohort, and add a comparison group of 8 T2D. It is hypothesized that impaired clearance of amyloid-β and tau may promote AD neuropathology. Likewise, recent observations suggest a relationship between impaired clearance and prediabetes. However, no study has directly correlated CSF flow with AD pathophysiology in the living primate brain, and there is no validated method to measure clearance. In preliminary studies we observed subarachnoid space (SAS) CSF flow was negatively correlated with PET-determined gray matter amyloid-β deposition, and we have optimized the phase-contrast sequences for vervets. We propose to assess SAS CSF flow with longitudinal phase-contrast MRI in the 15 older vervets in our imaging cohort and add a comparison group of 8 T2Ds. We will test the hypotheses that neurocognitive decline will be accelerated in vervet T2D, and synaptic density and CSF flow will decline with age and be accelerated in T2D. This research will yield proof-of-concept data for new dynamic MRI and PET biomarkers that may better reflect AD-like pathophysiology, and provide critical data illuminating temporal changes in neuropathology that increase AD risk in T2D. These data will be used to support further research on AD risk in humans with and without T2D.

本申请是对R24 AG073199早期AD样的Vervet模型的开发的补充 神经病理学和症状学。本补充的目的是：A）利用意想不到的 机会，适合在批准的工作范围内，收集和分析标本，从一个独特的 资源的2型糖尿病长尾，这将是显着延迟通过竞争性补充 途径;和B）利用自2000年以来可用的新的脑成像技术。 提交的申请将有助于完成R24的具体目标：突触的PET成像 功能和CSF流动的MRI成像。2型糖尿病（T2D）随着年龄的增长而增加， 阿尔茨海默病（AD）风险。淀粉样蛋白-β在人类T2D的大脑中积累，并可能涉及受损的 脑脊液清除率。在T2D小鼠模型中观察到突触丢失。长尾猴，一种建立在 早期AD样神经病理学模型，也易患T2D。我们建议增加8个T2D， vervet队列，并比较来自父母资助的所有表型（行为，液体生物标志物，成像）， 患有T2D的正常衰老黑尾长尾猴我们最近开发了两种评估大脑功能的新方法 特别适合T2D的神经病理学变化：PET的突触功能， 脑脊髓液流动与MRI。突触丢失是AD的早期病理改变。神经病理 研究已经报道了与对照相比AD中较低的突触密度。突触囊泡糖蛋白2A （SV2A）在所有突触中表达。在动物模型和AD患者中突触密度的变化是 目前使用基于SV2A的PET放射性示踪剂[18 F] UCBH进行研究，我们最近对其进行了表征， 为长尾猴做了优化。我们建议在我们的R24成像队列中评估15只老年黑尾长尾雉，并增加一个 对照组8例。假设淀粉样蛋白-β和tau蛋白的清除受损可能促进AD 神经病理学同样，最近的观察表明，清除障碍与 糖尿病前期然而，没有研究表明活灵长类动物的CSF流量与AD病理生理学直接相关 大脑，没有有效的方法来测量清除率。在初步研究中，我们观察到 蛛网膜下腔（SAS）CSF流量与PET确定的灰质淀粉样蛋白-β呈负相关 沉积，我们已经优化了vervets的相衬序列。我们建议评估SAS 在我们的成像队列中，用纵向相位对比MRI对15只老年长尾猴的CSF流动进行了研究，并增加了 对照组8例T2D。我们将检验神经认知能力下降会在 T2 D中，突触密度和CSF流量将随着年龄的增长而下降，并在T2 D中加速。本研究 将产生新的动态MRI和PET生物标志物的概念验证数据，这些生物标志物可能更好地反映AD样 病理生理学，并提供关键的数据，阐明在神经病理学的时间变化，增加AD T2D的风险这些数据将用于支持进一步研究患有和不患有T2D的人类的AD风险。