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.

该应用是R24 AG073199的补充 神经病理学和症状学。该补充的目的是：a）利用意外 适合批准的工作范围的机会，来自独特的标本的收集和分析 2型糖尿病性角色的资源，这将在竞争补充剂中大大延迟 路线; b）利用新的脑成像技术，自从 提交了申请，该申请将有助于完成R24特定目的：突触的PET成像 CSF流量的功能和MRI成像。 2型糖尿病（T2D）随着年龄的增长而增加，并显着增加 阿尔茨海默氏病（AD）风险。淀粉样蛋白β积累在人类T2D的大脑中，可能涉及受损 CSF许可。在T2D小鼠模型中观察到了突触损失。 Vervet Monkeys，已建立的 早期广告状神经病理学的模型也容易受到T2D的影响。我们建议将8 T2D添加到我们的衰老中 Vervet队列并比较父母赠款中的所有表型（行为，流体生物标志物，成像） 与T2DS的正常老化的黄斑。我们最近开发了两种新方法来评估大脑功能 T2D的神经病理学变化特别适合：使用PET的突触功能， MRI的脑脊液流动。突触损失是AD的早期病理变化。神经病理学 研究报道，与对照组相比，AD的突触密度较低。突触囊泡糖蛋白2a （SV2A）在所有突触中均表示。动物模型和AD患者突触密度的变化是 目前使用基于SV2A的PET radiotracer [18F] UCBH进行了研究，我们最近对此进行了表征和 针对天文进行了优化。我们建议评估R24成像队列中的15个较旧的天线，并添加一个 比较组8 t2d。假设淀粉样蛋白β和tau的清除率受损可能会促进AD 神经病理学。同样，最近的观察表明，间隙受损与 糖尿病。但是，没有研究直接将CSF流与活灵林中的AD病理生理相关联 大脑，没有验证的方法来测量清除率。在初步研究中，我们观察到 蛛网膜下腔空间（SAS）CSF流与宠物确定的灰质淀粉样蛋白β呈负相关 沉积，我们已经优化了黄斑的相位对比序列。我们建议评估SAS CSF在我们的成像队列中的15个较老的天线中具有纵向相位对比度MRI的流动，并添加一个 比较组8 T2D。我们将测试神经认知能力下降的假设将加速 Vervet T2D，突触密度和CSF流动将随着年龄的增长而下降，并在T2D中加速。这项研究 将产生新的动态MRI和PET生物标志物的概念验证数据，这些数据可能更好地反映类似AD的样子 病理生理学，并提供关键数据，以阐明神经病理学的临时变化，以增加AD T2D风险。这些数据将用于支持对有或没有T2D的人类中AD风险的进一步研究。