Quantifying synaptic density loss in a monkey model of early Alzheimer's Disease
量化早期阿尔茨海默病猴子模型中的突触密度损失
基本信息
- 批准号:9809280
- 负责人:
- 金额:$ 30.88万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-08-01 至 2021-04-30
- 项目状态:已结题
- 来源:
- 关键词:AD pathologyAddressAgeAlzheimer&aposs DiseaseAlzheimer&aposs disease riskAmyloid beta-ProteinAmyloid depositionAnimalsAtlasesAttenuatedAutopsyBehavioralBiological MarkersBiological ModelsBlood - brain barrier anatomyBrainBrain PathologyBrain regionCerebrumClinical ResearchControl AnimalDNA Sequence AlterationDataDevelopmentDiagnosisDiagnosticDisease ProgressionDoseEarly DiagnosisElementsFollow-Up StudiesFunctional disorderFutureGoalsGoldHealthHistologicHumanImaging TechniquesImpaired cognitionInfusion proceduresIntervention StudiesInvestigationLongitudinal StudiesMRI ScansMacaca mulattaMagnetic Resonance ImagingMapsMeasurementMeasuresMetabolicMetabolic dysfunctionMethodsMicroscopicModelingMolecularMonkeysNeuronsNuclearPathogenesisPathologicPathologyPatientsPatternPeptidesPhasePositron-Emission TomographyProcessResearchResearch DesignRodentRoleSample SizeScanningSignal TransductionSpatial DistributionStructureSynapsesTestingTherapeuticTissuesTreatment EffectivenessValidationabeta oligomerbasebrain tissuecerebral atrophycostdensitydesigndisabling diseasefluorodeoxyglucosefluorodeoxyglucose positron emission tomographyfollow-upglucose metabolismimaging modalityimprovedin vivoin vivo imagingindexinginterestlateral ventriclemultimodalityneuropathologynonhuman primatenovelpreclinical studypredictive markerradiotracerresponseserial imagingsexspatiotemporaltau aggregationtherapeutic evaluationtherapy designtreatment strategy
项目摘要
Project Summary/Abstract
Alzheimer’s disease (AD) is an extremely prevalent and severely disabling disease. Despite several decades
of research, AD pathogenesis continues to be poorly understood, and we currently lack reliable biomarkers to
spatiotemporally track and predict disease progression. Our overall goal is to address these challenges and
develop enhanced biomarkers for diagnosing AD-pathology early and objectively tracking treatments. To that
end, this proposal will utilize our highly translational monkey model of the early “synaptic phase” of AD to
assess the merits of in vivo imaging measures (from PET for synaptic density (using 11C-UCB-J) and glucose
metabolism (using 18F-FDG), with structural MRI) against postmortem, state-of-the-art microscopic and
histologic analysis of brain tissue, in a longitudinal study design. Our hypothesis is that PET measures, as
surrogates for quantifying synaptic loss and metabolic dysfunction, will serve as early, independent predictive
biomarkers for elevated AD risk and cognitive dysfunction. Our first specific aim will establish the correlation of
our in vivo imaging measures with postmortem tissue markers of AD-associated pathologies in our monkey
model versus age- and sex-matched control animals. Our second specific aim will map the spatiotemporal
patterns of PET synaptic loss versus cerebral glucose metabolism in our monkey model versus control animals
over a 12-week period. Completion of both aims will provide novel data to improve our understanding of
synaptic neuropathology in AD development. Therefore, this proposal is highly responsive to the PAR-18-760.
Positive findings would corroborate recent human studies investigating the role of synaptic dysfunction as a
major factor for increased AD risk. Validation of in vivo imaging strategies in a relevant model system will
contribute towards (i) optimizing the therapeutic window for future early AD treatments so that their efficacy can
be maximized; (ii) testing mechanistic hypotheses associated with the role/blockage of synapse loss; (iii)
rapidly evaluating new treatment strategies and their dose-response relationships. In summary, this project has
the potential to provide key translational elements that will inform human studies evaluating in vivo markers of
synaptic dysfunction.
项目摘要/摘要
阿尔茨海默病(AD)是一种极其普遍且严重致残的疾病。尽管几十年来
在研究中,AD的发病机制仍然知之甚少,目前我们缺乏可靠的生物标志物来
时空跟踪和预测疾病进展。我们的总体目标是应对这些挑战和
开发增强的生物标志物,用于早期诊断AD病理并客观跟踪治疗。到那时候
最后,这项提议将利用我们的高度翻译的阿尔茨海默病早期“突触阶段”的猴子模型来
评估体内成像方法的优点(来自PET的突触密度(使用11C-UCB-J)和葡萄糖
新陈代谢(使用18F-FDG),结构磁共振成像)对照身体,最先进的显微镜和
脑组织的组织学分析,采用纵向研究设计。我们的假设是,PET测量的结果是,
用于量化突触丢失和代谢功能障碍的代用品将作为早期的、独立的预测
AD风险升高和认知功能障碍的生物标志物。我们的第一个具体目标是建立
我们用死后组织标记物对猴子进行AD相关病理的活体成像测量
模型与年龄和性别匹配的对照动物。我们的第二个具体目标是绘制时空图
在我们的猴子模型和对照动物中,PET突触丢失与脑葡萄糖代谢的模式
超过12周的时间。完成这两个目标将提供新的数据,以提高我们对
阿尔茨海默病发生中的突触神经病理学。因此,这项提案对PAR-18-760具有很高的响应性。
积极的发现将证实最近人类研究突触功能障碍作为一种
AD风险增加的主要因素。在相关模型系统中验证体内成像策略将
有助于(I)优化未来早期AD治疗的治疗窗口,以便其疗效
最大化;(Ii)测试与突触丢失的作用/阻断相关的机械性假说;(Iii)
快速评估新的治疗策略及其剂量-反应关系。总而言之,这个项目有
提供关键翻译元件的可能性,将为人体研究评估体内标记提供信息
突触功能障碍。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Abhijit J Chaudhari其他文献
Beyond skin deep: total-body positron emission tomography to illuminate systemic inflammation in psoriatic arthritis
不仅仅是表面现象:全身正电子发射断层扫描揭示银屑病关节炎中的全身性炎症
- DOI:
10.1016/j.coi.2025.102587 - 发表时间:
2025-08-01 - 期刊:
- 影响因子:5.800
- 作者:
Abhijit J Chaudhari;Yasser G Abdelhafez;Lorenzo Nardo;Siba P Raychaudhuri - 通讯作者:
Siba P Raychaudhuri
Abhijit J Chaudhari的其他文献
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{{ truncateString('Abhijit J Chaudhari', 18)}}的其他基金
Multimodality PET/CT Scanner for Small Animal Imaging
用于小动物成像的多模态 PET/CT 扫描仪
- 批准号:
10429458 - 财政年份:2022
- 资助金额:
$ 30.88万 - 项目类别:
Total-body PET for assessing myofascial pain
用于评估肌筋膜疼痛的全身 PET
- 批准号:
10571508 - 财政年份:2022
- 资助金额:
$ 30.88万 - 项目类别:
Imaging biomarkers of early synaptic changes in a preclinical model of Alzheimer’s disease
阿尔茨海默病临床前模型中早期突触变化的成像生物标志物
- 批准号:
9980756 - 财政年份:2019
- 资助金额:
$ 30.88万 - 项目类别:
Total-Body PET/CT for assessing Rheumatoid Arthritis Disease Activity and Treatment Response
全身 PET/CT 用于评估类风湿性关节炎疾病活动性和治疗反应
- 批准号:
9817105 - 财政年份:2019
- 资助金额:
$ 30.88万 - 项目类别:
Total-Body PET/CT for assessing Rheumatoid Arthritis Disease Activity and Treatment Response
全身 PET/CT 用于评估类风湿性关节炎疾病活动性和治疗反应
- 批准号:
10220852 - 财政年份:2019
- 资助金额:
$ 30.88万 - 项目类别:
Imaging biomarkers of early synaptic changes in a preclinical model of Alzheimer’s disease
阿尔茨海默病临床前模型中早期突触变化的成像生物标志物
- 批准号:
9807999 - 财政年份:2019
- 资助金额:
$ 30.88万 - 项目类别:
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