The Striatum and Hippocampus: "Hubs" of White Matter Connections in Parkinson's Disease Cognitive Decline
纹状体和海马:帕金森病认知衰退中白质连接的“枢纽”
基本信息
- 批准号:10530631
- 负责人:
- 金额:$ 5.27万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-01-01 至 2024-12-31
- 项目状态:已结题
- 来源:
- 关键词:AccountingAlzheimer&aposs DiseaseAlzheimer&aposs disease related dementiaAreaAttentionAttentional deficitBasal GangliaBenignBrainBrain regionClinicalCognitionCognitiveCognitive deficitsCorpus striatum structureDataData SetDedicationsDeep Brain StimulationDementiaDevelopmentDiffusionDigit structureDiseaseEngineeringEnvironmentEquipmentExhibitsExtracellular SpaceFiberFoundationsFunctional disorderFutureHippocampusImpaired cognitionIncidenceInstitutionInvestigationKnowledgeLevodopaLongevityLongitudinal cohortMagnetic Resonance ImagingMeasuresMemoryMentorsNeurocognitiveNeurodegenerative DisordersNeuropsychological TestsNeurosciencesOutcomeParietalParkinson DiseasePathologyPatientsPatternPharmaceutical PreparationsPhysiciansPlayPopulationPositioning AttributeProcessPrognosisPublic HealthRecording of previous eventsResearchResearch SubjectsResourcesRoleShort-Term MemorySyndromeTechniquesTechnologyTestingTherapeuticTrainingTreatment outcomeVisuospatialWateraging populationcareercognitive changecognitive functioncognitive performancecohortcost effectivedementeddementia riskfollow-upglobal healthhealthy agingimprovedinsightmemory recallmotor disorderneuralneural circuitneuroimagingnovelprofiles in patientsprogression markerresponseskillstractographytreatment responsetreatment strategywhite matterwhite matter damage
项目摘要
Due to an aging population and increased lifespan, dementia is an increasing clinical and public health issue. The most common and well-known cause is Alzheimer’s disease (AD), but other important disorders are involved in the development of AD-related dementias (ADRD). What is less appreciated is that Parkinson’s disease (PD), the second most common neurodegenerative disease, while often associated with motor dysfunction, contributes to ADRD with an incidence of dementia as high as 80% in late stages in which most have AD co-pathology. Therefore, this population exhibits a range of cognitive deficits that enables insight into mechanisms involved in ADRD. There seem to be two distinct cognitive profiles in these patients. One is a benign frontal profile characterized by executive and attention deficits, whereas the other is a posterior profile characterized by memory and visuospatial deficits that is associated with faster progression to dementia, often with AD co-pathology. The premise of this application is that identifying the neural circuitry underlying frontal and posterior function may provide insight into structural alterations occurring in ADRD. Dopaminergic therapies are known to improve frontal circuitry function, but not posterior circuitry, leading to the hypothesis that posterior circuit alterations are due to non-dopaminergic pathology, such as AD co-pathology. If true, the pattern of frontal-vs-posterior involvement may lead to differential responses to current treatments in ADRD. I plan to apply diffusion tensor tractography, a sensitive and widely available MRI technique, to measure microstructural integrity of white matter (WM) connections between brain regions. My central hypothesis is that WM alterations in frontal and posterior circuitry occurs in PD (Aim 1); that these alterations are associated with specific cognitive deficits and relate to differing rates of progression to dementia (Aim 2); and the ratio of frontal to posterior damage (F/P ratio) modulates the cognitive response to treatment (e.g., levodopa, deep brain stimulation, Aim 3). These aims will be implemented by leveraging existing datasets allowing a cost-effective and impactful investigation. This study immediately will impact knowledge of WM circuits related to dementia with insight into underlying mechanisms and therapeutic strategies, as well as provide the foundational line of research for future study of microstructural signatures of AD/ADRD. I have assembled a world-class mentoring team with expertise in areas related to my research and a history of highly-successful mentoring. The environment and institutional resources available to me for this project are excellent with a well-developed training plan and access to required equipment and research datasets. The proposed project and training plan will position me at the intersection of neuroscience and engineering, and enable me to tackle important clinical problems with the latest technological advancements. My new skills in neuroimaging analysis and neuropsychological testing to probe neurocognitive circuitry will provide a foundation for my career as an independent physician-engineer focused on alleviating the burden of AD/ADRD.
由于人口老龄化和寿命延长,痴呆症是一个日益严重的临床和公共卫生问题。最常见和众所周知的原因是阿尔茨海默病(AD),但其他重要的疾病也参与了AD相关性痴呆(ADRD)的发展。人们不太了解的是,帕金森病(PD)是第二大最常见的神经退行性疾病,虽然通常与运动功能障碍有关,但它会导致ADRD,晚期痴呆的发病率高达80%,其中大多数伴有AD共病理。因此,这一人群表现出一系列认知缺陷,从而能够深入了解与ADRD相关的机制。这些患者似乎有两种截然不同的认知特征。一种是以执行力和注意力缺陷为特征的良性正面侧位,而另一种是以记忆和视觉空间缺陷为特征的后侧侧位,这与痴呆症的快速进展有关,通常伴有AD共病理。这项应用的前提是,识别额叶和后叶功能下的神经回路可以为ADRD中发生的结构改变提供见解。多巴胺能治疗已知能改善额神经回路功能,但不能改善后神经回路,导致后神经回路改变是由非多巴胺能病理引起的假设,如AD共病理。如果这是真的,额-后侧受累的模式可能导致对当前ADRD治疗的不同反应。我计划应用扩散张量神经束成像,一种灵敏且广泛使用的MRI技术,来测量大脑区域之间白质(WM)连接的微结构完整性。我的中心假设是,前额和后脑回路的WM改变发生在PD中(Aim 1);这些改变与特定的认知缺陷有关,并与不同的痴呆进展率有关(目的2);额后部损伤的比率(F/P比率)调节对治疗(如左旋多巴、深部脑刺激,Aim 3)的认知反应。这些目标将通过利用现有数据集来实现,从而实现具有成本效益和影响力的调查。这项研究将立即影响与痴呆症相关的WM电路的知识,深入了解潜在的机制和治疗策略,并为未来研究AD/ADRD的微观结构特征提供基础研究线索。我已经组建了一个世界级的指导团队,他们在与我的研究相关的领域具有专业知识,并且有着非常成功的指导经验。这个项目的环境和机构资源都很好,有完善的培训计划,可以使用所需的设备和研究数据集。所提出的项目和培训计划将使我处于神经科学和工程的交叉点,使我能够用最新的技术进步来解决重要的临床问题。我在神经成像分析和神经心理测试方面的新技能将为我作为一名独立的医生工程师的职业生涯奠定基础,专注于减轻AD/ADRD的负担。
项目成果
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Gregory L Brown其他文献
Gregory L Brown的其他文献
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{{ truncateString('Gregory L Brown', 18)}}的其他基金
The Striatum and Hippocampus: "Hubs" of White Matter Connections in Parkinson's Disease Cognitive Decline
纹状体和海马:帕金森病认知衰退中白质连接的“枢纽”
- 批准号:
10295121 - 财政年份:2021
- 资助金额:
$ 5.27万 - 项目类别: