Dopaminergic mechanisms of resilience to Alzheimer's disease neuropathology
阿尔茨海默病神经病理学恢复的多巴胺能机制
基本信息
- 批准号:10809199
- 负责人:
- 金额:$ 43.68万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-09-30 至 2025-09-29
- 项目状态:未结题
- 来源:
- 关键词:AddressAdultAffectAffinityAgingAllelesAlzheimer&aposs DiseaseAlzheimer&aposs disease pathologyAmyloid beta-ProteinAnti-Inflammatory AgentsAutomobile DrivingBehaviorBrainClinicalClinical dementia rating scaleCognitionCognitiveDRD2 geneDataData SetDementiaDevelopmentDopamineDopamine D2 ReceptorElderlyGenesGenetic PolymorphismGenotypeHeterogeneityHumanImpaired cognitionIndividualIndividual DifferencesInterventionLinkMaintenanceMeasuresMediatingMemoryNeuromodulatorPathologyPlayPopulationPositron-Emission TomographyProcessProxyPublishingResearchRoleStandardizationStructureSumSystemTestingThickThinnessVariantbeta amyloid pathologybrain healthcognitive functioncognitive performancecognitive reservedopamine systementorhinal cortexexecutive functionformycin triphosphategenetic variantinterestmild cognitive impairmentnerve supplyneuralneuroimagingneuroinflammationneuromechanismneuropathologyneuroprotectionnovelpre-clinicalpreservationreceptor bindingreceptor functionresilienceresilience factorsecondary analysistau Proteinstherapeutic targetuptakeβ-amyloid burden
项目摘要
PROJECT SUMMARY
While the development of Alzheimer’s disease (AD)-related β-amyloid (Aβ) and tau pathology is associated
with declines in brain structure and cognitive function on a population level, there is considerable heterogeneity
in these effects across individuals. Individual differences in the brain’s dopamine system represent a
compelling moderator of Aβ and tau pathology’s effects on brain structure and function. Previous research has
established that an “optimal” genetic polymorphism presumed to increase dopamine D2 receptor affinity
(DRD2 C957T; rs6277) is associated with greater cortical thickness. While the mechanisms driving this effect
are not known, dopamine can be neurotrophic and D2 receptors mediate a number of neuroprotective
functions that may counteract AD processes including reduction of neuroinflammation. Relevant to the
successful maintenance of cognitive function despite pathology, higher D2 receptor availability is associated
with better executive function and memory. We propose the DRD2 T/T genotype supports resilience to AD-
related tau and Aβ pathology. Analyses will focus on cognitively normal and mild cognitive impairment groups
for which establishing the mechanisms of successful AD resilience are most relevant. We will use the
Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset to pursue the following Specific Aims. We will first
establish a role of the DRD2 T/T genotype in conferring greater cortical thickness despite Aβ
([18F]Florbetapir/Florbetaben) and tau ([18F]Flortaucipir PET) pathology cross-sectionally (Aim 1). Next, we will
investigate the role of DRD2 T/T genotype in cognitive reserve by probing genotype x pathology interactions in
cross-sectional and longitudinal measures of executive function and memory using the Preclinical Alzheimer
Cognition Composite. We will test the hypothesis that the T/T genotype is associated with better-than-expected
cognition given tau and Aβ burden (Aim 2). Finally, we will track longitudinal clinical decline using the Clinical
Dementia Scale – Sum of Boxes and longitudinal decline in cortical thickness to determine the extent to which
the T/T genotype predicts slower clinical decline and brain maintenance (Aim 3). The successful completion of
these aims will provide novel evidence that the dopamine system interacts with AD pathology to affect aging
trajectories, and will support therapeutic targeting of the dopamine system for individuals predisposed to lower
D2 affinity.
项目总结
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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Anne Shively Berry其他文献
Anne Shively Berry的其他文献
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{{ truncateString('Anne Shively Berry', 18)}}的其他基金
Upregulated Norepinephrine Synthesis Capacity in Aging
衰老过程中去甲肾上腺素合成能力上调
- 批准号:
10447225 - 财政年份:2022
- 资助金额:
$ 43.68万 - 项目类别:
Upregulated Norepinephrine Synthesis Capacity in Aging
衰老过程中去甲肾上腺素合成能力上调
- 批准号:
10629346 - 财政年份:2022
- 资助金额:
$ 43.68万 - 项目类别:
Locus Coeruleus Biomarker Development for Early Detection of Alzheimers Disease in Humans
用于早期检测人类阿尔茨海默病的蓝斑生物标记物开发
- 批准号:
10194679 - 财政年份:2021
- 资助金额:
$ 43.68万 - 项目类别:
Locus Coeruleus Biomarker Development for Early Detection of Alzheimers Disease in Humans
用于早期检测人类阿尔茨海默病的蓝斑生物标记物开发
- 批准号:
10380028 - 财政年份:2021
- 资助金额:
$ 43.68万 - 项目类别:
Age effects on memory and reward systems in decision making
年龄对决策中的记忆和奖励系统的影响
- 批准号:
10187476 - 财政年份:2019
- 资助金额:
$ 43.68万 - 项目类别:
Dopaminergic modulation of networks mediating cognitive flexibility in older adul
介导老年人认知灵活性的网络多巴胺能调节
- 批准号:
8874736 - 财政年份:2014
- 资助金额:
$ 43.68万 - 项目类别:
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