Noradrenergic mechanisms of alcohol's impact on the development of MCI and early stage AD
酒精影响 MCI 和早期 AD 发展的去甲肾上腺素能机制
基本信息
- 批准号:10629209
- 负责人:
- 金额:$ 36.75万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-09-30 至 2025-05-31
- 项目状态:未结题
- 来源:
- 关键词:AccelerationAcuteAddressAgeAge-associated memory impairmentAgingAlcohol abuseAlcohol consumptionAlcoholsAlzheimer&aposs DiseaseAlzheimer&aposs disease pathologyAlzheimer&aposs disease related dementiaAlzheimer&aposs disease riskAutopsyBasal Nucleus of MeynertBrainBrain imagingBrain regionCellsCerebral cortexCessation of lifeChronicClinicalClinical ResearchClinical assessmentsCognitionCognitiveCognitive agingCognitive deficitsDataDementiaDevelopmentEarly Onset Alzheimer DiseaseElderlyEmotionalEmotionsEtiologyFunctional Magnetic Resonance ImagingFunctional disorderGoalsHeavy DrinkingHippocampusImageImpaired cognitionIndividualIntoxicationLifeLightLinkLiteratureLogisticsLongitudinal StudiesMagnetic Resonance ImagingMediatingMemoryMolecularNeocortexNerve DegenerationNeurofibrillary TanglesNeuronsNeuropil ThreadsPatientsPositron-Emission TomographyPrefrontal CortexProspective StudiesReportingRestRiskRoleSeveritiesSex DifferencesSignal TransductionSourceStagingStructureSystemThalamic structureTimeWithdrawalWomanabeta depositionage relatedalcohol effectalcohol exposurealcohol misuseburden of illnesscerebral atrophychronic alcohol ingestioncingulate cortexcognitive controlcognitive functioncognitive performancecognitive reservecognitive testingdementia riskdensitydrinkingentorhinal cortexepidemiology studyhealthy aginglocus ceruleus structuremild cognitive impairmentmodifiable riskneuralneuroinflammationneuromelaninneuron lossnoradrenergicpreclinical studyresponsesocial
项目摘要
ABSTRACT/SUMMARY
Alcohol misuse exacerbates cognitive aging. Prospective studies associate problem drinking to increased risk
and earlier onset of Alzheimer’s disease (AD) and related dementia (ADRD). On the other hand, studies of
mainly social drinkers reported no or mitigating effects of alcohol use on cognitive functions. Thus, alcohol use
may influence the risks of ADRD and the impacts likely depend on the severity of alcohol consumption.
Whereas the progression of ADRD is typically described in six stages in correlation with accumulation
of neurofibrillary tangles and neuropil threads in the cortex and hippocampus, other studies have implicated
functional and structural changes, including neuronal loss, in the locus coeruleus (LC) in early stage AD. LC
degeneration occurs during healthy aging, and longitudinal studies have suggested the LC as a critical
structure of cognitive reserve, in support of LC noradrenergic (NA) circuit dysfunction in the development of
ADRD. Alcohol misuse may cause allostatic changes in NA signaling and accelerate LC circuit dysfunction
during aging. A substantial body of studies provide evidence for the impact of alcohol misuse on central NA
circuits and NA dysfunction as a critical mechanism linking alcohol misuse and ADRD.
In support of this mechanistic link, we showed that LC neuromelanin imaging signals decreased more
rapidly with age in heavy as compared to light drinkers. Further, the prefrontal cortex and other structures of
the default mode network, which receives heavy NA projections from the LC, also showed significantly steeper
age-related changes in responses to cognitive control and during resting state in heavy vs. light drinkers.
Building on these data and a literature supporting hippocampal function in emotion memory, we propose to
combine MRI and longitudinal assessments of 120 old adult heavy and non/light drinkers (n=60 each, half
women, age matched) to address three aims: 1) Examine whether age-related changes in LC neuromelanin
signals vary with alcohol use and cognitive impairment and whether LC signals mediate the inter-relationship
between alcohol use and cognitive status; 2) Examine whether and how LC circuit connectivities in response to
cognitive control and emotional memory vary with alcohol use and whether the connectivity strength correlates
with LC neuromelanin signals; and 3) Examine whether and how LC neuromelanin signals and LC circuit
connectivities predict the decline in cognitive function and the potential transition from healthy aging to MCI or
from MCI to early stage AD. We will also perform exploratory analyses to examine sex differences and the
influences of other modifiable risk factors for dementia on the development of MCI and AD.
The overarching goal of the study is to investigate the effects of alcohol misuse and NA dysfunction on
the development of ADRD. We believe that the findings would not only address a critical mechanism of ADRD
but also shed light on the etiologies of other neurodegenerative conditions that implicate NA dysfunction.
抽象/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)
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Chiang-Shan Ray Li其他文献
Chiang-Shan Ray Li的其他文献
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{{ truncateString('Chiang-Shan Ray Li', 18)}}的其他基金
A noradrenergic mechanism of apathy and motivation deficit in MCI and AD
MCI 和 AD 中冷漠和动机缺陷的去甲肾上腺素能机制
- 批准号:
9895059 - 财政年份:2020
- 资助金额:
$ 36.75万 - 项目类别:
Noradrenergic mechanisms of alcohol's impact on the development of MCI and early stage AD
酒精影响 MCI 和早期 AD 发展的去甲肾上腺素能机制
- 批准号:
10401937 - 财政年份:2020
- 资助金额:
$ 36.75万 - 项目类别:
Noradrenergic mechanisms of alcohol's impact on the development of MCI and early stage AD
酒精影响 MCI 和早期 AD 发展的去甲肾上腺素能机制
- 批准号:
10264910 - 财政年份:2020
- 资助金额:
$ 36.75万 - 项目类别:
Aging and cerebral regulation of physiological responses to social emotions
衰老和大脑对社会情绪生理反应的调节
- 批准号:
9312926 - 财政年份:2017
- 资助金额:
$ 36.75万 - 项目类别:
Imaging Cognitive Control in Cocaine Dependence
可卡因依赖中的认知控制成像
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8307463 - 财政年份:2009
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$ 36.75万 - 项目类别:
Imaging Cognitive Control in Cocaine Dependence
可卡因依赖中的认知控制成像
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8513955 - 财政年份:2009
- 资助金额:
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