Genetic Contribution to Brain Arterial Dilatation and its Role in Cognition and dementia
遗传对脑动脉扩张的影响及其在认知和痴呆中的作用
基本信息
- 批准号:10088999
- 负责人:
- 金额:$ 40.5万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-08-15 至 2023-04-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectAgingAlzheimer&aposs DiseaseAlzheimer&aposs disease pathologyAlzheimer&aposs disease riskAmericanArteriesAtherosclerosisAtherosclerosis Risk in CommunitiesBiological AssayBlood Flow VelocityBlood VesselsBlood capillariesBrainBrain InfarctionCaliberCarbon DioxideCategoriesCerebral AtherosclerosesCerebrovascular CirculationCerebrovascular DisordersCerebrumClinicalCognitionCommunitiesConnective TissueConnective Tissue DiseasesDataDementiaDilatation - actionDiseaseDistalEventFunctional disorderFutureGeneral PopulationGenesGeneticGenetic DeterminismHealthHomeostasisImpaired cognitionIndividualInheritedIpsilateralLinkMagnetic Resonance AngiographyMeasurementMeasuresMechanicsMediatingMeta-AnalysisModificationOutcomeParticipantPathologicPatientsPhenotypePhysiologicalPopulationPopulation StudyPredisposing FactorPredispositionReportingResearch PriorityRiskRisk FactorsRoleSingle Nucleotide PolymorphismStatistical ModelsStenosisSyndromeTestingUncertaintyVascular DementiaVascular DiseasesWashingtonbasebrain healthcerebral hemodynamicscerebrovascular healthcognitive functioncognitive performancecognitive testingdementia riskepidemiology studyfollow-upgenetic approachgenetic risk factorgenome wide association studygenomic locushemodynamicsimaging biomarkermiddle cerebral arteryneuroimagingnew therapeutic targetnovelnovel therapeuticsprospectivetime usetraitvascular contributions
项目摘要
PROJECT SUMMARY/ABSTRACT:
Alzheimer disease is expected to affect over 13 million Americans by 2050. There is ample evidence that
relates vascular disease to Alzheimer disease, and the vascular contributions to cognitive decline and
dementia are a national research priority. Data from our group and others have demonstrated that brain large
artery disease is an important determinant of cerebrovascular health and, consequently, of cognitive function.
For example, narrowing of the brain arteries due to atherosclerosis has been associated with an increased risk
of Alzheimer disease and vascular dementia. The field has long focused on atherosclerosis and stenosis as
the sole contributors to cerebrovascular health, however. We believe that brain arterial dilatation may also be
deleterious to brain health. Consequently, we propose a change in the paradigm of brain large artery disease
that goes beyond atherosclerosis and/or stenosis, and incorporates brain arterial dilatation as a distinct
pathological phenotype. We postulated that, as with many anthropomorphic measurements, the diameters of
brain arteries are normally distributed and that the extremes of this distribution are pathological. We have
confirmed this hypothesis. We reported that among individuals with the largest or the smallest brain arterial
diameters, the risk of vascular event is higher. The increased risk of vascular events among these individuals
with extreme cerebral phenotypes is partially explained by the co-existence of systemic but not necessarily
cerebral atherosclerosis. We have also demonstrated that non-atherosclerotic brain arterial aging relates to
Alzheimer pathology independent of atherosclerosis and brain infarcts. We have gathered preliminary data
showing that brain arterial diameters are associated non-linearly with cognition, so that individuals with
narrowed or dilated brain arteries have poorer cognitive performance compared with those with average
arterial diameters. Because brain arterial dilatation is understudied, it will be the focus of our proposal. Brain
arterial dilatation may occur among patients with genetic syndromes predisposing to weaker connective tissue,
but it is unclear whether genetic predisposing factors exist in the general population. It is plausible that the
mechanical effects of brain arterial dilatation over the distal arteriolar and capillary flow may disrupt cerebral
autoregulation, and explain the relationship with parenchymal functions such as cognition. It remains unclear
whether these genetic factors are effect modifiers or direct contributors to cognition. This proposal aims to
address these uncertainties. In Aim 1, we will define genetic loci that relate to brain arterial dilatation in >5,000
participants of four well-characterized, population-based studies with longitudinal follow-up who also have
neuroimaging and cognitive assessments. In Aim 2, we will establish the hemodynamic consequences of brain
arterial dilatation by relating it to cerebral blood flow velocities and autoregulation. In Aim 3, we will first confirm
the relationship between brain arterial dilatation with cognitive performance and risk of dementia. We will then
perform a modification analysis using genetic loci related to brain arterial dilatation and measures of
autoregulation as presumed effect modifiers. At the conclusion of these studies, we will definitively establish a
role for brain arterial dilatation in cognition and dementia. We will identify genetic and physiological traits that
will help us identify mechanisms to pursue further with sequencing approaches and functional assays, which in
turn may enable discovery of novel therapeutic targets.
项目总结/摘要:
预计到2050年,阿尔茨海默病将影响超过1300万美国人。有充分的证据表明
将血管疾病与阿尔茨海默病联系起来,以及血管对认知能力下降和
老年痴呆症是国家研究重点。来自我们小组和其他人的数据表明,
动脉疾病是脑血管健康的重要决定因素,因此也是认知功能的重要决定因素。
例如,由于动脉粥样硬化导致的脑动脉狭窄与风险增加有关。
老年痴呆症和血管性痴呆症。该领域长期以来一直专注于动脉粥样硬化和狭窄,
脑血管健康的唯一贡献者。我们认为脑动脉扩张也可能是
对大脑健康有害。因此,我们建议改变脑大动脉疾病的模式,
这超出了动脉粥样硬化和/或狭窄,并结合脑动脉扩张作为一个独特的
病理表型我们假设,与许多拟人测量一样,
脑动脉是正常分布的,这种分布的极端是病态的。我们有
证实了这一假设。我们报告说,在脑动脉最大或最小的个体中,
直径越大,血管事件的风险越高。这些人中血管事件的风险增加
与极端的大脑表型的部分解释是共存的全身性,但不一定
脑动脉粥样硬化我们还证明了非动脉粥样硬化性脑动脉老化与以下因素有关:
阿尔茨海默病病理学独立于动脉粥样硬化和脑梗死。我们已经收集了初步数据
显示脑动脉直径与认知非线性相关,因此,
脑动脉狭窄或扩张的人的认知能力比那些
动脉直径由于脑动脉扩张研究不足,这将是我们建议的重点。大脑
动脉扩张可能发生在易患较弱结缔组织的遗传综合征的患者中,
但目前尚不清楚遗传易感因素是否存在于一般人群中。这是合理的,
脑动脉扩张对远端小动脉和毛细血管流动的机械作用可能会破坏脑动脉
自动调节,并解释与实质功能,如认知的关系。目前还不清楚
这些遗传因素是影响因素还是认知的直接贡献者。这项建议旨在
解决这些不确定性。在目标1中,我们将定义与> 5,000例脑动脉扩张相关的遗传位点,
四项特征良好的、基于人群的纵向随访研究的参与者,
神经成像和认知评估。在目标2中,我们将建立脑血流动力学后果
动脉扩张与脑血流速度和自动调节有关。在目标3中,我们将首先确认
脑动脉扩张与认知能力和痴呆风险之间的关系。然后我们将
使用与脑动脉扩张相关的遗传基因座进行修饰分析,
自动调节作为假定的效应调节剂。在这些研究结束时,我们将明确建立一个
脑动脉扩张在认知和痴呆中的作用。我们将鉴定遗传和生理特征,
将帮助我们确定机制,以进一步追求测序方法和功能测定,
这可能会发现新的治疗靶点。
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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Jose Gutierrez其他文献
Jose Gutierrez的其他文献
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{{ truncateString('Jose Gutierrez', 18)}}的其他基金
Vascular contributions to HIV-associated Neurocognitive Disorders (HAND)
血管对 HIV 相关神经认知障碍 (HAND) 的影响
- 批准号:
10673117 - 财政年份:2022
- 资助金额:
$ 40.5万 - 项目类别:
Vascular contributions to HIV-associated Neurocognitive Disorders (HAND)
血管对 HIV 相关神经认知障碍 (HAND) 的影响
- 批准号:
10405357 - 财政年份:2022
- 资助金额:
$ 40.5万 - 项目类别:
Accelerated non-atherosclerotic brain arterial aging relationship to Alzheimer's disease
加速非动脉粥样硬化性脑动脉老化与阿尔茨海默病的关系
- 批准号:
10018644 - 财政年份:2019
- 资助金额:
$ 40.5万 - 项目类别:
Accelerated non-atherosclerotic brain arterial aging relationship to Alzheimer's disease
加速非动脉粥样硬化性脑动脉老化与阿尔茨海默病的关系
- 批准号:
9891713 - 财政年份:2019
- 资助金额:
$ 40.5万 - 项目类别:
Accelerated non-atherosclerotic brain arterial aging relationship to Alzheimer's disease
加速非动脉粥样硬化性脑动脉老化与阿尔茨海默病的关系
- 批准号:
10414070 - 财政年份:2019
- 资助金额:
$ 40.5万 - 项目类别:
Accelerated non-atherosclerotic brain arterial aging relationship to Alzheimer's disease
加速非动脉粥样硬化性脑动脉老化与阿尔茨海默病的关系
- 批准号:
10615825 - 财政年份:2019
- 资助金额:
$ 40.5万 - 项目类别:
Genetic Contribution to Brain Arterial Dilatation and its Role in Cognition and dementia
遗传对脑动脉扩张的影响及其在认知和痴呆中的作用
- 批准号:
10155386 - 财政年份:2018
- 资助金额:
$ 40.5万 - 项目类别:
Genetic Contribution to Brain Arterial Dilatation and its Role in Cognition and dementia
遗传对脑动脉扩张的影响及其在认知和痴呆中的作用
- 批准号:
10394254 - 财政年份:2018
- 资助金额:
$ 40.5万 - 项目类别:
Genetic Contribution to Brain Arterial Dilatation and its Role in Cognition and dementia
遗传对脑动脉扩张的影响及其在认知和痴呆中的作用
- 批准号:
9761947 - 财政年份:2018
- 资助金额:
$ 40.5万 - 项目类别:
Genetic Contribution to Brain Arterial Dilatation and its Role in Cognition and dementia
遗传对脑动脉扩张的影响及其在认知和痴呆中的作用
- 批准号:
10083526 - 财政年份:2018
- 资助金额:
$ 40.5万 - 项目类别:
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