COVID-19-related blood-brain barrier and microstructural brain injury; Sex differences and synergy with Alzheimer's disease risk
COVID-19相关的血脑屏障和脑微结构损伤;
基本信息
- 批准号:10584896
- 负责人:
- 金额:$ 80.47万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-12-15 至 2027-11-30
- 项目状态:未结题
- 来源:
- 关键词:2019-nCoVACE2AccelerationAcuteAdultAgeAge-associated memory impairmentAgingAllelesAlzheimer&aposs DiseaseAlzheimer&aposs disease pathologyAlzheimer&aposs disease riskAnti-Inflammatory AgentsAttentionBindingBloodBlood - brain barrier anatomyBlood brain barrier dysfunctionBrainBrain InjuriesCOVID-19COVID-19 impactCOVID-19 mortalityCOVID-19 pandemicCOVID-19 patientCOVID-19 riskCOVID-19 severityCOVID-19 survivorsCentral Nervous SystemCerebrovascular DisordersCognitiveCognitive deficitsComplexConfusionDementiaDiffusionDiffusion Magnetic Resonance ImagingDiseaseDropsElderlyEndothelial CellsEstrogensExhibitsExtravasationGeneticGenetic RiskGonadal Steroid HormonesHippocampusHyperactivityImmuneImmune responseImpaired cognitionIndividualInfectionInfiltrationInflammationInflammatoryInjuryInvestigationLong COVIDMagnetic Resonance ImagingMeasuresMedialMediatingMemoryMenopauseMethodsMissionModificationNerve DegenerationNeurobehavioral ManifestationsNeurobiologyNeurologicNeurologic EffectNeurologic SymptomsNeurological outcomeNeuronsOutcomeParticipantPathogenesisPathogenicityPathologicPathologyPathway interactionsPatientsPermeabilityPlasmaPredispositionPublic HealthReportingResearchRestriction Spectrum ImagingRiskRisk AssessmentRisk EstimateRisk FactorsRoleSARS-CoV-2 infectionSex DifferencesStructureSymptomsTechniquesTestingTestosteroneTimeUnited States National Institutes of HealthVascular DiseasesViralWomanage relatedagedaging populationapolipoprotein E-4biomarker identificationblood-brain barrier permeabilizationbrain abnormalitiesbrain dysfunctionbrain healthbrain tissuecerebrovascularcognitive functioncognitive recoverycognitive testingcomorbiditycontrast enhancedexecutive functiongenetic risk factorhazardhigh risk populationhormone regulationhuman old age (65+)long term consequences of COVID-19menmental statemultimodal neuroimagingnerve injuryneuroimagingneuroinflammationneurologic sequelae of COVID-19neuropathologyneurovascularoutcome predictionpersonalized approachpost SARS-CoV-2 infectionpre-clinicalpreservationrespiratory virusresponsesevere COVID-19sexsynergismtau-1tool
项目摘要
PROJECT SUMMARY
COVID-19 is associated with cognitive impairment that may persist long after infection. COVID-19 risk
factors overlap with those for Alzheimer’s disease (AD), including older age, the APOE4 allele, and vascular
dysfunction, suggesting that pathology from one condition may exacerbate pathogenesis of the other. Blood-
brain barrier (BBB) dysfunction may serve as a common pathogenic mechanism, as BBB breakdown has been
identified in individuals at risk for AD and may facilitate COVID-19-related neural injury via binding of SARS-
CoV-2 to cerebrovascular endothelial cells or via virally-mediated neuroinflammation. Sex is also a risk factor
for both diseases, with increased AD risk for women and sex-specific risk for acute and chronic COVID-19
symptoms, which may be partially mediated by sex hormone regulation of SARS-CoV-2 binding, inflammation,
immune activity, or BBB dysfunction. The intersection of latent AD neuropathology with neuroinflammation or
cerebrovascular dysfunction triggered by COVID-19 among the aging population may ignite a perfect storm of
neurodegenerative changes. Yet despite potential for convergence of the COVID-19 pandemic upon a pre-
existing public health crisis of dementia, little research has been devoted to understanding the mechanistic
overlap between these conditions or the potentially catastrophic public health consequences of their synergy.
The proposed investigation will assess the neurobiological sequalae of COVID-19 in older adults along with
their modification by sex, AD pathology, and AD genetic risk. Restriction spectrum imaging to measure brain
microstructure and dynamic contrast-enhanced MRI to estimate BBB permeability will be conducted on adults
aged 50 years or older with previous COVID-19 infection (CV) and disease-related cognitive impairment, and
on uninfected healthy controls. Cognitive testing will be conducted at time of neuroimaging and annually for up
to four additional years. AD polygenic hazard scores (PHS), estrogen and testosterone levels, and plasma p-
tau181, will be measured for all participants, and lifetime estrogen exposure will be calculated for women. This
project will test the hypotheses that CV exhibit greater BBB breakdown, microstructural damage, and more
severe cognitive impairment and decline than controls (Aim 1). AD risk (Aim 2) and sex (Aim 3) are predicted
to modify effects of COVID-19 on brain and cognitive measures, with more severe disease-related brain injury,
BBB permeability, and cognitive decline for those with high PHS or abnormal p-tau181 and for women. In sex-
stratified analyses, testosterone and estrogen are expected to correlate with brain injury, BBB breakdown, and
cognitive deficits (Aim 3). This study will pioneer the most advanced diffusion and permeability MRI techniques
to clarify the yet elusive neurobiological effects of COVID-19 underlying its cognitive symptoms in older adults
at elevated risk for neurodegenerative changes. It will advance our understanding of the currently speculative
synergy between COVID-19 and AD pathogenesis as well as the complex role of sex and hormonal regulation
in COVID-19-related neurological sequalae.
项目摘要
COVID-19与感染后可能长期存在的认知障碍有关。COVID-19风险
与阿尔茨海默病(AD)的因素重叠,包括年龄较大,APOE 4等位基因和血管
功能障碍,表明一种疾病的病理可能会加剧另一种疾病的发病机制。血-
脑屏障(BBB)功能障碍可作为常见的致病机制,因为BBB破坏已被
在有AD风险的个体中发现,并可能通过结合SARS促进COVID-19相关的神经损伤-
CoV-2通过病毒介导的神经炎症作用于脑血管内皮细胞。性也是一个危险因素
对于这两种疾病,女性AD风险增加,急性和慢性COVID-19的性别特异性风险增加
症状,这可能部分由SARS-CoV-2结合的性激素调节,炎症,
免疫活性或BBB功能障碍。潜伏性AD神经病理学与神经炎症或
在老龄化人口中,COVID-19引发的脑血管功能障碍可能会引发一场完美的风暴,
神经退行性改变然而,尽管2019冠状病毒病大流行有可能与前疫情趋同,
尽管存在痴呆症的公共卫生危机,但很少有研究致力于了解痴呆症的机制。
这些疾病之间的重叠或其协同作用可能造成灾难性的公共卫生后果。
拟议的研究将评估老年人沿着的COVID-19神经生物学后遗症,
它们通过性别、AD病理学和AD遗传风险进行修饰。限制光谱成像测量大脑
将对成人进行显微结构和动态对比增强MRI,以估计BBB渗透性
50岁或以上,既往有COVID-19感染(CV)和疾病相关认知障碍,以及
未受感染的健康对照组。认知测试将在神经成像时进行,每年进行一次,
延长四年AD多基因危害评分(PHS)、雌激素和睾酮水平以及血浆p-
将测量所有参与者的tau 181,并计算女性的终生雌激素暴露量。这
该项目将测试CV表现出更大的BBB击穿,微结构损伤等假设
严重的认知障碍和下降比对照组(目标1)。预测AD风险(目标2)和性别(目标3)
改变COVID-19对大脑和认知指标的影响,使疾病相关的脑损伤更严重,
BBB通透性,以及PHS高或p-tau 181异常和女性的认知能力下降。在性方面-
分层分析显示,睾酮和雌激素与脑损伤、血脑屏障破坏和
认知缺陷(目标3)。这项研究将开创最先进的扩散和渗透性MRI技术
阐明COVID-19在老年人认知症状中的神经生物学效应,
神经退行性病变的风险增加它将促进我们对目前投机的理解
COVID-19和AD发病机制之间的协同作用以及性别和激素调节的复杂作用
与COVID-19相关的神经系统后遗症。
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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Emilie T. Reas其他文献
effects Animal model of methylphenidate ' s long-term memory-enhancing Material Supplemental
哌醋甲酯长期记忆增强物质补充动物模型的效果
- DOI:
- 发表时间:
2014 - 期刊:
- 影响因子:0
- 作者:
Stephanie A. Carmack;Kristin K. Howell;Kleou Rasaei;Emilie T. Reas;S. Anagnostaras - 通讯作者:
S. Anagnostaras
Sensitivity of restriction spectrum imaging to memory and neuropathology in Alzheimer’s disease
限制性光谱成像对阿尔茨海默病记忆和神经病理学的敏感性
- DOI:
- 发表时间:
2017 - 期刊:
- 影响因子:0
- 作者:
Emilie T. Reas;D. Hagler;N. White;J. Kuperman;H. Bartsch;Karalani Cross;Richard Q. Loi;Richard Q. Loi;A. Balachandra;M. J. Meloy;C. Wierenga;D. Galasko;J. Brewer;A. Dale;L. McEvoy - 通讯作者:
L. McEvoy
Blood‐brain barrier permeability is increased in early Alzheimer’s disease and correlates with brain microstructure
早期阿尔茨海默病的血脑屏障通透性增加,并与大脑微观结构相关
- DOI:
10.1002/alz.063948 - 发表时间:
2022 - 期刊:
- 影响因子:0
- 作者:
Emilie T. Reas;Amaryllis A. Tsiknia;S. Banks;Kenneth A. Rostowsky;M. Andrews;J. Brewer;D. S. Bolar - 通讯作者:
D. S. Bolar
Blood-brain barrier permeability varies by brain region and APOE4 status and correlates with brain microstructure among high-AD risk groups
在高阿尔茨海默病风险组中,血脑屏障通透性因大脑区域和载脂蛋白 E4 状态而异,并与大脑微结构相关。
- DOI:
10.1016/j.nicl.2025.103805 - 发表时间:
2025-01-01 - 期刊:
- 影响因子:3.600
- 作者:
Seraphina K. Solders;Qian Shen;Emilie T. Reas - 通讯作者:
Emilie T. Reas
Microstructural brain changes track cognitive decline in mild cognitive impairment
- DOI:
10.1016/j.nicl.2018.09.027 - 发表时间:
2018-01-01 - 期刊:
- 影响因子:
- 作者:
Emilie T. Reas;Donald J. Hagler;Nathan S. White;Joshua M. Kuperman;Hauke Bartsch;Christina E. Wierenga;Douglas Galasko;James B. Brewer;Anders M. Dale;Linda K. McEvoy - 通讯作者:
Linda K. McEvoy
Emilie T. Reas的其他文献
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{{ truncateString('Emilie T. Reas', 18)}}的其他基金
Association of blood-brain barrier breakdown with brain microstructure neuropathology in early Alzheimer's Disease
早期阿尔茨海默病中血脑屏障破坏与脑微结构神经病理学的关联
- 批准号:
10469657 - 财政年份:2021
- 资助金额:
$ 80.47万 - 项目类别:
Association of blood-brain barrier breakdown with brain microstructure neuropathology in early Alzheimer's Disease
早期阿尔茨海默病中血脑屏障破坏与脑微结构神经病理学的关系
- 批准号:
10633267 - 财政年份:2021
- 资助金额:
$ 80.47万 - 项目类别:
Association of blood-brain barrier breakdown with brain microstructure neuropathology in early Alzheimer's Disease
早期阿尔茨海默病中血脑屏障破坏与脑微结构神经病理学的关联
- 批准号:
10457085 - 财政年份:2021
- 资助金额:
$ 80.47万 - 项目类别:
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