Stroke Disordered Breathing and its Impact on Cognitive Decline in Aging, Alzheimer's Disease and Cerebral Amyloid Angiopathy
中风呼吸障碍及其对衰老认知能力下降、阿尔茨海默病和脑淀粉样血管病的影响
基本信息
- 批准号:10157596
- 负责人:
- 金额:$ 413.77万
- 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:2020-09-11 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:AffectAgeAgingAlzheimer&aposs DiseaseAlzheimer&aposs disease modelAmyloidAnimal ModelAnimalsApneaAreaAstrocytesBlood VesselsBrainBrain StemBreathingCell NucleusCerebral Amyloid AngiopathyCerebrumChemoreceptorsCognitionCognitiveCognitive deficitsComplement Factor BDataDevelopmentDiseaseDisease ProgressionFrequenciesFunctional disorderGliosisImpaired cognitionImpairmentIncidenceIndividualInfarctionInjectionsInterventionIschemic StrokeLinkMediatingMediator of activation proteinMiddle Cerebral Artery OcclusionModelingMolecularMotorMusNerve DegenerationOutcomePathologyPatientsPeriodicityPeripheralPharmacologyPhenotypePhysiologicalPhysiologyPrevalenceRecoveryRegulationRespirationRespiration DisordersSecondary toSerumSeveritiesSex DifferencesSignal TransductionSourceStrokeSurvivorsTg2576TherapeuticTidal VolumeTimeTransforming Growth Factor betaTransforming Growth FactorsTransgenic MiceTreatment EfficacyUnited StatesVascular DiseasesWorkage relatedagedamyloid pathologyastrogliosiscognitive functioncognitive recoverydisabilityhuman old age (65+)improvedinfancyinhibitor/antagonistknock-downmortalitymotor deficitmouse modelneurovascularnormal agingpost strokereceptorrespiratorysexstroke incidencestroke modelstroke patientstroke therapytherapy designventilationβ-amyloid burden
项目摘要
PROJECT SUMMARY
Stroke is the leading cause of long-term disability in the United States. The major contributors to stroke-related
disability are motor and cognitive deficits, which tend to worsen over time, especially in aged individuals. Stroke
also accelerates other age-related diseases, such as Alzheimer’s disease (AD) and cerebral amyloid angiopathy
(CAA). The prevalence of respiratory dysfunction is high in stroke patients and it impairs recovery and increases
mortality. Studies investigating the mechanisms underlying stroke-induced respiratory dysfunction (SIRD) are in
their infancy. Even less is known about how disordered breathing can influence motor and cognitive outcomes
after stroke, especially in aged individuals that have other features of neurodegeneration, including cerebral
amyloid. There are currently no animal models of post-stroke respiratory dysfunction, limiting our ability to
investigate the mechanism of respiratory dysfunction after stroke or to develop interventions to stabilize breathing
to improve cognition. Our preliminary data shows that stroke leads to the development of periodic breathing and
apnea in mice, the severity of which is correlated with both mortality and progressive cognitive decline in
survivors. Stroke is also very common in AD and CAA patients and SIRD may contribute to cognitive decline in
AD and CAA, increasing amyloid burden. Treatment of stroke disordered breathing may decrease Aβ burden
and reduce neurodegeneration and cognitive decline in AD and CAA patients with vascular disease. We have
recently discovered that stroke induces astrogliosis in brain areas remote from the infarct, including
chemoreceptor areas of the brainstem and reducing gliosis specifically in brainstem improves SIRD and
cognition. Mechanistically, we will determine the cellular source (likely astrocytes at the neurovascular interface),
the molecular mediators (likely transforming growth factor β, TGFβ), and the physiological contribution of this to
the development and progression of SIRD and cognitive decline. We have developed an animal model of post-
stroke respiratory dysfunction that recapitulates the physiology seen in stroke patients and is tightly linked to
post-stroke cognitive function. We will now investigate sex differences in this model and investigate if stroke
accelerates cognitive decline in transgenic mice that develop AD or CAA. Finally we will determine the
mechanisms responsible for stroke-induced respiratory pathophysiology and will attempt to develop therapeutic
approaches to stabilize breathing and enhance recovery of cognitive function. Our central hypothesis is that the
severity of disordered breathing correlates with cognitive and motor decline after stroke in wild-type, AD and
CAA mice and that this is secondary to widespread age-enhanced astrogliosis, leading to impaired
chemoreception and progressive apnea. The proposed work will determine how stroke affects control of
breathing in “normal” aging, in AD and in CAA, and whether treatments designed to improve this respiratory
phenotype reduce disease progression.
项目总结
项目成果
期刊论文数量(0)
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科研奖励数量(0)
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