Clarifying the overlapping pathology of delirium and dementia
Clarifying the overlapping pathology of delirium and dementia
批准号:
10202478
负责人:
ROBERT A PEARCE
金额:
$74.7万
依托单位国家:
美国
项目类别:
财政年份:
2019
资助国家:
美国
项目状态:
已结题
起止时间:
2019-08-15 至 2024-05-31
关键词:
AcuteAddressAffectAgingAlzheimer&aposs DiseaseAmyloidAmyloid depositionAnatomyAnteriorAtrophicBehaviorBiologicalBiological MarkersBrainCause of DeathCharacteristicsChronicCognitionCognitiveCognitive agingConfusionDataData CollectionDeliriumDementiaElderlyElectrodesElectroencephalogramElectrophysiology (science)FosteringHealthImageImpaired cognitionImpairmentIncidenceIndividualInflammationInflammatoryInterleukin-6LightLongitudinal cohort studyMagnetic Resonance ImagingMethodologyMissionMorbidity - disease rateNerve DegenerationNeuronal InjuryOperative Surgical ProceduresPathogenesisPathologicPathologyPatientsPerioperativePerioperative CarePilot ProjectsPlasmaPositron-Emission TomographyPostoperative PeriodPredispositionPreventivePublic HealthQuality of lifeResearchRiskRoleScreening procedureSeveritiesSourceTestingTherapeuticTimeUnited StatesUnited States National Institutes of HealthWakefulnessamyloid pathologybasecerebral atrophycingulate cortexcognitive changecohortcostcytokinedensityentorhinal corteximprovedinnovationinsightischemic injuryischemic lesionlongitudinal positron emission tomographymedical complicationmortalityneurofilamentnovelnovel markernovel therapeutic interventionnovel therapeuticspostoperative deliriumpreventprimary outcomescreeningserial imagingsystemic inflammatory responsetherapeutic development
中文摘要
项目摘要/摘要
痴呆症是美国第六大死亡原因,与生活质量下降和
独立;它是无法预防、治愈,甚至无法减缓的。精神错乱是一种突如其来的混乱状态,
与发病率和死亡率增加以及长期认知受损有关。尽管有
这两种疾病--经济、社会和个人--都付出了巨大的代价,精神错乱和痴呆症被剥夺了
治疗,很大程度上是由于对其发病机制的有限了解。心理障碍的双向倾向
痴呆症和精神错乱的相互作用为了解其重叠的病理机制提供了独特的机会
机制,并确定新的治疗方法。例如,精神错乱和痴呆症的倾向,
由淀粉样蛋白沉积表示的,与额叶阿尔法能量增加有关,这表明类似的变化
在任何一种情况发生之前,大脑动力学的变化都是显而易见的。皮层慢波活动(SWA)是一种共享的
衰老、精神错乱和痴呆症认知改变的电生理特征。我们建议
了解清醒状态下的SWA会影响所有这些情况,这将带来新颖的、相互提供信息的
对这些疾病的发病机制的洞察。我们最重要的假设是精神错乱是由
炎症与两种主要痴呆病理之间的相互作用,淀粉样蛋白和
神经变性,导致皮层SWA和受损的电生理障碍
连接性,这会导致精神错乱。在这项应用中,我们将测试淀粉样蛋白和神经退行性变
倾向于(特定目标1),并因(特定目标3)一次精神错乱而加剧。我们还将
研究炎症通过以下途径诱导精神错乱、SWA和连通性改变的机制作用
与淀粉样蛋白病理和神经变性的相互作用(特定目标2)。通过这种方式,我们可以理解如何
精神错乱与两种痴呆症病理的轨迹相互作用,同时理解SWA,因此
精神错乱的认知变化,可以如此突然地出现。我们的技术创新是用256路高
用密度脑电(HD-EEG)跟踪电生理变化与行为。我们将从
使用最先进的电极数字化重建SWA到个体对象解剖,以允许
SWA与受试者的磁共振成像(MRI)或正电子发射断层扫描的对应关系
(PET)淀粉样蛋白数据。绘制病理中的空间重叠图是我们的方法学创新,它增强了
任何关系在生物学上都是可信的。我们将追踪精神错乱是如何导致神经病变的。
这可能是手术后认知能力下降的原因。我们的数据将阐明
精神错乱和痴呆症,强调(I)筛选淀粉样蛋白的新途径/新的生物标志物终点
病理学或精神错乱的风险(额叶阿尔法功率)和(Ii)针对机械学的治疗进展
对大脑皮层SWA的理解是这些认知变化的基础。
英文摘要
Project Summary/Abstract
Dementia is the sixth leading cause of death in the United States and is associated with loss of quality of life and
independence; it cannot be prevented, cured, or even slowed. Delirium is a sudden state of confusion that is
associated with increased morbidity and mortality and impaired long-term cognition. Although there are
substantial costs to both conditions – financial, societal and individual – delirium and dementia are bereft of
therapies, largely due to the limited understanding of their pathogeneses. The bidirectional predisposition of
dementia and delirium to each other offers a unique opportunity to understand their overlapping pathological
mechanisms and to identify new therapeutic approaches. For example, predisposition to delirium and dementia,
denoted by amyloid deposition, is associated with increased frontal alpha power, suggesting that similar changes
in brain dynamics are evident before the onset of either condition. Cortical slow wave activity (SWA) is a shared
electrophysiological hallmark of cognitive changes in aging, delirium and dementia. We propose that
understanding SWA in wakefulness, which affects all these conditions, will lead to novel, mutually informative
insights into the pathogenesis of those conditions. Our overarching hypothesis is that delirium results from
an interaction between inflammation and two key dementia pathologies, amyloid and
neurodegeneration, leading to the electrophysiological disturbance of cortical SWA and impaired
connectivity, which results in delirium. In this application, we will test how amyloid and neurodegeneration
predispose to (Specific Aim 1) and are exacerbated by (Specific Aim 3) an episode of delirium. We will also
investigate the mechanistic role of inflammation to induce delirium, SWA, and connectivity changes through
interaction with amyloid pathology and neurodegeneration (Specific Aim 2). In this way, we can understand how
delirium interacts with the trajectory of two dementia pathologies, while understanding how SWA, and therefore
the cognitive changes of delirium, can arise so abruptly. Our technical innovation is to use 256 channel high-
density electroencephalogram (HD-EEG) to track the electrophysiological changes with behavior. We will source
reconstruct the SWA to individual subject anatomy using state-of-the-art electrode digitization to allow
correspondence of the SWA to a subject's magnetic resonance imaging (MRI) or positron emission tomography
(PET) amyloid data. Mapping spatial overlap in pathologies is our methodological innovation, which enhances
biological plausibility for any relationship. We will track how delirium contributes to neuropathological changes
that may account for the cognitive decline after surgery. Our data will illuminate the pathological overlap of
delirium and dementia, highlighting (i) new avenues for screening/novel biomarker endpoints for amyloid
pathology or risk of delirium (frontal alpha power) and (ii) therapeutic development targeted to a mechanistic
understanding of cortical SWA as an underpinning for those cognitive changes.
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会议论文
Clarifying the overlapping pathology of delirium and dementia
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批准号:10408717
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项目类别:
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资助金额:$76.97万
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财政年份:2019
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依托单位:
Clarifying the overlapping pathology of delirium and dementia
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Anesthetic Suppression of Memory through disinhibitory circuits in Hippocampus
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Inhaled Anesthestic Modulation of Hippocampal Circuits
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财政年份:2011
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负责人:ROBERT A PEARCE
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依托单位:
Inhaled Anesthestic Modulation of Hippocampal Circuits
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批准号:8672658
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项目类别:
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资助金额:$22.94万
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财政年份:2011
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Inhaled Anesthestic Modulation of Hippocampal Circuits
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批准号:8332254
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项目类别:
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资助金额:$28.31万
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财政年份:2011
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负责人:ROBERT A PEARCE
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依托单位:
Inhaled Anesthestic Modulation of Hippocampal Circuits
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批准号:8473886
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项目类别:
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资助金额:$27.55万
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财政年份:2011
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Roles of GABAAR Subunits in Hippocampal Inhibition and Oscillations
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资助金额:$32.16万
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财政年份:2007
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负责人:ROBERT A PEARCE
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依托单位:
Roles of GABAAR Subunits in Hippocampal Inhibition and Oscillations
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资助金额:$31.83万
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财政年份:2007
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负责人:ROBERT A PEARCE
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依托单位:
Roles of GABAAR Subunits in Hippocampal Inhibition and Oscillations
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批准号:7212752
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项目类别:
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资助金额:$32.16万
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财政年份:2007
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负责人:ROBERT A PEARCE
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依托单位:
Roles of GABAAR Subunits in Hippocampal Inhibition and Oscillations
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批准号:7571651
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项目类别:
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资助金额:$32.16万
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财政年份:2007
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负责人:ROBERT A PEARCE
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依托单位:
GABAA AND NMDA RECEPTORS: ELECTROPHYSIOLOGIC STUDIES
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批准号:6807224
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项目类别:
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资助金额:$21.59万
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负责人:ROBERT A PEARCE
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依托单位:
VOLATILE ANESTHETIC ACTIONS ON SYNAPTIC GABAA RECEPTORS
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财政年份:1997
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依托单位:
VOLATILE ANESTHETIC ACTIONS ON SYNAPTIC GABAA RECEPTORS
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批准号:6181149
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财政年份:1997
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负责人:ROBERT A PEARCE
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依托单位:
VOLATILE ANESTHETIC ACTIONS ON SYNAPTIC GABAA RECEPTORS
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批准号:2910319
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项目类别:
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资助金额:$19.75万
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财政年份:1997
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负责人:ROBERT A PEARCE
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依托单位:
Volatile Anesthetic Actions on Synaptic GABAA Receptors
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批准号:6929018
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项目类别:
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财政年份:1997
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负责人:ROBERT A PEARCE
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依托单位:
VOLATILE ANESTHETIC ACTIONS ON SYNAPTIC GABAA RECEPTORS
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依托单位:
海外基金