Non-contrast MR imaging of blood-brain-barrier permeability in Alzheimer's disease
阿尔茨海默病血脑屏障通透性的非对比磁共振成像
基本信息
- 批准号:10621142
- 负责人:
- 金额:$ 63.04万
- 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:2020-05-01 至 2025-04-30
- 项目状态:未结题
- 来源:
- 关键词:AccelerationAffectAlbuminsAlzheimer&aposs DiseaseAlzheimer&aposs disease brainAmyloidAmyloid ProteinsAnimal ModelAreaAstrocytesAutopsyBacteriaBenchmarkingBiochemicalBiological AssayBloodBlood - brain barrier anatomyBolus InfusionBrainBrain DiseasesCellsCentral Nervous SystemCerebrospinal FluidCerebrovascular CirculationClinicalClinical TrialsCognitionContrast MediaDevelopmentDextransDiseaseElderlyExtravasationFoot ProcessGadoliniumGenetic RiskGoalsHumanImaging TechniquesIndividualInflammatory ResponseInjuryLabelLinkLiteratureMagnetic Resonance ImagingMeasurementMeasuresMethodsMicroscopyModalityModelingMonitorMulticenter TrialsNerve DegenerationNeurodegenerative DisordersNeuronsNeurotoxinsOsmosisOutcomePathogenesisPatientsPericytesPermeabilityPersonsPhasePhysiologic pulsePhysiologicalProceduresProcessProteinsProtocols documentationRattusResearchRestSamplingScanningSchemeSenile PlaquesSignal TransductionSiteSpinal PunctureSurfaceTechniquesTestingTimeTissuesTranslatingVascular Endothelial CellVascular EndotheliumVeinsVenousWaterWorkapolipoprotein E-4arterial spin labelingblood-brain barrier crossingblood-brain barrier functionblood-brain barrier permeabilizationcerebral atrophyclinical applicationcognitive functioncontrast enhanceddesignin vivoindexinginterestmacromoleculenew therapeutic targetnovelpathogenscreeningvascular injuryverification and validationβ-amyloid burden
项目摘要
Project Summary/Abstract:
Because of disappointing outcomes of recent clinical trials of anti-amyloid therapy in Alzheimer’s Disease
(AD), the field is increasingly interested in elucidating alternative disease mechanisms which may lead to new
therapeutic targets that are complementary to anti-amyloid treatment. Extensive literature using post-mortem
tissue has suggested that damage to the blood-brain-barrier (BBB) is intricately involved in the pathogenesis of
AD. Furthermore, recent studies in animal models suggested a direct link between BBB damage and
accumulation of amyloid plaques, in that aggregation of the amyloid protein may be part of an inflammatory
response of the brain to pathogen entry, presumably following BBB leakage.
However, in vivo studies of BBB in AD are scarce. A method commonly used to evaluate BBB permeability
in humans is by administering Gadolinium (Gd) based contrast agent while measuring and modeling dynamic
contrast-enhanced (DCE) MRI signal. However, contrast-enhanced MRI is not a common procedure in AD
research and has not been used in large-scale or multi-site studies. Therefore, a non-contrast technique to
assess BBB permeability is of particular importance in AD research and, if successful, can feasibly translate to
clinical screening and monitoring of treatment.
The central goal of this application is to develop an MRI technique to measure BBB permeability to water,
without using any exogenous agent. MRI can probe water BBB permeability by determining what fraction of the
incoming arterial water enters the brain and what fraction remains in the vessel and drains to the vein. This
project consists of three logical aims. Aim 1 will develop novel MRI pulse sequences to quantitatively evaluate
permeability-surface-area product (PS) of BBB in both global and regional fashion. Aim 2 will validate the non-
contrast method with Gd-contrast based technique in humans and with fluorescent microscopy in animal
models following osmotic opening of BBB. Aim 3 will conduct clinical application of the technique in elderly
individuals who have an established genetic risk to develop Alzheimer’s Disease (AD), i.e. APOE4-carriers. We
will compare BBB permeability with amyloid burden and cognitive function, and study their causal relationship
through a mediational model analysis. We will also compare the non-contrast permeability results to those
using an invasive method of CSF sampling as well as using DCE MRI.
The impact of this work is that we will develop a novel non-contrast technique to evaluate BBB permeability
in humans. The technique can be completed within 5 minutes on a standard 3T MRI. The outcome of the
measurement is in physiological unit of ml water/100g brain/min, thus can be feasibly compared across sites or
modalities. This technique will have broad clinical utility, as injury of BBB is implicated in many brain diseases.
In this application, we will demonstrate the utility of this technique in AD.
项目摘要/摘要:
由于最近抗淀粉样蛋白疗法治疗阿尔茨海默病的临床试验结果令人失望
(AD),该领域越来越有兴趣阐明替代疾病机制,这可能会导致新的疾病机制
与抗淀粉样蛋白治疗互补的治疗靶点。使用尸检的大量文献
组织表明,血脑屏障(BBB)的损伤与该疾病的发病机制密切相关。
广告。此外,最近的动物模型研究表明 BBB 损伤与
淀粉样斑块的积累,因为淀粉样蛋白的聚集可能是炎症的一部分
大脑对病原体进入的反应,大概是在血脑屏障渗漏之后。
然而,BBB 在 AD 中的体内研究很少。评估BBB渗透性的常用方法
在人类中,通过使用基于钆 (Gd) 的造影剂,同时测量和建模动态
对比增强 (DCE) MRI 信号。然而,对比增强 MRI 并不是 AD 的常见治疗方法
研究尚未用于大规模或多地点研究。因此,采用非对比技术
评估 BBB 渗透性在 AD 研究中尤为重要,如果成功,可以切实转化为
临床筛查和治疗监测。
该应用的中心目标是开发一种 MRI 技术来测量 BBB 对水的渗透性,
不使用任何外源性制剂。 MRI 可以通过确定水 BBB 的比例来探测水 BBB 的渗透性。
进入的动脉水进入大脑,剩下的部分留在血管中并排入静脉。这
项目由三个逻辑目标组成。目标 1 将开发新型 MRI 脉冲序列来定量评估
全球和区域时尚中 BBB 的渗透性表面积乘积 (PS)。目标 2 将验证非
在人类中使用基于 Gd 对比技术的对比方法以及在动物中使用荧光显微镜的对比方法
BBB 渗透打开后的模型。目标3将在老年人中开展该技术的临床应用
具有罹患阿尔茨海默病 (AD) 的既定遗传风险的个体,即 APOE4 携带者。我们
将比较血脑屏障通透性与淀粉样蛋白负荷和认知功能,并研究它们的因果关系
通过中介模型分析。我们还将比较非对比渗透率结果与那些结果
使用侵入性脑脊液取样方法以及 DCE MRI。
这项工作的影响是我们将开发一种新颖的非对比技术来评估 BBB 渗透性
在人类中。该技术可以在标准 3T MRI 上 5 分钟内完成。的结果
测量的生理单位为毫升水/100克脑/分钟,因此可以在不同地点或地区进行可行的比较
方式。这项技术将具有广泛的临床实用性,因为血脑屏障损伤与许多脑部疾病有关。
在此应用中,我们将演示该技术在 AD 中的实用性。
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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Hanzhang Lu其他文献
Hanzhang Lu的其他文献
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{{ truncateString('Hanzhang Lu', 18)}}的其他基金
ISMRM Workshop on Perfusion MRI: From Head to Toe
ISMRM 灌注 MRI 研讨会:从头到脚
- 批准号:
10391735 - 财政年份:2022
- 资助金额:
$ 63.04万 - 项目类别:
TRD1: Quantitative Imaging of Physiological Markers
TRD1:生理标志物的定量成像
- 批准号:
10614608 - 财政年份:2021
- 资助金额:
$ 63.04万 - 项目类别:
MRI Resource for Physiologic, Metabolic and Anatomic Biomarkers
生理、代谢和解剖生物标志物的 MRI 资源
- 批准号:
10614604 - 财政年份:2021
- 资助金额:
$ 63.04万 - 项目类别:
MRI Resource for Physiologic, Metabolic and Anatomic Biomarkers
生理、代谢和解剖生物标志物的 MRI 资源
- 批准号:
10439901 - 财政年份:2021
- 资助金额:
$ 63.04万 - 项目类别:
TRD1: Quantitative Imaging of Physiological Markers
TRD1:生理标志物的定量成像
- 批准号:
10439903 - 财政年份:2021
- 资助金额:
$ 63.04万 - 项目类别:
TRD1: Quantitative Imaging of Physiological Markers
TRD1:生理标志物的定量成像
- 批准号:
10270098 - 财政年份:2021
- 资助金额:
$ 63.04万 - 项目类别:
MRI Resource for Physiologic, Metabolic and Anatomic Biomarkers
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- 批准号:
10270096 - 财政年份:2021
- 资助金额:
$ 63.04万 - 项目类别:
Blood-brain barrier dysfunction in Alzheimer's disease: from humans to animal models
阿尔茨海默病的血脑屏障功能障碍:从人类到动物模型
- 批准号:
10178195 - 财政年份:2021
- 资助金额:
$ 63.04万 - 项目类别:
Non-contrast MR imaging of blood-brain-barrier permeability in Alzheimer's disease
阿尔茨海默病血脑屏障通透性的非对比磁共振成像
- 批准号:
10390475 - 财政年份:2020
- 资助金额:
$ 63.04万 - 项目类别:
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脑部疾病的综合血管 MR 成像套件
- 批准号:
10330590 - 财政年份:2018
- 资助金额:
$ 63.04万 - 项目类别:
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