Validation of a Novel Magnetic Resonance Imaging (MRI) Technology for both Diagnostic Screening and Quantification of Brain Vascular Physiology in Alzheimer's-Disease-Related Dementias

验证一种新型磁共振成像 (MRI) 技术，用于诊断筛查和量化阿尔茨海默病相关痴呆症的脑血管生理学

• 批准号: 10547491
• 负责人: Codi Amir Gharagouzloo
• 金额: $ 91.59万
• 依托单位: IMAGINOSTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10547491
• 关键词: 3-Dimensional; Acute; Age; Alzheimer' s Disease; Alzheimer' s disease related dementia; Anatomy; Attention; Attenuated; Biological Markers; Blood - brain barrier anatomy; Blood Vessels; Brain; Brain Diseases; Brain Mapping; Carbon Dioxide; Cerebrovascular Circulation; Cerebrovascular Disorders; Clinical; Cognitive; Contrast Media; Dementia; Diagnosis; Diagnostic; Diffusion Magnetic Resonance Imaging; Early Diagnosis; Echo-Planar Imaging; Economics; Extravasation; Functional Magnetic Resonance Imaging; Functional disorder; Gadolinium; Hypercapnia; Image; Imaging technology; Impaired cognition; Individual; Infarction; Infusion procedures; Insurance Carriers; Language; Late Onset Alzheimer Disease; Left; Link; Liquid substance; Magnetic Resonance Imaging; Maps; Measurable; Measurement; Measures; Memory; Metabolic dysfunction; Modality; Modeling; Nature; Outcome; Pathology; Patients; Performance; Phase; Physiological; Physiology; Population; Predisposition; Prognosis; Rattus; Recovery; Research; Risk Factors; Savings; Scanning; Signal Transduction; Small Business Innovation Research Grant; Structure; Technology; Testing; Time; Translations; Validation; Vascular Dementia; Visit; Visuospatial; White Matter Hyperintensity; arterial spin labeling; base; biomarker panel; blood oxygen level dependent; blood-brain barrier permeabilization; cerebral blood volume; cerebral microbleeds; cerebrovascular; cognitive testing; comparative; contrast enhanced; density; diagnostic screening; drug development; early detection biomarkers; early screening; executive function; ferumoxytol; head impact; imaging agent; imaging approach; imaging biomarker; imaging modality; imaging study; interest; ischemic lesion; magnetic resonance imaging biomarker; mild cognitive impairment; mortality; neuroimaging; neuroimaging marker; neuropathology; neurovascular; neurovascular unit; novel; personalized medicine; pre-clinical; precision medicine; primary endpoint; prognostic; skills; social; soft tissue; technology development; vascular abnormality; vascular cognitive impairment and dementia

PROJECT SUMMARY Alzheimer’s disease (AD), a degenerative brain disorder, is responsible for 60-70% of all dementia. Currently no reliable biomarkers exist for precision-medicine-level, single-patient diagnostics for the early detection of Alzheimer’s disease and related dementias (AD/ADRD). Imaginostics proposes to clinically valdiate novel magnetic resonance imaging (MRI)-based proprietary biomarkers for the early detection of vascular pathology that predisposes individuals to develop dementia in patients with mild cognitive impairment (MCI). Further, we will validate biomarkers for measuring vascular abnormality in Vascular Dementia (VaD), which accounts for 10% of all dementia. Quantitative Ultra-short Time-to-Echo Contrast-Enhanced (QUTE-CE) MRI is unique in that it generates a quantitative signal directly representative of physiological information. The overall objective of Phase I proposal: Obtain clinical validation of the QUTE-CE imaging approach for our panel of biomarkers for measuring microvascular structure, function and leakage. This first validation is targeted at two groups: 1) MCI: for evaluating the prospects of detecting abnormality before dementia onset and 2) VaD: for evaluating the prospect of characterizing vascular related cognitive impairment (VCID) in the most pertinent dementia population. Their ability to detect dementia will be compared to age-matched individuals and also compared to state-of-the art neuroimaging biomarker approaches to more fully evaluate the potential of QUTE- CE MRI. Specific Aim 1: Establish the merit and feasibility of QUTE-CE MRI vascular imaging biomarkers for detecting vascular abnormality in vascular dementia. The study will include (n=24; 12M/12F) Vascular Dementia subjects and (n=24; 12M/12F) age-matched control subjects. Specific Aim 2: Establish the merit and feasibility of QUTE-CE MRI vascular imaging biomarkers for detecting vascular abnormality in Mild Cognitive Impairment (MCI). The study will include (n=24; 12M/12F) MCI subjects and (n=24; 12M/12F) age-matched control subjects. Primary Endpoints (Specific Aims 1 and 2): (1) Structure: Cerebral Blood Volume (QC-CBV) & Small Vessel Density (QC-SVD): (Hypothesis 1) We will test our hypotheses that QUTE-CE MRI can detect small and large vessel abnormality. (2) Function: Cerebrovascular reactivity (QC-CVR) & CBV-based Functional MRI (QC-fMRI): (Hypothesis 2) We will test our hypotheses that QUTE-CE MRI will outperform EPI-fMRI for cerebrovascular reactivity at the group level, and that QC-CVR can be mapped in individuals MCI and VaD for precision medicine. (3) Leakage: Blood-Brain Barrier leakage (QC-BBB): (Hypothesis 3) We will test our hypotheses that QUTE- CE MRI will outperform DCE-MRI for detecting BBB leakage at the group level, and that BBB leakage can be mapped in individuals MCI and VaD for precision medicine. Further, we will test our hypothesis (Hypothesis 4) that a multivariate model (CBV, CVR, BBB permeability) of neurovascular unit dysfunction will provide diagnostic maps indicating abnormality and correlate to cognitive decline better than any individual imaging measures due to their complementary nature in assessment vascular related neuropathology. In addition, fluid-attenuated inversion recovery (FLAIR), susceptibility-weighted imaging (SWI) and diffusion- weighted imaging (DWI) scans will be acquired to identify white matter hyperintensities (WMHs), cerebral microbleeds (CMBs) and ischemic lesions to quantify the focal burden of microvascular changes from CBV maps. Quantitative performance milestones will be comparative whole-brain biomarker analytics and the analysis of focal burden as identified in FLAIR, SWI and DWI using CBV for identifying the spatial-extent-of-burden, intra- subject left-right brain comparison, and volume-of-interest comparison to the healthy controls. We will also perform cognitive testing on all patients to evaluate the correlation to vascular pathology - as measured with QUTE-CE MRI vascular biomarkers - to clinical measures. We can measure vascular abnormality and metabolic dysfunction throughout the whole brain, so we should have a gamut of tests that can evaluate all cognitive domains: memory, language, attention, executive function, visuospatial skills.

项目摘要 阿尔茨海默氏病（AD）是一种退化性脑部疾病，占所有痴呆症的60-70％。目前没有 存在可靠的生物标志物，用于精密中等水平的单患者诊断，以早期检测 阿尔茨海默氏病和相关痴呆症（AD/ADRD）。想象力的提议临床上新型 磁共振成像（MRI）的专有生物标志物，用于早期检测血管病理学 这使人容易发展为轻度认知障碍患者（MCI）的痴呆症。此外，我们 将验证生物标志物来测量血管异常（VAD）的血管异常（VAD） 所有痴呆症的10％。定量超短偏差的回声对比度增强（qute-ce）MRI是独一无二的 它生成直接代表物理信息的定量信号。 第一阶段提案的总体目标：为我们 用于测量微血管结构，功能和泄漏的生物标志物面板。第一个验证是针对的 在两组中：1）MCI：用于评估痴呆发作前检测绝对的前景和2）VAD： 评估表征最相关的血管相关认知障碍（VCID）的前景 痴呆种群。他们检测到痴呆症的能力将与年龄匹配的人进行比较 与最新的神经影像学生物标志物方法相比 CE MRI。 特定目标1：确定Qute-CE MRI血管成像生物标志物的优点和可行性 检测血管痴呆中的血管异常。该研究将包括（n = 24; 12m/12f）血管 痴呆受试者和（n = 24; 12m/12f）年龄匹配的对照受试者。 特定目标2：确定Qute-CE MRI血管成像生物标志物的优点和可行性 在轻度认知障碍（MCI）中检测血管异常。该研究将包括（n = 24; 12m/12f） MCI受试者和（n = 24; 12m/12f）年龄匹配的对照受试者。 主要终点（特定目标1和2）： （1）结构：脑血容量（QC-CBV）和小血管密度（QC-SVD）：（假设1）我们将 测试我们的假设，即Qute-ce MRI可以检测到小血管异常。 （2）功能：基于脑血管反应性（QC-CVR）和基于CBV的功能MRI（QC-FMRI）：（假设 2）我们将测试我们的假设，即Qute-ce MRI的表现将优于Epi-FMRI的脑血管反应性。 小组级别，可以在个人MCI和VAD中映射QC-CVR，以进行精确医学。 （3）泄漏：血脑屏障泄漏（QC-BBB）：（假设3）我们将测试我们的假设，即qute- CE MRI的表现将胜过DCE-MRI用于检测小组级别的BBB泄漏，并且BBB泄漏可以 在个人MCI和VAD中映射以进行精确医学。 此外，我们将检验我们的假设（假设4），即多元模型（CBV，CVR，BBB渗透性） 神经血管单元功能障碍将提供指示异常并与认知相关的诊断图 由于其在评估血管中的完整性质而导致的任何成像措施的下降效果要好 相关神经病理学。 此外，流体衰减的反转恢复（FLAIR），易感加权成像（SWI）和扩散 - 将获得加权成像（DWI）扫描以识别白质超强度（WMHS），大脑 微血管（CMB）和缺血性病变，以量化CBV图的微血管变化的局灶性燃烧。 定量性能里程碑将是比较的全脑生物标志物分析和分析 使用CBV在Flair，SWI和DWI中鉴定出的局灶性燃烧，以识别空间 - 费用， 受试者左右的大脑比较，并与健康对照组进行比较。我们也会 对所有患者进行认知测试以评估与血管病理的相关性 - 如 Qute -CE MRI血管生物标志物 - 进行临床测量。我们可以测量血管异常和代谢 整个大脑的功能障碍，因此我们应该进行一系列可以评估所有认知的测试 域：记忆，语言，注意力，执行功能，视觉技能。