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 阿尔茨海默病（AD）是一种退行性脑疾病，占所有痴呆症的60-70%。目前没有 可靠的生物标志物存在于精确的医学水平，单个患者诊断中，用于早期检测 阿尔茨海默病和相关痴呆（AD/ADRD）。Imaginostics建议临床验证小说 基于磁共振成像（MRI）的专有生物标志物，用于早期检测血管病变 在轻度认知障碍（MCI）患者中，这种疾病使个体易于发展为痴呆症。我们还 将验证用于测量血管性痴呆（VaD）血管异常的生物标志物， 10%的老年痴呆症患者定量超短时间回波对比增强（QUTE-CE）MRI的独特之处在于， 它产生直接代表生理信息的定量信号。 I期提案的总体目标：获得QUTE-CE成像方法的临床验证， 用于测量微血管结构、功能和渗漏的生物标志物组。第一次验证的目标是 两组：1）MCI：用于评估痴呆发作前检测异常的前景，2）VaD： 用于评估在最相关的血管相关认知障碍（VCID）中表征血管相关认知障碍（VCID）的前景。 痴呆症人群他们检测痴呆症的能力将与年龄匹配的个体进行比较， 与最先进的神经影像学生物标志物方法相比，可以更全面地评估QUTE的潜力， CE MRI。 具体目标1：确定QUTE-CE MRI血管成像生物标志物的优点和可行性， 检测血管性痴呆中的血管异常。研究将包括（n=24; 12 M/12 F）血管 痴呆受试者和（n=24; 12 M/12 F）年龄匹配的对照受试者。 具体目标2：确定QUTE-CE MRI血管成像生物标志物的优点和可行性， 检测轻度认知障碍（MCI）中的血管异常。研究将包括（n=24; 12例男性/12例女性） MCI受试者和（n=24; 12 M/12 F）年龄匹配的对照受试者。 主要终点（具体目标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 验证我们假设QUTE-CE MRI可以检测小血管和大血管异常。 (2)功能：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在脑血管反应性方面优于EPI-fMRI， 群体水平，QC-CVR可以映射到个体MCI和VaD中，用于精准医疗。 (3)渗漏：血脑屏障渗漏（QC-BBB）：（假设3）我们将测试我们的假设，QUTE- CE MRI在检测组水平的BBB泄漏方面优于DCE-MRI，并且BBB泄漏可以 在个体MCI和VaD中进行映射，用于精准医疗。 此外，我们将检验我们的假设（假设4），即多变量模型（CBV，CVR，BBB通透性） 神经血管单位功能障碍将提供指示异常的诊断图，并与认知功能相关。 由于其在评估血管方面的互补性质，其下降优于任何单独的成像测量 相关神经病理学。 此外，液体衰减反转恢复（FLAIR），磁共振成像（SWI）和扩散- 将采集加权成像（DWI）扫描，以识别白色高信号（WMH）、大脑 微出血（CMB）和缺血性病变，以量化CBV图中微血管变化的局灶性负荷。 定量性能里程碑将是比较全脑生物标志物分析和 在FLAIR、SWI和DWI中使用CBV识别局灶性负荷，以识别负荷的空间范围， 受试者左右脑比较，以及与健康对照的感兴趣体积比较。我们还将 对所有患者进行认知测试，以评估与血管病理学的相关性-如用 QUTE-CE MRI血管生物标志物-临床测量。我们可以测量血管异常和代谢异常 所以我们应该有一系列的测试来评估所有的认知功能， 领域：记忆，语言，注意力，执行功能，视觉空间技能。