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.

项目概要 阿尔茨海默病 (AD) 是一种退行性脑部疾病，占所有痴呆症的 60-70%。 存在可靠的生物标志物，可用于精准医学水平的单患者诊断，以早期发现 阿尔茨海默氏病和相关痴呆症 (AD/ADRD) 提议对新型药物进行临床验证。 基于磁共振成像 (MRI) 的专有生物标志物，用于血管病理的早期检测 这使得患有轻度认知障碍（MCI）的患者容易患上痴呆症。 将验证用于测量血管性痴呆（VaD）血管异常的生物标志物，这解释了 定量超短时间回波对比增强 (QUTE-CE) MRI 的独特之处在于，占所有痴呆症的 10%。 它产生直接代表生理信息的定量信号。 第一阶段提案的总体目标：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首次验证是有针对性的。 分为两组：1) MCI：用于评估在痴呆症发作前检测异常的前景；2) VaD： 用于评估最相关的血管相关认知障碍（VCID）特征的前景 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生物标志物方法相比，可以更全面地评估 QUTE- 的潜力 CE 磁共振成像。 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 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。 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 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（具体目标 1 和 2）： (1)结构：脑血容量(QC-CBV)&小血管密度(QC-SVD)：(假设1)我们将 检验我们的假设，即 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) 我们将检验我们的假设，即 QUTE-CE MRI 在脑血管反应性方面将优于 EPI-fMRI QC-CVR 可以在个体 MCI 和 VaD 中进行映射，以实现精准医疗。 (3) 渗漏：血脑屏障渗漏 (QC-BBB)：（假设 3）我们将检验我们的假设 QUTE- 在检测群体水平的 BBB 渗漏方面，CE MRI 将优于 DCE-MRI，并且 BBB 渗漏可以 映射到个体 MCI 和 VaD 中以实现精准医疗。 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的诊断图并与 由于它们在评估血管方面的互补性，比任何单独的成像测量更好地下降 相关神经病理学。 此外，液体衰减反转恢复 (FLAIR)、磁化率加权成像 (SWI) 和扩散- 将采集加权成像 (DWI) 扫描来识别白质高信号 (WMH)、脑 微出血 (CMB) 和缺血性病变，以量化 CBV 图上微血管变化的局灶性负担。 定量性能里程碑将是比较全脑生物标志物分析和 使用 CBV 在 FLAIR、SWI 和 DWI 中确定的焦点负担，用于确定负担的空间范围、内部 我们还将对受试者的左右脑进行比较，并与健康对照进行兴趣体积比较。 对所有患者进行认知测试，以评估与血管病理学的相关性 - 通过测量 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。 整个大脑的功能障碍，所以我们应该有一系列的测试来评估所有的认知能力 领域：记忆、语言、注意力、执行功能、视觉空间技能。