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

项目总结 阿尔茨海默病(AD)是一种退行性大脑疾病，占所有痴呆症的60%-70%。目前没有 存在可靠的生物标志物，用于精确的医学级、单患者诊断，用于早期检测 阿尔茨海默病和相关痴呆(AD/ADRD)。意象学建议对小说进行临床验证 基于磁共振成像(MRI)的专有生物标志物用于血管病变的早期检测 这容易使患有轻度认知障碍(MCI)的患者患上痴呆症。此外，我们 将验证生物标记物用于测量血管性痴呆(VAD)的血管异常，这解释了 占所有痴呆症患者的10%。定量超短时间回声增强(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。 第一阶段提案的总体目标：获得QUTE-CE成像方法的临床验证 一组用于测量微血管结构、功能和渗漏的生物标志物。第一个验证是有针对性的 在两组中：1)MCI：用于评估痴呆发病前发现异常的前景；2)VAD： 为了评估血管相关性认知功能障碍(VCID)的特征在最相关的 痴呆症人群。他们发现痴呆症的能力将与年龄匹配的人进行比较，而且 与最先进的神经成像生物标记物方法相比，更全面地评估QUTE的潜力 CE核磁共振检查。 具体目标1：建立QUTE-CE MRI血管成像生物标志物的优点和可行性 检测血管性痴呆患者的血管异常。这项研究将包括(n=24；12m/12f)血管 痴呆组和年龄匹配的对照组(n=24；12男/12女)。 具体目标2：建立QUTE-CE MRI血管成像生物标志物的优点和可行性 轻度认知障碍(MCI)患者血管异常的检测这项研究将包括(n=24；12M/12F) MCI组和年龄匹配的对照组(n=24；12男/12女)。 主要终端(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 验证我们的假设，即QTE-CE MRI可以检测出大小血管的异常。 (2)功能：脑血管反应性(QC-CVR)和基于CBV的功能磁共振(QC-fMRI)：(假设 2)我们将测试我们的假设，即在脑血管反应性方面，Qute-CE MRI将优于EPI-fMRI 组水平和QC-CVR可以被映射到个体MCI和VAD中，以用于精确医学。 (3)渗漏：血脑屏障渗漏(QC-BBB)：(假设3)我们将检验我们的假设： 在检测组水平的血脑屏障渗漏方面，CE MRI将优于DCE-MRI，而且血脑屏障渗漏可以 定位于个体MCI和VAD，用于精准医学。 此外，我们将测试我们的假设(假设4)，即一个多变量模型(CBV，CVR，BBB渗透率) 神经血管单位功能障碍将提供诊断地图，指示异常并与认知相关 由于它们在评估血管方面的互补性，下降比任何单独的成像指标都要好 相关的神经病理学。 此外，流体衰减反转恢复(FLAIR)、磁化率加权成像(SWI)和弥散成像- 将进行加权成像(DWI)扫描，以识别脑白质高信号(WMH)、大脑 微出血(CMBS)和缺血灶，从CBV图量化微血管变化的局部负荷。 量化绩效里程碑将是比较全脑生物标记物分析和 FLAIR、SWI和DWI中确定的焦点负荷使用CBV来确定负荷的空间范围、内部 受试者左右脑比较，并与健康对照组进行兴趣区体积比较。我们还将 对所有患者进行认知测试，以评估其与血管病理的相关性 QUTE-CE磁共振血管生物标记物-临床措施。我们可以测量血管异常和新陈代谢 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 领域：记忆、语言、注意力、执行功能、视觉空间技能。

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.