Magnetic susceptibility and volume of microvascular lesions as proof-of concept biomarkers for mixed dementia

磁化率和微血管病变体积作为混合性痴呆的概念验证生物标志物

• 批准号: 10209809
• 负责人: Yu-chung Norman Cheng
• 金额: $ 43.72万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10209809
• 关键词: Air; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Alzheimer' s disease pathology; Alzheimer' s disease related dementia; Autopsy; Biological Markers; Blinded; Blood; Blood Vessels; Brain; Cessation of life; Clinical; Coagulation Process; Cognition; Cognitive; Complex; Data; Dementia; Diagnosis; Diagnostic; Disease; Evaluation; Event; Extravasation; Formalin; Funding; Future; Goals; Hemorrhage; Hemosiderin; Histologic; Hypertension; Image; Imaging Techniques; Impaired cognition; Impairment; Individual; Intervention; Legal patent; Lesion; Link; Lobe; Location; Low Prevalence; Magnetic Resonance Imaging; Magnetism; Measurement; Measures; Methods; Michigan; Microvascular Dysfunction; Outcome; Paraffin Embedding; Pathogenicity; Pathologic; Pathology; Patients; Predisposition; Prognosis; Property; Protocols documentation; Public Health; Research Personnel; Risk Factors; Sampling; Techniques; Testing; Therapeutic; Tissues; United States National Institutes of Health; Vascular Cognitive Impairment; Vascular Dementia; Veins; Water; Work; base; blind; calcification; cerebral microbleeds; cerebrovascular pathology; clinical Diagnosis; clinical imaging; cognitive function; comorbidity; demented; design; hazard; health goals; imaging biomarker; improved; in vivo imaging; innovation; insight; interest; metallicity; microvascular pathology; mild cognitive impairment; mixed dementia; non-demented; novel; predictive tools; research clinical testing; simulation; tool; white matter

Project Summary The objective of this R21 proposal is to give proof that magnetic susceptibility and volume of cerebral microbleeds quantified by an innovative MRI technique, CISSCO, and validated by pathological examination can differentiate postmortem brain samples from control and demented subjects. Microbleeds appear in varying numbers in images, but they are strongly associated with vascular cognitive impairment (VCI), small vessel diseases (SVD), and Alzheimer's disease (AD). They also appear in healthy older people at a lower prevalence. Current clinical diagnosis only counts the number of microbleeds and their mimics from images. However, the number of these “apparent” micro-objects is subject to imaging parameters (including the MRI field strength) and does not correlate well with the progression of cognitive decline. As microbleeds with hemorrhagic components show magnetic susceptibility effects in MRI, these investigators hypothesize that magnetic properties of microbleeds may help to differentiate certain clinical dementia subtypes. These novel quantitative parameters may be better markers for incipient dementia. They will advance our current understanding of the contribution of microbleeds to dementia beyond postmortem analysis and toward living patients. To design clinical imaging protocols and parameters, susceptibility values of microbleeds used to distinguish between control and demented subjects must be known first. The proposed aims are to image and pathologically examine micro-objects in postmortem samples obtained from the Michigan Brain Bank (MBB), which will blind these investigators to the clinical and neuropathological diagnosis of each subject until the late stage of this project. Formalin fixed, paraffin-embedded blocks where microvascular lesions are suspected will be obtained from subjects who died with no cognitive impairment or mixed dementia (including cases with high- and intermediate- likelihood of AD pathology). The CISSCO method will be applied to MR images of postmortem samples for accurate quantification of the magnetic susceptibility and volume of each micro-object. These micro-objects observed in MRI will then be co-registered and identified histologically in the same samples. These micro-objects, which are microbleeds and their mimics, will be categorized based on pathological results and quantified susceptibility values from MRI. They will also be compared between the diagnostic groups after the investigators are un-blinded. Cox hazard ratios will be calculated for different categorized results. If different magnetic properties can differentiate the clinical groups, then this outcome would indicate that magnetic properties of microbleeds is a potential advance in imaging biomarkers for dementia. With proof from this R21, future clinical testing plans will be proposed to NIH.

项目摘要 这项R21提案的目的是证明大脑的磁化率和体积 通过创新的MRI技术CISSCO量化微出血，并通过病理学检查验证 可以区分死后的大脑样本和正常人以及痴呆症患者微出血出现在 图像中的数量不同，但它们与血管性认知障碍（VCI）密切相关， 血管疾病（SVD）和阿尔茨海默病（AD）。它们也出现在健康的老年人中， 普遍性。目前的临床诊断仅从图像中计算微出血及其模拟物的数量。 然而，这些"明显的"微物体的数量受到成像参数（包括MRI）的影响。 场强），并且与认知衰退的进展没有很好的相关性。因为微出血 出血成分在MRI中显示出磁化率效应，这些研究者假设， 微出血的磁性可能有助于区分某些临床痴呆亚型。这些新颖 定量参数可能是早期痴呆的更好标记。他们将推动我们目前的 了解微出血对痴呆症的贡献，超越死后分析和生活 患者 设计临床影像学检查方案和参数，用微出血敏感值区分 必须首先了解对照组和痴呆症受试者之间的关系。建议的目标是形象和 从病理学上检查从密歇根脑库（MBB）获得的死后样本中的微观物体， 这将使这些研究者对每个受试者的临床和神经病理学诊断保持盲态， 这个项目的阶段。福尔马林固定，石蜡包埋块，其中怀疑微血管病变将 从没有认知障碍或混合性痴呆的死亡受试者（包括患有 AD病理学的高和中等可能性）。CISSCO方法将应用于以下的MR图像： 尸检样本用于精确量化每个微物体的磁化率和体积。 然后，在MRI中观察到的这些微物体将在相同的组织中共同配准和组织学识别。 样品这些微物体是微出血及其模仿物，将根据以下内容进行分类： 病理结果和来自MRI的量化的易感性值。它们也将在 研究者揭盲后的诊断组。将计算不同的考克斯风险比 分类结果。如果不同的磁特性可以区分临床组， 表明微出血的磁特性是成像生物标志物的潜在进展， 痴呆有了这个R21的证据，未来的临床试验计划将提交给NIH。