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

项目摘要 R21方案目的是证明大脑的磁化率和体积 微出血通过一种创新的MRI技术--Cisco进行量化，并通过病理检查进行验证 可以区分死后大脑样本与对照组和精神错乱受试者。微小出血出现在 图像中的数字各不相同，但它们与血管认知障碍(VCI)密切相关，规模较小 血管疾病(SVD)和阿尔茨海默病(AD)。它们在健康的老年人中也出现在较低的 流行率。目前的临床诊断只统计图像中微出血的数量及其模拟情况。 然而，这些明显的微对象的数量受成像参数(包括MRI)的影响 场强)，并不能很好地与认知衰退的进程相关联。就像微血一样 这些研究人员推测，出血性成分在MRI中显示出磁敏性效应 微量出血的磁性有助于区分某些临床痴呆亚型。这些小说 量化指标可能是早期痴呆更好的标志物。他们将推进我们目前的 对微量出血对痴呆的贡献的认识超越了尸检分析和对生活的影响 病人。 设计临床影像检查方案和参数，用微量出血敏感值区分 必须首先了解控制和精神错乱的受试者之间的关系。提议的目标是形象和 对从密歇根脑库(MBB)获得的尸检样本中的微小物体进行病理学检查， 这将使这些研究人员看不到每个受试者的临床和神经病理诊断，直到晚些时候 这个项目的阶段。福尔马林固定、石蜡包埋的疑似微血管病变的块将 从没有认知障碍或混合性痴呆死亡的受试者那里获得(包括有 AD病理的高、中可能性)。该方法将被应用于 用于准确量化每个微小物体的磁化率和体积的尸检样本。 然后，在MRI中观察到的这些微对象将被共同注册并在同一 样本。这些微物体，即微出血和它们的模拟物，将根据 病理结果和MRI的量化敏感值。他们还将被比较在 诊断小组在调查人员被解盲后。将计算不同类型的COX风险比 分类结果。如果不同的磁特性可以区分临床组，那么这一结果 将表明微出血的磁性是成像生物标记物的潜在进展 痴呆症。有了R21的证明，未来的临床试验计划将向NIH提出。

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.