Imaging brain iron and protein aggregation with MRI for assessing Alzheimer's disease pathology and progression

摘要 阿尔茨海默氏病（AD）影响超过500万美国人，预计在未来几年内将影响2-3倍 几十年AD与淀粉样蛋白-β（Ab）和磷酸化tau蛋白的聚集有关。 奇怪的是，Aβ负荷，传统上被认为是最重要的AD病理标志， 表明临床衰退或进展。例如，认知正常的老年人也可能携带高水平的Aβ 最近旨在降低Aβ的临床试验通常未能改善患者的病情。因此，我们认为， 需要开发能够更好地预测临床结果和进展的生物标志物。汇合证据 显示通过MRI测量的区域脑磁化率在AD患者和健康人之间存在差异 重要的是，这些变化可能预示着认知能力的下降。然而，目前还不清楚是什么原因导致这些 AD的易感性变化。虽然铁沉积已被广泛怀疑为根本原因，我们的 最近的研究已经发现Ab和tau的聚集本身产生强的抗磁性磁化率， 与铁沉积产生的顺磁性磁化率相反。相反的磁化率 铁和聚集的病理性蛋白质构成了一个重大的挑战，因为目前基于MRI的磁性 磁化率映射算法不能区分铁与其他共定位抗磁性磁化率 在同一个voxel中。我们的目标是开发一种新的技术， 磁化率的来源，并测试所产生的磁化率分量是否可以作为标记 进行性AD病理学我们将利用一种独特的能力来测试我们的技术和假设， 结合尸检头颅MRI和组织学检查。我们开发了创新的组织学 处理方法允许在3D中MRI和组织学之间进行体素到体素匹配，从而允许 检查磁化率成分和神经病理学之间的关系 AD.如果成功的话，我们的技术和发现可能最终允许检测AD相关的神经病理学 在更早的阶段，允许在神经元受到不可挽回的损伤之前进行非侵入性干预 评估疾病进展。这些技术一旦标准化，将具有很高的成本效益， 可在非专业临床成像中心访问并易于实施，从而更好地服务于日益增长的 AD患者群体。

Abstract Alzheimer’s disease (AD) affects over 5 million Americans and is expected to affect 2-3-fold more in the next few decades. AD is associated with aggregation of amyloid-beta (Ab) and phosphorylated tau proteins. Curiously, burden of Aβ, classically considered the most important AD pathological hallmark is not enough to indicate clinical decline or progression. For example, cognitive-normal elders may also carry high levels of Aβ and recent clinical trials aiming to reduce Aβ have generally failed to improve patients’ conditions. Therefore, developing biomarkers that can better predict clinical outcome and progression are needed. Confluent evidence shows that regional brain magnetic susceptibility measured by MRI differs between AD patients and healthy controls, and importantly such changes may predict cognitive decline. However, it is unclear what causes these susceptibility changes in AD. While iron deposition has been widely suspected as the underlying cause, our recent study has discovered that aggregation of Ab and tau by itself produces strong diamagnetic susceptibility, opposite of the paramagnetic susceptibility generated by iron deposition. The opposing magnetic susceptibility of iron and aggregated pathological proteins poses a significant challenge as current MRI-based magnetic susceptibility mapping algorithms cannot differentiate iron from other colocalizing diamagnetic susceptibility sources within the same voxel. Our goal is to develop a novel technique that can differentially quantify molecular sources of magnetic susceptibility and test whether the resulting susceptibility components can serve as markers of progressive AD pathology. We will test our techniques and hypothesis utilizing a unique capability that combines in cranio MRI at autopsy with histological examinations. We have developed innovative histological processing methods that allow voxel-to-voxel matching between MRI and histology in 3D, thus permitting the examination of the relationship between magnetic susceptibility components and the neuropathology underlying AD. If successful, our techniques and findings might ultimately allow the detection of AD-related neuropathology at much earlier stages, permit intervention before neurons become irretrievably damaged and non-invasively assess disease progression. These techniques, once standardized, will be highly cost-effective, widely accessible and readily implementable in non-specialized clinical imaging centers, thus better serving the growing population of AD patients.