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

摘要 阿尔茨海默病(AD)影响着500多万美国人，预计在接下来的一年里，影响将增加2-3倍 几十年了。AD与淀粉样β蛋白和磷酸化tau蛋白的聚集有关。 奇怪的是，Aβ的负担，经典地被认为是最重要的AD病理标志，并不足以 表示临床上的衰退或进展。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的临床试验通常都未能改善患者的病情。因此， 需要开发能够更好地预测临床结果和进展的生物标记物。一致的证据 显示阿尔茨海默病患者和健康人的MRI测量的局部脑磁化率不同 控制，重要的是，这样的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了这些 阿尔茨海默病易感性改变。虽然铁沉积被广泛怀疑是根本原因，但我们的 最近的研究发现，Ab和tau本身的聚集会产生很强的抗磁磁化率， 与铁沉积产生的顺磁磁化率相反。相反的磁化率 铁和聚集的病理蛋白构成了一个重大的挑战，因为目前基于MRI的磁化 磁化率映射算法无法将铁与其他共局域化的抗磁磁化率区分开来 同一体素内的源。我们的目标是开发一种新的技术，可以对分子进行差异量化 磁化率的来源，并测试由此产生的磁化率分量是否可以用作标记 进行性AD病理。我们将使用一种独特的能力来测试我们的技术和假设 尸检时结合颅脑核磁共振检查与组织学检查。我们开发了创新的组织学 允许在MRI和3D组织学之间进行体素到体素匹配的处理方法，从而允许 磁化率成分与神经病理基础关系的研究 广告。如果成功，我们的技术和发现可能最终允许检测与AD相关的神经病理 在更早的阶段，允许在神经元受到不可挽回的非侵入性损害之前进行干预 评估疾病进展情况。这些技术一旦标准化，将具有极高的成本效益，并得到广泛应用 在非专科临床影像中心易于访问和实施，从而更好地服务于不断增长的 阿尔茨海默病患者群体。

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.