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

使用 MRI 对脑铁和蛋白质聚集进行成像，以评估阿尔茨海默病的病理学和进展

• 批准号: 10563181
• 负责人: Lea Tenenholz Grinberg
• 金额: $ 65.22万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10563181
• 关键词: 3-Dimensional; Affect; Algorithms; Alzheimer disease detection; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; American; Amyloid; Amyloid beta-Protein; Area; Autopsy; Biological; Biological Markers; Brain; Brain imaging; Brain region; Characteristics; Clinical; Clinical Trials; Cognitive; Curiosities; Deposition; Development; Diagnosis; Diagnostic; Disease Progression; Elderly; Etiology; Goals; High Prevalence; Histologic; Histology; Human; Image; Imaging Techniques; Impaired cognition; Intervention; Ionizing radiation; Iron; Knowledge; Label; Link; Longevity; Magnetic Resonance Imaging; Magnetism; Maps; Measures; Methods; Molecular; Names; Neurons; Onset of illness; Pathologic; Pathology; Patients; Population; Positron; Positron-Emission Tomography; Predisposition; Prefrontal Cortex; Probability; Property; Proteins; Resolution; Scanning; Senile Plaques; Source; Specificity; Specimen; Staging; Standardization; Symptoms; Synapses; Techniques; Testing; Tissues; Tracer; Translating; Validation; Work; abeta accumulation; amyloid imaging; clinical care; clinical imaging; cohort; cost; cost effective; healthy volunteer; hyperphosphorylated tau; imaging facilities; improved; innovation; locus ceruleus structure; mouse model; neuropathology; novel; predict clinical outcome; protein aggregation; putamen; tau Proteins; tau aggregation; tau-1; β-amyloid burden

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.

抽象的 阿尔茨海默氏病（AD）影响了超过500万美国人，预计下一个美国人会影响2-3倍 几十年。 AD与淀粉样β（AB）和磷酸化的Tau蛋白的聚集有关。 奇怪的是，Aβ的Burnen经典认为是最重要的AD病理标志不足 表示临床下降或进展。例如，认知正常的长老也可能携带高水平的Aβ 最近的临床试验旨在减少Aβ通常无法改善患者的状况。所以， 需要开发可以更好地预测临床结果和进展的生物标志物。汇合证据 表明通过AD患者和健康的MRI测量的区域脑磁敏感性差异 控制，重要的是，这种变化可以预测认知能力下降。但是，目前尚不清楚是什么原因导致这些 AD的敏感性变化。尽管铁沉积已被广泛怀疑是根本原因，但我们 最近的研究发现，AB和TAU的聚集本身会产生强大的磁敏感性， 与铁沉积产生的顺磁敏感性相反。相反的磁化率 铁和聚集的病理蛋白的挑战是当前基于MRI的磁 敏感性映射算法不能区分铁与其他共定位磁敏感性 在同一体素内的来源。我们的目标是开发一种可以不同量化分子的新技术 磁化率的来源并测试结果易感性成分是否可以用作标记 进步广告病理学。我们将利用独特的能力来检验我们的技术和假设 在尸检时在Cranio MRI中结合了组织学检查。我们开发了创新的组织学 处理方法允许3D中MRI和组织学之间匹配体素到素的方法，从而允许 检查磁敏感性成分与基础神经病理学之间的关系 广告。如果成功，我们的技术和发现最终可能允许检测与广告相关的神经病理学 在更早的阶段，在神经元变得异常损害和无侵袭性之前允许干预 评估疾病进展。一旦标准化，这些技术将是高度成本效益的，广泛的 在非专业临床成像中心中可访问且易于实现，因此更好地为增长服务 广告患者的人口。