Developing Protein-based MRI Biomarkers for Alzheimer's Disease

开发基于蛋白质的 MRI 阿尔茨海默病生物标志物

• 批准号: 10636831
• 负责人: JINYUAN ZHOU
• 金额: $ 64.64万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10636831
• 关键词: Abeta clearance; Acceleration; Acidosis; Acute; Address; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Alzheimer’s disease biomarker; Amides; Amyloid; Amyloid beta-Protein; Amyloid deposition; Autopsy; Biological Markers; Brain; Brain Diseases; Brain Neoplasms; Brain region; Cell Density; Cerebral Ischemia; Cerebral cortex; Characteristics; Classification; Clinical; Clinical Research; Cognitive; Data; Dementia; Dementia with Lewy Bodies; Deposition; Development; Diagnosis; Disease; Early Diagnosis; Elderly; Event; Exposure to; FDA approved; Fingerprint; Foundations; Goals; Image; Imaging technology; Individual; Magnetic Resonance Imaging; Malignant neoplasm of brain; Measures; Medial; Methodology; Methods; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Pathogenesis; Patients; Pattern; Peptides; Positron-Emission Tomography; Production; Proteins; Protocols documentation; Protons; Research; Research Personnel; Sample Size; Senile Plaques; Sensitivity and Specificity; Signal Transduction; Stroke; Surrogate Markers; System; Techniques; Technology; Temporal Lobe; Time; Tissues; Translating; Visualization; abeta accumulation; age related; biomarker validation; clinical decision-making; extracellular; follow-up; frontal lobe; histopathological examination; imaging study; in vivo; innovation; magnetic resonance imaging biomarker; mild cognitive impairment; monomer; novel; pre-clinical; preclinical study; radio frequency; synaptic function; targeted biomarker; tau Proteins; transmission process; validation studies

Alzheimer's disease (AD), ABSTRACT the leading cause of dementia in the elderly, is a devastating neurodegenerative disease. The hallmarks of this devastating disease are the accumulation of amyloid plaques and neurofibrillary tangles, as revealed by standard histopathologic examination at postmortem. A large number of strides have been made in past years to identify and validate biomarkers for AD. Based on PET and CSF measures of the plaques and tangles of AD, we are now able to measure AD pathology in vivo at all stages: AD dementia, mild cognitive impairment (MCI), and preclinical AD. Notably, the recent NIA/AA AT(N) research framework focused on the diagnosis of AD with biomarkers in living individuals and encouraged the continued development of new, unrecognized AD biomarkers. Amide proton transfer (APT) imaging is a relatively new protein-based MRI technique that can generate contrast based on endogenous mobile proteins and peptides in tissue. Numerous previous studies have demonstrated that APT-weighted (APTw) imaging can detect malignant brain tumors based on increased cell density and acute cerebral ischemia due to tissue acidosis or decreased pH. Our effort has successfully developed this important MRI technology into an FDA-approved sequence on Philips 3T MRI systems for clinical use with brain cancer. Further translating this innovative protein-based technology to AD and non-AD proteinopathies, such as dementia with Lewy bodies (DLB), is encouraging. It is known that both extracellular amyloid and intracellular tau first exist as soluble monomers (APT-detectable). Our preliminary studies have clearly demonstrated that the abnormal accumulation of these proteins in MCI resulted in an increased APT effect and AD dementia had APTw-MRI signal characteristics distinct from DLB. The overall goals of this application are to refine quantitative whole-brain APT-MRI methodologies on 3T clinical MRI scanners and to demonstrate the feasibility and potential of protein-based APT-MRI as a surrogate biomarker for the characterization and diagnosis of AD and other forms of dementia, such as DLB. We have formulated three specific aims that we plan to address in the coming five years: (i) develop a time-efficient APT-MRI protocol for an imaging study of AD; (2) quantify the accuracy of APT-MRI in characterizing and diagnosing MCI; and (3) quantify the accuracy of APT-MRI in distinguishing between AD dementia and DLB. This proof-of-concept study will lay the foundation for a full validation study that will assess the impact of APT imaging on clinical decision-making in patients with AD and related dementias.

阿尔茨海默病（AD）， 抽象的 老年人痴呆症的主要原因是一种破坏性的神经退行性疾病 疾病。这种破坏性疾病的特点是淀粉样斑块和神经原纤维的积累 尸检时标准组织病理学检查显示缠结。大量的步伐已经 在过去的几年中，人们进行了一些研究来识别和验证 AD 的生物标志物。基于 PET 和 CSF 测量 AD 斑块和缠结，我们现在能够测量 AD 各个阶段的体内病理学：AD 痴呆、轻度 认知障碍 (MCI) 和临床前 AD。值得注意的是，最近的 NIA/AA AT(N) 研究框架重点关注 致力于利用活体生物标志物诊断 AD，并鼓励不断开发新的、 未被识别的 AD 生物标志物。酰胺质子转移 (APT) 成像是一种相对较新的基于蛋白质的 MRI 可以根据组织中的内源性移动蛋白和肽生成对比度的技术。很多的 先前的研究表明，APT加权（APTw）成像可以检测恶性脑肿瘤 基于细胞密度增加和由于组织酸中毒或 pH 值降低导致的急性脑缺血。我们的努力 已成功将这项重要的 MRI 技术开发为 FDA 批准的飞利浦 3T MRI 序列 用于临床治疗脑癌的系统。将这种基于蛋白质的创新技术进一步转化为 AD 和 非AD蛋白病，例如路易体痴呆（DLB），是令人鼓舞的。据了解，两者 细胞外淀粉样蛋白和细胞内 tau 蛋白首先以可溶性单体形式存在（APT 可检测）。我们的初步 研究清楚地表明，MCI 中这些蛋白质的异常积累导致了 APT 效应增加和 AD 痴呆具有与 DLB 不同的 APTw-MRI 信号特征。整体 该应用程序的目标是完善 3T 临床 MRI 的定量全脑 APT-MRI 方法 扫描仪并证明基于蛋白质的 APT-MRI 作为替代生物标志物的可行性和潜力 AD 和其他形式的痴呆症（例如 DLB）的特征和诊断。我们制定了三项 我们计划在未来五年内实现的具体目标： (i) 开发一种高效的 APT-MRI 协议 AD 的影像学研究； (2) 量化 APT-MRI 在表征和诊断 MCI 方面的准确性；和（3） 量化 APT-MRI 区分 AD 痴呆和 DLB 的准确性。这项概念验证研究 将为评估 APT 成像对临床影响的全面验证研究奠定基础 AD 和相关痴呆症患者的决策。