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: 10053946
• 负责人: JINYUAN ZHOU
• 金额: $ 66.23万
• 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/10053946
• 关键词: Abeta clearance; Acidosis; Acute; Address; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Alzheimer' s disease pathology; 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; Clinical; Clinical Research; Cognitive; Data; Dementia; Deposition; Development; Diagnosis; Disease; Early Diagnosis; Elderly; Event; Exposure to; FDA approved; Fingerprint; Foundations; Goals; Image; Imaging technology; Individual; Lewy Body Dementia; 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; abeta accumulation; age related; base; 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; 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.

阿尔茨海默氏病（AD）， 抽象的 老年痴呆的主要原因是毁灭性的神经退行性 疾病。这种毁灭性疾病的标志是淀粉样斑块和神经原纤维的积累 缠结，如验尸后标准的组织病理学检查所揭示的那样。大量大步 过去几年以识别和验证AD的生物标志物。基于PET和CSF的措施 AD的斑块和缠结，我们现在能够在各个阶段在体内测量AD病理学：AD痴呆，轻度 认知障碍（MCI）和临床前广告。值得注意的是，最近的NIA/AA（n）研究框架集中 关于在活着的人中诊断为生物标志物的广告，并鼓励新的新发展 无法识别的广告生物标志物。酰胺质子转移（APT）成像是一种相对较新的基于蛋白质的MRI 基于内源性移动蛋白和组织中的肽可以产生对比度的技术。很多的 先前的研究表明，经过加权（APTW）成像可以检测到恶性脑肿瘤 基于组织酸中毒或pH值降低引起的细胞密度和急性脑缺血。我们的努力 成功地将这种重要的MRI技术开发为Philips 3T MRI的FDA批准序列 用于脑癌临床使用的系统。进一步将这种创新蛋白质的技术转化为广告和 非AD蛋白质病，例如Lewy Bodies（DLB）的痴呆症，令人鼓舞。众所周知 细胞外淀粉样蛋白和细胞内tau首先作为可溶性单体（可探测）存在。我们的初步 研究清楚地表明，这些蛋白质在MCI中的异常积累导致 APT效应的增加和AD痴呆具有与DLB不同的APTW-MRI信号特性。总体 该应用的目标是在3T临床MRI上完善定量全脑APT-MRI方法论 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）的表征和诊断。我们已经制定了三个 我们打算在未来五年中解决的具体目标：（i）为时间效力的适用MRI协议开发 AD的成像研究； （2）量化APT-MRI在表征和诊断MCI方面的准确性； （3） 量化APT-MRI在区分AD痴呆和DLB方面的准确性。这项概念验证研究 将为全面验证研究奠定基础，该研究将评估APT成像对临床的影响 AD和相关痴呆症患者的决策。