Developing Protein-based MRI Biomarkers for Alzheimer's Disease

阿尔茨海默病（AD）， 摘要 老年痴呆症的主要原因，是一种破坏性的神经退行性疾病， 疾病这种毁灭性疾病的特征是淀粉样蛋白斑块和神经胶质细胞的积累。 缠结，如标准尸检组织病理学检查所示。大量的步伐已经 在过去的几年中，已经进行了识别和验证AD的生物标志物。根据PET和CSF测量， 由于AD的斑块和缠结，我们现在能够在所有阶段测量体内AD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）研究框架侧重于 在活体个体中使用生物标志物诊断AD，并鼓励继续开发新的， 未识别的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 可以基于组织中内源性移动的蛋白质和肽产生对比的技术。许多 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值降低引起的急性脑缺血。 已成功将这一重要的MRI技术开发为FDA批准的Philips 3 T MRI序列 用于脑癌临床治疗的系统。进一步将这种基于蛋白质的创新技术转化为AD， 非AD蛋白质病如路易体痴呆（DLB）是令人鼓舞的。据了解， 细胞外淀粉样蛋白和细胞内tau首先作为可溶性单体（可检测的APT）存在。我们的初步 研究已经清楚地表明，这些蛋白质在MCI中的异常积累导致了 增加的APT效应和AD痴呆具有与DLB不同的APTw-MRI信号特征。整体 本申请的目的是在3 T临床MRI上完善定量全脑APT-MRI方法 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（如DLB）的表征和诊断。我们制定了三个 我们计划在未来五年内实现的具体目标：（i）制定一项时间效率高的APT-MRI方案， AD的成像研究;（2）量化APT-MRI在表征和诊断MCI中的准确性;以及（3） 量化APT-MRI区分AD痴呆和DLB的准确性。这个概念验证研究 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和相关痴呆患者的决策。

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.