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毁灭性的神经退行性变 疾病。这种毁灭性疾病的特征是淀粉样斑块和神经原纤维的聚集。 身体的标准组织病理学检查显示有缠结。大踏步走了一大步 在过去的几年里，为了识别和验证AD的生物标记物而进行了研究。根据PET和脑脊液的测量结果 AD的斑块和缠结，我们现在能够在体内测量AD所有阶段的病理：AD痴呆，轻度AD 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 用活体生物标志物诊断阿尔茨海默病，并鼓励继续开发新的， 无法识别的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核磁共振成像。 一种可以基于组织中的内源性移动蛋白和多肽产生对比度的技术。数不胜数 先前的研究表明，APT加权(APTw)成像可以检测出恶性脑肿瘤。 基于细胞密度增加和由于组织酸化或pH降低而导致的急性脑缺血。我们的努力 已经成功地将这项重要的MRI技术开发成了FDA批准的飞利浦3T MRI序列 脑癌的临床应用系统。进一步将这一创新的基于蛋白质的技术转化为AD和 非阿尔茨海默病，如路易体痴呆(DLB)，令人鼓舞。众所周知，这两个 细胞外淀粉样蛋白和细胞内tau首先以可溶性单体形式存在(APT可检测到)。我们的预赛 研究清楚地表明，这些蛋白质在MCI中的异常积聚导致了 APT效应增强和AD痴呆具有不同于DLB的APTw-MRI信号特征。整体而言 此应用程序的目标是完善3T临床MRI上的定量全脑APT-MRI方法 并证明基于蛋白质的APT-MRI作为一种替代生物标志物的可行性和潜力 阿尔茨海默病和其他形式的痴呆症的特征和诊断，如痴呆。我们已经制定了三个方案 我们计划在未来五年内解决的具体目标：(I)开发一种省时的APT-MRI协议，用于 AD的影像研究；(2)量化APT-MRI对MCI定性和诊断的准确性；以及(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 将为评估APT成像对临床的影响的全面验证性研究奠定基础 阿尔茨海默病及相关痴呆患者的决策行为。

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.