Altered pH in early Alzheimer's disease detected by creatine chemical exchange saturation transfer MRI

通过肌酸化学交换饱和转移 MRI 检测到早期阿尔茨海默氏病 pH 值的改变

• 批准号: 10337352
• 负责人: JIadi Xu
• 金额: $ 44.43万
• 依托单位: HUGO W. MOSER RES INST KENNEDY KRIEGER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10337352
• 关键词: Affect; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease diagnosis; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer’s disease biomarker; Amyloid beta-Protein; Amyloid deposition; Animal Disease Models; Astrocytes; Biological Markers; Brain; Cell Survival; Cell physiology; Cells; Cerebrum; Chemicals; Clinical; Clinical Trials; Creatine; Data; Dementia; Deposition; Development; Disease; Disease Progression; Elderly; Etiology; Evaluation; Event; Fluorescence; Fluorescence Microscopy; Future; Gliosis; Goals; Green Fluorescent Proteins; Hypercapnia; Imaging Techniques; Ischemic Stroke; Lasers; Life; Longitudinal Studies; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Maps; Measurement; Measures; Methods; Microglia; Monitor; Mus; Nerve Degeneration; Neurofibrillary Tangles; Neurotic Disorders; Onset of illness; Pathology; Persons; Phase; Proteins; Protons; Regulation; Research Personnel; Resolution; Risk; Role; Scanning; Scheme; Signal Transduction; Symptoms; Synapses; Techniques; Time; Tissues; Translating; Water; Wild Type Mouse; amyloid imaging; base; cerebral atrophy; clinical application; clinically translatable; detection sensitivity; diagnostic value; early detection biomarkers; enzyme activity; experimental study; guanidinium; in vivo; insight; longitudinal design; mild cognitive impairment; molecular imaging; neurofibrillary tangle formation; neuroinflammation; novel; potential biomarker; protein folding; sensor; spatiotemporal; two-photon

Alzheimer’s disease (AD) is the most common cause of dementia and, currently, there are more than five million people with AD in the US alone. The etiology of Alzheimer’s disease is unknown, and therapies are just starting to be developed. The accumulation of neurotic plaques (Aβ) and neurofibrillary tangles (NFT), as well as widespread gliosis, loss of synapses, and degeneration of neurons are the major histopathological hallmarks of AD. However, a diagnosis of AD in the early stages of dementia cannot be determined simply by the amyloid imaging, because many healthy older adults with brain Aβ deposits never develop dementia in life. Therefore, additional markers that can provide more accurate information of neurodegeneration, particular at the early stage, are needed. Cerebral pH regulation is crucial for cell functioning, enzyme activity and protein folding and pH status provides information that pertains to cell viability and neuronal degeneration. Previous studies reveal that abnormal cerebral pH has an important role in the aggregation of Alzheimer’s associated proteins. Some studies also indicate that the reduced intracellular cerebral pH is a consequence of neuroinflammation involved in the development of AD, which is an early event in the AD patients and can be detected in MCI subjects, even when amyloid deposition is not detectable. Hence, in vivo assessment of cerebral pH could be a useful early biomarker for the differentiation between AD and healthy controls. Chemical exchange saturation transfer (CEST) MRI is a novel versatile technique that can achieve enhanced sensitivity and spatial resolution on the standard clinical scanner by exploiting the exchange of protons between water and various metabolites. Since the proton exchange rate is affected by cellular pH, CEST MRI can also be utilized to map pH in vivo. Our exciting preliminary data show that the exchange of protons between water and guanidinium protons from creatine (Cr) CEST is highly sensitive to pH change and the pH differs significantly between AD and wild type mice measured by CrCEST. Our long-term goal is to develop a clinically translatable CrCEST based MRI scheme that can non-invasively detect cerebral pH in the early-stage AD brain with much higher sensitivity than other MRI methods. To assess its potential, we here propose to verify this approach on mouse AD models. In order to achieve this goal, we have set the following aims: Aim 1: To identify spatiotemporal dynamics of pH changes in the AD mouse brain and to determine whether pH reduction progresses with disease and correlates with neuroinflammation. Aim 2: To assess the pH distribution at the cellular level in the AD mouse brain with the in vivo two-photon fluorescence microscopy.

阿尔茨海默病（AD）是痴呆症最常见的原因，目前有超过五种 仅在美国就有100万人患有AD。老年痴呆症的病因是未知的，治疗方法只是 开始发展。神经症性斑块（Aβ）和神经纤维缠结（NFT）的积累，以及 由于广泛的神经胶质增生、突触丢失和神经元变性是主要的组织病理学改变， AD的标志。然而，在痴呆的早期阶段AD的诊断不能简单地通过 淀粉样蛋白成像，因为许多健康的老年人与大脑Aβ沉积从来没有发展痴呆症的生活。 因此，可以提供更准确的神经变性信息的其他标志物，特别是在 早期阶段，需要。 大脑pH调节对细胞功能、酶活性和蛋白质折叠以及pH状态至关重要 提供关于细胞活力和神经元变性的信息。先前的研究表明， 异常的脑pH在阿尔茨海默病相关蛋白的聚集中具有重要作用。一些 研究还表明，细胞内脑pH值的降低是神经炎症的结果， 在AD的发展中，这是AD患者的早期事件，并且可以在MCI受试者中检测到， 即使当淀粉样蛋白沉积不可检测时。因此，脑pH值的体内评估可能是有用的， 用于区分AD和健康对照的早期生物标志物。 化学交换饱和转移（CEST）MRI是一种新型的多功能技术，可以实现 标准临床扫描仪的灵敏度和空间分辨率提高， 水和各种代谢物之间的质子。由于质子交换率受细胞pH值的影响， CEST MRI也可用于绘制体内pH。我们令人兴奋的初步数据显示， 来自肌酸（Cr）CEST的水和胍质子之间的质子对pH变化高度敏感， 通过CrCEST测量的AD和野生型小鼠之间的pH显著不同。我们的长期目标是 开发一种临床上可翻译的基于CrCEST的MRI方案，该方案可以非侵入性地检测大脑中的pH值。 早期AD大脑的灵敏度远远高于其他MRI方法。为了评估它的潜力，我们在这里 建议在小鼠AD模型上验证这种方法。为了实现这一目标，我们制定了以下措施： 目的：目的1：确定AD小鼠脑内pH值变化的时空动力学，并确定 pH值降低是否随疾病进展并与神经炎症相关。 目的2：利用在体双光子成像技术研究AD小鼠脑内细胞水平的pH值分布 荧光显微镜