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

阿尔茨海默病(AD)是导致痴呆症的最常见原因，目前有五种以上 仅在美国就有数百万阿尔茨海默病患者。阿尔茨海默病的病因尚不清楚，治疗方法也只是 开始被开发出来。神经症斑块(Aβ)和神经原纤维缠结(NFT)的积聚 作为广泛的胶质细胞增生症，突触丢失和神经元变性是主要的组织病理学 公元后的标志。然而，痴呆症早期阶段的阿尔茨海默病诊断不能简单地通过 淀粉样蛋白成像，因为许多有脑Aβ沉积的健康老年人在生活中从未患上痴呆症。 因此，可以提供更准确的神经变性信息的额外标记，特别是在 早期阶段，是需要的。 大脑pH调节对细胞功能、酶活性、蛋白质折叠和pH状态至关重要 提供与细胞存活和神经元退化有关的信息。此前的研究表明， 大脑pH值异常在阿尔茨海默病相关蛋白的聚集中起着重要作用。一些人 研究还表明，脑细胞内pH值的降低是神经炎症的结果 在AD的发展过程中，AD是AD患者中的早期事件，可以在MCI受试者中检测到， 即使在检测不到淀粉样蛋白沉积的时候也是如此。因此，在活体内评估大脑的pH值可能是有用的 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)磁共振成像是一种新的多功能技术，可以实现 通过利用交换来增强标准临床扫描仪的灵敏度和空间分辨率 水和各种代谢物之间的质子。由于质子交换率受细胞pH的影响， CEST MRI也可用于绘制活体pH图。我们令人兴奋的初步数据显示， 从肌酸(Cr)CEST得到的水和胍之间的质子对pH变化高度敏感，并且 用CrCEST测定AD小鼠和野生型小鼠的pH值有显著差异。我们的长期目标是 开发一种临床可翻译的基于CrCEST的MRI方案，该方案可以无创地检测大脑中的pH值 早期阿尔茨海默病的脑MRI检查敏感性明显高于其他MRI检查方法。为了评估它的潜力，我们在这里 建议在小鼠AD模型上验证该方法。为了实现这一目标，我们设定了以下内容 目的：目的1：确定AD小鼠脑内pH变化的时空动态，并确定 PH降低是否随着疾病的进展而发展，并与神经炎症相关。 目的2：利用在体双光子技术研究AD小鼠脑内细胞水平的pH分布 荧光显微镜。

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.