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

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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.