Cerebrospinal fluid exchange in Alzheimer's disease characterized by advanced MRI techniques

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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), 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 amyloid imaging, because many healthy older adults with brain Aβ deposits never develop dementia. Therefore, additional markers that can provide more accurate information of neurodegeneration, particular at the early stage, are needed. The brain lymphatic system, named the glymphatic system, is a recently discovered cerebrospinal fluid (CSF) circulation system that utilizes the perivascular channels to eliminate soluble proteins and metabolite. The dysfunction of the glymphatic system promotes Aβ deposition in the meninges and introduces perfusion reduction and cognitive impairment. A critical barrier for understanding CSF turnover including the glymphatic system is a lack of noninvasive methods that can be applied to interrogate multiple aspects of the glymphatic system in vivo. We recently developed several non-invasive MRI approaches that can assess CSF secretion and reabsorption in situ with MRI. These include a molecular imaging method, dynamic glucose-enhanced (DGE) imaging with on-resonance Variable Delay Multiple Pulse (onVDMP) MRI. as well as a set of spin- labeling based MRI methods, named magnetization transfer indirect spin labeling (MISL) and phase alternate labeling with null recovery (PALAN). These latter methods selectively label the paraventricular tissues by exploiting their significantly different protein concentration and water T1, T2, cand diffusion properties. The PALAN method can also assess the ISF flow in brain without contrast agents. Our long- term goal is to develop several clinically translatable MRI schemes that can non-invasively detect CSF and interstitial fluid water exchange in brain and apply them as potential MRI biomarkers for the early-stage AD.