Novel developments in non-contrast enhanced MRI of the perivascular clearance system: What are the possibilities for Alzheimer’s disease research?

The cerebral waste clearance system (i.e, glymphatic or intramural periarterial drainage) works through a network of perivascular spaces (PVS). Dysfunction of this system likely contributes to aggregation of Amyloid-β and subsequent toxic plaques in Alzheimer's disease (AD). A promising, non-invasive technique to study this system is MRI, though applications in dementia are still scarce. This review focusses on recent non-contrast enhanced (non-CE) MRI techniques which determine and visualise physiological aspects of the clearance system at multiple levels, i.e., cerebrospinal fluid flow, PVS-flow and interstitial fluid movement. Furthermore, various MRI studies focussing on aspects of the clearance system which are relevant to AD are discussed, such as studies on ageing, sleep alterations, and cognitive decline. Additionally, the complementary function of non-CE to CE methods is elaborated upon. We conclude that non-CE studies have great potential to determine which parts of the waste clearance system are affected by AD and in which stages of cognitive impairment dysfunction of this system occurs, which could allow future clinical trials to target these specific mechanisms.