Non-invasive MRI of blood-cerebrospinal fluid barrier function: addressing a critical failure in the middle aged brain (360G-Wellcome-225345_Z_22_Z)

Modern life has granted increased life expectancy. Yet, living longer means that we are more likely to develop and die from dementia, for which there is no cure. The development of an effective treatment is hampered by the late stage of detection. It is therefore critical to identify novel targets for diagnosis and therapy that are important drivers of disease progression earlier in life. The blood-CSF-barrier is thought to play an important role in the development of age related neurodegenerative disease and recent analysis of human post-mortem samples has found marked derangement to occur during middle age. I have recently developed the first non-invasive technique to assess blood-CSF-barrier function, using MRI. This now enables measurement every few seconds to dynamically capture the functional response to drugs in addition to longitudinal assessment across the aging process. Here we seek to leverage the unique advantages of this new technology to characterize the causal role of blood-CSF-barrier dysfunction in age-related cognitive decline. We will employ longitudinal multi-parametric imaging with comparison to gold- standard measures of CSF-secretion and CSF-mediated brain-clearance together with targeted pharmacological intervention. Together, therefore, this programme of work will greatly enhance our understanding of the role of the blood-CSF-barrier in dementia.