Development of Imaging Biomarkers to Evaluate Blood-Brain barrier Alterations in Ageing

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Maintaining healthy ageing is an important aspiration in modern societies due to the geriatric shift in demographies and the economic burdens associated with that. Age-related physiological alterations of the BBB can contribute to several brain pathologies. Alterations to the BBB can have a direct effect on neuronal and synaptic functions through changes in blood flow, BBB permeability, nutrient supply, faulty clearance of toxic molecules and altered secretion of trophic factors. These BBB alterations were reported both in normal ageing and patients with neurological conditions but with the greater impact observed in the diseased group. Most critically, there is no effective treatment strategy that can reverse age-related BBB alterations or the associated neurological consequences. The ability to identify early BBB alterations to selectively manipulate and restore the BBB function remains a largely unexplored area of research.Of special interest to this project are pericytes. Those are capillary mural cells located at the BBB that regulate cerebral blood flow, maintain BBB integrity, and traffic immune cells. They perform these functions via crosstalk with neighbouring cells including endothelial cells, glia and neurons. Gathering evidence supports the role of pericyte degeneration in the pathogenesis of both vascular and AD dementias. Loss of pericytes in the white matter leads to degeneration typical of human cerebral small vessel disease . Furthermore, pericyte loss appears to trigger an AD-like neurodegeneration, accelerating the deposition of parenchymal amyloid-B and development of tau. Despite these known effects in animal models, methods to track the changes in pericytes in vivo are lacking, particularly approaches capable of non-invasively mapping the early changes in pericyte distributions in deep brain structures, or even across the entire brain. A recent study demonstrated that pericytes degenerate with age, promoting vascular calcification and a shift in endothelial transport from ligand-specific receptor-mediated transcytosis to caveolar transcytosis . Caveolar transcytosis is non-specific and hence the aged BBB become 'leaky' to neurotoxic proteins excluded in young age, such as fibrin, thrombin and autoantibodies. Enhanced caveolar mediated transcytosis has also been demonstrated in other neurological conditions such as rodent models of ischemic stroke and often precede the irreversible neurological damage which highlights the benefit for early detection of BBB alteration. We have demonstrated recently in a rodent model of stroke. Those early-stage caveolar transcytosis can be a novel and a promising drug delivery opportunity through which we could selectively traffic lipid nanoparticles into the injured side of the brain. Therefore, this project aims to develop a non-invasive imaging biomarker to enable early detection of age-related alterations in BBB permeability and its association with pericytes dysfunction. To achieve this aim, our program of work includes:1. The development of liposomal based-contrast agent to enable early detection of BBB permeability in ageing and its association with pericytes loss.2. The examination of phenotypic changes in pericytes and other cellular components of the BBB using DSP using both rodent and human post-mortem tissues.