Imaging early blood-brain barrier dysfunction in dementia

点击翻译按钮获取中文摘要

The blood-brain barrier (BBB) actively regulates delivery of nutrients to the brain, as well as protecting the brain from microbes and toxins present in the blood. BBB breakdown occurs with ageing (Montagne et al.2015), and is an early pathological hallmark of vascular dementia (Farrall et al. 2009) and Alzheimer's disease (Van de Haar et al. 2016). The severity of BBB damage has been shown to correlate with cognitive impairment in patients with early signs of dementia (Nation et al.2019), suggesting that therapeutic restoration of BBB function may help delay dementia onset. Longitudinal studies of BBB dysfunction are needed to evaluate the diagnostic and prognostic importance of BBB changes, and to monitor the efficacy of novel BBB targeted treatments. Current methods for measuring regional BBB breakdown in humans rely on medical imaging techniques such as magnetic resonance imaging (MRI) (Dickie et al. 2019a, Thrippleton et al. 2019). MRI can be repeated multiple times in the same subject and provide a powerful tool for studying longitudinal BBB changes, however the spatial resolution of MRI is too limited to directly visualise changes in microscopic BBB components. We have recently developed a novel MRI measure of BBB integrity which quantifies how fast water exchanges across the BBB. The approach is more sensitive than contrast agent leakage measurements (Dickie et al. 2019). We have also developed high resolution 2-photon microscopy measurements of BBB damage based on dynamic monitoring of fluorescently labelled biomarkers to assess the BBB transport properties in real time at sub-micrometer spatial resolution in vivo (Al-Ahmady et al. 2019). This approach can directly image leakage at the level of single capillaries in the same animal over months and provides the ideal gold-standard comparator. This PhD project will use these novel MR- and 2-photon imaging techniques to determine longitudinal changes in BBB integrity in rodent models of Alzheimer's disease (TgF344-AD model) and vascular dementia (chronic cerebral hypoperfusion model), and also assess BBB changes associated with ageing. The ideal candidate will have a background in biomedical sciences with some familiarity of computer programming.The successful student will gain skills in advanced neuroimaging methods (MRI and 2-photon microscopy), state of the art 3D immunohistochemistry and neurosurgery in pre-clinical models. They will join our team of scientists working on excellent science focussed on cerebrovascular dysfunction in dementia and will have a major impact by enabling researchers to study the links between BBB dysfunction, neurodegeneration, and cognitive decline.