Imaging early blood-brain barrier dysfunction in dementia

血脑屏障（BBB）积极调节营养物质向大脑的输送，并保护大脑免受血液中存在的微生物和毒素的影响。BBB破坏随年龄增长而发生（Montagne et al.2015），是血管性痴呆（Farrall et al.2009）和阿尔茨海默病（货车de Haar et al.2016）的早期病理学标志。已证明BBB损伤的严重程度与出现痴呆早期症状的患者的认知障碍相关（Nation等人，2019），这表明BBB功能的治疗恢复可能有助于延迟痴呆的发作。需要对血脑屏障功能障碍进行纵向研究，以评估血脑屏障变化的诊断和预后重要性，并监测新的血脑屏障靶向治疗的疗效。 目前测量人体局部BBB破坏的方法依赖于医学成像技术，如磁共振成像（MRI）（Dickie等人，2019 a，Thrippleton等人，2019）。MRI可以在同一受试者中重复多次，并为研究纵向BBB变化提供了强大的工具，然而MRI的空间分辨率太有限，无法直接可视化微观BBB成分的变化。我们最近开发了一种新的BBB完整性的MRI测量方法，该方法可以量化水在BBB中的交换速度。该方法比造影剂泄漏测量更灵敏（Dickie等人，2019）。我们还开发了基于荧光标记生物标志物的动态监测的BBB损伤的高分辨率双光子显微镜测量，以亚微米空间分辨率在体内真实的时间评估BBB转运特性（Al-Ahmady等人，2019）。这种方法可以在同一动物的单个毛细血管水平上直接成像数月的泄漏，并提供理想的金标准比较。该博士项目将使用这些新的MR和双光子成像技术来确定阿尔茨海默病（TgF 344-AD模型）和血管性痴呆（慢性脑灌注不足模型）啮齿动物模型中BBB完整性的纵向变化，并评估与衰老相关的BBB变化。理想的候选人将具有生物医学科学背景，并熟悉计算机编程。成功的学生将获得先进的神经成像方法（MRI和双光子显微镜），最先进的3D免疫组织化学和神经外科临床前模型的技能。他们将加入我们的科学家团队，致力于研究痴呆症脑血管功能障碍的优秀科学，并将通过使研究人员能够研究BBB功能障碍，神经退行性变和认知能力下降之间的联系而产生重大影响。

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.