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

由于人口老龄化和与此相关的经济负担，保持健康老龄化是现代社会的一个重要愿望。血脑屏障相关的生理改变可导致多种脑病理。BBB的改变可以通过血流、BBB渗透性、营养供应、有毒分子的错误清除和营养因子分泌的改变对神经元和突触功能产生直接影响。在正常老化和神经系统疾病患者中均报告了这些BBB改变，但在患病组中观察到的影响更大。最重要的是，没有有效的治疗策略可以逆转年龄相关的BBB改变或相关的神经系统后果。识别早期血脑屏障改变以选择性地操纵和恢复血脑屏障功能的能力仍然是一个很大程度上未探索的研究领域。这些是位于BBB的毛细血管壁细胞，调节脑血流，维持BBB的完整性，并运输免疫细胞。它们通过与相邻细胞包括内皮细胞、神经胶质和神经元的串扰来执行这些功能。越来越多的证据支持周细胞变性在血管性痴呆和AD痴呆发病机制中的作用。白色物质中周细胞的缺失导致人类脑小血管疾病的典型变性。此外，周细胞损失似乎引发AD样神经变性，加速实质淀粉样蛋白B的沉积和tau的发育。尽管在动物模型中有这些已知的作用，但缺乏在体内追踪周细胞变化的方法，特别是能够非侵入性地绘制脑深部结构中周细胞分布的早期变化，甚至整个大脑的方法。最近的一项研究表明，周细胞随着年龄的增长而退化，促进血管钙化和内皮细胞转运从配体特异性受体介导的转胞吞转移到小窝转胞吞。小窝转胞吞是非特异性的，因此老年BBB对年轻时排除的神经毒性蛋白质（如纤维蛋白、凝血酶和自身抗体）变得“泄漏”。增强的小窝介导的转胞吞作用也已在其他神经学病症中得到证实，例如缺血性中风的啮齿动物模型，并且通常在不可逆的神经损伤之前，这突出了早期检测BBB改变的益处。我们最近在啮齿动物中风模型中证明了这一点。这些早期的小窝转胞吞作用可能是一个新的和有前途的药物递送机会，通过它我们可以选择性地将脂质纳米颗粒运输到大脑的受损侧。因此，该项目旨在开发一种非侵入性成像生物标志物，以早期检测BBB通透性的年龄相关变化及其与周细胞功能障碍的相关性。为实现这一目标，我们的工作计划包括：1.脂质体造影剂的发展，使早期检测血脑屏障通透性在老化及其与周细胞损失.使用啮齿类动物和人死后组织，使用DSP检查血脑屏障的周细胞和其他细胞组分的表型变化。

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.