Understanding novel disease processes underlying cerebral small vessel disease and determining whether they can be therapeutically modified

脑内小血管疾病（脑小血管疾病或SVD）导致约四分之一的中风，是血管性痴呆的主要原因。它对痴呆症的影响甚至更大，因为许多痴呆症病例，特别是老年人，是由中风样疾病（主要是SVD）与阿尔茨海默氏症等疾病的结合引起的。因此，它提出了一个重大的公共卫生问题，只会随着人口老龄化而增加。尽管SVD很重要，但治疗方法却很少。开发新疗法的一个主要问题是，我们并不完全了解是什么导致了这种疾病，又是什么使它发展。最近的数据表明，两个新的过程可能很重要。其中之一是将血管与脑组织分开的血脑屏障（BBB）渗漏。第二种是大脑发炎。现在有可能对SVD患者的这两个过程进行成像，这使我们第一次能够确定这些过程在疾病中的重要性。在初步研究中，我们已经证明我们可以使用这些脑成像技术检测SVD患者的异常情况。现在我们将在这个项目中更详细地应用这些技术。我们将使用MRI技术，通过注射造影剂（钆）来观察SVD患者血脑屏障的渗漏。我们将确定这种渗漏有多普遍，以及渗漏较多的患者是否患有进展更快的疾病。其次，我们将使用另一种称为正电子发射断层扫描（PET）的成像技术来成像大脑内的炎症。我们将确定血脑屏障渗漏是否与炎症有关，以及这两个过程是否与更快的疾病进展有关。在项目的最后一部分，我们将决定是否可以通过使用一种叫做二甲胺四环素的药物来“关闭”血脑屏障渗漏和炎症。这种药物被广泛用于其他目的，并在SVD动物模型中被证明可以关闭血脑屏障泄漏和炎症。如果我们能证明这些过程在人类SVD中很重要，并且可以通过药物关闭，这将为治疗人类这一重要疾病开辟一条全新的途径。

Disease of the small blood vessels within the brain (cerebral small vessel disease - or SVD) causes about a quarter of all strokes and is the main cause of vascular dementia. Its impact in causing dementia is even greater because many case of dementia particularly in the elderly are caused by a combination of stroke-like disease (primarily SVD) with diseases such as Alzheimer's. Therefore it presents a major public health problem which will only increase as the population ages. Despite its importance there are few treatments for SVD. A major problem in developing new treatments is that we don't fully understand what causes the disease and what makes it progress. Recent data has suggested two new processes may be important. One of these is leakiness of the blood brain barrier (BBB) which separates the blood vessels from the brain tissue. The second is inflammation within the brain. It is now possible to image both of these processes in patients with SVD and this is allowing us, for the first time, to determine how important these processes are in the disease. In pilot studies we have shown we can detect abnormalities in patients with SVD using these brain imaging techniques. We will now apply these techniques in more detail in this project. We will use an MRI technique in which one gives injection of a contrast agent (gadolinium) to look at leakiness of the BBB in patients with SVD. We will determine how common this leakiness is and whether patients with more leakiness have disease which progresses faster. Secondly we will use another imaging technique called positron emission tomography (PET) to image inflammation within the brain. We will determine whether BBB leakiness relates to inflammation and whether both these processes are associated with more rapid disease progression. In the final part of the project we will determine whether we can "switch off" BBB leakiness and inflammation by giving a drug called minocycline. This drug is widely used for other purposes and has been shown to switch off these both BBB leakiness and inflammation in an animal model of SVD. If we can show that these processes are important in SVD in man, and can be switched off by drugs, this will open up a completely new avenue in treatment of this important disease in man.