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

了解脑小血管疾病的新疾病过程并确定是否可以对其进行治疗修改

• 批准号: MR/N026896/1
• 负责人: Hugh Markus
• 金额: $ 161.05万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FN026896%2F1
• 关键词: Understanding; novel; disease; processes; underlying

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.

脑内小血管疾病（脑小血管疾病或SVD）约占所有中风的四分之一，是血管性痴呆的主要原因。它在引起痴呆症方面的影响甚至更大，因为许多痴呆症病例，特别是老年痴呆症是由中风样疾病（主要是SVD）与阿尔茨海默氏症等疾病的组合引起的。因此，它提出了一个重大的公共卫生问题，随着人口老龄化，这个问题只会增加。尽管其重要性，但SVD的治疗方法很少。开发新疗法的一个主要问题是，我们不完全了解是什么导致了这种疾病，是什么使它进展。最近的数据表明，两个新的过程可能很重要。其中之一是血脑屏障（BBB）的泄漏，血脑屏障将血管与脑组织分开。第二种是大脑内的炎症。现在可以对SVD患者的这两个过程进行成像，这使我们能够第一次确定这些过程在疾病中的重要性。在初步研究中，我们已经表明，我们可以使用这些脑成像技术检测SVD患者的异常。我们现在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，其中注射造影剂（钆）以观察SVD患者的BBB泄漏。我们将确定这种泄漏有多常见，以及泄漏更多的患者是否有进展更快的疾病。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。在项目的最后部分，我们将确定我们是否可以通过给予一种名为米诺环素的药物来“关闭”BBB泄漏和炎症。这种药物被广泛用于其他目的，并已被证明在SVD动物模型中关闭BBB泄漏和炎症。如果我们能够证明这些过程在人类SVD中很重要，并且可以通过药物关闭，这将为人类治疗这种重要疾病开辟一条全新的途径。

项目成果

NOTCH3 variants are common in the general population and associated with stroke and vascular dementia: an analysis of 200,000 participants

NOTCH3 变异在普通人群中很常见，并与中风和血管性痴呆相关：对 200,000 名参与者的分析

• DOI: 10.1101/2020.12.14.20248151
• 发表时间: 2020
• 作者: Cho B

MINocyclinE to Reduce inflammation and blood brain barrier leakage in small Vessel diseAse (MINERVA) trial study protocol

MINOcyclinE 减少小血管疾病中的炎症和血脑屏障渗漏 (MINERVA) 试验研究方案

• DOI: 10.17863/cam.84819
• 发表时间: 2022
• 作者: Brown R

MINocyclinE to Reduce inflammation and blood brain barrier leakage in small Vessel diseAse (MINERVA) trial study protocol.

• DOI: 10.1177/23969873221100338
• 发表时间: 2022-09
• 期刊: EUROPEAN STROKE JOURNAL
• 影响因子: 6.1
• 作者: Brown, Robin B.;Tozer, Daniel J.;Loubiere, Laurence;Hong, Young T.;Fryer, Tim D.;Williams, Guy B.;Graves, Martin J.;Aigbirhio, Franklin, I;O'Brien, John T.;Markus, Hugh S.
• 通讯作者: Markus, Hugh S.

Association of NOTCH3 variant position with stroke onset and other clinical features among patients with CADASIL

NOTCH3 变异位置与 CADASIL 患者中风发作和其他临床特征的关联

• DOI: 10.17863/cam.83243
• 发表时间: 2022
• 作者: Cho B

How often does white matter hyperintensity volume regress in cerebral small vessel disease?

• DOI: 10.1177/17474930231169132
• 发表时间: 2023-10
• 期刊: INTERNATIONAL JOURNAL OF STROKE
• 影响因子: 6.7
• 作者: Brown, Robin B.;Tozer, Daniel J.;Egle, Marco;Tuladhar, Anil M.;de Leeuw, Frank-Erik;Markus, Hugh S.
• 通讯作者: Markus, Hugh S.