Identifying causal pathways in cerebral small vessel disease

确定脑小血管疾病的因果途径

• 批准号: MR/Y014634/1
• 负责人: Alastair Webb
• 金额: $ 64.67万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FY014634%2F1
• 关键词: Identifying; causal; pathways; cerebral; small

Cerebral small vessel disease is the most common cause of neurological disability, seen on MRI scans as damage to the deep regions of the brain in over half of people by 65 years old. It causes 30% of strokes, falls, frailty, late-onset depression and up to 40% of dementia. However, it has no treatment due to limited understanding of the underlying mechanisms of the disease. Small vessel disease is strongly related to long-standing high blood pressure and to its effects on the body, including stiffer blood vessels and an increased variation in blood pressure during and between each heart beat. It is also related to reduced responsiveness of blood vessels in the brain, limiting their ability to compensate for blood pressure changes. Finally, genetic studies support the role of blood pressure but also identified genes responsible for the integrity of the tissue of the brain. As such, some patients may have more severe disease because their brains are more vulnerable to being damaged.We propose that small vessel disease is due to a balance between increased transmission of variable blood pressure to the brain, a reduced ability of the brain to compensate for this and an increased vulnerability of the brain to being damaged. However, no study has measured all these elements together in a large enough population to test this, and thus to identify and test potential treatments.This project will combine our groups' expertise to measure all aspects of this mechanism in UK Biobank. This study includes brain scans in more than 100,000 people, detailed medical history and lifestyle information and genetic testing. However, it has lacked measurement of changes in blood flow to the brain and its ability to compensate. By adapting the brain scans in UK Biobank, we have developed novel measures of variation in blood flow to the brain with each heart beat and the ability of the lining of the blood vessels in the brain to control blood flow, measured by spontaneous fluctuations in blood flow and blood flow responses whilst performing a visual task.The first part of this project will improve these measurements of control of blood flow to the brain. It will improve how specific they are to blood flow control rather than changes in cognitive function, focus on specific brain regions and will add direct tests of how fluctuations within blood vessels are transmitted to blood flow within the brain. Secondly, we will work with our collaborators to refine genetic measures of tissue vulnerability, including both single genes associated with vulnerability of the brain to injury and combined scores reflecting many genes to produce an overall estimate of an individual's vulnerability to injury, independently of genes affecting blood pressure.We will combine these new, unique measures with extensive medical history and lifestyle data, imaging measures of injury to the brain and resulting effects on cognitive function, risk of stroke and risk of dementia.This will allow us to screen >1000 risk factors for their effects on control of blood flow to the brain, and compare them with the same relationships with damage to the brain, stroke and dementia. We will use advanced statistics to test our proposed mechanism in a single mathematical model of this pathway. This will assess whether real data is more consistent with the hypothesised mechanism causing the disease, compared to alternative theories. Finally, we will use this model to identify new factors that affect this mechanism, particularly whether medications commonly used for other illnesses may improve the pathway, thus identifying potential new treatments to be tested in future studies.Overall, we will be able to test our hypothesised mechanism of small vessel disease within a single large population, improving our understanding of the cause of the disease, identifying new potential treatments and assessing their potential for testing in clinical trials.

脑小血管疾病是神经功能障碍的最常见原因，在 65 岁以上的人中，超过一半的人在 MRI 扫描中发现大脑深部区域受到损害。 30% 的中风、跌倒、虚弱、迟发性抑郁症和高达 40% 的痴呆症都是由它引起的。然而，由于对该疾病的潜在机制了解有限，目前尚无治疗方法。小血管疾病与长期高血压及其对身体的影响密切相关，包括血管僵硬以及每次心跳期间和每次心跳之间的血压变化增加。它还与大脑血管反应性降低有关，限制了它们补偿血压变化的能力。最后，遗传学研究支持血压的作用，但也确定了负责大脑组织完整性的基因。因此，一些患者可能会患有更严重的疾病，因为他们的大脑更容易受到损害。我们认为，小血管疾病是由于可变血压向大脑的传输增加与大脑补偿能力降低之间的平衡所致为此，大脑更容易受到损害。然而，还没有研究在足够大的人群中一起测量所有这些元素来测试这一点，从而识别和测试潜在的治疗方法。该项目将结合我们小组的专业知识来测量英国生物银行这一机制的所有方面。这项研究包括对超过 100,000 人的脑部扫描、详细的病史和生活方式信息以及基因检测。然而，它缺乏对大脑血流量变化及其补偿能力的测量。通过采用英国生物银行的脑部扫描，我们开发了新的测量方法，用于测量每次心跳时流向大脑的血流量的变化，以及通过血液的自发波动来测量大脑血管内壁控制血流量的能力。执行视觉任务时的流量和血流反应。该项目的第一部分将改进对大脑血流控制的测量。它将提高血流控制的特异性，而不是认知功能的变化，专注于特定的大脑区域，并将增加对血管内波动如何传递到大脑内血流的直接测试。其次，我们将与我们的合作者合作，完善组织脆弱性的遗传测量，包括与大脑易受伤害相关的单个基因和反映许多基因的综合评分，以产生个体易受伤害的总体估计，独立于影响基因血压。我们将把这些新的、独特的测量方法与广泛的病史和生活方式数据、大脑损伤的成像测量方法以及对认知功能、中风风险和痴呆症风险的影响相结合。这将使我们能够筛查 >1000 种风险影响血液控制的因素流向大脑，并将它们与大脑损伤、中风和痴呆症的相同关系进行比较。我们将使用先进的统计数据在该途径的单一数学模型中测试我们提出的机制。与其他理论相比，这将评估真实数据是否更符合假设的导致疾病的机制。最后，我们将使用这个模型来确定影响这一机制的新因素，特别是常用于其他疾病的药物是否可以改善这一途径，从而确定在未来的研究中测试的潜在新疗法。总的来说，我们将能够测试我们的研究成果。假设一个大群体内小血管疾病的机制，提高我们对疾病原因的理解，确定新的潜在治疗方法并评估其在临床试验中测试的潜力。