Identifying causal pathways in cerebral small vessel disease

脑血管疾病是导致神经功能障碍的最常见原因，在MRI扫描中，超过一半的65岁以上的人大脑深部区域受损。它导致30%的中风、跌倒、虚弱、迟发性抑郁症和高达40%的痴呆。然而，由于对这种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，包括血管变硬，每次心跳期间和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，基因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，一些患者可能会有更严重的疾病，因为他们的大脑更容易受到损伤。我们认为，小血管疾病是由于向大脑传递可变血压增加、大脑补偿能力下降和大脑受损脆弱性增加之间的平衡。然而，没有一项研究在足够大的人群中测量了所有这些因素来测试这一点，从而确定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衡量英国生物银行这一机制的各个方面。这项研究包括对10万多人进行脑部扫描，详细的病史和生活方式信息，以及基因检测。然而，它缺乏对流向大脑的血流量变化及其补偿能力的测量。通过调整英国生物银行的脑部扫描，我们开发了新的测量方法，可以测量每次心跳时流向大脑的血流量变化，以及大脑血管内壁控制血流量的能力，通过在执行视觉任务时血流量的自发波动和血流量反应来测量。这个项目的第一部分将改进这些测量控制流向大脑的血液。它将提高它们对血流控制的特异性，而不是对认知功能的改变，专注于特定的大脑区域，并将增加对血管波动如何传递到大脑血流的直接测试。其次，我们将与我们的合作者一起完善组织易损性的遗传测量，包括与大脑损伤易损性相关的单个基因和反映许多基因的综合得分，以产生对个体损伤易损性的总体估计，独立于影响血压的基因。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及其对认知功能、中风风险和痴呆风险的影响结合起来。这将使我们能够筛选1000个风险因素，看看它们对控制流向大脑的血液的影响，并将它们与大脑损伤、中风和痴呆的相同关系进行比较。我们将使用高级统计学来测试我们在这一途径的单一数学模型中提出的机制。与其他理论相比，这将评估真实数据是否更符合导致疾病的假设机制。最后，我们将使用该模型来确定影响该机制的新因素，特别是通常用于其他疾病的药物是否可能改善该途径，从而确定潜在的新治疗方法，以便在未来的研究中进行测试。总的来说，我们将能够在单个大人群中测试我们假设的小血管疾病机制，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的测试潜力。

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.