Noradrenergic Biomarkers and their relationship to Therapeutic Response in Clinical Alzheimer's Disease

注意力--专注于相关信息的行为--通常在阿尔茨海默病的早期受到影响。患者和他们的家人经常注意到注意力和注意力的早期和丧失能力的问题，这会恶化记忆问题。目前治疗阿尔茨海默病的方法主要集中在提高大脑化学物质乙酰胆碱的水平，这种化学物质对注意力的影响有限。大脑化学物质去甲肾上腺素对注意力尤为重要。在阿尔茨海默氏症中，产生去甲肾上腺素的大脑区域在早期就会受到损害，因此注意力会受到影响。尽管它很小，但这个大脑区域，蓝斑(LC)，现在可以在磁共振成像(MRI)扫描中看到。在阿尔茨海默病患者的扫描中可以看到LC的损害。我的目标是开发准确的方法来测量阿尔茨海默病患者LC的损害和去甲肾上腺素水平的降低。我还将评估患者的注意力和记忆力受到疾病影响的程度，并将其与我们测量的损害进行比较。这将使我们更好地了解与疾病相关的过程，这些过程导致注意力问题。它还有望让我们选择最需要提高去甲肾上腺素治疗的患者。我将招募完成一项正在进行的药物治疗试验的患者，该药物可提高去甲肾上腺素(称为鸟嘌呤)，并将测试测量去甲肾上腺素系统的损害是否可以预测谁对治疗有良好的反应。我将使用详细的核磁共振脑扫描来评估每个患者的去甲肾上腺素中枢-LC内的损伤。我还将开发一种新的方法，根据瞳孔大小的变化来测量去甲肾上腺素。使用令人惊讶的声音，我们可以引起瞳孔大小的变化，这取决于一个人大脑中去甲肾上腺素的水平。我将设计一个实验，利用声音来产生这些变化，并使用高质量的相机进行测量。我还会测量患者血液中去甲肾上腺素的水平，这应该会让我们知道他们的LC产生了多少。这三项指标：核磁共振、瞳孔波动和血液，将与注意力测试的表现有关。这些测试是公认的，经常被用来评估痴呆症患者的注意力。他们将在临床药物试验之前、期间和之后对患者进行测试，以确定金刚烷是否对他们的得分有任何影响。所有这些测试都将在帝国理工学院医疗信托基金和帝国理工学院伦敦分校进行。血液样本的分析将在伦敦大学学院(UCL)进行。我的首席导师是大卫·夏普教授--他是神经学顾问，帝国理工学院痴呆症研究所中心主任，是脑成像研究的世界领先者之一。帕雷什·马尔霍特拉博士是一名神经学顾问，专门研究注意力障碍痴呆症，他领导着这项临床药物试验。他将是该项目设计和实施的关键主管。亨里克·泽特伯格教授在伦敦大学学院工作，是脑部疾病血液样本分析方面的专家。皮特·拉利博士是一名物理学家，专门使用核磁共振技术详细观察脑干，他将积极参与这一项目。关于瞳孔测量，我将听取牛津大学的Kinan Muhammed博士的意见，他在这一领域有经验。这个项目的结果将帮助我们理解为什么阿尔茨海默病患者有不同程度的注意力问题，并可能提供方法，允许医生个性化他们治疗患者认知问题的方式。我们希望我们的发现能够转化为临床实践，并真正改善大量患者的生活质量。

Attention - the act of focusing on relevant information - is often affected early in Alzheimer's disease. Patients and their families frequently notice early and disabling problems with attention and concentration, which worsen memory problems. The current treatments for Alzheimer's disease mainly focus on boosting levels of the brain chemical acetylcholine, which has limited effects on attention.The brain chemical noradrenaline is particularly important for attention. In Alzheimer's disease, the brain region that produces noradrenaline is damaged early on, and as a result attention is affected. Despite its small size, this brain region, the locus coeruleus (LC), can now be seen on magnetic resonance imaging (MRI) scans. Damage to the LC is visible on the scans of patients with Alzheimer's disease.I aim to develop accurate ways of measuring damage to the LC and reduced noradrenaline levels in patients with Alzheimer's. I will also assess how much the patients' attention and memory is affected by the disease and compare it to the damage we have measured. This will give us better understanding of the processes associated with the disease that result in problems with attention. It will hopefully also allow us to select patients who are most in need of treatments that will boost their noradrenaline.I will recruit patients who have finished taking part in an ongoing treatment trial of a drug that boosts noradrenaline (called guanfacine) and will test whether measuring damage to the noradrenaline system can predict who will respond well to the treatment. I will use detailed MRI brain scans to assess damage within each patient's noradrenaline centre - the LC. I will also develop a new way of measuring noradrenaline based on changes in pupil size. Using surprising sounds, we can cause changes in pupil size, and this is dependent on the level of noradrenaline in a person's brain. I will design an experiment that uses sound to produce these changes and measure them using a high-quality camera. I will also look to measure the level of noradrenaline in the patients' blood which should give us an idea of how much is being produced by their LC. These 3 measures; MRI, pupil fluctuations and blood, will be related to performance on tests of attention. These tests are well established and frequently used to assess attention in patients with dementia. They will be done with the patients before, during and after the clinical drug trial to see whether guanfacine has any effect on their scores.All of this testing will be performed at Imperial College Healthcare Trust and Imperial College London. Analysis of the blood samples will be done at University College London (UCL).My principal supervisor is Professor David Sharp - he is a consultant neurologist, director of the Dementia Research Institute Centre at Imperial, and is one of the world-leaders in brain-imaging research. Dr Paresh Malhotra, a consultant neurologist who specialises in dementia disorders of attention, is leading the clinical drug trial. He will be a key supervisor in the design and implementation of this project. Professor Henrik Zetterberg works at UCL and is an expert in the analysis of blood samples in brain diseases. Dr Pete Lally is a physicist who specialises in using MRI to look in detail at the brain stem and will be heavily involved in this project. Regarding the pupillometry, I will have input from Dr Kinan Muhammed who works at Oxford University and has experience in this area.The results from this project will help us understand why patients with Alzheimer's disease have such varying degrees of attentional problems and may provide methods to allow doctors to personalise the way that they treat patients' cognitive problems. We would hope our findings could be translated to clinical practice and result in real improvements in the quality of life of a large number of patients.