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——经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致残性问题，这使记忆问题恶化。目前对阿尔茨海默病的治疗主要集中在提高大脑化学物质乙酰胆碱的水平，这种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特别重要。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受到了损伤，因此注意力受到了影响。尽管这个大脑区域很小，但在磁共振成像（MRI）扫描中可以看到蓝斑（LC）。在阿尔茨海默病患者的扫描图上可以看到LC的损伤。我的目标是开发准确的方法来测量老年痴呆症患者的LC损伤和去甲肾上腺素水平的降低。我还会评估病人的注意力和记忆力受到疾病影响的程度，并将其与我们测量到的损害进行比较。这将使我们更好地了解与导致注意力问题的疾病相关的过程。希望这也能让我们选择那些最需要治疗的病人来提高他们的去甲肾上腺素水平。我将招募那些已经完成了一项正在进行的去甲肾上腺素增强药物（称为胍法辛）治疗试验的患者，并将测试对去甲肾上腺素系统损伤的测量是否可以预测谁对治疗的反应良好。我将使用详细的核磁共振脑部扫描来评估每个病人去甲肾上腺素中心（LC）的损伤情况。我还将开发一种基于瞳孔大小变化来测量去甲肾上腺素的新方法。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，用声音来产生这些变化，并使用高质量的相机来测量它们。我还会测量病人血液中的去甲肾上腺素水平，这样我们就能知道他们的LC产生了多少。这三个措施；核磁共振成像、瞳孔波动和血液，将与注意力测试的表现有关。这些测试已经建立并经常用于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研究，以观察胍法辛是否对他们的评分有任何影响。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进行。血样的分析将在伦敦大学学院进行。我的主要导师是David Sharp教授，他是一名神经学家顾问，帝国大学痴呆症研究中心主任，是脑成像研究领域的世界领导者之一。帕雷什·马尔霍特拉（Paresh Malhotra）博士是一名专攻痴呆症注意力障碍的神经学家顾问，他领导了这项临床药物试验。他将是这个项目设计和实施的关键主管。Henrik Zetterberg教授就职于伦敦大学学院，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，他擅长使用核磁共振成像来详细观察脑干，他将大力参与这个项目。关于瞳孔测量，我将听取牛津大学的Kinan Muhammed博士的意见，他在这方面有经验。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如此不同程度的注意力问题，并可能提供方法，让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，并导致大量患者生活质量的真正改善。

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.