Does the central noradrenergic system play a role in agitation in Alzheimer's disease?

这项研究的背景是什么？阿尔茨海默病(AD)是痴呆症最常见的原因，随着疾病的发展，许多患有这种疾病的人会发展出令人痛苦和难以治疗的行为。最令人痛苦和最具挑战性的行为之一是激动，这是当痴呆症患者表现出情绪困扰、过度活动、言语或身体攻击时。躁动极大地降低了患者和照顾者的生活质量，经常促使患者进入医院或疗养院，并与疾病的快速进展和更早的死亡有关。痴呆症中治疗躁动的唯一获得许可的药物是一种抗精神病药物，这种药物主要通过镇静患者起作用，可能会导致危险的副作用，因此我们迫切需要更好、更安全、更有针对性的治疗躁动。阿尔茨海默病最早的大脑变化已被证明发生在靠近大脑底部的一个小结构，称为蓝斑(LC)。这种结构包含产生一种名为去甲肾上腺素(NA)的化学物质(神经递质)的细胞，去甲肾上腺素在控制大脑如何对环境的显著或重要方面做出反应方面发挥着重要作用。为了完成这一角色，LC连接并影响大脑中涉及控制情绪和抑制行为(反应抑制)的其他区域。有证据表明，在表现出攻击性或焦虑的年轻人以及焦虑不安的AD患者中，这些大脑区域功能失调。我们知道NA允许健康人的这些大脑区域正确地执行其功能，但还没有研究调查LC中与AD相关的变化(及其对NA活动的影响)是否会使AD患者更有可能出现躁动。为了支持这一概念，有来自尸检的一致证据表明，焦虑症AD患者的大脑中可能有一个更活跃的NA系统，以补偿更大的LC细胞损失。这项研究的目的是什么？将如何进行这项研究？为了调查大脑中的NA系统是否在AD的躁动中起作用，50名患有AD和躁动的参与者将被要求：1.接受磁共振成像(MRI)扫描，以测试更大的躁动是否与LC功能和结构恶化有关。2.完成行为测试，以衡量他们的大脑调节情绪和抑制反应的能力，以及这是否与激越分数有关。3.接受单剂量心得安(一种治疗高血压的常用药物，它也可以阻断脑部NA的作用)来测试这是否改善了情绪调节和反应抑制。健康的老年人被认为比AD患者拥有更完整的LC-NA系统，所以50名没有认知障碍的健康志愿者(对照组)也将完成行为和药理学研究(上文2和3)，以测试心得安是否影响健康老年人的情绪调节和反应抑制，以及这是否受到特质焦虑和愤怒分数的影响。潜在的影响和好处是什么？这项研究提供了一个独特的机会，让我们进一步了解阿尔茨海默病中潜在的兴奋的大脑过程，以及NA系统是否起到了作用。如果成功，这些发现有可能导致检测和治疗这种情况的新方法，例如使用针对NA系统的药物(例如心得安)。

WHAT IS THE CONTEXT OF THIS RESEARCH?Alzheimer's disease (AD) is the most common cause of dementia, and many individuals with this condition develop distressing and difficult-to-treat behaviours as the disease progresses. One of the most distressing and challenging behaviours is agitation, which is when an individual with dementia shows emotional distress along with overactivity, verbal or physical aggression. Agitation substantially reduces quality of life for patients and caregivers, frequently precipitates admission to a hospital or nursing home and is associated with rapid disease progression and earlier death. The only licensed medication for agitation in dementia is an antipsychotic drug, which works primarily by sedating patients and can lead to dangerous side effects, so we urgently need better, safer and more targeted treatments for agitation. The earliest brain changes in AD have been shown to occur in a small structure near the base of the brain called the locus coeruleus (LC). This structure contains cells that produce a chemical substance (neurotransmitter) called noradrenaline (NA), which plays an important role in controlling how the brain responds to noticeable or important aspects of the environment. To fulfil this role, the LC is connected to and influences other regions of the brain involved in controlling emotions and suppressing actions (response inhibition). There is evidence that these brain regions are dysfunctional in young adults who show aggression or anxiety, as well as in agitated patients with AD. We know that NA allows these brain regions to perform their function properly in healthy people, but no study has yet investigated whether AD-related changes in the LC (and its effects on NA activity) make an individual with AD more likely to have agitation. In support of this concept, there is consistent evidence from post-mortem studies that agitated patients with AD may have a more overactive NA system in their brains to compensate for greater LC cell loss. WHAT WILL THE RESEARCH AIM TO ACHIEVE AND HOW WILL IT BE CONDUCTED?To investigate whether the NA-system in the brain plays a role in agitation in AD, fifty participants with AD and agitation will be asked to:1. Undergo an magnetic resonance imaging (MRI) scan to test whether greater agitation is related to worse LC function and structure. 2. Complete behavioural tests to measure their brain's ability to regulate emotion and inhibit responses, and whether this is related to agitation scores. 3. Receive a single dose of propranolol (a commonly prescribed medication for high blood pressure, which also blocks the action of NA in the brain) to test whether this improves emotion regulation and response inhibition.Healthy older adults are presumed to have a more intact LC-NA system compared to patients with AD, so fifty healthy volunteers without cognitive impairment (controls) will also complete the behaviour and pharmacology studies (2 and 3 above) to test whether propranolol influences emotion regulation and response inhibition in healthy older adults, and whether this is influenced by trait anxiety and anger scores. WHAT ARE THE POTENTIAL IMPLICATIONS AND BENEFITS?This study provides a unique opportunity to further our understanding of the brain processes underlying agitation in AD, and whether there is a role for the NA system. If successful, the findings have potential to lead to new approaches for detecting and treating this condition, for example by using medications that target the NA system (e.g. propranolol).