A new noradrenergic strategy to treat Impulsivity in Progressive Supranuclear Palsy

进行性核上性瘫痪(PSP)是一种复杂的疾病，它对患者和家庭都是毁灭性的，它结合了一种对标准治疗没有反应的运动障碍，窒息，言语丧失，人格变化和痴呆。我们团队的研究表明，在英国大约有7000人患有PSP。尽管PSP在身体上非常残疾，但对生活质量影响最大的是PSP的认知和个性变化。尽管这些患者对许多活动反应迟缓，反应迟钝，但他们所做的事情往往是鲁莽和冲动的。例如，患有PSP的人可能会在没有考虑后果的情况下“仓促行事”或“草率下结论”，或者行为举止有很高的跌倒或窒息风险。这些问题也被称为“冲动”。冲动对PSP患者来说是高度危险的，在几个不同的方面。它可以让患者独自行走或走动，即使他们的平衡非常差并摔倒。窒息时吃得太快是另一种形式的冲动行为，可能会导致危及生命的胸部感染。冲动也会让照顾者和家人感到非常痛苦。目前还没有治愈PSP的方法，尽管包括冲动在内的一些症状可能是可以治疗的。然而，在我们对PSP患者脑细胞内发生的事情的了解与我们应该如何利用现有的治疗方法帮助PSP患者达到尽可能最佳的生活质量之间，仍然存在着很大的差距。因此，我们必须在基础研究和临床试验之间建立更好的“桥梁”。为了做到这一点，我们的团队将利用基础和临床神经科学中最先进的技术，利用成像、药理学和心理学的进步，进行一系列研究。我们将利用大脑化学物质去甲肾上腺素和行为控制之间的联系。去甲肾上腺素是由大脑中一个叫做蓝斑的小区域产生的。它作用于大脑的其他部分，特别是额叶，帮助控制行为，包括灵活的思维和行动控制。首先，我们将量化PSP患者蓝斑的变化，这些患者我们在临床上对他们的疾病进行了跟踪，然后将他们的大脑捐赠给剑桥脑库。其次，我们将测量活体PSP患者的蓝斑。蓝斑很小，用正常的脑扫描很难看到。我们将与来自马格德堡的Emrah Duzel教授合作，使用超高场磁共振成像的新技术(被称为“7特斯拉”)来测量蓝斑的大小和变性。他的团队已经开发出新的强大的工具来测量这个大脑区域。然后，我们将使用功能磁共振成像来测量蓝斑与额叶和其他大脑区域的连接情况。最后，我们将测量一种能增强去甲肾上腺素的特定药物(称为“托莫西汀”)对PSP患者冲动和认知的影响。我们的团队和合作者已经证明，这种药物可以改善相当大比例的帕金森氏症患者的冲动，并在冲动的动物模型中得到改善。它具有很好的耐受性，并被批准用于PSP的此类研究。我们相信，我们的研究结果将导致PSP冲动的临床试验，并最终将有助于提高PSP患者的生活质量。

Progressive Supranuclear Palsy (PSP) is as complex as it is devastating for patients and families, combining a kind of movement disorder that does not respond to standard therapies, choking, loss of speech, personality changes, and dementia. Research by our team has shown that in the UK around 7,000 people are living with PSP.Although physically very disabling, it is cognitive and personality changes in PSP that have the greatest impact on quality of life. Despite being slow and unresponsive for many activities, the same patients are often reckless and impulsive for actions that they do make. For example, a person living with PSP may "rush into things" and or "jump to conclusions" without thought for the consequences, or behave in a way that has high risks of falls or choking. These problems are also called "impulsivity". Impulsivity is highly dangerous for patients with PSP, in several different ways. It can make patients walking or moving around alone even though they have a very poor balance and fall. Eating too fast while choking is another form of impulsive behaviour which can lead to life-threatening chest infections. Impulsivity can also be highly distressing for carers and families. There is currently no cure for PSP, although some of the symptoms, including impulsivity, are potentially treatable. However, there is yet a big gap between our knowledge of what is happening in brain cells of patients with PSP and how we should use the available treatments to help people with PSP to achieve the best possible quality of life. We must therefore build better "bridges" between basic studies and clinical trials. To do this, our team will run a series of studies using the most advanced technologies in basic and clinical neuroscience, using advances in imaging, pharmacology, and psychology. We will take advantage of the link between a brain chemical, noradrenaline, and the control of behavior. Noradrenaline is made by a tiny region of the brain called the locus coeruleus. It acts on other parts of the brain, especially the frontal lobe, to help control behavior, including flexible thinking and action control. First, we will quantify the changes in the locus coeruleus, in PSP patients who we have followed through their illness in clinic and who then donated their brain to the Cambridge Brain Bank. Second, we will measure the locus coeruleus in living patients with PSP. The locus coeruleus is small, and hard to see with normal brain scans. Working with Prof Emrah Duzel from Magdeburg, we will use the new technology of ultra-high field magnetic resonance imaging (known as "7 Tesla") to measure the size and degeneration of the locus coeruleus. His groups have developed new robust tools to measure this brain region. We will then use functional magnetic resonance imaging to measure how well the locus coeruleus connects to the frontal lobe and other brain regions. Finally, we will measure the effects of a specific drug that enhances noradrenaline (called "atomoxetine") on impulsvity and cognition in PSP. This drug has been shown by our group and collaborators to improve impulsivity in a significant proportion of patients with Parkinson's disease, and in animal models of impulsivity. It is well tolerated, and approved for such research use in PSP. We believe that the results of our study will lead on to clinical trials for impulsivity in PSP and will eventually contribute to enhance the quality of life of people suffering from PSP.