A new noradrenergic strategy to treat Impulsivity in Progressive Supranuclear Palsy

治疗进行性核上性麻痹冲动的新去甲肾上腺素能策略

• 批准号: MR/P01271X/1
• 负责人: James Rowe
• 金额: $ 88.42万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FP01271X%2F1
• 关键词: new; noradrenergic; strategy; treat; Impulsivity

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.

进行性核上性麻痹（PSP）是一种复杂的疾病，对患者和家庭来说是毁灭性的，它结合了一种对标准治疗无效的运动障碍、窒息、语言丧失、性格改变和痴呆。我们团队的研究表明，在英国大约有7000人患有PSP。虽然在身体上非常残疾，但PSP患者的认知和性格变化对生活质量的影响最大。尽管对许多活动反应缓慢，反应迟钝，但同样的病人往往对他们所做的事情鲁莽和冲动。例如，患有PSP的人可能会“草率行事”或“草率下结论”而不考虑后果，或者以一种有很高摔倒或窒息风险的方式行事。这些问题也被称为“冲动”。冲动对PSP患者来说是非常危险的，表现在几个不同的方面。它可以使病人独自行走或四处走动，即使他们的平衡能力很差，也会摔倒。噎住时吃得太快是另一种冲动行为，会导致危及生命的胸部感染。冲动也会给照顾者和家庭带来很大的痛苦。目前还没有治愈PSP的方法，尽管包括冲动在内的一些症状是可以治疗的。然而，对于PSP患者的脑细胞发生了什么，以及我们应该如何使用现有的治疗方法来帮助PSP患者获得尽可能高的生活质量，我们的知识之间还有很大的差距。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”。为此，我们的团队将进行一系列研究，使用基础和临床神经科学领域最先进的技术，利用成像、药理学和心理学方面的先进技术。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，尤其是额叶，帮助控制行为，包括灵活的思维和行动控制。首先，我们将量化蓝斑座的变化，我们在临床跟踪了PSP患者的病情，然后将他们的大脑捐赠给剑桥脑库。其次，我们将测量活着的PSP患者的蓝斑座。蓝斑很小，用正常的脑部扫描很难看到。与来自马格德堡的Emrah Duzel教授合作，我们将使用超高场磁共振成像（称为“7特斯拉”）的新技术来测量蓝斑的大小和退化。他的团队已经开发出新的强大工具来测量这个大脑区域。然后，我们将使用功能性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，我们将测量一种增强去甲肾上腺素（称为“托莫西汀”）的特定药物对PSP患者冲动和认知的影响。我们的团队和合作者已经证明，这种药物可以改善很大比例帕金森病患者的冲动性，也可以改善冲动性的动物模型。它具有良好的耐受性，并被批准用于PSP的研究。我们相信，我们的研究结果将导致PSP患者冲动的临床试验，并最终有助于提高PSP患者的生活质量。

项目成果

A Deep Graph Neural Network Architecture for Modelling Spatio-temporal Dynamics in resting-state functional MRI Data

• DOI: 10.1101/2020.11.08.370288
• 发表时间: 2020-11
• 期刊: bioRxiv
• 作者: Tiago Azevedo;Alexander Campbell;R. Romero-García;L. Passamonti;R. Bethlehem;P. Lio’;N. Toschi

Artificial Intelligence Applications and Innovations - 15th IFIP WG 12.5 International Conference, AIAI 2019, Hersonissos, Crete, Greece, May 24-26, 2019, Proceedings

人工智能应用与创新 - 第 15 届 IFIP WG 12.5 国际会议，AIAI 2019，希腊克里特岛赫索尼索斯，2019 年 5 月 24-26 日，会议记录

• DOI: 10.1007/978-3-030-19823-7_40
• 发表时间: 2019
• 作者: Azevedo T