MICA: How does the pedunculopone nucleus influence treatment responses in Parkinson's disease, and can it be targeted for new treatment strategies

MICA：脚核如何影响帕金森病的治疗反应，是否可以作为新治疗策略的目标

• 批准号: MR/X005267/1
• 负责人: Nicola Ray
• 金额: $ 104.31万
• 依托单位: Manchester Metropolitan University
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FX005267%2F1
• 关键词: MICA; How; does; pedunculopone; nucleus

Parkinson's disease (PD) is the second most common neurodegenerative disorder (second only to Alzheimer's disease). It is characterized by a progressive loss of motor ability over time. Partly due to the world's ageing population, PD is now one of the leading causes of disability worldwide. We know that PD is associated with a loss of dopamine cells in the brain. Treatment with dopamine replacement medications is highly effective in the early stages of the disease. Unfortunately however, over time, people become resistant to this medication, and develop new motor symptoms as a result. The symptoms that are particularly resistant to dopamine medications include balance impairment, and changes to the way people walk. As these complications progress, they impair quality of life, and eventually lead to falls and a loss of independence. We know that a small region of the brainstem, called the pedunculopontine nucleus (PPN), is involved in the control of balance and walking. We also know, primarily from work in animals, that the PPN can influence dopamine levels in the brain regions from which dopamine is lost in PD. However, we understand very little about the PPN and how it is connected with the rest of the brain in humans. As a result, therapies that have been developed to target the PPN have so far failed to meet our clinical expectations for improving balance and walking impairments. There are two recent technological advances that will help us to address this problem.First, new advances in how we image the brain have recently made it possible to examine the structure of the brain in more detail. Our study will apply these advances to investigate how the PPN might be targeted for new treatment strategies in PD. Second, we will take advantage of a new development in deep brain stimulation technology. Deep brain stimulation is a treatment for PD that applies electrical stimulation to the regions of brain that become disrupted by the disease. This is a highly effective treatment, but it does not work for everyone, and is extremely costly and invasive. When the deep brain stimulation electrodes are implanted in the brain however, researchers can record from the electrodes to understand more about how PD effects the brain. This approach has lead to the understanding that activity in the brain regions targeted by deep brain stimulation is aberrant in PD, and that this activity can be 'normalised' by dopamine medication. Until very recently these recordings could only be made around the time of the brain surgery, when people are generally immobile and fatigued. Now however, it is possible to record from the electrodes wirelessly, meaning people can fully recover from the surgery before taking part in research. As a result, we can now ask people to carry out some of the motor tasks that we know depend on the PPN, and record brain activity at the same time. By combining the information we can get about the brain from these two technologies when people are on and off their dopamine medications, we have the opportunity to examine how the PPN modifies how the brain uses dopamine to perform motor functions in the human for the first time. We can also examine how the PPN might participate in treatment responses to both dopamine replacement and deep brain stimulation. These findings will guide the development of new therapies that can target the PPN, and will enable us to personalise current treatment approaches to improve their effectiveness

帕金森病（PD）是第二常见的神经退行性疾病（仅次于阿尔茨海默病）。其特征在于随着时间的推移运动能力逐渐丧失。部分由于世界人口老龄化，PD现在是全球残疾的主要原因之一。我们知道PD与大脑中多巴胺细胞的损失有关。多巴胺替代药物治疗在疾病的早期阶段非常有效。然而，不幸的是，随着时间的推移，人们对这种药物产生抗药性，并因此产生新的运动症状。对多巴胺药物特别耐药的症状包括平衡障碍和人们走路方式的改变。随着这些并发症的进展，它们会损害生活质量，并最终导致福尔斯跌倒和丧失独立性。我们知道，脑干的一个小区域，称为脚桥核（PPN），涉及平衡和行走的控制。我们还知道，主要是从动物的工作中，PPN可以影响PD中多巴胺丢失的大脑区域的多巴胺水平。然而，我们对PPN以及它如何与人类大脑的其他部分连接知之甚少。因此，迄今为止，针对PPN开发的疗法未能满足我们改善平衡和行走障碍的临床期望。最近有两项技术进步可以帮助我们解决这个问题：第一，我们对大脑成像的新进展使我们有可能更详细地检查大脑的结构。我们的研究将应用这些进展来研究PPN如何成为PD新治疗策略的靶点。其次，我们将利用脑深部电刺激技术的新发展。脑深部电刺激是一种治疗PD的方法，它将电刺激应用于被疾病破坏的大脑区域。这是一种非常有效的治疗方法，但它并不适用于所有人，而且成本极高且具有侵入性。然而，当深部脑刺激电极植入大脑时，研究人员可以从电极记录更多关于PD如何影响大脑的信息。这种方法使人们认识到，脑深部刺激所针对的大脑区域的活动在PD中是异常的，并且这种活动可以通过多巴胺药物“正常化”。直到最近，这些记录只能在脑部手术前后进行，当时人们通常是不动和疲劳的。然而，现在可以通过无线方式从电极记录，这意味着人们可以在参加研究之前从手术中完全恢复。因此，我们现在可以要求人们执行一些我们知道依赖于PPN的运动任务，同时记录大脑活动。通过结合我们可以从这两种技术中获得的关于大脑的信息，当人们服用和停用多巴胺药物时，我们有机会研究PPN如何改变大脑如何使用多巴胺来执行人类的运动功能。我们还可以研究PPN如何参与多巴胺替代和脑深部电刺激的治疗反应。这些发现将指导针对PPN的新疗法的开发，并使我们能够个性化目前的治疗方法，以提高其有效性