Defining the microstructural basis of tremor in vivo to identify novel therapeutic targets

定义体内震颤的微观结构基础以确定新的治疗靶点

• 批准号: MR/W030519/1
• 负责人: Amit Batla
• 金额: $ 32.4万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FW030519%2F1
• 关键词: Defining; microstructural; basis; tremor; vivo

Tremor, a shaking or trembling in part the body that cannot be controlled, is a common and disabling condition that affects many people. Common causes of tremor include Essential Tremor Syndrome (ET), Parkinson's disease (PD) and a rarer condition called dystonia. It can significantly impact day to day activities and quality of life, and is highly variable between sufferers, posing a challenge both with diagnosis and treatment. Half of all tremor patients do not respond to any of the medication currently available. In these individuals, more invasive treatments are often considered such as deep brain stimulation (DBS) or focused ultrasound, that interrupt the brain circuits that carry the abnormal tremor signals, often targeting a deep region known as ventralis intermedius nucleus of the thalamus (Vim). However, there are many other bran areas and networks involved in the generation and propagation of tremor. A better understanding of these could allow non-invasive "neuromodulation" treatments in the future, using targeted electrical stimulation to dampen the abnormal brain signals. To develop better treatments for tremor, a greater understanding of the neural circuits that underpin tremor in humans is required. This requires mapping how focal brain regions, and the connections between these, are altered in tremor sufferers, to better understand how different patterns of damage to these structures modify tremor properties such as body regions affected, severity or response to treatment.Some parts of the brain known to be affected in tremor, such as Vim, cannot be seen on routine MRI. Advanced MRI techniques, using quantitative MRI (qMRI), not only allow these areas to be defined but also provide measurements that reflect different properties of brain tissue and allow the connections between region to be mapped. Furthermore, it is now possible to use openly available "big data" resources, such as the UK Biobank, to link ("annotate") focal changes in brain regions to the genes that are related to these brain structures, and in doing so allow us to identify possible biochemical pathways that may represent avenues for future treatments. This study will focus on ET and PD, the most common causes of tremor with the following objectives1. To map the changes in brain tissue associated with different tremor properties using qMRI 2. To map connections between regional brain changes and identify genes associated with these brain structures3. To use these maps to identify potential treatment options, using either neuromodulation or drugs, that are targeted to specific tremor subtypes/propertiesThe study will run over three years and use data from 40 people with PD tremor and 70 normal people, from an existing study led by Dr Lambert(Quantitative MRI for Anatomical Phenotyping in Parkinson's disease (qMAP-PD). We will add 40 additional participants with tremor who will undergo the same assessments as qMAP-PD study. We will characterize the tremor using standardized scales and advanced video recording of tremors with a smart watch like device to generate detailed tremor recordings. Detailed qMRI of will allow us to identify and map the structures and networks that give rise to the different tremor characteristics. Once we have identified brain regions, we will link these to genes based on an existing resource (UK biobank). In this process we will mark or annotate these genes on brain regions (gene annotation). Using existing knowledge, we will identify factors that influence function in these regions. This will allow identification of potential new medical treatment options from existing knowledge resources. This combined approach will deliver three key outputs with wide applications to direct precision therapies for tremor: (1) Maps of the brain regions that underpin tremor characteristics (2) Potential targets for modulation through electrical stimulation or focused ultrasound and (3) New treatment options for tremor

震颤是一种无法控制的身体部分颤抖或颤抖，是一种影响许多人的常见且致残的疾病。震颤的常见原因包括特发性震颤综合征 (ET)、帕金森病 (PD) 和一种称为肌张力障碍的罕见疾病。它可以显着影响日常活动和生活质量，并且患者之间差异很大，给诊断和治疗带来挑战。一半的震颤患者对目前可用的任何药物都没有反应。对于这些个体，通常会考虑更具侵入性的治疗，例如深部脑刺激 (DBS) 或聚焦超声，它们会中断携带异常震颤信号的大脑回路，通常针对称为丘脑腹中间核 (Vim) 的深层区域。然而，还有许多其他麸皮区域和网络参与震颤的产生和传播。更好地了解这些可以在未来实现非侵入性“神经调节”治疗，使用有针对性的电刺激来抑制异常的大脑信号。为了开发更好的震颤治疗方法，需要更好地了解人类震颤的神经回路。这需要绘制震颤患者的大脑焦点区域以及这些区域之间的连接如何改变的图谱，以更好地了解这些结构的不同损伤模式如何改变震颤特性，例如受影响的身体区域、严重程度或对治疗的反应。已知受震颤影响的大脑某些部分（例如 Vim）无法在常规 MRI 中看到。使用定量 MRI (qMRI) 的先进 MRI 技术不仅可以定义这些区域，还可以提供反映脑组织不同属性的测量结果，并绘制区域之间的连接图。此外，现在可以使用公开可用的“大数据”资源，例如英国生物库，将大脑区域的焦点变化与这些大脑结构相关的基因联系起来（“注释”），从而使我们能够识别可能代表未来治疗途径的生化途径。本研究将重点关注 ET 和 PD（震颤最常见的原因），其目标如下1。使用 qMRI 绘制与不同震颤特性相关的脑组织变化 2。绘制区域大脑变化之间的联系并识别与这些大脑结构相关的基因3。为了使用这些图来确定潜在的治疗方案，使用针对特定震颤亚型/特性的神经调节或药物。该研究将运行三年多的时间，并使用来自 Lambert 博士领导的一项现有研究（帕金森病解剖表型定量 MRI (qMAP-PD)）的 40 名 PD 震颤患者和 70 名正常人的数据。我们将增加 40 名额外的震颤参与者，他们将接受相同的治疗 qMAP-PD 研究的评估。我们将使用标准化尺度和先进的震颤视频记录来表征震颤，并使用类似智能手表的设备生成详细的震颤记录。详细的 qMRI 将使我们能够识别和绘制引起不同震颤特征的结构和网络。一旦我们确定了大脑区域，我们就会将它们与基于现有资源（英国生物库）的基因联系起来。在这个过程中我们会对这些基因进行标记或注释 关于大脑区域（基因注释）。利用现有知识，我们将确定影响这些区域功能的因素。这将使我们能够从现有的知识资源中识别出潜在的新的医疗选择。这种组合方法将提供三个具有广泛应用的关键成果，以指导震颤的精准治疗：（1）支持震颤特征的大脑区域图（2）通过电刺激或聚焦超声进行调节的潜在目标以及（3）震颤的新治疗方案

项目成果

Outcome Measures for Disease-Modifying Trials in Parkinson's Disease: Consensus Paper by the EJS ACT-PD Multi-Arm Multi-Stage Trial Initiative.

• DOI: 10.3233/jpd-230051
• 发表时间: 2023
• 期刊: JOURNAL OF PARKINSONS DISEASE
• 影响因子: 5.2
• 作者: Gonzalez-Robles, Cristina;Weil, Rimona S.;van Wamelen, Daniel;Bartlett, Michele;Burnell, Matthew;Clarke, Caroline S.;Hu, Michele T.;Huxford, Brook;Jha, Ashwani;Lambert, Christian;Lawton, Michael;Mills, Georgia;Noyce, Alastair;Piccini, Paola;Pushparatnam, Kuhan;Rochester, Lynn;Siu, Carroll;Williams-Gray, Caroline H.;Zeissler, Marie-Louise;Zetterberg, Henrik;Carroll, Camille B.;Foltynie, Thomas;Schrag, Anette
• 通讯作者: Schrag, Anette