Experimental medicine approach linking brain and peripheral immune mechanisms mediating sickness behaviours in people with rheumatoid arthritis

连接大脑和外周免疫机制介导类风湿性关节炎患者疾病行为的实验医学方法

• 批准号: MR/S035753/1
• 负责人: Jonathan Cavanagh
• 金额: $ 153.19万
• 依托单位: University of Glasgow
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FS035753%2F1
• 关键词: Experimental; medicine; approach; linking; brain

Sickness behaviours - including mood change and fatigue - that occur in people with immune-mediated inflammatory disorders (IMIDs) such as rheumatoid arthritis (RA) are a major unmet clinical need. Behaviours of this kind have a significant additional negative impact on prognosis, therapeutic response and outcomes. Importantly, they are consistently among the most commanding of patients' concerns. Therapeutic progress in this area requires a more profound understanding of the mechanisms underpinning the symptoms Here we propose to use an exquisitely specific intervention of proven benefit in RA, targeting TNF, to leverage a mechanistic understanding of the peripheral immune to brain communications that drive sickness behaviour. We will combine the administration of a clinically indicated therapy with highly innovative neuroimaging technologies to obtain mechanistic data in humans that has hitherto only been available in animal studies. The proposal will build on a small number of prior studies that have used neuroimaging to show abnormal brain pathways in the context of IMIDs such as RA and changes in these neuroimaging parameters following TNF inhibition. A putative mechanism linking peripheral inflammatory proteins to sickness behaviour, implicated by extensive pre-clinical and animal studies, is monocyte ingress to the brain and subsequent neural change effected by monocyte-derived TNF, most notably via glutamatergic action. Thus using ultra high-field (7T) MRI and MRS alongside innovative SPECT-CT to measure CNS infiltration by circulating labelled monocytes, we will test the following hypotheses: i) Anti-TNF therapy will effect changes in brain network connectivity and glutamate quantification in the brain.ii) RA patients will show changes in brain network connectivity and glutamate quantification correlated with sickness behaviours.iii) RA patients will show changes in monocyte infiltration to the brain that are correlated with sickness behaviours.These imaging endpoints (plus secondary cognitive-behavioural, clinical and peripheral immune endpoints) will be measured at baseline and 4 weeks later in up to 50 patients with RA, randomised 1:1 to treatment with anti-TNF antibody or placebo infusion. The baseline data will allow us to test the two key hypotheses of peripheral monocyte infiltration and glutamatergic excitoxicity as mechanisms contributing to sickness behaviour. TNF inhibitor administration will address our third hypothesis.Together this study will provide insight to the mechanisms that sub-serve sickness behaviours, and thereby new tools and targets to support future development of innovative drug treatments for such behaviours in RA and other IMIDs.

类风湿性关节炎 (RA) 等免疫介导的炎症性疾病 (IMID) 患者出现的疾病行为（包括情绪变化和疲劳）是未满足的主要临床需求。此类行为对预后、治疗反应和结果具有显着的额外负面影响。重要的是，它们始终是患者最关心的问题之一。这一领域的治疗进展需要对症状背后的机制有更深入的了解。在这里，我们建议使用一种经过证明对 RA 有益的精确特异性干预措施，以 TNF 为目标，以利用对驱动疾病行为的外周免疫与大脑通讯的机制理解。我们将把临床指示疗法的管理与高度创新的神经影像技术相结合，以获得迄今为止仅在动物研究中获得的人类机制数据。该提案将建立在少量先前研究的基础上，这些研究使用神经影像学来显示 IMID 背景下的异常大脑通路（例如 RA）以及 TNF 抑制后这些神经影像学参数的变化。广泛的临床前和动物研究表明，将外周炎症蛋白与疾病行为联系起来的一种推定机制是单核细胞进入大脑以及随后由单核细胞衍生的 TNF 引起的神经变化，最显着的是通过谷氨酸能作用。因此，使用超高场 (7T) MRI 和 MRS 以及创新的 SPECT-CT 来测量循环标记单核细胞的 CNS 浸润，我们将测试以下假设： i) 抗 TNF 治疗将影响大脑网络连接和谷氨酸定量的变化ii) RA 患者将表现出与疾病行为相关的大脑网络连接和谷氨酸定量的变化。iii) RA 患者将表现出与疾病行为相关的单核细胞浸润到大脑的变化这些影像学终点（加上次要认知行为、临床和外周免疫终点）将在基线时和 4 周后对最多 50 名 RA 患者进行测量，按 1:1 随机分配接受抗 TNF 抗体治疗或安慰剂输注。基线数据将使我们能够测试外周单核细胞浸润和谷氨酸兴奋毒性作为导致疾病行为的机制的两个关键假设。 TNF 抑制剂的给药将解决我们的第三个假设。这项研究将共同​​深入了解促进疾病行为的机制，从而提供新的工具和目标来支持未来针对 RA 和其他 IMID 中此类行为的创新药物治疗的开发。

项目成果

Delirium and the risk of developing dementia: a cohort study of 12 949 patients.

• DOI: 10.1136/jnnp-2022-328903
• 发表时间: 2022-05-23
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Reduced circulating BMP9 and pBMP10 in hospitalized COVID-19 patients.

• DOI: 10.1002/pul2.12192
• 发表时间: 2023-01
• 期刊: PULMONARY CIRCULATION
• 影响因子: 2.6
• 作者: Dunmore, Benjamin J.;Upton, Paul D.;Auckland, Kate;Samanta, Romit J.;Lyons, Paul A.;Smith, Kenneth G. C.;Graf, Stefan W.;Summers, Charlotte;Morrell, Nicholas
• 通讯作者: Morrell, Nicholas

Peripheral inflammation is associated with alterations in brain biochemistry and mood: evidence from in vivo proton magnetic resonance spectroscopy study

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• DOI: 10.1515/pac-2022-1119
• 发表时间: 2023
• 期刊: Pure and Applied Chemistry
• 影响因子: 1.8
• 作者: Mumuni A

Cognitive Function in People With Familial Risk of Depression.

有家族抑郁风险的人的认知功能。

• DOI: 10.1001/jamapsychiatry.2023.0716
• 发表时间: 2023
• 期刊: JAMA psychiatry
• 影响因子: 25.8
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Regulation of ICAM-1 in human neutrophils

人中性粒细胞中 ICAM-1 的调节

• DOI: 10.17863/cam.107511
• 发表时间: 2024
• 作者: Farahi N