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.

疾病行为-包括情绪变化和疲劳-发生在免疫介导的炎症性疾病（IMID），如类风湿性关节炎（RA）的人是一个主要的未满足的临床需求。这种行为对预后、治疗反应和结果具有显著的额外负面影响。重要的是，它们始终是患者最关心的问题之一。在这一领域的治疗进展需要更深刻的理解的机制的基础症状在这里，我们建议使用一个精致的特定的干预证明在类风湿关节炎的好处，靶向肿瘤坏死因子，利用机械的理解外周免疫大脑通信驱动疾病的行为。我们将联合收割机与高度创新的神经影像学技术相结合，以获得迄今为止仅在动物研究中获得的人体机制数据。该提案将建立在少量先前研究的基础上，这些研究使用神经成像来显示IMID（如RA）背景下的异常脑通路以及TNF抑制后这些神经成像参数的变化。广泛的临床前和动物研究表明，一种将外周炎性蛋白与疾病行为联系起来的假定机制是单核细胞进入大脑，随后受单核细胞衍生的TNF影响的神经变化，最明显的是通过神经元能作用。因此，使用超高场（7 T）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，我们将检验以下假设：i）抗TNF治疗将影响脑网络连接和脑中谷氨酸定量的变化。ii）RA患者将显示与疾病行为相关的脑网络连接和谷氨酸定量的变化。这些影像学终点（加上次要认知行为、临床和外周免疫终点）将在基线和4周后在多达50名RA患者中进行测量，这些患者以1：1的比例随机接受抗TNF抗体或安慰剂输注治疗。基线数据将使我们能够测试两个关键的假设，外周单核细胞浸润和神经元兴奋毒性的机制有助于疾病的行为。TNF抑制剂管理将解决我们的第三个hypothesis.Together，这项研究将提供深入了解的机制，subserve疾病的行为，从而新的工具和目标，以支持未来的开发创新的药物治疗类风湿关节炎和其他IMID的行为。

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
• 期刊: Journal of neurology, neurosurgery, and psychiatry

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

周围炎症与大脑生化和情绪的改变有关：来自体内质子磁共振波谱研究的证据

• 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

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

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
• 作者: Cullen B