Understanding the pathogenesis of autonomic dysfunction in chronic fatigue syndrome and its relationship with cognitive impairment

慢性疲劳综合征（CFS）发生在欧洲人口的0.2-0.4%，可影响所有年龄段，目前其病因尚不清楚。自主神经系统异常在超过四分之三的CFS患者中被识别，并且可能是CFS和其他慢性疾病中疲劳症状的特征生理介质。自主神经系统功能障碍的特征是站立时出现头晕和头晕的症状，我们已经证明，近90%的CFS患者都有这些症状，而且这些症状的严重程度已经被证明可以预测CFS患者的功能（比疲劳的严重程度更重要）。尽管如此，自主神经功能障碍在慢性疲劳综合征患者中产生的机制尚不清楚，因此治疗受到限制。这项研究填补了这一空白，通过使用新的方法探索导致CFS自主神经功能障碍的原因，特别是它是上游（与控制自主神经系统的大脑中心异常有关）还是下游（由于外周体积或血管问题）的起源。在非慢性疲劳综合症疾病中，自主神经功能障碍也被证明与认知障碍有关。超过80%的CFS患者描述了记忆和注意力问题，因此本研究还将确定自主神经功能障碍与CFS患者常见的这些认知问题之间的关系，以及CFS患者自主神经功能障碍的改善是否会导致认知功能的改变。利用这一综合研究创造的巨大资源，该项目将利用创新的系统方法开发诊断性生物标志物。该计划有两个互补的阶段：1)一项探索性研究，利用突破性的动态MR模式，研究CFS的大脑功能，以及这与自主和认知功能的关系。2)结合多个工作包的下游研究，以确定心脏和血管功能在自主神经功能障碍中的相对贡献。3)干预阶段，将在“概念验证”研究中检查CFS中自主功能和认知功能之间关系的方向。4)利用独特的数据集探索参数之间的相互关系及其生物标志物开发潜力的系统医学建模方法。了解导致慢性疲劳综合症患者自主神经功能障碍的机制将是一个范式转变。该项目将为申请人和其他人的研究奠定基础，这些研究将使未来的一套诊断工具、基于功能障碍的系统解释、新一代疗法和最终的临床方案成为可能，这些方案将对抗一系列疾病中支撑疲劳的生物过程。本提案将使用最先进的技术，如动态脑功能磁共振成像来测量自主神经系统压力源valsalva动作（被认为是大脑自动调节的测试）期间的脑血流量，以了解导致自主神经功能障碍和相关认知障碍的机制，这些机制在大多数CFS患者中看到。本研究将在CFS患者队列中进行，这些患者已完全确定特征，并将进行随访，以探索自主神经功能调节是否会改变认知症状。该项目将通过提高我们对CFS中自主神经功能障碍的产生及其与认知功能的关系的理解，直接使患者受益。这种加深的理解将导致针对临床试验的靶向治疗的发展，旨在扭转这些异常。

Chronic fatigue syndrome (CFS) occurs in 0.2-0.4% of Europe's population, can affect all ages and currently its cause is unclear. Abnormality of the autonomic nervous system is recognised in over three quarters of those with CFS and is a plausible physiological mediator of the symptoms that are characteristic of CFS and fatigue in other chronic diseases. Autonomic nervous system dysfunction is characterised by symptoms of dizziness and lightheadedness when standing up, symptoms that we have shown to be present in nearly 90% of people with CFS, and the severity of which have been shown to predict the ability of CFS patients to function (more so than the severity of fatigue). Despite this, the mechanisms by which autonomic dysfunction arises in those with chronic fatigue syndrome are not understood and as a result treatments limited. This study fills this gap by setting out to explore what leads to autonomic dysfunction in CFS using novel methodologies particularly whether it is upstream (related to abnormalities in centres in the brain that control the autonomic nervous system) or downstream (due to a peripheral volume or vascular problem) in origin. In non-CFS diseases autonomic dysfunction has also been shown to be associated with cognitive impairment. Over 80% of those with CFS describe problems with memory and concentration, so this study will also determine the relationship between autonomic dysfunction and these cognitive problems frequently found in those with CFS, and whether improving autonomic dysfunction in CFS leads to changes in cognitive function. Utilising the enormous resource created by this integrated study, the programme will look to develop diagnostic biomarkers using an innovative systems approach. The programme has two complementary phases: 1) an exploratory study that utilises ground breaking dynamic MR modalities that will allow study of brain function in CFS and how this relates to autonomic and cognitive function. 2) a downstream study which combines a number of work packages to define the relative contribution of cardiac and vascular function in autonomic dysfunction. 3) an intervention phase which will examine the direction of relationship between autonomic and cognitive function in CFS in a 'proof of concept' study. 4) a systems medicine modelling approach utilising the unique dataset to explore the interrelationships between parameters and their potential for biomarker development. Understanding the mechanisms that lead to autonomic dysfunction in those with CFS will be a paradigm shift. This programme will lay a foundation for research by the applicant and others that will enable a future set of diagnostic tools, system based explanations of dysfunction, a new generation of therapies and ultimately clinical protocols that will counter the biological processes that underpin fatigue in a range of diseases. This proposal will use state of the art techniques such as dynamic brain FMRI to measures cerebral blood flow during the autonomic nervous system stressor of the valsalva manoeuvre (considered to be a test of cerebral autoregulation) to understand the mechanisms that lead to autonomic dysfunction and the associated cognitive impairment seen in the majority of those with CFS. This study will be performed in a cohort of CFS patients who have been fully characterised and who will be followed up to explore whether cognitive symptoms change when autonomic function is modulated. This project will directly benefit patients through improving our understanding of how autonomic dysfunction arises in CFS and how it associates with cognitive function. This enhanced understanding will lead to the development of targetted appropriate treatments for clinical trials which will be aimed at reversing these abnormalities.