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

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.

Chronic Fatigue Syndrome (CFS) is a debilitating disease that can affect all ages and profoundly influences a sufferer's ability to function. Despite its impact, the cause of CFS remains unknown and there are no effective treatments. One consistent theme in the CFS literature is of compromise of the autonomic nervous system which has led to the concept that abnormality of regulation of the autonomic nervous system (autonomic dysfunction (AD)) underpins the pathogenesis and/or clinical expression of CFS. AD has been associated with cognitive impairment and risk of cognitive decline in non-CFS groups. Defining the pathogenesis of AD and its relationship with cognitive impairment would be of immense value for both the study of the pathogenesis and treatment of CFS, and the clinical management of fatigued patients.
Hypothesis Autonomic dysfunction in CFS arises dues to combination of central ('upstream') and peripheral ('downstream') abnormalities in blood pressure regulation. This ledas to symptoms of brain hypoperfusion which is a cause of cognitive dysfunction. The aim of this study is to define the underlying physiological abnormalities that lead to autonomic dysfunction in CFS and its relationship with cognitive impairment. .
Methodology Pathogenesis of AD will be determined using novel state of the art MR technologies developed for this application in CFS patients with an autonomic phenotype (with newly diagnosed and established disease) compared to CFS without autonomic phenotype and sedentary controls. The relationship between AD and cognitive impairment will be explored in a proof of concept intervention study and data modelled using a systems approach.
Deliverables Having a comprehensive understanding of the pathogenesis of AD in CFS and its relationship with cognitive impairment will lead to targeted clinical trials that will improve autonomic symptoms, enhance functional ability and reduce cognitive impairment.

The proposed project has significant potential for impact within the CFS patient population and amongst those who care for CFS patients, with a clear and transparent route to that impact being realised. The potential impacts of the project, and the routes to realisation are as follows.

1. DETERMINATION OF THE PATHOGENESIS OF AUTONOMIC DYSFUNCTION IN CFS PATIENTS TO WILL ALLOW APPLICATION OF TARGETED EFFECTIVE TREATMENTS IN CLINICAL TRIALS: Autonomic dysfunction and its associated symptoms are a frequent finding in over 80% of those with CFS. Understanding the physiological basis of autonomic dysfunction will allow us to develop appropriate treatments (which might already be available and established in the treatment of autonomic dysfunction - but applied for the first time to CFS). The availability of treatments to improve autonomic dysfunction have the greatest potential likelihood of benefit for improving functional ability in patients with CFS and therefore the greatest impact. Clinical trials of therapies will need to be further validated for broad clinical practice in a large scale HTA funded trial involving appropriate subject screening.

2.VALIDATION OF CLINICALLY IMPORTANT BIOMARKERS FOR CFS: One of the issues which has limited research in CFS to date is the lack of valid biomarkers for key processes other than perception of fatigue itself. This project will further validate our existing autonomic assessments and MR-based biomarkers for haemodynamic responses to dynamic stressors such as the valsalva and will, using a systems modelling approach, add additional data of intergrated responses to key functional abnormality and its response to modulation. Utilisation of these biomarkers in future large scale clinical trials such as an HTA trial of autonomic modulation by tilt training will validate their use in this setting.

3.EVALUATION OF THE CLINICAL CONSEQUENCES OF AUTONOMIC DYSFUNCTION IN CFS; MOST NOTABLY COGNITIVE IMPAIRMENT: A key element of this proposal is expansion of our pilot work which has confirmed that cognitive symptoms are prevalent in CFS, associates with objectively assessed cognitive impairment and that these associate (as in other autonomic associated diseases) with actual brain abnormalities on MRI the severity of which associates in our pilot studies with autonomic symptoms. Recognition of the presence of objectively measured abnormalities in CFS that associate with markers that can successfully be modulated is a paradigm shift in our understanding of this disease. By performing our studies in CFS patients with early and established disease we will begin to explore the natural history of cognitive problems in CFS and the direction of the relationship which will be further 'teased' appart in a proof of concept intervention study. The value of autonomic modulation using non-invasive tilt training will be established in the context of this project through its ability to determine change in cognitive function. Further clarification of the effectiveness of specific autonomic interventions will be trialled in large scale applications to the HTA.

4. DEVELOPMENT OF A CRITICAL MASS OF RESEARCHERS WITH SPECIFIC EXPERTISE IN THEIR OWN AREA APPLIED TO UNDERSTANDING THE PATHOPHYSIOLOGY OF CFS
The proposed project will further enhance the reputation of Newcastle as a Fatigue Research Centre and encourage researchers to work in this important area.

This project will therefore have impact for patients immediately in terms of defining the pathogenesis of autonomic dysfunction, demonstration (we anticipate) of benefit in selected patients from tilt training, with the development of logical paradigms for subject identification in the future which will facilitate the application of specific interventions in practice. It will also have longer term impact in developing key underpinning technologies for the medium and long term development of novel drug and other intervention based approaches.