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

Lead Research Organisation: Newcastle University
Department Name: Institute for Ageing and Health

Abstract

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.

Technical Summary

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.

Planned Impact

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.

Publications

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Clark JE (2018) Rethinking childhood adversity in chronic fatigue syndrome. in Fatigue : biomedicine, health & behavior

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Hale M (2012) Fatigue in primary biliary cirrhosis. in BMJ (Clinical research ed.)

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Hester KL (2012) Fatigue in bronchiectasis. in QJM : monthly journal of the Association of Physicians

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Newton JL (2012) Managing fatigue in the syncope unit. in Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology

 
Description Action for ME
Amount £25,000 (GBP)
Organisation Action for M.E. 
Sector Charity/Non Profit
Country United Kingdom
Start 04/2013 
End 03/2016
 
Description Action for ME
Amount £11,000 (GBP)
Funding ID n/a 
Organisation Action for M.E. 
Sector Charity/Non Profit
Country United Kingdom
Start 08/2012 
End 03/2014
 
Description ME Association
Amount £18,000 (GBP)
Funding ID n/a 
Organisation ME Association 
Sector Charity/Non Profit
Country United Kingdom
Start 04/2014 
End 12/2014
 
Description ME Research UK
Amount £100,000 (GBP)
Organisation ME Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 12/2013 
End 12/2015
 
Description NIHR RCF
Amount £16,000 (GBP)
Funding ID N/A 
Organisation Newcastle upon Tyne Hospitals NHS Foundation Trust 
Sector Public
Country United Kingdom
Start 10/2014 
End 09/2015
 
Title Measuring liver volume via MR in response to the autonomic stressor of the valsalva 
Description We have developed a novel MR methodology that allows us to measure liver volume in response to the autonomic stressor of the valsalva manoeuvre. Using this technique we have been exploring the role of the liver in blood pressure homeostasis in those with chronic fatigue syndrome. 
Type Of Material Physiological assessment or outcome measure 
Year Produced 2014 
Provided To Others? Yes  
Impact We have begun to explore the role of the liver in blood pressure control in CFS but this method has important applications in other fields that consider blood pressure physiology. 
 
Description Altogether Better and NHS England 
Organisation Altogether Better
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution Altogether Better is funded by the Big Lottery and works with NHS England NE We have been working with them to develop Health Champions who are patients with CFS who will work with us in the clinic in order to enhance the experience of those who come to our clinic.
Collaborator Contribution They have facilitated the work shops and will train and lead the health champions
Impact Health champions identified and invited to a training session
Start Year 2014
 
Description Anne McArdle - Liverpool 
Organisation University of Liverpool
Country United Kingdom 
Sector Academic/University 
PI Contribution Recent visits to discuss collaborative work around muscle function
Collaborator Contribution Initial discussions
Impact none yet
Start Year 2014
 
Description Cross MRC cfs Collaboration 
Organisation Newcastle University
Country United Kingdom 
Sector Academic/University 
PI Contribution Cross collaboration between the two MRC grants awarded to Newcastle from the CFS call has allowed us to maximise the impact from both grants. We have been working very much together in order to ensure that we do not miss opportunities by the greater of the whole.
Collaborator Contribution see above
Impact We have just been awarded funding from NIHR RCF to allow us to develop a data resource that maximises the opportunities for analysis across both grants.
Start Year 2013
 
Description Faisel Khan - Dundee 
Organisation University of Dundee
Country United Kingdom 
Sector Academic/University 
PI Contribution Samples collected as part of the MRC funded cohort have been supplied to collaborators in Dundee
Collaborator Contribution Use of samples
Impact Faisel acquired an ME R UK grant to underpin the lab costs for the analysis of the samples
Start Year 2014
 
Description Griffiths University Gold Coast 
Organisation Griffith University
Country Australia 
Sector Academic/University 
PI Contribution Visited Griffiths University and obtained funding from URC to support a post doc exchange. Samples shared
Collaborator Contribution See above JN given status as adjunct professor
Impact Not currently
Start Year 2013
 
Description Karl Morten Oxford 
Organisation University of Oxford
Department Department of Chemistry
Country United Kingdom 
Sector Academic/University 
PI Contribution Visited Oxford group and PhD student has been down to learn new techniques which she has now bought back to Newcastle
Collaborator Contribution See above
Impact None as yet
Start Year 2014
 
Description Northumbria University 
Organisation Northumbria University
Department Sleep Research Centre
Country United Kingdom 
Sector Academic/University 
PI Contribution Working closely together and enhancing expertise
Collaborator Contribution Equal partnership playing to each others strengths
Impact Action for ME & ME association grants - currently working up an EME application
Start Year 2012
 
Description Pawel Zalewski 
Organisation Nicolaus Copernicus University in Torun
Country Poland 
Sector Academic/University 
PI Contribution Development of autonomic testing algorhithms that ensure adequate data cleaning
Collaborator Contribution see above
Impact Pawel has set up a study in Poland that replicates work performed in Newcastle. We are writing this up currently.
Start Year 2012
 
Description UK CFS Research Collaborative 
Organisation UK CFS Research Collaborative
Country United Kingdom 
Sector Academic/University 
PI Contribution Inaugural member of the new UK CFS Research Collaborative
Collaborator Contribution Executive member and our team participated in the launch event.
Impact On-going positive interaction with the scientific community and patient groups. Dissemination of research outputs and overall positive vibe.
Start Year 2013
 
Description Action for ME AGM Nov 9th 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Review of Action for ME blog

Approached by a number of other charities who are interested in meeting me
Year(s) Of Engagement Activity 2013
 
Description Action for ME visit Nov 5th 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Type Of Presentation Paper Presentation
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Further funding promised

CEO blog from Action for ME which was extremely positive about our work www.actionfor me.org
Year(s) Of Engagement Activity 2013
 
Description Advisor to POTS UK 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Participants in your research and patient groups
Results and Impact I provide comment upon medical issues and have participated in the guideline development by DWP for PoTS

see above
Year(s) Of Engagement Activity 2013
 
Description Altogether better - NHS England 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact This is a recent opportunity that has arisen to work with the Altogether better team and NHS England.

We have held 1 design group to date, identified health champions and are working towards a training session for health champions in December.
Year(s) Of Engagement Activity 2014
 
Description BACME 2013 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Health professionals
Results and Impact Talk to national meeting

None yet
Year(s) Of Engagement Activity 2013
URL http://www.bacme.org.uk
 
Description BOARD MEMBER IACFSME 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact I am the only European representative on the Board of IACFS/ME - this organisation comments upon and informs international policy, it is a non-profit organisation based in the US. I am one of only 2 clinicians on the board. The newsletter to which I contribute is e-blasted to over 1000 members worldwide 4 times a year.

see above
Year(s) Of Engagement Activity 2014
 
Description ME North East conference 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Conference organised by the local patient support group ME North East to allow us to disseminate our research

increased awareness of research going on in the NE
Year(s) Of Engagement Activity 2014
 
Description Medical Advisor to ME Research UK 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Advising on issues in the press and defining research strategy

Influencing policy and defining strategy
Year(s) Of Engagement Activity 2012
 
Description Mini medical school Newcastle 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Regional
Primary Audience Schools
Results and Impact >400 students registered for the event, great interaction - they particularly loved the patient we asked along to describe their experiences of CFS

Great questions - changed the perception of students regarding CFS as a disease
Year(s) Of Engagement Activity 2013
URL http://www.ncl.ac.uk/biomedicine/news/mms/
 
Description Royal College of Psychiatry Brighton 2014 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact well received

n/a
Year(s) Of Engagement Activity 2014
 
Description SNG Meeting 2013 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Regional
Primary Audience Postgraduate students
Results and Impact Invited lecture

Contacted by researcher about establishing collaboration
Year(s) Of Engagement Activity 2013
 
Description UK CFSME Research Collaborative 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Changed perception of CFS

Annual conference
Year(s) Of Engagement Activity 2012
 
Description liverpool university 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Potential collaboration

see above
Year(s) Of Engagement Activity 2014
 
Description telegraph article 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Front page article in Telegraph with coverage in Daily Mail regarding paper published in BMJ OPEN

Increased awareness
Year(s) Of Engagement Activity 2014