Research: The SARS-CoV-2 receptor ACE2 in ME/CFS

Posted on 09/08/2021 by wames

The SARS-CoV-2 receptor angiotensin-converting enzyme 2 (ACE2) in  Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: a meta-analysis of public DNA methylation and gene expression data, by João Malato, Franziska Sotzny, Sandra Bauer, Helma Freitag, André Fonseca, Anna D Grabowska, Luís Graça, Clara Cordeiro, Luís Nacul, Eliana M Lacerda, Jesus Castro-Marrero, Carmen Scheibenbogen, Francisco Westermeier, Nuno Sepúlveda in Heliyon 2021 Jul 29;7(8):e07665 [doi: 10.1016/j.heliyon.2021.e07665]

 

Research abstract: 

Protein_ACE2_PDB_1r42

People with myalgic encephalomyelitis/ chronic fatigue syndrome (ME/CFS) often report a high frequency of viral infections and flu-like symptoms during their disease course. Since this reporting is in line with different immunological abnormalities and altered gene expression profiles observed in the disease, we aimed to explore whether the expression of the human angiotensin-converting enzyme-2 (ACE2), the major cell entry receptor for SARS-CoV-2, is also altered in this neglected clinical population. In particular, a low expression of ACE2 is usually indicative of a high risk of developing COVID-19.

We then performed a meta-analysis of public data on CpG DNA methylation and gene expression of this enzyme and its homologous ACE protein in peripheral blood mononuclear cells and related subsets. We found that patients with ME/CFS have decreased methylation levels of four CpG probes in the ACE locus (cg09920557, cg19802564, cg21094739, and cg10468385) and of another probe in the promoter region of the ACE2 gene (cg08559914). We also found a decreased expression of ACE2 but not of ACE in patients with ME/CFS when compared to healthy controls.

Accordingly, in newly collected data, we found evidence for a higher proportion of samples with an ACE2 expression below the limit of detection in patients with ME/CFS than in healthy controls.

Altogether, patients with ME/CFS could be at a higher COVID-19 risk when infected by SARS-CoV-2. To further support this conclusion, similar research should be conducted for other human cell entry receptors and other cell types, namely, those mainly targeted by the virus.

Comment:

ME Association: Research Summary – Are people with ME/CFS at higher risk of complications from COVID infection?

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Treatment Research: Cortene’s InTime trial of CT38 results in sustained symptom improvement in ME/CFS

Posted on 09/07/2021 by wames

Acute Corticotropin-Releasing Factor Receptor Type 2 Agonism Results in Sustained Symptom Improvement in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, by Gerard Pereira, Hunter Gillies, Sanjay Chanda, Michael Corbett, Suzanne D. Vernon, Tina Milani and Lucinda Bateman in Front. Syst. Neurosci., 01 Sep 2021 [doi.org/10.3389/fnsys.2021.698240]

 

Research abstract:

Background:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex multi-symptom disease with widespread evidence of disrupted systems. The authors hypothesize that it is caused by the upregulation of the corticotropin-releasing factor receptor type 2 (CRFR2) in the raphé nuclei and limbic system, which impairs the ability to maintain homeostasis. The authors propose utilizing agonist-mediated receptor endocytosis to downregulate CRFR2.

Materials and Methods:

This open-label trial tested the safety, tolerability and efficacy of an acute dose of CT38s (a short-lived, CRFR2-selective agonist, with no known off-target activity) in 14 ME/CFS patients. CT38s was subcutaneously-infused at one of four dose-levels (i.e., infusion rates of 0.01, 0.03, 0.06, and 0.20 μg/kg/h), for a maximum of 10.5 h. Effect was measured as the pre-/post-treatment change in the mean 28-day total daily symptom score (TDSS), which aggregated 13 individual patient-reported symptoms.

Results:

ME/CFS patients were significantly more sensitive to the transient hemodynamic effects of CRFR2 stimulation than healthy subjects in a prior trial, supporting the hypothesized CRFR2 upregulation. Adverse events were generally mild, resolved without intervention, and difficult to distinguish from ME/CFS symptoms, supporting a CRFR2 role in the disease. The acute dose of CT38s was associated with an improvement in mean TDSS that was sustained (over at least 28 days post-treatment) and correlated with both total exposure and pre-treatment symptom severity. At an infusion rate of 0.03 μg/kg/h, mean TDSS improved by −7.5 ± 1.9 (or −25.7%, p = 0.009), with all monitored symptoms improving.

Conclusion:

The trial supports the hypothesis that CRFR2 is upregulated in ME/CFS, and that acute CRFR2 agonism may be a viable treatment approach warranting further study.

Comments:

Biospace: Clinical trial provides preliminary evidence of a cure for myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) and Long Covid

Cortene believes the CRFR2 pathway is upregulated and therefore overactive, leading to the wide variety of symptoms in ME/CFS.  “The conventional approach would be to block the overactive pathway. Instead, our counterintuitive approach seeks to overstimulate CRFR2, causing it to downregulate, without the need for chronic treatment.”

Health arising: The Cortene drug trial results for ME/CFS are in

Dr. Bateman indicated that many of the participants reported subtle but noticeable improvements of their symptoms over the 1-2 years following the trial.

In an interview, Cortene proposed that partial downregulation of the CRFR2 receptor had indeed occurred, and that further trials would determine if they could fully return it and the stress response system in ME/CFS to a healthy state.

Cortene hopes to embark on a 60-person $4 million trial next.

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Research: An alternative model of CBT for CFS/ME

Posted on 09/06/2021 by wames

‘A life I can cope with’. An alternative model of cognitive behavioural therapy (CBT) for CFS/ME, by Catherine Clark, Sue Holttum in Health Expectations 2021 [DOI: 10.1111/h ex.13326]

 

Research abstract:

Objectives

This study aimed to explore the experience of cognitive behavioural therapy (CBT) aimed at better management of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME), rather than increasing activity.

Design

This was a qualitative study using grounded theory analysis.

Methods

Semi-structured interviews were conducted with 13 adults who had engaged in CBT at a specialist CFS/ME service in which CBT is aimed at improved management of the condition.

Results

A model was produced in which participants felt more able to cope with CFS/ME. Reduced fatigue did not seem to be a necessary precondition to managing. This has implications for CBT for CFS/ME.

Conclusions

Specialist CBT for CFS/ME may result in improved coping and reduced distress, independently of changes in fatigue.

I don’t think in any way it helped my ME, but it did help my mind. (Sarah)

I don’t want to say reduced the symptoms, but probably have slightly fewer relapses and maintain a slightly better level quality of life. (Susan)

I came away just with that re-focus on putting myself first and not being afraid to do that actually, it is okay to do that when you are not well. (Sarah)

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WAMES responds to NICE ’roundtable’ announcement

Posted on 09/02/2021 by wames

WAMES writes to NICE re ‘Roundtable event’

 

On 27th August, 10 days after publication of the ME/CFS guideline was ‘paused’, NICE made another announcement. Yet again this gave the bare minimum of information – their plan to invite stakeholders to a roundtable discussion in September ‘to better understand the issues raised and determine how it can gain support for the guideline to ensure effective implementation.

No information was given about the nature of the challenge or the people making the challenge, or the rules and regulations governing this unprecedented move.

In the media and on social media, the critics of the guideline have made it clear that:

  • they believe GET and CBT are the only valid evidence based interventions that can help patients
  • the PACE trial should be upgraded from low quality and that this could be done if the diagnostic criteria was widened.

NICE says they believe it is possible to reach an agreement. Whether that is realistic or wishful thinking remains to be seen.

It is now September, so WAMES has written to NICE to express our commitment to continuing to work towards publication of the guideline.

 

Dear Prof Leng, Mr Chrisp and Ms Stafford,

As a stakeholder in the ME/CFS NICE guideline revision process, and a charity working with the estimated 13,000 people with ME in Wales, we confirm our interest in being part of the Roundtable event. WAMES supports the publication of the guideline as soon as possible, as it was developed by following a search for best evidence and represents years of hard work and emotional investment from all involved.

We hope this will be an inclusive event with virtual participation from a wide range of stakeholders as we are concerned about the lack of transparency surrounding the challenge to the guideline and ‘pause’ in publication. This has severely damaged NICE’s credibility in the ME community and future openness will be critical in achieving ‘a guideline that will have the support of people living with ME/CFS’.

We therefore look forward to receiving the following in advance, so we have plenty of time to prepare:

  • Full details of the challenge to the publication of the guideline
  • Details of the procedure by which others can also challenge the publication of the guideline in its current form
  • Details of any expert witnesses that are being called or further evidence being gathered
  • A clear plan for the steps and timescale that will be followed until publication
  • Details of all stakeholders invited and the role they will play in this, both in person and via written submission
  • Details of any stakeholders who are not invited to the Roundtable and how they can contribute
  • The plan of action if agreement cannot be achieved
  • An assurance that ongoing delay to publication will be accompanied by a warning on the current guideline that GET can cause deterioration for people with PEM, thus preventing further harm.

Yours sincerely,

Jan Russell   Chair of WAMES

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Research: An audit of UK hospital doctors’ knowledge & experience of ME

Posted on 08/31/2021 by wames

An audit of UK hospital doctors’ knowledge and experience of Myalgic Encephalomyelitis, by Keng Ngee Hng, Keith Geraghty and Derek FH Pheby in Medicina 2021, 57(9), 885; [doi.org/10.3390/medicina57090885] 27 August 2021 (This article belongs to the Special Issue ME/CFS: Causes, Clinical Features and Diagnosis)

 

Research abstract:

Background and Objectives:

There is some evidence that knowledge and understanding of ME among doctors is limited. Consequently, an audit study was carried out on a group of hospital doctors attending a training event to establish how much they knew about ME and their attitudes towards it.

Materials and Methods:

Participants at the training event were asked to complete a questionnaire, enquiring about prior knowledge and experience of ME and their approaches to diagnosis and treatment. A total of 44 completed questionnaires were returned. Responses were tabulated, proportions selecting available options determined, 95% confidence limits calculated, and the significance of associations determined by Fisher’s exact test.

Results:

Few respondents had any formal teaching on ME, though most had some experience of it. Few knew how to diagnose it and most lacked confidence in managing it. None of the respondents who had had teaching or prior experience of ME considered it a purely physical illness. Overall, 91% of participants believed ME was at least in part psychological.

Most participants responded correctly to a series of propositions about the general epidemiology and chronicity of ME. There was little knowledge of definitions of ME, diagnosis, or of clinical manifestations. Understanding about appropriate management was very deficient. Similarly, there was little appreciation of the impact of the disease on daily living or quality of life.

Where some doctors expressed confidence diagnosing or managing ME, this was misplaced as they were incorrect on the nature of ME, its diagnostic criteria and its treatment.

Conclusion:

This audit demonstrates that most doctors lack training and clinical expertise in ME. Nevertheless, participants recognised a need for further training and indicated a wish to participate in this. It is strongly recommended that factually correct and up-to-date medical education on ME be made a priority at undergraduate and postgraduate levels. It is also recommended that this audit be repeated following a period of medical education.

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ME/CFS guideline (US): ME/CFS Essentials of diagnosis & management

Posted on 08/27/2021 by wames

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: essentials of diagnosis and management (see authors below) in Mayo Proceedings, Aug 25 2021 [doi.org/10.1016/j.mayocp.2021.07.004]

 

Consensus recommendations – introduction abstract:

Despite myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) affecting millions of people worldwide, many clinicians lack the knowledge to appropriately diagnose or manage ME/CFS.

Unfortunately, clinical guidance has been scarce, obsolete, or potentially harmful. Consequently, up to 91% of patients in the United States remain undiagnosed, and those diagnosed often receive inappropriate treatment.

These problems are of increasing importance because after acute COVID-19, a significant percentage of people remain ill for many months with an illness similar to ME/CFS. In 2015, the US National Academy of Medicine published new evidence-based clinical diagnostic criteria that have been adopted by the US Centers for Disease Control and Prevention. Furthermore, the United States and other governments as well as major health care organizations have recently withdrawn graded exercise and cognitive-behavioral therapy as the treatment of choice for patients with ME/CFS.

Recently, 21 clinicians specializing in ME/CFS convened to discuss best clinical practices for adults affected by ME/CFS. This article summarizes their top recommendations for generalist and specialist health care providers based on recent scientific progress and decades of clinical experience.

There are many steps that clinicians can take to improve the health, function, and quality of life of those with ME/CFS, including those in whom ME/CFS develops after COVID-19. Patients with a lingering illness that follows acute COVID-19 who do not fully meet criteria for ME/CFS may also benefit from these approaches.

Routine Diagnostic Tests Recommended for All Patients

  • Complete blood count with differential
  • Comprehensive metabolic panel (Chem20 panel)a
  • Antinuclear antibody
  • C-reactive protein
  • Erythrocyte sedimentation rate
  • Ferritin
  • Rheumatoid factor
  • Four-point salivary cortisol (eg, wakening, at noon, 4:00 pm, & bedtime), am cortisol
  • Thyroid-stimulating hormone, free thyroxine
  • Vitamin B12
  • Vitamin D, 25-dihydroxy
  • Urinalysis
[Adapted from Testing Recommendations for Suspected ME/CFS,104 with permission of the US ME/CFS Clinician Coalition.
a The Chem20 panel is a set of common laboratory tests ordered by health care professionals in the United States. It consists of 20 tests that provide information on the patient’s chemical balance and metabolism.
For more information, see https://www.ucsfhealth.org/medical-tests/003468]

 

Excerpt from Management Approach:

  • Validate the Patient’s Experience
  • Assess Needs and Provide Support
  • Teach Pacing
  • Treat the Symptoms of ME/CFS
  • Treat Comorbidities
  • Schedule Regular Follow-up Visits
  • Address Questions on Prognosis

Authors – ME/CFS Clinician Coalition:

Lucinda Bateman, MD; Alison C. Bested, MD; Hector F. Bonilla, MD; Bela V. Chheda, MD; Lily Chu, MD, MSHS; Jennifer M. Curtin, MD; Tania T. Dempsey, MD; Mary E. Dimmock, BA; Theresa G. Dowell, DNP, MPT; Donna Felsenstein, MD; David L. Kaufman, MD; Nancy G. Klimas, MD; Anthony L. Komaroff, MD; Charles W. Lapp, MBME, MD; Susan M. Levine, MD; Jose G. Montoya, MD; Benjamin H. Natelson, MD; Daniel L. Peterson, MD; Richard N. Podell, MD, MPH; Irma R. Rey, MD; Ilene S. Ruhoy, MD, PhD; Maria A. Vera-Nunez, MD, MSBI; Brayden P. Yellman, MD

Articles:

US ME/CFS Clinician Coalition: Updated Clinical Guidance for ME/CFS may also help long COVID patients  25 Aug 2021

The updated clinical guidance from the U.S. ME/CFS Clinician Coalition focuses on adults and includes:

  • New diagnostic criteria requiring post-exertional malaise and other key features to improve diagnostic accuracy
  • Efficient use of interview questions, physical examination findings, and diagnostic testing
  • Alternative diagnoses and co-existing conditions to consider
  • Pharmacological and nonpharmacological treatments
  • A discussion of why previously-recommended treatments-cognitive behavioral therapy and graded exercise therapy-can be harmful and are no longer recommended

Medscape: New Recommendations Address ME/CFS Diagnosis and Management by Miriam Tucker 27 February 2021

 

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Biomarker research: The case for hyperbaric oxygen therapy in CFS biomarker identification

Posted on 08/25/2021 by wames

Chronic fatigue syndrome and epigenetics: the case for hyperbaric
oxygen therapy in biomarker identification, by Rajit J Shah in J Pulmonol Respir Res. 2021; 5: 027-030. [DOI: 10.29328/journal.jprr.1001020]

 

Review abstract:

Chronic fatigue syndrome (CFS) is a poorly-understood respiratory condition that affects millions of individuals. Hyperbaric oxygen therapy (HBOT) is a treatment option being considered to address CFS as it is suggested to combat fatigue and increase oxygenation.

HBOT provides two opportunities in advancing research of CFS: it may provide data on symptom amelioration and be utilized in the search for a biomarker.

By either identifying biomarkers before using HBOT to compare epigenomes of patients before and after treatment or using HBOT to find epigenetic discrepancies between patients with and without treatment, matching epigenetic regulation with symptom amelioration may significantly advance the understanding of the etiology and treatment mechanism for CFS.

EPAS1/HIF-2α is a leading candidate for an epigenetic biomarker as it responds differentially to hypoxic and normoxic conditions, which degrades more slowly in hypoxic conditions. Epigenetic regulation of EPAS1/HIF-2α in
such differential conditions may be explored in HBOT experiments.

In addition to HBOT as a promising treatment option for CFS symptoms, it may aid the identification of biomarkers in CFS. Further research into both outcomes is strongly encouraged.

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Research: Feeling like ‘a damaged battery’: …lived experiences of UK university students with ME/CFS

Posted on 08/23/2021 by wames

Feeling like ‘a damaged battery’: Exploring the lived experiences of UK university students with ME/CFS, by Frances Waite, Dely Lazarte Elliot in Fatigue: Biomedicine, Health & Behavior, 23 Aug 2021 [doi.org/10.1080/21641846.2021.1969800]

 

Research abstract:

Introduction:

Research regarding students with myalgic encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS) has been limited. This study aimed to understand how their subjective well-being had been affected by their condition by exploring their experiences and sense-making processes.

Methods:

Semi-structured interviews were conducted with eight students using video-calling software and were enriched by asking participants to think of a metaphor to describe their illness. Interpretative Phenomenological Analysis was used to analyze the interviews.

Results:

Three themes were developed: University as

  • (de)legitimizing,

This was demonstrated in participants’ accounts of experiencing a lack of understanding and validation from their tutors and the disability services at their university.

  • Negotiating disclosure

 The invisible nature of the illness meant that participants were actively deciding whether to disclose their illness. Participants discussed stigma and the struggles they experienced advocating for themselves. This illustrated how participants felt judged and marginalized.

  • Loss and adaptation.

…the participants’ sense of loss of their academic persona, as they could no longer achieve the high standards they were used to… Six participants reported adapting to their new capabilities, such as not setting themselves such high academic standards, making friends with those who did not have such high expectations, and taking up less strenuous relaxation activities.

Rosenberg’s conceptualization of self-esteem was used as a framework to explore the findings as it reflected participants’ accounts and provided an insight into their subjective well-being. Participants discussed their reduced self-esteem through experiences of delegitimization and stigma at their universities, as well as how they became more accepting of their illness and increased their self-esteem.

Conclusion:

This study provides an understanding of how the lives of students with ME/CFS have been affected by their condition, including their experiences at university and in their social context. Participants raised potential avenues in which universities can act in a supportive manner to be empowering and enhance self-esteem, which is important due to the debated nature of the illness.

Extract: Implications

…The practical implications of this research are that universities need to provide further support. Tutors, support staff and students could be provided with information about ME/CFS, delivered in the form of workshops, information sessions or information booklets, and could cover a range of similar illnesses which are also subject to stigma, such as fibromyalgia.

It is important that universities enable students to be the expert on their own illness, by asking them what symptoms they have, and what support they require. This information should be collected by the disability services, put on a student’s file and, with the student’s permission, provided to university staff to prevent students needing to repeat their story. Receiving this legitimization could result in an increase in students’ self-esteem and subjective wellbeing.

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WAMES ponders the NICE guideline shockwave

Posted on 08/20/2021 by wames

WAMES ponders the NICE guideline shockwave

How far will it extend?

 

People with ME/CFS have been looking forward to the publication of the revised NICE guideline on 18th August 2021, since the review process began in early 2018. Frustratingly the publication date has been delayed twice. Once, due to the pandemic, and once due to the large amount of consultation feedback they had to sift through.

The ‘pause’

On the afternoon of the 17th August, just hours before publication was due, NICE announced they were ‘pausing’ publication ‘because of issues raised during the pre-publication period’. These came from professionals who didn’t want to implement them and the media storm that followed showed they were supporters of the Biopsychosocial (BSP) treatments of GET and CBT. WAMES wrote to NICE expressing our shock and seeking more information but we will have been one of hundreds, if not thousands, so we don’t expect a speedy response!

New guidance

The revised guideline was due to advise against services aiming to cure ME using GET and CBT. Graded Exercise Therapy (GET) treats muscle deconditioning, which is not proven to be any more of an issue in ME than any other chronic illness. Cognitive Behavioural Therapy (CBT) has been adapted to treat the ‘faulty’ illness belief that patients were physically unwell, though research has in fact found multi-system dysfunction. The guideline would also have acknowledged the key characteristic of Exercise Intolerance, which leads to Post Exertional Malaise (PEM), a worsening of symptoms following physical or cognitive exertion.

NICE’s impartiality now under question

The NICE committee came to their decision after examining lots of research, clinicians’ testimony and patient stories. They also accepted the research showing that the trial said to support the use of GET and CBT had altered the statistics to fraudulently make their point.

The announcement of the ‘pause’ in publication caused shock and dismay to patients and all those who had contributed to the process. But it also raises questions about the impartiality of NICE, who claim to oversee a ‘rigorous methodology and process’. They have been accused of ‘capitulating to vested interests’ and ‘throwing millions of people under the bus’, and returning to the ‘medieval catch-all of prescribing a course of leeches’ (see The Canary). It is unlikely they have applied their own rules and regulation to this action, but they did not follow up the announcement with an explanation of what would happen next, so we will have to wait before fully judging that.

Many questions abut the future

If the guideline is published in an altered form, will patients, ME clinicians and researchers be able to support it? Will it affect services positively or will commissioners back off from such furious controversy?

And what will health professionals think?  NICE guidelines are touted as the ‘Gold standard’ but patient surveys show that many doctors appear not to have allowed the 2007 CFS/ME guideline to affect their dealings with patients. A survey in ‘Pulse Today’ (the GP magazine) in 2015 revealed that GPs deliberately ignored the guidelines for a number of conditions because they felt they were unhelpful. This ‘circus’ is unlikely to change their views.

Can NICE regain everyone’s respect? Could a loss of confidence extend to guidelines for other conditions? How might this affect the healthcare offered to patients beyond the ME community?

There are so many questions and we have no idea what the future holds for the estimated 13,000 people with Myalgic Encephalomyelitis (ME) in Wales, or the 250,000 people across the UK!

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Research: Diffusion tensor imaging (MRI) reveals neuronal microstructural changes in ME/CFS

Posted on 08/20/2021 by wames

Diffusion tensor imaging reveals neuronal microstructural changes in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, by Kiran Thapaliya, Sonya Marshall-Gradisnik, Don Staines, Leighton Barnden in European Journal of Neuroscience, August 6, 2021 [doi/10.1111/ejn.15413]

 

Research abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) patients suffer from a variety of physical and neurological complaints indicating the central nervous system plays a role in ME/CFS pathophysiology.

Diffusion tensor imaging (DTI) has been used to study microstructural changes in neurodegenerative diseases. In this study, we evaluated DTI parameters to investigate microstructural abnormalities in ME/CFS patients.

We estimated DTI parameters in 25 ME/CFS patients who met Fukuda criteria (ME/CFSFukuda), 18 ME/CFS patients who met International Consensus Criteria (ICC) (ME/CFSICC) only and 26 healthy control (HC) subjects. In addition to voxel-based DTI-parameter group comparisons, we performed voxel-based DTI-parameter interaction-with-group regressions with clinical and autonomic measures to test for abnormal regressions.

Results of voxel-based group comparisons of AD, MD and MO. (a) decreased AD in ME/CFS (ICC).

Group comparisons between ME/CFSICC and HC detected significant clusters (a) with decreased axial diffusivity (p = .001) and mean diffusivity (p = .01) in the descending cortico-cerebellar tract in the midbrain and pons and (b) with increased transverse diffusivity in the medulla. The mode of anisotropy was significantly decreased (p = .001) in a cluster in the superior longitudinal fasciculus region.

Voxel-based group comparisons between ME/CFSFukuda and HC did not detect significant clusters. For ME/CFSICC and HC, DTI parameter interaction-with-group regressions were abnormal for the clinical measures of information processing score, SF36 physical, sleep disturbance score and respiration rate in both grey and white matter regions.

Our study demonstrated that DTI parameters are sensitive to microstructural changes in ME/CFSICC and could potentially act as an imaging biomarker of abnormal pathophysiology in ME/CFS. The study also shows that strict case definitions are essential in investigation of the pathophysiology of ME/CFS.

Excerpt from Conclusion:

Our DTI study detected axonal microstructural abnormalities in ME/CFS patients. The group analysis using a voxel-based method detected differences in diffusion metrics in ascending and descending tracts in the medulla, pons and midbrain of the brainstem in ME/CFS patients, but only for those meeting ICC criteria.

This demonstrated the importance of strict case definitions for ME/CFS. Our DTI parameter interaction-with-group regressions with clinical measures showed involvement of multiple brain regions. These novel analyses can contribute to understanding the pathophysiology of ME/CFS patients. Brainstem abnormality may be an imaging diagnostic marker for ME/CFS.

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