Evidence of widespread metabolite abnormalities in ME/CFS: assessment with whole-brain magnetic resonance spectroscopy (2019) Younger et al.

Cheshire

Cheshire

Senior Member (Voting Rights)
Christina Mueller, Joanne C. Lin, Sulaiman Sheriff, Andrew A. Maudsley, Jarred W. Younger

Previous neuroimaging studies have detected markers of neuroinflammation in patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Magnetic Resonance Spectroscopy (MRS) is suitable for measuring brain metabolites linked to inflammation, but has only been applied to discrete regions of interest in ME/CFS. We extended the MRS analysis of ME/CFS by capturing multi-voxel information across the entire brain. Additionally, we tested whether MRS-derived brain temperature is elevated in ME/CFS patients. Fifteen women with ME/CFS and 15 age- and gender-matched healthy controls completed fatigue and mood symptom questionnaires and whole-brain echo-planar spectroscopic imaging (EPSI). Choline (CHO), myo-inositol (MI), lactate (LAC), and N-acetylaspartate (NAA) were quantified in 47 regions, expressed as ratios over creatine (CR), and compared between ME/CFS patients and controls using independent-samples t-tests. Brain temperature was similarly tested between groups. Significant between-group differences were detected in several regions, most notably elevated CHO/CR in the left anterior cingulate (p < 0.001). Metabolite ratios in seven regions were correlated with fatigue (p < 0.05). ME/CFS patients had increased temperature in the right insula, putamen, frontal cortex, thalamus, and the cerebellum (all p < 0.05), which was not attributable to increased body temperature or differences in cerebral perfusion. Brain temperature increases converged with elevated LAC/CR in the right insula, right thalamus, and cerebellum (all p < 0.05). We report metabolite and temperature abnormalities in ME/CFS patients in widely distributed regions. Our findings may indicate that ME/CFS involves neuroinflammation.
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Behind a paywall
https://link.springer.com/article/10.1007/s11682-018-0029-4
 
Previous neuroimaging studies have detected markers of neuroinflammation in patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS).

Magnetic Resonance Spectroscopy (MRS) is suitable for measuring brain metabolites linked to inflammation, but has only been applied to discrete regions of interest in ME/CFS.

We extended the MRS analysis of ME/CFS by capturing multi-voxel information across the entire brain.
Additionally, we tested whether MRS-derived brain temperature is elevated in ME/CFS patients.

Fifteen women with ME/CFS and 15 age- and gender-matched healthy controls completed fatigue and mood symptom questionnaires and whole-brain echo-planar spectroscopic imaging (EPSI).

Choline (CHO), myo-inositol (MI), lactate (LAC), and N-acetylaspartate (NAA) were quantified in 47 regions, expressed as ratios over creatine (CR), and compared between ME/CFS patients and controls using independent-samples t-tests.

Brain temperature was similarly tested between groups.

Significant between-group differences were detected in several regions, most notably elevated CHO/CR in the left anterior cingulate (p < 0.001).

Metabolite ratios in seven regions were correlated with fatigue (p < 0.05).

ME/CFS patients had increased temperature in the right insula, putamen, frontal cortex, thalamus, and the cerebellum (all p < 0.05), which was not attributable to increased body temperature or differences in cerebral perfusion.

Brain temperature increases converged with elevated LAC/CR in the right insula, right thalamus, and cerebellum (all p < 0.05).

We report metabolite and temperature abnormalities in ME/CFS patients in widely distributed regions.
Our findings may indicate that ME/CFS involves neuroinflammation.
 
Without having read the paper, two items posted here jumped out: Why were only women tested, and what's with "fatigue and mood symptom questionnaires"? Mood symptoms??

Whatever he may be glimpsing with MRS metrics, what footprints does he imagine he is seeing, as they may not be ME/CFS.
 
duncan said:
Why were only women tested,
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Jarred Younger has said that because they only have funding for small studies it's important to study as homogeneous group as possible.

Other researchers have found significant differences in biochemistry between male and female people with ME, so it makes sense for a small study to narrow it down by gender to get as clear a picture as possible of the situation for that group. For example, Nancy Klimas is researching three separate groups - men, and pre and post menopausal women.

I'm sure the hope would be to widen it when more funding is available.
 
Trish said:
Jarred Younger has said that because they only have funding for small studies it's important to study as homogeneous group as possible.
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Perhaps. I'm not sure this approach does not incorporate the same pitfalls with which we are now so familiar with decades of research that excluded women for diseases that impacted both genders, much to the detriment of women. Moreover, there may be an argument that says any cohort should attempt to reflect the population under study.

Of course, none of this relieves my concerns with the fatigue/mood symptom questioning, unless the mood symptom thing was part of a screening process. I am also leery of anyone who might be conflating fatigue with ME/CFS - including researchers.
 
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duncan said:
That also does not relieve my concerns with the fatigue/mood disorder screening.
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It looks from the list @John Mac linked that out of the 15 one had comorbid depression and 3 anxiety. I would think the mood questionnaire would be to help screen out any effects on the brain from comorbid mood disorders. Mood is not mentioned in the abstract, so I'm guessing they didn't find any correlations between mood and the brain findings in either controls or ME patients.

As to fatigue questionnaires and whether they had ME, I think we'd need to read the full paper before we cast judgement on whether he selected his sample appropriately for an ME study. I don't know which diagnostic criteria he uses.
 
Trish said:
It looks from the list @John Mac linked that out of the 15 one had comorbid depression and 3 anxiety. I would think the mood questionnaire would be to help screen out any effects on the brain from comorbid mood disorders. Mood is not mentioned in the abstract, so I'm guessing they didn't find any correlations between mood and the brain findings in either controls or ME patients.

As to fatigue questionnaires and whether they had ME, I think we'd need to read the full paper before we cast judgement on whether he selected his sample appropriately for an ME study. I don't know which diagnostic criteria he uses.
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He uses fukuda as far as I know...im hoping any Researcher working with OMF or with any interest in ME would consider pem mandatory for participants. At least I hope so.
 
Not currently enough clarity to read properly but have found the bits on patient selection:

Inclusion criteria:
(i) age between 18 and 55 years;
(ii) met Fukuda case definition criteria for ME/CFS (Fukuda et al. 1994), without the Reeves et al. (2005) modifications but with additional criteria proposed by Jason et al. (2010); and
(iii) average self-reported daily fatigue rating of ≥6 on an 11-point scale.

Exlcusion included diagnosed neurological, major psychiatric, autoimmune, rheumatologic, or inflammatory disorders and use of certain drugs.
 
No need to bristle at the inclusion of a mood questionnaire. It's wrong to reject something just because it includes psych issues because BPS abuses. This is an obvious biomedical study done by a knowledgeable reseacher. The inclusions of mood symptoms is probably because he's interested in brain inflammation, which is known to be heavily linked to mood disorders and whose symptoms often impact the mood. So, he had to match them at the beginning to notice legit changes.
 
dreampop said:
The inclusions of mood symptoms is probably because he's interested in brain inflammation, which is known to be heavily linked to mood disorders and whose symptoms often impact the mood.
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I would have measured cognitive functioning. Associating mood disorders with ME/CFS - IF that is something he was approaching - is potentially playing into the wrong hands needlessly. Work with word choice or reasoning or abstract thought or basic math deficits. Why venture into such an area historically marked by abuse?

Researchers need to frame their efforts in part by the politics that characterize this community, imo, or at least be informed by them.
 
I had an MRS done late last year to look for elevated lactate and I haven't seen the actual report but according to the metabolic specialist it didn't show anything abnormal. Does anyone know if even if they're looking for a specific metabolite like lactate do these scans also report on other metabolites? I wonder if the differences shown in the study are statistically significant when compared against controls but might still be within normal range for an MRS done in a clinical setting?
 
For those who can’t access the paper, here are its conclusions:
Conclusions
This study is the first to investigate whole-brain MRS markers of neuroinflammation in ME/CFS. We report metabolite and temperature abnormalities in ME/CFS patients in widely distributed brain areas, suggesting ME/CFS is driven by diffuse pathophysiological processes affecting the whole brain, rather than regionally limited, which is consistent with the heterogeneity of its clinical symptoms. Our findings add support to the hypothesis that ME/CFS is the result of chronic, low-level neuroinflammation. While the whole-brain results are preliminary, we note that they largely agree with past publications that use MRS in ME/CFS. These results should be replicated in future studies with larger samples to further establish the profile of pathophysiological abnormalities in the brains of ME/CFS patients. Ultimately, the development of sensitive MRI markers of ME/CFS could supplement clinical tests to help guide treatment decisions.
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If anyone wants help accessing the full paper, pm me.
 
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