Trial Report Imbalanced Brain Neurochemicals in long COVID and ME/CFS: A Preliminary Study using MRI, 2024, Thapaliya et al

[Dolphin]

https://www.sciencedirect.com/science/article/pii/S000293432400216X

Imbalanced Brain Neurochemicals in long COVID and ME/CFS: A Preliminary Study using MRI

Kiran Thapaliya, PhD 1*, Sonya Marshall-Gradisnik, PhD 1 , Natalie Eaton-Fitch, PhD 1 , Zeinab Eftekhari BSc (Honours)2 ,Maira Inderyas MSc.1 , and Leighton Barnden, PhD 1

1 National Centre for Neuroimmunology and Emerging Diseases (NCNED), Griffith University, Australia

2 Centre for Advanced Imaging, The University of Queensland, Australia

CofI: None

Author’s contribution: KT: conceptualization, formal analysis, and writing–original draft. KT and ZF: methodology. KT, LB, NE-F, ZF, MI, and SM-G: writing–review and editing. KT, MI: Data curation, LB and SM-G: supervision. LB, KT, SM-G, NE-F; funding acquisition.

All authors contributed to the article and approved the submitted version.
open access

Abstract
Purpose
Long COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) patients experience multiple complex symptoms, potentially linked to imbalances in brain neurochemicals. This study aims to measure brain neurochemical levels in long COVID and ME/CFS patients as well as healthy controls to investigate associations with severity measures.

Methods
Magnetic resonance spectroscopy (MRS) data was acquired with a 3T Prisma MRI scanner. We measured absolute levels of brain neurochemicals in the posterior cingulate cortex in long COVID (n=17), ME/CFS (n=17), and healthy controls (n=10) using Osprey software. The statistical analyses were performed using SPSS version 29. Age and sex were included as nuisance covariates.

Results
Glutamate levels were significantly higher in long COVID (p=0.02) and ME/CFS (p=0.017) than in healthy controls. No significant difference was found between the two patient cohorts. Additionally, N-acetyl-aspartate levels were significantly higher in long COVID patients (p=0.012). Importantly, brain neurochemical levels were associated with self-reported severity measures in long COVID and ME/CFS.

Conclusion
Our study identified significantly elevated Glutamate and N-acetyl-aspartate levels in long COVID and ME/CFS patients compared with healthy controls. No significant differences in brain neurochemicals were observed between the two patient cohorts, suggesting a potential overlap in their underlying pathology. These findings suggest that imbalanced neurochemicals contribute to the complex symptoms experienced by long COVID and ME/CFS patients.

Keywords
long COVID
ME/CFS
glutamate
N-acetyl-aspartate (NAA)
brain neurochemicals
and MRI


Clinical Significance

• People with long COVID and ME/CFS have elevated glutamate and N-acetyl-aspartate levels compared to healthy controls in the posterior cingulate cortex, potentially causing multiple symptoms in both conditions.
  
  
• Similarities in brain neurochemicals between long COVID and ME/CFS provide further evidence for a significant link between the two conditions.
  
  
• Associations between brain neurochemicals and severity measures in long COVID and ME/CFS, may highlight the role of neurochemicals in these conditions.

Funding
This research is funded by ME Research UK (SCIO Charity Number SC036942) with the financial support of The Fred and Joan Davies Bequest. Other funding bodies include The Stafford Fox Medical Research Foundation (489798), the National Health and Medical Research Council (1199502), Talei Foundation, Buxton Foundation (4676), Henty Community (4879), Henty Lions Club (4880), Blake Beckett Trust Foundation (4579), Alison Hunter Memorial Foundation (4570), and the Change for ME Charity (4575).

https://twitter.com/user/status/1777325225866047863

https://twitter.com/user/status/1777327034026295504

 

[Joan Crawford]

Interesting to see this. I cannot comment on the method etc used but if replicated could make a lot of sense regarding patients symptoms especially the cognitive dysfunction.

I suspect that this is an effect of something else resulting in raised cerebral glutamate and NAA. Infection? Antigen? Multiple causes resulting in same/similar bodily defensive response?

Info from Cleveland Clinic website re glutamate:
"Glutamate plays a major role in shaping learning and memory. Glutamate needs to be present at the right concentrations in the right places at the right time. Too much glutamate in your brain, in the wrong place, in too high of a concentration and for too long can cause brain cell damage or death. Some neurodegenerative diseases associated with having too much glutamate exciting nerve cells include Parkinson’s disease, Alzheimer’s disease and Huntington’s disease."

 

[EndME]

Interesting to see this. I cannot comment on the method etc used but if replicated could make a lot of sense regarding patients symptoms especially the cognitive dysfunction.

I think that's the crucial point. From what I've seen if history is anything to go by we won't be seeing a meaningful replication of this work.

 

[Joan Crawford]

I think that's the crucial point. From what I've seen if history is anything to go by we won't be seeing a meaningful replication of this work.

And that would be sad.

Can anyone comment on the method and cost of such a study? And whether this is something a neurologist would take interest in?

 

[Joan Crawford]

"In ME/CFS, we found a positive association between glutamine and Cr+PCr levels and ‘physical activity’, indicating that lower physical activity is associated with reduced levels of these neurochemicals."

Perhaps another clue regarding the inability of pwME to maintain activity and exercise. And why GET is contraindicted.

 

[Slamdancin]

Could this be a clue as to why benzodiazepines seem to increase capacity/functionality acutely?

This is anecdotal of course but it seems to at least be true for other patients as well.

“Thus, in vivo low concentrations of benzodiazepines may reduce synaptic glutamate concentrations by increased uptake, providing an additional mechanism to modulate neuronal excitability.”

https://pubmed.ncbi.nlm.nih.gov/10582598/

 

[FMMM1]

I think that's the crucial point. From what I've seen if history is anything to go by we won't be seeing a meaningful replication of this work.

I've very little knowledge but my understanding is that "Magnetic resonance spectroscopy (MRS)" or "MRI" is considered a reliable technique - just wondering why e.g. Jonas Bergquist wouldn't have picked this up in his CSF studies?

 

[Hutan]

This study investigates neurochemical differences in the posterior cingulate cortex which is critically involved in cognitive processes and has a high metabolic rate (its metabolic rate is 40% greater than the brain average)21.

Beyond that, they don't say why they only looked at the PCC. I wonder if they looked at other parts of the brain.

The methods section says they looked at all of these molecules:
Alanine, Aspartate, Cr, PCr, γ-Aminobutyric acid (GABA), Glucose, Gln, Glu, GPC, PCh, Glutathione, Ins, Lactate, NAA, N-acetyl-aspartyl-glutamate, Scyllo, and Taurine. They corrected for multiple group comparisons.

In total, 17 long COVID patients as defined by the WHO clinical case definition4, 17 ME/CFS patients fulfilling the CCC and/or ICC criteria2, and 10 age-matched healthy controls were included

The numbers of participants is actually reported in the abstract and, although not large, is not a tiny study. Leighton Barnden, the senior author, has produced some good and careful research.

Not perfect matching by age - mean ages Long Covid 47; ME/CFS 41; Healthy controls 39
I'm not sure if that could make a difference.
The ME/CFS group looks to be more disabled - mean measure SF-36 physical function Long Covid 65; ME/CFS 33; HC 100

 

[Hutan]

Missing values

For the correlation analysis, four data points were unavailable for ‘cognitive impairment’ and ‘pain’ scores, three for ‘physical function’, one for ‘unrefreshing sleep’ for long COVID patients, and five for ‘physical function’, ‘cognitive impairment’, and ‘pain’, and three for ‘unrefreshing sleep’ for ME/CFS patients. These participants were excluded from the correlation analysis.

That's a lot of missing values, relative to the sample sizes. I don't know why they didn't do better getting this data.

Glutamate levels

Here's the chart - ME/CFS, LC, HC. It's fairly convincing that a significant proportion of the disease groups has high levels compared to the controls, I think. But I do wonder if age is confounding things. Only the ME/CFS group was different from the HC group after correction.

For ME/CFS only:

We observed a significant positive correlation between Gln, Glx, and Cr+PCr and ‘physical function’ (Gln: r=0.83, p=0.004, Glx: r=0.72, p=0.019; Cr+PCr: r=0.73, p=0.016) (see Table 3, Fig 5). There was also a significant negative correlation between Cr, Cr+PCr, and severity measures: ‘cognitive impairment’ (Cr: r=-0.68, p=0.035; Cr+PCr: r=-0.66, p=0.035 and ‘unrefreshing sleep’ (Cr: r=-0.55, p=0.04) (see Table 3).

Gln is Glutamate; Glx is glutamate and glutamine. That's a bit odd - more glutamate was correlated with better physical function.

There looks to be quite a lot of random results. In the LC group, Glx was negatively correlated with physical function. I don't think it is all really holding together as a coherent story.

NAA levels
Figure 3 only shows the levels for LC and HC - the ME/CFS data is not shown. The LC-HC difference looks quite compelling, but maybe it is just chance if the ME/CFS data isn't significant.

 

[Hutan]

Yeah, although it would be good to have the study replicated, I think the data is all over the place and there isn't a real result here. There's a big problem with the absence of data for a whole lot of the disease measurements that they are trying to correlate with molecule levels. If you only have 17 ME/CFS participants and e.g. 5 of them haven't provided physical function data, then results could be due to chance, or real correlations might be not significant.

We found significant associations between brain neurochemicals and several severity measures, including ‘physical function’, ‘cognitive impairment’, ‘unrefreshing sleep’, ‘pain’, and ‘duration’ of illness. These findings suggest that the severity of key long COVID and ME/CFS symptoms is linked to brain neurochemical levels.

I don't think that's a valid thing to say, because the findings for the associations aren't the same in the two disease groups. And the fact that high glutamate is supposedly a marker of the ME/CFS and LC groups, but, in ME/CFS, higher glutamate correlated with better physical function. And there was no correlation between glutamate and physical function in LC.

The discussion is frustrating in that it is trying hard to make corroborating stories to bolster such inconclusive results.

Our study demonstrated significantly elevated Glu and NAA levels in long COVID and ME/CFS patients compared to healthy controls with no significant differences between the two patient cohorts, suggesting common underlying pathology.

That's not really true - Glutamate levels weren't elevated in LC after FDR correction, and NAA levels in ME/CFS weren't elevated at all, they looked just like those of healthy controls.

I think the presentation of the results is needlessly confusing.

 

[FMMM1]

I've very little knowledge but my understanding is that "Magnetic resonance spectroscopy (MRS)" or "MRI" is considered a reliable technique - just wondering why e.g. Jonas Bergquist wouldn't have picked this up in his CSF studies?

Jarred Younger is another person who may have MRS/MRI data re Glutamate levels, or at least would be able to check these findings.

 

[dave30th]

Perhaps another clue regarding the inability of pwME to maintain activity and exercise. And why GET is contraindicted.

Ah, but our friends could interpret this as indicating that lower physical activity is causing the reduced neurochemical levels rather than the other way around.

 

[Joan Crawford]

Ah, but our friends could interpret this as indicating that lower physical activity is causing the reduced neurochemical levels rather than the other way around.

Hmmm, the glutamate and NAA levels were found to be raised in pwME and LC so that kinda kicks their theory a bit more, maybe.

I was thinking the more activity and exercise that patients do, the higher these levels might get.... or have I got that back to front

 

[Jonathan Edwards]

I haven't looked at the paper but I don't understand why they are just reporting on the posterior cingulate cortex.

If their findings are specific to the PCC I am sceptical that they would be telling us something about the cause of the problem. I would expect abnormal signalling causing symptoms to be mediated through hypothalamus or brain stem.

Cingulate has a lot to do with mood and self-aware thinking. I wouldn't be surprised if wearing a 40Kg rucksack led to changes in glutamate in the PCC but the changes wouldn't explain any sense of exhaustion.

To be much use I think measurements like these need to be compared with other illnesses, other time points, time of day and all sorts.

 

[poetinsf]

First, dopamine and norepinephrine in NIH paper. Now, glutamate. All these chemicals are involved in excitatory response to novel stimuli. Tiny cohorts notwithstanding, the positive correlation to symptom reduction is interesting to me because of my experience with becoming symptom-free when living on the road in my car, as I'm doing right now. But then, nicotine patch didn't prevent my PEM when I'm home, so maybe there is nothing to it. Just a non scientific observation with n=1.

 

[Hutan]

Hmmm, the glutamate and NAA levels were found to be raised in pwME and LC so that kinda kicks their theory a bit more, maybe.

No, they really weren't, although they do claim that.

Glutamate levels weren't elevated in LC after FDR correction, and NAA levels in ME/CFS weren't elevated at all, they looked just like those of healthy controls.

 

[Hutan]

Tiny cohorts notwithstanding, the positive correlation to symptom reduction is interesting to me because of my experience with becoming symptom-free when living on the road in my car, as I'm doing right now.

I'm not sure what you are saying there.

... high glutamate is supposedly a marker of the ME/CFS and LC groups, but, in ME/CFS, higher glutamate correlated with better [self-reported] physical function. And there was no correlation between glutamate and physical function in LC.

The data really does not support a coherent story - the sample sizes, especially taking into account missing data, are too small and I don't think the findings hang together.

 

[poetinsf]

I'm not sure what you are saying there.

I'm referring to NIH paper on deep phenotyping which showed positive correlation between catechol level and the performance. This paper on glutamate, as understand, also showed association of the functioning and glutamate level in PCC. Understood, it's tiny study that doesn't mean much. I was just reflecting it on my personal experience of being able to get away with doing more when I'm in a novel environment and my brain is wide awake.

 

[horton6]

And the fact that high glutamate is supposedly a marker of the ME/CFS and LC groups, but, in ME/CFS, higher glutamate correlated with better physical function. And there was no correlation between glutamate and physical function in LC.

I'm not totally sure how to ask this in a sensible way, but is there any reason to think that the disease process / biomarkers may be somewhat different between milder and more severe forms of ME? As in, it's not that it's straightforwardly "this molecule is causing problems, and the severity of your problems is correlated to the level you have of this molecule" but more something like: a normal process in your body has gone awry, and there are a couple of backup processes that the body can use to sort of get around it and survive. And maybe one of them involves producing more glutamate, but there's a cap on how much of that is possible, and the sicker you are the more you use up that glutamate? So that perhaps the highest levels of glutamate would be found in moderately ill pwME, because those who are milder would produce less and those who are severe would produce more but also use it up more? (Just using glutamate as an example because that's what's reported by this paper, my question is about the shape of findings.)

 

[Hutan]

So that perhaps the highest levels of glutamate would be found in moderately ill pwME, because those who are milder would produce less and those who are severe would produce more but also use it up more? (Just using glutamate as an example because that's what's reported by this paper, my question is about the shape of findings.)

I think in this case, the ME/CFS people with less physical dysfunction supposedly had more glutamate, but high levels of glutamate supposedly characterised ME/CFS versus healthy controls. So, presumably the people with mildest ME/CFS had more glutamate.

I doubt that the range of severity in ME/CFS was enough in this study to shed much light on the theory of a metabolite for which high levels characterises ME/CFS but which doesn't get higher, and even gets lower, with increasing severity. I note that the NIH Walitt study found that norepinephrine increased in a lot of the people in the ME/CFS group but not all, and not in the healthy controls, in an orthostatic challenge. I think glutamate can stimulate norepinephrine release. So, maybe what we are seeing here in a handful of the participants is a reaction to orthostatic stress that allows the person to keep functioning? But, I'm speculating way beyond what the data tells us.