Decadelong low basal ganglia NAA/tCr from elevated tCr supports ATP depletion from [Mt] dysfunction and neuroinflammation in [GWI], 2025, Cheshkov+
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Chandelier
Senior Member (Voting Rights)
Decadelong low basal ganglia NAA/tCr from elevated tCr supports ATP depletion from mitochondrial dysfunction and neuroinflammation in Gulf War illness
Abstract
Abstract Reduced N-acetylaspartate (NAA)/total creatine (tCr) ratio found with long echo-time proton magnetic resonance imaging ( 1 H-MRS) of deep brain structures in a Seabees Battalion in 1997–1998 was soon replicated by two studies but not in a later one using intermediate echo time.
We undertook this study in 2008–2009 to repeat the previous long echo-time 1 H-MRS study with 1 H-MRS at both long (TE = 270 ms) and short (TE = 30 ms) echo time and higher field strength (3T) to test whether the abnormality of NAA/tCr affecting this Battalion had normalized or been obscured by effects of the T 2 decay curve.
Under investigator blinding, 39 Seabees in the three GWI variant groups and 16 Seabees controls prospectively underwent 1 H-MRS at both short (TE = 30 ms) and long (TE = 270 ms) echo time to measure metabolites and at five TE values between 60 ms and 270 ms to measure transverse relaxation time (T 2 ) in the basal ganglia.
A mixed-effects linear model adjusting for age tested group differences. Findings supported the observations of the prior studies, demonstrating that veterans with GWI no longer had reduced NAA/tCr at long echo time but had significantly lower basal ganglia NAA/tCr than controls at short echo time (left: 1.22 ± 0.02 vs. 1.38 ± 0.03, P < 0.0001; right: 1.12 ± 0.02 vs. 1.18 ± 0.03, P = 0.059). The group differences were mainly due to higher [tCr] (left: 14.1%, P = 0.0001; right: 9.1%, P = 0.009) rather than lower [NAA] in the ill groups.
Longer echo time substantially reduced the sensitivity of 1 H-MRS. Chronic metabolite abnormalities persisted in GWI for 10 more years but remained detectable only at short echo time. That reduced NAA/tCr is due primarily to increased [tCr] rather than decreased [NAA] supports recent studies implicating mitochondrial dysfunction with ATP depletion and neuroinflammation as causative factors and therapeutic targets in GWI.
Web | DOI | PMC | PDF | Scientific Reports
Cheshkov, Sergey; Krishnamurthy, Lisa C.; Chang, Audrey; Baek, Hyeon-Man; Ganji, Sandeep; Babcock, Evelyn; Spence, Jeffrey S.; Briggs, Richard W.; Haley, Robert W.
Abstract
Abstract Reduced N-acetylaspartate (NAA)/total creatine (tCr) ratio found with long echo-time proton magnetic resonance imaging ( 1 H-MRS) of deep brain structures in a Seabees Battalion in 1997–1998 was soon replicated by two studies but not in a later one using intermediate echo time.
We undertook this study in 2008–2009 to repeat the previous long echo-time 1 H-MRS study with 1 H-MRS at both long (TE = 270 ms) and short (TE = 30 ms) echo time and higher field strength (3T) to test whether the abnormality of NAA/tCr affecting this Battalion had normalized or been obscured by effects of the T 2 decay curve.
Under investigator blinding, 39 Seabees in the three GWI variant groups and 16 Seabees controls prospectively underwent 1 H-MRS at both short (TE = 30 ms) and long (TE = 270 ms) echo time to measure metabolites and at five TE values between 60 ms and 270 ms to measure transverse relaxation time (T 2 ) in the basal ganglia.
A mixed-effects linear model adjusting for age tested group differences. Findings supported the observations of the prior studies, demonstrating that veterans with GWI no longer had reduced NAA/tCr at long echo time but had significantly lower basal ganglia NAA/tCr than controls at short echo time (left: 1.22 ± 0.02 vs. 1.38 ± 0.03, P < 0.0001; right: 1.12 ± 0.02 vs. 1.18 ± 0.03, P = 0.059). The group differences were mainly due to higher [tCr] (left: 14.1%, P = 0.0001; right: 9.1%, P = 0.009) rather than lower [NAA] in the ill groups.
Longer echo time substantially reduced the sensitivity of 1 H-MRS. Chronic metabolite abnormalities persisted in GWI for 10 more years but remained detectable only at short echo time. That reduced NAA/tCr is due primarily to increased [tCr] rather than decreased [NAA] supports recent studies implicating mitochondrial dysfunction with ATP depletion and neuroinflammation as causative factors and therapeutic targets in GWI.
Web | DOI | PMC | PDF | Scientific Reports
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Wirth saw it coming:
mitodicure.com
Pipeline – Mitodicure
mitodicure.com
Utsikt
Senior Member (Voting Rights)
Wirth saw it coming:
Pipeline – Mitodicure
MDC002 is targeting skeletal muscles, not the brain.
There is evidence (from their model) that MDC002 has vascular / perfusion-improving effects in the brain, too.
That said, the brain effects are more about blood flow and edema, not necessarily the same molecular ionic processes that they target in muscle.
It took 16 years to analyze and publish?
Yann04
Senior Member (Voting Rights)
I think it’s long term longitudinal. Like they mention measurments at “10 years”.
But still 6 years is a massive amount of time to wait before publishing if they think they’re publishing something that will advance the field.
It seems to me like "10 years" refers to the span between the 1998 study and this study:
Utsikt
Senior Member (Voting Rights)
So purely hypothetical?
Is there any evidence of cerebral edema in GWI, ME/CFS, FM, etc?
Science Blog summary of the paper. Looks like a fair write-up, though not to be confused with our own @ME/CFS Science Blog.
https://scienceblog.com/exhausted-cell-batteries-not-dead-neurons-may-drive-gulf-war-illness/
https://scienceblog.com/exhausted-cell-batteries-not-dead-neurons-may-drive-gulf-war-illness/
There is a lot of evidence converging toward mitochondria (I haven’t read this paper!) as key drivers of complex, chronic, multisystem diseases. Honestly, would that be surprising?
Why do we understand so little about these diseases?
A reasonable answer is that we still understand very little about the brain, very little about mitochondria, and even less about mitochondria in the living brain.
Is ME/CFS (or GWI) a mitochondrial disease? Not within the current category of primary mitochondrial diseases, and not within the ill-defined category of secondary mitochondrial diseases. But it seems likely to me that it is “a mitochondrial disease” in the same broad, functional sense that Parkinson’s disease is.
And just in case someone claims we already know “a lot about mitochondria”: I have had several private discussions with Prof. Wallace, and he says we don’t. So I’ll go with that.
More related to GWI, there was a very interesting finding some years ago showing that patients with the most dysfunctional mitochondria had the lowest inflammatory markers. I always found this very intriguing. I think this could be relevant for ME/CFS, too.
Also, somewhat related: I am a very severe ME patient, and I was part of a very small cohort of patients with different severities testing GDF-15. I was the most severe, and there was another young woman roughly as severe. We had the lowest values (lower than HC), the complete opposite of what would be expected. All kind of factors could explain this, but I always thought this might be downstream of 'not enough mitochondria'. Some researchers I spoke to in the aftermath thought that this is moronic, some thought that's interesting.
Why do we understand so little about these diseases?
A reasonable answer is that we still understand very little about the brain, very little about mitochondria, and even less about mitochondria in the living brain.
Is ME/CFS (or GWI) a mitochondrial disease? Not within the current category of primary mitochondrial diseases, and not within the ill-defined category of secondary mitochondrial diseases. But it seems likely to me that it is “a mitochondrial disease” in the same broad, functional sense that Parkinson’s disease is.
And just in case someone claims we already know “a lot about mitochondria”: I have had several private discussions with Prof. Wallace, and he says we don’t. So I’ll go with that.
More related to GWI, there was a very interesting finding some years ago showing that patients with the most dysfunctional mitochondria had the lowest inflammatory markers. I always found this very intriguing. I think this could be relevant for ME/CFS, too.
Also, somewhat related: I am a very severe ME patient, and I was part of a very small cohort of patients with different severities testing GDF-15. I was the most severe, and there was another young woman roughly as severe. We had the lowest values (lower than HC), the complete opposite of what would be expected. All kind of factors could explain this, but I always thought this might be downstream of 'not enough mitochondria'. Some researchers I spoke to in the aftermath thought that this is moronic, some thought that's interesting.
The information comes from their homepage.
They mention that it improves “muscle/brain perfusion.”
I did not say that edema occurs in GWI or ME/CFS; that claim also comes from their homepage. They state that it may help reduce “edema” and relieve pain.
Problems with blood flow might play an important role in many ME/CFS symptoms, such as brain fog, dizziness, and fatigue.
See, for example: https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-025-06954-w
The question will probably be, why there is less ATP and dysfunctional mitochondria, and in that case, the blood flow issue fits quite well.
Utsikt
Senior Member (Voting Rights)
As far as I know that is still hypothetical - they have no conducted human studies yet.
Well, that’s still hypothetical. And if there is no edema in ME/CFS, then how would reducing edema help?
Thread here:
If there are any problems with bloodflow in the brain in ME/CFS, wouldn’t it be reduced bloodflow? And how would that tie into Mitodicure’s drugs?
Wouldn’t that lead to structural cell damage? I don’t think there is much evidence for that.
Yeah, totally, I’m with you. It’s clear the whole drug is based on a hypothesis. Most of the testing so far has been done in rats (according to Patrick Ussher’s book), simply because it isn’t approved for humans yet.
What I was trying to say in my post is that Wirth’s drug is basically trying to restore ATP. And it focuses on two things: the sodium-calcium exchanger you mentioned, and blood flow. Since the findings in Gulf War Illness point to an ATP shortage, Wirth’s drug might actually help, which is probably why it’s in his pipeline.
And the idea that something’s off with blood flow or microcirculation isn’t just Wirth’s theory. Fluge, Mella, and Scheibenbogen are also looking at this with their monoclonal antibody studies, trying to remove those beta-receptor autoantibodies that mess with microcirculation and vasodilation.
Wirth’s take is a bit different, though. He thinks immune exhaustion comes from low ATP because the mitochondria aren’t working efficiently. And that mitochondrial issue starts because of poor microcirculation, which again is caused by those beta-receptor autoantibodies, basically a vicious cycle. If you fix ATP levels, the autoantibody problem should theoretically calm down too, because the immune system can then control them properly.
Wirth’s paper does mention a few small studies showing cell damage. But yeah, a direct, solid proof that his whole cascade actually leads to ATP failure and cell death in real patients hasn’t been confirmed by big clinical trials yet. You’re right about that.
I’m just a big fan of his hypothesis, especially because it’s the only drug being developed specifically for ME/CFS.
Utsikt
Senior Member (Voting Rights)
This is where I don’t follow. There are many ways that bloodflow can be affected, and there are many ways that ATP production can be disrupted.
If the aim of the drug is to reduce edema, but the issue in ME/CFS is reduced blood flow, I don’t understand how the drug would even help.
The same goes for APT production. The section of the webpage I quoted mentions muscular APT production, and I’m assuming that’s different to how neurons in the brain produces ATP?
Have they published anything that demonstrates that beta-receptor autoantibodies are causing issues in pwME/CFS?
I don’t follow.
In which cells is mitochondrial ATP production impaired?
And what is immune exhaustion?
Forget about edema, I’m not even sure why it’s mentioned. As you correctly noted, it has nothing to do with ME/CFS or GWI. It might be relevant for other conditions, but not these.
The brain is highly dependent on a constant supply of energy and oxygen. If blood flow is impaired, mitochondria in the brain may not get enough oxygen, which makes it difficult for them to produce ATP efficiently.
Several groups have published studies showing elevated antibodies against beta receptors in subsets of patients. Patient IgG can alter β-AR signaling in functional assays, and removing IgG via immunoadsorption can temporarily improve symptoms.
See:
Immunoadsorption to remove ß2 adrenergic receptor antibodies in Chronic Fatigue Syndrome CFS/ME
Introduction Infection-triggered disease onset, chronic immune activation and autonomic dysregulation in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) point to an autoimmune disease directed against neurotransmitter receptors. We had observed elevated autoantibodies against ß2...
journals.plos.org
There are also trials with Daratumumab, which aims to eliminate the B cells that produce these antibodies. A phase 1 study already showed some impressive results.
The drug from mitodicure mainly targets muscle cells. Here’s why: According to their ME/CFS hypothesis, mitochondria switch to an anaerobic state because muscles don’t get enough oxygen. This affects the sodium–calcium exchanger.
Rob Wüst’s muscle biopsy study showed that after exertion, sodium builds up outside muscle cells, a clear sign the sodium–calcium exchanger isn’t working properly. This excess sodium causes cells to take in more calcium. Too much calcium inside the cell damages mitochondria.
As a result, mitochondria produce only about 2 ATP instead of roughly 32, switching to anaerobic energy production. Glucose is used instead of fatty acids, and lactate forms. This contributes to muscle fatigue in ME/CFS. Reactive oxygen species (ROS) are also generated, adding oxidative stress.
In ME/CFS, the immune system can become overworked and stop responding effectively. T cells need a lot of energy (ATP) to work properly, and if their energy supply is low, they can become “exhausted.” This immune exhaustion can make it harder for the body to control latent viruses like EBV. As a result, the immune system may produce more antibodies because it can’t fully keep the virus in check.
Recommended video for explanation:
Utsikt
Senior Member (Voting Rights)
It doesn’t seem like that claim holds up under scrutiny:The brain is highly dependent on a constant supply of energy and oxygen. If blood flow is impaired, mitochondria in the brain may not get enough oxygen, which makes it difficult for them to produce ATP efficiently.
Several groups have published studies showing elevated antibodies against beta receptors in subsets of patients. Patient IgG can alter β-AR signaling in functional assays, and removing IgG via immunoadsorption can temporarily improve symptoms.
See:
Immunoadsorption to remove ß2 adrenergic receptor antibodies in Chronic Fatigue Syndrome CFS/ME
Introduction Infection-triggered disease onset, chronic immune activation and autonomic dysregulation in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) point to an autoimmune disease directed against neurotransmitter receptors. We had observed elevated autoantibodies against ß2...
I’m well aware of the Daratumumab pilot. If there is a real effect, we have no idea about why there is an effect. Tying it to specific autoanitbodies is very speculative.
All of this is still hypothetical, we’re very far off from knowing the pathology. So designing a drug around it seems to me to be a bit premature.
Immune cells are not muscle cells, though. So how would a drug targeting muscular ATP production affect T cells’s ATP production?
There isn’t really any evidence of latent EBV infections being involved in ME/CFS.
Even if you’d accept this hypothesis that lower APT production in EBV-antibodies or other immune cells result in more EBV-antibodies being produced, how would increased EBV-antibodies cause any issues like those we see in ME/CFS?