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Multimodal and simultaneous assessments of brain and spinal fluid abnormalities in CFS

Kati

Patient in training
Messages
5,497
Multimodal and simultaneous assessments of brain and spinal fluid abnormalities in chronic fatigue syndrome and the effects of psychiatric comorbidity

Benjamin H Natelson, Xiangling Mao, Aaron J Stegner, Gudrun Lange,
Diana Vu, Michelle Blate , Guoxin Kang , Eli Soto, Tolga Kapusuz,
Dikoma C Shungu


The purpose of this study was to investigate whether CFS patients without comorbid psychiatric diagnoses differ from CFS patients with comorbid psychiatric diagnoses and healthy control subjects in neuropsychological performance, the proportion with elevated spinal fluid protein or white cell counts, cerebral blood flow (CBF), brain ventricular lactate and cortical glutathione (GSH).

The results of the study did not show any differences in any of the outcome measures between CFS patients with and without psychiatric comorbidity, thus indicating that psychiatric status may not be an exacerbating factor in CFS.

Importantly, significant differences were found between the pooled samples of CFS compared to controls.

These included lower GSH and CBF and higher ventricular lactate and rates of spinal fluid abnormalities in CFS patients compared to healthy controls.

Thirteen of 26 patients had abnormal values on two or more of these 4 brain-related variables.

These findings, which replicate the results of several of our prior studies, support the presence of a number of neurobiological and spinal fluid abnormalities in CFS.

These results will lead to further investigation into objective biomarkers of the disorder to advance the understanding of CFS.

Highlights

As a group, CFS patients have higher brain ventricular lactate, more abnormal spinal fluid results, lower brain GSH, and reduced cerebral blood flow relative to healthy sedentary controls

Psychiatric comorbidity does not influence any of these potential biological markers of CFS

50% of the patients had more than one of these abnormalities

The subgroup of patients with brain abnormalities may have an underlying encephalopathy producing their illness


This research was supported by NIH grant NS-075653 to BHN.
 

Research 1st

Severe ME, POTS & MCAS.
Messages
768
A previous study from Natelson & Shungu "Increased Ventricular Lactate in CFS" discussed here

http://forums.phoenixrising.me/index.php?threads/increased-ventricular-lactate-in-cfs.14392/

Thanks for this previous study to the one we are discussing, you reminded me of other studies that came before Ben Natelson et al's work that could help bolster it:

Namely back in 2009:


And then 2010:


So I make that four studies from three different research groups, regarding brain lactate?
Two from Natelson et al (2012, 2017), and one from Matthew et al (2009), and one from Murrough et al (2010) that demonstrate elevated lactate in the spinal fluid/brain of CFS patients.


I hope Ron Davis is aware of this research as it could tie in precisely with his groups and allied groups findings that
the brain is going to get totally smashed by being so energy deficient.

Also if you knock the GSH out of your brain as the latest Natelson et al paper shows, it'll likely to age faster, and we've seen signs of brain abnormalities on scans before:

Such as this from last year:

 

Mohawk1995

Senior Member
Messages
287
Psychiatric comorbidity does not influence any of these potential biological markers of CFS

Exactly! Just because there are issues with brain biochemistry and neuro-physiology does not mean there is a psychiatric disorder. An "adjustment issue" related to having one of the most devastating diseases on planet earth...of course, but not a medical condition created by a psychiatric disorder. It appears that even if there is a psychiatric comorbidity it may have no greater influence on the person with CFS than if they did not have it.
 
Messages
43
This could be a strong proof for those who believe this is "somathic".
It's our time to refuse and condemn the idea of somatic illness.
Not because medicine can't explain what we have, it does mean all is in our mind.
 

Cohen2

Senior Member
Messages
119
Location
New Zealand
This is specifically known to happen in MELAS, a genetic mitochondrial disease which produces symptoms very similar to ME. Though I wouldn't be surprised if there's other known causes as well.

Is there any way to check whether you might have MELAS through 23Andme results?
 

Dolphin

Senior Member
Messages
17,567
This could be a strong proof for those who believe this is "somathic".
It's our time to refuse and condemn the idea of somatic illness.
Not because medicine can't explain what we have, it does mean all is in our mind.
Somatic = of the body/relating to the body (rather than, say, the mind).

So if somebody says it is a somatic illness that is not usually a problem.
 
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Research 1st

Severe ME, POTS & MCAS.
Messages
768
Is there any way to check whether you might have MELAS through 23Andme results?

From memory 23and ME isn't DNA sequencing but genotyping. Also they only look at part of your genes, not all, hence the cost is low. I think last year the first DNA sequencing tests came out, but they're around $1,000+? Also those tests don't show you if you 'have it' - a disease. At best, they show if you carry the gene for it, which is not a diagnostic tool.

If you had MELAS you'd have a rare form of dementia that can be diagnosed using biopsies:
http://www.medicinenet.com/melas_syndrome/article.htm#what_are_the_symptoms_of_melas

Although I believe science will show in the next few years, that severe ME lasting many decades will increase your chances of developing dementia (or share actual components of the causes of some dementia states - e.g certain infections or prions) we know that ME isn't currently known to be 'a' dementia state like MELAS even if it may share some components not yet agreed upon - such as high lactic acid.

The cruel thing is, without taking a dremel tool to ME CFS patients deceased bodies decades ago, no one has much knowledge - currently. For example how many of us on this forum have had a brain or a muscle biopsy? Or worse, how many people do we know who lost their lives to ME CFS have these tests on autopsy after their passing?

The knowledge we have is so poor, hence it's so easy to deny the legitimacy of our claims to relentless suffering, through blocking appropriate levels of research funding that would have given us much better knowledge than we currently have. Collectively, as patients, we know more than your average GP about our condition on a research level, on a mental health level and on a physical level. As they went to medical school and we didn't but we depend on them to stay alive - this is somewhat worrying...
 
Messages
15,786
Is there any way to check whether you might have MELAS through 23Andme results?
They miss the most common SNP to cause it, and also would miss any deletions or repeats which can cause it. Mine is A3796G (rs28357970) on MT-DN1. 23andMe hides it with one of their "i" numbers, i3002114. I started a list of other mutations causing mitochondrial disease, and plan to get back to working on that soon :p

Diagnosis of MELAS would primarily be through muscle biopsy. It can also be diagnosed through genetic sequencing of the mitochondria, but often must come from the affected tissue to show the relevant mutation. Due to heteroplasmy, it's very likely that saliva and blood won't contain the mutation, but the muscles will. Measurement of lactate in the CSF can also be part of the diagnostic process, and intermittent elevations of blood lactate also support a diagnosis.

If you had MELAS you'd have a rare form of dementia that can be diagnosed using biopsies:
This isn't true at all. People having repeated stroke-like episodes can certainly end up with severe neurological problems, but dementia or any other specific symptom is not required for diagnosis. That site seems to be of very poor quality, and they're listing some "symptoms" which are actually "signs".

Mitochondrial disease is primarily diagnosed genetically or via biopsy of the affected tissue. Due to the way mitochondrial diseases are passed on from the mother to the fetus, most tissues can lack the mutation at birth. The mutated cells can spread however, and take over a specific type of tissue. A common manifestation is in the eyes (LHON), and another features deafness & diabetes (MIDD). Dystonia can be caused as well.

MELAS is just another cluster of mitochondrial disease signs and symptoms, rather than a completely discrete disease itself, but where the muscles are significantly impacted. Exactly the same disease mutations can cause the different syndromes, depending on which cells are getting the bad mitochondria during fetal development.

And exactly the same mutation can cause onset at different ages, depending on how wide-spread the mutation is in the fetus. If there's a higher load of the mutated mitochondria, it'll be very apparent at birth or soon after. But it can also take decades for the mutated mitochondria to outnumber the healthy mitochondria, take over a tissue or organ, and trigger the associated symptoms.

The mutations can affect any part of the body, so can cause pretty much any symptom. However some symptoms are more common (or at least more commonly result in diagnosis), and some are also pretty distinctive, such as the hemiplegic episodes.
 
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Cohen2

Senior Member
Messages
119
Location
New Zealand
@Valentijn Thanks for your response. Its a shame 23andMe miss the related SNPs. I wonder how many people diagnosed with ME have mitochondrial diseases, as you say they can appear after childhood and seems that they may not be that easy to diagnose. Thats great that your compiling a list of mutations causing mitochondrial disease.

Im getting my mitochondria tested in a study im in. Im not sure exactly what theyre looking at yet but hopefully they find something. I have had at least three hemeplegic like episodes.
 
Messages
43
Neither do I.
I think "something" is affecting our body and this reacts with high inmunological response that affects ( among others ) nervous s.
As most neorological illness, our nervous sistem is malfuncioning and this biological impair translate in behaviour : slow, confused, cognitive impair, etc.
 

Snow Leopard

Hibernating
Messages
5,902
Location
South Australia
So I make that four studies from three different research groups, regarding brain lactate?
Two from Natelson et al (2012, 2017), and one from Matthew et al (2009), and one from Murrough et al (2010) that demonstrate elevated lactate in the spinal fluid/brain of CFS patients.

I think this is the fourth study from Shungu too.

It would be interesting to ask Natelson and Shungu to what these studies mean in terms of treatments.
 

Dolphin

Senior Member
Messages
17,567
I think this is the fourth study from Shungu too.

It would be interesting to ask Natelson and Shungu to what these studies mean in terms of treatments.

This was presented at the last IACFS/ME conference by them:

N-Acetylcysteine Alleviates Cortical Glutathione Deficit and Improves Symptoms in CFS: An In Vivo Validation Study using Proton Magnetic Resonance Spectroscopy

N. Weiduschata, X. Maoa, D. Vub, M. Blateb, G. Kanga, H.S. Mangatc, A. Artisd, S. Banerjeed, G. Langeb, C. Henchcliffec, B.H. Natelsonb, D.C. Shungua
a Departments of Radiology, c Neurology and Neuroscience, and d Healthcare Policy and Research, Weill Cornell Medicine, New York, NY, USA; b Department of Neurology, Mount Sinai Beth Israel Medical Center, New York, NY, USA;

OBJECTIVES We previously reported a robust 36% deficit of occipital cortex glutathione (GSH) – the primary tissue antioxidant – in patients with CFS compared to healthy comparison (HC) subjects, a finding that implicated oxidative stress in the disorder. The primary objective of the present study was to assess whether supplementing CFS patients with the GSH synthetic precursor N-acetylcysteine (NAC) daily for 4 weeks would spur in situ synthesis and significant elevation of cortical GSH compared to baseline, as assessed in vivo with proton magnetic resonance spectroscopy (1H MRS).

METHODS For this pilot clinical study, we recruited 16 medication-free patients meeting the CDC criteria for CFS and 15 HC subjects. Following baseline measurement of occipital cortex GSH with 1H MRS and administration of a battery of clinical assessments, both CFS and HC participants received a 4-week supplement of 1800mg NAC/day. After 4 weeks, identical 1H MRS scan and clinical assessments were conducted to determine the effect of NAC on cortical GSH levels and on CFS symptoms as assessed with the CDC CFS symptom inventory.

RESULTS At baseline, controlling for age and race, cortical GSH levels were 15% lower in CFS than in HC (95%CI: -0.0005,0; p=0.04, one-tailed as the differences and direction of changes were postulated a priori). Following 4 weeks of daily NAC supplementation, cortical GSH levels rose significantly relative to baseline (95%CI: 0.0001,0.0006; p=0.004, one-tailed) in CFS patients to match those in HC, which did not differ compared to baseline (95%CI: -0.0002,0.0003; p=0.33, one-tailed). Lastly, NAC supplementation markedly improved symptoms in CFS patients, with significant decreases in CDC CFS symptom inventory total scores (95%CI: -51.5-9.6; p=0.006), case definition scores (95%CI: -28.2-2 .0; p=0.03) and “other symptoms” scores (95%CI: -24.0-7.3; p<0.001). However, GSH levels did not correlate with any clinical measure.

CONCLUSION The results of this study have provided the very first direct evidence that NAC crosses the blood-brain barrier to spur in situ synthesis and elevation of cortical GSH. Significantly, increasing cortical GSH levels with NAC ameliorated symptoms in CFS patients. Future studies evaluating the clinical efficacy, and optimal dose and treatment duration of NAC are warranted.

Dikoma C. Shungu, Ph.D., Professor of Physics in Radiology, Fellow of the International Society for Magnetic Resonance in Medicine (FISMRM); Chief, Laboratory for Advanced MRS Research Citigroup Biomedical Imaging Center, Weill Cornell Medicine; 516 E 72nd Street, New York, NY 10065. Email: dcs7001@med.cornell.edu. Funding source: NIH Grant # 1 R21 NR013650. There are no conflicts of interest to declare or disclose.