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Increased Ventricular Lactate in CFS

Discussion in 'Latest ME/CFS Research' started by merylg, Jan 28, 2012.

  1. merylg

    merylg Senior Member

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    Sydney, NSW, Australia
  2. Glynis Steele

    Glynis Steele Senior Member

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    Love this bit - "Chronic fatigue syndrome (CFS) is a complex illness, which is often misdiagnosed as a psychiatric illness"

    Increased ventricular lactate in chronic fatigue syndrome. III. Relationships to cortical glutathione and clinical symptoms implicate oxidative stress in disorder pathophysiology.


    Shungu DC, Weiduschat N, Murrough JW, Mao X, Pillemer S, Dyke JP, Medow MS, Natelson BH, Stewart JM, Mathew SJ.
    SourceDepartment of Radiology, Weill Medical College of Cornell University, New York, NY, USA. dcs7001@med.cornell.edu.

    Abstract
    Chronic fatigue syndrome (CFS) is a complex illness, which is often misdiagnosed as a psychiatric illness. In two previous reports, using (1) H MRSI, we found significantly higher levels of ventricular cerebrospinal fluid (CSF) lactate in patients with CFS relative to those with generalized anxiety disorder and healthy volunteers (HV), but not relative to those with major depressive disorder (MDD). In this third independent cross-sectional neuroimaging study, we investigated a pathophysiological model which postulated that elevations of CSF lactate in patients with CFS might be caused by increased oxidative stress, cerebral hypoperfusion and/or secondary mitochondrial dysfunction. Fifteen patients with CFS, 15 with MDD and 13 HVs were studied using the following modalities: (i) (1) H MRSI to measure CSF lactate; (ii) single-voxel (1) H MRS to measure levels of cortical glutathione (GSH) as a marker of antioxidant capacity; (iii) arterial spin labeling (ASL) MRI to measure regional cerebral blood flow (rCBF); and (iv) (31) P MRSI to measure brain high-energy phosphates as objective indices of mitochondrial dysfunction. We found elevated ventricular lactate and decreased GSH in patients with CFS and MDD relative to HVs. GSH did not differ significantly between the two patient groups. In addition, we found lower rCBF in the left anterior cingulate cortex and the right lingual gyrus in patients with CFS relative to HVs, but rCBF did not differ between those with CFS and MDD. We found no differences between the three groups in terms of any high-energy phosphate metabolites. In exploratory correlation analyses, we found that levels of ventricular lactate and cortical GSH were inversely correlated, and significantly associated with several key indices of physical health and disability. Collectively, the results of this third independent study support a pathophysiological model of CFS in which increased oxidative stress may play a key role in CFS etiopathophysiology. Copyright 2012 John Wiley & Sons, Ltd.
    ahimsa likes this.
  3. Vitalic

    Vitalic Senior Member

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    Seems to fit with the partial methylation cycle block hypothesis, although oxidative stress is most likely an effect rather than the root cause so unfortunately it doesn't get us any closer to the holy grail.
  4. alex3619

    alex3619 Senior Member

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    This is the latest update on an old saga. I was first reading about this kind of thing since the 90s. It points strongly to a defect in energy metabolism, but doesn't identify the cause by itself. Bye, Alex
  5. ramakentesh

    ramakentesh Senior Member

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    Increased oxidisive stress is also associated with chronic inflammatory diseases and in POTS at least, high plasma levels of Angiotensin II
  6. Marco

    Marco Old blackguard

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    Unless there is more discussion in the full paper, it seems strange to start the abstract with the statement that "Chronic fatigue syndrome (CFS) is a complex illness, which is often misdiagnosed as a psychiatric illness" and then present results that appear to show no diffference (on these measures anyway) between CFS and major depressive disorder (MDD).


    Not that this causes a problem for those who support the cytokine theory of depression.
  7. richvank

    richvank Senior Member

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    Hi, all.


    In this paper, Dr. Shungu et al. found:

    (1) elevated lactate in the ventricular cerebrospinal fluid, as they had found earlier,

    (2) depletion of glutathione in the occipital cortex, and

    (3) decreased regional blood flow in the left anterior cingulate cortex and right lingual regions of the brain, together with a trend in the data suggesting more widespread hypoperfusion in the brain.

    I think this is a very significant paper. It appears to provide some support for Marty Pall's NO-ONOO- model, for my Glutathione Depletion--Methylation Cycle Block (GD-MCB) model, and I think also for Ritchie Shoemaker's capillary hypoperfusion model. I must leave it to Prof. Pall and Dr. Shoemaker to comment on how it fits with their models.

    As far as the GD-MCB model is concerned, I would say that the results of this study are very consistent with it. To have a direct measurement of glutathione in the brain, and to find that it is depleted, is very supportive of this model.

    As with most studies, while it gives us some important data, it also leaves some questions unanswered. As we know, correlation does not show causality. The elevated lactate suggests that the mitochondria are not functioning properly, which has been shown very well for the mitochondria (at least in the neutrophils) by Dr. Sarah Myhill et al. Mito dysfunction is also a component of the GD-MCB model, in which it is proposed that the depletion of glutathione and the concomitant oxidative stress (which can be either a cause or an effect of glutathione depletion, or both) is the first contributor to mitochondrial dysfunction.

    Decreased cerebral blood flow has been shown in ME/CFS before, and there are a number of possible contributing causes, some of which are suggested in the GD-MCB model.

    One thing that they did not find was evidence of an impact on the ATP supply, which suggests either that the mitochondria were not extremely dysfunctional, or that the deficit in ATP production is being made up for by increased glycolysis, or both. I suspect that the latter is the case, given the observed elevated lactate. Because the brain operates in an isolated manner from the peripheral tissues of the body, I don't think there is a conflict between the Myhill et al. study and this one.

    Best regards,

    Rich
    Snow Leopard likes this.
  8. kaffiend

    kaffiend Senior Member

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    Hi Rich,

    Are you familiar with the lactate shuttle hypothesis? As I understand it (probably poorly), lactate produced from anaerobic glycolysis in astrocytes is then released from astrocytes and provides the primary metabolic fuel for neurons. When oxidative phosphorylation is activated in neurons (dendrites), it causes a decrease in mitochondrial NADH content. Recovery of the mitochondrial NADH in dendrites is accomplished by stimulation of the TCA cycle, fueled by lactate from the extracellular pool. This part of the cycle apparently needs a constant supply of NAD+. I had been thinking a while back that an error in this cycle is revealed as elevated lactate in the ventricles and CSF.

    I wonder if there are any established links between GSH status and this supply...
  9. richvank

    richvank Senior Member

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    Hi, kaffiend.

    I have read about the lactate shuttle hypothesis. I may be misunderstanding what you are asking, but it seems to me that when oxidative phosphorylation is activated, NADH will be converted to NAD+ by giving up and electron and hydrogen. So the NAD+ will then be available to be converted again to NADH by the TCA cycle.

    I don't know of a link between GSH and NAD+ supply directly. However, it is known that when GSH is oxidized to GSSG excessively, both the TCA cycle and the respiratory chain are inhibited. This constitutes mitochondrial dysfunction, and when it occurs, glycolysis speeds up to make up for the loss in ATP production by the mitochondria.

    Best regards,

    Rich
  10. ramakentesh

    ramakentesh Senior Member

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    It will be interesting to see how this pans out as previously Julian Stewart's team have focused purely on brain blood flow, POTS and perhaps ROS vasoconstriction.
  11. Snow Leopard

    Snow Leopard Senior Member

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  12. Enid

    Enid Senior Member

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    Nice to see this one - thanks meryl.
  13. Guido den Broeder

    Guido den Broeder *****

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    Has anyone read the full text?
  14. Dolphin

    Dolphin Senior Member

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    Yes, I just did. Well worth a read. It's a more thoughtful paper than the abstract suggests - they don't give up on the other theories and even point out why there could have been problems with their study which might put some theories back in the frame.
    A big problem was that it was relatively underpowered. But I like how they investigate issues which might otherwise have been skipped e.g. there was a fairly consistent low level of hypoperfusion in the MDD and CFS groups although it didn't reach significance in most places (but they add the percentages together to show the total effect). (This is covered in Figure 8).
    -----
    The MATERIALS AND METHODS could probably be skipped by most people as it's generally not discussing CFS specifically and is also the most technical part.
    Here are bits in it that I underlined:

    (It is later pointed out that the Puri paper didn't deal with this issue well which might have caused a problem in it)

  15. Dolphin

    Dolphin Senior Member

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    I think it might have benefited from discussion of some of the biological abnormalities that have been found in Major Depressive Disorder (MDD). I'm not an expert but I have seen various names of studies by Michael Maes MD PhD where he makes some comparisons between MDD and CFS - and from memory, they were about oxidative stress. No Maes paper is mentioned.

    This makes the correlations in Table 3 between more physical measures and (separately) GSH and lactate (in the three groups combined) more interesting. They also give the individual data in Figures 6 which I always like (although it's only for a few of the measures).

    Similarly they give scatter plots in Figure 4 for the GSH and lactate levels for the three groups (rather than just getting the mean and SD).
  16. ramakentesh

    ramakentesh Senior Member

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    Anyone else ever wonder whether the blood brain barrier is comprimised in CFS?
  17. Snow Leopard

    Snow Leopard Senior Member

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    I don't so much wonder whether it is compromised all the time, but whether it was compromised during the initial onset of the disease...
  18. ramakentesh

    ramakentesh Senior Member

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    The reason I ask is the consistent reports from patients of peripheral-acting medications causing CNS symptoms and sensitivities. Sympathetic activity alone can alter blood brain barrier permiability.
    merylg likes this.

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