Tuesday, 12 April 2016

CSF lactate is a brain health indicator

Albanese M, Zagaglia S, Landi D, Boffa L, Nicoletti CG, Marciani MG, Mandolesi G, Marfia GA, Buttari F, Mori F, Centonze D.

Cerebrospinal fluid lactate is associated with multiple sclerosis disease progression. 

J Neuroinflammation. 2016 ;13(1):36. doi: 10.1186/s12974-016-0502-1.

BACKGROUND:Altered cerebrospinal fluid (CSF) levels of lactate have been described in neurodegenerative diseases and related to mitochondrial dysfunction and neuronal degeneration. We investigated the relationship between CSF lactate levels, disease severity, and biomarkers associated with neuroaxonal damage in patients with multiple sclerosis (MS).

METHODS:One-hundred eighteen subjects with relapsing-remitting multiple sclerosis (RRMS) were included, along with one-hundred fifty seven matched controls. CSF levels of lactate, tau protein, and neurofilament light were detected at the time of diagnosis. Patients were followed-up for a mean of 5 years. Progression index (PI), multiple sclerosis severity scale (MSSS), and Bayesian risk estimate for multiple sclerosis (BREMS) were assessed as clinical measures of disease severity and progression. Differences between groups and correlation between CSF lactate, disease severity and CSF biomarkers of neuronal damage were explored.

RESULTS:CSF lactate was higher in RRMS patients compared to controls. A negative correlation was found between lactate levels and disease duration. Patients with higher CSF lactate concentration had significantly higher PI, MSSS, and BREMS scores at long-term follow-up. Furthermore, CSF lactate correlated positively and significantly with CSF levels of both tau protein and neurofilament light protein.

CONCLUSIONS:Measurement of CSF lactate may be helpful, in conjunction with other biomarkers of tissue damage, as an early predictor of disease severity in RRMS patients. A better understanding of the alterations of mitochondrial metabolic pathways associated to RRMS severity may pave the way to new therapeutic targets to contrast axonal damage and disease severity.



When things go badly, they go stupendously wrong - it's a long habit that is hard to kick in life, and the human body is no different

Lactate, whether in serum or in the CSF, is one such indicator of this, and not very specific for a particular disease process (unlike the implications in the opening sentence of the abstract above). Indeed, I have found raised lactate levels to be useful in supporting my suspicions of a seizure, bacterial meningitis, stroke, and a mitochondrial disorder, in the past

CSF lactate is produced by anaerobic metabolism in the brain (see figure above) and increases in any condition that causes a decrease in brain oxygen supply. The investigators did not find any correlations with contrast-enhancing lesions on MRI (not surprising as this only a snap shot of the brain) or relapses (reporter dependent and excludes sub-clinical relapses). They do, however, report a weak correlation with markers of axonal damage Tau and neurofilament light chain (r=0.26 and 0.32, respectively).

This doesn't mean it's useless marker, in fact, it has a place as a diagnostic test for establishing rapidly and reliably that there's something wrong in the brain. Further more targeted testing can always be performed afterwards in order to establish the specifics.

12 comments:

  1. Why is there no oxygen available in MS patients that causes this production of this CSF lactic acid?

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    1. There is oxygen otherwise you would be dead, however the brain uses the most energy of any organ, you know that when you excerise your muscles make lactic acid.

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    2. Why, in MS patients, is there increased anaerobic metabolism (less brain oxygen supply not zero oxygen supply) and increased CSF production of lactate in comparison to the normal population? Is there local vasoconstriction or lack of blood flow in areas damaged by MS in the CNS that contributes to this hypoxia and increased CSF lactic acid?

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    3. The hypothesis is that there is dysfunction of the mitochondria which leads to alternate pathways being utilised.

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    4. Interestingly, the opposite effect, upregulation of oxidative phosphorylation (inverse Warburg effect), may be involved in neurodegeneration in Alzheimer's and Parkinson's diseases. Why is MS different?

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    5. The reverse Warburg effect I suspect is a compensatory response in AD and PD to boost energy production. MS doesn't get into this problem as there is sufficient number of mitochondria which can keep the status quo, although there is evidence of stress as reflected by the increase in lactate production. The problem in MS is probably being driven by external reactive oxygen species predominantly which then results in mitochondrial dysfunction. By the time PD is evident in subjects the deterioration in the system is much further along the line. If you look at MPTP (drug) induced parkinsonism the defect is at Complex I of the electron transport chain, which parallels what we observe in MS. Although, all of this is pure speculation.

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    6. Very interesting speculations, thank you.

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  2. Does lactate in the blood correlate with lactate in the CNS? it would be very nice to have a simple blood test to monitor MS.

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    1. I agree a blood test would be useful, but unfortunately blood lactate levels don't correlate with CSF levels. Blood lactate levels are often an indication of muscle lactic acid production e.g seen in mitochondrial disease and during a generalised seizure where there is vigorous muscle contraction.

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  3. NDG is there any paper analyzing Creatine for mitochondrial ATP production deficiency in those with MS?

    I've read about research on the Coenzyme Q10 (Idebenone, Mito Q, etc.) and Vitamin B12 (in methylcobalamin form) for the treatment of poorly functioning mitochondria in MS, I'm just not finding where I saved the links of studies ...

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    1. If you put Coenzyme or Idebenone in the search box you'll come across the previous posts.
      With creatine - J Diet Suppl. 2008;5(1):20-32. Effect of creatine supplementation on muscle capacity in individuals with multiple sclerosis. Malin SK1, Cotugna N, Fang CS.

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