Neuroinflammation in Patients with CFS/ME: PET study

[RustyJ]

Source: PubMed

J Nucl Med. 2014 Mar 24. [Epub ahead of print]

Neuroinflammation in Patients with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: An 11C-(R)-PK11195 PET Study.

Nakatomi Y1, Mizuno K, Ishii A, Wada Y, Tanaka M, Tazawa S, Onoe K, Fukuda S, Kawabe J, Takahashi K, Kataoka Y, Shiomi S, Yamaguti K, Inaba M, Kuratsune H, Watanabe Y.

Abstract
Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a disease characterized by chronic, profound, disabling, and unexplained fatigue. Although it is hypothesized that brain inflammation is involved in the pathophysiology of CFS/ME, there is no direct evidence of neuroinflammation in patients with CFS/ME. Activation of microglia or astrocytes is related to neuroinflammation. 11C-(R)-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinoline-carboxamide (11C-(R)-PK11195) is a ligand of PET for a translocator protein that is expressed by activated microglia or astrocytes. We used 11C-(R)-PK11195 and PET to investigate the existence of neuroinflammation in CFS/ME patients.

METHODS:
Nine CFS/ME patients and 10 healthy controls underwent 11C-(R)-PK11195 PET and completed questionnaires about fatigue, fatigue sensation, cognitive impairments, pain, and depression. To measure the density of translocator protein, nondisplaceable binding potential (BPND) values were determined using linear graphical analysis with the cerebellum as a reference region.

RESULTS:
The BPND values of 11C-(R)-PK11195 in the cingulate cortex, hippocampus, amygdala, thalamus, midbrain, and pons were 45%-199% higher in CFS/ME patients than in healthy controls. In CFS/ME patients, the BPND values of 11C-(R)-PK11195 in the amygdala, thalamus, and midbrain positively correlated with cognitive impairment score, the BPND values in the cingulate cortex and thalamus positively correlated with pain score, and the BPND value in the hippocampus positively correlated with depression score.

CONCLUSION:
Neuroinflammation is present in widespread brain areas in CFS/ME patients and was associated with the severity of neuropsychologic symptoms. Evaluation of neuroinflammation in CFS/ME patients may be essential for understanding the core pathophysiology and for developing objective diagnostic criteria and effective medical treatments.

 

[RustyJ]

I haven't read the full paper and probably wouldn't understand it anyway, but the levels indicated seem staggering but what I find most bewildering is that it has taken so long for this study to be undertaken.

 

[Beyond]

Not only is has taken long to do the study but it will take longer before the medical community at large acknowledges this and what it means in CFS/ME therapeutics.

 

[Marco]

Source: PubMed

J Nucl Med. 2014 Mar 24. [Epub ahead of print]

Neuroinflammation in Patients with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: An 11C-(R)-PK11195 PET Study.

Nakatomi Y1, Mizuno K, Ishii A, Wada Y, Tanaka M, Tazawa S, Onoe K, Fukuda S, Kawabe J, Takahashi K, Kataoka Y, Shiomi S, Yamaguti K, Inaba M, Kuratsune H, Watanabe Y.

Abstract
Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a disease characterized by chronic, profound, disabling, and unexplained fatigue. Although it is hypothesized that brain inflammation is involved in the pathophysiology of CFS/ME, there is no direct evidence of neuroinflammation in patients with CFS/ME. Activation of microglia or astrocytes is related to neuroinflammation. 11C-(R)-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinoline-carboxamide (11C-(R)-PK11195) is a ligand of PET for a translocator protein that is expressed by activated microglia or astrocytes. We used 11C-(R)-PK11195 and PET to investigate the existence of neuroinflammation in CFS/ME patients.

METHODS:
Nine CFS/ME patients and 10 healthy controls underwent 11C-(R)-PK11195 PET and completed questionnaires about fatigue, fatigue sensation, cognitive impairments, pain, and depression. To measure the density of translocator protein, nondisplaceable binding potential (BPND) values were determined using linear graphical analysis with the cerebellum as a reference region.

RESULTS:
The BPND values of 11C-(R)-PK11195 in the cingulate cortex, hippocampus, amygdala, thalamus, midbrain, and pons were 45%-199% higher in CFS/ME patients than in healthy controls. In CFS/ME patients, the BPND values of 11C-(R)-PK11195 in the amygdala, thalamus, and midbrain positively correlated with cognitive impairment score, the BPND values in the cingulate cortex and thalamus positively correlated with pain score, and the BPND value in the hippocampus positively correlated with depression score.

CONCLUSION:
Neuroinflammation is present in widespread brain areas in CFS/ME patients and was associated with the severity of neuropsychologic symptoms. Evaluation of neuroinflammation in CFS/ME patients may be essential for understanding the core pathophysiology and for developing objective diagnostic criteria and effective medical treatments.

Finally!

If this is the same study, the abstract appeared a few years ago as a poster but for some reason wasn't published.

Time (overdue) for a proof of concept trial using minocycline; low dose naltraxone or similar?

 

[A.B.]

How reliable is this test for diagnostic purposes?

 

[Seven7]

I argue with my Neuro that I have inflamation and he said that is imposible (I feel it in brain and spine too). And I could prove it because after I just saw him (was not able to sleep at all even on sleep meds for 2 weeks) the citokine profile inflamatory citokines were throguh the roof. I also get bumps in my head like I fell or got hit by a bat. Arggggg This is so important I hope we could help fund more of this work.

 

[user9876]

What looks particularly interesting is their result that says the values in different parts of the brain correlate with fatigue, pain and depression scores. With such a small sample it seems dangerous to make too many conclusions but its good to see some form of correlation which might hint at mechanism. Hence it would be good to see them hypothesize a model or two which could then be tested further.

In CFS/ME patients, the BPND values of 11C-(R)-PK11195 in the amygdala, thalamus, and midbrain positively correlated with cognitive impairment score, the BPND values in the cingulate cortex and thalamus positively correlated with pain score, and the BPND value in the hippocampus positively correlated with depression score.

 

[snowathlete]

Looks like it could be a signficant finding.
It's the sort of thing which deserves an article because it helps give exposure to the findings, and increases the chance of them doing more research into it.

 

[Gijs]

This study needs to be replicated in a big cohort. Then this will be a significant finding! I don't know how much the cost is for one PET scan.

 

[Firestormm]

Finally!

If this is the same study, the abstract appeared a few years ago as a poster but for some reason wasn't published.

Time (overdue) for a proof of concept trial using minocycline; low dose naltraxone or similar?

See today's conference article - Day Four IACFS/ME. This was presented there I believe and Komaroff makes reference to it in his summation.

 

[RustyJ]

See today's conference article - Day Four IACFS/ME. This was presented there I believe and Komaroff makes reference to it in his summation.

Did Komaroff make an assessment of the study, eg its significance? Can't see it.

It is not so easy to dismiss this study just because of small cohort. As noted, the fact that reported symptoms correlate with pet scans, and are the same reported symptoms of major community, means that this study appears to be on the right track.

 

[Sidereal]

I hope these preliminary findings are replicated in a larger sample. The medical community frequently asserts that there is no evidence for the -itis (signifying inflammation) part of myalgic encephalomyelitis and that it is a bogus name patients use to add grandeur to some trivial imaginary non-disease they have.

 

[Seven7]

Probably because u Have the ME Vs the wates baskets, Vs Lyme Vs all soubgroups. I have the feeling this is only a soubgroup.

 

[Marco]

See today's conference article - Day Four IACFS/ME. This was presented there I believe and Komaroff makes reference to it in his summation.

Thanks Firestorm

Actually I should amend my previous post re any potential 'proof of concept' therapeutic trials. Of course replication with a larger cohort would be desirable plus there may be other potential markers of neuroinflammation (elevated quinolinic, kynurenic acid resulting from the Trycat/IDO pathway; other objective measures such as aberrant ERPs as seen in other conditions where neuroinflammation is suspected) that might provide converging evidence.

Even then a therapeutic intervention may not be straightforward. As I understand it, generally short term neuroinflammation (following injury or CNS infection) is considered neuroprotective while chronic neuroinflammation is neurotoxic - but this is very much a simplification/generalisation. Neuroinflammatory processes appear to be both neuroprotective and neurotoxic depending on many factors. If you had an ongoing infection of the CNS for example then neuroinflammation may be playing a protective role. Activated microglia produce elevated TNF-a amongst many other 'pro-inflammatory' messengers. The temptation might be to block TNF-a, but if I remember correctly such an approach actually hastened disease progression in MS.

Which is a very long-winded way of saying that considerable caution is warranted but I'd REALLY like to see these findings followed up.

 

[Seven7]

What did Ramsey used??? Or the guy that came up w the ME name? I forgot I think it was from the hopkins place maybe we can find his study and try to duplicate.

 

[user9876]

As I understand it what is being detected is activated microglia rather than inflammation but they normally associate.

The PK11195 binds with high affinity to TSPO receptors on activated microglial cells and is also radio labelled so that it can be picked up by the PET scan.

I found this slide set quite interesting talking about the technique and using it to explore cognitive dis-function in HIV patients.

http://www.bhiva.org/documents/Conferences/2012Birmingham/Presentations/120419/LucyGarvey.pdf

 

[Marco]

I hope these preliminary findings are replicated in a larger sample. The medical community frequently asserts that there is no evidence for the -itis (signifying inflammation) part of myalgic encephalomyelitis and that it is a bogus name patients use to add grandeur to some trivial imaginary non-disease they have.

Problem is the lack of evidence for 'itis' is due to the old fashioned notion that inflammation must inevitably result in gross (and visible) physiological damage such as edema or tissue loss. In the same manner that ME/CFS is not usually considered a peripheral inflammatory disorder such as rheumatoid arthritis since there is no detectable tissue damage. Ramsey's use of 'itis' in this context became a big bullseye to be shot at by those pushing other 'models'.

More recently a more subtle neuroimmune mediated neuroinflammation is being recognised in a wide range of disorders from autism to Alzheimers that often doesn't result in obvious structural change but can be detected via techniques such as functional MRI, radiolabeled ligands and PET (as in this study) or examination of CSF metabolites etc. Perhaps analogous to the 'low grade systemic' inflammation found peripherally in conditions like diabetes.

 

[Marco]

Probably because u Have the ME Vs the wates baskets, Vs Lyme Vs all soubgroups. I have the feeling this is only a soubgroup.

I'd tend to disagree. I've a feeling that neuroinflammation may be the common end point and core pathology in those labeled with ME/CFS despite what are likely to be a wide range of triggers.

 

[SOC]

I hope these preliminary findings are replicated in a larger sample. The medical community frequently asserts that there is no evidence for the -itis (signifying inflammation) part of myalgic encephalomyelitis and that it is a bogus name patients use to add grandeur to some trivial imaginary non-disease they have.

What I remember hearing is that they object to the -myelitis part -- that we don't have evidence of inflammation of the myelin sheath. This research does not support -myelitis, as far as I can tell. According to this research, we might be more appropriately be said to have Myalgic Encephalitis, if I'm reading things correctly (which I don't guarantee).

Not that there haven't been people saying there's no evidence of encephalitis, either, but their argument has never been very strong given the number and nature of neurological difficulties we exhibit.

 

[A.B.]

I'd tend to disagree. I've a feeling that neuroinflammation may be the common end point and core pathology in those labeled with ME/CFS despite what are likely to be a wide range of triggers.

Neuroinflammation also makes it easier to explain/accept the heterogeneousness of symptoms.