Thursday, May 22, 2014

Evidence of Encephalitis in ME/CFS

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21 May 2014 <<<<
Editorship : j.van.roijen@chello.nl                                 
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References:

ME/CFS- Neuroinflammation-
11C-(R)-PK11195 PET Study, Help ME Circle,
26 March 2014 - Co-Cure: http://bit.ly/Q2goiC
 
PET Scan Diagnostic Test ME/cfs, Help ME
Circle, 9 April 2014 - Co-Cure: 
bit.ly/1mCWDL4

~jvr

````

http://bit.ly/1jqjNV6

Phoenix Rising

First Direct Evidence of
Neuroinflammation -
'Encephalitis' - in ME/CFS

April 29, 2014

Simon McGrath reports on the new study that
indicates low-grade encephalitis in ME/CFS …

A small study ( http://1.usa.gov/1gXZSpv) with
just nine patients has captured the attention of
patients and researchers alike after reporting
direct evidence of inflammation in the brain of
ME/CFS patients. The finding was one of the
highlights picked out by Professor Anthony
Komaroff in his IACFS/ME conference round up
( http://bit.ly/1jBbTXd).

Back to the future

What makes this study so fascinating is that it
provides tantalising evidence supporting not only
of current views that inflammation in the brain is
central to understanding the disease, but also of
Melvin Ramsay's original name of 'myalgic
encephalomyelitis' ( http://bit.ly/1lyBkGp).

Encephalomyelitis is inflammation of the brain
and spinal column, and critics of the name
pointed to the lack of direct evidence for
inflammation of either. This study only looked at
the brain, not the spinal column (so could only
find encephalitis), but the immune cells found to
be activated in the brain are also present in the
spinal column.

The study

To see if there is immune activation in the brain,
researchers need to look inside the brain -
which is not so easy if you want patients to still
be alive when your study is done.

The scientists in this study, led by Dr. Yasuyoshi
Watanabe from the RIKEN institute in Japan,
used PET & MRI (
http://1.usa.gov/1jHwNA3)
imaging to peer into the brain.

What make this study work is the use of tiny
quantities of a radioactive tracer that binds to
specific proteins that appear on activated
microglia (the main immune cells of the brain)
but crucially doesn't bind to non-activated
microglia. The marker also binds to activated
astrocytes, which play an immune role in the
brain. The brains of nine ME/CFS patients
meeting both Fukuda and International
Consensus Criteria were compared with those
of 10 healthy controls.

The results showed that neuroinflammation
markers were higher for patients than controls
across many brain areas including the thalamus,
the pons and the midbrain. They also found that
the severity of symptoms correlated with the
degree of inflammation in multiple brain regions,
particularly for cognitive functioning.

It was the correlation between a biological
finding -  neuroinflammation -  and clinical
problems that Komaroff found so exciting about
this work, because it suggests a biologically
plausible explanation for the symptoms of
ME/CFS:

"[If replicated] it would, for me, say that there
is a low-grade, chronic encephalitis in these
patients
, that the image we clinicians have of
encephalitis as an acute and often dramatic
clinical presentation that can even be fatal has
-  may have -  blinded us to the possibility that
there may be that long-lasting -  many years
long -  cyclic chronic neuroinflammation is
underlying the symptoms of this illness."


Representative PET scans showing activated
microglia in a CFS/ME patient.
Key to brain regions: AMY, amygdala; CC,
cingulate cortex; HIP, hippocampus; MID,
midbrain; THA, thalamus; and PON: pons.
Photo credit: Image courtesy of RIKEN

Intriguingly, the midbrain, thalamus and
amygdala -  all regions where cognitive problems
correlate with neuroinflammation -  are also all
part of neural circuits involved in awareness,
arousal and attention. Concentration problems
are typical of ME/CFS, and one of the problems
found most consistently in laboratory testing
( http://bit.ly/1oCcThB).

Replication needed

While tantalising, these findings are far from
conclusive, as the authors acknowledge. The
study has only nine patients, albeit diagnosed
with ICC criteria. The tracer used to identify
activated immune cells produces a very 'noisy'
signal, giving rather indistinct readings, and the
overall level of neuroinflammation was relatively
low.

Although cognitive issues correlated with
neuroinflammation in several areas, generally
other symptoms, including fatigue, did not
significantly correlate with inflammation.

There was almost no sign of inflammation in the
prefrontal cortex, the region of the brain most
involved in higher cognitive functions, that might
be expected to be a problem in ME/CFS. And
there was a potential technical weakness in the
way the study was run.

Commenting on the neuroinflammation, Komaroff
emphasised the need for replication:

"If it were confirmed by multiple other
investigators … these data are consistent with
[encephalitis], but I would feel more strongly if
other labs using same technology came up with
the same result."

The good news is that the authors of this study
are already working on a new study using the
same patients but with a newer and more
sensitive tracer to pick up neuroinflammation.
They will address the earlier technical issue, and
to make the study more powerful they will also
be looking at neurotransmitter activity in the
brain, following up their previous findings
( http://1.usa.gov/1gEb9Ci) of neurotransmitter
abnormalities.

Hopefully independent groups will try to replicate
this finding too – and in the U.K., Dr. Charles
Shepherd of the ME Association has already said
it would welcome applications to fund a
replication attempt.

Microglia -  key to ME/CFS?

So neuroinflammation -  specifically activation of
microglia -  correlates with cognitive problems,
but how might microglial activation cause the
problem?


The most plausible answer is through what is
termed 'sickness behaviour' -  a characteristic
set of responses to infection, including fatigue,
malaise joint and muscle pain and problems
concentrating -  which might just sound familiar
to ME/CFS sufferers. ['Sickness behaviour' is a
lousy name for biological phenomenon, as Dr.
Dan Peterson has noted (
http://bit.ly/1iZjwTg)].

Microglia are known to play a key role in
regulating sickness behaviour, and that's a big
reason this study has attracted so much
attention in ME/CFS.

The fatigue, malaise, problems concentrating,
etc., of sickness behaviour help us survive an
infection by forcing us to rest so our body can
devote all its resources to the energy-greedy
immune system.

However, sickness behaviour is normally a
short-lived response to an acute infection,
designed to temporarily divert resources to
ensure a swift recovery. If that doesn't happen,
e.g., if there is a chronic infection, or the
process goes wrong, for instance, if microglia
remain activated after an infection has been
cleared, then sickness behaviour can itself be a
problem. ME/CFS may be an example of this.
  
Cytokines in the spotlight

Cytokines are a key trigger for sickness
behaviour, and researchers have often found
elevated cytokines in patients, but the findings
have been inconsistent and in small studies.

The new studies reported on by Dr. Jose
Montoya at the Stanford conference and Dr.
Mady Hornig at the IACFS/ME conference are
helping to firm up these findings in huge cohorts.

Probably the most important piece of work on
the role of sickness behaviour -  and cytokines
-  in ME/CFS came from the landmark "Dubbo"
studies.

The researchers found that about 11% of those
with (
http://1.usa.gov/1tiaDfo) glandular fever
and two other infections developed CFS after six
months.

And crucially, what predicted the length of the
illness (and chance of developing CFS) wasn't
psychological factors, but the severity of the
initial 'acute illness', or sickness behaviour.

The researchers also showed
( http://1.usa.gov/1mVV3nJ) that those with
more active genes for the pro-inflammatory
cytokine Interferon-gamma had a more severe
sickness behaviour (and longer illness) than
those with regular versions, linking cytokine
response to sickness behaviour and ME/CFS.

The Dubbo study did not look at
inflammation in the brain, but the authors
did speculate that the cause of CFS could be
long-term activation of microglia and
astrocytes.

And that is exactly what was found in this
new PET imaging study.

As with all research findings, replication is
essential, and a new version of the Dubbo study
is currently under way in Sydney, Australia.

The new imaging study from Japan has found
provisional evidence of activated astrocytes and
microglia cells (both types of glial cell) in the
brain of ME/CFS patients. This is support for the
suggestion from the Dubbo team that ME/CFS
develops from certain infections as a result of
activation of brain microglia.

Dr. Michael VanElzakker's recent vagus nerve
infection hypothesis ( http://bit.ly/1j6Jnsz) also
features glial cells heavily. And recently
Professor Hugh Perry, who has studied microglial
cells in neurodegenerative diseases such as
Parkinson's disease, proposed that primed
microglia ( http://bit.ly/1qTOiXF) and sickness
behaviour lie at the heart of ME/CFS.
  
Neuroinflammation and Sickness
Behaviour the final common path
in ME/CFS?

It may prove to be that 'neuroinflammation' -
i.e., activated microglia in the brain/spinal
column -  is a common endpoint of numerous
triggers, including glandular fever (EBV), other
infections, vaccines -  or even, as Dr. Lipkin has
proposed, disturbances in the microbiome
(http://bit.ly/R7daul ).

Discovering if this is the case -  and firming up
the finding of neuroinflammation is key -  could
be a big step forward in understanding and then
treating ME/CFS.

And those it is still very early days, it is possible
this approach could eventually show that Dr
Ramsay was right about 'encephalomyeltitis'.

Watch out for a new blog on sickness behaviour,
microglia, cytokines and their role in ME/CFS,
coming soon.

``
        
Harvard Professor Tony Komaroff on these PET
findings, and their potential importance:

Starts at 30' 10'', Q&A re encephalomyelitis @ 37'
http://bit.ly/1n0Oss5



Simon McGrath

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