Article: Australian CFS Science Symposium Overview by Rosamund Vallings

You can view the page at http://forums.aboutmecfs.org/content.php?309-Australian-CFS-Science-Symposium-Overview-by-Rosamund-Vallings

 

Choline on the Brain

This is from an article I wrote about increased choline findings in the brain in ME/CFS

http://www.aboutmecfs.org/Rsrch/CholineBrain.aspx

Putting It All Together CFS is a Disease of Increased Phospholipase (PLA) Activity - Chaudhuri and Behan suggest increased choline levels contribute to cognitive dysfunction (effortful task processing) and reduced ATP levels impair aerobic metabolism and contribute to the exercise intolerance seen in CFS. What might increased brain choline and decreased ATP production have in common? Chaudhuri and Behan believe both are due to increased phospholipase (PLA) activity. This appears to suggest they believe increased PLA activity occurs not just in the brain but is system wide. Since PLA is ubiquitous in the body increased PLA activity could affect a wide variety of tissues.


Phospholipases (PLAs) Phospholipase activity releases factors that exert widely varying effects in the cell. Phospholipids play a key role in regulating the release of arachidonic acid, the precursor of eicocanisoid synthesis. The eicocansoids (prostaglandins, thromboxanes, leukotrienes) mediate (trigger) the inflammatory process. A marker of cellular injury, the inflammatory process begins with the release of AA. AA is broken up to produce pro-inflammatory mediators such as prostaglandins (SEE MERUK research) (COX 1, 2) and leukotrienes. Prostaglandins then combine with cellular receptors to initiate signaling cascades which utilize G-proteins and cyclic CMP (cAMP) to produce pro-inflammatory substances.

TRIGGERING PHOSPHOLIPASE ACTIVITY - Why phospholipase activity would be increased in CFS patients is unclear. CFS patients appear to be subject, however, to several factors (infection, increased neurotransmitter/ cytokine levels, oxidative stress, neurotoxins) that could trigger phospholipase activity. Chaudhuri et. al. note that infection and/or neurotoxins can produce prolonged changes in membrane functioning (Chaudhuri et. al. 2003). The authors suggest the adaptation of the host cell to either a pathogen or its exotoxin (neurotoxin) could result in a long term derangement of the membranes.

Viruses Viruses can induce phospholipase activation and the release of lipids including choline by effecting membrane permeability.Indeed, many bacteria, viruses and parasites utilize lipid rich membrane domains as routes of entry into the cell. Does the lack of immune activation (inflammation) in the brains of CFS patients suggests either an ongoing pathogenic attack is not involved or that it occurs without evoking an immune response (?).The possibility that a neurogenic pathogen could trigger PLA activity immediately brings up the question of two viruses, HHV6 and EBV, that have been historically linked with CFS.

HHV6 infects the very cells Chaudhuri and Behan posit may be producing the choline peaks in CFS. The HHV6 foundation suggests HHV6 activity in the glial cells could cause fatigue by altering ion channel function. HHV6 is ubiquitous in the human population; almost everyone has been exposed to it by third year. The lack of an antigenic response to HHV6 in healthy controls suggests it remains in its latent state most of the time. In vitro studies indicate HHV6 is able to infect a number of nervous system cells including neurons, astrocytes, oligodendrocytes, microglial cells).

Astrocytes, in particular, appear to function as latent reservoirs for the virus. Antigenic responses to HHV6 in MS and a type of encephalitis indicates HHV6 reactivation occurs in some neurological disorders. PCR analysis has indicated HHV6 is present in encephalitis, meningitis, febrile seizure and encephalopathy. HHV6 reactivation occurs in two neurological diseases, multiple sclerosis (MS) and Guillain-Barre syndrome, in which fatigue is a prominent symptom (Dewhurst 2004).

 

Brainstem

Brainstem grey matter changes suggest a failure of cerebrovascular auto-regulation, potentially mediated by astrocytes. Astrocyte dysfunction may therefore be central to CFS pathogenesis. There seems to be disrupted autonomic nervous system homeostasis. He does not feel it is reduced blood volume that will be causing this.

Here's from a Baraniuk Paper - Spinal Tapping for ME/CFS

http://www.aboutmecfs.org/News/BrainProteomeMar10.aspx

Focus on the Brainstem - In particular hes focused on the gating mechanisms in the lower part of the brain that filter the amount of information that the upper part of the brain receives. He believes that the neural circuits running from the spinal cord to the brainstem are not working properly and that the system that should close and latch those gates is dysfunctional.

These gates filter out unnecessary information and protect the brain from being flooded with too much information. He believes theyve been left wide open in chronic fatigue syndrome (ME/CFS). The most critical neural circuit appears to be the Papez Circuit which ties together the anterior cingulate, amygdala and hippocampus. Its associated with heightened awareness and anxiety and effects autonomic nervous system functioning.

Interestingly studies have shown that the gating mechanisms involving pain are wide open in fibromyalgia patients. (FM patients display over activation of the pain producing and under activation of the pain inhibiting circuits in the brain. Dr. Baraniuk believes ME/CFS, FM, GWS, etc. are all subsets of each other.) Which problem is accentuated in each person may depend on where small ruptures in the blood vessels occur.
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Marvellous news Cort - thanks for posting. At last seems to tackle all the problems one intuitively knows/experiences in ME. All the world ahead of the UK now. Well done Oz. Still stuck in maladaptive behaviour here.

 

A lot of information!! Appears that they are getting closer and closer. I believe sometime in the 26th century there will be a such thing as "money for research!"

 

Hi Rosamund, thanks for this summary.

I find the MRI of the brainstem issue a little worrying. Reduced white matter volume means less connection between nerve cells. This implies less coordination of autonomic regulation at a physiological level. While it is theoretically reversible, since the nerves aren't gone, it will require a lot of time and hard work (rehab) to restore them. Worse, there is probably not enough research in this area to suggest how to rehab this system. So even with a "cure", there will still be autonomic dysregulation.

I find it amusing that the research is now moving back to where I was at in the 90s. Autonomic dysregulation was a big thing with my doctor/researcher back then, and he had been tracking and treating autonomic dysregulation in ME/CFS since the late 80s. Nobody would listen to him however, and his published papers didn't even make a splash.

It is also amusing that he showed symptom variation in women depending on hormone cycles, in the late 90s. The research world is finally starting to catch up to where he was, but it still has a way to go. His name: Dr. Andriya Martinovic, Brisbane, Australia.

Bye
Alex

PS I tried posting this earlier, but as it looked like crashing I cut and pasted my comment. Sure enough, it crashed.

 

Peterson - He then went on to discuss the importance of looking at viral infections in CFS. Leukotropic herpes viruses particularly HHV6, HCMV and EBV are among a number of major candidates in CFS. He reported on large studies in which active HHV6 was detected in 28%, HCMV in 29% and EBV in 51%. 10% were co-infected. Active EBV infection significantly correlates with the presence of auto-antibodies, with antibodies directed at thyroid peroxidase and parietal cells.

Up to 30% of patients may respond to antiviral medication.

Here's the first subset I think - the herpesvirus/viral subset. This is what the CDC, in particular, has missed all these years. And how interesting about all this auto-immune stuff that starts showing up - active EBV somehow triggers antibodies directed at a thyroid enzyme....there's the apparent Rituximab success - either at dampening down auto-immune processes or herpesvirus infections....The CAA tried to get grants for TWO auto-immune studies that were just loaded with new investigators.....this thing seems like its teetering on the edge..

Not alot of co-infections, thank god - just finding out who in the 30% has what and trying to treat them.....Obviously we need more studies...if this is going to get out - it has to be published, which Montoya is apparently about to do.

 

A lot of information!! Appears that they are getting closer and closer. I believe sometime in the 26th century there will be a such thing as "money for research!"

That is just too funny

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I hope earlier - if the State of the Knowledge conference digs into this kind of stuff - we're in good shape I think

 

Are we actually getting a post-exertional malaise - the BIGGIE in ME/CFS? (Look at what the Pacific Fatigue lab has done - exercise challenges are re-writing the research map in CFS; making people with ME/CFS exercise is how you get measurable results - too bad they didn't figure that out 20 years ago but now they have.....)

Exercise produces an inflammatory cascade that wipes out natural killer cells ability to function (and probably T cells as well - since they use perforin too)...

It appears to freak out IL-1. Here's what Il-1 does: it causes a wide spectrum of metabolic, physiological, haematopoietic activities, and plays one of the central roles in the regulation of the immune responses. (Bye-bye homeostasis ). Although there are many interactions of IL-1α with other cytokines, the most consistent and most clinically relevant is its synergism with TNF. (the big bad pro-inflammatory cytokine) There are, in fact, few examples in which the synergism between IL-1α and TNFα has not been demonstrated. These include radioprotection, the Shwartzman reaction, PGE2 synthesis, sickness behavior, nitric oxide production, nerve growth factor synthesis, insulin resistance, loss of mean body mass, and IL-8 and chemokine synthesis.[14] (So many connections)

The exercise challenge was 8 minutes on an exercycle with measurement of VO2 max. The gene expression showed significant differences in those with GWI and CFS. (By case definition GWI and CFS meet the same criteria). Immunological pathways were similarly affected – these were mainly inflammatory, and the immune cascade led to many symptoms 4 hours later. Symptoms involved the endocrine, immune, autonomic and neurological systems. The genes regulating NK function which included abnormal perforin and granzyme levels were affected.

She then went on to describes Broderick’s 3 basic elements of analysis of immune signals, and related this to the states after the 8 minute challenge:

1. Those that looked different
2. Those that hang out with a different crowd
3. Those that behave differently (altered response dynamics)

In this study there was persistent inflammation, a surge in immune interaction and an IL-1 “splash” effect. There was a huge cascade effect in 8 minutes and persisting 4 hours later. Homeostasis is “messed up” and needs to remodel.

 

Using ROC, NPY was found to be 80% sensitive in CFS, (which is better than the PSA test we use to help diagnose cancer of the prostate). NPY also correlates with markers of disease severity. Other potential biomarkers using this technique included 10 of 16 cytokines measured, NK cell cell function and dipepdyl peptidase/CD26 which is indicative of immune activation. This is all part of a complex integrated system.

In the futureexercise challenge will be included in testing this paradigm, and computer analysis will be developed to stimulate research in further clinical trials. These abnormalities may have applications in other diseases.

She didn't even NEED to do an exercise challenge to get at NPY; imagine what she'll find when she makes people with ME/CFS hop up on a bike! NPY is associated with irritability and aggressiveness - my irritability goes through the rough when I exercise too much. My body feels hot and angry.......I imagine my NPY levels are through the roof which makes sense since exercise will trigger SNS activity.

 

She didn't even NEED to do an exercise challenge to get at NPY; imagine what she'll find when she makes people with ME/CFS hop up on a bike! NPY is associated with irritability and aggressiveness - my irritability goes through the rough when I exercise too much. My body feels hot and angry.......I imagine my NPY levels are through the roof which makes sense since exercise will trigger SNS activity.

I have noticed an immense anger in me, that sometimes surfaces. I have attributed it to the fact I am frustrated I am sick (I didn't feel this anger before I got sick). But maybe the sickness is actually causing part of the anger... interesting.

 

I too recall the emotion side being very much involved. Sometimes actually "witnessing" an anger surge for no apparent reason (as if some mechanism in the brain is malfunctioning). And again the reverse and for no apparent reason "witnessing" (not depressed) but sudden onset streaming eyes and nose - all associated with sorrow out of control. Frankly too tired (sleeping mostly) to find the emotion to be sorry about anything at all at the time.

 

Lol, have you read the d-lactic thread? Anger is commonly reported, irritability, abusive behaviour, as well as the usual, lethargy etc

Glynis

 

Good idea Glynis - its past time to do that.

:innocent1::innocent1::innocent1::innocent1::innocent1:

 

Can I add that although disabled from reactives (my Neurologist said so - Osteoarthritis - until viral research finds which) impairment to brain function is reversible. From not being able to recall my own name to conversing here (plus the Times Crossword now) is evidence.

 

Lol, have you read the d-lactic thread? Anger is commonly reported, irritability, abusive behaviour, as well as the usual, lethargy etc

Glynis

Oh yes and treating it, ME much more than that, no particular gut problems at onset, came later. Not abusive I hope?

 

Enid, do you mean you have tested positive for dla? Deffo not abusive Who tested you for it, a GI?

 

Hi Cort,

Yay, hope someone "goes for it". They would need to be tested as late in the day as poss, as dla builds up during the day, after each carb containing meal, carbing up is good too. And to check the path lab can test for it, as a lot can't. Needs a d-lactate assay kit.

Best

Glynis

 

Can I add that although disabled from reactives (my Neurologist said so - Osteoarthritis - until viral research finds which) impairment to brain function is reversible. From not being able to recall my own name to conversing here (plus the Times Crossword now) is evidence.

Congratulations ENID! How did you do it?

 

Enid, do you mean you have tested positive for dla? Deffo not abusive Who tested you for it, a GI?

We are tested for very little here. Just NHS basics. So one is left from very early on to try to understand all the escalating symptoms and aid oneself (plus family etc) Now I,m able to eat I treat acidosis with good proprietries knowing it is an aid only.