Article: Ottawa IACFS/Conference Reports V: The Brain.....

You can view the page at http://forums.phoenixrising.me/content.php?548-Ottawa

 

Awesome article with terrific broad overview, thank you Cort.
Al'

 

Awesome article with terrific broad overview, thank you Cort.
Al'

Thanks! I like how all these brain regions are connected to each other and the results are starting to converge. Miller will be an interesting guy to keep an eye on as well as the epigenetic stuff. Dr. Vernon said they recently learned that epigenetic changes can occur almost instantly - thereby providing a gene silencing mechanism that might be able to account for rapid onset.

Check this out - and please don't worry about the description of ME/CFS as a 'behavioral disorder' since what he is suggesting is that an immune factor, the same as seen in people with IFN-a induced fatigue in hepatitis - is present in CFS. The amazing thing is that that oligoadenylate synthetase is good old RNase L!

RNase L has been a dead duck in CFS research for years now and all of a sudden it pops up - in this study of fatigued hepatitis patients. (RNase L is a product of the IFN system - so it does make sense that it might pop up - but to link to fatigue in this group of patients - that's pretty darn good!

I was bowled over when I say Miller mention CFS in the abstract.

Psychol Med. 2011 Dec 9:1-13. [Epub ahead of print]
Molecular signatures of peripheral blood mononuclear cells during chronic interferon-? treatment: relationship with depression and fatigue.
Felger JC, Cole SW, Pace TW, Hu F, Woolwine BJ, Doho GH, Raison CL, Miller AH.

BACKGROUND:

Interferon-alpha (IFN-?) treatment for infectious disease and cancer causes high rates of depression and fatigue, and has been used to investigate the impact of inflammatory cytokines on brain and behavior. However, little is known about the transcriptional impact of chronic IFN-? on immune cells in vivo and its relationship to IFN-?-induced behavioral changes.MethodGenome-wide transcriptional profiling was performed on peripheral blood mononuclear cells (PBMCs) from 21 patients with chronic hepatitis C virus (HCV) either awaiting IFN-? therapy (n=10) or at 12 weeks of IFN-? treatment (n=11).

RESULTS:

Significance analysis of microarray data identified 252 up-regulated and 116 down-regulated gene transcripts. Of the up-regulated genes, 2'-5'-oligoadenylate synthetase 2 (OAS2), a gene linked to chronic fatigue syndrome (CFS), was the only gene that was differentially expressed in patients with IFN-?-induced depression/fatigue, and correlated with depression and fatigue scores at 12 weeks (r=0.80, p=0.003 and r=0.70, p=0.017 respectively).

Promoter-based bioinformatic analyses linked IFN-?-related transcriptional alterations to transcription factors involved in myeloid differentiation, IFN-? signaling, activator protein-1 (AP1) and cAMP responsive element binding protein/activation transcription factor (CREB/ATF) pathways, which were derived primarily from monocytes and plasmacytoid dendritic cells. IFN-?-treated patients with high depression/fatigue scores demonstrated up-regulation of genes bearing promoter motifs for transcription factors involved in myeloid differentiation, IFN-? and AP1 signaling, and reduced prevalence of motifs for CREB/ATF, which has been implicated in major depression.

CONCLUSIONS:

Depression and fatigue during chronic IFN-? administration were associated with alterations in the expression (OAS2) and transcriptional control (CREB/ATF) of genes linked to behavioral disorders including CFS and major depression, further supporting an immune contribution to these diseases.

 

Thanks Cort - it's all on way now and very interesting to follow. (Can't help thinking just how much ME is advancing the whole of medical understanding).

 

I wish some more of the recognized names in ME research would do more in this area. There is rightly a lot of research done on the immune system but I think more could be done on the brain. I've been thinking for a while that advances will probably come from a different field such as research into autism, MS, Alzheimers, etc. It's discouraging and surprising that there isn't a whole lot to show in those diseases that have been recognized to have damage to the brain; and they receive so much more funding.

 

I wish some more of the recognized names in ME research would do more in this area. There is rightly a lot of research done on the immune system but I think more could be done on the brain. I've been thinking for a while that advances will probably come from a different field such as research into autism, MS, Alzheimers, etc. It's discouraging and surprising that there isn't a whole lot to show in those diseases that have been recognized to have damage to the brain; and they receive so much more funding.

I agree Floydguy. My gut says the brain is key here. It is interesting how little researchers look to neurological disorders to understand ME/CFS. Chaudhuri and Behan did about 10 years ago - they neurologically fatiguing disorders directly to ME/CFS but after that there isn't alot. I wonder about ADHD as well - my guess is that there's alot of it in ME/CFS.

It'll be interesting to see what the Biovista drug project funded by the CAA will turn up. I wouldn't be surprised if it focuses on drugs used to treat other neurological disorders.

 

What does any of this mean in terms of tests we and order and treatments that can be prescribed to us... today? Time is running out, my condition only worsens year by year, and there's no telling how much of the damage is recoverable.

 

Dr. Miller wasnt sure, though, that whatever started the problem is still there, and he talked about an alternative culprit to pathogens. Studies have shown that immune activation can trigger the methylation process to turn genes on or off permanently causing what is called epigenetic changes.

I am glad researchers are seriously looking at methylation as one of the culprits. Global hypomethylation with local hypermethylation is one characteristic on cancer, for instance. I am convinced, thanks to Rich Van Konynenburg, that normalizing methylation is one of the most important steps in the path to recovery.

By the way, Rich Van Konynenburg generally hangs out in the "Detox: Methylation\B12\Glutathione\Chelation\..." forum.

 

Great article with a wonderfully broad sweep across brain research, thanks, I learned a lot.

That was some session with Andrew Miller, I would love to have been there (OK, I wouln't have lasted 5 minutes, but you know what I mean), really fascinating and such a shame he won't be pursuing his work on CFS - he has a fine record in brain research. Do you know when his paper will be published?

A note of caution, though. Brain studies are rarely, if ever, conclusive. Most brain-probing equipment e.g. MRI are expensive and time-consuming to use, so sample sizes tend to be very small. Without multiple replications the findings are indicative rather than definitive. That's certainly the case for the studies (well, abstracts) I've just looked at linking fatigue with dopamine or the basal ganglia. These are still early days.

I like the way Ben Natelson and Dikoma Shungu are evaluating several different brain abnormalities at once: assessing cognitive performance, blood flows and biochemical composition (eg lactate) [Research 1st article you link to]. If they can replicate multiple abnormalities in the same patients that will start to look really convincing.

A recent Miller paper suggested that the same processes occurring in IFN-a induced fatigue in hepatitis may be occurring in ME/CFS. Tying the fatigue processes in hepatitis C treatment and ME/CFS together would be a huge boost for ME/CFS

That's very interesting - do you have a reference? The MRC recently agreed funding for a UK study on fatigue and IFN-alpha (which I blogged about here).

Re molecular signatures during IFN-a therapy:

Genome-wide transcriptional profiling was performed on peripheral blood mononuclear cells (PBMCs) from 21 patients with chronic hepatitis C virus (HCV) either awaiting IFN-? therapy (n=10) or at 12 weeks of IFN-? treatment (n=11).

That's an awfully small sample for gene expression profiling, especially using a genome-wide chip, where false positives are very likely because of the huge number of genes analysed. The Lights, who have significantly larger samples in their work, use Quantitative Real-Time PCR (QT-PCR) to measure transciption, which is a more accurate process than microarrays. Best practice is, apparently, to use microarray chips (on larger samples) to identify interesting genes then follow-up with QT-PCR on those interesting genes. So this study is an intriguing pointer, but I'm not sure its any more than that at this stage.

And I agree the Insular Cortex is a really interesting candidate for playing a key role in ME. Incidentally, there is some evidence that the Insular Cortex works intimately with the Anterior Cingulate Cortex (ACC), which your piece also mentions as having a possible role in ME.

(Can't help thinking just how much ME is advancing the whole of medical understanding).

I certainly agree that when we finally do crack ME it will involve a breakthrough in understanding how the body/brain works. Whatever the 'thing' is that is broken in ME/CFS is, I strongly suspect it is something that is largely unknown to medicine today.

It's discouraging and surprising that there isn't a whole lot to show in those diseases that have been recognized to have damage to the brain; and they receive so much more funding.

Maybe we shouldn't be so surprised, or discouraged: the brain is regularly described as 'the last great frontier in biology' and is easily the most complex thing in the known universe - so getting anywhere is not going to be easy.

 

Thanks Oceanblue,

Miller was just a great guy - he was very willing to talk and obviously very interested in the subject. It would have been great to have you there to make sense of it all

Don't know about the date of the paper - it will certainly be this year - the CDC has already stated that - but don't know when.

Thanks for insight on the sample size - something I often don't think to check. I imagine that its all pretty exploratory until we get big sample sizes and multiple validations. I wonder how in the world with all that data they will be able to zero on the same factor or gene.......

 

I am glad researchers are seriously looking at methylation as one of the culprits. Global hypomethylation with local hypermethylation is one characteristic on cancer, for instance. I am convinced, thanks to Rich Van Konynenburg, that normalizing methylation is one of the most important steps in the path to recovery.

By the way, Rich Van Konynenburg generally hangs out in the "Detox: Methylation\B12\Glutathione\Chelation\..." forum.

I'm not sure how it all fits together but it certainly does make methylation more interesting.....I didn't know that it played such a crucial part in gene expression. Dr. Vernon recently that epigenetic changes can occur almost overnight and Miller indicates that they may be able to be changed almost overnight...

 

Thanks Oceanblue,

Miller was just a great guy - he was very willing to talk and obviously very interested in the subject. It would have been great to have you there to make sense of it all

Don't know about the date of the paper - it will certainly be this year - the CDC has already stated that - but don't know when.

Thanks for insight on the sample size - something I often don't think to check. I imagine that its all pretty exploratory until we get big sample sizes and multiple validations. I wonder how in the world with all that data they will be able to zero on the same factor or gene.......

Thanks for all that. Generally, the more data you have, the easier it is to see the real signal (gene, factor, whatever) against the 'noise' (false positives) - it's a statistics thing.

 

I have to say (and I need to read it all through again more carefully) but I am delighted and reassured at the same time to hear that brain-related research has not been lost in the mists of time.

I understand that it is often the case only autopsies reveal physical damage when performed on patients with ME and that it isn't always clear whether any damage is due to the condition - largely because the research just has never been there.

There is I think more that can be done with scanning on live patients and through the establishment of biobanks as well as means to register oneself for autopsy-tissue analysis upon death.

Also pleased to see Behan and Chaudhri getting a mention. Ten years! Blimey. Just goes to show that the ball may have been dropped but has now perhaps bounced (hopefully)

 

Also pleased to see Behan and Chaudhri getting a mention. Ten years! Blimey. Just goes to show that the ball may have been dropped but has now perhaps bounced (hopefully)

Balls dropped but getting picked up again

• Chaudhuri and Behan's neurological findings
• Heart stuff from Peckerman/Natelson by the Japanese
• ??????

 

What does any of this mean in terms of tests we and order and treatments that can be prescribed to us... today? Time is running out, my condition only worsens year by year, and there's no telling how much of the damage is recoverable.

I'm sorry to hear that.... I really don't know. All I can say is that researchers are converging on several areas of th brain - and that is good news. How long it will all take to produce something concrete that will help I have no idea. Things can happen quickly in medicine or take a long time. The more minds focused on a subject the better.

I was just talking to one Dr. Peterson's assistants and the CFI Lipkin pathogen study is really something...that study should start getting results later this year. Montoya should be publishing this year ..

Some people who are in terrible, terrible shape do recover....I don't think there's necessarily a point beyond which you can not return. Good luck!

 

You are avoiding me Cort - great guys or not is of no relevance - this is not a popularity poll. THIS is about the scientific/medical understanding of a disease known as ME/CFS - sorry. Stick with science/findings. And try not to expose your own personal animosities against those who tried/try to unravel.

And the poor rats - try amygdela training .

Why are you so foolish. Have you not known the very worst. Obviously not.

No I haven't known the very worst - not even clse- its never been pleasant...Not sure how I'm avoiding you though...