Two-Strike Alzheimer's Theory, B12, methylation blocks and ME/CFS
Writing, as always, as an enthusiastic amateur...
ETA: These thoughts seem to be rather off-topic now but arose from thoughts around discussions earlier in the thread and from further thoughts after reading Dr Cheny's comments - do let me know if I should take them elsewhere...
This reminds me of the three strike theory on the cause of CFS (and often mentioned in autism too):
Underlying Immune Defect/Genes (ex: polymorphisms, methylation etc)
Infection (ex: Viral/retroviral/Lyme)
Toxin (ex: Mold, Mercury, Carbon Monoxide etc)
OR
Trauma (something that destabilizes the immune system)
Infection
Toxin
you get the picture...
The theory is it takes all three in a short period of time to cause an illness like CFS.
The more I look at it the more it seems to make sense - it unifies a number of other proposed causes.
Elisabeth
I agree Elisabeth, that a picture seems to emerge...
I find a number of further confirmations in Dr Cheney's comments that seem very consistent not only with a model of XMRV latent and reactivated infection, but also with the rather broader proposed models of both ME/CFS and neuro-immune pathophysiology. As I explore around this I even begin to wonder about some aspects of neuro-psychiatric disease also.
It might or might not help if I broaden the picture considerably in considering the first model above. I came across the following "2-strike" model from the Institute of Psychiatric Research, Indiana University, which seems to me to be similar to one of the "3-strike" models, in that the two strikes may only hit home at those with specific vulnerabilities, but note that this model allows that they need not take place within a short space of time.
The proposed vulnerabilities, in the case of ME/CFS at least, that enable the two-strike process are that (eg) APOBEC3 and RNAsel mutations may mean that some of the
DNA methylation defence mechanisms are unable to "tidy up" certain types of infected cells - they can no longer mutate the infected DNA so as to render rogue sequences harmless.
So here's the '2-strike' theory affecting those with genetic vulnerabilities...in Alzheimer's...extracts from the abstract...
http://www.ncbi.nlm.nih.gov/pubmed/20064601
The neurodegenerative disorder Alzheimer's disease (AD) is the 6th leading cause of death in the USA. In addition to neurological and psychiatric symptoms, AD is characterized by deficiencies in S-adenylmethionine (SAM), vitamin B12, and folate. Deficiency in these nutrients has been shown to result in gene promoter methylation with upregulation of AD-associated genes.
While some cases of AD are due to specific mutations in genes such as presenilin 1 (PSEN) and the amyloid-beta peptide precursor protein (APP), these familial AD (FAD) cases account for a minority of cases. The majority of genetic contribution consists of risk factors with incomplete penetrance.
Several environmental risk factors, such as cholesterol and diet, head trauma, and reduced levels of exercise, have also been determined for AD. Nevertheless, the majority of risk for AD appears to be established early in life.
We propose to explain this via the LEARn (Latent Early-life Associated Regulation) model. LEARn-AD (LAD) would be a "two-hit" disorder, wherein the first hit would occur due to environmental stress within the regulatory sequences of AD-associated genes, maintained by epigenetic changes such as in DNA methylation. This hit would most likely come in early childhood. The second hit could consist of further stress, such as head trauma, poor mid-life diet, or even general changes in expression of genes that occur later in life independent of any pathogenesis. Given that the primary risk for LAD would be maintained by DNA (hypo)methylation, we propose that long-term nutritional remediation based on the LEARn model, or LEARn-based nutritional gain (LEARnING), beginning early in life, would significantly reduce risk for AD late in life.
The model seems to be quite similar:
1. In early life, environmental stress (in the broadest sense) can affect the regulation of relevant genes through the DNA methylation process. In effect, certain genes become 'tagged' in what amounts to a long-term memory mechanism. Hypo-methylation, or a block in the methylation process, maintains this process.
2. Later in life, under extreme stress (perhaps repeating the same or similar environmental conditions and/or with the same or similar deficiencies of SAM, B6, B9, B12?) a second hit occurs and reactivates the latent learned environmental damage.
This only seems to make sense to me by imagining the situation as an invasion which is sufficiently severe as to 'breach the inner walls' and infect the system itself - the situation can be brought under control, but whenever the same type of invader is encountered again, there are enemies lurking inside the walls...and the immune vulnerabilities are essentially weaknesses in the process for identifying and rooting out those intruders.
Thinking more generally there are several connections which the above-mentioned paper highlights which overlap with ME/CFS - the hypo-methylation, the B12 deficiency, the role of genetic vulnerabilities, the 2-strike hypothesis: the combination of early environmental risk factors and later severe stress and trauma; perhaps most importantly the result being neurological symptoms...I find myself particularly struck by the involvement in this story of two more connections which I've saved to last in this list: psychiatric symptoms and trauma in early childhood - because at this point we may risk wandering into the territory of neuropsychiatry...
And yet perhaps we must: As I peruse the exclusionary conditions for a Fukuda diagnosis I'm struck by the thought that the following Fukuda exclusionary conditions lie in the range of
ideopathic psychiatric conditions, and that these too presumably ultimately involve neuropathology: major depressive disorder with psychotic or melancholic features; bipolar affective disorders; schizophrenia of any subtype; delusional disorders of any subtype; dementias of any subtype; anorexia nervosa; or bulimia nervosa.
These conditions are, presumably, specifically exclusionary because they may otherwise present with the same or similar symptomology to ME/CFS - and if so, then might there be aspects of the pathophysiology in common also? It seems possible, at least. Perhaps a clue lies in the role of B12 deficiency in both of the above proposed models of the pathophysiology: a recent study in Alzheimer's adds to the evidence associating B12 and B6 deficiency with an increased rate of loss of neural tissue.
Here are some papers on B12 deficiencies in Alzheimer's and in CFS:
http://www.ncbi.nlm.nih.gov/pubmed/19276548
http://www.ncbi.nlm.nih.gov/pubmed/7976784
http://www.ncbi.nlm.nih.gov/pubmed/20815176
http://www.ncbi.nlm.nih.gov/pubmed/11365011
And also if the gut is dysfunctional and unable to absorb B12 and/or B6, perhaps even due to a deficient enzyme produced by a messed-up gene...then neural degeneration and further breakdown of the methylation process might be expected and there is the potential for a vicious cycle of inability to cope with DNA degradation.
Moreover that vicious cycle is only maintained in the case of XMRV by cortisol and hormones - which will eventually be depleted causing the replication process to subside, whereupon XMRV can be seen as parasite (as indeed can any such "corruption sequence" that thrives on the body's stress responses be seen as parasite), replicating only when the host is able to mount a "fight" mode, as soon as the host becomes energetic, and otherwise lying dormant in or around the regulator genes - potentially still causing deficiencies such as selected vitamin uptake inhibition, and thus impairing neurological maintenance and other fuctions.
This whole pattern seems to fit the strange patterns of ME/CFS symptomology very well. We seem to be describing an immune deficiency syndrome in which the pathogen is somewhat synergistic with the host, via its dependence on the host's stress responses.
Finally, what's also striking to me is the way that these emerging theories seem so consistent with anecdotal observations about both the common patterns of personal histories of ME/CFS illness progression, and also accounts of family histories. There is quite a bit of interest already, of course, in sporadic ME/CFS/XMRV connections to early-onset and childhood Alzheimer's, which I've most recently seen discussed in this thread of Gerwyn's:
http://www.mecfsforums.com/index.php/topic,1715.0/prev_next,next.html#new
Of course what would be needed to confirm all of the above, is more evidence - and so as we know only too well, of one thing we can be confident: more research is required...