“The decreased production [of BDNF] in those with CFS was unexpected and a novel finding. This finding could reflect a reduced ability to maintain neuronal structure and function in … CFS.” Authors
ME/CFS gets paired with another neuroimmune disorder and the results are illuminating
Chronic fatigue syndrome and multiple sclerosis don’t get paired in studies very often, and that’s a shame. Both are neuro-immune disorders and both are associated with enormous fatigue. The authors of this study suggested MS could provide something of a guide to research possibilities in ME/CFS, and after this study it’s hard to see how it could not.
Two Extremely Fatiguing Disorders
In the face of the neurological devastation visited upon people with MS we sometimes forget that fatigue is the most common and often the most disabling symptom present. It is fatigue that is the greatest contributor to disability in MS, and fatigue more than any other symptom determines the quality of life MS patients experience; the more fatigued an MS patient is, the lower their quality of life.
Note that, while fatigue is commonly found in diseases, the very severe and often disabling type of fatigue found in ME/CFS and MS is not common at all and is only shared by relatively few disorders.
As in ME/CFS, the cause of the fatigue in MS remains obscure. Pro-inflammatory cytokines with their ability to invoke ‘sickness behavior’ are a possibility. As in ME/CFS, the pro-inflammatory cytokine situation in MS is a complex one. Pro-inflammatory cytokines could both be part of the disease process and could be elevated by the psychological stressor associated with having MS.
Fatigue may be common in medicine but few diseases have the degree of fatigue found in Chronic Fatigue Syndrome and mulitiple sclerosis
Increased levels of tumor necrosis factor a (TNF-a) have been associated both with the demyelination processes occurring in MS and the stress associated with having the disease. TNF-a‘s contribution to the disease process in MS means that psychological stressors which elevate TNF-a in MS patients could worsen their MS.
Factors other than fatigue may bind ME/CFS and MS together. One of the first ME/CFS findings to appear was the presence of small white-matter hyperintensities in the brains of some people with ME/CFS. Those unidentified bright objects – most of them found in the frontal lobes – could reflect an immunological disease process in the central nervous system that has some similarity to that found in MS.
We’ve got immune and neurological problems and a large symptom overlap in ME/CFS and MS. What’s not to like about a study comparing the two?
Brain Derived Neurotrophic Factor (BDNF)
BDNF is a neurotrophic factor. Calling neurotrophic factors important nervous system agents is like calling eggs important ingredients in omelettes. Neurotrophic factors are involved in the proliferation, differentiation, maintenance, plasticity, survival and function of neurons in both the central and peripheral nervous systems. (What else is left?)
BDNF is the most abundant neurotrophic factor in our central nervous system. BDNF regulates the growth of nerve axons, neuron differentiation, proliferation and survival. It’s a key player in neuroplasticity – the ability of the brain to adapt to new situations – across the central nervous system as well as with neural regeneration across the body.
BDNF is a key player neuroplasticity – the ability of the brain to adapt to new situations
BDNF also protects against damage occurring during ischemia – the low blood flows some studies suggest may be present in ME/CFS.
BDNF issues have been implicated in both neurological and neuropsychiatric disorders and it probably plays a role in the small fiber neuropathies found in the periphery (the body). Down regulation of BDNF has also been tied to neuronal atrophy in the hippocampus and the progression of stress induced depression. Reduced BDNF levels in different parts of the brain have been tied to Alzheimer’s, Parkinson’s and Huntington’s disorders.
BDNF is getting a lot of study these days and it’s become a major molecular target for drug companies seeking to treat neurological disorders.
Given the neuronal atrophy in MS and the neuro-immune components of ME/CFS, it made sense to take a look at BDNF levels in both disorders. Blood BDNF levels (measured as peripheral blood mononucleated cells orPBMCs) in stimulated and unstimulated cultures were assessed in 15 people with ME/CFS, 57 MS patients, and 37 healthy controls.
The results were astonishing.
Results
The researchers probably suspected the MS patients would have abnormal BDNF levels given the amount of neuronal destruction present, but no one suspected what they found in the ME/CFS patients. Both the MS and the ME/CFS patients’ BDNF levels were a paltry 25% of those found in the healthy controls. This highly significant finding (p<.001) suggested, of course, that a key factor in neuron repair was hardly present in either group.
Very low BDNF levels in both the ME/CFS and MS patients suggest low rates of neuron repair are present in both
Adding factors to the blood (phorbol myristate acetate or PMA, and pyridoxalated-hemoglobin-polyoxyethylene conjugate or PHP) that are designed to stimulate BDNF revealed profound deficits in BDNF production in the MS patients, significant deficits in BDNF production in ME/CFS patients, and normal increases in BDNF production in healthy controls.
The small numbers of ME/CFS patients in the study made this essentially a pilot study for ME/CFS.
The authors suggested that low levels of nerve repair agents could be responsible for the small central nervous system lesions found in the frontal lobes of some people with ME/CFS. The fact that fatigue scores are correlated with frontal lobe lesions in MS suggest these lesions could play a role in the fatigue in ME/CFS. Low hippocampal BDNF levels were also found in a mouse model of ME/CFS.
(When we talk about weakened nerves the term neurasthenia does come to mind. It has some negative connotations but the original term referred to ‘weakened nerves’ and ‘nervous system exhaustion’ – two factors that could be explained by low levels of the key neuron repair and proliferation protein – BDNF.)
Conclusion
The study was small but strikingly low levels of a key nerve factor (BDNF) in both ME/CFS (and multiple sclerosis) suggested that both neuron repair and proliferation could be inhibited in Chronic Fatigue Syndrome. The low BDNF levels could explain the abnormal frontal lobe MRI findings in ME/CFS which in turn could be associated with fatigue. Similarly low BDNF findings in different parts of the brain occur in several neurological and neuropsychiatric disorders.
- In Part II of our BDNF and ME/CFS series, “Breaking the BDNF Blues“, Dr. Courtney Craig examines and fleshes out the BDNF situation in ME/CFS, suggests it may be linked to findings of neuroinflammation, and provides treatment options.
Well, they’ve always said it was all in our head.
🙂
What we see going on in the head is a “result’ not a cause, in my opinion.
I am surprised, they were surprised, to find many correlations with M/S and CFS. It is surprising they haven’t found more. I have CFS, my sister has M/S! Perhaps siblings like us need to be looked at closer? RP
The smart supplement noopept has been shown to increase BDNF as well as NGF (nerve growth factor). See here:
http://www.ncbi.nlm.nih.gov/pubmed/19240853
It might be worth trying noopept for ME/CFS.
Noopept is inexpensive and readily available online. Noopept doses are in the 10 mg to 40 mg range, taken sublingually. If you read some accounts online, people often anecdotally report a great cognitive boost with noopept initially, followed by a loss of effect after some days. However, the above-cited study found that BDNF was still boosted even after 28 days of taking noopept daily, so noopept would seem to have long term benefits with regards to BDNF boosting.
Cort, great article review!
One thing that impressed me about this research was that they seemed to try hard to obtain a well-defined ME/CFS cohort. Too bad they didn’t have more ME/CFS subjects. I read the paper and I thought this was an interesting quote:
……It is then apparent there are ties between the expression of BDNF and exercise…….
Another thought that comes to mind immediately is the question about the possibility of BDNF being a potential biomarker. There are plenty of blood tests on the market for detecting BDNF (and at a somewhat reasonable cost) that could be used by clinicians.
I’d love to see Dr. Cox speculate on if BDNF could be quickly be put in place as a potential biomarker and what BDNF research would be next in line..
And of course, the exercise connection is very intriguing.
Thanks for what you do. I made a donation.
Yes, exercise increases BDNF! Too bad that option is not open to most people with ME/CFS. I wonder if lack of exercise decreases it?
Thanks for helping out 🙂
Fascinating!
My illness began with myelitis – inflammation of the spinal cord resulting in loss of bladder and bowel function and loss of sensation on one side. Suspected diagnosis over the first several years was MS, which was finally ruled out and replaced with CFS. It’s encouraging to see some links finally being established between the 2 conditions.
http://www.ncbi.nlm.nih.gov/pubmed/?term=((herbal+OR+phytotherapy+OR+herbals+OR+herbalism+OR+(botanical+AND+(medicinal+OR+remedy+OR+remedies+OR+therapy+OR+therapeutic+use+OR+treatment+OR+preparation+OR+preparations))+OR+eclecticism+OR+kneipp+OR+kneipp+S+OR+chinese+herbal+drugs+OR+herbal+drugs+OR+herbal+medicine+OR+medicinal+plants+OR+plant+extracts+OR+botanicals))+AND+bdnf
Upregulate BDNF WITH BOTANICALS
I think low levels of BDNF would be due to increased nitric oxide. Nitric oxide rapidly down-regulates BDNF, as the following study confirms.
http://www.pnas.org/content/99/5/3282.long
Patients with MS and ME/CFS both have elevated levels of nitric oxide. Here is a study on the involvement of nitric oxide in MS.
The potential role of nitric oxide in multiple sclerosis.
Govannoni G, Heales SJ, Land JM, Thom Yorkepson EJ. 1998. Mult Scler. 4(3):212-6.
“Nitric oxide (NO) and its reactive derivative peroxynitrite have been implicated in the pathogenesis of multiple sclerosis (MS). They are cytotoxic to oligodendrocytes and neurons…”
Here is a study on the increased levels of nitric oxide in ME/CFS. .
http://www.researchgate.net/…/240741786_Levels_of…
Nitric oxide is elevated in CFS and MS due to increased levels of the amino acid homocysteine.
A nitric oxide connection in MS as well. Who knew? Thanks!
Yet more evidence that the problem is in the brain / CNS.
Andrew Lloyd in Australia has been talking for years that CFS results from an initial insult (eg. virus), but is not perpetuated by that insult, but rather impacts on the brain / CNS.
I’m really glad to see this as I have been advocating for the brain over the past 2-3 years.
I’m confident we will find some positive answers in this area.
I just hope that research can build on this type of work rather than the dead-end that is viral research (25 years and counting and nothing of substance)
Hi Matthias I also think this is an area worth looking into. What does andrew Lloyd suggest apart from CBS?
You there Matthias? My experience with has been how Geoff describes. He isn’t interested and just says to do CBT.
Matthias just when did Lloyd say this i certainly don’t remember this all i remember him as completely ignoring myalgic encephalomyelitis and causes great confusion by his opinions he looks down on people doing good work this is common knowledge in australian me mcs fm circles
Interesting stuff Cort.
I’m looking forward to part II as on the face of it these findings seemed to contradict the recent findings of neuroinflammation as activated microglia should release more BDNF. Should being the operative word I suppose.
If we have neuroinflammation plus reduced release of BDNF then wouldn’t that be a double whammy hitting the brain?
Same with exercise. Exercise should induces the release of BDNF so it should help – but what if it doesn’t in ME/CFS patients? You have to assume BDNF is released for a reason (it also support muscle regeneration and knockout/knockdown mice have delayed muscle regeneration following injury :
http://www.molbiolcell.org/content/21/13/2182.full
Plus exercise increased BDNF release may not always be beneficial :
“BDNF thus encourages neurogenesis [9, 10], axonal, and dendritic sprouting [89], and NMDA receptor-mediated transmission [96] in a Trk-B-dependent manner [12], which are generally considered to be beneficial effects on neuronal function. However, these same mechanisms may lead to hyperexcitable circuits in the DG [89, 90, 97], which may eventually lead to spreading excitotoxicity. This condition can therefore become a self-sustaining cycle of sprouting and hyperexcitability, fueled in part by activity-dependent BDNF release”
DG = the dentate gyrus of the hippocampus
http://www.hindawi.com/journals/ijpep/2011/654085/
Complicated!
From reduced heat shock proteins following exercise to reduced antioxidant status and reduced NK function to this – we do seem to be lacking in some pretty basic protective/repair mechanisms.
nicotine reduces microglia activation and increases BDNF
Further to Rich having CFS and his sister having M S – my father’s three sisters all had MS and a cousin now has it as well, while I and my two daughters all have M E. Coincidence?
And incidentally an ancestor who died in 1648, was said to have had ‘fatigue and drowsy disease’.
All purely anecdotal, yes, but it’s enough to convince me that there is a connection between the two diseases and that there IS a hereditary factor – at the very least giving a propensity to one or the other of the diseases.
http://www.sciencedirect.com/science/article/pii/S0306452212009761
Progesterone, brain-derived neurotrophic factor and neuroprotection
Abstract
While the effects of progesterone in the CNS, like those of estrogen, have generally been considered within the context of reproductive function, growing evidence supports its importance in regulating non-reproductive functions including cognition and affect. In addition, progesterone has well-described protective effects against numerous insults in a variety of cell models, animal models and in humans. While ongoing research in several laboratories continues to shed light on the mechanism(s) by which progesterone and its related progestins exert their effects in the CNS, our understanding is still incomplete. Among the key mediators of progesterone’s beneficial effects is the family of growth factors called neurotrophins. Here, we review the mechanisms by which progesterone regulates one important member of the neurotrophin family, brain-derived neurotrophic factor (BDNF), and provides support for its pivotal role in the protective program elicited by progesterone in the brain.
Highlights
► Progesterone is neuroprotective. ► Progesterone increases the expression of BDNF. ► Progesterone’s protective effects are mediated, in part, by enhancing the expression and/or function of BDNF.
Thanks Ruth! I had no idea. I know of two people who were helped a lot by progesterone. Very interesting 🙂
I waz told the ‘bright objects’ on MRI were normal for a person my age,i was 41..
hi
when will part 2 be appearing? would like to print off for my GP. doubt it will get me anywhere but worth a try!
thanks for the info
Sam
My apologies Sam, I should have posted a link – http://www.cortjohnson.org/blog/2014/06/11/bdnf-blues-dr-courtney-craig-ii-natural-ways-raise-bdnf-chronic-fatigue-syndrome/
I have believed for many years that I have CFS. But the CDC definition of CFS says, I’ll paraphrase it as saying – if you can find a physical marker, then it’s not CFS. After all CFS has no physical markers the CDC in it’s infinite wisdom believes. My neurologist found the white spots on my brain MRI and called them demyelinating lesions. She said it wasn’t normal for someone my age. I was about 56 at the time. She had reason to suspect MS so she ordered a spinal tap. The results of the spinal tap said I had oligoclonal bands, increasing the likelihood that I had MS. But since I didn’t have typical MS symptoms she sent me to one of the foremost experts on MS at Georgetown University Hospital. That doctor spent six hours with me asking me every question under the sun. I’d never had anything so thorough done before. Usually doctors just blow me off. At the end of the six hours – knowing of the white spots on the brain MRI and knowing of the oligoclonal bands, this expert in MS said, you don’t have MS you have Chronic Fatigue Syndrome. I said but the CDC says if I have these physical markers you can’t have CFS. He rolled his eyes. He said I see these things all the time in CFS. They have many, many similarities. This from a renown MS expert. My neurologist takes the medical codes seriously so she labels me as having ‘atypical MS.’ But in our conversations we call if CFS. Having atypical MS gives you more rights with insurance companies than does having CFS. My doctor, because of elevated inflammatory agents in my blood work, codes me as having ‘autoimmune disease.’ Everyone dances around the term CFS because of its stigma and insurance concerns. We are most definitely an orphaned group.
Wow – very interesting Carol – thanks for sharing…
Cort, I can’t find a link to or a title of the study you are reviewing… Is it my brain fog…?