Science at the UK CMRC Conference, 1-2 Sept 2014

[Snow Leopard]

1. How did these findings compare to controls, or were there no controls?

Good question.
The Jason/Chicago study found 24% in controls, the CDC Wichita study data was reported in a followup and was 30.8% for having been treated for depression at some time in their life. The rate of depression in the CDC study wasn't reported separately, but there was approximately 30.7% lifetime diagnosis in controls. I believe the diagnoses were reported by the participants in an interview.

 

[Jonathan Edwards]

I think measuring numbers of microglia would need something like PET scanning in a clinical setting and it might be difficult to distinguish from receptor upregulation, but that might not matter.

My understanding of priming is that tis is any situation where a cell has responded to a first signal and is then 'set up' to respond more strongly to a second signal when it comes along. One cytokine might induce upregulation of receptors for a second cytokine for instance.

 

[Marco]

This is a fairly recent review of the impact of aging on microglial response to immune challenge :

Microglia of the Aged Brain: Primed to be Activated and Resistant to Regulation

Nonetheless, there are major differences in microglial biology between young and old age when the immune system is challenged and microglia are activated. In this context, microglial activation is amplified and prolonged in the aged brain compared with adults. The cause of this amplified microglial activation may be related to impairments in several key regulatory systems with age that make it more difficult to resolve microglial activation. The consequences of impaired regulation and microglial hyper-activation following immune challenge are exaggerated neuroinflammation, sickness behaviour, depressive-like behaviour and cognitive deficits. Therefore the purpose of this review is to discuss the current understanding of age-associated microglial priming, consequences of priming and reactivity, and the impairments in regulatory systems that may underlie these age-related deficits.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3553257/

They suggest that microglial proliferation is limited to the specifc case of traumatic CNS injury and the enhanced 'proinflammatory' phenotype associated with aging is unlikely to be due to numbers. Microglia appear to be comparatively 'long lived' :

The limited replication and turnover of microglia make them a relatively stable population that is maintained throughout life.

Impaired cellular repair mechanisms (e.g. in response to oxidative stress) appear to play a part.

Whether or not this activation is sufficiently large or persistent enough to be a useful model for ME/CFS is debateable.

 

[Valentijn]

The numbers in the Jason study are legit, contact him if you want more details, he is usually happy to explain things.

I know that in some studies he uses DSM guidelines for the interview. When there's no known biological diagnosis, the interviewers are allowed to interpret physical symptoms as an indication of depression. And I do know that in at least one of those studies of his, patients weren't acknowledged as having a biological diagnosis for the purposes of the interview.

Hence I wouldn't be surprised if many of his study subjects are getting a depression label simply due to having physical symptoms which prevent them from doing fun stuff. Honestly, the only questionnaire or interview I can think of that would be of any use for assessing depression in patients with a chronic and disabling and marginalized illness would have just one question: "Are you depressed?"

 

[Jonathan Edwards]

This is a fairly recent review of the impact of aging on microglial response to immune challenge :

Microglia of the Aged Brain: Primed to be Activated and Resistant to Regulation



http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3553257/

They suggest that microglial proliferation is limited to the specifc case of traumatic CNS injury and the enhanced 'proinflammatory' phenotype associated with aging is unlikely to be due to numbers. Microglia appear to be comparatively 'long lived' :



Impaired cellular repair mechanisms (e.g. in response to oxidative stress) appear to play a part.

Whether or not this activation is sufficiently large or persistent enough to be a useful model for ME/CFS is debateable.

Many thanks for flagging that up Marco. I will have a detailed look over the next day or two.

What bothers me, however, is that ME is not a disease of ageing, or at least not as far as I know. In fact my impression is that it may peak rather earlier than a lot of other conditions - maybe 35-55. Whatever these people are describing as inflammatory priming in the aged brain would seem to be something that has nothing to do with our problem?

This is why I get very cautious about these 'one size fits all' approaches to solving questions. 'Neuroinflammation' is trendy. Ageing is trendy. Let's write a paper on neuroinflammation in ageing and get a few grants in (and citations for the annual research audit).

What they specifically do not mention is the receptor I think would be of interest - CD64. They mention complement receptor 3, which usually goes with another Fc receptor CD16 but not CD64. They also refer to MHCII as 'inflammatory', which is about as dumbed down a way of talking as you can get, to my mind.

Anyway, it looks to be full of referenced data, even if a lot from mice (which will not help us). It may be very helpful in pointing to what is NOT what we are looking for!!

 

[MeSci]

Yes I am aware he's thorough but as you pointed out, he did not separate depression from sleep disturbance. I would think close to 50% of people with ME have that as a primary issue.

I think that it's highly questionable as to whether sleep problems are a primary issue in ME. It is one theory amongst many, and I am very sceptical about it.

 

[Marco]

What bothers me, however, is that ME is not a disease of ageing

Sure feels like it sometimes

In fact my impression is that it may peak rather earlier than a lot of other conditions - maybe 35-55. Whatever these people are describing as inflammatory priming in the aged brain would seem to be something that has nothing to do with our problem?

Agreed. In fact its the major reason for school absence according to some reports. But I'm not sure we can say that there is zero connection. Is 'aging' a matter of time only or a progressive breakdown in cellular repair mechanisms? The paper I linked to does clearly state that this age associated 'glial priming' varies between individuals so it can't just be a matter or years (my grandmother passed last month aged 100 - she was much sharper and more active than me up to the end).

This is why I get very cautious about these 'one size fits all' approaches to solving questions. 'Neuroinflammation' is trendy. Ageing is trendy. Let's write a paper on neuroinflammation in ageing and get a few grants in (and citations for the annual research audit).

They also refer to MHCII as 'inflammatory', which is about as dumbed down a way of talking as you can get, to my mind.

I'm too trusting - I'll work on the cynicism

Anyway, it looks to be full of referenced data, even if a lot from mice (which will not help us). It may be very helpful in pointing to what is NOT what we are looking for!!

No bad thing!

 

[Wildcat]

@Jonathan Edwards

Jonathon wrote: "What bothers me, however, is that ME is not a disease of ageing, or at least not as far as I know. In fact my impression is that it may peak rather earlier than a lot of other conditions - maybe 35-55. Whatever these people are describing as inflammatory priming in the aged brain would seem to be something that has nothing to do with our problem?

This is why I get very cautious about these 'one size fits all' approaches to solving questions. 'Neuroinflammation' is trendy. Ageing is trendy. Let's write a paper on neuroinflammation in ageing and get a few grants in (and citations for the annual research audit)."

.
Surely, by the same reckoning, one could also say that fatigue is also 'trendy'.

.

 

[lansbergen]

What bothers me, however, is that ME is not a disease of ageing, or at least not as far as I know. In fact my impression is that it may peak rather earlier than a lot of other conditions - maybe 35-55.

I was 40 when it started. It peaked at 50 and now at 69 I am much better.

Even children get it. It seems a disease of all ages.

 

[Seven7]

@Jonathan Edwards I have 2 things I would like to share with you.
1) I do feel inflammation in the brain and spinal. I feel pain the base of my scull. My inflammation is very palpable, if you touch my skull it changes form, like when you get hit with a bat and get a bump. One day I got one so visible in the head so close to the forehead that actually people were freaking out about it (I regret not going to ER then so I know that it is). I feel the beat like when something is inflamed (like heart beats in the area), my eyes in the back feel like they are coming out of sucket with the pressure. The spine feels stiff and painful to move and all around. This pain comes and goes. My MRI just showed some small white lesions. I do not have MS according to Spinal Tap and the opening CSF pressure was normal. The excuse for a neuro I have says it is impossible for me to get brain inflammation and that was that. To be honest, I think we get inflammation maybe in the sense of high pressure CSF???? or some fluid variability? at least is what it feels like to me.

2)The other point I have is more a philosophical one. If we all get tired after exertion, then the source should be aggravated or started at the muscle level. The people that are not as disabled have less dysautonomia like symptoms. Some people here say they do not have dys, but me reading on their issues (burning muscle when trying to move, need to sit after long time standing.....) tells me they just don't recognize it as such, but they are actually having some form of Dys.

For us getting treated for CFS and Dys, is easier to put apart the feelings of autonomic system (muscles, activity, sleep....) Vs Cfs (flue like, infections......).

So I guess my point is if we can untangle the 2, maybe by treating one and not the other, there may be more head ways to know what is what and the order of events can give a clear picture of the initiating system. Or getting people as soon as possible w CFS before they develop the Dysautonomia issues, like it is in the case of the gradual cases.

 

[A.B.]

With all this talk about the brain, I want to point out that there is also the gut. Many CFS patients report intestinal symptoms. A diagnosis of IBS is common.

In my experience, whenever I have intestinal symptoms, I also have increased fatigue, pain, concentration problems and mood problems. Since this tends to start after meals, the gut seems to be the starting point of these symptoms.

The gut also seems to play a role in the development of autoimmunity.

 

[charles shepherd]

Could you remind me/us how priming can occur?



Aren't PET scans expensive? So much emphasis is placed on affordability in the NHS and probably other health systems, especially at the moment, that short-term cost concerns might put doctors off referring people for PET scans, might they not?

I have been refused cheaper scans in recent years - liver/abdominal ultrasound and bone mineral density, and they are relatively inexpensive, I think.

Yes - the sort of PET scans used in the Japanese 'neuroinflammation' study are very expensive to perform

This is one of the reasons why, as a charity, we haven't been able to move forward with possibly commissioning someone reputable to look at repeating these very interesting findings

The neurological colleagues I have spoken to feel that this study is worth repeating

But if this is going to be done in the UK I think someone is going to have to apply to the MRC…...

 

[Marco]

What they specifically do not mention is the receptor I think would be of interest - CD64. They mention complement receptor 3, which usually goes with another Fc receptor CD16 but not CD64. They also refer to MHCII as 'inflammatory', which is about as dumbed down a way of talking as you can get, to my mind.

Any chance of explaining (relatively simply) why you are particularly interested in that particular receptor in relation to glial cells?

This paper (hopefully better quality) discusses the various immune 'signals' that get microglia all hot and bothered :

Neuroimmune crosstalk in the central nervous system and its significance for neurological diseases

http://www.smssupportgroup.co.uk/PD...ts significance for neurological diseases.pdf

CD64 is mentioned but only that it is 'minimally expressed in resting microglia' and doesn't seem to expand on that :

Resting microglia acquire a ramified but nevertheless active morphology normally, with minimal expression of myeloidmonocytic markers such as Fc receptors-cluster of differentiation (CD) 32 and CD64, complement receptors (CR)-3 and −4, (also named as CD11b and CD11c integrins, respectively), major histocompatibility complex (MHC) class I and II, and CD45 [17] (Table 1).

Once challenged by inflammation, microglia become rapidly ameboid and up-regulate a variety of cell surface receptors involved in innate immune responses. These receptors include pattern recognition receptors (PRR), such as toll-like receptors (TLR) and receptors for advanced glycation end products (RAGE) and scavenger receptors (CD36, CD91), as well as phagocytic receptors, such as CR-3, -4, and triggering receptor expressed on myeloid cells (TREM) (Tables 1 and 2) [17,18].

 

[Leopardtail]

I think that it's highly questionable as to whether sleep problems are a primary issue in ME. It is one theory amongst many, and I am very sceptical about it.

meaning not 'one step down' from depression. Many medics who deal effectively with ME (e.g. Myhill) regard it as a central issue, That is not to say of course that it is without cause...

 

[Jonathan Edwards]

Is 'aging' a matter of time only or a progressive breakdown in cellular repair mechanisms? The paper I linked to does clearly state that this age associated 'glial priming' varies between individuals so it can't just be a matter or years (my grandmother passed last month aged 100 - she was much sharper and more active than me up to the end).

Any chance of explaining (relatively simply) why you are particularly interested in that particular receptor in relation to glial cells?

On the first point I think it is worth being strict. Ageing is ageing is being old. They found microglia behaved in a certain way X in aged brains. But certain way X is certain way X, not ageing. And as you say you might have certain way X younger in some people. The upshot is that if certain way X was the 'microglial priming' explanation for the persistence of ME we are looking for then we are saying that getting an infection and being the way you will be in forty years time explains ME. But it doesn't, does it. (Note no question mark, this is a statement.) People forty years older getting infections do not get much ME. Hypothesis refuted, move on to something more subtle - like CD64.

The reason for thinking of CD64 goes like this. There are three Fc receptors (of interest here), conveniently named by powers of 2 CD16, CD32 and CD64. CD16 and CD32 have moderate affinity for antibody. This means that if they find a soluble antibody molecule they cannot really be bothered to bind to it for more than a picosecond. But if antibody is already immobilised on an antigen as part of an immune complex CD16 and CD32 will bind stably and fire out cytokines from the macrophage.

Antibodies that can form immune complexes on their own must have high affinity for their target antigen and so ought to show up on immunofluorescence tests of patient serum put on to neural tissues. In ME nobody may have looked properly but it is likely that if they were there someone would have noticed by now. So if microglia were binding to immune complexes through CD16 or CD32 we ought to have found the autoantibodies. There is also the point that these receptors, particularly CD16 generate a brisk TNF response and there is no brisk TNF response anywhere else in ME. If there was there would be a raised CRP. Add to that the fact that only macrophages in a few tissues use CD16 and it looks as if microglia are not on the list. If they were people with RA would have encephalitis.

So this leads us to consider CD64, which is a bit of an 'orphan' receptor because nobody understands why it wants to bind soluble antibody with high affinity. It will get gummed up with any old antibody, regardless of whether there is any antigen around. But a reasonable answer is that it is there to bind nonspecific 'natural' antibody that might be useful right at the beginning of an infection. This time the immobilisation of the antibody that increases stability of binding will be the receptor-antibody link (for CD16 it is the antibody-antigen link). Another feature of CD64 is that it is specifically regulated by gamma interferon, which is a signal used in early intracellular infection.

That is probably enough to give an idea why I think CD64 might be the 'invisible go-between' in ME. If not properly regulated it can cause trouble using ordinary natural antibody rather than needing high specificity autoantibody. And for CD64 the priming would be a specific gamma IFN priming, not an LPS or TLR priming. That is why I am so keen to get this specific and not just talk of 'neuroinflammation'.

 

[Marco]

@Jonathan Edwards

Thanks for keeping it simple

 

[Marco]

On the first point I think it is worth being strict. Ageing is ageing is being old. They found microglia behaved in a certain way X in aged brains. But certain way X is certain way X, not ageing. And as you say you might have certain way X younger in some people. The upshot is that if certain way X was the 'microglial priming' explanation for the persistence of ME we are looking for then we are saying that getting an infection and being the way you will be in forty years time explains ME. But it doesn't, does it. (Note no question mark, this is a statement.) People forty years older getting infections do not get much ME. Hypothesis refuted, move on to something more subtle - like CD64..

Sorry but I'm not buying that. Osteoporosis is an affliction of old age but certain conditions can result in early onset, cachexia is a symptom of late old age but associated with certain pathologies such as COPD at much younger ages. There are many such examples. No older people do not appear to develop ME/CFS but they do share the same characteristics including fatigue/reduced stamina; cognitive problems; diffuse pains, increased anxiety etc.

I'm not being so literal as to suggest that ME/CFS and aging are the same thing - to say that aging results in microglial activation is simply a description of an association - it says nothing about the underlying pathophysiology. Who's to say that whatever processes that underlie glial priming/activation in aging aren't exaggerated in ME/CFS?

 

[Marco]

@Jonathan Edwards

Just to add - if you were a GP faced with an elderly patient reporting a recent very severe flu or trauma and complained of extreme fatigue, cognitive problems, diffuse pain etc - what would you diagnose?

ME/CFS based on what is 'known' about the age profile or just plain old old age?

 

[Jonathan Edwards]

Sorry but I'm not buying that. Osteoporosis is an affliction of old age but certain conditions can result in early onset, cachexia is a symptom of late old age but associated with certain pathologies such as COPD at much younger ages. There are many such examples. No older people do not appear to develop ME/CFS but they do share the same characteristics including fatigue/reduced stamina; cognitive problems; diffuse pains, increased anxiety etc.

I'm not being so literal as to suggest that ME/CFS and aging are the same thing - to say that aging results in microglial activation is simply a description of an association - it says nothing about the underlying pathophysiology. Who's to say that whatever processes that underlie glial priming/activation in aging aren't exaggerated in ME/CFS?

And I ain't buying that neither Marco. Actually, I think we are a bit at cross purpose and probably agree. 'Ageing' is not an extra process or set of processes but the situation where certain processes X,Y, Z etc happen to have arisen through a causal sequence of 90 odd years. People talk of premature or apparently speeded up 'ageing' but I think one has to be careful because the causal sequence is probably different.

It is quite interesting, as you say, that old people seem to have several features of 'CFS'. Yet my 92 year old mum
would not be diagnosed as CFS by anybody. She has to sit down after walking a quarter of a mile, joking 'it's me legs doctor' but I am not sure what she is feeling has any similarity to CFS 'fatigue'. I can remember post viral fatigue and it felt hostile and alien. More recently I have found that I cannot ski deep powder snow the way I could ten years ago. I get 'it's me legs, doctor' but there is no threat, just a sense of nostalgia for the legs I once had. I forget names. Mum forgets almost everything. But there is no sense of brain fog. I have pains in lots of places now but I know they are all due to this or that bit of bone rubbing on something. Mum gets neck ache, that's about all.Nothing is unexplained. And neither of us is anxious. We never get PEM.

Maybe it goes to show how hopeless all the clinical criteria sets are. We need better words for ME symptoms I suspect.

I agree that in ME there might be the same glial priming as in old age but my point is that this cannot explain anything because if it was this priming that explained the real ME symptoms then old people would have to have them too, or at least be more likely to have them. Case dismissed, I think. But we might get him on another related charge. This to me is the beauty of piecing together these diseases - each one is unique in some way or another. ME looks to me to be a very precise bug in the neuroimmune computer software. Other sort of worn-outness may tell us where to look but I think more where not to look when it comes to the detail.

 

[lansbergen]

@Jonathan Edwards

Is this correct?

CD64 is constitutively found on only macrophages and monocytes, but treatment of polymorphonuclear leukocytes with cytokines like IFNγ and G-CSF can induce CD64 expression on these cells