Associations between clinical symptoms, plasma norepinephrine and deregulated immune gene...

[Moof]

...networks in subgroups of adolescent with Chronic Fatigue Syndrome.

https://www.ncbi.nlm.nih.gov/pubmed...43_Vjc80nOaWo9Z3gdAa8Ah8c3MgjabK4VwsPg_hVRGm8

Preview:

RESULTS
A group of 29 immune-gene sets was shown to differ patients from controls and detect subgroups within CFS. Group 1P (high PDS, low norepinephrine, low naïve CD4+ composition) had strong association with levels of serum C-reactive protein and Transforming Growth Factor-beta. Group 2P (low PDS, high norepinephrine, high naïve CD4+ composition) had strong associations with neuroendocrine/autonomic markers. The corresponding plasma norepinephrine level delineated 91 patients into two subgroups with significant differences in fatigue score.

 

[Murph]

Brain Behav Immun. 2018 Nov 9. pii: S0889-1591(18)30796-7. doi: 10.1016/j.bbi.2018.11.008. [Epub ahead of print]
Associations between clinical symptoms, plasma norepinephrine and deregulated immune gene networks in subgroups of adolescent with Chronic Fatigue Syndrome.
Nguyen CB1, Kumar S2, Zucknick M3, Kristensen VN4, Gjerstad J5, Nilsen H6, Wyller VB7.
Author information
Abstract
BACKGROUND:
Chronic fatigue syndrome (CFS) is one of the most important causes of disability among adolescents while limited knowledge exists on genetic determinants underlying disease pathophysiology.

METHODS:
We analyzed deregulated immune-gene modules using Pathifier software on whole blood gene expression data (29 CFS patients, 18 controls). Deconvolution of immune cell subtypes based on gene expression profile was performed using CIBERSORT. Supervised consensus clustering on pathway deregulation score (PDS) was used to define CFS subgroups. Associations between PDS and immune, neuroendocrine/autonomic and clinical markers were examined. The impact of plasma norepinephrine level on clinical markers over time was assessed in a larger cohort (91 patients).

RESULTS:
A group of 29 immune-gene sets was shown to differ patients from controls and detect subgroups within CFS. Group 1P (high PDS, low norepinephrine, low naïve CD4+ composition) had strong association with levels of serum C-reactive protein and Transforming Growth Factor-beta. Group 2P (low PDS, high norepinephrine, high naïve CD4+ composition) had strong associations with neuroendocrine/autonomic markers. The corresponding plasma norepinephrine level delineated 91 patients into two subgroups with significant differences in fatigue score.

CONCLUSION:
We identified 29 immune-gene sets linked to plasma norepinephrine level that could delineate CFS subgroups. Plasma norepinephrine stratification revealed that lower levels of norepinephrine were associated with higher fatigue. Our data suggests potential involvement of neuro-immune dysregulation and genetic stratification in CFS.

Copyright © 2018. Published by Elsevier Inc.

KEYWORDS:
CD4+ naïve T cells; Chronic Fatigue Syndrome; Myalgic Encephalomyelitis; Pathifier; fatigue score; genetic stratification; heart rate variability; immune alteration; neuro-immune dysregulation; neurotransmitter; norepinephrine; pathway deregulation analysis

PMID:
30419269
DOI:
10.1016/j.bbi.2018.11.008

 

[Murph]

Looks like a decent study. Out of Norway, focuses on important questions around immunity and genetics. Norepinephrine is a hormone that directly stimulates adrenergic receptors in the autonomous nervous system.

I'm really excited about the idea of defining good stable subgroups because I fear research might see little going wrong on average when each patient has their own problems.

My concern here is they took in 29 patients and found 29 different patterns!

 

[Cam Newton]

Could this have something to do with the success of SNRI’s like cymbalta?

 

[sb4]

Could it also have to do with my improvements from Mirtazapine; which blocks aA2 causing more norepinephrine to be released?

 

[Moof]

My concern here is they took in 29 patients and found 29 different patterns!

That struck me too, although it doesn't necessarily mean that every participant was different – there were only two distinct sub-groups, and they eventually managed to place 91 patients in one or t'other of them. But you're absolutely right – accurate subgrouping is crucial, both in unpicking disease mechanisms and when it comes to predicting treatment outcomes where heavy-duty drugs are being considered.

 

[nandixon]

Plasma norepinephrine stratification revealed that lower levels of norepinephrine were associated with higher fatigue.

Upon reading the full text one learns that “lower” means that one of two groups of patients has lower norepinephrine relative to the other group. The group with the lower levels actually has perfectly normal epinephrine levels relative to the controls. The authors suggest that this normal level is effectively abnormal when they state:

Furthermore, Group 2P had significantly higher level of plasma norepinephrine compared to patients in Group 1P, whose plasma norepinephrine levels were comparable to healthy controls. Our result might indicate that enhanced sympathetic nervous activity, causing elevated norepinephrine levels, may play a role in maintaining immune homeostasis in CFS individuals in the Group P2, whereas the lower level of norepinephrine in Group 1P corresponds with a more extensive alteration of immune pathways in this group. Thus, this finding is in line with previous observations and hypotheses of the immune-brain communication 36-38 and also agrees with general notions of norepinephrine as a mediator of anti-inflammatory effects37.

and

Generally, the cohort with the highest plasma norepinephrine levels [Group 2P] had less serious symptoms and disabilities, supporting the idea of increased sympathetic activity in CFS patients as a compensatory mechanism in order to maintain immune homeostasis.

Another possibility, of course, is that rather than there being subgroups, is that not all the patients even have the same disease, which seems likely given:

In agreement with clinical guidelines, we applied a ‘broad’ case definition of CFS, requiring three months of unexplained, disabling chronic/relapsing fatigue of new onset 20. We did not require that patients meet any other accompanying symptom criteria.

Given no requirement of PEM and an exceptionally short symptom period, this doesn't appear to be a study about ME/CFS. I think the authors are using the term “CFS” incorrectly and what they actually mean is that they performed a study of “chronic fatigue” in adolescents.

 

[pattismith]

Could it also have to do with my improvements from Mirtazapine; which blocks aA2 causing more norepinephrine to be released?

Block of Alpha 2 Adrenergic receptors seems to enhance norepinephrine and serotonine, but Mirtazapine has many other effects, and also increases dopamine (maybe via 5HT1A activation...)

Mirtazapine: Uses, Interactions, Mechanism of Action | DrugBank Online

 

[sb4]

@pattismith Indeed it could be a number of things. Interestingly enough I recently quit mirtazapine cold turkey. For years I have been having adrenaline type nightmares where I would wake up with a pounding heart (which is my worst symptom anyway) and have trouble getting back to sleep. This was happening like every night.

I originally put it down to dysautonomia causing an increased sympathetic system but knowing mirtazapine increased adrenaline I googled mirtazapine and nightmares. Got quite a few hits so went cold turkey on it after taking it daily for around 6 years.
My sleep was horrendous for the first month. When I would first take mirtazapine it would knock me out (probably due to the anti histamine effect) but after a couple months it would have no effect. The same happened in reverse when going of it. I am now sleeping roughly 6-7hrs a night with minimal nightmares.

I got pretty depressed for a while too but thats eased off considerably although now I am more depressed than I was when on it.

In the first month my heart rate took off big time, going above 100bpm frequently whilst just sitting in my chair. That has calmed down too though it feels like my heart rate is slightly higher than when on mirtazapine.

My gastroparesis is noticably worse off it too. Mirtazapine is known to increase appetite.

Overall I would say I am glad to be off it. There are pros and cons to it and it helped me out when I was really bad years ago.

 

[pattismith]

@pattismith

When I would first take mirtazapine it would knock me out (probably due to the anti histamine effect) but after a couple months it would have no effect.

Thank you very much to share your experience with Mirtazapine, it's precious.

My Psy doctor wants me to take it, despite daytime sleepiness is my main problem....

Needless to say that I can't wait two months to get used to the antihistamine effect, it's too long. Even one week to wait is too long, I need something to help me quicker.

I read a case report of a woman taking some mirtazapine as sleeping pill, and she noticed the effect was fading after a week, so she was doing a three days break between two round of Mirtazapine,

These drugs have so many different effects on the brain, it's impossible to predict how one will react.