The buspirone challenge test clearly distinguishes ME/CFS patients from healthy controls: why is it not being developed and deployed?

forestglip said:
The blood levels of sex hormones seem normal in ME/CFS, though, so another possibility is that estrogens produced in the brain are influencing prolactin response. In which case, we might see some increased brain aromatase activity in ME/CFS.
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I think they would have to be produced very locally within the hypothalamus or pituitary itself I guess. I am not convinced that this is likely.

Thanks anyway.
 
Jonathan Edwards said:
I have lost the plot here, sorry. Can someone recap what an aromatase PET study would tell us? I am gearing up to do the rounds of London neurologists next week.
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In addition to what @forestglip said, aromatase is also known to spike locally with brain injury and various challenges, so is probably a non-specific response to some immunogenic signals.
 
Jonathan Edwards said:
I think they would have to be produced very locally within the hypothalamus or pituitary itself I guess. I am not convinced that this is likely.
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If the hypothalamus is already responding to signals from elsewhere I don't think it's that unlikely. I'm thinking that the same signal which induces some sickness-related symptoms in the hypothalamus could change lactotroph behavior via aromatase induction
 
Estradiol provision via neural aromatization decreases neuro-inflammation and –degeneration, but almost nothing is known about the interactions between the peripheral immune system and brain aromatase. Given the vulnerability of the CNS we reasoned that brain aromatization may protect circuits from the threats of peripheral infection; perhaps shielding cells that are less resilient from the degeneration associated with peripheral infection or trauma. Lipopolysaccharide (LPS) or vehicle was administered peripherally to adult zebra finches and sickness behavior was recorded 2 or 24 hours later. The central transcription of cytokines and aromatase was measured, as were telencephalic aromatase activity and immunoreactive aromatase (24 hour time point only). Two hours post LPS, sickness-like behaviors increased, the transcription of IL-1β was higher in both sexes, and TNFα was elevated in females. 24 hours post-LPS, the behavior of LPS birds was similar to controls, and cytokines had returned to baseline, but aromatase mRNA and activity were elevated in both sexes. Immunocytochemistry revealed greater numbers of aromatase-expressing neurons in LPS birds. These data suggest that the activation of the immune system via peripheral endotoxin increases neuronal aromatase; a mechanism that may rapidly generate a potent anti-neuroinflammatory steroid in response to peripheral activation of the immune system.
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Activation of the peripheral immune system regulates neuronal aromatase in the adult zebra finch brain

Note: the aromatase-expressing neurons induced by peripheral cytokines were specifically in the hypothalamus. I think this is interesting since it suggests that aromatase could be a long-lasting byproduct of temporary immune signaling
 
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Jonathan Edwards said:
I think they would have to be produced very locally within the hypothalamus or pituitary itself I guess. I am not convinced that this is likely.
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There is evidence that estrogens are produced in the pituitary and in the hypothalamus:

Local Transformations of Androgens into Estradiol by Aromatase P450 Is Involved in the Regulation of Prolactin and the Proliferation of Pituitary Prolactin-Positive Cells
The aromatase-mRNA was seen to be located in the cytoplasm of 41% of pituitary cells and was well correlated with the immunocytochemical staining. After in vivo treatment with fadrozole, the size (cellular and nuclear areas) of prolactin cells, as well as the percentage of prolactin-positive cells and the percentage of proliferating-prolactin cells, was significantly decreased.
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Aromatization and 5α-Reduction of Androgens in Discrete Hypothalamic and Limbic Regions of the Male and Female Rat
The medial preoptic nucleus-anterior hypothalamic nucleus exhibited the highest aromatase activity and the second highest conversion to DHT. The lateral preoptic and lateral hypothalamic nuclei showed little aromatase activity yet exhibited high rates of formation of DHT. The medial basal hypothalamus showed the second highest level of aromatase activity but consistently formed the lowest amount of DHT.
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Though I think the evidence suggesting aromatization is increased in ME/CFS is still pretty slim.
 
chillier said:
Possible connection to pain from buspirone is the raphe nuclei: apparently the vast majority of CNS serotonergic neurons project from there including the ones to the hypothalamus regulating prolactin. The Wikipedia page says buspirone acts there. It seems to be predominantly involved in pain perception, sleep wake cycles and thermoregulation according to wikipedia.
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Something related to that area would makes a lot of sense to me. Chronic pain is something most of us with ME/CFS experience. My circadian rhythm often gets pushed later by one to three hours when in PEM (but thankfully I've learnt I can sometimes force it back for my early classes with melatonin). I've always struggled with thermoregulation. Since I was a teenager, I sometimes overheat like crazy from a simple meal, especially in the summer. I'll need to lay down or get a fan going. I do best in cooler temperatures, but I also am the coldest one in my in-laws' house, needing many layers while some wear t-shirts or a thin sweater.

Maybe I should find an easy biology video about the hypothalamus. It seems really important to us.
 
forestglip said:
Though I think the evidence suggesting aromatization is increased in ME/CFS is still pretty slim.
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Just to check I went back to the cerebrospinal fluid metabolomics/lipidomics study:
www.nature.com

Cerebrospinal fluid metabolomics, lipidomics and serine pathway dysfunction in myalgic encephalomyelitis/chronic fatigue syndroome (ME/CFS) - Scientific Reports

We proposed that cerebrospinal fluid would provide objective evidence for disrupted brain metabolism in myalgic encephalomyelitis/chronic fatigue syndroome (ME/CFS). The concept of postexertional malaise (PEM) with disabling symptom exacerbation after limited exertion that does not respond to...
www.nature.com www.nature.com
Unfortunately they did a targeted panel so it looks like steroid hormones were not assessed.

This proteomic analysis of CSF did not detect aromatase at all but I wouldn't expect it to since it's not secreted:

Proteomic signatures in cerebrospinal fluid and their clinical associations in patients with ME/CFS - PMC

This study evaluated the cerebrospinal fluid (CSF) proteomes from 31 patients diagnosed with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). We quantified 902 proteins, each expressed in at least eleven samples, and systematically ...
pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov

I don't know if any other studies could have picked up any signal related to brain-specific aromatase
 
Jonathan Edwards said:
I am just thinking of the anatomy and all the potential calibration problems around PET tracers.
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Fair enough. Interestingly the aromatase tracers showed a high signal from the BNST, which is that other brain region with cytokine-responsive CRH neurons from that mouse study. So you can at least get good signal close to the hypothalamus and pituitary


There might still be calibration issues I suppose
 
jnmaciuch said:
I don't know if any other studies could have picked up any signal related brain-specific aromatase
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It's not really clear to me if this one analyzed estradiol in the CSF, or just in plasma. They don't seem to have reported the CSF result, so if it was tested, I would assume it wasn't very different. Though the Bonferroni correction with many different tests might have obscured a finding.

Cerebrospinal fluid immune phenotyping reveals distinct immunotypes of myalgic encephalomyelitis/chronic fatigue syndrome (2025, Bastos et al)
Both CSF and plasma samples were assessed for cytokines, hormones, and MMPs. For each sample type, only samples run simultaneously on the same assay were included for analysis. For CSF analysis, only soluble factors with at least 70% of individual values above lower levels of quantification for each marker were included.
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The 6-plex consisted of cortisol, estradiol, progesterone, T3, T4, and testosterone
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forestglip said:
It's not really clear to me if this one analyzed estradiol in the CSF, or just in plasma. They don't seem to have reported the CSF result, so if it was tested, I would assume it wasn't very different. Though the Bonferroni correction with many different tests might have obscured a finding.
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They did, but this study was only able to get CSF from ME/CFS not the healthy controls. They had a bunch of questionnaire scales too so they tried to do associations with them, but from what I remember chatting with the author a while back, there were no strong trends. Which could have been due to substantial inconsistency between the different outcome measures (like the same person could have had the worst score in one of the "general health" scores but also reported their fatigue as minimal and had the fastest walk speed). I don't think any of these people were severely affected anyways if they could travel for a lumbar puncture and do a bunch of assessments so it would be hard to see a strong correlation with disease severity (especially at this sample size).
 
Given PRLR receptors are cytokine family and the potential link to chemicals of brain injury (with it without brain injury) would it make sense to look at whatever we can in a brain imaging study in conjunction with this drug challenge? Could we look at different things in different participants as a layer of study alongside the basic response test as a bit on an exploratory angle?

Cytokines and gaba/glutamate seem interesting as both have cropped up in discussions (and some analysis) before. Then there’s the various sex hormones. Anything else that can affect dopamine or receptors?

Is this the sort or thing being suggested? Is it feasible?
 
hotblack said:
Is this the sort or thing being suggested? Is it feasible?
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I think aromatase could be a feasible thing to bring up just because it fits the story in several ways (has been shown to have a direct effect on prolactin, links to immune signaling/symptoms in ME/CFS, etc.). If there's something else that fits equally well and people can be identified who are already working on experimental methods to assess it, I don't see any harm in reaching out
 
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jnmaciuch said:
If there's something else that fits equally well and people can be identified who are already working on experimental methods to assess it, I don't see any harm in reaching out
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Ah. I suppose I was thinking the reverse. What can we measure which may be directly or indirectly related here? What PET tracers or whatever are available? We wouldn’t be able to measure everything in everyone but we could test a broader range of things overall to perhaps get more information and a jump start on the next stage of understanding if there are other changes which correlated.
 
hotblack said:
Ah. I suppose I was thinking the reverse. What can we measure which may be directly or indirectly related here? What PET tracers or whatever are available? We wouldn’t be able to measure everything in everyone but we could test a broader range of things overall to perhaps get more information and a jump start on the next stage of understanding if there are other changes which correlated.
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I mean I think the main hurdle here is convincing people that investigating XYZ is likely to have relevant implications for ME/CFS. We can ask people to explore anything and everything but unless we're directly offering money to do it, the case needs to be pretty solid for why it's worth their time. Right now the promise is "The buspirone test shows a strong difference. Therefore, things that are already known to affect prolactin secretion may also show a strong difference. We've looked at a lot of literature and think that specific factor X is the most promising. If you want to take the gamble, you get the glory."
 
hotblack said:
Thanks @jnmaciuch I think I’m still off in the blissful land of the theoretical unconstrained by the pesky details of the practical :) useful reminder.
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But don’t let me discourage you from reaching out to a researcher if you see a connection! You never know if someone has other reasons for already looking into X Y or Z and you’re just shedding light on a new application. I’ve mostly just trying to help spitball about the best strategy here given the limit on everyone’s energy
 
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