Yes, me too. Except that the 2 day CPET differences in ME/CFS are still not entirely beyond question - a replication in a very well conducted, adequately sized NIH investigation would have been extremely helpful.
DOPA, DOPAC and DPHG
Re Evergreen's
query above:
L-DOPA is the
precursor to the
neurotransmitters dopamine,
norepinephrine (noradrenaline), and
epinephrine(adrenaline), which are collectively known as
catecholamines.
In the neuronal cytoplasm dopamine undergoes not only enzymatic oxidation to form DOPAC but also spontaneous oxidation to form 5-S-cysteinyl-dopamine (Cys-DOPA).
DHPG is a metabolite of norepinephrine.
Norepinephrine is more commonly known as noradrenalin in the UK, it is a catecholamine. It mobilises the body for action, and is increased at times of stress.
Lower levels of these catecholamines are a key part of the exertion preference story:
So, yes, first, how strong is the evidence of lower levels in ME/CFS?
Figure 6a-c
21 healthy volunteers; 16 ME/CFS
The paper notes that some of the participants were taking central-acting medications, but it doesn't say if the charts and significance analysis exclude the data from these participants, and it does say that excluding them didn't change the results. It could be worth checking out the analysis using the source data.
View attachment 21174
DOPA - 6a
summary - most ME/CFS data points looked like healthy control data points. no good evidence of a problem
the p value of 0.02 indicates significance but not strong significance. Regardless of cohort, most of the values are in the range 550 to 800 pg/ml. There are a few outliers in both cohorts that are making most of the difference to the p value. Given that most of the ME/CFS results look like most of the HV results, it's hard to make a story of lower levels of DOPA being an important part of ME/CFS pathology. That's particularly true given the levels of dopamine and norepinephrine which are downstream of DOPA weren't different.
I found a reference suggesting that a low level of DOPA is less than 2.62 pmol/mL and that level increased the risk of developing Parkinsons. I think that makes for a value of 518.6 pg/mL. In that case, most of the participants with ME/CFS did not have abnormally low levels of DOPA, maybe 2 did. Obesity and stress are said to reduce DOPA levels - the ME/CFS cohort had higher BMIs.
DOPAC - 6b
summary - ME/CFS data points essentially fall within the range of healthy control data points. no good evidence of a problem
the p value of 0.02 indicates significance but not strong significance. The ME/CFS values are almost entirely within the range of the healthy controls. So, yes, the median is lower, but I don't think it's possible to make much of a story out of it. Also, DOPAC is a metabolite of dopamine, and dopamine levels were found to be normal.
I found a reference with a mean level of DOPAC in controls of 2.15 nmol/L. I make that 362 pg/mL, which is close to the median reported for the healthy controls. So, yes the ME/CFS results may be mostly on the low side of average, but not abnormally so.
DHPG - 6c
summary - ME/CFS data points essentially fall within the range of the healthy control data points, although on the low side. Interesting
the p value is a bit stronger for this molecule, but still, the ME/CFS data points fall pretty much within the range of the healthy controls. So, again, there's really no basis here for saying that lower levels of catechols are causing problems with cardiovascular function.
Again, the control's median here matches the mean value I found via google for healthy controls. So again, the ME/CFS results are on the low side of average, but there are plenty of healthy controls with similar levels. The upstream molecule, norepinephrine, was reported as being not different from controls.
I did however find
a paper that reported levels of DHPG associated with what they called synucleinopathies - Parkinsons, multiple system atrophy and pure autonomic failure (the latter features prominent orthostatic hypotension from sympathetic noradrenergic denervation). Mean levels (as I calculate them from the nmol/L in that paper) were 1615, 1419 and 1065 pg/mL respectively. There is a group of ME/CFS participants with values in that low range - could they be misdiagnosed? The people in that synucleinopathies paper were on a whole range of medication which might have affected results.
My conclusion
So.. I think the findings are interesting and it would be good to find out more about the molecules, and diseases where the molecules are low. I think it's a stretch to say low levels of these molecules are a problem in ME/CFS when there is so much overlap with the healthy controls. It would be very nice to have these investigations replicated in larger cohorts with better matched controls, as well as in people who have had ME/CFS for longer or who have more severe disease.
It would also be good to check the technique used to determine the molecule levels. Edit - I'd like to know if the data was analysed in batches - there look to be two separate groups in each of the DHPG cohorts, maybe corresponding to some variation in technique?
It would also be good to know how the levels of the various catechol molecules related to each other in individuals. e.g. were there people with reliably low levels of a number of molecules, perhaps identifiable in a PCA?
