Neuroinflammation in post-acute sequelae of COVID-19 (PASC) as assessed by [11C]PBR28 PET correlates with vascular disease measures, 2023, VanElzakker

Andy

Andy

Retired committee member
Published version linked in this later post here

Preprint
Abstract

The COVID-19 pandemic caused by SARS-CoV-2 has triggered a consequential public health crisis of post-acute sequelae of COVID-19 (PASC), sometimes referred to as long COVID. The mechanisms of the heterogeneous persistent symptoms and signs that comprise PASC are under investigation, and several studies have pointed to the central nervous and vascular systems as being potential sites of dysfunction.

In the current study, we recruited individuals with PASC with diverse symptoms, and examined the relationship between neuroinflammation and circulating markers of vascular dysfunction. We used [11C]PBR28 PET neuroimaging, a marker of neuroinflammation, to compare 12 PASC individuals versus 43 normative healthy controls.

We found significantly increased neuroinflammation in PASC versus controls across a wide swath of brain regions including midcingulate and anterior cingulate cortex, corpus callosum, thalamus, basal ganglia, and at the boundaries of ventricles. We also collected and analyzed peripheral blood plasma from the PASC individuals and found significant positive correlations between neuroinflammation and several circulating analytes related to vascular dysfunction.

These results suggest that an interaction between neuroinflammation and vascular health may contribute to common symptoms of PASC.

https://www.biorxiv.org/content/10.1101/2023.10.19.563117v1?ct=
 
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No substantial criticisms from me so far. As they say in the preprint, next steps are more numbers and comparison with recovered Covid convalescents. Ideally as well, non-Covid/pre-pandemic ME/CFS patients of varying duration.
 
Quotes on perivascular spaces (FYI @Michelle and others interested in this) —

We found increased PET uptake in some regions that tend to have dilated perivascular spaces. For example, we found significantly increased PET signal especially within left lentiform nucleus of the basal ganglia. The basal ganglia are a group of subcortical nuclei with many small, thin blood vessels that are common sites of unique perivascular anatomy and enlarged/dilated perivascular spaces
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In neuroradiology, dilated perivascular spaces on the lenticulostriate arteries projecting into the basal ganglia are relatively common and referred to as "Type 1." Enlarged Type 1 perivascular spaces are sometimes seen in normal healthy aging but are associated with disease severity in some neurological conditions and in one study were associated with sleep dysfunction in PASC.
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fibrinogen and sL-selectin were two analytes from the vascular health multiplex panel that were significantly correlated with neuroinflammation-related PET signal. [...] Related to neuroinflammation, fibrinogen persistently activates glia at the glymphatic perivascular spaces that surround neurovasculature.
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One of the markers that positively correlated with neuroinflammation was haptoglobin. In box 1 they say —

Haptoglobin protein circulating in plasma scavenges extracellular hemoglobin and is thought to have a protective effect against hemoglobin-induced vasoconstriction, however in murine models vascular endothelial dysfunction prevents this function (Graw et al., 2017). The gut permeability marker zonulin, which is reduced in the post-acute COVID condition multisystem inflammatory syndrome in children (MIS-C) (Yonker et al. 2021) is the precursor for haptoglobin-2.
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Yonker et al. is Multisystem inflammatory syndrome in children is driven by zonulin-dependent loss of gut mucosal barrier (2021, The Journal of Clinical Investigation)

I think that should be "The gut permeability marker zonulin, which is increased in the post-acute COVID condition multisystem inflammatory syndrome in children (MIS-C)".

This was also discussed in yesterday's PolyBio Fall Symposium by the lead author Lael Yonker in the "Pediatric COVID-19: Working toward solutions" talk. They are enrolling in a trial using Larazotide targeting zonulin (project page and NCT05747534).
 
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Van Elzakker responded to a tweet that he has been recruiting pwME since before the pandemic for this same study design but no one volunteered! (I find that hard to comprehend)

I note from his talk on the symposium he selected the 12 LC according to the MEICC which he just labelled ICC.
 
Hubris said:
There's no way this is true.
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I can definitely see this being true, especially as it seems that many people, including me, weren't aware of such a study for ME in the first place (recruitment appears to still be open www.twitter.com/MBVanElzakker/status/1715765815717335210). Several Long-Covid studies and trials are struggling with patient recruitment for various different reasons. The Polybio studies or even the DecodeME study for the Long Covid subsets really shouldn't be having these struggles.

I wish there was a central website where sensible trials and studies would be collected in a useful manner (unlike clinicaltrials.gov), possibly employing a ranking system (so that you aren't bombarded with Vitamin C studies) and that trials and studies could be sorted by region. I think this could be a major gain for this field. Especially if the website is known to clinicians and they refer their clients to suitable trials/studies. https://twitter.com/postviraltrials does a very good job at keeping Twitter up to date, but I feel Twitter is not the right space for this, either something gets reposted a handful of times or it gets lost forever (apart from the fact that one would have to be active on Twitter which can be another hurdle for patients and especially doctors).
 
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EndME said:
even the DecodeME study for the Long Covid subsets really shouldn't be having these struggles.
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If we were 'simply' recruiting Long Covid patients then I would imagine that we would see a larger number of post-Covid patients but we are recruiting post-Covid patients who have been officially diagnosed with ME/CFS, and it is that diagnosis which seems to be the issue.

However, in general, I do agree that there is a significant lack of established pathways between research studies and potential participants. In the UK there is UK: Be Part of Research registry, and there are various disease specific registries that are being set, but in the UK there is no simple, organised and well-known route for that connection to be made between researcher and patient.
 
EndME said:
I can definitely see this being true, especially as it seems that many people, including me, weren't aware of such a study for ME in the first place (recruitment appears to still be open www.twitter.com/MBVanElzakker/status/1715765815717335210). Several Long-Covid studies and trials are struggling with patient recruitment for various different reasons. The Polybio studies or even the DecodeME study for the Long Covid subsets really shouldn't be having these struggles.

I wish there was a central website where sensible trials and studies would be collected in a useful manner (unlike clinicaltrials.gov), possibly employing a ranking system (so that you aren't bombarded with Vitamin C studies) and that trials and studies could be sorted by region. I think this could be a major gain for this field. Especially if the website is known to clinicians and they refer their clients to suitable trials/studies. https://twitter.com/postviraltrials does a very good job at keeping Twitter up to date, but I feel Twitter is not the right space for this, either something gets reposted a handful of times or it gets lost forever (apart from the fact that one would have to be active on Twitter which can be another hurdle for patients and especially doctors).
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Yeah I most of the time I don’t know about studies till they’re finished or abandoned!
Also I do hear about interesting studies that aren’t in my country or area. I bet there are many people close enough who would also really like to participate but don’t even hear about it.
We really need a proper system for this a one stop shop with a directory for your condition and the field of research.

I would love to be in Michaels study!
But too far away.
 
It appears that this is the study vanElzakker (which is the study mentioned above by @Andy) was referring to (see also
www.twitter.com/MBVanElzakker/status/1487878902651527172)

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