Blood–brain barrier disruption and sustained systemic inflammation in individuals with long COVID-associated cognitive impairment, 2024, Greene et al

Erm...aren't blood vessels supposed to leak?

So as to supply 'stuff' to bits that aren't actually inside the blood vessel surely the blood needs to get out of the blood vessel somehow, presumably this would constitute a 'leak'?

Leaking is surely the primary, if not only, purpose of blood vessels?
 
Wonko said:
Erm...aren't blood vessels supposed to leak?

So as to supply 'stuff' to bits that aren't actually inside the blood vessel surely the blood needs to get out of the blood vessel somehow, presumably this would constitute a 'leak'?

Leaking is surely the primary, if not only, purpose of blood vessels?
Click to expand...

There is I guess a qualitative difference between leaking and supplying.
 
There are some overlaps with other papers discussed on this forum that also used the MOCA, which might be worthy of further exploration. Several other papers (including one by Nath) have also used the MOCA test. Some of these are:
If the MOCA had any use in differentiating LC "brain-fog" from ME/CFS "brain-fog" a lot would already have been won.
 
I wonder if anyone remembers research from the 1990s or early 2000s, possibly in Scotland, where something similar was proposed as the cause of ME/CFS? I just feel like this might be familiar, I have a vague recollection of something like this but I do not have details - or the memory to recall them!
 
Wonko said:
Erm...aren't blood vessels supposed to leak?

So as to supply 'stuff' to bits that aren't actually inside the blood vessel surely the blood needs to get out of the blood vessel somehow, presumably this would constitute a 'leak'?

Leaking is surely the primary, if not only, purpose of blood vessels?
Click to expand...

I have been trying to figure out how DCE-MRI works and what is shows regarding BBB disfunction.

They inject a contrast agent, in this case gadobenate dimeglumine, which can pass through vascular endothelium into the extracellular spaces of most tissues. However, in the brain the BBB prevents this from happening and the contrast agent typically can't get into the brains of controls. However, if there is a disruption in the BBB then more contrast will pass into the brain, increase in concentration, and be detected by the MRI. This is done by taking images before, during and after the injection of contrast and determining the blood flow, number of blood vessels and their permeability. In this study to be highly permeable, the slope of the contrast agent (measuring how much over time I think) had to be in the top 95th percentile of a previous control group. They then looked at the total number of areas that had high permeability to figure out a global marker of BBB dysfunction. Please let me know if any of this seems wrong :)

Also this method of measuring BBB dysfunction has had validation studies in MS and a different study looking at TBI amongst others.
https://pubmed.ncbi.nlm.nih.gov/30417928/
https://www.sciencedirect.com/science/article/pii/S2213158222003011

I think these are exactly the kind of studies we need.
 
A few references for DCE-MRI (chronological order) —

Quantitative measurement of blood-brain barrier permeability in human using dynamic contrast-enhanced MRI with fast T1 mapping (2011, Magnetic Resonance in Medicine)

Imaging Blood-Brain Barrier Dysfunction in Football Players (2014, JAMA Neurology)

Blood–brain barrier permeability measured using dynamic contrast-enhanced magnetic resonance imaging: a validation study (2019, The Journal of Physiology)

Dynamic Blood–Brain Barrier Regulation in Mild Traumatic Brain Injury (2019, Journal of Neurotrauma)

Slow blood-to-brain transport underlies enduring barrier dysfunction in American football players (2020, Brain)

Blood-Brain Barrier Permeability in Patients With Reversible Cerebral Vasoconstriction Syndrome Assessed With Dynamic Contrast-Enhanced MRI (2021, Neurology)

Blood–brain barrier damage and new onset refractory status epilepticus: An exploratory study using dynamic contrast-enhanced magnetic resonance imaging (2023, Epilepsia)

Dynamic contrast-enhanced MRI shows altered blood–brain barrier function of deep gray matter structures in neuroborreliosis: a case–control study (2023, European Radiology Experimental)
 
Simon M said:
"exposure of brain endothelial cells to serum from patients with long COVID induced expression of inflammatory marker"

Interesting, though I couldn't see the relevant figure (happy to look if someone points me to it).
Click to expand...

I believe this should be in reference to

We next examined immunovascular interactions in PBMCs isolated from patients with COVID-19 and found increased adhesion of PBMCs to human brain endothelial cells in the cohort with long COVID compared to unaffected individuals, which was heightened in the presence of TNF and only modestly affected by blocking antibodies against ICAM-1 and VCAM-1 (Extended Data Fig. 8a,b). Furthermore, exposure of human brain endothelial cells to 10% serum from recovered individuals and individuals with long COVID resulted in the upregulation of ICAM1, VCAM1 and TNF transcripts compared to sera from unaffected individuals (Extended Data Fig. 8c,d). Previous studies indicated a role for S protein persistence in coagulation dysregulation and brain injury, so we explored how S protein affects endothelial cell activity. Exposure of human brain endothelial cells to S1 protein led to a dose-dependent increase in TNF, TGFβ, ICAM1 and VCAM1 mRNA (Extended Data Fig. 8e) after 72-h treatment with 0–400 nM S1 spike protein.
Click to expand...

The figures are

41593_2024_1576_Fig14_ESM.jpg


Description: a, b) Peripheral blood mononuclear cells (PBMCs) from Long COVID participants show greater adherence to the human brain endothelial cell line, hCMEC/d3, in the presence or absence of 10 ng/ml TNFa (n = 5 Control, n = 7 Long COVID). Error bars are mean ± s.d. Data in a was analysed by two-way ANOVA with Tukey correction. Each datapoint represents one patient. c) PBMCs from long COVID patients in the presence of IgG, VCAM-1 or ICAM-1 blocking antibodies (n = 6 long COVID patients). Data was analysed by repeated measures one-way ANOVA with Tukey correction for multiple comparisons. Each datapoint represents one patient. d) Schematic of experiments to assess the effect of long COVID patient serum or spike protein on human brain endothelial cells. e) Exposure of hCMEC/d3 cells to 10 % serum from healthy or long COVID participants and quantification of gene expression changes by q-RT-PCR. Long COVID serum significantly increased TNF (P = 0.0006) and VCAM1 (P < 0.0001) vs control serum. f) Exposure of hCMEC/d3 cells to vehicle or 4, 40 or 400 nM S1 spike protein and quantification of gene expression changes by q-RT-PCR. 400 nM S1 spike protein significantly increased TNF (P = 0.024), TGFB1 (P = 0.0274), VCAM1 (P < 0.0001), MCP1 (P = 0.0269) and SNAI1 (P = 0.0389) vs vehicle. For e, n = 4 healthy serum samples and n = 8 long COVID serum samples were used. Scale bar – 50 µm. Schematics in a and d created with BioRender.com.

The source data can be found here:Source Data Extended Data Fig. 8
 
Since these are all samples from early in the pandemic I was wandering how "new" these findings were. It indeed turns out they submitted the paper in November 2022. I'd be suprised if they wouldn't have continued with this work and have already obtained some more results, positive or null (the largest problem with the paper are really the miniscule sample sizes). If that was the case I hope they'll publish a preprint this time around.
 
EndME said:
Since these are all samples from early in the pandemic I was wandering how "new" these findings were. It indeed turns out they submitted the paper in November 2022. I'd be suprised if they wouldn't have continued with this work and have already obtained some more results, positive or null (the largest problem with the paper are really the miniscule sample sizes). If that was the case I hope they'll publish a preprint this time around.
Click to expand...

I haven't found anything on ongoing work or grants, but they mention that they are looking at biomarkers and therapeutics and other post-viral illnesses in many of the press reports (as always take these with a massive pile of salt)

"While the study focuses on long Covid patients, Campbell said the results might have relevance to people with brain fog relating to other conditions – such as ME – although extensive work would be needed to confirm that."

"Without doubt, similar mechanisms are at play across many disparate types of viral infection and we are now tantalisingly close to understanding how and why they cause neurological dysfunction in patients.”

"The concept that many other viral infections that lead to post-viral syndromes might drive blood vessel leakage in the brain is potentially game changing and is under active investigation by the team.”

www.theguardian.com/society/2024/feb/22/long-covid-brain-fog-may-be-due-to-leaky-blood-brain-barrier-study
https://www.tcd.ie/news_events/arti...ng-cause-of-brain-fog-linked-with-long-covid/
 
EndME said:
Since these are all samples from early in the pandemic I was wandering how "new" these findings were. It indeed turns out they submitted the paper in November 2022. I'd be suprised if they wouldn't have continued with this work and have already obtained some more results, positive or null (the largest problem with the paper are really the miniscule sample sizes). If that was the case I hope they'll publish a preprint this time around.
Click to expand...

Wow 15 months for the paper to be published seems crazy.
 
ME Research UK

Cognitive difficulties (sometimes referred to as “brain fog”) are a key symptom of ME/CFS - and one of four required for “suspecting ME/CFS” in the 2021 NICE guidelines alongside fatigue, post exertional malaise and unrefreshing sleep. Brain fog is also experienced by many people with long COVID.

The overlap in symptom between ME/CFS and long COVID means that an article (https://go.nature.com/48PRbPM) published in February this year which aimed to investigate whether the blood brain barrier (BBB) – a membrane which carefully regulates movement of molecules between the blood and the brain, may be associated with brain fog in people with long COVID is important to consider.

Read more here: https://tinyurl.com/r34fahvh
 
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