[Preprint] Blood-brain barrier disruption in Long COVID-associated cognitive impairment, 2023

Blood-brain barrier disruption in Long COVID-associated cognitive impairment
Chris Greene, Ruairi Connolly, Declan Brennan, Aoife Laffan, Eoin O'Keeffe, Lilia Zaporojan, Emma Connolly, Cliona Ni Cheallaigh, Niall Conlon, Colin Doherty, Matthew Campbell

Vascular disruption has been heavily implicated in COVID-19 pathogenesis and may predispose the neurological sequelae associated with the condition now known as long COVID. To date, no studies have objectively assessed blood-brain barrier (BBB) function in individuals with neurological complications stemming from prior SARS-CoV-2 infection.

Here, we explored the neurobiological effects of SARS-CoV-2 infection in humans with acute infection (n = 76) and those with persistent long COVID with and without neurological impairment. Following acute infection, patients with neurological impairment had increased serum S100β, indicative of BBB disruption.

Furthermore, using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in long COVID patients (n = 32), we observed elevated BBB permeability in distinct neuroanatomical regions including the frontal cortex, occipital lobe and temporal lobes which correlated with global brain volume and white matter volume deficits in patients with neurological impairment.

Patients with neurological impairment had increased levels of blood-based biomarkers including GFAP, TGFβ and IL8 with levels of TGFβ that correlated with BBB permeability and structural brain changes. Peripheral blood mononuclear cells isolated from unaffected and long COVID patients had persistent upregulation of inflammatory markers including IFNA/G and showed increased adhesion to human brain endothelial cells in vitro.

Finally, exposure of endothelial cells to serum from long COVID patients induced increases in ICAM-1, VCAM-1 and TNF irrespective of neurological sequelae.

Together, these data suggest that sustained systemic inflammation and persistent localised BBB dysfunction is a feature of long COVID-associated neurological impairment. Importantly, this may also be therapeutically relevant in the treatment and clinical management of this patient group.

https://www.researchsquare.com/article/rs-2069710/v2

 

If these findings are replicated and confirmed later, is there anything that can be done as a treatment for this permeability itself?

Or instead would the mechanisms underlying it need to be understood before you could do anything?

Or nothing can be done at all?

 

Ok good. Hopeful!

I am personally convinced of lingering infection. So I hope we can find some ways to handle this sooner rather than later.

 

So pleased to see this study. Waiting hopefully for medications to be proven and available here.

edit: had to take a quick look at the non BBB things.

@SNT Gatchaman. The cortical thinning is troubling and the areas affected. This could have cumulative future effects on brain function.

 

There is some evidence of reduced grey and white matter in people with severe ME on autopsy.

Things like shrinkage of size in the heart, also seen in ME, are potently reversible, but any damage to the brain is likely to be irreversible. It is likely that most of our brain fog is down to a general issue such as reduced cerebral profusion, but it is also possible that any general and presumably reversible issue also gradually causes some structural damage. So I suspect even if effective treatments become available people like myself, nearly 30 years into my ME, will continue to experience some on going cognitive deficits. Certainly earlier on in the course of my ME, I had periods where my brain function would return to normal during times I experienced some level of remission in my ME, however that is not something I have experienced more recently.

[corrected typos]

 

Yes, the ramifications are very concerning for the pwME/LC, unfortunately I can picture many scenarios in the mental health sector and people are going to need a lot more health services, across the board, as once it is gone, it cannot be regrown as science stands currently.

 

It might not just be severe patients. My neuropsychological test points to abnormalities across those regions.

 

I agree, but it is just one more thing that needs investigating in relation to ME and now Long Covid, especially as we don’t have pre and post morbid scans looking at changes in individuals and also can not conclude anything about causal relationships on the basis of an association.

For example would a smaller heart size be a direct consequence of the ME pathology or an indirect result related to reduced physical activity, could loss of brain cells be caused by whatever is the underlying mechanism involved in brain fog or is it an indirect result of changed behaviour by a long term disabled person?

At least as a result of Long Covid we are seeing a much wider range of studies, though lets hope the pattern of interesting small studies that are never replicated with larger cohorts or left unfollowed up that we have seen in ME [is not repeated].

 

Yes, I agree with both of you, if we look at the ME’s known neuropsych effects, (so global for @living lighter, mine was in processing speed and working memory about 15 years ago and I think it has worsened with age and maybe if I could afford or get referred to one it is likely to have some new deficits) and the new and emerging understanding within ME science around orthostatic stress and reduced blood flow to the brain

Neuropsych tests cognitive function (for simplicity I am encapsulating this to the central regulatory regions of attention, concentration etc (mainly temporal and frontal) with connections into the hormonal and blood chemistry regulatory system (hypothalamus).

Then we add the central mechanisms that show suggestions of being impaired too due to orthostatic stress eg brainstem (regulator of a variety of things but especially cerebrovascular and respiratory function) but also the hippocampus and it’s connections to the main hormonal regulator glands (pitutiary and pineal).

If you start thinning these regulatory pathways, with age and other things (the list is long but to name a few, head injury, substance abuse, genetic vulnerability to brain disorders eg, dementia), and now have an endemic virus which we are all likely to get at some stage, it doesn’t bode well.

Then there will be the known neuropsychiatric effects of the virus whereby thinning your cortex of white and grey matter has effects on executive control, impulse control, mood, anxiety, worsening of pre-existing developmental disorders, substance abuse disorders, psychotic disorders etc

 

https://www.nature.com/articles/s41586-022-04569-5 (link to thread)