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

Preprint
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
*****
Now published - abstract and link here

 

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)

 

Published
https://www.nature.com/articles/s41593-024-01576-9

Abstract

Vascular disruption has been implicated in coronavirus disease 2019 (COVID-19) pathogenesis and may predispose to the neurological sequelae associated with long COVID, yet it is unclear how blood–brain barrier (BBB) function is affected in these conditions. Here we show that BBB disruption is evident during acute infection and in patients with long COVID with cognitive impairment, commonly referred to as brain fog. Using dynamic contrast-enhanced magnetic resonance imaging, we show BBB disruption in patients with long COVID-associated brain fog. Transcriptomic analysis of peripheral blood mononuclear cells revealed dysregulation of the coagulation system and a dampened adaptive immune response in individuals with brain fog. Accordingly, peripheral blood mononuclear cells showed increased adhesion to human brain endothelial cells in vitro, while exposure of brain endothelial cells to serum from patients with long COVID induced expression of inflammatory markers. Together, our data suggest that sustained systemic inflammation and persistent localized BBB dysfunction is a key feature of long COVID-associated brain fog.

 

https://www.irishtimes.com/health/2...-people-with-long-covid-can-suffer-brain-fog/

The scientists at TCD’s Smurfit Institute of Genetics and neurologists in the school of medicine have also uncovered a novel form of MRI scan that shows how long Covid can affect the brain’s delicate network of blood vessels.

“For the first time, we have been able to show that leaky blood vessels in the human brain, in tandem with a hyperactive immune system, may be the key drivers of brain fog associated with long Covid,” said Matthew Campbell, professor in genetics and principal investigator at FutureNeuro research facility.

“This is critically important, as understanding the underlying cause of these conditions will allow us to develop targeted therapies for patients in the future.”

“Undertaking this complicated clinical research study at a time of national crisis and when our hospital system was under severe pressure is a testament to the skill and resource of our medical trainees and staff. The findings will now likely change the landscape of how we understand and treat post-viral neurological conditions,” said neurologist and head of TCD’s school of medicine Prof Colin Doherty.

“It also confirms that the neurological symptoms of long Covid are measurable with real and demonstrable metabolic and vascular changes in the brain.”
——

“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,” Prof Campbell said.

“Our findings have now set the stage for further studies examining the molecular events that lead to post-viral fatigue and brain fog,” said lead author Dr Chris Greene.

 

Merged thread

Long COVID has remained an on-going public health issue in the years following the global pandemic. Here, we report blood–brain barrier disruption in patients with acute SARS-CoV-2 infection and brain fog, and patients presenting with long COVID, brain fog and cognitive decline, compared to those with long COVID without any neurological symptoms.

https://www.nature.com/articles/s41593-024-01577-8


News item on the study in the Guardian (link to study in Guardian not working - use above link)
https://www.theguardian.com/society...may-be-due-to-leaky-blood-brain-barrier-study

 

This seems to be a really strong biomarker!

“While standard diagnostic MRI scans showed no clinically relevant pathological findings in any participant, DCE-MRI imaging revealed significantly increased whole-brain leakage in patients with long COVID with brain fog (Fig. 2d–f), with an increased percentage of brain volume with leaky blood vessels in the cohort with brain fog compared to the cohort without brain fog. Stratifying the cohort into recovered, long COVID without brain fog and long COVID with brain fog revealed significantly increased BBB permeability in the cohort with brain fog compared to recovered patients and patients with long COVID without brain fog.”

 

no,no,no,… these blood vessels are simply not showing enough effort, but, it's not their fault,… they just can't help themselves,…

 

From the Discussion section:

"Patients with long COVID had elevated levels of IL-8, GFAP and TGFβ, with TGFβ specifically increased in the cohort with brain fog. GFAP is a robust marker of cerebrovascular damage and is elevated after repetitive head trauma, reflecting BBB disruption, as seen in contact sport athletes and in individuals with self-reported neurological symptoms in long COVID26,52,53. Interestingly, TGFβ was strongly associated with BBB disruption and structural brain changes. TGFβ has been implicated in the pathogenesis of chronic fatigue syndrome, a condition with clinical similarities to long COVID."

 

Cohort selection:

There's 2 sets of groups. Group 1 was used for the first bit of bloodwork (inflammatory, coagulation and BBB dysfunction markers) whilst Group 2 was used for the imaging work and the following bloodwork (biomarkers of neuroinflammation and BBB dysfunction & gene expressions).

Group 1:

• n=25 prepandemic unexposed controls
• n=76 acute Covid patients (March-April 2020) (acute infection status: 23 severe acute, 43 mild, 10 moderate, 25 unaffected)

Group 2 ( (B)-(D) had a mild acute illness):

• (A) n=60 healthy controls from a public dataset
• (B) n=10 recovered patients
• (C) n=11 Long-Covid patients without brain-fog
• (D) n=11 Long-Covid patients with brain-fog

It's unclear to me whether there are overlaps between Group 1 and Group 2 (it's certainly possible, but the way the paper is written one would assume it isn't the case).

Cohort characteristics:

This analysis will be focused on Group 2 since this is the Long-Covid cohort. The 4 sets of cohorts are all female dominated (F/M ratios are (A)=18/42, (B)=4/6, (C)=2/9, (D)=0/11), not too old (average ages are (A)-(D): 40-46) and they are well matched on the Comorbidity score. A small problem might be the age matching, with the LC patients with brain-fog being quite a bit older than all other groups. The scans were taken this many days after their acute infection (B):46 (C):170 (D):211.

Naturally, no patients in the recovered group had ansomia whilst 8 people in both LC groups had anosmia. They evaluated anosmia via testing (Q-SIT-based method). Unfortunately, other symptoms or their LC severity weren't reported, however with the study being focused on brain-fog this seems forgivable (but some details would be highly appreciated).

A very positive aspect of the study is that they objectively evaluated the brain fog in the LC group via a test that seems highly standardised, the Montreal Cognitive Assessment test (MOCA). The brain fog group had an average MOCA score of 24.9, and six scores of those scores ranged from 18–25 (a score of 25 and under implies mild cognitive impairment), allegedly there were also "deficits in recall, executive functioning and word finding" but it isn't specified what this could mean.

Overall reading the paper for the first time, the cohort seems to be decently chosen and the authors outline details of the cohort better than same others have. The largest problem will be the very small sample size of the LC cohort. The use of the MOCA would be a further strength as they verified that people indeed had cognitive impairment. It remains questionable what LC in these cohorts mean as no details of symptomology are provided.

It might be worthwhile to compare the MOCA results to some of the tests in the intramural study as well SRT and NVT used in this LC study.

 

They think they leak, therefore they leak!