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

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!

 

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?

 

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:

• Cortical thickness alterations and systemic inflammation define long-COVID patients with cognitive impairment, July 2023, Bestecher et al
• Predictors of non-recovery from fatigue and cognitive deficits after COVID-19: a prospective, longitudinal, population-based study 2024 Hartung et al
• Widespread white matter oedema in subacute COVID-19 patients with neurological symptoms , 2023, Rau et al
• Acute blood biomarker profiles predict cognitive deficits 6 and 12 months after COVID-19 hospitalization, 2023, Taquet et al
• Longterm course of neuropsychological symptoms and ME/CFS after SARS-CoV-2-infection: a prospective registry study 2023 Reuken et al
• Deep Phenotyping of Neurologic Postacute Sequelae of SARS-CoV-2 Infection, Mina, Nath et al, 2023
• The Montreal Cognitive Assessment Test (MoCA) as a screening tool for cognitive dysfunction in fibromyalgia, 2022, Elkana et al
• Neuropsychological profiles and cerebral glucose metabolism in neurocognitive Long COVID-syndrome, 2021, Dressing et al

If the MOCA had any use in differentiating LC "brain-fog" from ME/CFS "brain-fog" a lot would already have been won.

 

Sky news:

https://news.sky.com/story/cause-of...-from-leaky-blood-vessels-study-says-13078199

 

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!

 

Something in the blood? @Simon M

 

Press release (includes a two-minute video):
https://www.tcd.ie/news_events/arti...ng-cause-of-brain-fog-linked-with-long-covid/

 

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.

 

This looks strong.

 

The protective action of oestrogens on blood brain barrier

https://www.sciencedirect.com/science/article/abs/pii/S0889159115300040

 

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)

 

"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).