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

[EndME]

It's only an animal model, but could potentially be of relevance:
SARS-CoV-2 induces blood-brain barrier and choroid plexus barrier impairments and vascular inflammation in mice.

 

[Hutan]

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

The abstract of the preprint is in 2023 is in the first post and the published abstract is at this post. It looks as though the paper received quite a bit more polishing. Also, there's substantially more on gene expression.

 

[Hutan]

Coming back to this, given that Nath recently said that he was confident that there is no blood brain barrier dysfunction in Long Covid.

The findings on blood-brain barrier dysfunction based on the MRI scanning with contrast still look pretty good.

 

[Hutan]

I note the affiliation of the senior author:
Matthew Campbell
View ORCID ID profile

• Smurfit Institute of Genetics, Trinity College Dublin, Dublin, Ireland
• FutureNeuro, Science Foundation Ireland Research Centre for Chronic and Rare Neurological Diseases, Royal College of Surgeons in Ireland, University of Medicine and Health Sciences, Dublin, Ireland

That's an interesting organisation to have working on Long Covid.


From the new section on gene expression:
White blood cells from patients with COVID-19 activate brain endothelial cells

Given the prevalence of circulating markers indicative of BBB dys- function and immune cell activation, we examined gene expression changes in peripheral blood mononuclear cells (PBMCs) isolated from unaffected (n = 7), recovered (n = 5) and patients with long COVID with (n = 6) or without (n = 5) brain fog using RNA sequencing (RNA-seq).

Compared to unaffected individuals:

In the recovered cohort and the cohort without brain fog, upregulated terms included those related to the coagulation system, such as blood coagulation (for example, F13A1, PROS1), platelet activa- tion (for example, F2R, PF4, PF4V1), platelet degranulation (for example, SELP, VCL, CLU) as well as megakaryocyte development, immunoglobu- lin production and complement activation (Extended Data Fig. 7d,e and Supplementary Tables 4 and 5–12). In the cohort with brain fog, there were changes in genes associated with vitamin A metabolism (for example, DGAT2, DHRS9) and regulation of leukocyte homeostasis (for example, CXCL10, IL6R) (Extended Data Fig. 7f and Supplementary Tables 4 and 5–12).

Interesting to see IL6R mentioned - I think we have seen that mentioned in another recent paper.

comparing the cohort with brain fog to the recovered and long COVID cohorts:

Principal component analysis (PCA) plots showed a clear separation of the cohort with brain fog from the recovered and long COVID cohorts (Fig. 6a–d). Compared to the recovered cases, there was a strong enrichment in upregulated terms for pathways related to T cell differentiation and activation (for example, PRDM1, TNF), TGFβ signaling (for example, SMAD3, SNAI1, SMURF1) and regulation of angiogenesis (for example, HES1, DLL1, HIF1A), while there was downregulation in genes involved in platelet activation, signaling and aggregation (for example, PF4V1, PF4, TREML1) and hemostasis (for example, F13A1, GP1BA, GP1BB) (Fig. 6e and Supplementary Tables 4 and 5–12).

Figure 6a - PCA: Recovered in green, with brain fog in red


Figure 6c - PCA: Long Covid without brain fog in green, with brain fog in red

We also compared the transcriptome profile of individuals with and without brain fog in our cohort with long COVID. Upregulated genes were enriched in pathways related to T cell differentiation and activation (for example, RUNX3, IFNG, TNFSF9), negative regulation of the immune response (for example, WASL, ID2, TNFAIP3) and circa- dian regulation of gene expression (for example, RORA, PER1, NRIP1) (Fig. 6f,j–l). Pathways related to immunoglobulin, production, defense responses and B cell activation were among those downregulated, including immunoglobulin production (IGKV1–12, IGKV1–17), adaptive immune response (for example, CX3CR1, FCGR1BP) and B cell activa- tion (HDAC9, CD180, MNDA) (Extended Data Fig. 7 and Supplemen- tary Tables 4 and 5–12). In agreement with previous studies, several factors involved in the coagulation pathway were downregulated specifically in the cohort with brain fog, including PF4, PF4V1 and SELP (Fig. 6g–i)32.

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 indi- viduals (Extended Data Fig. 8c,d).

 

[Hutan]

From the discussion:

Structurally, there was reduced brain and WM volume in individuals with brain fog and recovered patients, suggesting that these changes do not primarily drive the fatigue and cognitive impairment associated with brain fog.

Persistence of viral components, such as S protein, has beenhypothesized to be responsible for long COVID-associated neurological symptoms57–59. S protein persistence may be involved in neurological sequelae as direct brain injection was associated with coagulationdysregulation and neurodegeneration. This suggests that S protein may have a long half-life in the body. In support of this, immune cells were identified with S protein up to 15 months after infection60. Further- more, we showed that exposure of brain endothelial cells to S protein resulted in an activated endothelial cell phenotype with upregulation of inflammatory cytokines and cell adhesion molecules and probably has a role in long COVID-associated brain fog. Reinforcing these find- ings, previous studies showed that S protein promoted tight junction degradation, endothelial cell activation and increased adherence of immune cells23,61. The long-lasting influence of S protein on cerebro- vascular function is unknown and should be investigated in future studies, especially considering the longevity of brain endothelial cells.

Our study is also limited by a small sample size. Future studies with larger patient cohorts should perform unbiased proteome profil- ing on blood and CSF samples. In agreement with our study, another study also found elevated levels of markers of neurological injury and BBB disruption, such as GFAP, in individuals with long COVID with self-reported neurological symptoms53. Ultimately, expanding the use of clinical tools focused on understanding the role of the BBB in postviral illnesses may lead to better treatment and management strategies for patients in the future.

Ref #53 is
Plasma Markers of Neurologic Injury and Inflammation in People With ... Neurologic Post acute Sequelae of SARS-CoV-2 Infection, 2022, Peluso et al
That study only found elevated GFAP early in the disease of those with Long Covid, and not later.

I get the impression that the team think Long Covid is important, and that they are motivated to do more.