Neurovascular injury with complement activation and inflammation in COVID-19, 2022, Lee ... Nath et al

Neurovascular injury with complement activation and inflammation in COVID-19
Myoung-Hwa Lee, Daniel P. Perl, Joseph Steiner, Nicholas Pasternack, Wenxue Li, Dragan Maric, Farinaz Safavi, Iren Horkayne-Szakaly, Robert Jones, Michelle N. Stram, Joel T. Moncur, Marco Hefti, Rebecca D. Folkerth, Avindra Nath

The underlying mechanisms by which severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) leads to acute and long-term neurological manifestations remains obscure. We aimed to characterize the neuropathological changes in patients with coronavirus disease 2019 and determine the underlying pathophysiological mechanisms.

In this autopsy study of the brain, we characterized the vascular pathology, the neuroinflammatory changes and cellular and humoral immune responses by immunohistochemistry.

All patients died during the first wave of the pandemic from March to July 2020. All patients were adults who died after a short duration of the infection, some had died suddenly with minimal respiratory involvement. Infection with SARS-CoV-2 was confirmed on ante-mortem or post-mortem testing. Descriptive analysis of the pathological changes and quantitative analyses of the infiltrates and vascular changes were performed.

All patients had multifocal vascular damage as determined by leakage of serum proteins into the brain parenchyma. This was accompanied by widespread endothelial cell activation. Platelet aggregates and microthrombi were found adherent to the endothelial cells along vascular lumina. Immune complexes with activation of the classical complement pathway were found on the endothelial cells and platelets. Perivascular infiltrates consisted of predominantly macrophages and some CD8+ T cells. Only rare CD4+ T cells and CD20+ B cells were present. Astrogliosis was also prominent in the perivascular regions. Microglial nodules were predominant in the hindbrain, which were associated with focal neuronal loss and neuronophagia.

Antibody-mediated cytotoxicity directed against the endothelial cells is the most likely initiating event that leads to vascular leakage, platelet aggregation, neuroinflammation and neuronal injury. Therapeutic modalities directed against immune complexes should be considered.

Link to DOI | PDF

 

9 patients (7 males, 2 females, 24–73 years) died during the first wave. Co-morbidities included diabetes, hypertension and substance use disorder. 5 patients had died suddenly, 4 at home. The remaining patients died within days to weeks after onset of symptoms.

The control group consisted of 9 males and 1 female, 43–74 years. They were diagnosed with pulmonary infections, systemic infections, hypertension, bipolar disorder and substance use disorder. Doesn't look like diabetes in control group.

 

Some quotes (slightly edited) —

 

So, naively, if they think something (antibodies or antibodies + spike) is binding to ACE-2 on endothelial cells, that seems like something you could test in vitro with acute Covid or Long Covid patient plasma.

 

Adhesion molecules are cell surface proteins that mediate the interaction between cells, or between cells and the extracellular matrix (ECM). There are four families of adhesion molecules: immunoglobulin-like adhesion molecules, integrins, cadherins and selectins.

ME/CFS was associated with increased expression of cadherins in a proteomics study by Hanson. Would cadherins fit with the process that the paper is suggestng is occurring?

 

Watch in what way? The idea behind a GWAS is that it is hypothesis free and reports on what has been found by the analysis, rather than going searching for results in an attempt to support a particular idea.

 

Unless I've forgotten something I think Simon was asking for particular questions to put into the optional additional DecodeME questionnaire that will be offered to participants to complete.

 

The review paper @Hutan referenced above probably warrants its own thread. There's a lot in it — fibrinogen has unusual characteristics that are important. The relationship between fibrinogen and the innate immune system and neuroinflammation looks potentially very relevant. (There is also reference to rheumatoid arthritis and other peripheral inflammatory diseases.)

This thread's paper is discussing evidence for antibody-mediated BBB disruption. In part, the 2018 review article discusses the (substantial) links between fibrinogen and amyloid-β. I would also wonder whether the process could involve amyloid-form fibrinogen directly. Perhaps it might be more inflammogenic and could promote an endotheliitis, thereby disrupting the blood brain-barrier, which then allows (amyloid-) fibrinogen etc into the perivascular parenchyma. Normal fibrinogen promotes Aβ but could amyloid form fibrinogen accelerate this?

 

Hanson et al did not report which type of cadherin was elevated in ME/CFS, if any. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7931008/

If one type of cadherin stood out from the others, it would hint which type of tissue was involved. VE-cadherin would suggest a vascular problem and whatever other tissues also happen to express the VE type. N-cadherin would suggest a brain problem. There are many types of cadherins. This approach might be a way to find out where in the body things are going wrong.

 

I remember this from when they started because of how atypical the cohort was, and therefore a stretch to connect it to me/cfs. This is@Forbin 's quoting Nath during an NIH call.