COVID Brain Problems May Stem From Attack on Endothelial Cells

Antibodies that attack the endothelial cells lining the brain’s blood vessels may lead to inflammation and neurologic damage in people with COVID-19, a small autopsy study suggested.

All nine COVID patients in the study had multifocal vascular damage with serum proteins leaking into the brain parenchyma, according to Avindra Nath, MD, clinical director of the National Institute of Neurological Disorders and Stroke in Bethesda, Maryland, and co-authors.

This damage was accompanied by widespread endothelial cell activation, Nath and colleagues reported in Brain. Platelet aggregates and microthrombi were found adhering to endothelial cells along vascular lumina, and deposits of immune complexes were found on endothelial cells and platelets.

Consistent with other studies, SARS-CoV-2 virus was not detected in the brain.

The findings suggested that COVID-19 triggers the formation of immune complexes activating the classical complement pathway, the researchers noted.

“Deposition of complement cascade and immunoglobulins suggests an immune-mediated injury to the endothelial cells,” they wrote. “The inflammatory process results in microglia activation causing neuronal injury and neuronophagia.”

The group had previously shown blood vessel damage and inflammation in patients’ brains at autopsy, “but we didn’t understand the cause of the damage,” Nath said in a statement. “I think in this paper we’ve gained important insight into the cascade of events.”

The researchers examined brain tissue from a subset of participants in their earlier study, selecting nine people 24 to 73 years old (seven men and two women) with microvascular abnormalities on post-mortem MRI and comparing them with 10 controls.

Participants died during the first wave of the pandemic from March to July 2020. Five died suddenly; four were found dead at home and one in a subway. The others died within days to weeks of symptom onset.

SARS-CoV-2 infection was confirmed with testing. All participants had evidence of lung involvement at the time of autopsy, but only one required ICU admission.

Immunohistochemistry showed perivascular infiltrates consisting predominantly of macrophages. CD8+ T cells, CD4+ T cells, and very few CD20+ B cells also were present.

Astrogliosis was prominent in the perivascular regions. Microglial nodules were predominant in the hindbrain, which were associated with focal neuronal loss and neuronophagia.

Complement components 1q and 4d were seen on endothelial cells and platelets; this was associated with deposits of immunoglobulins G (IgG) and M (IgM).

The antigen this immune response was targeted against remains unknown, Nath and co-authors noted. Antibodies against SARS-CoV-2 spike protein may bind to the ACE2 receptor used by the virus to enter cells, they suggested, but more research is needed to explore this hypothesis.

The study may have implications for treating long-term neurologic manifestations of COVID-19, which include headache, fatigue, smell loss, sleep problems, and brain fog.

“It is quite possible that this same immune response persists in long COVID patients, resulting in neuronal injury,” Nath observed.

“There could be a small indolent immune response that is continuing, which means that immune-modulating therapies might help these patients,” he added. “So these findings have very important therapeutic implications.”