New insights into how Long COVID affects the brain

Long COVID is a condition marked by multiple persistent symptoms that sometimes occur even after mild infections. Among these, memory loss, brain fog and sleep disturbances indicate brain involvement. MRI scans done before and after COVID-19 show shrinkage in certain brain regions, pointing to tissue loss. This raises crucial questions: how does a respiratory virus go on to affect the brain? And what drives brain inflammation in these patients? Two recent papers provide insights into how the virus might indirectly affect the brain.

A study published in Cell Host & Microbe concludes that continued presence of the virus spike protein could be triggering inflammation and neurodegenerative changes in the brain. The spike also activates inflammatory pathways. When researchers injected spike protein into the skulls of mice, they observed brain inflammation along with behavioural changes.

The authors found that spike protein-based vaccines do not have similar effects. They found that vaccinated mice infected with the virus had lower spike protein levels. Moreover, Long COVID symptoms are rarely linked to vaccination. This suggests that it is the immune response to the virus, not vaccination, that is responsible for the widespread presence of spike protein in the body.

In human studies, the researchers identified spike protein within the skulls of people who died of causes other than COVID. This indicates that spike protein stays in the body long after the initial infection, which may have occurred several months earlier. Long COVID patients with persistent spike protein also had elevated levels of biomarkers such as tau protein in their cerebrospinal fluid. These biomarkers are released when brain cells are damaged.

What is so special about spike protein being found within the skull? The hollow core of the skull houses a unique type of bone marrow which is different from that found inside other bones. Connected directly to the coverings of the brain through blood vessels, the skull bone marrow plays a role in brain health and disease. Immune activity within the skull’s bone marrow can influence both progression and recovery of various brain disorders.

The next question is how exactly these immune alterations lead to brain damage. A paper published in Brain, Behavior, and Immunity – Health examines the interaction between the virus and microglia, the brain’s resident immune cells. These cells function similarly to macrophages found in the rest of the body, clearing debris, eliminating viruses, and coordinating immune responses. Like a gardener trimming a hedge to maintain its shape, microglia also prune unwanted connections between brain cells, a process essential for early brain development and neuroplasticity. However, dysregulation of this pruning can contribute to various brain disorders. Under normal conditions, microglia remain at rest. However, when activated — such as after COVID-19 — they can trigger prolonged brain inflammation, potentially leading to memory problems and other symptoms.

Other pathways also warrant study. Early in the pandemic, loss of smell lasting months or years suggested the virus might access the brain through the olfactory nerve, a direct shortcut from the nose. Alternatively, COVID-19 could breach the blood-brain barrier, the brain’s protective shield, allowing harmful particles to enter.

So it appears that this virus leaves a footprint in the body long after it has gone, resulting in persistent health problems in a few. Currently, there is no definitive cure for Long COVID, though some individuals improve over time. The lack of specific treatment reflects an incomplete understanding of the involved mechanisms, and the challenge of effectively targeting these complex pathways without harming the body. Understanding these pathways could pave the way for treatments that prevent or alleviate symptoms, and restore quality of life for people living with Long COVID.

(Rajeev Jayadevan is co-chairman of the National IMA COVID task Force)