How does COVID-19 affect the brain?

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Neurologic complications from COVID-19 are common and can range from decreased mental clarity to stroke.
A recent perspective article outlines what we know about these complications so far.
The authors explain how prior assumptions that the virus directly affected brain cells have been disproven.
Instead, nervous system injury is likely a result of severe inflammation and neurovascular injury.
Neurologic insults from SARS-CoV-2 infection could increase the incidence and severity of neurodegenerative diseases, such as Alzheimer’s and Parkinson’s disease, in future generations.

Early in the pandemic, researchers observed that people recovering from COVID-19 were not returning to their pre-illness state of health — this is now commonly known as “Long COVID.”

Among the myriad persistent symptoms, many people experience headaches, memory issues, and cognitive deterioration.

Researchers from Northwestern University in Chicago, IL, were the first to report that even non-hospitalized people with COVID-19 demonstrated significant cognitive dysfunction that persisted well beyond 6 weeks from the acute infection.

In the journal Science, Dr. Serena Spudich and Dr. Avindra Nath review our current understanding of the neurologic consequences of COVID-19.

Building on clinical observations, autopsy, and laboratory findings, the authors propose theories of causality about how COVID-19 may result in long-term neurologic symptoms.

Neurologic complications of COVID-19 include:

loss of smell (anosmia)
stroke
delirium — a mental state characterized by an inability to rest, illusions, and incoherent thought and speech patterns
encephalopathy — a temporary or permanent state of altered brain function
psychiatric symptoms
peripheral neuropathy — a condition where nerve damage alters the communication between the central nervous system and the rest of the body

Immune system in overdrive

The authors acknowledge that the mechanisms by which COVID-19 can wreak havoc on the human nervous system are not well understood.

Cerebrovascular complications, such as a stroke, can occur early in the infection — even before the respiratory effects of the disease. Central inflammatory conditions and peripheral nerve symptoms occur later, typically 2 weeks after the acute infection.

These disparate timelines suggest that the cause of these neurologic symptoms may differ. Studying the cerebrospinal fluid (CSF) offers clues as to underlying mechanisms for neurologic damage in people with COVID-19.

CSF is a fluid that surrounds the spinal cord and brain.

Scientists have observed increases in certain immune-related compounds in the CSF, including:

Interleukin-1 (IL-1) and IL-2 proteins, which are inflammatory cytokines produced by the body.
Expression of genes controlled by interferon, an infection-fighting protein present during viral infections.
Activated T-cells and natural killer cells, which combat viral antigens.
Markers that indicate the presence of monocytes — large white cells that fight infection.
Breakdown proteins suggesting nerve damage.

Conversely, researchers have not found evidence that the SARS-CoV-2 virus directly impacts the nervous system. For instance, research has shown that the following factors are reduced or absent in people with a SARS-CoV-2 infection:

Cells that cause inflammation are not found clustered around the brain, which normally occurs in cases of viral encephalitis — a swelling of the brain.
The CNS does not contain viral RNA.
Limited presence of SARS-CoV-2 nucleic acid or viral protein in the brain cells of people who died from COVID-19.

When asked about the lack of virus in the CSF and brain cells, Dr. Santosh Kensari, chair, and professor of translational neurosciences and neurotherapeutics at St. Johns’ Cancer Institute in Santa Monica, CA, commented:

“If the virus isn’t there, it’s not directly [causing] the problem — that would be encephalitis — but the viruses can cause systemic problems, like the inflammation that [can] affect every organ system, including the brain — its an indirect effect.”

‘The whole is greater than the sum of its parts’

Adding and subtracting the positive and negative findings helped the authors of the perspective article to formulate a theory regarding the cause of nervous system consequences of SARS-CoV-2 infection.

They do not rule out that the virus may transiently infect the brain very early in infection. However, the authors ultimately conclude that inflammation and widespread vascular dysfunction may be the vector of neurologic damage in people with COVID-19.

Compared with people with influenza, individuals with COVID-19 exhibit an increased risk of stroke. When scientists studied the blood of people who experienced a stroke, they found elevated blood markers of vascular inflammation, tissue death, and thrombosis, which are clots that obstruct blood flow.

Radiologic testing also provides evidence of injury in people who experienced COVID-19. MRIs confirm microvascular damage and brain atrophy, or shrinkage. Positron emission tomography confirms decreased metabolic activity in the brains of people diagnosed with Long COVID.

This evidence, coupled with the system-wide vascular dysfunction seen in people with severe COVID-19, points to vascular injury as a potential cause of stroke, brain, and nerve injury.

Cause and effect

The authors conclude that SARS-CoV-2 is absent and markers of inflammation and vascular dysfunction are increased in the brains of people with COVID-19. So, the effects of COVID-19 are likely the result of an intersection of disease-causing mechanisms:

Generalized neuroinflammation supported by the presence of immune cells, cytokines, antibodies, and activated microglia, which are specialized neuron damage-fighting cells.
Damage to the cells lining the brain’s blood vessels (endothelium).
Elevated levels of blood-clotting proteins.
Individual susceptibility, including genetics, preexisting health conditions, and immune strength.

For MNT, Dr. Santosh Kensari addressed why some people might be more susceptible to neuropsychiatric complications from COVID-19 infection.

“I don’t think we know fully, but I suspect it is a variety of factors,” he explained. He believes these probably include the severity of COVID-19 and other cardiovascular risk factors, such as type 2 diabetes.

“My philosophy in medicine has completely changed. For example, inflammation is probably 90% of aging. Cancer, dementia, all are due to immune function. COVID-19 is making all these things worse because it is driving inflammation.”

– Dr. Santosh Kensari

While laboratory and radiologic evidence support their theories, there is only conjecture on the exact mechanisms at this time.

The authors note that people living with Long COVID may have long lasting immune activation, persistent autoimmune disturbance, or ongoing damage to the endothelium.

The long run

Medical experts around the world are worried about the long-term prognosis for people recovering from COVID-19.

From a neurologic standpoint, Dr. Spudich and Dr. Nath are concerned that the neuroinflammation and neuronal injury caused by acute SARS-CoV-2 infection may “accelerate or trigger future development of neurodegenerative diseases, such as Alzheimer’s or Parkinson’s disease.”

And they feel that the neurodevelopmental influences of SARS-CoV-2 infection on children remain unknown.

For MNT, Dr. Santosh Kensari added:

“Chronic inflammation has many causes, including diabetes, obesity, and nutrition. These are a predisposition to autoimmune disorders, and they cause and accelerate the risk of brain-related disorders.”

Given the number of individuals who have experienced COVID-19, the researchers note that the neurologic consequences of COVID-19 represent a global public health problem.

In response to this challenge, the National Institute of Health has established a COVID-19 NeuroDataBank and NeuroBioBank to allow doctors to report and quantify neurologic events from COVID-19.

Drs. Spudich and Nath recommend that rigorous study and interventional trials are needed to dissect why some patients have an acute neurologic illness and others develop chronic disease late in their illness. They propose that understanding the immune dysregulation in individuals with Long COVID holds promise for treatment and long-term management.

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