This article has been updated at 1:35 pm on Jan. 29 to note the Alzheimer’s Association’s funding role in the study of Covid-19 and brain health.
During the 1918 influenza pandemic, a different disease began to crop up. The condition, encephalitis lethargica, led to symptoms like sleep disruption, headache and lethargy. It could progress to drowsiness or even coma in some. Others developed movement problems, like restlessness and tremors.
Encephalitis lethargica has been associated with the 1918 flu virus, but whether that virus, either directly or indirectly, led to the neurological condition is still up for debate. Since then, scientists have linked other respiratory viruses, like SARS-CoV-2, the virus that causes Covid-19, to neurological symptoms.
Early in the pandemic, neurological problems started to appear in a subset of patients. Scientists and physicians were finding signs that the virus could affect the nervous system, in some cases seeing inflammation and vascular issues in the brains of Covid patients. They started asking what this could mean for the long-term brain health of Covid-19 survivors.
A team of researchers from around the world came together to track the impacts of Covid-19 on the brain up to a year and a half after infection. This project, the SARS CoV-2 Impact on Behavior and Cognition international study, will track brain-related outcomes in thousands of Covid-19 survivors in about 40 countries.
"If you look at past pandemics like the 1918 flu, the SARS pandemic or MERS pandemic, there have been reports following those [outbreaks] of memory impairment, sleep disruption and some other behavioral issues," said Heather Snyder, vice president of medical and scientific relations at the Alzheimer's Association, who is part of the global research endeavor.
Snyder and her colleagues are concerned that damage to the brain — either directly from the virus or from other consequences of the disease, like lack of oxygen — during the course of Covid-19 could have enduring impacts. A major concern is the possibility that Covid-19 could lead to cognitive decline or increased risk for Alzheimer's disease and other dementia.
The idea that SARS-CoV-2 could affect the brain in the long term isn't far-fetched. The role of viruses and other pathogens in Alzheimer's disease is still an active area of research, but there's evidence of a connection. For example, herpes simplex virus 1 (HSV1) could be associated with Alzheimer's disease later in life, though it causes minor or no symptoms in most of the 3.7 billion people it infects around the world.
A recent study found that in lab-grown brain tissue, known as brain organoids, HSV1 led to the formation of amyloid plaques, a hallmark of Alzheimer's disease in human brains, and triggered the brain cells to produce proteins known to raise the risk of Alzheimer's. Evidence from studies of humans, however, is still inconclusive.
Conducting research on Covid-19 survivors now could reveal both whether the disease imparts an increased risk for later life neurological problems, including dementia, and whether any treatments or interventions can alter that course.
"A big question is what is that long term effect, understanding the potential impact of the pandemic following the acute effects a person may experience," said Snyder. "Do we understand if there's an impact on a person's later life risk for Alzheimer's or another dementia? What does that look like? We don't know the answers to that."
Currently, with initial funding from the Alzheimer’s Association, the consortium's researchers are enrolling participants in the study in parts of the U.S. and other countries. They plan to follow up with participants six, nine and eighteen months after infection and test their cognition, as well as social and emotional wellness. At sites with the capability, researchers will also collect blood samples and perform MRI brain scans to get a more detailed look at any brain-related changes over time.
What happens to the brain during Covid-19?
One of the first signs the new coronavirus could affect the nervous system was loss of smell. When that began to emerge as a symptom in late February, that caught the attention of brain researchers and neurologists. Soon other neurological symptoms started showing up.
"It's not a complete surprise," said Robert Stevens, pointing to the neurological symptoms that appeared in patients during the SARS and MERS outbreaks. Stevens is the director of Precision Medicine for Anesthesiology and Critical Care Medicine at Johns Hopkins University School of Medicine.
Neurological symptoms don't affect everyone with Covid-19, but some common symptoms are temporary loss of smell and taste. "There's a range of different things that have been reported," said Stevens. "Those include relatively benign symptoms like headaches or muscle pains." Some patients have more serious symptoms that impair their cognition, affecting their ability to think, remember things or concentrate. Covid-19 can also cause a state of confusion called delirium.
"When people are sick we've seen an increased presence of delirium," said Snyder. Critical care teams are seeing more delirium cases than normal in their ICUs, and some people present with delirium as their only symptom of Covid-19.
A number of Covid-19 long haulers, people with "long Covid-19" who experience symptoms months after they first recover from acute disease, have also been reporting brain fog, which makes it difficult to think or focus. Headache, sleep problems and long-term loss of taste and smell affect some long haulers too.
Covid-19 also seems to increase the risk of stroke, even in young patients, and some have experienced brain hemorrhages, both of which permanently damage brain tissue.
How does it happen?
Exactly how the virus might do all these things to the brain and cause these symptoms remains unclear. "There is some suggestion that the virus is getting directly into the brain," said Snyder. One strong suggestion comes from post mortems; scientists have found SARS-CoV-2 particles in the brain after death.
The virus may get into the brain through the structure responsible for processing smell information, the olfactory bulb. Its cells express ACE2 receptors, the receptors the virus uses to infect cells. In mice, scientists have seen that the virus does get to the brain through olfactory cells, and from there infects other neurons.
But it might turn out that the virus isn't directly entering the brain. Through MRI scans, physicians have found brain abnormalities in some hospitalized Covid-19 patients that could be from immune reactions, seizures or lack of oxygen.
"There is potential that it's actually the immune response that is triggering an impact in the brain," said Snyder, which could breakdown the protective border surrounding the brain, the blood brain barrier.
"There's increasing evidence that this immunological response triggered by the virus can also affect the brain and cause different types of brain damages such as neuronal cell death and inflammatory changes in the brain," said Stevens.
Scientists are particularly concerned about the breakdown of the blood brain barrier. This protective layer breaks down in Alzheimer's disease and other dementias.
In the SARS CoV-2 Impact on Behavior and Cognition international study, scientists are just starting to enroll participants and collect the information that will help get at these questions of long-term brain health. According to Snyder, tracking brain function globally with common standards could not only reveal the neurological issues people might face, but also show how Covid-19 treatments and vaccines affect those outcomes.
“Understanding the full picture of what might impact a person's life, a person's lived experience and overall risk [for Alzheimer’s disease] is really important as we think about how we can intervene at an earlier time point and impact that trajectory,” she said.
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