Virus World

If you've had COVID-19, it may still be messing with your brain. Those who have been infected with the virus are at increased risk of developing a range of neurological conditions in the first year after the infection, new research shows. Such complications include strokes, cognitive and memory problems, depression, anxiety and migraine headaches, according to a comprehensive analysis of federal health data by researchers at Washington University School of Medicine in St. Louis and the Veterans Affairs St. Louis Health Care system. Additionally, the post-COVID brain is associated with movement disorders, from tremors and involuntary muscle contractions to epileptic seizures, hearing and vision abnormalities, and balance and coordination difficulties as well as other symptoms similar to what is experienced with Parkinson's disease. The findings are published Sept. 22 in Nature Medicine.  Overall, COVID-19 has contributed to more than 40 million new cases of neurological disorders worldwide, Al-Aly said. Other than having a COVID infection, specific risk factors for long-term neurological problems are scarce. "We're seeing brain problems in previously healthy individuals and those who have had mild infections," Al-Aly said. "It doesn't matter if you are young or old, female or male, or what your race is. It doesn't matter if you smoked or not, or if you had other unhealthy habits or conditions." 

Few people in the study were vaccinated for COVID-19 because the vaccines were not yet widely available during the time span of the study, from March 2020 through early January 2021. The data also predates delta, omicron and other COVID variants. A previous study in Nature Medicine led by Al-Aly found that vaccines slightly reduce -; by about 20% -; the risk of long-term brain problems. "It is definitely important to get vaccinated but also important to understand that they do not offer complete protection against these long-term neurologic disorders," Al-Aly said. The researchers analyzed about 14 million de-identified medical records in a database maintained by the U.S. Department of Veterans Affairs, the nation's largest integrated health-care system. Patients included all ages, races and sexes. They created a controlled data set of 154,000 people who had tested positive for COVID-19 sometime from March 1, 2020, through Jan. 15, 2021, and who had survived the first 30 days after infection. Statistical modeling was used to compare neurological outcomes in the COVID-19 data set with two other groups of people not infected with the virus: a control group of more than 5.6 million patients who did not have COVID-19 during the same time frame; and a control group of more than 5.8 million people from March 2018 to December 31, 2019, long before the virus infected and killed millions across the globe.

The researchers examined brain health over a year-long period. Neurological conditions occurred in 7% more people with COVID-19 compared with those who had not been infected with the virus. Extrapolating this percentage based on the number of COVID-19 cases in the U.S., that translates to roughly 6.6 million people who have suffered brain impairments associated with the virus. Memory problems -; colloquially called brain fog -; are one of the most common brain-related, long-COVID symptoms. Compared with those in the control groups, people who contracted the virus were at a 77% increased risk of developing memory problems. "These problems resolve in some people but persist in many others," Al-Aly said. "At this point, the proportion of people who get better versus those with long-lasting problems is unknown." Interestingly, the researchers noted an increased risk of Alzheimer's disease among those infected with the virus. There were two more cases of Alzheimer's per 1,000 people with COVID-19 compared with the control groups. "It's unlikely that someone who has had COVID-19 will just get Alzheimer's out of the blue," Al-Aly said. "Alzheimer's takes years to manifest. But what we suspect is happening is that people who have a predisposition to Alzheimer's may be pushed over the edge by COVID, meaning they're on a faster track to develop the disease. It's rare but concerning." Also compared to the control groups, people who had the virus were 50% more likely to suffer from an ischemic stroke, which strikes when a blood clot or other obstruction blocks an artery's ability to supply blood and oxygen to the brain. Ischemic strokes account for the majority of all strokes, and can lead to difficulty speaking, cognitive confusion, vision problems, the loss of feeling on one side of the body, permanent brain damage, paralysis and death.

"There have been several studies by other researchers that have shown, in mice and humans, that SARS-CoV-2 can attack the lining of the blood vessels and then then trigger a stroke or seizure," Al-Aly said. "It helps explain how someone with no risk factors could suddenly have a stroke." Overall, compared to the uninfected, people who had COVID-19 were 80% more likely to suffer from epilepsy or seizures, 43% more likely to develop mental health disorders such as anxiety or depression, 35% more likely to experience mild to severe headaches, and 42% more likely to encounter movement disorders. The latter includes involuntary muscle contractions, tremors and other Parkinson's-like symptoms. COVID-19 sufferers were also 30% more likely to have eye problems such as blurred vision, dryness and retinal inflammation; and they were 22% more likely to develop hearing abnormalities such as tinnitus, or ringing in the ears. "Our study adds to this growing body of evidence by providing a comprehensive account of the neurologic consequences of COVID-19 one year after infection," Al-Aly said. Long COVID's effects on the brain and other systems emphasize the need for governments and health systems to develop policy, and public health and prevention strategies to manage the ongoing pandemic and devise plans for a post-COVID world, Al-Aly said. "Given the colossal scale of the pandemic, meeting these challenges requires urgent and coordinated -; but, so far, absent -; global, national and regional response strategies," he said.

Cited research published in Nature Medicine (Sept. 22, 2022):

https://doi.org/10.1038/s41591-022-02001-z 

Researchers identify a protein that stops the brain from connecting memories, and regulating it could help improve memory loss treatment.  Throughout our lives, significant events are saved by the brain’s neurons and stored as memories. But memories don’t sit alone. Normally, they are connected to a number of others, making a reasonable reconstruction of events in a rational timeline. “Real-world memories are formed in a particular context and are often not acquired or recalled in isolation,” wrote a group of scientists led by Alcino Silva from the University of California, Los Angeles (UCLA). “Time is a key variable in the organization of memories, as events that are experienced close in time are more likely to be meaningfully associated, whereas those that are experienced with a longer interval are not.” The team is interested in exploring mechanisms involved in memory formation to better understand the process of linking memories — how one memory can trigger the recall of another in a sequential series of events that took place within a certain period of time. In a recent study, the UCLA team reported that the activation of a protein called CCR5 acts as a biological switch that defines the size of the time window that connects subsequent memories together — manipulating it could lead to better memory loss treatment.

This was intriguing to the team as CCR5 is a protein found in immune cells and has been studied extensively as a result of the role it plays in the inflammatory response during HIV infections, as the virus uses it to enter human cells. “Discovering the involvement of CCR5 in memory was a surprise,” said Silva, professor of neurobiology and psychology at the UCLA. “Years ago, our research team was looking for ‘new’ proteins involved in memory, and to our amazement, we found that CCR5 was one of them.” In mouse models, they found that CCR5 activation in neurons of the hippocampus — a brain region involved in memory formation — stops connecting memories to one another in mice subjected to behavioral models of memory. The mice were exposed to two different events separated by an increasing period of time. The scientists observed that if CCR5 activation occurred in between both events, mice weren’t able to relate one event to the other, but when both events occured before CCR5 activation, the mice related the memory of the first event to the second.   The precise coordination of memory systems in the human brain is very important, as when dysfunction in memory linking occurs it can lead to problems which manifest in diseases such as dementia, schizophrenia, and Alzheimer’s disease. “There are so many causes for memory loss affecting the lives of millions of people and there’s so little that we can do for them,” said Silva. “Memory dysfunction can appear in cases of post-traumatic stress disorder, depression, and even in patients undergoing cancer treatment.”

Gradual memory loss also occurs naturally during aging — an event that also occurs in mice.  As a result, the team used a middle-aged mouse model to study how CCR5 manipulation could help improve memory loss treatment in this scenario. The solution presented itself in the form of a drug named maravidoc, which blocks the activity of CCR5 and has been used to treat HIV infection where the molecule binds CCR5 proteins, interfering with virus’ ability to enter cells. After treating middle-aged mice with the drug, they observed that the size of the time window in which mice could link memories together was extended, and their memory recovered similar features to those seen in younger mice. “When we used maraviroc, we were able to reverse the memory deficits in middle-aged mice,” said Silva. This discovery suggests that maravidoc could be a potential memory loss treatment to help people suffering from memory dysfunction. Repurposing maravidoc could be straight forward as it is already in clinical use and has been proven to be safe over long periods of time in patients with HIV. Importantly, different studies have shown that maravidoc reaches the brain when given systemically, providing an opportunity to target CCR5 in neurons without the need for invasive procedures. “There’s a great need for memory drugs,” said Silva. “The few memory drugs that are being used in the clinic help patients, but with a very little effect. The wonderful thing about this study is that we already know that maravidoc is relatively safe and it’s very likely that people suffering from memory deficits may be able to use it for extended periods of time.”

Cited article published in Nature (May 25, 2022):

 https://doi.org/10.1038/s41586-022-04783-1