Virus World

Cognitive impairment is one of the most prevalent symptoms of post Severe Acute Respiratory Syndrome COronaVirus 2 (SARS-CoV-2) state, which is known as Long COVID. Advanced neuroimaging techniques may contribute to a better understanding of the pathophysiological brain changes and the underlying mechanisms in post-COVID-19 subjects. We aimed at investigating regional cerebral perfusion alterations in post-COVID-19 subjects who reported a subjective cognitive impairment after a mild SARS-CoV-2 infection, using a non-invasive Arterial Spin Labeling (ASL) MRI technique and analysis. Using MRI-ASL image processing, we investigated the brain perfusion alterations in 24 patients (53.0 ± 14.5 years, 15F/9M) with persistent cognitive complaints in the post COVID-19 period.

Voxelwise and region-of-interest analyses were performed to identify statistically significant differences in cerebral blood flow (CBF) maps between post-COVID-19 patients, and age and sex matched healthy controls (54.8 ± 9.1 years, 13F/9M). The results showed a significant hypoperfusion in a widespread cerebral network in the post-COVID-19 group, predominantly affecting the frontal cortex, as well as the parietal and temporal cortex, as identified by a non-parametric permutation testing (p < 0.05, FWE-corrected with TFCE). The hypoperfusion areas identified in the right hemisphere regions were more extensive. These findings support the hypothesis of a large network dysfunction in post-COVID subjects with cognitive complaints. The non-invasive nature of the ASL-MRI method may play an important role in the monitoring and prognosis of post-COVID-19 subjects.

Published in Scientific Reports (April 10, 2023):

https://doi.org/10.1038/s41598-023-32275-3 

Growing evidence links COVID-19 with acute and long-term neurological dysfunction. However, the pathophysiological mechanisms resulting in central nervous system involvement remain unclear, posing both diagnostic and therapeutic challenges. Here we show outcomes of a cross-sectional clinical study (NCT04472013) including clinical and imaging data and corresponding multidimensional characterization of immune mediators in the cerebrospinal fluid (CSF) and plasma of patients belonging to different Neuro-COVID severity classes. The most prominent signs of severe Neuro-COVID are blood-brain barrier (BBB) impairment, elevated microglia activation markers and a polyclonal B cell response targeting self-antigens and non-self-antigens. COVID-19 patients show decreased regional brain volumes associating with specific CSF parameters, however, COVID-19 patients characterized by plasma cytokine storm are presenting with a non-inflammatory CSF profile. Post-acute COVID-19 syndrome strongly associates with a distinctive set of CSF and plasma mediators. Collectively, we identify several potentially actionable targets to prevent or intervene with the neurological consequences of SARS-CoV-2 infection. Both acute and chronic COVID-19 disease (also known as long-COVID) may affect the central nervous system. Here authors characterize the immunological profile of peripheral blood and cerebrospinal fluid of COVID-19 patients in order to identify the main factors that contribute to neurological impairment and the severity of neurological symptoms in Sars-CoV-2 infection.

Published in Nature Communications (Nov. 09, 2022):

https://doi.org/10.1038/s41467-022-34068-0 

Of the more than 16,000 patients examined, 13% developed serious neurological conditions including, most commonly, encephalopathy at admission.  A peer-reviewed study published in April in the journal Critical Care Explorations found a correlation between neurological conditions and the severity of COVID-19 symptoms.  It has already been documented that people with pre-existing conditions affecting the cardiovascular or immune systems are more likely to become seriously ill or hospitalized when contracting COVID-19. This new international study examined otherwise healthy patients who have developed neurological impairments after being admitted to the hospital with a diagnosis of COVID-19. Of the more than 16,000 patients examined, 13% developed serious neurological conditions including, most commonly, encephalopathy upon admission. Encephalopathy is an umbrella term for brain disease or damage that causes a marked change in the way the brain works, or how the brain and body interact. 

Researchers also observed stroke and seizure, as well as meningitis/encephalitis which are both characterized by inflammation of or around the brain, and were counted in the same category. All of these neurological manifestations were much less common than encephalitis and were associated with increased ICU support needs and more severe disease in general.  “Given the association of neurologic manifestations with poorer outcomes," concluded the study's author, Dr. Anna Cervantes-Arslanian, "further study is desperately needed to understand why these differences occur and what can be done to intervene."

Published April 2022 in the Journal of Critical Care Explorations:

https://journals.lww.com/ccejournal/Fulltext/2022/04000/Neurologic_Manifestations_of_Severe_Acute.22.aspx?context=LatestArticles 

Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), has been associated mainly with a range of neurological symptoms, including brain fog and brain tissue loss, raising concerns about the virus's acute and potential chronic impact on the central nervous system. In this study, we utilized mouse models and human post-mortem tissues to investigate the presence and distribution of the SARS-CoV-2 spike protein in the skull-meninges-brain axis. Our results revealed the accumulation of the spike protein in the skull marrow, brain meninges, and brain parenchyma. The injection of the spike protein alone caused cell death in the brain, highlighting a direct effect on brain tissue. Furthermore, we observed the presence of spike protein in the skull of deceased long after their COVID-19 infection, suggesting that the spike's persistence may contribute to long-term neurological symptoms. The spike protein was associated with neutrophil-related pathways and dysregulation of the proteins involved in the PI3K-AKT as well as complement and coagulation pathway. Overall, our findings suggest that SARS-CoV-2 spike protein trafficking from CNS borders into the brain parenchyma and identified differentially regulated pathways may present insights into mechanisms underlying immediate and long-term consequences of SARS-CoV-2 and present diagnostic and therapeutic opportunities.

Preprint in bioRxiv (April 5, 2023):

https://doi.org/10.1101/2023.04.04.535604 

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 

SARS-CoV-2 generally attacks the lungs, but researchers are also stressing its effects on the brain in a fraction of patients. Newly described case reports add to growing evidence that COVID-19 infections can result in severe, long-lasting neurological complications—including inflammation, psychosis, delirium, nerve damage, and strokes—even among patients experiencing mild cases of the virus with few other symptoms. In some instances, the new study claims, these neurological effects were the first manifestation of the disease. In a paper published today (July 8) in the journal Brain, neurologists in the UK noted an uptick this spring in cases of a potentially fatal condition called acute disseminated encephalomyelitis (ADEM). While ADEM is usually diagnosed in younger children after a viral infection, researchers at the college’s Institute of Neurology tell The Guardian that they saw two or three cases per week among coronavirus patients during April and May. Ordinarily, the hospital sees about two ADEM cases per month among adults. “We’re seeing things in the way Covid-19 affects the brain that we haven’t seen before with other viruses,” says Michael Zandi, a consulting neurologist at the university’s hospital and the study’s senior author. “What we’ve seen with some of these Adem patients, and in other patients, is you can have severe neurology, you can be quite sick, but actually have trivial lung disease,” he adds.

COVID-19 is primarily a respiratory disease that attacks the lungs, but it has also manifested seemingly unrelated symptoms, such as a loss of taste and smell or memory loss, that can persist for months beyond the initial diagnosis. These oddities suggest a neurological source. The study detailed the neurological symptoms of 43 patients hospitalized in the National Hospital for Neurology and Neurosurgery in London with confirmed or suspected cases of COVID-19. A dozen were diagnosed with inflammation of the central nervous system, including nine cases of ADEM. A further 10 patients experienced delirium or psychosis. Eight patients suffered strokes, including one that was fatal, and another eight had peripheral nerve damage. At least two patients also developed strange behaviors shortly after being discharged from the hospital. One woman, as described in the paper, repeatedly donned and took off her coat, and began hallucinating lions and monkeys inside her home. Another woman became drowsy and ultimately needed emergency surgery to relieve the pressure on her brain...