Opinions | How long covid reshapes the brain — and how we might treat it

Authors: Wes Ely August 25, 2022 The Washington Post

The young man pulled something from behind both ears. “I can’t hear anything without my new hearing aids,” said the 32-year-old husband and father. “My body is broken, Doc.” Once a fireman and emergency medical technician, he’d had covid more than 18 months before and was nearly deaf. He was also newly suffering from incapacitating anxiety, cognitive impairment and depression. Likewise, a 51-year-old woman told me through tears: “It’s almost two years. My old self is gone. I can’t even think clearly enough to keep my finances straight.” These are real people immersed in the global public health catastrophe of long covid, which the medical world is struggling to grasp and society is failing to confront.

As such stories clearly indicate, covid is biologically dangerous long after the initial viral infection. One of the leading hypotheses behind long covid is that the coronavirus is somehow able to establish a reservoir in tissues such as the gastrointestinal tract. I believe the explanation for long covid is more sinister.

The science makes it increasingly clear that covid-19 turns on inflammation and alters the nervous system even when the virus itself seems to be long gone. The virus starts by infecting nasal and respiratory lining cells, and the resulting inflammation sends molecules through the blood that trigger the release of cytokines in the brain. This can happen even in mild covid cases. Through these cell-to-cell conversations, cells in the nervous system called microglia and astrocytes are revved up in ways that continue for months — maybe years. It’s like a rock weighing down on the accelerator of a car, spinning its engine out of control. All of this causes injury to many cells, including neurons. It is past time we recognized this fact and began incorporating it into the ways we care for those who have survived covid.

For too long, the mysteries of long covid led many health-care professionals to dismiss it as an untreatable malady or a psychosomatic illness without a scientific basis. Some of this confusion comes down to the stuttering cadence of scientific progress. Early in the pandemic, autopsy findings from patients who died of covid “did not show encephalitis or other specific brain changes referable to the virus” as one report noted. Patients with profound neurological illnesses resulting from covid-19 had no trace of the virus in the cerebrospinal fluid encasing their brains.

These studies left most medical professionals mistakenly convinced that the virus was not damaging the brain. Accordingly, we narrowed our focus to the lungs and heart and then scratched our heads in wonder at the coma and delirium found in more than 80 percent of covid ICU patients. A robust study from the Netherlands showed that at least 12.5 percent of covid patients end up with long covid three months afterward, yet because “brain fog” wasn’t identified until later in the pandemic, these investigators didn’t include cognitive problems or mental health disorders in the data they collected. Thus, this otherwise beautifully executed study almost certainly underestimated the rate of long covid.

Since the early days of the pandemic, we’ve learned a great deal about the neurological effects of SARS-CoV-2. Earlier this year, the UK Biobank neuroimaging study showed that even mild covid can lead to an overall reduction in the size of the brain, with notable effects in the frontal cortex and limbic system. These findings help explain the profound anxiety, depression, memory loss and cognitive impairment experienced by so many long-covid patients.

new study published in the Lancet of more than 2.5 million people matched covid-19 patients with non-covid patients to determine the rate of recovery from mental health complaints and neurological deficits like the depression and brain fog in my own patients. What it revealed is partly encouraging and partly devastating: The anxiety and mood disorders in long covid tend to resolve over months, while serious dementia-like problems, psychosis and seizures persist at two years.

How immune response triggered by COVID-19 may damage the brain

Findings could give insight into long-term neurological symptoms of COVID-19

Date:July 5, 2022Source:NIH/National Institute of Neurological Disorders and Stroke

Summary:A new study describes the immune response triggered by COVID-19 infection that damages the brain’s blood vessels and may lead to short- and long-term neurological symptoms. The study examined brain changes in nine people who died suddenly after contracting the virus.

A study from the National Institutes of Health describes the immune response triggered by COVID-19 infection that damages the brain’s blood vessels and may lead to short- and long-term neurological symptoms. In a study published in Brain, researchers from the National Institute of Neurological Disorders and Stroke (NINDS) examined brain changes in nine people who died suddenly after contracting the virus.

The scientists found evidence that antibodies — proteins produced by the immune system in response to viruses and other invaders — are involved in an attack on the cells lining the brain’s blood vessels, leading to inflammation and damage. Consistent with an earlier study from the group, SARS-CoV-2 was not detected in the patients’ brains, suggesting the virus was not infecting the brain directly.

Understanding how SARS-CoV-2 can trigger brain damage may help inform development of therapies for COVID-19 patients who have lingering neurological symptoms.

“Patients often develop neurological complications with COVID-19, but the underlying pathophysiological process is not well understood,” said Avindra Nath, M.D., clinical director at NINDS and the senior author of the study. “We had previously shown blood vessel damage and inflammation in patients’ brains at autopsy, but we didn’t understand the cause of the damage. I think in this paper we’ve gained important insight into the cascade of events.”

Dr. Nath and his team found that antibodies produced in response to COVID-19 may mistakenly target cells crucial to the blood-brain barrier. Tightly packed endothelial cells help form the blood-brain barrier, which keeps harmful substances from reaching the brain while allowing necessary substances to pass through. Damage to endothelial cells in blood vessels in the brain can lead to leakage of proteins from the blood. This causes bleeds and clots in some COVID-19 patients and can increase the risk of stroke.

For the first time, researchers observed deposits of immune complexes — molecules formed when antibodies bind antigens (foreign substances) — on the surface of endothelial cells in the brains of COVID-19 patients. Such immune complexes can damage tissue by triggering inflammation.

The study builds on their previous research, which found evidence of brain damage caused by thinning and leaky blood vessels. They suspected that the damage may have been due to the body’s natural inflammatory response to the virus.

To further explore this immune response, Dr. Nath and his team examined brain tissue from a subset of patients in the previous study. The nine individuals, age 24 to 73, were chosen because they showed signs of blood vessel damage in the brain based on structural brain scans. The samples were compared to those from 10 controls. The team looked at neuroinflammation and immune responses using immunohistochemistry, a technique that uses antibodies to identify specific marker proteins in the tissues.

As in their earlier study, researchers found signs of leaky blood vessels, based on the presence of blood proteins that normally do not cross the blood brain barrier. This suggests that the tight junctions between the endothelial cells in the blood brain barrier are damaged.

Dr. Nath and his colleagues found evidence that damage to endothelial cells was likely due to an immune response — discovering deposits of immune complexes on the surface of the cells.

These observations suggest an antibody-mediated attack that activates endothelial cells. When endothelial cells are activated, they express proteins called adhesion molecules that cause platelets to stick together. High levels of adhesion molecules were found in endothelial cells in the samples of brain tissue.

“Activation of the endothelial cells brings platelets that stick to the blood vessel walls, causing clots to form and leakage to occur. At the same time the tight junctions between the endothelial cells get disrupted causing them to leak,” Dr. Nath explained. “Once leakage occurs, immune cells such as macrophages may come to repair the damage, setting up inflammation. This, in turn, causes damage to neurons.”

Researchers found that in areas with damage to the endothelial cells, more than 300 genes showed decreased expression, while six genes were increased. These genes were associated with oxidative stress, DNA damage, and metabolic dysregulation. This may provide clues to the molecular basis of neurological symptoms related to COVID-19 and offer potential therapeutic targets.

Together, these findings give insight into the immune response damaging the brain after COVID-19 infection. But it remains unclear what antigen the immune response is targeting, as the virus itself was not detected in the brain. It is possible that antibodies against the SARS-CoV-2 spike protein could bind to the ACE2 receptor used by the virus to enter cells. More research is needed to explore this hypothesis.

The study may also have implications for understanding and treating long-term neurological symptoms after COVID-19, which include headache, fatigue, loss of taste and smell, sleep problems, and “brain fog.” Had the patients in the study survived, the researchers believe they would likely have developed Long COVID.

“It is quite possible that this same immune response persists in Long COVID patients resulting in neuronal injury,” said Dr. Nath. “There could be a small indolent immune response that is continuing, which means that immune-modulating therapies might help these patients. So these findings have very important therapeutic implications.”

The results suggest that treatments designed to prevent the development of the immune complexes observed in the study could be potential therapies for post-COVID neurological symptoms.

This study was supported by the NINDS Division of Intramural Research (NS003130) and K23NS109284, Roy J. Carver Foundation, and the Iowa Neuroscience Institute.

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Materials provided by NIH/National Institute of Neurological Disorders and StrokeNote: Content may be edited for style and length.


Journal Reference:

  1. Myoung Hwa Lee, Daniel P Perl, Joseph Steiner, Nicholas Pasternack, Wenxue Li, Dragan Maric, Farinaz Safavi, Iren Horkayne-Szakaly, Robert Jones, Michelle N Stram, Joel T Moncur, Marco Hefti, Rebecca D Folkerth, Avindra Nath. Neurovascular injury with complement activation and inflammation in COVID-19Brain, 2022; DOI: 10.1093/brain/awac151

Age- and Sex-Specific Incidence of Cerebral Venous Sinus Thrombosis Associated With Ad26.COV2.S COVID-19 Vaccination

Authors: Aneel A. Ashrani, MD, MS1Daniel J. Crusan, BS2Tanya Petterson, MS2et al

JAMA Intern Med. 2022;182(1):80-83. doi:10.1001/jamainternmed.2021.6352

Recent reports14 suggest a possible association between Ad26.COV2.S (Johnson & Johnson/Janssen) COVID-19 vaccination and cerebral venous sinus thrombosis (CVST). Estimates of postvaccination CVST risk require accurate age- and sex-specific prepandemic CVST incidence rates; however, reported rates vary widely.5 We compared the age- and sex-specific CVST rates after Ad26.COV2.S vaccination with the prepandemic CVST rate in the population.Methods

In this population-based cohort study, to estimate the risk of CVST after Ad26.COV2.S vaccination, we first identified all incident cases of CVST in Olmsted County, Minnesota from January 1, 2001, through December 31, 2015 (eMethods in the Supplement). Sex-and age-adjusted incidence rates were adjusted to the 2010 US census population. We used CDC Vaccine Adverse Event Reporting System (VAERS) data from February 28, 2021 (vaccine approval date) to May 7, 2021, to estimate the incidence of CVST after Ad26.COV2.S vaccination assuming 3 (15, 30, and 92 days) plausible postvaccination periods during which individuals were considered to be at risk of CVST. We then compared post-Ad26.COV2.S vaccination CVST rates with prepandemic rates to estimate postvaccination CVST risk. This study was approved by the Mayo Clinic institutional review board. Medical records of Olmsted County residents with CVST were reviewed only if the residents had signed an authorization for accessing their medical records for research purposes. SAS, version 9.4 (SAS Institute Inc) and R, version 4.0.3 (R Project for Statistical Computing) were used for statistical analyses. Significance was set at a 2-sided P < .05.Results

From 2001 through 2015, 39 Olmsted County residents developed acute incident CVST. A total of 29 patients (74.4%) had a predisposing venous thromboembolism risk factor (eg, infection, active cancer, or oral contraceptives [for women]) within 92 days before the event. The median age at diagnosis was 41 years (range, 22-84 years); 22 residents with CVST (56.4%) were female. The overall age- and sex-adjusted CVST incidence was 2.34 per 100 000 person-years (PY) (95% CI, 1.60-3.08 per 100 000 PY). Age-adjusted CVST rates for female and male individuals were 2.46 per 100 000 PY (95% CI, 1.43-3.49 per 100 000 PY) and 2.34 per 100 000 PY (95% CI, 1.22-3.46 per 100 000 PY), respectively. Men aged 65 years or older had the highest CVST rate (6.22 per 100 000 PY; 95% CI, 2.50-12.82 per 100 000 PY), followed by women aged 18 to 29 years (4.71 per 100 000 person-years; 95% CI, 2.26-8.66 per 100 000 PY) (Table 1).

As of May 7, 2021, 8 727 851 Ad26.COV2.S vaccine doses had been administered in the US; 46 potential CVST events occurring within 92 days after Ad26.COV2.S vaccination were reported to VAERS. Eight events were excluded because they were potentially duplicate reports (4) or were not objectively diagnosed (4). Twenty-seven of 38 objectively diagnosed cases of CVST after Ad26.COV2.S vaccination (71.1%) occurred in female individuals. The median patient age was 45 years (range, 19-75 years). The median time from vaccination to CVST was 9 days (IQR, 6-13 days; range, 1-51 days); 31 of 38 cases of CVST (81.6%) occurred within 15 days after vaccination, and 36 (94.7%) occurred within 30 days.

The overall incidence rate of post–Ad26.COV2.S vaccination CVST was 8.65 per 100 000 PY (95% CI, 5.88-12.28 per 100 000 PY) at 15 days, 5.02 per 100 000 PY (95% CI, 3.52-6.95 per 100 000 PY) at 30 days, and 1.73 per 100 000 PY (95% CI, 1.22-2.37 per 100 000 PY) at 92 days (Table 2). The 15-day postvaccination CVST incidence rates for female and male individuals were 13.01 per 100 000 PY (95% CI, 8.24-19.52 per 100 000 PY) and 4.41 per 100 000 PY (95% CI, 1.90-8.68 per 100 000 PY), respectively. The postvaccination CVST rate among females was 5.1-fold higher compared with the pre-COVID-19 pandemic rate (13.01 vs 2.53 per 100 000 PY; P < .001) (Table 2). This risk was highest among women aged 40 to 49 years (29.50 per 100 000 PY; 95% CI, 13.50-55.95 per 100 000 PY), followed by women aged 30 to 39 years (26.50 per 100 000 PY; 10.65-54.63 per 100 000 PY).Discussion

In this population-based cohort study, we found that the CVST incidence rate 15 days after Ad26.COV2.S vaccination was significantly higher than the prepandemic rate. However, the higher rate of this rare adverse effect must be considered in the context of the effectiveness of the vaccine in preventing COVID-19 (absolute reduction of severe or critical COVID-19 of 940 per 100 000 PY).6

Most CVST events occurred within 15 days after vaccination, which is likely the highest at-risk period. The postvaccination CVST rate among females was higher than the prepandemic rate among females. The highest risk was among women aged 30 to 49 years, but the absolute CVST risk was still low in this group (up to 29.5 per 100 000 PY among women aged 40-49 years). The reason that women had a higher incidence of postvaccination CVST is unclear; concomitant CVST risk factors or autoantibody production might have been involved.2 The overall prepandemic CVST incidence rate was slightly higher in our study than in other studies (0.22-1.57 per 100 000 PY)5 likely because we captured all objectively diagnosed incident CVST cases in a well-defined population, including those discovered at autopsy.

The present study avoided referral bias and included only objectively diagnosed and confirmed cases. Only cases with adequate details or imaging findings reported on VAERS were used. Study limitations include possible ascertainment bias by including only objectively diagnosed CVST cases. VAERS reporting is voluntary and subject to reporting biases. VAERS monitors vaccine adverse events but does not prove causality.Back to topArticle Information

Accepted for Publication: September 12, 2021.

Published Online: November 1, 2021. doi:10.1001/jamainternmed.2021.6352

Corresponding Author: Aneel A. Ashrani, MD, MS, Division of Hematology, Department of Internal Medicine, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (ashrani.aneel@mayo.edu).

Author Contributions: Dr Ashrani and Mr Crusan had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Ashrani, Petterson, Bailey, Heit.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Ashrani, Crusan, Petterson.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Crusan, Petterson, Bailey.

Obtained funding: Ashrani, Heit.

Administrative, technical, or material support: Ashrani, Heit.

Supervision: Ashrani, Petterson, Bailey, Heit.

Conflict of Interest Disclosures: Dr Ashrani reported receiving grants from the National Heart, Lung and Blood Institute (NHLBI), National Institutes of Health (NIH) during the conduct of the study. Mr Crusan reported receiving grants from the NIH during the conduct of the study. Dr Heit reported receiving grants from the NHLBI, NIH during the conduct of the study. No other disclosures were reported.

Funding/Support: This study was supported in part by grant R01HL66216 from the NHLBI, NIH (Drs Ashrani and Bailey), the Rochester Epidemiology Project (grant R01AG034676 from the National Institute on Aging, NIH), and the Mayo Foundation.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

References

1.Centers for Disease Control and Prevention. Cases of cerebral venous sinus thrombosis with thrombocytopenia after receipt of the Johnson & Johnson COVID-19 vaccine New release. April 13, 2021. Accessed April 21, 2021.  https://emergency.cdc.gov/han/2021/han00442.asp

2.See  I, Su  JR, Lale  A,  et al.  US case reports of cerebral venous sinus thrombosis with thrombocytopenia after Ad26.COV2.S vaccination, March 2 to April 21, 2021.   JAMA. 2021;325(24):2448-2456. doi:10.1001/jama.2021.7517
ArticlePubMedGoogle ScholarCrossref

3.Shay  DK, Gee  J, Su  JR,  et al.  Safety monitoring of the Janssen (Johnson & Johnson) COVID-19 vaccine—United States, March-April 2021.   MMWR Morb Mortal Wkly Rep. 2021;70(18):680-684. doi:10.15585/mmwr.mm7018e2PubMedGoogle ScholarCrossref

4.Shimabukuro  T. Update: thrombosis with thrombocytopenia syndrome (TTS) following COVID-19 vaccination. Paper presented at: Advisory Committee on Immunization Practices; May 12, 2021.

5.Devasagayam  S, Wyatt  B, Leyden  J, Kleinig  T.  Cerebral venous sinus thrombosis incidence is higher than previously thought: a retrospective population-based study.   Stroke. 2016;47(9):2180-2182. doi:10.1161/STROKEAHA.116.013617PubMedGoogle ScholarCrossref

6.Sadoff  J, Gray  G, Vandebosch  A,  et al; ENSEMBLE Study Group.  Safety and efficacy of single-dose Ad26.COV2.S vaccine against COVID-19.   N Engl J Med. 2021;384(23):2187-2201. doi:10.1056/NEJMoa2101544PubMedGoogle ScholarCrossref

‘We Made a Big Mistake’ — COVID Vaccine Spike Protein Travels From Injection Site, Can Cause Organ Damage

Authors:  Children’s Health Defense

COVID vaccine researchers had previously assumed mRNA COVID vaccines would behave like traditional vaccines. The vaccine’s spike protein — responsible for infection and its most severe symptoms — would remain mostly in the injection site at the shoulder muscle or local lymph nodes.

But new research obtained by a group of scientists contradicts that theory, a Canadian cancer vaccine researcher said last week.

“We made a big mistake. We didn’t realize it until now,” said Byram Bridle, a viral immunologist and associate professor at University of Guelph, Ontario. “We thought the spike protein was a great target antigen, we never knew the spike protein itself was a toxin and was a pathogenic protein. So by vaccinating people we are inadvertently inoculating them with a toxin.”

Bridle, who was awarded a $230,000 grant by the Canadian government last year for research on COVID vaccine development, said he and a group of international scientists filed a request for information from the Japanese regulatory agency to get access to Pfizer’s “biodistribution study.”

Biodistribution studies are used to determine where an injected compound travels in the body, and which tissues or organs it accumulates in.

“It’s the first time ever scientists have been privy to seeing where these messenger RNA [mRNA] vaccines go after vaccination,” Bridle said in an interview with Alex Pierson where he first disclosed the data. “Is it a safe assumption that it stays in the shoulder muscle? The short answer is: absolutely not. It’s very disconcerting.”

The Sars-CoV-2 has a spike protein on its surface. That spike protein is what allows it to infect our bodies, Bridle explained. “That is why we have been using the spike protein in our vaccines,” Bridle said. “The vaccines we’re using get the cells in our bodies to manufacture that protein. If we can mount an immune response against that protein, in theory we could prevent this virus from infecting the body. That is the theory behind the vaccine.”

“However, when studying the severe COVID-19, […] heart problems, lots of problems with the cardiovascular system, bleeding and clotting, are all associated with COVID-19,”  he added. “In doing that research, what has been discovered by the scientific community, the spike protein on its own is almost entirely responsible for the damage to the cardiovascular system, if it gets into circulation.”

When the purified spike protein is injected into the blood of research animals, they experience damage to the cardiovascular system and the protein can cross the blood-brain barrier and cause damage to the brain, Bridle explained.

The biodistribution study obtained by Bridle shows the COVID spike protein gets into the blood where it circulates for several days post-vaccination and then accumulates in organs and tissues including the spleen, bone marrow, the liver, adrenal glands and in “quite high concentrations” in the ovaries.

“We have known for a long time that the spike protein is a pathogenic protein, Bridle said. “It is a toxin. It can cause damage in our body if it gets into circulation.”

A large number of studies have shown the most severe effects of SARS-CoV-2, the virus that causes COVID, such as blood clotting and bleeding, are due to the effects of the spike protein of the virus itself.

A recent study in Clinical and Infectious Diseases led by researchers at Brigham and Women’s Hospital and the Harvard Medical School measured longitudinal plasma samples collected from 13 recipients of the Moderna vaccine 1 and 29 days after the first dose and 1-28 days after the second dose.

Out of these individuals, 11 had detectable levels of SARS-CoV-2 protein in blood plasma as early as one day after the first vaccine dose, including three who had detectable levels of spike protein. A “subunit” protein called S1, part of the spike protein, was also detected.

Spike protein was detected an average of 15 days after the first injection, and one patient had spike protein detectable on day 29 –– one day after a second vaccine dose –– which disappeared two days later.

The results showed S1 antigen production after the initial vaccination can be detected by day one and is present beyond the injection site and the associated regional lymph nodes.

Assuming an average adult blood volume of approximately 5 liters, this corresponds to peak levels of approximately 0.3 micrograms of circulating free antigen for a vaccine designed only to express membrane-anchored antigen.

In a study published in Nature Neuroscience, lab animals injected with purified spike protein into their bloodstream developed cardiovascular problems. The spike protein also crossed the blood-brain barrier and caused damage to the brain.

It was a grave mistake to believe the spike protein would not escape into the blood circulation, according to Bridle. “Now, we have clear-cut evidence that the vaccines that make the cells in our deltoid muscles manufacture this protein — that the vaccine itself, plus the protein — gets into blood circulation,” he said.

Bridle said the scientific community has discovered the spike protein, on its own, is almost entirely responsible for the damage to the cardiovascular system, if it gets into circulation.

Once in circulation, the spike protein can attach to specific ACE2 receptors that are on blood platelets and the cells that line blood vessels, Bridle said. “When that happens it can do one of two things. It can either cause platelets to clump, and that can lead to clotting — that’s exactly why we’ve been seeing clotting disorders associated with these vaccines. It can also lead to bleeding,” he added.

Both clotting and bleeding are associated with vaccine-induced thrombotic thrombocytopenia (VITT). Bridle also said the spike protein in circulation would explain recently reported heart problems in vaccinated teens.

Stephanie Seneff, senior research scientists at Massachusetts Institute of Technology, said it is now clear vaccine content is being delivered to the spleen and the glands, including the ovaries and the adrenal glands, and is being shed into the medium and then eventually reaches the bloodstream causing systemic damage.

“ACE2 receptors are common in the heart and brain,” she added. “And this is how the spike protein causes cardiovascular and cognitive problems.”

Dr. J. Patrick Whelan, a pediatric rheumatologist, warned the U.S. Food and Drug Administration (FDA) in December mRNA vaccines could cause microvascular injury to the brain, heart, liver and kidneys in ways not assessed in safety trials.

In a public submission, Whelan sought to alert the FDA to the potential for vaccines designed to create immunity to the SARS-CoV-2 spike protein to instead cause injuries.

Whelan was concerned the mRNA vaccine technology utilized by Pfizer and Moderna had “the potential to cause microvascular injury (inflammation and small blood clots called microthrombi) to the brain, heart, liver and kidneys in ways that were not assessed in the safety trials.”