H5N1

SARS-CoV-2 spike protein induces cognitive deficit and anxiety-like behavior in mouse via non-cell autonomous hippocampal neuronal death

Via Nature Scientific Reports:SARS-CoV-2 spike protein induces cognitive deficit and anxiety-like behavior in mouse via non-cell autonomous hippocampal neuronal death. The abstract:

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is accompanied by chronic neurological sequelae such as cognitive decline and mood disorder, but the underlying mechanisms have not yet been elucidated. We explored the possibility that the brain-infiltrating SARS-CoV-2 spike protein contributes to the development of neurological symptoms observed in COVID-19 patients in this study. 

Our behavioral study showed that administration of SARS-CoV-2 spike protein S1 subunit (S1 protein) to mouse hippocampus induced cognitive deficit and anxiety-like behavior in vivo. These neurological symptoms were accompanied by neuronal cell death in the dorsal and ventral hippocampus as well as glial cell activation. Interestingly, the S1 protein did not directly induce hippocampal cell death in vitro. Rather, it exerted neurotoxicity via glial cell activation, partially through interleukin-1β induction. 

In conclusion, our data suggest a novel pathogenic mechanism for the COVID-19-associated neurological symptoms that involves glia activation and non-cell autonomous hippocampal neuronal death by the brain-infiltrating S1 protein.

SARS-CoV-2 is associated with changes in brain structure in UK Biobank

Via Nature: SARS-CoV-2 is associated with changes in brain structure in UK Biobank. This seems likely to become a very important paper. The abstract:

There is strong evidence for brain-related abnormalities in COVID-19. It remains unknown however whether the impact of SARS-CoV-2 infection can be detected in milder cases, and whether this can reveal possible mechanisms contributing to brain pathology. 

Here, we investigated brain changes in 785 UK Biobank participants (aged 51–81) imaged twice, including 401 cases who tested positive for infection with SARS-CoV-2 between their two scans, with 141 days on average separating their diagnosis and second scan, and 384 controls. The availability of pre-infection imaging data reduces the likelihood of pre-existing risk factors being misinterpreted as disease effects. 

We identified significant longitudinal effects when comparing the two groups, including: (i) greater reduction in grey matter thickness and tissue-contrast in the orbitofrontal cortex and parahippocampal gyrus, (ii) greater changes in markers of tissue damage in regions functionally-connected to the primary olfactory cortex, and (iii) greater reduction in global brain size. The infected participants also showed on average larger cognitive decline between the two timepoints. Importantly, these imaging and cognitive longitudinal effects were still seen after excluding the 15 cases who had been hospitalised. 

These mainly limbic brain imaging results may be the in vivo hallmarks of a degenerative spread of the disease via olfactory pathways, of neuroinflammatory events, or of the loss of sensory input due to anosmia. Whether this deleterious impact can be partially reversed, or whether these effects will persist in the long term, remains to be investigated with additional follow up.

What can a medical mystery from Guam teach New Brunswick about its own strange, deadly disease?

Via The Globe and Mail: What can a medical mystery from Guam teach New Brunswick about its own strange, deadly disease? Excerpt:

They called it lytico-bodig. As the Second World War drew to a close, U.S. military doctors stationed on Guam noticed many of the Pacific island’s Chamorro people were suffering from a baffling and devastating illness. 

The local name for the progressive and fatal disease – said to have come from the Spanish “paralytico” – provided a label for what Islanders described as an illness that disconnects one from one’s family. It captured a constellation of symptoms, including muscle wasting, paralysis, muscle rigidity, shaking, confusion and memory loss. Doctors and researchers observed this strange illness shared characteristics of amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig’s disease), Parkinson’s disease and Alzheimer’s disease, and they clamoured to try to understand it, with the hope it would shed light on other neurodegenerative disorders. 

In a collection of case reports published in 1961, early investigators documented the deterioration over 12 years of their first patient, whom they described as a “Chamorro housewife.” Her initial chief complaint was of weakness in both her hands. “When last observed in August, 1960, the patient was helpless, bedridden, almost immobile and in a terminal state,” the authors wrote. 

The disease was still a mystery when Canadian chemist Susan Murch travelled to Guam as a postdoctoral fellow in 2003 to study a neurotoxin researchers believed might hold the key to solving the puzzle. What she and the scientists she worked with discovered there provided not only what they considered a possible source of the illness, but may also offer clues to a new medical mystery in New Brunswick, where dozens of people have developed unexplained neurological symptoms. 

Dr. Murch, working with principal investigator Paul Cox, a U.S. ethnobotanist, found that a toxin produced by blue-green algae called beta-methylamino-L-alanine, or BMAA, was present in cycad trees, a source of food for the island’s residents. They found the same toxin in the animals residents consumed, such as pigs, deer and bats that ate the seeds, fruit and other parts of the cycad plants. And they also found it in the brain tissue of several Chamorro patients who died of the mysterious disease. 

Dr. Cox, together with famed British neurologist Oliver Sacks, hypothesized that neurotoxic BMAA, the amounts of which were magnified as people consumed animals at higher levels of the food chain, might offer a long-sought explanation for what was causing damage to people’s bodies and brains. Today, that hypothesis is still debated. But investigators of the new illness in New Brunswick are revisiting the work of Dr. Murch and her colleagues. 

As of mid-July, 48 cases of an unknown neurological syndrome, including six deaths, have been reported in the province, mostly in the Moncton area and the Acadian peninsula. Doctors and researchers investigating the illness say they are looking into various potential causes – among them, BMAA or an algal toxin like it.

Profound brain changes found in patients who died of COVID-19

Via Medscape.comProfound Brain Changes Found in Patients Who Died of COVID-19.

The most comprehensive molecular study to date of brain tissue from people who died of COVID-19 provides clear evidence that SARS-CoV-2 causes profound molecular changes in the brain, despite no molecular trace of the virus in brain tissue. 

"The signature the virus leaves in the brain speaks of strong inflammation and disrupted brain circuits and resembles signatures the field has observed in Alzheimer's or other neurodegenerative diseases," senior author Tony Wyss-Coray, PhD, professor of neurology and neurological sciences, Stanford University School of Medicine, Stanford, California, told Medscape Medical News. 

The study was published online June 21 in Nature. 

Signs of Distress 

"We know that up to a third of SARS-CoV-2-infected people show brain symptoms including brain fog, memory problems, and fatigue, and a growing number of people have such symptoms long after they seemingly recovered from virus infection," said Wyss-Coray. 

"However, we have very little understanding of how the virus causes these symptoms and what its effects are on the brain at a molecular level," he added. 

Using single-cell RNA sequencing, the researchers profiled the transcriptomes of 65,309 nuclei isolated from frontal cortex and choroid plexus samples from eight patients who died of COVID-19 and 14 controls who died of other causes. 

There was no molecular evidence of SARS-CoV-2 in brain tissue samples from the patients who died of COVID-19.

Yet, "we were very surprised to learn that no matter which type of cell we studied (different types of nerve cells, immune cells, or different support cells in the brain) there were prominent changes" compared with brain tissue samples from controls who died of other causes, said Wyss-Coray. 

The changes in the COVID-19 brains showed signatures of inflammation, abnormal nerve cell communication, and chronic neurodegeneration. 

"Across cell types, COVID-19 perturbations overlap with those in chronic brain disorders and reside in genetic variants associated with cognition, schizophrenia, and depression," the researchers report. 

"Viral infection appears to trigger inflammatory responses throughout the body that may cause inflammatory signaling across the blood–brain barrier, which in turn could 'trip off' neuroinflammation in the brain," Wyss-Coray said. 

The findings may help explain the brain fog, fatigue, and other neurological and psychiatric symptoms of long COVID. 

"While we studied only brains from people who died of COVID-19, we believe it is likely that similar, but hopefully weaker, signs of inflammation and chronic neurodegeneration will be found in COVID-19 survivors, especially those with chronic brain symptoms," Wyss-Coray said.

Pan-Canadian survey reveals long-term harm of COVID to brain health

Via newswire.ca: Pan-Canadian Survey Reveals Long-term Harm of COVID to Brain Health. Excerpt:

VANCOUVER, BC and MONTREAL, June 3, 2021 /CNW/ - A pan-Canadian survey of more than 1,000 COVID long-haulers, individuals with COVID-19 symptoms that last weeks or months, reveals the impact of Long COVID on brain health. From coast to coast, cognitive impairment or "brain fog" was among the top reported symptoms, along with fatigue and shortness of breath. Additional brain-related symptoms included headaches, dizziness, and anxiety. 

Over 80% of respondents experienced symptoms for more than three months, and almost 50% experienced symptoms for 11 months or more. While vaccines and physical distancing are important to prevent and mitigate COVID-19, the survey suggests the impact of COVID-19 on brain health will last beyond the pandemic. 

A detailed report on the survey is forthcoming and will be available on the website of the alliance members listed below. Survey results are consistent with other scientific findings, including that Long COVID is disproportionately impacting women in their middle years. This is the largest publicly available survey of people living with Long COVID in Canada to date. 

"It is our hope that the data collected from this survey will highlight the implications of Long COVID on brain health. Creating awareness through lived experiences and patient collaboration will magnify the urgency to act on funding for research and rehabilitation of long-haulers," said COVID Long-Haulers Support Group Canada Founder Susie Goulding. 

The survey is the result of an alliance between Viral Neuro Exploration (VINEx), COVID Long Haulers Support Group Canada, and Neurological Health Charities Canada (NHCC) to build awareness and increase funding for research and care on Long COVID. The alliance leverages science, clinical research, and lived experiences from patient groups, and is reaching out to other organizations with an interest in the lasting and long-term impacts of COVID-19. 

"The survey underlines earlier observations that COVID-19 can cause neurological damage which persists months after the initial infection. It clearly indicates that Canada needs action on brain health in COVID and post-COVID contexts," said Neurological Health Charities Canada Manager Deanna Groetzinger. 

According to the survey, nearly half of respondents received care for long-lasting symptoms in a healthcare clinic more than five times. Nearly a third received care more than 10 times. Six out of 10 had to take leave from work as a consequence of living with Long COVID, for weeks or months at a time, sometimes leading to early retirement. The responses suggest ongoing economic, health and societal costs with ripple effects into the public health sector and labour force.

Global incidence of neurological manifestations among patients hospitalized with COVID-19—A report for the GCS-NeuroCOVID Consortium and the ENERGY Consortium

Via JAMA Network Open:Global Incidence of Neurological Manifestations Among Patients Hospitalized With COVID-19—A Report for the GCS-NeuroCOVID Consortium and the ENERGY Consortium. The key points and abstract: 

Key Points 

Question  What are the incidence of and outcomes associated with neurologic manifestations in patients with COVID-19? 

Findings  In this cohort study of 3744 patients in 2 large consortia, neurological manifestations were found in approximately 80% of patients hospitalized with COVID-19; the most common self-reported symptoms included headache (37%) and anosmia or ageusia (26%), whereas the most common neurological signs and/or syndromes were acute encephalopathy (49%), coma (17%), and stroke (6%). Presence of clinically captured neurologic signs and/or syndromes was associated with increased risk of in-hospital death. 

Meaning  These findings suggest that neurological manifestations are prevalent among patients hospitalized with COVID-19 and are associated with higher in-hospital mortality. 

Abstract 

Importance  The COVID-19 pandemic continues to affect millions of people globally, with increasing reports of neurological manifestations but limited data on their incidence and associations with outcome. 

Objective  To determine the neurological phenotypes, incidence, and outcomes among adults hospitalized with COVID-19. 

Design, Setting, and Participants  This cohort study included patients with clinically diagnosed or laboratory-confirmed COVID-19 at 28 centers, representing 13 countries and 4 continents. The study was performed by the Global Consortium Study of Neurologic Dysfunction in COVID-19 (GCS-NeuroCOVID) from March 1 to September 30, 2020, and the European Academy of Neurology (EAN) Neuro-COVID Registry (ENERGY) from March to October 2020. Three cohorts were included: (1) the GCS-NeuroCOVID all COVID-19 cohort (n = 3055), which included consecutive hospitalized patients with COVID-19 with and without neurological manifestations; (2) the GCS-NeuroCOVID COVID-19 neurological cohort (n = 475), which comprised consecutive patients hospitalized with COVID-19 who had confirmed neurological manifestations; and (3) the ENERGY cohort (n = 214), which included patients with COVID-19 who received formal neurological consultation. 

Exposures  Clinically diagnosed or laboratory-confirmed COVID-19. 

Main Outcomes and Measures  Neurological phenotypes were classified as self-reported symptoms or neurological signs and/or syndromes assessed by clinical evaluation. Composite incidence was reported for groups with at least 1 neurological manifestation. The main outcome measure was in-hospital mortality. 

Results  Of the 3055 patients in the all COVID-19 cohort, 1742 (57%) were men, and the mean age was 59.9 years (95% CI, 59.3-60.6 years). Of the 475 patients in the COVID-19 neurological cohort, 262 (55%) were men, and the mean age was 62.6 years (95% CI, 61.1-64.1 years). Of the 214 patients in the ENERGY cohort, 133 (62%) were men, and the mean age was 67 years (95% CI, 52-78 years). A total of 3083 of 3743 patients (82%) across cohorts had any neurological manifestation (self-reported neurological symptoms and/or clinically captured neurological sign and/or syndrome). 

The most common self-reported symptoms included headache (1385 of 3732 patients [37%]) and anosmia or ageusia (977 of 3700 patients [26%]). The most prevalent neurological signs and/or syndromes were acute encephalopathy (1845 of 3740 patients [49%]), coma (649 of 3737 patients [17%]), and stroke (222 of 3737 patients [6%]), while meningitis and/or encephalitis were rare (19 of 3741 patients [0.5%]). 

Presence of clinically captured neurologic signs and/or syndromes was associated with increased risk of in-hospital death (adjusted odds ratio [aOR], 5.99; 95% CI, 4.33-8.28) after adjusting for study site, age, sex, race, and ethnicity. Presence of preexisting neurological disorders (aOR, 2.23; 95% CI, 1.80-2.75) was associated with increased risk of developing neurological signs and/or syndromes with COVID-19. 

Conclusions and Relevance  In this multicohort study, neurological manifestations were prevalent among patients hospitalized with COVID-19 and were associated with higher in-hospital mortality. Preexisting neurological disorders were associated with increased risk of developing neurological signs and/or syndromes in COVID-19.

In New Brunswick, experts try to figure out why dozens have been affected by a mystery brain disease

Via The Globe and Mail: In New Brunswick, experts try to figure out why dozens have been affected by a mystery brain disease. Excerpt:

It typically starts with uncharacteristic irritability, anxiety and depression. Then comes pain, along with insomnia, and a constellation of other devastating symptoms, including terrifying hallucinations, a loss of balance and co-ordination, and in a few cases, Capgras delusion – the irrational belief that family members or other familiar people have been replaced by imposters. 

By now, Dr. Alier Marrero knows what a mysterious brain illness that has sickened dozens of New Brunswickers looks like. 

But what he can’t tell you is how to best help these patients – or how to prevent others from suffering the same fate. Because before Dr. Marrero can tackle these questions, he must find the answer to another, more basic one: What has made all these people in his province ill in the first place? 

Without knowing the cause, “it’s very difficult to go out there and shoot in the dark,” said Dr. Marrero, a neurologist at Dr. Georges-L.-Dumont University Hospital Centre in Moncton, explaining the best he and his team can do for the patients is to treat their symptoms. “But still, the puzzle is not solved.” 

Dr. Marrero is leading an investigation into this unknown brain disease that has affected residents mostly in the Moncton area and the Acadian Peninsula, and has attracted the attention of scientists around the world. As of Friday, there have been 47 cases, including six patients who have died, and more possible cases are being investigated. 

Working in the shadow of a global pandemic, he and his colleagues are looking for clues in a hunt that leads down multiple potential paths. One line of pursuit suggests what they’re seeing may be akin to Creutzfeldt-Jakob disease, the human form of mad cow disease. Another hints at a possible environmental toxin, similar to a 1987 outbreak that sickened more than 100 Canadians who ate contaminated Atlantic shellfish. And yet another suggests answers may be found by revisiting a mysterious neurological disease that was detected in the Pacific island of Guam in the 1940s. 

“In many ways, it’s the worst thing that could happen, to have this happen in the middle of COVID-19, because what you need are boots on the ground,” said Michael Strong, professor of neurology at Western University and president of the Canadian Institutes of Health Research. 

Dr. Strong, an expert in neurodegenerative diseases, explained investigating potential environmental toxins would require going into communities and individual households to look for commonalities between cases, including examining things such as water supply, fishing and hunting habits. It also requires taking soil and water samples, and studying them back in the lab. 

“If the worse-case scenario is that this is something new that we haven’t seen before, then truly bringing the whole of the government response that’s working on this now and bringing the academic community to bear on this ... it’s what we’ve got to do,” he said. 

Since the first case in 2015, the illness has shown up in more individuals over the past three years, ranging in age from 18 to 86. And researchers say they are a long way from solving the mystery.

One in three COVID-19 patients in US developed a neurological or psychiatric condition, study finds

Via The Globe and Mail; One in three COVID-19 patients in U.S. developed a neurological or psychiatric condition, study finds. Excerpt:

A study of more than 236,000 people in the United States who contracted COVID-19 last year has found that one in three developed a neurological or psychiatric condition and one in 50 of those who became seriously ill received their first diagnosis of dementia within six months. 

The most common conditions were anxiety and mood disorders, which occurred in 17 per cent and 14 per cent respectively of those studied. Among patients admitted to intensive care, the researchers found that 7 per cent suffered a stroke and almost 2 per cent developed dementia – which could have been present before COVID-19 but went undiagnosed. They added that more study is needed to fully establish the link between COVID-19 and dementia. 

“I think we can have more confidence that there is an increased risk of stroke and an increasing risk of at least uncovering dementia with COVID, and that that really goes along with the severity of the illness,” said Masud Husain, a professor of neurology and cognitive neuroscience at the University of Oxford who co-authored the study.

The research, published Tuesday in The Lancet Psychiatry, also compared people who had contracted COVID-19 to those who had the flu or another respiratory illness, such as pneumonia or acute bronchitis. The researchers found a 44-per-cent greater risk of neurological and mental health diagnoses after infection with COVID-19 than with the flu and a 16-per-cent greater risk than with other respiratory diseases. 

The study is the largest of its kind, and the researchers said the results could have a profound effect on the demand for mental health services and other medical care once the pandemic eases. “What we hope is our data can provide some of the best findings upon which people can begin to model the implications for public health and the health services generally,” said Paul Harrison, a professor of psychiatry at Oxford who was also among the co-authors.

Mystery brain disorder baffles Canadian medicine

Via The Guardian: Mystery brain disorder baffles Canadian medicine. Excerpt:

Doctors in Canada are concerned they could be dealing with a previously unknown brain disease amid a string of cases involving memory loss, hallucinations and muscle atrophy. 

Politicians in the province of New Brunswick have demanded answers, but with so few cases, experts say there are far more questions than answers and have urged the public not to panic. 

For more than a year public health officials have been tracking a “cluster” of 43 cases of suspected neurological disease in the province with no known cause. 

Residents first learned of the investigation last week after a leaked memo from the province’s public health agency asked physicians to be on the lookout for symptoms similar to Creutzfeldt-Jakob disease – a rare, fatal brain disease caused by misformed proteins known as prions. 

“We are collaborating with different national groups and experts; however, no clear cause has been identified at this time,” said the memo. 

A number of the symptoms including memory loss, vision problems and abnormal jerking movements triggered an alert with Canada’s CJD surveillance network. Despite the initial similarities, screening produced no confirmed cases of CJD. 

“We don’t have evidence to suggest it’s a prion disease,” said Dr Alier Marrero, the neurologist leading New Brunswick’s investigation. 

Now a team of researchers, including federal scientists, are racing to determine if they are dealing with a previously unknown neurological syndrome, or a series of unrelated, but previously known – and even treatable – ailments. 

 Marrero says patients initially complained of unexplained pains, spasms and behavioural changes – all symptoms that could be easily diagnosed as anxiety or depression. 

But over 18 to 36 months they began developing cognitive decline, muscle wasting, drooling and teeth chattering. A number of patients also began experiencing frightening hallucinations, including the feeling of insects crawling on their skin. 

In order for a new case to be included in the New Brunswick “cluster”, Marrero and his team conduct an extensive study of the patient’s history, as well as a battery of tests including brain imaging, metabolic and toxicology tests and spinal taps, to rule out other possible illnesses like dementia, neurodegenerative disorders, autoimmune disorders and possible infections. 

Only a single suspected case was recorded in 2015, but in 2019 there were 11 cases and 24 in 2020. Researchers believe five people have died from the illness. 

“We have not seen over the last 20-plus years a cluster of diagnosis-resistant neurological disease like this one,” said Michael Coulthart, head of Canada’s CJD surveillance network.

Women in 40s, 50s who survive COVID-19 more likely to suffer persistent problems: UK studies

Via Reuters: Women in 40s, 50s who survive COVID more likely to suffer persistent problems: UK studies. Excerpt:

LONDON (Reuters) - Women in their 40s and 50s appear more at risk of long-term problems following discharge from hospital after COVID-19, with many suffering months of persistent symptoms such as fatigue, breathlessness and brain fog, two UK studies found on Wednesday.

One study found that five months after leaving hospital, COVID-19 patients who were also middle-aged, white, female, and had other health problems such as diabetes, lung or heart disease, tended to be more likely to report long-COVID symptoms. 

“Our study finds that those who have the most severe prolonged symptoms tend to be white women aged approximately 40 to 60 who have at least two long term health conditions,” said Chris Brightling, a professor of respiratory medicine at Leicester University who co-led the study known as PHOSP-COVID

A second study led by the International Severe Acute Respiratory and emerging Infections Consortium (ISARIC) found that women under 50 had higher odds of worse long-term health outcomes than men and than older study participants, even if they had no underlying health conditions. 

“It’s becoming increasingly clear that COVID-19 has profound consequences for those who survive the disease,” said Tom Drake, a clinical research fellow at Edinburgh University who co-led the ISARIC study.