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Over-stimulated immune system may drive post-COVID cognitive changes – Small US study

An over-stimulated immune system – possibly triggered by ongoing vascular injury and repair – may be behind persistent post-COVID cognitive changes, according to preliminary work presented at the American Academy of Neurology annual meeting (2-7 April in Seattle, 24-26 April – virtual).

Researchers led by Dr Joanna Hellmuth of the University of California San Francisco, found an “inflammatory signature” in the cerebrospinal fluid of 13 people who had lingering cognitive problems 10 months after they had their first COVID symptoms.

People with persistent cognitive problems after mild COVID-19 had higher levels of two inflammatory markers in their spinal fluid – C-reactive protein and serum amyloid A – compared with those who had COVID and no cognitive symptoms, Hellmuth and co-authors reported. Vascular endothelial growth factor markers were also higher in these people, with some measures specific to people who experienced cognitive changes soon after being infected.

“This is an important observation,” said Dr Avindra Nath, clinical director of the National Institute of Neurological Disorders and Stroke at the National Institutes of Health (NIH), who wasn’t involved with the study. “It suggests vascular injury and repair in the brain may set up the inflammation,” he told MedPage Today.

“Many millions of people experience persistent cognitive issues after SARS-CoV-2 infection, which can impact even young, healthy adults who had a mild case of COVID,” Hellmuth noted. “However, there are not yet effective laboratory tests or treatments for COVID-associated cognitive changes, in part because we do not understand the underlying biology.”

This was a very small study, Hellmuth acknowledged, but the findings, if true, implied that inflammation within the brain may contribute to cognitive changes after COVID, and COVID infection could trigger immunovascular dysregulation through endothelial activation and dysfunction.

Changes in the brain

Earlier research found damage caused by thinning and leaky blood vessels in brain tissue samples of people who died with COVID, but did not link those changes and resulting inflammation with post-COVID cognition.

Other studies established that post-COVID cognitive changes were similar to symptoms seen after other viral infections like HIV or Ebola, or after chemotherapy.

“The symptoms of cognitive impairment after COVID-19 infection – impaired attention, concentration, memory, speed of information processing, and executive function – bear striking clinical similarities to the symptoms of cancer therapy-related cognitive impairment,” Stanford University researcher Dr Michelle Monje told MedPage Today. “Given these clinical similarities between ‘chemo fog’ and ‘COVID fog’, we asked if there were also neurobiological similarities.”

In preprint research awaiting journal publication, Monje and co-authors found parallels between the type of cell dysregulation that happens after chemotherapy and mild COVID-19. “We found the same pattern of white matter-predominant microglial reactivity in the brains of people with COVID-19 that we found in the people after chemotherapy,” Monje said.

Recent research has shown that people with mild COVID had a greater decline in executive function, notably in their ability to perform complex tasks, that dovetailed with brain changes seen before and after COVID on MRI. In a UK Biobank study, 401 COVID patients showed a greater loss of grey matter volume and more brain tissue damage an average of 4.5 months after infection compared with people who never were infected.

“The UK Biobank study shows the first truly compelling data of a measurable change in the brain structure in people with COVID-19,” said Dr Serena Spudich, a Yale University neurologist specialising in nervous system infections, who wasn’t involved with the research.

A key aspect of this study was its focus on people with mild COVID-19, Spudich told MedPage Today. “Only 4% of patients were hospitalised during their bout of acute COVID-19, so the findings come from a population that parallels the experience of most people worldwide who’ve been infected.”

What drives cognitive symptoms?

What drives post-COVID cognitive changes is still a mystery. “The mechanisms have not been very well studied,” Nath said. “The indications are that there’s at least a subset of persistent immune activation. Now the question is, what type of immune activation are we seeing?

“My guess is that we’re seeing largely macrophage activation, or what I call markers of innate immune response,” he added. “What we see in the brain at autopsy is activation of microglia. Once those cells get turned on, they’re very hard to turn off. Persistent symptoms are likely to come from that kind of immune activation.”

A clinical trial could help move treatment forward while shedding light on what causes post-COVID brain changes, Nath suggested. “We have a lot of drugs that affect the immune system in various ways. We may be able to figure out what part of the immune system is really impaired and what is not, what is responding to treatment and what is not, and how that is corresponding to recovery.”

The NIH plans to start a treatment trial of people with post-COVID cognitive problems, testing intravenous high-dose corticosteroids, intravenous immunoglobulin, and placebo soon, he noted.

“People say you need to know the mechanism behind this,” Nath said. “And I would say, yes, that’s absolutely true: you don’t want to rush because you don’t want to cause harm.

“But an argument I would make is that with COVID, you’re dealing with a very different beast. You’ve got billions of people infected. It takes years to figure out mechanisms. Can we really afford to wait that long?”

Study details

Mild respiratory SARS-CoV-2 infection can cause multi-lineage cellular dysregulation and myelin loss in the brain

Anthony Fernández-Castañeda, Peiwen Lu, Anna C. Geraghty, Eric Song, Myoung-Hwa Lee, Jamie Wood, Belgin Yalçın, Kathryn R. Taylor, Selena Dutton, Lehi Acosta-Alvarez, Lijun Ni, Daniel Contreras-Esquivel, Jeff Gehlhausen, Jon Klein, Carolina Lucas, Tianyang Mao, Julio Silva, Mario A. Peña-Hernández, Alexandra Tabachnikova, Takehiro Takahashi, Laura Tabacof, Jenna Tosto-Mancuso, Erica Breyman, Amy Kontorovich, Dayna McCarthy, Martha Quezado, Marco Hefti, Daniel Perl, Rebecca Folkerth, David Putrino, Avi Nath, Akiko Iwasaki, Michelle Monje.

Posted on bioRXiv on 10 January 2022


Survivors of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infection frequently experience lingering neurological symptoms, including impairment in attention, concentration, speed of information processing and memory. This long-COVID cognitive syndrome shares many features with the syndrome of cancer therapy-related cognitive impairment (CRCI).

Neuroinflammation, particularly microglial reactivity and consequent dysregulation of hippocampal neurogenesis and oligodendrocyte lineage cells, is central to CRCI. We hypothesised that similar cellular mechanisms may contribute to the persistent neurological symptoms associated with even mild SARS-CoV-2 respiratory infection. Here, we explored neuroinflammation caused by mild respiratory SARS-CoV-2 infection – without neuroinvasion – and effects on hippocampal neurogenesis and the oligodendroglial lineage. Using a mouse model of mild respiratory SARS-CoV-2 infection induced by intranasal SARS-CoV-2 delivery, we found white matter-selective microglial reactivity, a pattern observed in CRCI. Human brain tissue from nine individuals with COVID-19 or SARS-CoV-2 infection exhibits the same pattern of prominent white matter-selective microglial reactivity.

In mice, pro-inflammatory CSF cytokines/chemokines were elevated for at least 7-weeks post-infection; among the chemokines demonstrating persistent elevation is CCL11, which is associated with impairments in neurogenesis and cognitive function.
Humans experiencing long-COVID with cognitive symptoms (48 subjects) similarly demonstrate elevated CCL11 levels compared with those with long-COVID who lack cognitive symptoms (15 subjects). Impaired hippocampal neurogenesis, decreased oligodendrocytes and myelin loss in subcortical white matter were evident at one week, and persisted until at least seven weeks, following mild respiratory SARS-CoV-2 infection in mice.

Taken together, the findings presented here illustrate striking similarities between neuropathophysiology after cancer therapy and after SARS-CoV-2 infection, and elucidate cellular deficits that may contribute to lasting neurological symptoms following even mild SARS-CoV-2 infection.

UK Biobank study details

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

Gwenaëlle Douaud, Soojin Lee, Fidel Alfaro-Almagro, Christoph Arthofer, Chaoyue Wang, Paul McCarthy, Frederik Lange, Jesper Andersson, Ludovica Griffanti, Eugene Duff, Saad Jbabdi, Bernd Taschler, Peter Keating, Anderson Winkler, Rory Collins, Paul Matthews, Naomi Allen, Karla Miller, Thomas Nichols & Stephen Smith.

Published in Nature on 7 March 2022


There is strong evidence for brain-related abnormalities in COVID-191–13. 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.


MedPage Today article – What Drives Post-COVID Cognitive Changes? (Open access)


bioRXiv article – Mild respiratory SARS-CoV-2 infection can cause multi-lineage cellular dysregulation and myelin loss in the brain (Open access)


Nature article – SARS-CoV-2 is associated with changes in brain structure in UK Biobank (Open access)


See more from MedicalBrief archives:


Nearly a quarter of hospitalised COVID-19 patients have ‘brain fog’ — Mount Sinai registry


COVID -19 may cause neurological tissue damage, grey matter loss – Oxford


Neurological injury biomarkers in acute COVID-19 normalise in the long term – Swedish study


SARS-CoV-2: No brain infection but can inflict significant damage — 40 autopsies




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