Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation, 2021, Fernandez, Monje, Nath et al

Andy

Andy

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

Preprint Abstract

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 hypothesized 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 9 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 to 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 1 week, and persisted until at least 7 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.

https://www.biorxiv.org/content/10.1101/2022.01.07.475453v1

Mod note: The abstract of the final version is below
 
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How nice it would have been if brain fog hadn't been dismissed forever, we could have compared with other cohorts with brain fog. At least chemo fog seems a good proxy for it, but it's pretty amazing that something this important having been dismissed for decades is apparently of no concern to anyone but those suffering. Literally not even bothering giving this crippling symptomology a name. Still not even happening yet.

Cognitive dysfunction is simply inadequate, frankly. Too vague. Man, does medicine need to get their language straightened up, it's embarrassing to be this dysfunctional at basic vocabulary. Imagine still being stuck at the first level for decades and not being bothered by it. I frankly can't.
 
what is a good definition of brain fog? my symptoms include extreme crippling versions of some aspects of executive dysfunction.

which itself gets confusing compared to autistic inertia and non-hyperactive add.

part of the mix is extreme problems with decsion making, planning, scheduling and for lack of a better term GETTING THINGS DONE [i wish i could make this more specific]. also initiating and completing tasks. sequencing, prioritizing, doing, doing without stress pem.

getting things done can include a project [/listing/ desperately needed vitamins to be ordered can take years to accomplish] or merely reaching out to get food when i am hungry that i was told repeatedly is there. just reaching the arm out is for some reason not possible.

i want a name and credible diagnosis for stuff like that. this is NOT normal. but idk if fits with paper or with brain fog definitions.

also stm and remembering that something is there or that i need to do something at a time or at all. todo lists completely unmanageable.

which of those things, if any, are brain fog, vs. other stuff? like from the paper.

paper abstract> impairment in attention, concentration, speed of information processing and memory

is this specified in detail in teh paper or in standard credible neuro tests or ugh questionnaires?
 
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Merged thread

Full title: Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation
Authors: 17 authors including Avindra Nath, Akiko Iwasaki, David Putrino
Published: June 12, 2022
Journal: Cell
Open access: https://www.cell.com/cell/fulltext/S0092-8674(22)00713-9


COVID survivors frequently experience lingering neurological symptoms that resemble cancer therapy-related cognitive impairment, a syndrome for which white-matter microglial reactivity and consequent neural dysregulation is central. Here, we explored the neurobiological effects of respiratory SARS-CoV-2 infection and found white-matter-selective microglial reactivity in mice and humans. Following mild respiratory COVID in mice, persistently impaired hippocampal neurogenesis, decreased oligodendrocytes and myelin loss were evident together with elevated CSF cytokines/chemokines including CCL11. Systemic CCL11 administration specifically caused hippocampal microglial reactivity and impaired neurogenesis. Concordantly, humans with lasting cognitive symptoms post-COVID exhibit elevated CCL11 levels. Compared to SARS-CoV-2, mild respiratory influenza in mice caused similar patterns of white matter-selective microglial reactivity, oligodendrocyte loss, impaired neurogenesis and elevated CCL11 at early timepoints, but after influenza only elevated CCL11 and hippocampal pathology persisted. These findings illustrate similar neuropathophysiology after cancer therapy and respiratory SARS-CoV-2 infection which may contribute to cognitive impairment following even mild COVID.
 
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Capturing some of Dr. Monje's sub-tweets from the above thread. (My bolding)

One of the chemokines elevated is CCL11, known to be associated with cognitive impairment. We found elevated CCL11 levels in people suffering from Long COVID with cognitive symptoms compared to those with no cognitive symptoms.

Building on foundational work by @VilledaLab, we tested direct effects of systemic CCL11 administration and found that CCL11 causes microglial reactivity: but ONLY in the hippocampus.
Click to expand...

(The region/circuit-specific effect of a chemokine was unexpected, and raises the possibility that various immune challenges, eliciting different cytokine/chemokine profiles, may increase risk for overlapping yet distinct constellations of neurological & psychiatric symptoms).

Like the effects of microglial reactivity after cancer therapy, we found impairment in hippocampal neurogenesis. CCL11 was sufficient to cause this loss of new hippocampal neurons.
Click to expand...

Together, the findings in these mouse models of mild respiratory COVID and influenza highlight the principle that the immune response to infections outside of the brain can cause neuroinflammation and consequently neural cell dysregulation that can affect brain function.

There are stark parallels between the cellular dysregulation that can happen after chemotherapy and even mild COVID. Understanding the neurobiological underpinnings of Long COVID will lay the groundwork for therapeutic strategies to address this neurological health crisis.
Click to expand...
 
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