Clinical and CSF single-cell profiling of post-COVID-19 cognitive impairment 2024 Hu et al

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Highlights

  • Improvement from post-COVID-19 cognitive impairment (CI) is slow

  • Post-COVID-19 CI is molecularly distinct from Alzheimer’s disease

  • Post-COVID-19 CI is associated with CSF monocyte recruitment and gene alterations

  • Improvement from post-COVID-19 CI is linked to greater CSF interferon responses
Summary
Natural history and mechanisms for persistent cognitive symptoms (“brain fog”) following acute and often mild COVID-19 are unknown. In a large prospective cohort of people who underwent testing a median of 9 months after acute COVID-19 in the New York City/New Jersey area, we found that cognitive dysfunction is common; is not influenced by mood, fatigue, or sleepiness; and is correlated with MRI changes in very few people. In a subgroup that underwent cerebrospinal fluid analysis, there are no changes related to Alzheimer’s disease or neurodegeneration. Single-cell gene expression analysis in the cerebrospinal fluid shows findings consistent with monocyte recruitment, chemokine signaling, cellular stress, and suppressed interferon response—especially in myeloid cells. Longitudinal analysis shows slow recovery accompanied by key alterations in inflammatory genes and increased protein levels of CXCL8, CCL3L1, and sTREM2. These findings suggest that the prognosis for brain fog following COVID-19 correlates with myeloid-related chemokine and interferon-responsive genes.
 
Clinical and CSF single-cell profiling of post-COVID-19 cognitive impairment
William T. Hu; Milota Kaluzova; Alice Dawson; Victor Sotelo; Julia Papas; Alexander Lemenze; Carol Shu; Mini Jomartin; Ashima Nayyar; Sabiha Hussain

Link | PDF (Cell Reports Medicine) [Open Access]
 
This seems... significant? Interferon response is specifically antiviral, so this would make sense with viral reservoirs, complete or not. Could suggest suppression of interferons, which if I understood it correctly is a common viral defense.

A growing model seems to form around cells being infected, but not taken over by viruses. Recovery could involve clearance of those cells, which would be much longer if long-lived cells, or more cells, are infected. The viruses don't multiply enough to destroy the cells, but affect their functioning. Then many possible triggers could produce the right conditions for viruses to spread out to other cells, until they're all cleared, and if not, then a lifetime of disabling chronic symptoms.
 
Longitudinal analysis shows slow recovery accompanied by key alterations in inflammatory genes and increased protein levels of CXCL8, CCL3L1, and sTREM2. These findings suggest that the prognosis for brain fog following COVID-19 correlates with myeloid-related chemokine and interferon-responsive genes.

Compare to late-life major depressive disorder —

Evidence for reduced anti-inflammatory microglial phagocytic response in late-life major depression (2024)
Reichert Plaska; Heslegrave; Bruno; Ramos-Cejudo; Han Lee; Osorio; Imbimbo; Zetterberg; Blennow; Pomara

Major depressive disorder (MDD) is associated with Alzheimer’s disease (AD) but the precise mechanisms underlying this relationship are not understood. While it is well established that cerebrospinal fluid (CSF) soluble levels of triggering receptor expressed on myeloid cells 2 (sTREM2) increase during early stages of AD, how sTREM2 levels behave in subjects with MDD is not known.

In a longitudinal study, we measured CSF sTREM2 levels in 27 elderly cognitively intact individuals with late-life major depression (LLMD) and in 19 healthy controls. We tested the hypothesis that, similarly to what happens in early stages of AD, CSF sTREM2 would be elevated in MDD. In addition, we compared the associations of CSF sTREM2, pro- and anti- inflammatory, and AD biomarkers in LLMD and control subjects.

Surprisingly, we found that mean CSF sTREM2 levels were significantly reduced in LLMD compared to controls. This reduction was no longer significant at the 3-year follow-up visit when depression severity improved. In addition, we found that CSF sTREM2 was associated with AD biomarkers and proinflammatory cytokines in controls but not in LLMD.

These findings suggest that impaired microglia phagocytic response to AD pathology may be a novel link between MDD and AD.

Link | Paywall (Brain, Behavior, and Immunity)
 
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Psychology Today: Long COVID Looks Like Acute Infection in the Brain
12 June 2024
By Alison Escalante M.D.


Long COVID has the biological signature of an acute infection in the brain, according to a new research study. For patients with difficulty thinking or concentrating due to Long COVID, which has lasted over four years in some, this may be caused by ongoing COVID-19 infection. In addition, 50 percent of people with Long COVID brain fog do not get better, but in the 50 percent that do, the critical immune system pathway involves interferon.

A research team from Rutgers has isolated the molecular makeup of the immune system’s response to Long COVID in the brain by extensively testing cerebral spinal fluid (CSF). By mapping the proteomics of the CSF in Long COVID patients, the team has made an important step toward resolving an ongoing debate about the cause of Long COVID. Long COVID looks like an acute infection. It does not fit the pattern of a post-infectious autoimmune process or Alzheimer’s disease. Further, brain fog is not caused by anxiety or depression and is not “all in the patient’s head.”

Fifty percent of people with Long COVID brain fog recover slowly
Once the researchers determined that the spinal fluid’s genetic and protein pattern was consistent with acute COVID-19 infection, they wanted to know what was different about the people whose brain fog was slowly improving. They compared the proteomic signature, or protein pattern, in the CSF of the study subjects with existing databases to see which patterns they matched.

This analysis made it clear that the difference between those who were improving and those who were not was in the immune system’s interferon-led response to the virus. Interferons are proteins that act like the body’s alarm system against viruses and other harmful invaders. When a virus infects a cell, the cell sends out interferons to warn nearby cells. These nearby cells then prepare to defend themselves, making it harder for the virus to spread. All of these responses produce specific biological signatures that have been determined in various experiments and exist in databases.

Interferon responses are critical to Long COVID recovery
By comparing the study samples with existing databases, Hu’s team found that the three interferon pathways, which are intermixed and interrelated, were all important in Long COVID. Both interferon alpha and gamma were under-activated in people with long COVID, but it was interferon lambda that differentiated the people who got better from those who did not.


Interferon lambda is the least studied and least understood of the three interferons. Yet, this was the critical pathway for Long COVID. Hu’s team found that interferon lambda-2 levels were actually higher in people who do not recover. But higher levels are not always better: In this case, Hu’s team believes that the higher interferon lambda levels are a sign of something going wrong. Lambda remained high because it was not sufficiently activating the defense pathways that were needed to fight off the COVID-19 infection.

Directions for research into Long COVID treatment
In February 2023, a study was published in the New England Journal of Medicine on the use of Pegylated Interferon Lambda for acute COVID-19 infection. That study found that administering the pegylated interferon lambda to outpatients with acute COVID-19 reduced their later need for ER visits or hospitalization.

Based on their own findings, Hu’s team suspects that interferon lambda needs to be supplemented. “That is going to be very difficult either in the human model or the animal model,” says Hu. “The easiest path to determine whether interferon lambda works would be in a clinical trial.” To that end, Hu’s team is reaching out to other researchers and to those involved with the NIH RECOVER efforts to make them aware of this exciting lead.

Link
 
Early Treatment with Pegylated Interferon Lambda for Covid-19
8 February 2023
Authors: Gilmar Reis, M.D., Ph.D., Eduardo A.S. Moreira Silva, M.D., Ph.D., Daniela C. Medeiros Silva, M.D., Ph.D., Lehana Thabane, Ph.D., Vitoria H.S. Campos, Thiago S. Ferreira, M.D., Castilho V.Q. Santos, Ana M.R. Nogueira, M.D., Ana P.F.G. Almeida, M.D., Leonardo C.M. Savassi, M.D., Ph.D., Adhemar D. Figueiredo-Neto, M.D., Ph.D., Ana C.F. Dias, Ph.D., Adelino M. Freire Júnior, M.D., Ph.D., Carina Bitarães, R.N., Aline C. Milagres, R.N., Eduardo D. Callegari, M.D., Maria I.C. Simplicio, B.Sc.Pharm., Luciene B. Ribeiro, R.N., M.P.H., Rosemary Oliveira, Ofir Harari, Ph.D., Lindsay A. Wilson, M.Sc., Jamie I. Forrest, Ph.D., M.P.H., Hinda Ruton, M.Sc., Sheila Sprague, Ph.D., Paula McKay, M.Sc., Christina M. Guo, B.Com., Eve H. Limbrick-Oldfield, Ph.D., Steve Kanters, Ph.D., Gordon H. Guyatt, M.D., Craig R. Rayner, Pharm.D., Christopher Kandel, M.D., Mia J. Biondi, Ph.D., Robert Kozak, Ph.D., Bettina Hansen, Ph.D., M. Atif Zahoor, Ph.D., Paul Arora, Ph.D., Colin Hislop, M.B., B.S., Ingrid Choong, Ph.D., Jordan J. Feld, M.D., M.P.H., Edward J. Mills, Ph.D., F.R.C.P., and Jeffrey S. Glenn, M.D., Ph.D., for the TOGETHER Investigators

Abstract
Background
The efficacy of a single dose of pegylated interferon lambda in preventing clinical events among outpatients with acute symptomatic coronavirus disease 2019 (Covid-19) is unclear.

Methods
We conducted a randomized, controlled, adaptive platform trial involving predominantly vaccinated adults with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in Brazil and Canada. Outpatients who presented with an acute clinical condition consistent with Covid-19 within 7 days after the onset of symptoms received either pegylated interferon lambda (single subcutaneous injection, 180 μg) or placebo (single injection or oral). The primary composite outcome was hospitalization (or transfer to a tertiary hospital) or an emergency department visit (observation for >6 hours) due to Covid-19 within 28 days after randomization.

Results
A total of 933 patients were assigned to receive pegylated interferon lambda (2 were subsequently excluded owing to protocol deviations) and 1018 were assigned to receive placebo. Overall, 83% of the patients had been vaccinated, and during the trial, multiple SARS-CoV-2 variants had emerged. A total of 25 of 931 patients (2.7%) in the interferon group had a primary-outcome event, as compared with 57 of 1018 (5.6%) in the placebo group, a difference of 51% (relative risk, 0.49; 95% Bayesian credible interval, 0.30 to 0.76; posterior probability of superiority to placebo, >99.9%). Results were generally consistent in analyses of secondary outcomes, including time to hospitalization for Covid-19 (hazard ratio, 0.57; 95% Bayesian credible interval, 0.33 to 0.95) and Covid-19–related hospitalization or death (hazard ratio, 0.59; 95% Bayesian credible interval, 0.35 to 0.97). The effects were consistent across dominant variants and independent of vaccination status. Among patients with a high viral load at baseline, those who received pegylated interferon lambda had lower viral loads by day 7 than those who received placebo. The incidence of adverse events was similar in the two groups.

Conclusions
Among predominantly vaccinated outpatients with Covid-19, the incidence of hospitalization or an emergency department visit (observation for >6 hours) was significantly lower among those who received a single dose of pegylated interferon lambda than among those who received placebo.

Link

Proposed as treatment for long COVID by authors of above study.
 
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It looks as though there was a flurry of excitement about it on PR a few years ago, and some people tried it. But there doesn't seem to have been amazing recoveries. There is talk of bad batches of the PEG-Interferon lambda, and ideas about feeling worse being proof that the treatment is working.

It seems the OP of the thread experienced profound results, and still improved after over 200 days. Only 7 people tried the first batch, a few of whom had some modest improvements (one went from 1 walk/stand per day to 4). 3 people, including OP, tried the second batch, but didn't experience further improvement.

Also, OP reported that they were on 23 other meds/supplements. The treatment with peginterferon - at least in OP - was done alongside GS-441524.

Wikipedia said:
GS-441524 is a nucleoside analogue antiviral drug which was developed by Gilead Sciences. It is the main plasma metabolite of the antiviral prodrug remdesivir, and has a half-life of around 24 hours in human patients. Remdesivir and GS-441524 were both found to be effective in vitro against feline coronavirus strains responsible for feline infectious peritonitis (FIP), a lethal systemic disease affecting domestic cats. Remdesivir was never tested in cats (though some vets now offer it[1]), but GS-441524 has been found to be effective treatment for FIP.
 
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Yes, and even then, my impression from what the OP said in the latest posts was that they are not recovered.

That's not dismissing the idea of PEG-interferon lambda potentially being of use - perhaps the quality of what was used was not good, perhaps the dosage wasn't right... It's just that, having read that thread, my rating of the chance of it working has gone down.
 
This seems... significant? Interferon response is specifically antiviral, so this would make sense with viral reservoirs, complete or not. Could suggest suppression of interferons, which if I understood it correctly is a common viral defense.

A growing model seems to form around cells being infected, but not taken over by viruses. Recovery could involve clearance of those cells, which would be much longer if long-lived cells, or more cells, are infected. The viruses don't multiply enough to destroy the cells, but affect their functioning. Then many possible triggers could produce the right conditions for viruses to spread out to other cells, until they're all cleared, and if not, then a lifetime of disabling chronic symptoms.

This is more or less the model that many of the "ME/CFS = EV infection" proponents use. I think it's somewhat plausible. What is important to add is that there are celltypes not only long lived but that don't differentiate and/or are not getting replaced, at least not in sufficient numbers?
 
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