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

Highlights

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  Improvement from post-COVID-19 cognitive impairment (CI) is slow
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  Post-COVID-19 CI is molecularly distinct from Alzheimer’s disease
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  Post-COVID-19 CI is associated with CSF monocyte recruitment and gene alterations
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  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.

 

Graphical abstract

 

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)

 

Corroborating blood findings in Cortical thickness alterations and systemic inflammation define long-COVID patients with cognitive impairment (2023, Brain, Behavior, and Immunity) —

Additionally, we discovered a distinct immunophenotype, with elevated levels of IL-10, IFN-gamma, and sTREM2 in long-COVID patients, especially in the group suffering from cognitive impairment.

Wikipedia — soluble TREM2.

 

Psychology Today: Long COVID Looks Like Acute Infection in the Brain
12 June 2024
By Alison Escalante M.D.

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.

 

Thread on Phoenix Rising about peginterferon lambda.

 

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.

 

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?