Characterization and Biomarker Analyses of Post-COVID-19 Complications and Neurological Manifestations, 2021, Sun et al

[rvallee]

https://www.mdpi.com/2073-4409/10/2/386


Abstract

As the SARS-CoV-2 pandemic continues, reports have demonstrated neurologic sequelae following COVID-19 recovery. Mechanisms to explain long-term neurological sequelae are unknown and need to be identified. Plasma from 24 individuals recovering from COVID-19 at 1 to 3 months after initial infection were collected for cytokine and antibody levels and neuronal-enriched extracellular vesicle (nEV) protein cargo analyses. Plasma cytokine IL-4 was increased in all COVID-19 participants. Volunteers with self-reported neurological problems (nCoV, n = 8) had a positive correlation of IL6 with age or severity of the sequalae, at least one co-morbidity and increased SARS-CoV-2 antibody compared to those COVID-19 individuals without neurological issues (CoV, n = 16). Protein markers of neuronal dysfunction including amyloid beta, neurofilament light, neurogranin, total tau, and p-T181-tau were all significantly increased in the nEVs of all participants recovering from COVID-19 compared to historic controls. This study suggests ongoing peripheral and neuroinflammation after COVID-19 infection that may influence neurological sequelae by altering nEV proteins. Individuals recovering from COVID-19 may have occult neural damage while those with demonstrative neurological symptoms additionally had more severe infection. Longitudinal studies to monitor plasma biomarkers and nEV cargo are warranted to assess persistent neurodegeneration and systemic effects.​

Not sure how informative but this image is included as a graphical abstract:

 

[Hutan]

Neuronal-enriched EVs (nEVs) can be isolated using antibodies against the L1 cell adhesion molecule (L1CAM), which is expressed on neurons. nEVs likely reflect the state of the neuron in real time [18,19]. nEVs containing the neurotoxic proteins amyloid beta (Aβ), neurofilament light (NFL), p-T181-tau, and/or the inflammatory protein HMGB1 have been isolated from individuals with HIV cognitive impairment [20,21], Alzheimer’s disease (AD) [22], and traumatic brain injury (TBI) [23–25]. These nEV proteins may pre- dict neurological pathologies years in advance, as reported in AD

We have pre- viously used nEVs as biomarkers for cognitive impairment in HIV and to differentiate HIV-associated cognitive impairment from AD [21,28]. Examining interactions at the cel- lular level may help elucidate the mechanisms behind these long-term symptoms.

We report results that may differentiate individuals with nCoV from CoV and healthy controls

The premise is really interesting. It seems that they can isolate particular extracellular vesicles using antibodies against a cell adhesion molecule that is expressed on neurons. I'm not quite sure if that means that the vesicles with the neuronal cell adhesion molecule have come from neuron cells, or are destined to be absorbed by neuron cells, or both.

And it seems that the EV cargo can differentiate a range of health conditions, and certain proteins are a marker for cognitive impairment in a range of conditions. I find it tremendously exciting that researchers with this type of background are turning their attention to post-Covid issues. And they seem to understand Long-covid - there isn't the idea that it's 'just fatigue'.

Long-term health problems, including neurological symptoms such as headache, fa- tigue, dizziness, memory loss, confusion, and difficulty focusing, are associated with post- COVID-19 infection [10]. Over 30% of post-COVID-19 individuals complained of memory loss [11]. As many of these individuals experience a myriad of physical, cognitive and mental issues post COVID, some investigators have suggested using a general functional scale for assessing symptoms or quality of life [12,13]. One study lists the top 3 debilitating symptoms of “Long COVID” as fatigue, malaise, and cognitive dysfunction [

 

[Hutan]

There wasn't much in the cytokine analysis, in terms of differentiating post-Covid participants with (nCov) and without (Cov) neurological symptoms.

I thought the IgG levels measured was interesting - these are in confirmed cases of Covid-19, with some of them having no or very low antibodies to Covid. People who had had Covid and have neurological symptoms (nCov) were more likely to have Covid antibodies than people who had had Covid and don't have neurological symptoms.

Surprisingly, three CoV participants had negative IgG levels (<1.4; Table 2). IgG levels did not correlate with days till visit (

The researchers seem quite happy that the EVs they are labelling neuronal EVs (nEV) do indeed come from neurons, because they carry higher levels of synaptophysin.

Here are the levels of proteins associated with neural damage and inflammation that they looked for:


Levels do seem to be elevated in the people who have had Covid, compared to the controls. But the levels are, if anything, a bit higher in the people without post-Covid neurological symptoms (Cov) than those with them (nCov).

I mean, read this description for HMGB1:

HMGB1 is a ubiquitous nuclear protein that, when released extracellularly, promotes inflammation and cytokine release [38]. Im- portantly, this release within the brain can activate microglia, and when released via EVs into the periphery, can activate monocytes to promote further inflammation. We previ- ously reported that nEV HMGB1 and NFL were elevated in HIV-infected individuals with cognitive impairment

You might think the people with headaches and and an inability to think well would have loads of the stuff. And they did have more than the controls, but, on average, less than the post-Covid people without lingering neurological symptoms.


It's a small study, with acknowledged problems, including 50% of the nCov having been hospitalised, while only 19% of the Cov group were.

But, investigation of these neuronal EV's might be a really good alternative to analysis of cerebrospinal fluid for ME/CFS and Long Covid research. I hope we see a bigger study from this group.