Pre-print: Post-acute COVID-19 cognitive impairment and decline uniquely associate with kynurenine pathway activation, 2022, Brew et al

Full title of study: Post-acute COVID-19 cognitive impairment and decline uniquely associate with kynurenine pathway activation: a longitudinal observational study

Abstract
Cognitive impairment and function post-acute mild to moderate COVID-19 are poorly understood. We report findings of 128 prospectively studied SARS-CoV-2 positive patients. Cognition and olfaction were assessed at 2-, 4- and 12-months post-diagnosis. Lung function, physical and mental health were assessed at 2-month post diagnosis. Blood cytokines, neuro-biomarkers, and kynurenine pathway (KP) metabolites were measured at 2-, 4-, 8- and 12-months. Mild to moderate cognitive impairment (demographically corrected) was present in 16%, 23%, and 26%, at 2-, 4- and 12-months post diagnosis, respectively. Overall cognitive performance mildly, but significantly (p<.001) declined. Cognitive impairment was more common in those with anosmia (p=.05), but only at 2 months. KP metabolites quinolinic acid, 3-hydroxyanthranilic acid, and kynurenine were significantly (p<.001) associated with cognitive decline. The KP as a unique biomarker offers a potential therapeutic target for COVID-19-related cognitive impairment.

 

This thread has been split from the "Long Covid in the media and social media 2022" thread.

 

I'm only part of the way through the methodology, but this is looking like a solid study.

People have been followed longitudinally (3, 5, 9 and 13 months) and the study is ongoing (the Sydney St. Vincent’s Hospital COVID-19 ADAPT prospective study). The people had to have a confirmed Covid-19 infection. It should be noted that the study isn't specifically of people with Long Covid - it's a prospective study and includes 128 people covering mild, moderate and hospitalised patients. I guess I have the question of, 'is the study big enough to pick up enough people developing ME/CFS?'

They have assessed a lot of things and checked for relationships between them. They seem to have taken good approaches and are transparent about what they did and about things like dropouts (which weren't high). It almost sounds as though the world might have it's act together - there's mention of the International Neuropsychology COVID-19 taskforce's recommendations for cognitive studies "where consideration of disease severity, demographics, mental health, objectively tested olfaction, and co-morbidities is conducted a priori."

Cognitive assessment
The International Neuropsychology COVID-19 taskforce informed their choice of the CogState Computerized Battery (CCB)

They've considered issues like practice effects, and the different cognitive performances of different demographics and adjusted cognitive performance data to produce z values (as in, indications for departures from the expected value, given the person's demographic groups). The CCB has normative Australian data that was used in that standardisation process.


Peripheral biomarkers of brain injury
neuro-axonal with Neurofilament Light Chain (NFL);
astrogliosis with Glial fibrillary acidic protein (GFAP);
blood brain barrier permeability (BBB), brain injury and astrocytosis with S100β;
macrophage and granulocyte proliferation with Granulocyte macrophage colony-stimulating factor (GMCSF)),
and because each is abnormally elevated in COVID-19 infection (NFL28; GFAP29; S100β30; GMCSF31).


A range of blood cytokines and components of the kynurenine pathway
(Interferons (IFNs), major Interleukins, monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor-α (TNF-α),

Evaluation of recovery

Evaluation of mental health
I thought the 'Depression in the Medically Ill' questionnaire sounded interesting

Inter-relationships between measures

 

This finding of a trend to increasing prevalence of clinically significant cognitive impairment over time (with quite a big increase from 16% to 26%) I think probably isn't important. It's not statistically significant. Although there weren't a lot of dropouts, perhaps the less cognitively disabled were less likely to be motivated to keep coming along to the study assessments. Perhaps there was something a bit off with their adjustments to the data for practice effects.

That's quite an important finding, although it sounds as though some of the authors weren't very happy with it. It seems that they had expected to find something different, and they are recommending more studies to find that 'something different'.

 

Seems that loss of smell and cognitive dysfunction aren't associated.

And cognitive dysfunction wasn't associated with illness severity or lung function.

 

Finally to the most interesting bit, but I'm running out of steam. All those cytokines and brain injury markers and yet all they report finding that was abnormal related to the kynurenine pathway.

If it was just the KP data, we might assume that this is just related to the acute illness, with the effects wearing off over time. But, the fact that there was an association with cognitive dysfunction makes it a lot more interesting for us.

I'm going to sign off for the night, but it would be interesting to poke around in the KP data.

I do hope Long Covid and ME/CFS researchers will eventually stop doing studies on broad swathes of peripheral blood cytokines. There must be enough literature around now to suggest that the answer isn't going to be found there.

 

Gilles Guillemin is listed as the second to last author. Brew and Guillemin were both co-authors of that other recent KP paper mentioned in the first post of this thread.