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

[SNT Gatchaman]

Aussie breakthrough on the long Covid condition that leaves sufferers with symptoms similar to 'traumatic brain injury (Daily Mail - no really)

• Australian researchers have brought the world a step closer to curing brain fog
• Researchers have proven there is a physical reason for the nebulous condition
• Trials can now begin for treatments for the condition after pin-pointing a toxin
• The findings show 'brain fog' could take a huge toll on patients
• Long Covid isn't in the brain; a complex series of reactions is responsible
• Stimulated chemicals lead to nerve damage which can lead to brain fog

(Kynurenine)


ETA: Dr Bruce Brew recently co-authored Recent advances in clinical trials targeting the kynurenine pathway (Pires et al, 2021)

 

[Art Vandelay]

Aussie breakthrough on the long Covid condition that leaves sufferers with symptoms similar to 'traumatic brain injury (Daily Mail - no really)

@SNT Gatchaman beat me to it!

Research finds that long Covid causes brain fog and memory loss for more than a year

“What we’re finding is it’s actually affecting younger people, and they’re finding it really difficult to be able to continue working,” Professor Faux said.

Professor Steven Faux who assists in the running of the long Covid clinic at St Vincent’s Hospital in Darlinghurst, Sydney said he had eight to 10 new patients attend at the clinic a week with the disease, primarily young people.

No mention of ME/CFS at all, which is a huge oversight given that they're investigating cognitive problems following a viral infection. This sort of ignorance is typical for the Australian medical profession when it comes to post-viral illness.

Link to pre-print:
Post-acute COVID-19 cognitive impairment and decline uniquely associate with kynurenine pathway activation: a longitudinal observational study

 

[Midnattsol]

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.

 

[Midnattsol]

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

 

[Hutan]

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)

is a widely used and validated cognitive screening test that is culturally fair. The CCB version used in this study included Detection (reaction time), Identification (reaction time), One Card Learning (accuracy), and One Back (reaction time and accuracy).

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),

The cytokines and chemokines that were quantified include GMCSF, IFN-γ, Interleukin-1beta (IL-1β), IL-1 receptor antagonist (IL-1 Ra), IL-2, IL-4, IL-5, IL-6, IL-8, IL- 10, IL-12p40, IL-12p70, IL-13, MCP-1, and TNF-α.

The selection of the biomarkers is founded on previous immunological findings in the same cohort, where persistently elevated IFNs (i.e., elevated expression of type I IFN (IFN-β) and type III IFN (IFN-λ1)) was associated with chest pain, and dyspnea20 up to 8-month post diagnosis.

Next, we elected to test the components of the plasma kynurenine pathway (KP)21, 22 which is an IFN23, 24 stimulated myeloid cell mediated tryptophan degradation pathway important in immune tolerance, neurotoxicity, and vascular injury.

The fluorescence detector was set at excitation/emission wavelength of 280nm/438nm for detection of tryptophan (TRP) and 320 nm/438 nm for detection of 3-hydroxyanthranilic acid (3HAA) and anthranilic acid (AA). Kynurenine (KYN) and 3-hydroxykynurenine (3HK) were detected using a UV detector set to measure absorbance at 365 nm

Evaluation of recovery

At 2- and 4-month post diagnosis, the participants completed a COVID-19 functional status scale answering the four following statements: I have fully recovered after COVID-19; I feel confident returning to my pre-COVID work; I have returned to my usual activities of daily living; I have returned to my normal exercise level. For each statement, the participant rated whether they strongly agree, agree, slightly agree, slightly disagree, disagree, or strongly disagree, rated from 1 to 6.

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

Mental health was assessed with three screening tools to capture anxio-depressive symptoms at the first assessment, 2 months post diagnosis. In addition, participants reported whether they had been formally diagnosed with any psychiatric conditions. We used the Depression in the Medically Ill (DMI-10) which is a 10-item questionnaire. The DMI-10 accounts for confounding factors of the physical illness by focusing on cognitive symptoms of depression and avoiding measuring physical symptoms common to both depression and physical illnesses (e.g., changes in sleep, appetite, and body weight). DMI-10 scores range from 0 to 30 and a score of 9 or greater reflects a possible major depressive episode.

Inter-relationships between measures

Moreover, the clinical significance of CI [cognitive impairment] was assessed against functional status. The pathogenic axes assessed included systemic disease severity (and indirectly hypoxia), lung function, objectively tested olfaction, pre-existing and illness-associated anxiety and depression, medical comorbidities, initial visit CI, blood cytokines, the KP and peripheral biomarkers of brain injury. Time-variant predictors (all biomarkers but IFN-β IFN-λ1, olfaction) were tested for their main and time association with overall cognitive performance. The KP was also tested for its trajectory and its dynamic links to other biomarkers.

 

[Hutan]

The prevalence of clinically significant CI increased slightly across time (16% to 26%), albeit not to a statistically significant extent. Importantly, the severity of CI was within the mild and moderate deficit range and no patients progressed towards severe cognitive deterioration which is commensurate with what is expected from mild to moderate COVID in the sample’s age range7, 8. The detected pattern resembles the “brain fog” that has been widely reported by patients and is now recognized as a long-term consequence of COVID-19 infection43. The mild to moderate CI detected via the version of Cogstate battery used involves attention/working memory, psychomotor speed, and new learning. This type of cognitive deficit has been observed in other cognitive studies post mild to moderate COVID-197, 8. Mild to moderate CI can cause difficulties in cognitively demanding tasks and employment44, as shown in the current study.

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.

Importantly, there was no association between cognition and anxio-depression, both pre- morbid and current.

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'.

Specific studies dedicated to better understanding the connection between mental health and cognition in COVID-19 will be needed. Such studies that will ideally consider a wider socio-economic spectrum than the current study, in addition to pre-morbid mental health status, acute disease severity and ongoing life stressors.

 

[Hutan]

In the current study, olfaction and cognitive change had different dynamics, but were initially associated at the 2-month post diagnosis visit. The pathogenetic significance of this is unclear but the lack of association on subsequent visits argues against an olfactory nerve brain entry route in accordance with other literature52.

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

Moreover, whilst disease severity was associated with reduced lung function, there was no association between disease severity or lung function with mild cognitive decline, suggesting that symptoms of acute COVID-19 infection are not necessarily associated with cognitive function in the months following COVID-19 infection. Our finding of no association between CI and disease severity including respiratory function is in keeping with other studies (Table S1)2. This finding has major public health and economic implications: relying on disease severity (especially mild to moderate distinction) to estimate disease burden will result in a significant underestimate.

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

 

[Hutan]

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.

Indeed, KP metabolites (3HAA, QUIN and KYN) were the only blood markers associated with mild cognitive decline.

Moreover, KP activation was associated with IFN-β, a known inducer of the KP reinforcing the biological plausibility of our findings

Normative reference range for the KP are known39, 40 and we show that up to 60% of the sample have an activated KP using QUIN age-norms standards

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.

 

[Hutan]

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.

 

[rvallee]

We used the Depression in the Medically Ill (DMI-10) which is a 10-item questionnaire. The DMI-10 accounts for confounding factors of the physical illness by focusing on cognitive symptoms of depression and avoiding measuring physical symptoms common to both depression and physical illnesses (e.g., changes in sleep, appetite, and body weight). DMI-10 scores range from 0 to 30 and a score of 9 or greater reflects a possible major depressive episode.

Uh, would you look at that, someone who can think about things rationally. Can't remember having seen this in the many years looking at research for mental illness in the physically ill.

The choice of instruments, even poor ones, is a matter of judgment. There is no science that gives the right answer, it's a conscious choice. Very telling that this is never used in BPSland. Even when they do the thing where they pretend like it's legitimate to argue of a "functional overlay" when disease may explain illness, just not to their satisfaction.

Obviously this questionnaire would give opposite results to what BPS ideologues seek out. That's why they keep inventing more BS questionnaires that give them the answers they want.

 

[Jaybee00]

Does anyone have an actual copy of this paper…Recent advances in clinical trials targeting the kynurenine pathway (Pires et al, 2021)? Didn’t come up on sci-hub.

 

[Ravn]

Uh, would you look at that, someone who can think about things rationally. Can't remember having seen this in the many years looking at research for mental illness in the physically ill.

The DMI with instructions, scoring etc can be downloaded here:
https://www.blackdoginstitute.org.au/education-services/health-professionals/psychological-toolkit/

The 10 questions are:

1. Are you stewing over things?
2. Do you feel more vulnerable than usual?
3. Are you being self-critical and hard on yourself?
4. Are you feeling guilty about things in your life?
5. Do you find that nothing seems to be able to cheer you up?
6. Do you feel as if you have lost your core and essence?
7. Are you feeling depressed?
8. Do you feel less worthwhile?
9. Do you feel hopeless or helpless?
10. Do you feel more distant from other people?

Certainly less bad than some we've seen but still plenty of potential for misinterpretation for pwME (and, I suspect, other conditions, too). Q10 for example. Some pwME could easily feel more distant from other people because they really are more distant. Just being physically unable to see other people in person creates distance, both real and felt. Whether a person is depressed or not because of that distance is a separate question.

For diagnostic purposes, I really don't understand why they can't just ask Q7 and be done with it. Why would an ambiguous questionnaire be better at identifying depression than the person themselves?

The other questions could be useful as follow-up if a person said that yes they are depressed, to drill deeper into the problem and work out the best way to help. Discussing, not just tick-boxing, the questions could help identify what aspects are genuine depression and what aspects are more practical problems caused by their medical illness (e.g. someone might feel depressed and helpless because they live alone and can't cope with the cooking and cleaning, in which case home help would be a better prescription than pills). Using the questions that way would make sense but that's different from diagnostic use.

 

[rvallee]

Ugh. Nevermind, awful. Not sure why I expected otherwise.

In hindsight, medicine being more accepting of mental illness may have been the worst thing to happen to mental health. What a mess of things they made.

Although the fact that it was mostly accepted because of how easy it is to abuse the concept and kick people out of medical care may have been a bit of a tell about where things would go. And that it was largely driven by psychiatrists working with insurance companies. And many other giant red flags.

 

[LarsSG]

The very brief PHQ-2 might be best for depression in ME (or Long Covid, etc) and is already well known:

Over the last 2 weeks, how often have you been bothered by the following problems?
1.Little interest or pleasure in doing things
2.Feeling down, depressed or hopeless

Though even question 1 could arguably measure ME symptoms rather than depression, depending how people read it. Much better than the PHQ-9 in any case.

 

[SNT Gatchaman]

Published —

The kynurenine pathway relates to post-acute COVID-19 objective cognitive impairment and PASC (2023, Annals of Clinical and Translational Neurology)