Cognitive impairment in long COVID and short duration ME patients is mediated by orthostatic hemodynamic changes, 2023, Vernon et al

[John Mac]

Full title:
Cognitive impairment in post-acute sequelae of COVID-19 and short duration myalgic encephalomyelitis patients is mediated by orthostatic hemodynamic changes

Introduction:
Cognitive impairment is experienced by people with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and post-acute sequelae of COVID-19 (PASC). Patients report difficulty remembering, concentrating, and making decisions. Our objective was to determine whether orthostatic hemodynamic changes were causally linked to cognitive impairment in these diseases.

Methods:
This prospective, observational cohort study enrolled PASC, ME/CFS, and healthy controls. All participants underwent clinical evaluation and assessment that included brief cognitive testing before and after an orthostatic challenge. Cognitive testing measured cognitive efficiency which is defined as the speed and accuracy of subject’s total correct responses per minute. General linear mixed models were used to analyze hemodynamics and cognitive efficiency during the orthostatic challenge. Additionally, mediation analysis was used to determine if hemodynamic instability induced during the orthostatic challenge mediated the relationship between disease status and cognitive impairment.

Results:
Of the 276 participants enrolled, 256 were included in this study (34 PASC, 71 < 4 year duration ME/CFS, 69 > 10 year ME/CFS duration, and 82 healthy controls).
Compared to healthy controls, the disease cohorts had significantly lower cognitive efficiency scores immediately following the orthostatic challenge.
Cognitive efficiency remained low for the >10 year ME/CFS 2 and 7 days after orthostatic challenge.
Narrow pulse pressure less than 25% of systolic pressure occurred at 4 and 5 min into the orthostatic challenge for the PASC and ME/CFS cohorts, respectively.
Abnormally narrow pulse pressure was associated with slowed information processing in PASC patients compared to healthy controls (−1.5, p = 0.04).
Furthermore, increased heart rate during the orthostatic challenge was associated with a decreased procedural reaction time in PASC and < 4 year ME/CFS patients who were 40 to 65 years of age.

Discussion:
For PASC patients, both their disease state and hemodynamic changes during orthostatic challenge were associated with slower reaction time and decreased response accuracy during cognitive testing. Reduced cognitive efficiency in <4 year ME/CFS patients was associated with higher heart rate in response to orthostatic stress. Hemodynamic changes did not correlate with cognitive impairment for >10 year ME/CFS patients, but cognitive impairment remained. These findings underscore the need for early diagnosis to mitigate direct hemodynamic and other physiological effects on symptoms of cognitive impairment.

https://www.frontiersin.org/articles/10.3389/fnins.2023.1203514/full

 

[Hutan]

It's looking like the study has been well done. There is good attention to diagnosis for selection, and to appropriate controls.
Heather Day1, Brayden Yellman2, Sarah Hammer2, Candace Rond2, Jennifer Bell2, Saeed Abbaszadeh2, Greg Stoddard1, Derya Unutmaz3, Lucinda Bateman2 and Suzanne D. Vernon2*
1 is the University of Utah School of Medicine; 2 is the Bateman Horne Center and 3 is the Jackson Lab.

10 minute lean test
I'm surprised that they didn't give the percentages of dropouts (due to dizziness or fainting) during the lean test in Table 2. The percentages were PASC 9%
ME/CFS <4 years 10%
ME/CFS >10 years 13%
Healthy controls 9%
I was surprised to see the healthy controls so affected (3 out of the 7 who dropped out are reported as actually fainting). So, if there is a disease effect, it seems to be less about what happens during the orthostatic challenge, and more about how quickly the body recovers.

I'm not completely sure what comparisons were done in the tests of significance - change from baseline for each disease group compared to that for the controls? And I'm not sure what the error bars are.
Systolic blood pressure was not significantly different. Diastolic blood pressure at the 10 minute mark in the lean test was lower for all three disease cohorts versus controls. Heart rates are higher in the disease cohorts at 10 minutes.



I'm really pleased to see some assessment of pulse pressure, as I have found it a good measure of orthostatic symptoms and an indicator of a bad day. Both the PASC and ME/CFS <4 years had pulse pressures that dropped below 25% of systolic blood pressure - their mean PPs over the 10 minute test both look quite different to the healthy controls. Surprisingly, the pulse pressure pattern of the ME/CFS > 10 years group looked like that of the healthy controls.

 

[Hutan]

Post-orthostatic challenge cognition
All three disease groups performed significantly worse than controls at baseline, and got even worse after the lean test. Here's an example chart, but there were three types of cognition test. See how the controls (in grey) actually improved from the baseline, presumably as a result of a learning effect.

 

[SNT Gatchaman]

I was surprised to see the healthy controls so affected (3 out of the 7 are reported as actually fainting).

HCs were average age 40.0 (±13.3) and 63% female. There might be some effect from study participation of course, but a 10 minute resting supine HR average of 81 at baseline doesn't sound especially fit.

Surprisingly, the pulse pressure pattern of the ME/CFS > 10 years group looked like that of the healthy controls.

That's interesting. I wonder if this represents some sort of balancing out with a change in priority of opposing effects with disease progression or maybe longer term compensations. I'm sure this will be complicated and multi-factorial. Excluding the things like cardiac valve disease and raised intracranial pressure, simplistically, factors like low blood volume and systolic impairment would lead to lower pulse pressure. Endothelial dysfunction ("arterial stiffness") leads to higher PP. There is evidence of both in ME.

---
Pulse pressure is a predictor of vascular endothelial function in middle-aged subjects with no apparent heart disease (2010, Vascular Medicine)
Endothelial Function Is Associated With Pulse Pressure, Pulse Wave Velocity, and Augmentation Index in Healthy Humans (2006, Hypertension)

 

[Hutan]

That's interesting. I wonder if this represents some sort of balancing out with a change in priority of opposing effects with disease progression or maybe longer term compensations. I'm sure this will be complicated and multi-factorial.

Yes, I agree. When I last had a detailed look at my blood pressure, which was nearer 10 years post onset than 4 years post onset, I was still getting low pulse pressures sometimes. I doubt that the difference between the two ME/CFS groups is a replicable result, especially if the ages of both groups were similar.

 

[Hutan]

From the Discussion, on pulse pressure:

Abnormally narrowed pulse pressures occur in several diseases including heart failure (decreased pump effectiveness), blood loss, (decreased blood volume), aortic stenosis (reduced stroke volume), and cardiac tamponade (decreased filling time) and are due to decreases in systolic pressures while diastolic pressures remain stable (Homan et al., 2022). In contrast, we found that the narrow PP in PASC and < 4 year ME/CFS cohorts was due to a rise in DBP with relatively stable SBP. The mechanistic basis for the elevated DBP and narrowing pulse pressure during the orthostatic challenge is not clear for PASC but we hypothesize it may be a physiologically adaptive mechanism designed to mitigate the physiological stress of hemodynamic challenge. Research on ME/CFS patients indicates hemodynamic changes during orthostatic or exercise challenge results in reduced ventricular filling caused by the peripheral circulatory changes rather than primary cardiopulmonary perturbation (Lee et al., 2020; Singh et al., 2022).

There have been two reports of abnormally narrowed PP due to increased DBP in PASC and ME/CFS patients (van Campen and Visser, 2022; Vernon et al., 2022)

 

[Hutan]

From the Discussion, on cognitive impairment:

Slowed reaction time is one of the most sensitive measures of impaired cognitive functioning and is one of the cognitive domains with consistent evidence to be impaired in ME/CFS (Institute of Medicine, 2015; Coffman et al., 2018).

it is possible that just being in an upright posture contributes to intermittent brain hypoperfusion and cognitive impairment. This could explain why the three disease cohorts all had low baseline cognitive efficiency scores; even coming to the clinic to participate in the study was an orthostatic stress. It is possible that the day 2 and 7 cognitive efficiency scores returned to baseline levels because testing was done at home.

It is possible that a cognitive impairment could be explained by oxidative stress from repeated ischemia–reperfusion injury that accompanies orthostatic intolerance and occurs from daily living with ME/CFS (Kell and Pretorius, 2022). This underscores the need for early diagnosis of PASC and ME/CFS to mitigate cognitive impairment and improve quality of life.

I'm not sure about the idea that permanent cognitive impairment is a consequence of the disease. I think a lot of us feel that the impairment fluctuates, although normal performance often can't be sustained. It would be good if there was a study that looked at cognitive performance when well rested and lying down, versus after cognitive and physical exertion and standing.

 

[Sean]

but we hypothesize it may be a physiologically adaptive mechanism designed to mitigate the physiological stress of hemodynamic challenge.

The general concept of secondary adaptation and mitigation to underlying primary pathology has serious explanatory power for much of what we see in ME, both physiological and psycho-behavioural.

 

[ME/CFS Skeptic]

Interesting study. They did some simple cognitive tests before and after a 10-minute NASA lean test. The ME/CFS and Long Covid patients did worse before the lean test than controls. They also got worse after the lean test while the healthy controls did better than before. The main results are in figure 3:

The mediation analyses are a bit more difficult to understand. It seems that hemodynamic changes did not correlate with
cognitive impairment for ME/CFS patients that have been ill for more than 10 years even though their cognitive impairment remained. it is also interesting that their pulse pressure (PP) is more like healthy controls than the PP of long Covid patients and ME/CFS patients who have been ill for less than 4 years.

I suspect that it was simply the energy expenditure that caused the drop in cognitive performance and not so much changes in heart or pulse rate?