Cerebrovascular recovery drives restoration of neurometabolite levels after mild COVID-19, 2026, Coe et al.

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Cerebrovascular recovery drives restoration of neurometabolite levels after mild COVID-19

Spoiler: Authors

Devin B Coe; Francesca Branzoli; Nicholas Shaff; Sephira G Ryman; Davin K Quinn; Henry C Lin; Erik B Erhardt; Arvind Caprihan; Dhruba P Adhikari; Dinesh K Deelchand; Alisha N Parada; Aleksandr Birg; Harm J van der Horn; Haley E J Prather; Natalie Hoffman; Lizza H O’Connell; Andrei A Vakhtin

SARS-CoV-2 infection can trigger broad acute-stage endothelial dysfunction that is often followed by neurocognitive post-acute sequelae (PASC) chronically. It is thus of interest to evaluate long-term post-infection cerebrovascular function dynamics and their effects of neuronal health.

Using functional magnetic resonance imaging (fMRI), we examined cerebrovascular reactivity (CVR) magnitude and delay across a broad post-infection timeline (3–59 months) in 69 participants who previously had mild cases of COVID-19. We also assessed the relationships between CVR and neurometabolite markers of neuronal health using magnetic resonance spectroscopy (MRS) in the thalamic region and the corona radiata.

Increasing time since infection (TSI) was associated with shorter CVR delay in global gray (GM) and white matter (WM), with no effects of TSI on CVR magnitude. Parcellation of the GM revealed TSI-dependent decreases in CVR delays in nine of the 10 examined GM regions. CVR delay was inversely related to total choline (tCho), creatine (tCr), and N-acetylaspartate (tNAA) levels in the thalamic region, but not in the corona radiata.

The results suggest slower cerebrovascular reactivity follows mild COVID-19 and eventually resolves spontaneously, albeit on a protracted timeline. Further, improved levels of tCho, tCr, and tNAA in the GM are associated with this functional cerebrovascular recovery.

Web | DOI | PDF | Journal of Cerebral Blood Flow & Metabolism | Paywall

 

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We used functional magnetic resonance imaging (fMRI) of CVR [Cerebrovascular Reactivity] to measure the ability of brain blood vessels to respond to hypercapnia, which was induced by respiring of a gas mixture of CO2 —a rapid and potent vasodilator.

With hypercapnia induced in an intermittent manner over several blocks of alternating administration of CO2 gas mixture and normal room air, the paradigm allows for the measurements of two main response variables: CVR magnitude and delay. Specifically, CVR magnitude refers to the increase of the blood oxygenation level dependent (BOLD) signal in response to a rise in arterial partial pressure of CO2, and CVR delay is the temporal lag of this response relative to the onset of CO2 administration.

Collectively, these two metrics evaluate the ability of brain vasculature to respond to exogenous vasoactive stimuli, which is highly reflective of general cerebrovascular endothelial health.

Our overarching hypothesis is that SARS-CoV-2 inflicts endothelial damage that subsequently results in lasting cerebrovascular dysfunction. Testing this necessitates accurate identification and recruitment of healthy control participants who have never had COVID-19—an increasingly challenging task given that the majority of the population has been infected with SARS-CoV-2 at some point. As such, in this analysis we examined the post-infection trajectories of CVR dynamics in a cohort consisting entirely of participants who previously had mild COVID-19, with time since infection (TSI) being the main predictor of interest.

Our specific predictions were that CVR magnitude and delay would be diminished and long, respectively, in the early post-infection timeframe, and that long-term normalization would be observed as increases in CVR magnitude and decreases in its delay.

 

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Specifically, we quantified the effects of CVR magnitude and delay on total concentrations of choline-containing compounds (tCho), creatine (tCr), and N-acetylaspartate (tNAA) in the brain. These neurometabolites are highly abundant in brain tissue and serve as reliable markers of neuronal health.

Choline-containing compounds maintain cellular lipid membranes, support synthesis of neurotransmitter acetylcholine, and are glial markers. While choline is recycled via membrane turnover, its de novo brain supply is entirely dependent on transport from blood, highlighting the importance of healthy cerebrovascular function for cholinergic homeostasis.

Creatine and phosphocreatine play important roles in supporting neuronal metabolism by buffering adenosine triphosphate (ATP), and while ATP is synthesized locally via astrocyte–neuron coupling, around 50% is transported into the brain from the circulation, thus being partially dependent on healthy brain vascular function.

Neuronal mitochondria synthesize NAA, which is involved in myelination and lipid synthesis and serves as a reliable indicator of overall brain tissue health. While all NAA is produced locally, its levels are indirectly influenced by cerebrovascular malnourishment, resulting in mitochondrial dysfunction and myelin lipid synthesis.

Collectively, tCho, tCr, and tNAA levels serve as excellent markers of neuronal health, and are expected to be affected by any potential dysregulation of cerebrovascular function. We hypothesized that levels of major metabolite concentrations would be associated with any post-infection temporal changes in CVR metrics, as these cerebrovascular dynamics are highly reflective of oxygen delivery that supports ATP synthesis and mitochondrial function in brain tissue.

 

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Our results demonstrated a significant decrease in CVR delay as a factor of time since SARS-CoV-2 infection, suggesting that brain vasculature may be functionally impaired in the early post-infection phase, recovering spontaneously over the following months and years. Importantly, this was observed in individuals who had mild COVID-19

It remains of interest whether cerebrovascular dysfunction is driving long COVID symptomology alone, or if it emerges due to a combination of cerebrovascular deficits with SARS-CoV-2-induced damage in other organs.

CVR analyses are often framed in the context of vascular dysfunction having effects on neuronal health, yet few studies have evaluated this link directly. We showed that GM CVR delay was associated with tCho, tCr, and tNAA levels in the thalamic region, which served as a proxy for global GM. Unlike CVR delay itself, the concentrations of these metabolites did not exhibit spontaneous normalization as a function of post-infection time, but rather appeared to depend on vascular recovery.

While all examined metabolites are markers of neuronal health, they differ in the mechanisms through which they rely on cerebrovascular function. In the context of COVID-19, the relationship between longer CVR delay and lower NAA may reflect diminished mitochondrial function. Constrained ATP synthesis is coupled with oxygen dependent dysregulation of its buffering by Creatine, undermining its distribution to meet neuronal energy demands. Vascular choline undersupply jeopardizes healthy cell membrane turnover, which is exacerbated by the aforementioned under-production of ATP and distribution.

the main objective of the described analysis is to characterize chronic physiological CVR trajectories in a sufficiently powered sample without granular parcellation of post-infection symptomology. Given the downward trend in CVR delay across time and its associated improvements in neurometabolite levels, the intuitive hypothesis would be that long COVID patients experience longer CVR delays to exogenous vascular stimuli than healthy individuals.

However, we do not dismiss the possibility of the opposite scenario in long COVD patients, whereas it is possible for them to exhibit shorter CVR delays reflective of hyper-reactive vasculature. Patients with PASC commonly report symptoms consistent with postural tachycardia syndrome (POTS)—a condition with subtypes that can involve reduced peripheral vascular resistance, excessive vasodilation, and reduced stress response. While several studies have reported CBF autoregulation impairments in POTS based solely on metrics that are similar to CVR magnitude, the timing of vascular responses has not been explicitly evaluated.

the highly significant downward trends in CVR delay in both GM and WM across time offers compelling evidence that this may be the case, and that brain vascular function exhibits spontaneous recovery over a protracted timeline. The observed trends were also quite consistent, with no significant heteroskedasticity observed in the TSI [Time Since Infection] × CVR delay relationship in either the GM or the WM

Our group is actively working on the disentanglement of complex multi-faceted symptomology profile of PASC in the context of the described cerebrovascular patterns, yet these associations remain beyond the scope of this report.

Concluding —

We demonstrated in individuals with histories of mild COVID-19 that the ability of brain vasculature to respond to exogenous vasoactive stimuli is delayed in the early relative to late post-infection timeframes. Diminishing CVR delay over time suggests spontaneous cerebrovascular recovery and that endothelial damage inflicted by SARS-CoV-2 may be reversible. While it remains unknown if this is the case in PASC, our findings potentially implicate endothelial dysfunction in this condition. Importantly, we demonstrated that recovery of brain vasculature corresponds to the restoration of neuronal health, bolstering the feasibility of using vascular interventions to alleviate neurocognitive symptoms in PASC patients.