Preprint Multimodal imaging suggests potential immune-vascular contributions to altered regional brain perfusion and oxygen metabolism in [LC], 2026, Martins+

[SNT Gatchaman]

Multimodal imaging suggests potential immune-vascular contributions to altered regional brain perfusion and oxygen metabolism in Post-COVID-19 Syndrome

Spoiler: Authors

Daniel Martins; Matthew Burrows; Owen Daily; Ziyuan Cai; Nicole Mariani; Alessandra Borsini; Valeria Mondelli; Brandi Eiff; Silvia Rota; Tim Nicholson; Laila Rida; Adam Hampshire; Federico E Turkheimer; Catherine Morgan; David Lythgoe; Steve Cr Williams; Fernando Zelaya

Post-COVID-19 Syndrome (PCS) frequently presents with persistent fatigue, cognitive impairment, and emotional symptoms. Although structural brain changes remain subtle, growing evidence implicates functional and metabolic disruptions in ongoing symptomatology. We used multimodal MRI to investigate cerebral perfusion and oxygen metabolism in PCS and examined their associations with cognitive function and peripheral biomarkers.

We enrolled 40 individuals with prior mild SARS-CoV-2 infection, including 20 with persistent fatigue and 20 recovered controls matched for age, sex, BMI, and acute COVID-19 severity. Participants underwent structural MRI, arterial spin labelling (ASL) to quantify regional cerebral blood flow (CBF), and asymmetric spin echo imaging to estimate oxygen extraction fraction (OEF) and cerebral metabolic rate of oxygen consumption (CMRO₂). We assessed cognition using an online battery and measured serum levels of TNF-α, IL-6, IL-8, IL-13, IFN-γ, GFAP, and S100β, alongside blood routine tests. We performed ANCOVAs on predefined regions of interest (hippocampus, anterior cingulate cortex [ACC], insula, amygdala, striatum), followed by Bayesian inference and exploratory whole-brain analyses.

PCS participants showed increased CMRO₂ in the hippocampus and decreased CMRO₂ in the ACC. Subfield analysis revealed elevated OEF and CMRO₂ across most hippocampal regions, excluding the entorhinal cortex. Whole-brain analyses identified increased perfusion in salience-related regions (insula, ACC, thalamus) and decreased perfusion in posterior cortical and cerebellar areas, in the absence of grey matter volume differences. Higher hippocampal metabolism positively correlated with cognitive performance, suggesting compensatory adaptation to sustain function. In contrast, lower ACC CMRO₂ correlated with depressive symptoms, reduced motivation, and elevated TNF-α and GFAP, consistent with neurovascular uncoupling possibly driven by immune-glial activation.

These findings reveal distinct physiological disruptions in PCS, with potential implications for stratified, metabolism-focused interventions.

Web | DOI | PDF | bioRxiv | Open Access

 

[SNT Gatchaman]

The groups were matched for age, sex, ethnicity, and body mass index (BMI), with no significant differences observed across these variables. However, groups differed significantly in years of education, with HC participants reporting higher educational attainment. PCS participants also had a significantly longer duration since first SARS-CoV-2 infection, and were significantly less likely to have been vaccinated prior to infection.

Group comparisons of routine blood parameters revealed no major differences between PCS and HC participants. However, PCS participants showed numerically higher creatinine and Gamma-GT levels […] Platelet count also trended higher in the PCS group

No statistically significant differences were observed in circulating levels of IFN-γ , IL-1 β, IL-6, IL-8, IL-10, IL-13, TNF-α or GFAP

For rCBF and OEF, we could not find any significant differences between the two groups for any of our chosen bilateral ROIs (amygdala, striatum, ACC, anterior and posterior insula, or hippocampus). However, for CMRO2 , we found significant decreases and increases in PCS compared to recovered controls for the ACC and hippocampus ROIs, respectively.

Within the hippocampus, we also inspected four sub-regions […] For rCBF, we could not find group differences for any of the hippocampal subregions ROIs. For OEF and CMRO2, we found significant increases in PCS compared to recovered controls for all hippocampal subregions, with the exception of the entorhinal cortex

 

[SNT Gatchaman]

No significant group effects on GMV were observed between patients and controls when accounting for age, gender, dexterity, and TIV [total intracranial volume]. This suggests that the observed neurovascular and metabolic alterations in PCS are not attributable to structural atrophy.

For rCBF [resting cerebral blood flow], we found four significant clusters where PCS showed higher rCBF than controls. These clusters were located primarily in the middle and anterior cingulate cortex (cluster 1), right insula, superior temporal and precentral gyri (cluster 2), left insula, thalamus and caudate (cluster 3), and right middle and inferior frontal gyri, right insula and putamen (cluster 4). We also found two clusters where PCS showed lower rCBF than controls. These clusters spanned the left posterior cingulate, occipital gyri, cerebellum (cluster 5) and left parahippocampal gyrus and striatum (cluster 6). For the OEF and CMRO2 , no clusters survived correction for multiple comparison at the whole-brain level.

Cluster 1 (anterior/mid cingulate) showed positive correlations with disease duration, blood urea, free T4 levels and cognitive performance during the Spotter task, while Cluster 2 (right insula and superior temporal cortex) was positively associated with disease duration, autonomic symptoms, phosphatase level and negatively correlated with the counts of basophils and the amount of blood proteins (including albumin). Cluster 3 (left insula, thalamus, caudate) showed positive correlations with MOCA scores, MCV and MCH, and negative correlations with serum IL-10, platelet count and total proteins. Cluster 4 (right frontal operculum and putamen) only showed negative correlations with the severity of PEM. Cluster 5 (posterior cingulate, occipital, cerebellum), where PCS patients showed hypoperfusion, was negatively associated with anxiety symptoms and cognitive performance during the blocks task. Finally, Cluster 6 (hippocampal-striatal) showed a positive correlation with cognitive performance during the blocks task and a negative correlation with autonomic symptoms. No other associations met the significance threshold of punc ≤ 0.05.

 

[SNT Gatchaman]

region-specific analyses revealed focal alterations in brain energetics and perfusion, particularly within circuits implicated in memory, motivation, and interoception. In a normal homeostatic regime, rCBF and OEF would compensate each other to maintain CMRO2 , but our data shows that in some regions this is not the case. Several regions demonstrated dissociations between perfusion and metabolic demand consistent with neurovascular uncoupling - and perfusion patterns correlated with symptom severity, immune markers, and blood rheological parameters. Together, these findings suggest that immune–vascular interactions may contribute to regional brain dysfunction in PCS

Within the hippocampus, PCS participants exhibited significantly elevated CMRO2 and OEF across multiple subregions[…] in the absence of CBF changes. This pattern suggests that increased oxygen demand was met through enhanced extraction rather than increased supply, potentially reflecting compensatory upregulation of cellular metabolism or altered neuroglial coupling.

In contrast, the ACC exhibited reduced CMRO2 in PCS despite increased perfusion a hallmark of disrupted neurovascular coupling. Under normal conditions, CBF is tightly linked to metabolic demand; thus, this mismatch may reflect impaired autoregulation, possibly driven by inflammatory signalling or autonomic dysregulation, which are prevalent in PCS. This interpretation is supported by negative correlations between ACC metabolism and inflammatory markers (TNF- α, ESR), glial activation (GFAP), and motivational and cognitive performance.

These findings identify the ACC as a metabolically vulnerable hub in PCS.

This is the second paper this week to identify the anterior cingulate cortex as metabolically vulnerable in LC.

Reduced ATP-to-phosphocreatine ratios in neuropsychiatric post-COVID condition: Evidence from 31P magnetic resonance spectroscopy (2026) —

In conclusion, our study provides the first in vivo evidence of impaired high-energy phosphate metabolism in the brains of patients with PCCo. These metabolic alterations, particularly in the anterior cingulate cortex, correlate with cognitive impairment and likely reflect limitation of CK-mediated energy buffering or intracellular energy transfer potentially together with mitochondrial dysfunction. Our findings contribute to a growing body of evidence suggesting that cellular bioenergetic failure may be a key pathophysiological mechanism in PCCo, potentially explaining many of the persistent symptoms experienced by patients.

 

[ScoutB]

Basic question as I'm so foggy right now -- do these *arterial spin labelling* and *asymmetric spin echo imaging* techniques mean this paper avoids the pitfalls of using fMRI to monitor blood and oxygen changes in the brain? E.g. are these results more likely to actually be representative of what's going on?