Review Metabolic brain changes in post-acute COVID-19: systematic review and meta-analysis of [18F]-FDG-PET findings, 2025, Siqueira et al

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Metabolic brain changes in post-acute COVID-19: systematic review and meta-analysis of [18F]-FDG-PET findings

Izabella Fernanda Bastos Siqueira, Lais Almeida Figueiredo, Camila Emanuele Moreira Fernandes, Leandro Pinheiro Cintra, Glauber Fernandes de Oliveira, Maria Angélica Rios, Ricardo Maciel, Rodrigo Ferretjans, Nathalia Sernizon Guimarães & Luiz Alexandre Viana Magno

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Abstract
Individuals with long COVID exhibit neurological and psychiatric symptoms that often persist well beyond the initial SARS-CoV-2 infection. Studies using [18F]-FDG positron emission tomography (FDG-PET) have revealed diverse abnormalities in brain glucose metabolism during the post-acute phase of COVID-19.

We conducted a systematic review and meta-analysis to assess the spatial distribution and heterogeneity of brain metabolic changes in patients in the post-acute phase of COVID-19 relative to controls. We searched the MEDLINE, EMBASE, and CENTRAL databases in June 2025 for studies reporting FDG-PET data in patients with post-acute COVID-19 who have persistent neurological symptoms.

Of the 14 eligible studies (584 scans), 13 reported glucose hypometabolism across frontoparietal regions, with the frontal cortex being the most consistently affected. This finding was confirmed by meta-analysis, which revealed a large and significant effect in the frontal cortex (Hedges’ g = 1.34; 95% CI: 0.79–1.88; p < 0.001), despite high heterogeneity (I<em>2</em> = 93.6%).

The systematic review indicates that brain metabolism generally improves over time, with widely varying recovery timelines, and consistently correlates hypometabolism with neurological symptom burden.

These findings underscore the clinical relevance of frontoparietal hypometabolism in post-acute COVID-19 and its association with neurocognitive deficits, highlighting the need for longitudinal, quantitative PET studies to elucidate temporal dynamics and inform therapeutic development.

Web | Brain Structure and Function | Paywall
 
In limitations —

First, most studies focus on patients with persistent neurological symptoms and minimal neurological improvement, unlike the broader long COVID population, many of whom have experienced substantial recovery over time. This focus on more severe or refractory cases may bias the findings toward overestimating the prevalence and severity of metabolic abnormalities associated with long COVID.

Second, there was significant variability in the reported areas of cerebral hypometabolism, necessitating the consolidation of brain regions to ensure a systematic analysis. While this enabled us to perform the meta-analysis, aggregating multiple brain clusters into broader anatomical regions may obscure localized effects and introduce overgeneralization. To improve spatial precision and facilitate future meta-analyses, studies comparing cases and controls should report detailed t-scores with corresponding MNI coordinates, allowing for more granular and reproducible localization of metabolic abnormalities.

Third, most controls consisted of brain scans stored in databases, with slight imbalances in sex and age. While the control groups were not perfectly matched for these variables, age was included as a covariate in the analyses to mitigate potential confounding effects. Finally, some controls were patients with other non-neurological diseases.
 
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