Structural brain changes in post-COVID condition and its relationship with cognitive impairment
Authors: Pacheco-Jaime Laura , Garcia-Vicente Carla , Ariza Mar , Cano Neus , Garolera Maite , Carreras-Vidal Lourdes , Roura Ignacio , Capdevila-Lacasa Clara , Oltra Javier , Pardo Jèssica , Martín-Barceló Cristina , Campabadal Anna , Sala-Llonch Roser , Bargalló Núria , Barrué Cristian , Bejar Javier , Cortés Claudio U , Junqué Carme , Segura Bàrbara ,   NAUTILUS-Project Collaborative Group, Arauzo Vanesa , Bernia Jose A , Balague-Marmaña Marta , Valles-Pauls Berta , Caballero Jesús , Gonzalez-Aguado Ester , Tayó-Juli Carme , Forcadell-Ferreres Eva , Reverte-Vilarroya Silvia , Forné Susanna , Bartes-Plans Anna , Muñoz-Padros Jordina , Muñoz-Moreno Jose A , Prats-Paris Anna , Rico Inmaculada , Sabé Nuria , Almeria Marta , Casas Laura , Ciudad Maria José , Ferré Anna , Garzon Tamar , Lozano Manuela , Cullell Marta , Vega Sonia , Alsina Sílvia , Maldonado-Belmonte Maria J , Vazquez-Rivera Susana , Baillès Eva , Navarro Sandra , Hernández Ayoze González , Molina Yaiza , Olive Victoria , Cañizares Silvia 
Published: February 2025

Abstract
It has been estimated that ∼4% of individuals infected with SARS-CoV-2 will be diagnosed with post-COVID condition. Previous studies have evidenced the presence of cognitive dysfunction and structural brain changes in infected individuals; however, the relationship between structural changes and cognitive alterations in post-COVID condition is still not clear. Consequently, the aim of this work is to study structural brain alterations in post-COVID condition patients after almost 2 years of infection and their likely relationship with patients’ cognitive impairment. Additionally, the association with blood biomarkers and clinical variables was also explored. One hundred and twenty-eight individuals with post-COVID condition and 37 non-infected healthy controls from the Nautilus Project (ClinicalTrials.gov IDs: NCT05307549 and NCT05307575) underwent structural brain magnetic resonance imaging and a comprehensive neuropsychological assessment. A subsample of 66 post-COVID participants also underwent blood extraction to obtain levels of blood biomarkers. Cortical thickness and subcortical volumes were obtained and analysed using FreeSurfer (v7.1). FMRIB Software Library software (v6.0.4) was used to perform grey matter voxel-based analysis and to study microstructural white matter integrity. Patients with post-COVID performed significantly worse in working and verbal memory, processing speed, verbal fluency and executive functions, compared to healthy controls. Moreover, patients with post-COVID showed increased cortical thickness in the right superior frontal and the right rostral middle frontal gyri that negatively correlated with working memory performance. Diffusion tensor imaging data showed lower fractional anisotropy in patients in the right superior longitudinal fasciculus, the splenium and genu of the corpus callosum, the right uncinate fasciculus and the forceps major, that negatively correlated with subjective memory failures. No differences in blood biomarkers were found. Once patients were classified according to their cognitive status, post-COVID clinically cognitively altered presented increased cortical thickness compared to those classified as non-cognitively altered. In conclusion, our study showed that grey and white matter brain changes are relevant in this condition after almost 2 years of infection and partly explain long-term cognitive sequelae. These findings underscore the critical importance of monitoring this at-risk population over time.