Assessing Cognitive Deterioration After COVID-19 Infection (The ACDC Study): An Exploratory Multimodal Neuroimaging...

Background: Cognitive difficulties are common after SARS-CoV-2 infection, yet their neurobiological underpinnings remain uncertain. Cognitive symptoms in post-COVID-19 condition (PCC) are often characterised by attentional and executive dysfunction, although the relationship between subjective symptoms and objective neurobiological changes remains uncertain. Methods: Adults previously hospitalised with COVID-19 who reported persistent cognitive symptoms underwent neuropsychological testing and 3 T MRI. The protocol included high-resolution volumetric imaging, diffusion-based tractography, and magnetic resonance spectroscopy (MRS) of frontal white matter. Data were compared with age- and sex-matched controls from a pre-COVID-19 cohort and against pooled normative MRS datasets. Analyses adjusted for intracranial volume, sex, and time since infection, with false-discovery-rate correction. This study was exploratory and hypothesis-generating in design. Results: Thirty participants were recruited; twenty-nine completed MRI acquisition. Participants (mean age 58 years; 62% female; approximately two years post-infection) demonstrated selective impairments in attention, working memory, and verbal fluency. No widespread volumetric or white-matter differences were identified, although reduced posterior hypothalamic volume and altered occipito-parietal connectivity were observed. MRS demonstrated reduced N-acetylaspartate and elevated choline, myo-inositol, and glutamate-glutamine ratios relative to normative reference ranges. No significant associations were observed between imaging measures and cognitive or symptoms outcomes after correction. Conclusions: PCC is characterised by circumscribed cognitive changes and subtle neural differences, but these objective changes do not closely align with subjective symptom severity. This mismatch shares phenotypic features with functional cognitive disorder and suggests that post-COVID-19 "brain fog" is not driven by structural or neurochemical changes alone. Instead, it potentially reflects a combination of mild neurobiological effects and functional cognitive processes. Together, these findings highlight the importance of considering both brain-based and functional contributors to persistent cognitive complaints after SARS-CoV-2 infection.