SARS-CoV-2 is associated with changes in brain structure in UK Biobank

Abstract

There is strong evidence for brain-related pathologies in COVID-19, some of which could be a consequence of viral neurotropism. The vast majority of brain imaging studies so far have focused on qualitative, gross pathology of moderate to severe cases, often carried out on hospitalised patients. It remains unknown however whether the impact of COVID-19 can be detected in milder cases, in a quantitative and automated manner, and whether this can reveal a possible mechanism for the spread of the disease. UK Biobank scanned over 40,000 participants before the start of the COVID-19 pandemic, making it possible to invite back in 2021 hundreds of previously-imaged participants for a second imaging visit. Here, we studied the effects of the disease in the brain using multimodal data from 782 participants from the UK Biobank COVID-19 re-imaging study, with 394 participants having tested positive for SARS- CoV-2 infection between their two scans. We used structural and functional brain scans from before and after infection, to compare longitudinal brain changes between these 394 COVID- 19 patients and 388 controls who were matched for age, sex, ethnicity and interval between scans. We identified significant effects of COVID-19 in the brain with a loss of grey matter in the left parahippocampal gyrus, the left lateral orbitofrontal cortex and the left insula. When looking over the entire cortical surface, these results extended to the anterior cingulate cortex, supramarginal gyrus and temporal pole. We further compared COVID-19 patients who had been hospitalised (n=15) with those who had not (n=379), and while results were not significant, we found comparatively similar findings to the COVID-19 vs control group comparison, with, in addition, a greater loss of grey matter in the cingulate cortex, central nucleus of the amygdala and hippocampal cornu ammonis (all |Z|>3). Our findings thus consistently relate to loss of grey matter in limbic cortical areas directly linked to the primary olfactory and gustatory system. Unlike in post hoc disease studies, the availability of pre- infection imaging data helps avoid the danger of pre-existing risk factors or clinical conditions being mis-interpreted as disease effects. Since a possible entry point of the virus to the central nervous system might be via the olfactory mucosa and the olfactory bulb, these brain imaging results might be the in vivo hallmark of the spread of the disease (or the virus itself) via olfactory and gustatory pathways.

“I can’t cope with multiple inputs”: Qualitative study of the lived experience of ‘brain fog’ after Covid-19

“…More recently concern has been raised that such effects may also extend to adolescents and children -a group generally considered to be at 'low risk' from Covid-19 infection [20]. A range of possible pathophysiologies have been identified, including direct neuroinvasion [21], viral persistence and chronic inflammation [22], neuronal injury or toxicity and glial activation [21], microvascular injury [23], activation of autoimmune mechanisms [24], and Lewy body production [25] amongst others, with imaging studies demonstrating a differential loss of grey matter in Covid patients in a number of key brain regions [26].…”

Reliability of multi-modal MRI-derived brain phenotypes for multi-site assessment of neuropsychiatric complications of SARS-CoV-2 infection

“…For the COVID-CNS project, it provides insights that can guide the design of harmonisation strategies for the project. More broadly, the study is of relevance to the expanding number of studies utilising multi-modal imaging protocols derived from the UK Biobank, including a number of additional studies focused on the neurological impact of COVID-19 (Douaud et al, 2021;Raman et al, 2021) . Overall, our results demonstrate generally good to excellent levels of between-site reliability of imaging derived phenotypes estimated across a wide range of brain MRI modalities in data collected from 4 UK sites participating in a national COVID research consortium.…”

“…T2 FLAIR and swMRI sequences were slightly modified from UKB standards in order to more closely match corresponding sequences in the C-MORE protocol. A multi-post label delay (PLD) 3D-GRASE ASL sequence (Günther et al, 2005) was used identically to that planned to be adopted by UKB COVID study (Douaud et al, 2021) (different to the 2D multi-slice sequence used in C-MORE); a single delay ASL sequence was additionally used to match the ASL imaging pulse sequence of the GE scanner.…”

“…Where protocols matched exactly, analysis pipelines were identical to those used in the C-MORE COVID study Raman et al, 2021) . Summaries of pre-processing and IDP estimation are provided below for individual modalities, with further details available in (Douaud et al, 2021;Griffanti et al, 2021) . For presentation, IDPs reflecting the same phenotypic properties were grouped together into IDP classes (Douaud et al, 2021;Elliott et al, 2018) .…”

Brain Renin–Angiotensin System as Novel and Potential Therapeutic Target for Alzheimer’s Disease

“…There were reports of neurological symptoms, and a recent imaging study from the UK Biobank (pre-peer reviewed) demonstrated volume loss in the left parahippocampal, orbitofrontal and insular regions, even after mild COVID- 19 infection, showing that the central nervous system is also affected by COVID-19. These neurologic effects may involve the RAS [5], especially since ACE2 is expressed in neurons and microglia (Figures 1 and 2). Agtr2-Type-2 angiotensin II receptor.…”