Structural and functional brain markers of cognitive impairment in healthcare workers following mild [COVID], 2024, González-Rosa+

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Structural and functional brain markers of cognitive impairment in healthcare workers following mild SARS-CoV-2 infection during the original stream
González-Rosa, Javier J; Gómez-Molinero, María P; Lozano-Soto, Elena; Fernández-Rosa, Silvia P; Campos-Silvo, Marina; García-Rodríguez, María Paula; Cano-Cano, Fátima; Sanmartino, Florencia; Rashid-López, Raúl; Macías-García, Paloma; Gómez-Ramírez, Jaime D; Espinosa-Rosso, Raúl; Paz-Espósito, José; Gómez-Molinero, Rocío; Forero, Lucía; Cruz-Gómez, Álvaro J

Severe acute respiratory syndrome coronavirus 2 infection often involves the nervous system, leading to cognitive dysfunctions, fatigue and many other neurological signs that are becoming increasingly recognized. Despite mild forms of the disease accounting for most cases worldwide, research on the pathophysiology driving mild coronavirus disease 2019 (COVID-19) has received little attention. In this respect, recent evidence has pointed out that around 30–40% of non-critical, mild-to-moderate severity COVID-19 survivors may display cognitive disturbances several months post-illness. Hence, the impact of COVID-19 on the brain structure and function, through potential neuropathological mechanisms underpinning cognitive alterations in post-mild COVID-19 infections, remains largely unexplored.

This retrospective multicentre observational cohort study, entirely based on a healthcare worker sample (n = 65; 55% females, aged 21–61), investigated the cognitive status and the structural and functional brain integrity among non-hospitalized individuals who developed mild COVID-19 symptoms during the occurrence of severe acute respiratory syndrome coronavirus 2 variants Alpha to Delta, compared with healthy controls tested before the pandemic onset. All evaluations were performed at an average of 9-month follow-up post-infection period.

Participants completed a comprehensive neuropsychological assessment and structural and functional MRI exams. Radiological inspection sought to detect the presence of white matter hyperintensities on axial fluid-attenuated inversion recovery images. Global and regional grey matter integrity assessment, analysing changes in grey matter volumes and cortical thinning, and functional connectivity alterations of resting-state brain networks were also conducted. Regression analyses tested the relationships between the presence of specific cognitive impairments and potential structural and functional brain findings.

Our results revealed that clinical, cognitive screening and neuropsychological examinations were average between both groups, except for specific impairments related to executive functions in the mild COVID-19. Compared to healthy controls, mild COVID-19 subjects exhibited increased juxtacortical white matter hyperintensities, thalamic and occipital volume loss and diminished resting-state functional connectivity involving the left precuneus and cuneus in default-mode network and affecting the right angular gyrus and left precuneus in the dorsal attentional network. Reduced thalamic volume was the only variable selected in the final model explaining the observed executive function impairment in mild COVID-19. The presence of cognitive, structural and functional brain abnormalities over time suggests that the action of widespread neurovascular and inflammatory phenomena on the nervous system might also occur in mild forms following COVID-19 infection rather than permanent brain damage linked to the direct or indirect action of the virus.

Our findings emphasize the need to pay attention to the long-term brain-related consequences of mild COVID-19 infections during the original stream.

Link | PDF (Brain Communications) [Open Access]
 
The exclusion criteria were (i) required hospitalization or admission to intensive care units due to COVID-19 complications; (ii) previous manifestation of moderate-to-severe COVID-19 symptoms, such as shortness of breath, dyspnoea or abnormal chest imaging, moderate or severe fatigue, neurological sequelae or confirmed PCS; (iii) presence of neurological, psychiatric or severe medical conditions; and (iv) contraindications for MRI assessment.

No significant differences between groups were found regarding fatigue severity levels and psychiatric scores, while COVID-19 showed a statistical trend towards higher levels of state anxiety and depression.
 
Cognitive impairment was interpreted as a failure on two or more neuropsychological tests, while test failure was determined as scoring lower than 1.5 standard deviation from the average of the HC group. Following this criteria, nine COVID-19 subjects (36%) were classified as cognitively impaired.

Remarkably, our results also revealed a statistically significant increase (P = 0.020) of juxtacortical WMHs [white matter hyperintensities] in mild COVID-19 (37.50%) compared to HC (5.71%).

ROI-based analysis showed a significant GM volume reduction in mild COVID-19 affecting bilateral thalamic ventral lateral (TVL) nuclei and in the right middle occipital gyrus (MOG) (P < 0.05, Holm–Bonferroni corrected).

only atrophy of the right TVL nucleus remained significant in the final model, explaining the reduced cognitive performance of the mild COVID-19 in the PASAT-3 (R 2 = 0.225, P = 0.019).
 
Discussion —

The findings of this study underlined that non-hospitalized healthcare workers who had mild COVID-19 during the first surges […], with no specific neurological manifestations, and compared to an HC group assessed before the onset of the pandemic, exhibited both subclinical cognitive impairments and altered structural and functional brain integrity at 9-month follow-up.

Importantly, although some studies suggest a positive association between cognitive impairment and disease severity, […] recent evidence suggests that these deficits could also be noted in outpatient individuals, moderate COVID-19 cases or asymptomatic patients. Furthermore, this sustained subclinical cognitive impairment in healthcare workers with COVID-19 could develop subtly, regardless of the sub-acute or post-acute phase of evaluation

Interestedly, despite the healthcare workers with COVID-19 of our study not indicating subjective cognitive complaints, most of them displayed reduced neuropsychological performance, which is in line with recent reports demonstrating the presence of unnoticed cognitive deficits even in individuals who apparently ‘fully’ recovered from a mild form of COVID-19 without expressing subjective complaints. These results point out that the sole administration of self-reported cognitive assessments and cognitive screening tests could underestimate the presence of cognitive dysfunction

Remarkably, our study also revealed no signs of brain atrophy or GM volume abnormalities at the global level, nor any alterations associated with global or regional thinning in cortical regions in mild COVID-19. Nevertheless, the regional volumetric analysis revealed reduced bilateral thalamic volumes (concretely within the TVL in mild COVID-19 cases, comparable to the middle occipital gyrus). To our understanding, no studies have reported occipital GM loss in patients with mild COVID-19.

We speculate that the pathophysiological mechanisms behind structural changes in the middle occipital gyrus observed in mild COVID-19 might be the result of the widespread brain abnormalities and disruption of functional intrinsic brain activity and disease-related adaptations in sensory cortices, which could be linked to the functional connectivity alterations in visual processing-related areas also observed in mild COVID-19. In fact, our results showed that disrupted [resting-state] network connection patterns can impact DMN and DAN and involve occipital network-related regions.

Generally, thalamic volume loss is hypothesized to result from axonal degeneration secondary to white matter injury. Thalamic degeneration is usually prominent due to its extensive connections between subcortical areas and the neocortex through a large number of WM tracts, which include both the motor and visual cortex.

Our findings showed that the presence of multifocal juxtacortical WM abnormalities, hyperintense on axial FLAIR images, was higher in mild COVID-19, compared to HC, assessed an average of 9 months after COVID-19

could be caused by indirect viral pathogenesis through an immune mediated mechanism and (or) by a detrimental neuroinflammatory response, which may result in small ischaemic processes, hypoxia injury and inflammation where abundant WM fibre tracts and highly myelinated fibre bundles exist. Moreover, juxtacortical WM, which is mainly made up of U-fibres rather than long WM tracts, is generally supplied by short vessels at the boundary of the WM and cortex, which would be easily influenced by brain microvascular damage and brain inflammation, and that represent some of the main COVID-19-related pathological consequences.
 
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