Evidence for a Link of COVID-19-Associated Long-Term Neurologic Symptoms and Altered Brain Integrity?

A substantial number of individuals who have contracted coronavirus disease 2019 (COVID-19) experience prolonged symptoms. In total, it is estimated that between 6% and 10% of patients will develop a “post-Covid condition” (PCC) or “postacute sequelae of Severe Acute Respiratory Syndrome (SARS)-CoV-2” (PASC).^1⇓-3 Among the most prevalent symptoms are fatigue and neurocognitive deficits, which can markedly contribute to the overall disease burden.⁴ At present, there is no definitive pathophysiologic explanation for this condition. However, the brain is a region of interest that may warrant further investigation.⁵ In light of the debilitating nature of this condition and its substantial socioeconomic implications,⁶ the identification of cerebral changes associated with PCC/PASC represents an important contribution to the understanding of this pathology.

Several recent studies have identified an association between PCC and altered cerebral integrity. These findings include gray matter atrophy,^7⇓-9 altered functional connectivity,^8,10 and altered microstructural integrity.^7,8,10,11

In a recent study conducted by the University of Maryland School of Medicine in Baltimore,¹² O’Connor et al identified alterations in both macro- and microstructure of the brain in a total of 31 patients diagnosed with neuro-postacute sequelae of SARS-CoV-2 infection (NeuroPASC). In this study, the researchers conducted an analysis of MRI data from patients with NeuroPASC approximately 1 year after the infection compared with a group of 41 matched healthy controls. The authors reported an increase in white matter volume in the prefrontal and anterior temporal regions of patients with NeuroPASC, along with alterations in cerebral microstructure indicating a reduction in integrity. A voxel-based analysis revealed an increase in gray matter volume in the prefrontal cortex. Neurocognitive testing demonstrated a reduction in attention, concentration, processing speed, and verbal learning abilities in patients with NeuroPASC. A cytokine panel revealed elevated interferon λ1 and λ2/3 levels in the NeuroPASC group.

The most noteworthy finding of the study of O’Connor et al¹² is the substantial alteration in white matter, particularly evident in the frontal regions and encompassing the brainstem. The observation of altered diffusivity in these areas is consistent with patterns reported in previous studies by Díez-Cirarda et al⁸ and Paolini et al.¹⁰ Specifically, O’Connor et al¹² observed a higher mean kurtosis in NeuroPASC, indicating a more complex microstructure or increased tissue heterogeneity. This finding aligns with the previously observed reduction in mean diffusivity.⁸ However, the increase in gray matter volume in the prefrontal cortex observed by O'Connor et al¹² contradicts existing data, which report volume or cortical thickness reduction in the frontal and limbic regions^8,9 or widespread gray matter microstructural alterations.¹¹

In larger cohorts, associations between altered microstructure and clinical symptoms have been established. For instance, reduced microstructural integrity has been linked to cognitive dysfunction,^8,10,11 fatigue,^7,11 and diminished olfactory performance.¹¹ In addition to their imaging findings, O’Connor et al¹² present data from comprehensive neurocognitive assessments and elevated levels of type III interferon subtypes. Type III interferon receptors are expressed on epithelial cells and selected immune cells, mediating their antiviral effects primarily in barrier tissues. Given these characteristics, their potential involvement in the pathogenesis of virus-mediated autoimmune disorders is gaining increasing attention.¹³ In the present study, no association between clinical and serologic data was reported, but this may be the subject of future work.

Beyond PCC/NeuroPACS, the effects of COVID-19 infection per se on the brain are not yet fully understood. There is evidence of altered cerebral integrity in otherwise healthy individuals following COVID-19.^11,14 Further research is needed to distinguish the specific patterns of brain changes associated with COVID-19 itself from those associated with PCC or NeuroPACS.

In conclusion, the findings of O’Connor et al¹² complement existing literature and indicate that patients with PCC/NeuroPASC exhibit macro and microstructural alterations in the brain. Further research is required to demonstrate the temporal kinetics of these changes in a longitudinal study and to integrate serologic and immunologic markers in a multimodal approach to gain a comprehensive understanding.

• © 2024 by American Journal of Neuroradiology