Heterogeneity in Regional Damage Detected by Neuroimaging and Neuropathological Studies in Older Adults With COVID-19: A Cognitive-Neuroscience Systematic Review to Inform the Long-Term Impact of the Virus on Neurocognitive Trajectories

Abstract

Background: Other than its direct impact on cardiopulmonary health, Coronavirus Disease 2019 (COVID-19) infection affects additional body systems, especially in older adults. Several studies have reported acute neurological symptoms that present at onset or develop during hospitalisation, with associated neural injuries. Whilst the acute neurological phase is widely documented, the long-term consequences of COVID-19 infection on neurocognitive functioning remain unknown. Although an evidence-based framework describing the disease chronic phase is premature, it is important to lay the foundations for future data-driven models. This systematic review aimed at summarising the literature on neuroimaging and neuropathological findings in older over-60 patients with COVID-19 following a cognitive neuroscientific perspective, to clarify the most vulnerable brain areas and speculate on the possible cognitive consequences.Methods: PubMed and Web of Science databases were searched to identify relevant manuscripts published between 1st March 2020 and 31th December 2020. Outputs were screened and selected by two assessors. Relevant studies not detected by literature search were added manually.Results: Ninety studies, mainly single cases and case series, were included. Several neuroimaging and neuropathological findings in older patients with COVID-19 emerged from these studies, with cerebrovascular damage having a prominent role. Abnormalities (hyperintensities, hypoperfusion, inflammation, and cellular damage) were reported in most brain areas. The most consistent cross-aetiology findings were in white matter, brainstem and fronto-temporal areas. Viral DNA was detected mainly in olfactory, orbitofrontal and brainstem areas.Conclusion: Studies on COVID-19 related neural damage are rich and diverse, but limited to description of hospitalised patients with fatal outcome (i.e., in neuropathological studies) or severe symptoms (i.e., in neuroimaging studies). The damage seen in this population indicates acute and largely irreversible dysfunction to neural regions involved in major functional networks that support normal cognitive and behavioural functioning. It is still unknown whether the long-term impact of the virus will be limited to chronic evolution of acute events, whether sub-clinical pathological processes will be exacerbated or whether novel mechanisms will emerge. Based on current literature, future theoretical frameworks describing the long-term impact of COVID-19 infection on mental abilities will have to factor in major trends of aetiological and topographic heterogeneity.

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

“…org/10.21203/rs.3.rs-1139035/v1), or of virus-induced neuroinflammation [3][4][5] (https://doi.org/10.1101/2021.02. 23.432474): neurological and cognitive deficits demonstrated by patients 6,7 , with an incidence of neurological symptoms in more than 80% of the severe cases 8 , radiological and post mortem tissue analyses demonstrating the impact of COVID-19 on the brain 9,10 , and the possible presence of the coronavirus in the central nervous system found in some studies [11][12][13] .…”

“…There is strong evidence for brain-related abnormalities in COVID-19 [1][2][3][4][5][6][7][8][9][10][11][12][13] . It remains unknown however whether the impact of SARS-CoV-2 infection can be detected in milder cases, and whether this can reveal possible mechanisms contributing to brain pathology.…”

Visual interpretation of brain hypometabolism related to neurological long COVID: a French multicentric experience

“…According to this retrospective review in a predefined period of inclusion, the mild-to-moderate and severe hypometabolic long-COVID patterns represent 47% of patients. Other studies involving long-COVID patients found hypometabolism mainly in the fronto-orbital regions [ 9 , 10 ] or a similar long-COVID pattern on MRI scans with a more pronounced reduction in grey matter thickness and contrast in the orbitofrontal cortex and parahippocampal gyrus, as well as involvement of the brainstem region [ 2 , 3 ]. This also means that the previously reported hypometabolic pattern is not visually found in all patients with suspected neurological long COVID.…”

“…In such suspected cases, patients can be referred to the Nuclear Medicine Departments for brain 18 F-FDG PET scans to contribute to the workup of a differential diagnosis, and to potentially identify the hypometabolic pattern previously reported at the group level in a recent monocentric study for this new entity involving fronto-orbital olfactory regions and other limbic/paralimbic regions, as well as the brainstem and cerebellum [ 4 ]. Brain areas that composed this hypometabolic pattern have also been reported in an MRI study measuring cortical atrophy before and after COVID infection [ 2 ], as well as in a review of ninety studies [ 3 ]. Validation of this long-COVID hypometabolic PET pattern is consequently needed at the individual and multicentric levels to easily apply it in clinical routine for nuclear physicians.…”

“…Long COVID, defined by the persistence or recurrence of symptoms 3 months after an initial severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, represents a serious public issue since it affects approximately 10–15% of patients, with emerging evidence of brain impairment [ 1 – 3 ]. In such suspected cases, patients can be referred to the Nuclear Medicine Departments for brain 18 F-FDG PET scans to contribute to the workup of a differential diagnosis, and to potentially identify the hypometabolic pattern previously reported at the group level in a recent monocentric study for this new entity involving fronto-orbital olfactory regions and other limbic/paralimbic regions, as well as the brainstem and cerebellum [ 4 ].…”