Conceptual foundations of acetylcarnitine supplementation in neuropsychiatric long COVID syndrome: a narrative review.

Post-acute sequelae of COVID-19 can present as multi-organ pathology, with neuropsychiatric symptoms being the most common symptom complex, characterizing long COVID as a syndrome with a significant disease burden for affected individuals. Several typical symptoms of long COVID, such as fatigue, depressive symptoms and cognitive impairment, are also key features of other psychiatric disorders such as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and major depressive disorder (MDD). However, clinically successful treatment strategies are still lacking and are often inspired by treatment options for diseases with similar clinical presentations, such as ME/CFS. Acetylcarnitine, the shortest metabolite of a class of fatty acid metabolites called acylcarnitines and one of the most abundant blood metabolites in humans can be used as a dietary/nutritional supplement with proven clinical efficacy in the treatment of MDD, ME/CFS and other neuropsychiatric disorders. Basic research in recent decades has established acylcarnitines in general, and acetylcarnitine in particular, as important regulators and indicators of mitochondrial function and other physiological processes such as neuroinflammation and energy production pathways. In this review, we will compare the clinical basis of neuropsychiatric long COVID with other fatigue-associated diseases. We will also review common molecular disease mechanisms associated with altered acetylcarnitine metabolism and the potential of acetylcarnitine to interfere with these as a therapeutic agent. Finally, we will review the current evidence for acetylcarnitine as a supplement in the treatment of fatigue-associated diseases and propose future research strategies to investigate the potential of acetylcarnitine as a treatment option for long COVID.

Cortical thickness alterations and systemic inflammation define long-COVID patients with cognitive impairment.

As the heterogeneity of symptoms is increasingly recognized among long-COVID patients, it appears highly relevant to study potential pathophysiological differences along the different subtypes. Preliminary evidence suggests distinct alterations in brain structure and systemic inflammatory patterns in specific groups of long-COVID patients. To this end, we analyzed differences in cortical thickness and peripheral immune signature between clinical subgroups based on 3 T-MRI scans and signature inflammatory markers in n = 120 participants comprising healthy never-infected controls (n = 30), healthy COVID-19 survivors (n = 29), and subgroups of long-COVID patients with (n = 26) and without (n = 35) cognitive impairment according to screening with Montreal Cognitive Assessment. Whole-brain comparison of cortical thickness between the 4 groups was conducted by surface-based morphometry. We identified distinct cortical areas showing a progressive increase in cortical thickness across different groups, starting from healthy individuals who had never been infected with COVID-19, followed by healthy COVID-19 survivors, long-COVID patients without cognitive deficits (MoCA ≥ 26), and finally, long-COVID patients exhibiting significant cognitive deficits (MoCA < 26). These findings highlight the continuum of cortical thickness alterations associated with COVID-19, with more pronounced changes observed in individuals experiencing cognitive impairment (p < 0.05, FWE-corrected). Affected cortical regions covered prefrontal and temporal gyri, insula, posterior cingulate, parahippocampal gyrus, and parietal areas. Additionally, we discovered a distinct immunophenotype, with elevated levels of IL-10, IFNγ, and sTREM2 in long-COVID patients, especially in the group suffering from cognitive impairment. We demonstrate lingering cortical and immunological alterations in healthy and impaired subgroups of COVID-19 survivors. This implies a complex underlying pathomechanism in long-COVID and emphasizes the necessity to investigate the whole spectrum of post-COVID biology to determine targeted treatment strategies targeting specific sub-groups.

Larger gray matter volumes in neuropsychiatric long-COVID syndrome.

Neuropsychiatric symptoms are the most common sequelae of long-COVID. As accumulating evidence suggests an impact of survived SARS-CoV-2-infection on brain physiology, it is necessary to further investigate brain structural changes in relation to course and neuropsychiatric symptom burden in long-COVID. To this end, the present study investigated 3T-MRI scans from long-COVID patients suffering from neuropsychiatric symptoms (n = 30), and healthy controls (n = 20). Whole-brain comparison of gray matter volume (GMV) was conducted by voxel-based morphometry. To determine whether changes in GMV are predicted by neuropsychiatric symptom burden and/or initial severity of symptoms of COVID-19 and time since onset of COVID-19 stepwise linear regression analysis was performed. Significantly enlarged GMV in long-COVID patients was present in several clusters (spanning fronto-temporal areas, insula, hippocampus, amygdala, basal ganglia, and thalamus in both hemispheres) when compared to controls. Time since onset of COVID-19 was a significant regressor in four of these clusters with an inverse relationship. No associations with clinical symptom burden were found. GMV alterations in limbic and secondary olfactory areas are present in long-COVID patients and might be dynamic over time. Larger samples and longitudinal data in long-COVID patients are required to further clarify the mediating mechanisms between COVID-19, GMV and neuropsychiatric symptoms.