The authors from the United States used proton magnetic resonance spectroscopy to investigate whether alterations in neurometabolites that indicate neuroinflammation, neuronal damage and glial dysfunction can be detected in the brains of patients with long COVID syndrome and persistent neuropsychiatric symptoms.
Neuronal damage or loss is associated with reduced neuronal metabolites, total N-acetyl-compounds (N-acetylaspartate + N-acetylaspartyl-glutamate) and glutamate + glutamine. Neuroinflammation is typically associated with increase in glial marker myo-inositol and often concomitantly elevated choline compounds and total creatine due to their higher concentrations in glia than in neurons.
Previous autopsy studies of patients with COVID-19 demonstrated neuroinflammation and activated microglia. Also, elevated levels of plasma glial fibrillary acidic protein (glial activation marker) and neurofilament light chain protein (neuronal damage marker) were found in patients with acute COVID-19. Based on findings from clinical and postmortem studies conducted in patients with COVID-19, but also in patients with different neuropsychiatric diseases, researchers hypothesized that alterations in markers of neuronal injury, neuroinflammation and glial function could be found in the brains of individuals with long COVID syndrome.
About the study
The study included 54 participants. 29 participants had symptoms of long COVID (mean age, 42.4 years) and 25 participants were healthy controls matched by age, sex, and education. The long COVID group was evaluated at a mean 242 ± 156 days after acute illness. Nine patients with long COVID were hospitalized and required supplemental oxygen and/or ventilation. More healthy controls than patients were vaccinated against SARS-CoV-2.
To meet the inclusion criteria, participants with long COVID must have documented diagnosis of COVID-19 ≥six weeks earlier and at least one neuropsychiatric symptom that emerged after COVID-19. The healthy controls had no prior COVID-19 diagnosis, and they had a negative PCR test for SARS-CoV-2 infection within one week, or rapid antigen test on the day of evaluation. Exclusion criteria were: any significant neurologic or psychiatric disorder (eg, stroke, encephalitis from any cause except COVID-19, neurodegenerative disorder, schizophrenia, uncontrolled major depression or anxiety disorder requiring medication prior to COVID-19, traumatic brain injury with loss of consciousness for >1 hour requiring hospitalization), severe substance use disorders except for tobacco or cannabis use, or any contraindication for magnetic resonance imaging (MRI).
All 54 participants were assessed by using quantitative neurobehavioral measures from the National Institutes of Health Toolbox–Cognition Battery and Motor Battery. All participants with long COVID completed a standardized symptom severity questionnaire.
In all participants, localized proton magnetic resonance spectroscopy data were acquired in the anterior cingulate cortex gray matter and in the frontal white matter in order to assess neurometabolite concentrations. The anterior cingulate cortex gray matter was chosen as the major node for the attention network required for all cognitive tasks, while the frontal white matter was selected bacause neuroinflammation is often present in this brain region during viral neuroinfections (eg, HIV, John Cunningham virus, and hepatitis C virus).
The most frequent neuropsychiatric complaints in participants with long COVID were problems with concentration (93%), memory (79%), fatigue (86%), and depression or anxiety (68%). Despite high prevalence of concentration and memory complaints, they had similar performance as controls for all domains assessed by the NIH Toolbox–Cognition Battery. However, the long COVID group had poorer endurance on the NIH Toolbox–Motor Battery, namely on the 2-Minute Endurance Walk Test, the 4-Meter Walk Gait Speed Test and 9-Hole Pegboard Dexterity Test (dominant hand). On the PROMIS surveys, long COVID patients displayed more symptoms, including depression, fatigue, anxiety, and pain, with poorer global mental and physical health scores.
The proton magnetic resonance spectroscopy findings showed alterations in neurometabolites in the brains of patients with long COVID. Compared with controls, participants with long COVID and persistent neuropsychiatric symptoms had lower total N-acetyl compounds and glutamate + glutamine in the frontal white matter, as indicator of neuronal damage or loss. The markedly reduced glutamate + glutamine in the frontal white matter in long COVID group provided evidence for neuronal damage, since most neurons (∼80%) are glutamatergic.
In addition, total N-acetyl compounds in the anterior cingulate cortex gray matter were lower in the long COVID group. As N-acetylaspartate, the major component of the total N-acetyl compounds, is synthesized in mitochondria, the authors proposed that mitochondrial dysfunction could potentially result in a lower level of total N-acetyl compounds. The authors further stated that the results of lower total N-acetyl compounds in both brain regions and glutamate + glutamine in the frontal white matter are in line with their hypothesis and suggest neuronal damage in participants with long COVID.
Compared with controls, participants with long COVID had lower myo-inositol, a marker of neuroinflammation, in the frontal white matter. According to the authors, lower myo-inositol indicates glial dystrophy or dysfunction, rather than neuroinflammation.
Importantly, only patients with long COVID syndrome who were hospitalized showed age-related increase in myo-inositol, choline compounds, and total creatine, as markers of neuroinflammation. Nonhospitalized patients with long COVID had lower levels of brain metabolites than controls, especially in the frontal white matter. The relatively higher myo-inositol in the hospitalized patients indicates that neuroinflammation with glial activation remained prominent, which is consistent with the previous reports of increased microglial activation in patients with severe COVID-19. In contrast, the patients with long COVID who were not hospitalized lacked significant glial activation and likely had glial dystrophy, which can be an important contributory factor to the persistent neuropsychiatric symptoms.
In all participants, lower total N-acetyl-compounds in the frontal white matter and higher myo-inositol in anterior cingulate cortex gray matter predicted poorer performance on several cognitive measures. Additionally, lower N-acetyl-compounds in the anterior cingulate cortex gray matter predicted lower endurance on the 2-minute walk.
This study demonstrated that alterations in neurometabolites indicative of neuronal damage and glial dysfunction can be detected in the brains of patients with long COVID syndrome. The authors concluded that these results suggest that SARS-CoV-2 infection may cause neuronal injury or loss and glial dysfunction in the frontal brain regions, which may contribute to neuropsychiatric symptoms in patients with long COVID.
This article was published in The Journal of Infectious Diseases.
Ernst T et al. Neuronal and Glial Metabolite Abnormalities in Participants With Persistent Neuropsychiatric Symptoms After COVID-19: A Brain Proton Magnetic Resonance Spectroscopy Study. The Journal of Infectious Diseases. 2023; jiad309. (Open Access). https://doi.org/10.1093/infdis/jiad309