In this study, the authors from the United States used brain proton magnetic resonance spectroscopy (MR spectroscopy) to investigate the neurometabolites that indicate neuroinflammation, neuronal damage, and glial dysfunction in patients with long COVID syndrome and neuropsychiatric symptoms. MR spectroscopy is a supplement to standard diagnostic MR imaging. Protons in different molecules have slightly different magnetic properties, and this difference enables MR spectroscopy to detect small molecules. Therefore, MR spectroscopy can reveal metabolic changes that precede pathological structural changes in the brain tissue.
Glutamate (Glu) is the most abundant excitatory neurotransmitter, and gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the mature central nervous system (CNS). The nervous system-specific metabolite N-acetyl aspartate (NAA) is synthesized from aspartate and acetyl-coenzyme A in neurons and is present at exceptionally high concentrations in the brain. It is a direct precursor for the enzymatic synthesis of the neuron-specific dipeptide N-acetyl aspartyl-glutamate, the most concentrated neuropeptide in the human brain.
In addition to the water signal, the dominant peaks in the MR spectra of the brain are from choline (Cho), creatine (Cr), and NAA which appear in all spectra. The changes in these signals can often be linked to pathology. Neuroinflammation and the proliferation of microglia are typically associated with increased glial marker myo-inositol (MI). increased MI levels are associated with concomitantly increased levels of Cho and total Cr due to their higher concentration in glia than in neurons.
A multicellular metabolic pathway known as the Glu/GABA/glutamine (Gln) cycle maintains the balance between the metabolites that play a critical role in several brain functions, such as learning, memory, pain, synaptogenesis, motor stimuli, and neuronal synaptic transmission. An altered Glu/GABA/Gln balance is associated with brain damage in several neurodegenerative diseases, such as Alzheimer’s, Parkinson’s, and neuroHIV. In neuro HIV, changes in Glu/GABA/Gln balance contribute to neuronal and glial dysfunction, and cognitive impairment identified in HIV-associated neurocognitive disorder (HAND). The results of MR spectroscopy demonstrated that a decrease in Cr, total N-acetyl compounds, and Glu/Gln levels, and an increase in Cho and MI levels are the most common findings in neuroHIV. A decrease in total N-acetyl compounds (NAA + N-acetyl aspartyl-glutamate) and Glu/Gln levels shows irreversible neuronal dysfunction, injury, or loss in affected brain areas.
Brain Proton Magnetic Resonance Spectroscopy: Metabolic maps showing the ratio of MI and NAA
About the study
The study included participants diagnosed with long COVID syndrome and at least one neuropsychiatric symptom that emerged after COVID-19 and 25 healthy controls matched by age, sex, and education. The participants were excluded if they had any significant neurologic or psychiatric disorder, such as stroke, encephalitis from any cause except COVID-19, neurodegenerative disorder, schizophrenia, uncontrolled major depression or anxiety disorder requiring medication before COVID-19, traumatic brain injury with loss of consciousness for more than one-hour that required hospitalization, severe substance use disorders except for tobacco or cannabis use, and any contraindication for MRI.
Participants diagnosed with long COVID syndrome had acute COVID-19 more than six weeks before enrollment (a mean of 242 ± 156 days). Healthy controls did not have COVID-19. They tested negative for SARS-CoV-2 on the polymerase chain reaction test within a week or had a negative rapid antigen test on the evaluation day. More healthy controls than patients with long COVID received COVID-19 vaccines.
All participants were evaluated by the National Institutes of Health Toolbox–Cognition Battery and Motor Battery. To assess the neurometabolite concentrations, all patients underwent brain proton MR spectroscopy of the gray matter in the anterior cingulate cortex and frontal white matter. According to the authors, the anterior cingulate cortex was chosen as the major node of the attention network required for all cognitive tasks. The frontal white matter was chosen because neuroinflammation is often found in this brain region during viral neuroinfections (e.g., HIV, John Cunningham virus, and hepatitis C virus).
Results
The study included 54 participants, 29 diagnosed with neuropsychiatric symptoms of long COVID syndrome, and 25 healthy controls. The mean age of patients with long COVID was 42.4 years. Nine of them were hospitalized and required supplemental oxygen and/or ventilation during acute COVID-19.
The most frequent neuropsychiatric symptoms were difficulties with concentration (93%) and memory (79%), fatigue (86%), and depression or anxiety (68%). Despite the high prevalence of complaints regarding concentration and memory, their performance in all domains assessed by the NIH Toolbox–Cognition Battery was similar to that observed in healthy controls. Nonetheless, on the PROMIS surveys, individuals diagnosed with long COVID syndrome had a greater number of symptoms such as depression, fatigue, anxiety, and pain, and poorer global mental and physical health scores.
Importantly, participants with long COVID syndrome had poorer scores on the Motor Battery tests, especially on the 2-minute endurance walk test, the 4-meter walk gait speed test, and the 9-hole pegboard dexterity test (test of dominant hand). These findings are consistent with a recent functional MRI study that investigated brain activation during a working memory task and demonstrated that participants with long COVID and neuropsychiatric symptoms performed worse than healthy controls in the domains of endurance, locomotion, and dominant hand manual dexterity. https://discovermednews.com/patients-with-post-covid-syndrome-and-neuropsychiatric-symptoms-have-different-brain-activation-during-the-working-memory-task/
Brain proton MR spectroscopy in patients with long COVID and neuropsychiatric symptoms
Brain proton MR spectroscopy revealed changes in brain neurometabolites in long COVID patients with neuropsychiatric symptoms. Compared to healthy controls, they had a decrease in total N-acetyl compounds, Glu/Gln, and MI levels in the frontal white matter. Since most neurons (∼80%) in the frontal white matter are glutamatergic, the marked decrease in Glu/Gln levels suggests damage or loss of glutamatergic neurons. Since NAA, the major component of total N-acetyl compounds is synthesized in mitochondria, the authors suggested that a reduced level of total N-acetyl compounds could potentially result from mitochondrial dysfunction.
In all participants, a decrease in total N-acetyl-compound levels in the frontal white matter predicted poorer performance on several cognitive measures. Lower N-acetyl-compound levels in the gray matter of the anterior cingulate cortex were associated with lower endurance on the 2-minute walk test.
Importantly, MI, Cho compounds, and total Cr levels were increased only in participants hospitalized during acute COVID-19. As neuroinflammation is typically associated with elevated MI levels, the authors stated that the lower MI levels in long COVID patients who were not hospitalized represent glial dystrophy or dysfunction rather than neuroinflammation and glial activation. In contrast, increased MI levels in participants hospitalized during acute COVID-19 might indicate persistent neuroinflammation and glial activation.
These findings are consistent with the results of brain MR spectroscopy in HIV-1-positive patients. A decrease in Cr, NAA, and Glu levels and an increase in Cho and MI levels in neuroHIV indicate neuroinflammation, microglial proliferation, and neuronal injury or loss. A decrease in NAA and Glu/Gln levels of the cortical gray matter observed in early HIV-1 infection indicates that HIV-1 causes neuronal and astroglial dysfunction within a short time after infection. In HIV-1 infected individuals, a decreased Glu/Cr ratio was shown to correlate with worse performance on verbal recall, psychomotor speed, and reaction time.
Conclusion
In this study, brain proton MR spectroscopy demonstrated decreased tNAA and Glu/Gln levels, increased Cho and tCr levels, and altered MI levels (decreased or increased depending on the severity of acute COVID-19) in the frontal brain regions of long COVID patients with neuropsychiatric symptoms. The observed changes in Glu/Gln balance, total N-acetyl-compound levels, and MI provided evidence of neuronal injury or loss, as well as of persistent neuroinflammation and glial dysfunction in the brains of long COVID patients. These findings are consistent with the results of proton MR spectroscopy in other neurodegenerative diseases, such as neuroHIV.
This article was published in the Journal of Infectious Diseases.
Journal Reference
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
