Neuronal and Glial Metabolite Abnormalities in Participants With Persistent Neuropsychiatric Symptoms After COVID-19: A Brain Proton Magnetic Resonance Spectroscopy Study

J Infect Dis. 2023 Nov 28;228(11):1559-1570. doi: 10.1093/infdis/jiad309.


Background: The aim of this study was to determine whether neurometabolite abnormalities indicating neuroinflammation and neuronal injury are detectable in individuals post-coronavirus disease 2019 (COVID-19) with persistent neuropsychiatric symptoms.

Methods: All participants were studied with proton magnetic resonance spectroscopy at 3 T to assess neurometabolite concentrations (point-resolved spectroscopy, relaxation time/echo time = 3000/30 ms) in frontal white matter (FWM) and anterior cingulate cortex-gray matter (ACC-GM). Participants also completed the National Institutes of Health Toolbox cognition and motor batteries and selected modules from the Patient-Reported Outcomes Measurement Information System.

Results: Fifty-four participants were evaluated: 29 post-COVID-19 (mean ± SD age, 42.4 ± 12.3 years; approximately 8 months from COVID-19 diagnosis; 19 women) and 25 controls (age, 44.1 ± 12.3 years; 14 women). When compared with controls, the post-COVID-19 group had lower total N-acetyl compounds (tNAA; ACC-GM: -5.0%, P = .015; FWM: -4.4%, P = .13), FWM glutamate + glutamine (-9.5%, P = .001), and ACC-GM myo-inositol (-6.2%, P = .024). Additionally, only hospitalized patients post-COVID-19 showed age-related increases in myo-inositol, choline compounds, and total creatine (interaction P = .029 to <.001). Across all participants, lower FWM tNAA and higher ACC-GM myo-inositol predicted poorer performance on several cognitive measures (P = .001-.009), while lower ACC-GM tNAA predicted lower endurance on the 2-minute walk (P = .005).

Conclusions: In participants post-COVID-19 with persistent neuropsychiatric symptoms, the lower-than-normal tNAA and glutamate + glutamine indicate neuronal injury, while the lower-than-normal myo-inositol reflects glial dysfunction, possibly related to mitochondrial dysfunction and oxidative stress in Post-COVID participants with persistent neuropsychiatric symptoms.

Keywords: COVID-19; N-acetylaspartate; myo-inositol; neuropsychiatric symptoms; proton magnetic resonance spectroscopy.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Aspartic Acid / metabolism
  • Brain / diagnostic imaging
  • Brain / metabolism
  • COVID-19 Testing
  • COVID-19* / metabolism
  • Female
  • Glutamates / metabolism
  • Glutamine* / metabolism
  • Humans
  • Inositol / metabolism
  • Middle Aged
  • Proton Magnetic Resonance Spectroscopy / methods
  • Protons


  • Glutamine
  • Protons
  • Inositol
  • Glutamates
  • Aspartic Acid