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Study reveals no neuroinflammation in long COVID patients with neuropsychiatric symptoms

In a recent study published in JAMA Network Open, researchers examined cerebrospinal fluid (CSF) markers of neuroinflammation in individuals with post-coronavirus disease 2019 (COVID-19) condition (PCC) and neuropsychiatric symptoms.

PCC, also known as long COVID, represents a diverse group of symptoms that last for months post-acute COVID-19. Some individuals with PCC have neuropsychiatric symptoms (neuro-PCC), and the underlying mechanisms are poorly understood. CSF provides a means to evaluate neuropathology, given that it circulates the central nervous system (CNS) and serves as a window to the brain.

Research Letter: Self-Reported Neuropsychiatric Post–COVID-19 Condition and CSF Markers of Neuroinflammation. Image Credit: Donkeyworx / Shutterstock

About the study

In the present study, researchers assessed CSF markers of neuroinflammation in people with neuro-PCC and COVID-19-naïve individuals. Neuro-PCC subjects were recruited to the COVID Mind Study if they reported neuropsychiatric symptoms ≥ three months after COVID-19. Asymptomatic individuals recruited before 2020 (pre-COVID-19) served as controls.

The control group also included a COVID-19-naïve participant recruited in 2022, with laboratory evidence supporting the seronegative status. Individuals with a history of immunocompromising conditions and psychiatric or neurologic illness and those taking immunosuppressive medications were excluded.

Data on COVID-19 test dates/results and vaccination were obtained from medical records and interviews. Participants provided consent for blood sampling and lumbar puncture. CSF and plasma were evaluated using a multiplex cytokine laser bead assay. Enzyme-linked immunosorbent assay (ELISA) was used to measure neopterin (microglia activation marker).

Ethnicity and race were self-reported by participants. Group comparisons for clinical and demographic data were performed using t-tests, while a two-proportion z-test was used for comparisons of race. Mann-Whitney tests were used to compare cytokine data between controls and neuro-PCC subjects, controlling for false discovery rates.


The study included 37 individuals with neuro-PCC and 22 controls. Neuro-PCC subjects tested positive for COVID-19 from March 2020 to July 2022. Most individuals with neuro-PCC were White (78.4%) and female (73%). Only four participants (11%) in the neuro-PCC group were vaccinated at the time of infection, while 89% remained non-vaccinated. However, 46% were partially or fully vaccinated at the PCC study visit.

A majority of neuro-PCC participants had acute disease when severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Alpha was the predominant variant. Cognitive impairment, brain fog, and excess fatigue were the most common PCC symptoms. The neuro-PCC group did not exhibit elevated protein levels and white blood cell counts. Moreover, the CSF-to-blood albumin ratio, which changes during the breakdown of the blood-brain barrier, was not elevated in the neuro-PCC group.

There was no evidence of intrathecal production of immunoglobulins. However, interleukin-6 (IL-6) and monocyte chemoattractant protein-1 were reduced, while tumor necrosis factor-alpha levels were elevated in the CSF of neuro-PCC subjects relative to controls, albeit not statistically significant when accounted for multiple comparisons. Besides, other chemokines and cytokines in the plasma or CSF were not significantly different. Furthermore, neopterin levels were not elevated in neuro-PCC subjects.


Taken together, the study did not find evidence of neuroinflammation and blood-brain barrier dysfunction in participants with neuro-PCC relative to control participants. The findings suggest persistent CNS immune activation does not drive neurologic long COVID. The study’s limitations were the small sample size, increased rates of alcohol use and smoking, reduced rates of antidepressants among controls, and discrepancies in the race and gender of neuro-PCC subjects relative to controls.

Journal reference:
  • Farhadian SF, Reisert HD, McAlpine L, et al. Self-Reported Neuropsychiatric Post–COVID-19 Condition and CSF Markers of Neuroinflammation. JAMA Netw Open, 2023, DOI: 10.1001/jamanetworkopen.2023.42741,

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Tags: Albumin, Alcohol, Assay, Blood, Brain, Brain Fog, Cell, Central Nervous System, Chemokines, Coronavirus, Coronavirus Disease COVID-19, covid-19, Cytokine, Cytokines, ELISA, Enzyme, Fatigue, Interleukin, Interleukin-6, Laboratory, Microglia, Monocyte, Necrosis, Nervous System, Protein, Research, Respiratory, SARS, SARS-CoV-2, Severe Acute Respiratory, Severe Acute Respiratory Syndrome, Smoking, Syndrome, Tumor, Tumor Necrosis Factor, White Blood Cell

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Tarun Sai Lomte

Tarun is a writer based in Hyderabad, India. He has a Master’s degree in Biotechnology from the University of Hyderabad and is enthusiastic about scientific research. He enjoys reading research papers and literature reviews and is passionate about writing.