Brain Inflammation May Not Drive Persistent Long COVID Symptoms, New Imaging Study Finds

New research challenges the prevailing assumption that ongoing neuroinflammation underlies chronic neuropsychiatric symptoms in patients with long COVID, pointing instead to altered brain activity in emotion-regulating regions as a more likely contributor.^1,2

Long COVID continues to affect a staggering number of patients worldwide. Global estimates suggest that at least 65 million individuals have experienced the condition since the start of the pandemic, with a pooled global prevalence of approximately 36% among individuals with a confirmed COVID-19 diagnosis. Neurological and psychiatric manifestations, including fatigue, brain fog, depression, anxiety, and cognitive impairment, rank among the most debilitating and persistent sequelae, with one systematic review reporting anxiety rates of up to 47.8% and depression rates of up to 37.3% in long COVID patients. These symptoms frequently interfere with work capacity and quality of life, generating enormous demand for effective, targeted pharmacotherapeutic strategies.^3,4

Study Design: PET Imaging Meets Long COVID

A new study published in the Journal of Neurology from researchers at the University of Turku, Finland, used advanced positron emission tomography (PET) neuroimaging to directly evaluate whether widespread brain inflammation could account for these chronic symptoms. The study enrolled 14 individuals with long COVID, 11 healthy controls (HC), and 13 patients with multiple sclerosis (MS), an established neuroinflammatory disease used as a positive control.^1,2

All participants underwent [¹¹C]PK11195 translocator protein (TSPO) PET scanning alongside 3T magnetic resonance imaging (MRI), with TSPO availability measured as distribution volume ratio (DVR). TSPO PET detects glial cell activation, a hallmark of neuroinflammation. Blood samples were also analyzed for serum neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) as biomarkers of neuronal and astrocytic injury. Long COVID participants completed validated mental health assessments, including the PHQ-9, GAD-7, and fatigue questionnaires.¹

Key Findings: No Widespread Neuroinflammation Detected

The study's primary finding was that TSPO availability did not differ significantly between long COVID participants and healthy controls in any brain region examined. As expected, MS patients showed markedly higher TSPO availability than both long COVID and HC groups, validating the imaging methodology. Serum NfL and GFAP levels were likewise comparable between long COVID patients and controls, suggesting no ongoing neurodegeneration at a group level.^1,2

However, participants imaged within 16 months of their SARS-CoV-2 diagnosis showed significantly higher white matter DVR compared to those with longer disease duration (1.05 vs. 1.02; p = 0.04), indicating that neuroinflammation may be more prominent early after infection and subside over time.^1,2

The Limbic System Connection

Despite the absence of globally elevated neuroinflammation, a compelling pattern emerged in the long COVID cohort—symptom severity correlated strongly with TSPO availability in the limbic system, specifically the hippocampus, amygdala, and thalamus. Higher depression scores (PHQ-9) and anxiety scores (GAD-7) correlated positively with DVRs in the hippocampus and amygdala (P = 0.75–0.97), while lower quality of life was associated with higher DVRs across all three limbic regions (ρ = −0.83 to −0.70). More than 12 of 13 statistically significant correlations concentrated in the limbic system, representing a greater than threefold enrichment over chance (permutation P = 0.006).¹

"This study highlights the need to continue investigating the complex biological mechanisms underlying long COVID. Understanding these processes is essential for developing targeted treatments," said lead author Laura Airas, MD, PhD, a professor of neuroimmunology at the University of Turku, in a news release.²

The authors note that elevated TSPO availability is not specific to inflammation alone but may also reflect increased glial metabolic activity or neuronal activation in mood-related circuits.¹

Implications for Pharmacists and Clinical Management

These findings carry meaningful clinical implications for pharmacists counseling patients with long COVID. Current evidence supports a range of management strategies for long COVID-related neurological symptoms, including nonpharmacological approaches (olfactory training, cognitive rehabilitation, and physical therapy) and pharmacological agents such as gabapentinoids, tricyclic antidepressants, and investigational options, including N-acetylcysteine and guanfacine. Pharmacists play an essential role in identifying symptom patterns and optimizing individualized treatment plans.⁵

The Finnish study reinforces that blanket anti-inflammatory strategies may not benefit all long COVID patients, particularly those presenting primarily with mood and cognitive symptoms months to years after infection. Pharmacists should be vigilant in screening for depression, anxiety, and fatigue using validated tools and should recognize that these symptoms may reflect persistent limbic system dysregulation rather than active neuroinflammation.²

Looking Ahead

The study's small sample size (n = 14 for long COVID) is an acknowledged limitation, and larger, well-characterized cohorts are needed to confirm these results and evaluate subgroup differences. The study authors also note that earlier PET studies reporting elevated TSPO in long COVID focused on patients imaged within 6 months of infection, consistent with this study's observation that white matter inflammation appears highest in the early disease phase.^1,2

Together, these data suggest a dynamic neurobiological trajectory in long COVID: acute neuroinflammation that resolves over time, giving way to persistent alterations in limbic system activity that may drive chronic neuropsychiatric symptoms. For the pharmacy community, this evolving picture underscores the importance of tailored, symptom-targeted care and continued interdisciplinary collaboration in managing this complex condition.

REFERENCES

1. Tuomaala J, Saraste M, Smith E, et al. Association between post-COVID-19 neuropsychiatric symptoms and persistent glial activation in the limbic system: a TSPO PET study. J Neurol. 2026;273:298. doi:10.1007/s00415-026-13842-w

2. Brain inflammation is unlikely to explain persistent long COVID symptoms. EurekAlert!. May 22, 2026. Accessed June 5, 2026. https://www.eurekalert.org/news-releases/1129343

3. Hou Y, Gu T, Ni Z, et al. Global prevalence of long COVID, its subtypes and risk factors: an updated systematic review and meta-analysis. Open Forum Infect Dis. 2025. doi:10.1101/2025.01.01.24319384

4. Rocha DM, Pedroso AO, Menegueti MG, et al. Predictors of anxiety, depression, and stress in long COVID: systematic review of prevalence. Int J Environ Res Public Health. 2025;22(6):867. doi:10.3390/ijerph22060867

5. Abdulameer S, Gor P, Ileni M, et al. Strategies for mitigating the neurologic impact of long COVID. US Pharmacist. 2025;50(1):4-9. https://www.uspharmacist.com/article/strategies-for-mitigating-the-neurologic-impact-of-long-covid