Scientists thought brain inflammation was driving long COVID, but scans tell a different story
The years-long scientific hypothesis that the brains of patients experiencing long COVID symptoms harbour inflammation has not been confirmed in a new imaging study. According to Science Daily Health, the study led by the Department of Neurology at Massachusetts General Hospital (MGH) has been published in the journal Brain.
The study examined 47 long COVID patients and 33 healthy control participants using high-resolution positron emission tomography (PET) and fluid-based magnetic resonance imaging (MRI). The hypothesis was that signatures of activation and inflammation at the microglia level (the brain's immune cells) would be observed in long COVID patients' brains.
Lead author Dr Jeanne Lemaitre of the MGH Department of Neurology said the results 'came out different from what we expected'. PET scanner data did not show a significant increase in TSPO (Translocator Protein) receptor binding in the brains of long COVID patients despite the hypothesis. 'This may mean brain inflammation is not the primary driver of long COVID symptoms,' Lemaitre said.
Alternative mechanisms remain under examination. The study observed findings pointing to white matter connectivity changes and cerebrovascular changes. The loss of white matter connectivity may be at the heart of patients' cognitive dysfunction. Yale School of Medicine neurologist Prof. Dr Akiko Iwasaki, who participated in the study, interpreted the results saying, 'Rather than withdrawing the microglia hypothesis, we need to pay more attention to the heterogeneity of long COVID.'
Long COVID is a condition affecting approximately 65 million people globally and currently has no accepted treatment. WHO Long COVID Working Group chair Dr Maria Van Kerkhove said, 'Understanding the mechanism is the biggest obstacle to developing targeted treatment. This new data may necessitate a research direction shift.'
For clinical practice, the study results may explain why existing anti-inflammatory treatments (steroids, methotrexate, IL-6 inhibitors) may have limited effect on long COVID. The US National Institutes of Health's RECOVER programme may move some of the current clinical trials into a reassessment phase. RECOVER director Dr Walter Koroshetz said, 'We have initiated discussions with the clinical research community to integrate this imaging data into the RECOVER treatment guidance.'
UK data from NHS Long COVID clinics also points to limited effect of existing anti-inflammatory treatments. Imperial College London's Prof. Sir Peter Openshaw, in commentary on BBC Radio 4, said, 'Long COVID may have multiple biological substrates; this study weakens the single-point anti-inflammation hypothesis.'
Patient advocacy groups evaluated the study as both a source of hope and a basis for future research needs. Long COVID Action UK spokesperson Claire Hastie said in a statement, 'These results support our efforts to better understand the complex biology of long COVID; more investment is needed for treatment.' In Turkey, Turkish Thoracic Society Long COVID Working Group chair Prof. Dr Caglar Kuas also described the study results as 'valuable but unexpected'.
Limitations of the study include the relatively small sample (80 total participants) and the absence of long-term follow-up data. Larger studies are expected. The NIH RECOVER programme has announced an imaging sub-study targeting 25,000 patients for 2027.
Clinical recommendations for long COVID patients have not changed; existing supportive treatments (rehabilitation, physiotherapy, symptom management) should continue. This article is not a substitute for individual medical advice; consult your doctor for treatment decisions.
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