Overview: Long COVID brain fog and a search for molecular clues
Long COVID has emerged as one of the most persistent health challenges of the post-pandemic era. Among its most troubling consequences is cognitive impairment, commonly referred to as “brain fog,” which disrupts memory, attention, and problem-solving for many patients. While neuroimaging has revealed structural differences in some cases, the molecular underpinnings of brain fog have remained elusive. A new study from Yokohama City University in Japan, reported in Brain Communications on October 1, 2025, offers a compelling glimpse into the biology behind these cognitive symptoms.
The breakthrough: imaging AMPA receptors in living brains
The research team led by Professor Takuya Takahashi proposed that disruptions in AMPA receptors (AMPARs) — crucial proteins for learning and memory — might underlie the brain fog experienced by many Long COVID patients. To test this, they employed a novel imaging approach using the tracer [11C]K-2 AMPAR PET, enabling direct visualization and quantification of AMPAR density in living human brains. This method marks a departure from previous studies that inferred molecular changes indirectly.
What the study found
In a cross-sectional analysis, researchers scanned 30 patients with Long COVID who reported cognitive difficulties and 80 healthy controls. The findings were striking: a broad, systemic increase in AMPAR density across numerous brain regions in the Long COVID group. Moreover, the magnitude of this receptor upregulation correlated with the severity of cognitive impairment, suggesting a direct link between molecular changes and functional symptoms.
The team went further by examining inflammatory markers. They observed that several inflammatory signals tracked with AMPAR levels, implying a potential interaction between systemic or neuroinflammation and receptor regulation. While the precise mechanism remains to be clarified, the data point toward an inflammatory milieu contributing to receptor expression patterns that accompany cognitive symptoms.
Implications for diagnosis and treatment
The study positions AMPARs as a tangible biomarker for Long COVID brain fog. In a subset of analyses, imaging data could distinguish patients from healthy controls with 100% sensitivity and 91% specificity, highlighting the potential for an objective diagnostic tool where clinical criteria alone are uncertain. This is a significant step toward standardizing how Long COVID brain fog is identified and tracked over time.
From a therapeutic perspective, the results open a window to targeted interventions. Since the observed cognitive symptoms correlated with increased AMPAR activity, drugs that dampen AMPAR signaling could be explored as a strategy to mitigate brain fog. The authors caution that this is an early, exploratory direction, and any treatment plan would require rigorous clinical testing to balance benefits with potential side effects. Nonetheless, the concept of molecularly targeted therapies marks a hopeful shift in a field where treatment options have been limited.
Context, limitations, and next steps
As with any single-study advance, several caveats apply. The sample size, while informative, is modest, and replication in diverse populations is essential to confirm the generalizability of the AMPAR upregulation pattern. Longitudinal work will be needed to determine whether AMPAR densities change with recovery, therapy, or progression of symptoms. Additional research should also explore how inflammation, comorbidities, and demographic factors influence AMPAR dynamics in Long COVID.
Professor Takahashi emphasized that this work represents a proof of concept: “By applying our newly developed AMPA receptor PET imaging technology, we aim to provide a novel perspective and innovative solutions to the pressing medical challenge that is Long COVID,” he said. He also underscored the need for further studies to translate these insights into clinically available diagnostics and treatments.
Looking ahead: a new chapter in Long COVID care
The discovery of systemic AMPAR upregulation linked to cognitive symptoms helps resolve long-standing questions about the biology of Long COVID brain fog. If replicated, these findings could spur the development of standardized diagnostic imaging protocols and targeted pharmacotherapies, offering relief for millions affected by this condition and enabling healthier, more productive lives in the wake of the pandemic.
