New Molecular Insight into Long COVID Brain Fog
As the world continues to grapple with the consequences of SARS-CoV-2 infection, Long COVID — a condition characterized by lingering symptoms after the acute illness — remains poorly understood. Among the most disabling manifestations is cognitive impairment, colloquially known as brain fog, which affects a significant portion of those with Long COVID and poses a substantial public health burden. A groundbreaking study led by Professor Takuya Takahashi of the Graduate School of Medicine at Yokohama City University, published in Brain Communications on October 1, 2025, offers a direct glimpse into the brain’s molecular underpinnings of this symptom cluster.
A novel imaging approach to observe brain molecules in living people
The research team employed a cutting-edge method: [11C]K-2 AMPAR PET imaging. This tracer binds to AMPA receptors (AMPARs), the glutamate receptors central to fast synaptic transmission, learning, and memory. For the first time, the researchers quantified AMPAR density across the living human brain in a comparative study that included 30 Long COVID patients with brain fog and 80 healthy controls. The goal was straightforward: determine whether aberrant AMPAR expression could explain cognitive symptoms and, if so, whether PET imaging could serve as a biomarker for diagnosis and treatment response.
What the findings reveal about AMPARs and cognition
The most striking result was a systemic increase in AMPAR density across multiple brain regions in patients with Long COVID brain fog. This upregulation correlated strongly with the severity of cognitive impairment, including problems with attention, processing speed, and memory. Importantly, the pattern was not confined to a single region but appeared as a widespread neurochemical signal, suggesting a global alteration in glutamatergic signaling rather than a localized injury.
Inflammation appears to play a role
In addition to receptor trends, the study measured inflammatory markers in the blood and, in a subset of participants, cerebrospinal fluid. The data revealed correlations between elevated inflammatory signals and higher AMPAR densities, hinting at an interaction between systemic or neuroinflammation and glutamatergic receptor regulation. If inflammation stimulates changes in AMPAR expression, anti-inflammatory or receptor-targeted therapies might hold therapeutic promise.
Implications for diagnosis and treatment
The study’s quantitative AMPAR imaging offers a potential objective biomarker for Long COVID brain fog. According to the authors, applying this AMPAR PET approach distinguished patients from healthy controls with 100% sensitivity and 91% specificity within the study cohort, underscoring its potential utility in specialized clinics and clinical trials to monitor disease progression or treatment response.
From a therapeutic perspective, the researchers suggest that treatments aimed at tempering excessive AMPAR activity could mitigate brain fog symptoms. While further research is needed to determine the safety and efficacy of such strategies, the findings identify glutamatergic signaling as a tangible target and reinforce the idea that brain fog has a measurable molecular basis rather than being purely subjective.
What this means for the future of Long COVID care
This work represents a crucial advance in resolving long-standing questions about Long COVID’s biology. By linking cognitive symptoms to a concrete molecular change, it paves the way for objective diagnostics and targeted therapies that could reduce the public health and economic impact of Long COVID. The authors acknowledge that replication in larger and more diverse populations is essential, and they emphasize the need for longitudinal studies to determine whether AMPAR density fluctuates with recovery or responds to specific interventions.
Conclusion
In sum, the Yokohama City University team’s discovery of widespread AMPAR upregulation in Long COVID brain fog offers a credible, testable mechanism for the cognitive symptoms that many patients experience. As research progresses, AMPAR PET imaging could become a valuable tool in diagnosing brain fog, guiding treatment, and ultimately improving quality of life for millions affected by Long COVID.
