Researchers employed a specialized brain imaging technique to identify a potential biomarker and therapeutic target for Long COVID.
More than four years after the onset of the COVID-19 pandemic, scientists are still working to fully understand the lingering effects of infection with SARS-CoV-2. One of the most concerning outcomes is Long COVID, a chronic condition that can emerge after the initial illness and bring a wide range of lasting health problems.
Among its most common and disruptive symptoms is cognitive impairment, often described as “brain fog.” Studies suggest that over 80% of people living with Long COVID experience this issue, which can make it difficult to work or handle daily responsibilities. With hundreds of millions of cases worldwide, the condition has become both a major public health concern and a growing socioeconomic burden.
Despite how widespread Long COVID is, its root causes remain unclear. Some imaging studies have revealed changes in brain structure, but these findings have not explained the molecular processes that lead to cognitive symptoms. Because the molecules that regulate communication between neurons are extremely difficult to study directly, researchers currently lack objective biomarkers that could confirm a Long COVID diagnosis or guide the development of effective treatments.
A Breakthrough in Brain Imaging
To address this challenge, a research team led by Professor Takuya Takahashi from the Graduate School of Medicine at Yokohama City University, Japan, has made a significant breakthrough in understanding the cause of Long COVID brain fog.
As explained in their paper, published in Brain Communications on October 1, 2025, the team hypothesized that patients with brain fog might exhibit disrupted expression of AMPA receptors (AMPARs)—key molecules for memory and learning—based on prior research into psychiatric and neurological disorders such as depression, bipolar disorder, schizophrenia, and dementia. Thus, they used a novel method called [11C]K-2 AMPAR PET imaging to directly visualize and quantify the density of AMPARs in the living human brain.
By comparing imaging data from 30 patients with Long COVID to 80 healthy individuals, the researchers found a notable and widespread increase in the density of AMPARs across the brains of patients. This elevated receptor density was directly correlated with the severity of their cognitive impairment, suggesting a clear link between these molecular changes and the symptoms. Additionally, the concentrations of various inflammatory markers were also correlated with AMPAR levels, indicating a possible interaction between inflammation and receptor expression.
Toward New Diagnostic and Treatment Strategies
Taken together, the study’s findings represent a crucial step forward in addressing many unresolved issues regarding Long COVID. The systemic increase in AMPARs provides a direct biological explanation for the cognitive symptoms, highlighting a target for potential treatments. For example, drugs that suppress AMPAR activity could be a viable approach to mitigate brain fog. Interestingly, the team’s analysis also demonstrated that imaging data can be used to distinguish patients from healthy controls with 100% sensitivity and 91% specificity.
“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,” remarks Prof. Takahashi.
While further efforts will be needed to find a definitive solution for Long COVID, this work is a promising step in the right direction. “Our findings clearly demonstrate that Long COVID brain fog should be recognized as a legitimate clinical condition. This could encourage the healthcare industry to accelerate the development of diagnostic and therapeutic approaches for this disorder,” concludes Prof. Takahashi.
In summary, the team’s findings resolve key uncertainties about the biological basis of Long COVID brain fog and may pave the way for novel diagnostic tools and effective therapies for patients suffering from this condition.
Reference: “Systemic increase of AMPA receptors associated with cognitive impairment of long COVID” by Yu Fujimoto, Hiroki Abe, Tsuyoshi Eiro, Sakiko Tsugawa, Meiro Tanaka, Mai Hatano, Waki Nakajima, Sadamitsu Ichijo, Tetsu Arisawa, Yuuki Takada, Kimito Kimura, Akane Sano, Koichi Hirahata, Nobuyuki Sasaki, Yuichi Kimura and Takuya Takahashi, 1 October 2025, Brain Communications.
DOI: 10.1093/braincomms/fcaf337
This clinical trial project was supported by donations from the READYFOR crowdfunding platform (https://readyfor.jp/). This project was partially supported by Takeda Science Foundation (T.T.), the Japan Agency for Medical Research and Development (AMED) under grant numbers JP24wm0625304 (T.T.), and JST through the Establishment of University Fellowships Towards the Creation of Science Technology Innovation program, under grant JPMJFS2140 (Y.F.).
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