Despite its growing prevalence, the underlying causes of Long COVID and associated cognitive issues such as brain fog remain poorly understood. Previous imaging studies have indicated some structural changes in the brain, yet they have failed to identify the specific molecular dysfunctions responsible for these cognitive symptoms. The challenge lies in the difficulty of directly observing the molecules that regulate communication between brain cells, leaving researchers without objective biomarkers to confirm a Long COVID diagnosis or to develop effective therapies.
To tackle this significant challenge, a research team led by Professor Takuya Takahashi from the Graduate School of Medicine at Yokohama City University in Japan has made a groundbreaking discovery in understanding the causes of Long COVID brain fog. Their findings, detailed in a paper published in Brain Communications on October 1, 2025, propose that patients suffering from brain fog may exhibit disrupted expression of AMPA receptors (AMPARs), which are crucial molecules involved in memory and learning.
The research builds upon previous investigations into psychiatric and neurological disorders such as depression, bipolar disorder, schizophrenia, and dementia. To visualize and quantify the density of AMPARs in the living human brain, the team employed a novel method called 11CK-2 AMPAR PET imaging. By comparing imaging data from 30 patients diagnosed with Long COVID to that of 80 healthy individuals, the researchers discovered a significant and widespread increase in the density of AMPARs in the brains of the patients.
This elevated receptor density was directly correlated with the severity of cognitive impairment, suggesting a clear connection between these molecular changes and the associated symptoms. Furthermore, the concentrations of various inflammatory markers were found to correlate with AMPAR levels, indicating a potential interaction between inflammation and receptor expression.
The findings from this study represent a crucial advancement in addressing long-standing questions regarding Long COVID. The systemic increase in AMPARs offers a direct biological explanation for the cognitive symptoms experienced by patients, highlighting a new target for potential treatments. For instance, medications that suppress AMPAR activity could serve as a viable approach to alleviate brain fog.
Interestingly, the analysis conducted by the team demonstrated that imaging data could successfully differentiate patients from healthy controls with 100% sensitivity and 91% specificity. Professor Takahashi stated, "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." This statement underscores the potential of their findings to revolutionize the understanding and management of this condition.
While additional efforts are necessary to find a definitive solution for Long COVID, this research marks a promising step forward. Professor Takahashi emphasizes that the findings clearly demonstrate that Long COVID brain fog should be recognized as a legitimate clinical condition. Recognition of this condition could spur the healthcare industry to expedite the development of diagnostic and therapeutic strategies for affected individuals.
In summary, the research team's findings address critical uncertainties regarding the biological basis of Long COVID brain fog and may pave the way for innovative diagnostic tools and effective therapies aimed at helping patients suffering from this debilitating condition.
This clinical trial project received support through donations from the READYFOR crowdfunding platform. Additionally, it was partially backed by the 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.).
