Uncovering the molecular basis of long COVID brain fog

Even though many years have passed since the start of the COVID-19 pandemic, the effects of infection with SARS-CoV-2 are not completely understood. This is especially true for Long COVID, a chronic condition that can develop after COVID-19 that causes a variety of lasting symptoms. Among the most common and debilitating of these is cognitive impairment, often referred to as “brain fog,” which affects over 80% of people with Long COVID. Given the hundreds of millions of global cases, Long COVID represents a massive public health and socioeconomic challenge, as it severely impacts people’s ability to work and perform daily activities.

Unfortunately, despite its prevalence, the underlying causes of Long COVID and brain fog remain poorly understood. Previous imaging studies have shown some structural changes in the brain, but they could not pinpoint the molecular dysfunctions responsible for the cognitive symptoms. Since it’s difficult to observe the molecules that govern communication between brain cells directly, researchers are left without objective biomarkers to confirm a Long COVID diagnosis or develop therapies.

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 01, 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.

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.

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Reference       
DOI: 10.1093/braincomms/fcaf337

About Yokohama City University
Located in the international city of Yokohama, Yokohama City University has 4 campuses, 5 schools, 6 graduate schools, 2 affiliated research centers, and 2 affiliated hospitals that serve as the bases for education, research, and medical care. Research emerging from Yokohama City University contributes to state-of-the-art technology with a global outlook. Aiming to contribute to the advancement of science and the global community, Yokohama City University also provides support to an array of global standard research programs.

About Professor Takuya Takahashi from Yokohama City University
Dr. Takuya Takahashi obtained a PhD from Yale University in 2000. He joined Yokohama City University in 2006, where he currently serves as a full Professor. He specializes in neuroscience and brain research, particularly in AMPA receptor synaptic migration as a molecular mechanism of synaptic plasticity, with potential for diagnostic and treatment advances in psychiatric and neurological diseases. He has published over 60 papers on these topics.

Funding information
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.).