Unraveling the Molecular Causes of Long COVID Brain Fog

Even after several years since the onset of the COVID-19 pandemic, the full scope of SARS-CoV-2's long-term effects remains unclear. Among these, long COVID—a persistent condition following infection—presents a major health challenge, with symptoms that can last for months or even longer. One of the most troubling symptoms reported is cognitive impairment, commonly called "brain fog," which impacts over 80% of individuals suffering from long COVID.

This cognitive difficulty hampers memory, concentration, and mental clarity, significantly affecting daily functioning and quality of life. The widespread nature of long COVID and its profound effects underscore the urgent need to understand its underlying mechanisms.

Despite its prevalence, the root causes of long COVID and associated brain fog have eluded scientists. Earlier neuroimaging studies revealed some structural brain changes, but these did not clarify the molecular dysfunctions responsible for cognitive issues. Because direct observation of the molecules involved in brain cell communication is challenging, clinicians lack definitive biomarkers to diagnose long COVID accurately or develop effective treatments.

Addressing this gap, a research team led by Professor Takuya Takahashi from Yokohama City University, Japan, has made significant strides in understanding the molecular basis of long COVID brain fog. Their recent study, published in Brain Communications, hypothesized that altered expression of AMPA receptors (AMPARs)—integral to learning and memory—may be involved in the condition. This inference was based on previous findings linking AMPAR disruptions to psychiatric and neurological disorders such as depression, bipolar disorder, schizophrenia, and dementia.

To investigate this, the researchers employed advanced [11C]K-2 AMPAR PET imaging technology, a novel method to visualize and quantify AMPAR levels in the living brain. They compared brain scans from 30 long COVID patients with cognitive impairment to those of 80 healthy controls. The results revealed a widespread increase in AMPAR density in the brains of affected individuals, which was closely associated with the severity of their cognitive symptoms.

Furthermore, the study found correlations between elevated AMPAR levels and inflammatory markers, suggesting an interaction between inflammation and receptor expression. This systemic increase in AMPARs offers a biological explanation for brain fog in long COVID, pointing towards potential therapeutic targets—such as drugs that suppress overactive AMPAR activity.

Remarkably, the imaging technique demonstrated perfect sensitivity and high specificity in distinguishing long COVID patients from healthy individuals, highlighting its diagnostic potential. Professor Takahashi emphasized that this technology could provide new insights and innovative solutions for managing long COVID.

While further research is necessary to develop definitive treatments, these findings mark an important step forward. Recognizing long COVID brain fog as a legitimate clinical condition could encourage the healthcare industry to accelerate the development of diagnostic tools and therapies. Ultimately, this research enhances our understanding of the biological basis of long COVID, paving the way for improved patient care and outcomes.

Source: https://medicalxpress.com/news/2025-10-uncovering-molecular-basis-covid-brain.html