A RECENT neuroimaging study has identified widespread increases in synaptic AMPA receptor density in patients with cognitive symptoms of long COVID (Cog-LC), suggesting a potential diagnostic and therapeutic target.
Long COVID Linked to Excess Synaptic Activity
Long COVID, particularly in patients experiencing persistent cognitive symptoms (Cog-LC), continues to present a major healthcare challenge. Despite global concern, the underlying neural mechanisms driving cognitive impairment post-COVID remain elusive. Researchers from a new study used advanced PET imaging with [11C]K-2, a marker for AMPA receptor (AMPAR) density, to assess synaptic changes in patients with Cog-LC. As AMPARs play a key role in neural communication and memory, their abnormal expression could underpin the persistent cognitive symptoms reported in these individuals. This insight could pave the way for novel diagnostic and therapeutic strategies aimed at the synaptic level.
Advanced PET Scan Reveals Widespread AMPAR Upregulation
The study compared PET scans from 30 patients with Cog-LC and 80 healthy controls, using statistical parametric mapping to assess differences in AMPAR density across brain regions. Results showed significantly elevated AMPAR density in widespread areas of the brain in patients with long COVID. These findings were consistent across both voxel-based and volume-of-interest analyses, with correlations noted between AMPAR levels and plasma concentrations of cytokines TNFSF12 (positive) and CCL2 (negative). These biomarkers may reflect underlying neuroinflammatory or excitotoxic processes contributing to cognitive dysfunction.
Diagnostic Accuracy and Therapeutic Potential in Long COVID
Using a partial least squares classification algorithm, the researchers achieved 100% sensitivity and 91.2% specificity in distinguishing Cog-LC patients from healthy individuals based on AMPAR density. This strong diagnostic performance highlights [11C]K-2 PET as a promising clinical tool for identifying Cog-LC. Moreover, the observed upregulation of AMPARs raises the hypothesis that AMPAR antagonists, such as perampanel, may offer therapeutic benefits. The authors call for large-scale clinical trials to validate these findings and explore targeted interventions.
This study identifies abnormal AMPAR-mediated excitatory signalling as a potential mechanism of cognitive dysfunction in long COVID and introduces [11C]K-2 PET as a candidate diagnostic modality. Future trials are needed to confirm therapeutic avenues.
Reference
Fujimoto Y et al. Systemic increase of AMPA receptors associated with cognitive impairment of long COVID. Brain Commun. 2025;7(5):fcaf337.
