Association of synaptic density and cognitive performance in temporal lobe epilepsy: Humans and animals PET imaging study with [18F]SynVesT-1

Aim: Cognitive impairment is a common comorbidity in individuals with temporal lobe epilepsy (TLE), yet the underlying mechanisms remain unknown. This study explored the putative association between in vivo synaptic loss and cognitive outcomes in TLE patients by PET imaging of synaptic vesicle glycoprotein 2A (SV2A). Methods: We enrolled 16 TLE patients and 10 cognitively normal controls. All participants underwent SV2A PET imaging using [F-18]SynVesT-1 and cognitive assessment. Lithium chloride-pilocarpine-induced rats with status epilepticus (n = 20) and controls (n = 6) rats received levetiracetam (LEV, specifically binds to SV2A), valproic acid (VPA), or saline for 14 days. Then, synaptic density was quantified by [F-18]SynVesT-1 micro-PET/CT. The novel object recognition and Morris water maze tests evaluated TLE-related cognitive function. SV2A expression was examined and confirmed by immunohistochemistry. Results: Temporal lobe epilepsy patients showed significantly reduced synaptic density in hippocampus, which was associated with cognitive performance. In the rat model of TLE, the expression of SV2A and synaptic density decreased consistently in a wider range of brain regions, including the entorhinal cortex, insula, hippocampus, amygdala, thalamus, and cortex. We treated TLE animal models with LEV or VPA to explore whether synaptic loss contributes to cognitive deficits. It was found that LEV significantly exerted protective effects against brain synaptic deficits and cognitive impairment. Conclusion: This is the first study to link synaptic loss to cognitive deficits in TLE, suggesting [F-18]SynVesT-1 PET could be a promising biomarker for monitoring synaptic loss and cognitive dysfunction. LEV might help reverse synaptic deficits and ameliorate learning and memory impairments in TLE patients.