Imaging correlates of behavioral impairments: An experimental PET study in the rat pilocarpine epilepsy model

Psychiatric comorbidities are prevalent in patients with epilepsy and greatly contribute to the overall burden of disease. The availability of reliable biomarkers to diagnose epilepsy-associated comorbidities would allow for effective treatment and improved disease management. Due to their non-invasive nature, molecular imaging techniques such as positron emission tomography (PET) are ideal tools to measure pathologic changes. In the current study we investigated the potential of [¹⁸F]fluoro-2-deoxy-d-glucose ([¹⁸F]FDG) and 2'-methoxyphenyl-(N-2'-pyridinyl)-p-¹⁸F-fluoro-benzamidoethylpiperazine ([¹⁸F]MPPF) as imaging correlates of neurobehavioral comorbidities in the pilocarpine rat model of epilepsy. Findings from rats with epilepsy revealed a regional reduction in [¹⁸F]FDG uptake indicating thalamic hypometabolism. In addition, an increase in septal [¹⁸F]MPPF binding was observed in rats with spontaneous recurrent seizures. Both thalamic [¹⁸F]FDG and septal [¹⁸F]MPPF data proved to correlate with behavioral alterations including decreases in luxury behavior such as burrowing and social interaction, and changes in behavioral patterns in anxiety tests. A correlation with seizure frequency was confirmed for thalamic [¹⁸F]FDG data. Moreover, thalamic [¹⁸F]FDG and septal [¹⁸F]MPPF data exhibited a correlation with brain-derived neurotrophic factor (BDNF) serum concentrations, which were lowered in rats with epilepsy. In conclusion, μPET data from rats with pilocarpine-induced epileptogenesis indicate altered septal 5-HT_1A receptor binding. Further research is necessary assessing whether septal 5-HT_1A receptor binding may serve as an imaging correlate of neuropsychiatric comorbidities in epilepsy patients and for severity assessment in rodent epilepsy models. In contrast, we obtained evidence that [¹⁸F]FDG uptake also reflects the severity of epilepsy and, thus, might not constitute a biomarker with sufficient specificity for psychiatric comorbidities. Evidence has been obtained that BDNF might serve as a peripheral circulatory biomarker. Further experimental and clinical assessment is necessary for validation of the marker candidates.