Abstract
Brain inflammation is an important factor in the conversion of a healthy brain into an epileptic one, a phenomenon known as epileptogenesis, offering a new entry point for prognostic tools. The development of anti-epileptogenic therapies to treat before or at disease onset is hampered by our inability to predict the severity of the disease outcome. In a rat model of temporal lobe epilepsy we aimed to assess whether in vivo non-invasive imaging of brain inflammation at disease onset was predictive of spontaneous recurrent seizures (SRS) frequency and severity of depression-like and sensorimotor-related comorbidities. To this end, translocator protein, a biomarker of inflammation, was imaged by means of positron emission tomography (PET) 2 and 4weeks post-status epilepticus using [18F]-PBR111. Translocator protein was highly upregulated 2weeks post-status epilepticus in limbic structures (up to 2.1-fold increase compared to controls in temporal lobe, P<0.001), whereas 4weeks post-status epilepticus, upregulation decreased (up to 1.6-fold increase compared to controls in temporal lobe, P<0.01) and was only apparent in a subset of these regions. Animals were monitored with video-electroencephalography during all stages of disease (acute, latent – first seizures appearing around 2weeks post-status epilepticus – and chronic phases), for a total of 12weeks, in order to determine SRS frequency for each subject (range 0.00–0.83SRS/day). We found that regional PET uptake at 2 and 4weeks post-status epilepticus correlated with the severity of depression-like and sensorimotor-related comorbidities during chronic epilepsy (P<0.05 for each test). Regional PET imaging did not correlate with SRS frequency, however, by applying a multivariate data-driven modeling approach based on translocator protein PET imaging at 2weeks post-status epilepticus, we accurately predicted the frequency of SRS (R=0.92; R2=0.86; P<0.0001) at the onset of epilepsy. This study not only demonstrates non-invasive imaging of translocator protein as a prognostic biomarker to ascertain SRS frequency, but also shows its capability to reflect the severity of depression-like and sensorimotor-related comorbidities. Our results are an encouraging step towards the development of anti-epileptogenic treatments by providing early quantitative assessment of SRS frequency and severity of comorbidities with high clinical relevance.
Highlights
Epilepsy is one of the most common chronic neurological disorders, with an estimated prevalence of nearly 65 million people worldwide (Ngugi et al, 2010)
Relatively little progress has been made in identifying biomarkers and developing new therapies directed at comorbidities (BrooksKayal et al, 2013)
We found that regional TSPO positron emission tomography (PET) imaging at disease onset and at established disease correlated with depression-like and somatosensory-related comorbidities during chronic epilepsy (Fig. 2 and Table 1)
Summary
Epilepsy is one of the most common chronic neurological disorders, with an estimated prevalence of nearly 65 million people worldwide (Ngugi et al, 2010). The medicinal therapies available are purely symptomatic, they can have unwanted cognitive or neurobehavioral side effects, and they are ineffective in up to 30% of patients with epilepsy (Kwan and Brodie, 2000), resulting in poor quality of life (Pugliatti et al, 2007). As a consequence, both the prediction and prevention of epilepsy are important public health issues and require urgent attention. These biomarkers will increase our understanding of epileptogenesis and enable early detection and treatment of epilepsy and its comorbidities (Pitkanen et al, 2016)
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