Low doses of Perampanel protect striatal and hippocampal neurons against in vitro ischemia by reversing the ischemia-induced alteration of AMPA receptor subunit composition.

Energy depletion caused by ischemic brain insults may result in persistent neuronal depolarization accompanied by hyper-stimulation of ionotropic glutamate receptors and excitotoxic phenomena, possibly leading to cell death. The use of glutamate receptor antagonists, such as the AMPARs antagonist Perampanel (PER), might be a pharmacological approach to counteract the excessive over-activation of glutamate receptors providing neuroprotective effects. Using electrophysiological and molecular analyses, we investigated the effect of PER against in vitro ischemia obtained by oxygen and glucose deprivation (OGD) in rat slices of two brain structures particularly sensitive to ischemic insults, the nucleus striatum and the hippocampus. We found that in these regions PER was able to avoid the OGD-induced neuronal suffering, at low doses not reducing basal excitatory synaptic transmission and not altering long-term potentiation (LTP) induction. Furthermore, in both the analysed regions, PER blocked a pathological form of LTP, namely ischemic LTP (iLTP). Finally, we hypothesized that the protective effect of PER against OGD was due to its capability to normalize the altered synaptic localization and function of AMPAR subunits, occuring after an ischemic insult. Taken together these findings support the idea that PER is a drug potentially effective to counteract ischemic damage.

Cognitive performances in patients affected by late-onset epilepsy with unknown etiology: A 12-month follow-up study.

INTRODUCTION: Epilepsy has a growing frequency, particularly in the elderly. Several triggers may cause late-onset epilepsy; however, more than 20% of epilepsies, manifesting in the elderly, has an unknown etiology. Although cognition is frequently altered in patients affected by epilepsy, there is a paucity of studies specifically evaluating cognition in patients affected by late-onset epilepsy. The aim of the present study was to assess the cognitive profile of patients affected by late-onset epilepsy with an unknown etiology and followed for 12 months. METHODS: Patients affected by diagnosed late-onset epilepsy with unknown etiology were included in this observation. All patients were evaluated at the time of diagnosis (baseline) and at follow-up (12 months later). We distributed patients in subgroups based on seizure type (focal seizures [FS], secondarily generalized seizures [SGS], primarily generalized seizures [GS]) and antiepileptic drug (AED) regimen (mono- vs. polytherapy). Cognition was evaluated through standardized neuropsychological testing. RESULTS: Fifty-eight patients were included in this observation and distributed in three groups: 29 affected by FS, 14 affected by SGS, 15 affected by GS. Forty-five patients were in monotherapy, and 13 in polytherapy. The most frequent treatments were levetiracetam (n = 12), valproic acid (VPA) (n = 9), carbamazepine (n = 9), and oxcarbazepine (n = 7). We documented a significant decrease of Mini-Mental State Examination (MMSE) and memory scores at follow-up in the whole group. Verbal learning decreased exclusively in VPA users. CONCLUSION: Patients affected by late-onset epilepsy with unknown etiology showed a significant decline of cognition at follow-up, independently from number and efficacy of AEDs received. These results deserve verification in larger longitudinal cohorts.

Alzheimer's disease and late-onset epilepsy of unknown origin: two faces of beta amyloid pathology.

Although amyloid pathology plays a role in epilepsy, little is known about the relationship between beta amyloid and progression to Alzheimer's disease (AD) among patients with late-onset epilepsy of unknown origin (LOEU). This multicenter, observational, prospective study enrolled 40 consecutive nondemented adults diagnosed with LOEU, together with 43 age- and sex-matched healthy controls. All patients completed neuropsychological tests, core CSF AD biomarkers assessment (Aß1-42, total tau, and phosphorylated tau), and follow-up for a mean of 3 years to verify cognitive decline. Despite age and baseline cognitive performance were similar to healthy controls, patients with LOEU had significant prevalence of CSF pathological Aß1-42 (<500 pg/mL; 37.5%), 7.5% displaying an AD-like CSF pattern. Moreover, 17.5% of patients with LOEU converted to AD dementia, versus none among healthy controls (p < 0.005). Patients with LOEU with pathological Aß1-42 had a hazard ratio 3.4 (CI 0.665-17.73) for progression to AD dementia at follow-up. Patients with LOEU have a high prevalence of abnormal CSF Aß1-42 and progression to AD dementia compared with healthy controls, and therefore should be monitored for cognitive decline.