Cognitive Deficits in Temporal Lobe Epilepsy and Alzheimer-like Pathologies

Post by Amanda McFarlan

What's the science?

Temporal lobe epilepsy (TLE) is a chronic, debilitating disorder characterized by spontaneous, recurring focal seizures originating in the temporal lobe. TLE is commonly treated with antiepileptic drugs, however, approximately one-third of individuals with TLE are resistant to drug-related treatments. Importantly, recent studies in brain imaging have shown that drug-resistant individuals with TLE exhibit signs of advanced brain aging, similar to what is observed in patients with Alzheimer’s disease. This week in Brain, Gourmand and colleagues investigated the link between cognitive dysfunction, amyloid and tau pathologies, and epileptogenesis in individuals with drug-resistant TLE.

How did they do it?

The authors acquired brain tissue from three groups: individuals with TLE, individuals with Alzheimer’s disease (positive control group), and a control group. For the TLE group, they obtained brain tissue that was collected during an anterior temporal lobe resection in 19 patients with drug-resistant TLE. All the TLE patients were given a neuropsychological exam to assess their memory, language, and executive function before undergoing their surgical procedure. Additionally, the authors obtained post-mortem temporal lobe tissue collected from 22 individuals (control group) and 9 individuals (Alzheimer’s group) with no prior history of seizures. They used western blot analysis and immunohistochemistry to identify and compare the expression of proteins involved in amyloid and tau pathologies in the tissue samples from all three groups.

What did they find?

The authors found a significant increase in phosphorylated amyloid precursor protein (this protein yields amyloid beta peptide when cut by cleaving enzymes) in both the hippocampus and temporal cortex of the TLE group and Alzheimer’s group compared to controls. They also found increased expression of amyloid-Beta42 (a product of amyloidogenic processing) in the hippocampus of the TLE group and Alzheimer’s group compared to controls. Next, they showed that the temporal cortex had increased expression of BACE1 (cleaving enzyme involved in amyloidogenic processing), but no change in the expression of ADAM10 (cleaving enzyme involved in non-amyloidogenic processing) in the TLE group and Alzheimer’s group compared to controls. Together, these findings suggest that individuals with drug-resistant TLE exhibit amyloid pathologies similar to those observed in individuals with Alzheimer’s disease. Next, the authors showed that the expression of hyperphosphorylated tau was upregulated in the hippocampus and temporal cortex of the TLE and Alzheimer’s groups compared to controls, however, the increase was much higher in the Alzheimer’s group. Notably, the authors determined that the TLE group did not show any evidence of aggregated tau (i.e. neurofibrillary tangles) that are present in Alzheimer’s disease, suggesting that tau pathology in individuals with TLE is not as prominent as that observed in Alzheimer’s disease. Finally, the authors showed that hippocampal phosphorylated amyloid precursor protein and hyperphosphorylated tau were negatively correlated with executive function in individuals with drug-resistant TLE, suggesting that upregulation of these proteins may be involved in impaired cognitive function in individuals with TLE. 

What’s the impact?

This is the first study to show that brain tissue from individuals with drug-resistant TLE exhibits similar amyloid and tau pathologies as observed in Alzheimer’s disease. The authors also showed that increased expression of molecular markers associated with amyloid and tau production was correlated with impairment in executive function in individuals with TLE. Together, these findings suggest that amyloid and tau pathologies may underlie the cognitive dysfunction observed in drug-resistant TLE. Therefore, targeting these pathways for therapeutic intervention may help to treat or stop cognitive decline in individuals with TLE.

Gourmand et al. Alzheimer-like amyloid and tau alterations associated with cognitive deficit in temporal lobe epilepsy. Brain (2019). Access the original scientific publication here.