Assessment of tau phosphorylation and β-amyloid pathology in human drug-resistant epilepsy.

Abstract

Epilepsy can be comorbid with cognitive impairments. Recent evidence suggests the possibility that cognitive decline in epilepsy may be associated with mechanisms typical of Alzheimer's disease (AD). Neuropathological hallmarks of AD have been found in brain biopsies surgically resected from patients with drug-resistant epilepsies. These include hyperphosphorylation of the tau protein (p-tau) that aggregates into neuropil threads (NT) or neurofibrillary tangles (NFT), as well as the presence of β-amyloid (Aβ) deposits. While recent studies agree on these AD neuropathological findings in epilepsy, some contrast in their correlation to cognitive decline. Thus, to further address this question we determined the abundance of p-tau and Aβ proteins along with their association with cognitive function in 12 cases of refractory epilepsy. Cortical biopsies surgically extracted from the temporal lobes of patients with refractory epilepsy were processed for immunohistology and enzyme-linked immunoassays to assess distribution and levels, respectively, of p-tau (Antibodies: Ser202/Thr205; Thr205; Thr181) and Aβ proteins. In parallel, we measured the activation of mechanistic target of rapamycin (mTOR) via p-S6 (Antibodies: Ser240/244; Ser235/236). Pearson correlation coefficient analysis determined associations between these proteins and neurophysiological scores for full-scale intelligence quotient (FSIQ). We found a robust presence of p-tau (Ser202/Thr205)-related NT and NFT pathology, as well as Aβ deposits, and p-S6 (Ser240/244; Ser235/236) in the epilepsy biopsies. We found no significant correlations between p-tau (Thr205; Thr181), Aβ, or mTOR markers with FSIQ scores, although some correlation coefficients were modest to strong. These findings strongly support the existence of hyperphosphorylated tau protein and Aβ deposits in patients with human refractory epilepsy. However, their relation to cognitive decline is still unclear and requires further investigation.