Abstracts

Rationale: Patients with chronic active epilepsy suffer from accelerated cognitive decline, and are at greater risk of developing Alzheimer's disease, but the exact underlying mechanisms are unknown. We hypothesize that a neurodegenerative process involving hyperphosphorylated tau protein and its neurofibrillary tangle aggregate form, a hallmark of Alzheimer's disease, occurs in epilepsy patients.Methods: We performed pathological examination on tissue from 33 patients who had undergone temporal lobectomy at ages between 50 and 65 years to treat refractory epilepsy secondary to hippocampal sclerosis. Tau protein was identified using immunohistochemistry for AT8 and a modified tau score and limited Braak staging was recorded. Pathology findings were correlated with clinical data including pre-operative and one year post-operative neuropsychometry.Results: Twenty-nine of 33 cases (87.8%) showed evidence of hyperphosphorylated tau in the form of neuropil threads and neurofibrillary tangles. The distribution follows an early Braak pattern with transentorhinal cortex involvement before the entorhinal cortex. Braak staging I to IV were observed (higher stages limited by available resected tissue). The modified tau score, between 0-6, allowed quantification of lower levels of hyperphosphorylated tau burden with greater sensitivity than the incomplete Braak staging. There was no correlation between modified tau score vs. pre-operative neuropsychometry, patient age or duration of epilepsy. Modified tau score correlated with drop in cognitive scores over time between pre-operative and one year post-operative neuropsychometry, including verbal learning z-score drop (Pearson correlation, r=0.53, p<0.05) (Figure 1.) and visual delay z-score drop (Pearson correlation, r=0.18). From the study cohort, one patient developed Alzheimer's disease two years post-operatively with no evidence of the disease on pre-operative assessment. This patient had the highest modified tau score (6) in the study.Conclusions: Our study offers a unique opportunity to assess cognitive change over time in relation to pathological findings and provides evidence for a contributory neurodegenerative process, accelerated from normal ageing, involving hyperphosphorylated tau and neurofibrillary tangles in refractory epilepsy patients. Our findings also support previous observations that tau pathology occurs early within the disease time course of Alzheimer's disease, up to several years, before development of initial memory impairment (pre-symptomatic phase).