Hyperphosphorylated tau pathology in patients with epilepsy and dementia - Neuropathological insights from a historical autopsy cohort.

OBJECTIVE: Accumulation of hyperphosphorylated tau (pTau) is a proposed mechanism for dementia associated with epileptic seizures but the evidence directly linking seizures and pTau accumulation remains weak. Here, we aimed at determining the burden of pTau pathology in a historical cohort of epilepsy patients who developed dementia hypothesizing an association between seizure onset zone and pTau accumulation. METHODS: Post-mortem brain tissue was obtained from the Danish Brain Collection comprising autopsies from psychiatric patients that died between 1945 and 1982. Sections from the middle frontal gyrus, thalamus, and medial temporal lobe from both hemispheres were stained for pTau and beta-amyloid and quantified by a blinded assessor. Comparisons were conducted using non-parametric tests. RESULTS: Thirty-two patients (median age 61.5 years, 59.4% men) were included. pTau pathology was detected in 22 brains (68.8%), with Tau Burden Scores (0-100) ranging from 2 (almost undetectable) to 94 (high load; median 6.5). pTau burden was significantly associated with age at death (Spearman's rho = 0.62, p < 0.001) and duration of epilepsy (Spearman's rho = 0.47, p = 0.02), but not with other clinical variables. Among 11 patients with focal seizures, a significantly higher pTau (p = 0.02) but not a higher beta-amyloid burden (p = 1.0) was observed in the epileptogenic hemisphere. 81.3% of all patients (n = 26) had a competing dementia diagnosis: three patients fulfilled the pathological criteria of Alzheimer's dementia, 13 patients had clinical and/or autoptic diagnosis of vascular dementia. SIGNIFICANCE: In this cohort, dementia epileptica was associated with increased pTau burden in the epileptogenic hemisphere and time since diagnosis supporting the concept of seizure-induced pTau accumulation. However, pTau is unlikely to be the primary neuropathological link between epilepsy and dementia in the cohort studied given the overall mild pathology and competing diagnoses.