The neuropathology of 'dementia epileptica'

ObjectiveAccumulation of hyperphosphorylated tau (pTau) is a proposed mechanism for demen{-}tia associated with epileptic seizures but the evidence directly linking seizures and pTau accumula{-}tion remains weak. Here, we aimed at determining the burden of pTau pathology in a historical co{-}hort of epilepsy patients who developed dementia hypothesizing an association between seizure onset zone and pTau accumulation. MethodsPost-mortem brain tissue was obtained from the Danish Brain Collection comprising autopsies from psychiatric patients that died between 1945-1982. 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. ResultsThirty-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 (0-108) ranging from 2 (almost unde-tectable) to 94 (high load; median 6.5). pTau burden was significantly associated with age at death (Spearmans rho = 0.62, p < 0.001) and duration of epilepsy (Spearmans 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 hemi{-}sphere. 81.3% of all patients (n=26) had a competing dementia diagnosis: three patients fulfilled the pathological criteria of Alzheimers dementia, 13 patients had clinical and/or autoptic diagnosis of vascular dementia. SignificanceIn 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.