Neurofibrillary tangle pathology and Braak staging in chronic epilepsy in relation to traumatic brain injury and hippocampal sclerosis: a post-mortem study

Abstract

The long-term pathological effects of chronic epilepsy on normal brain ageing are unknown. Previous clinical and epidemiological studies show progressive cognitive decline in subsets of patients and an increased prevalence of Alzheimer's disease in epilepsy. In a post-mortem series of 138 patients with long-term, mainly drug-resistant epilepsy, we carried out Braak staging for Alzheimer's disease neurofibrillary pathology using tau protein immunohistochemistry. The stages were compared with clinicopathological factors, including seizure history and presence of old traumatic brain injury. Overall, 31% of cases were Braak Stage 0, 36% Stage I/II, 31% Stage III/IV and 2% Stage V/VI. The mean age at death was 56.5 years and correlated with Braak stage (P < 0.001). Analysis of Braak stages within age groups showed a significant increase in mid-Braak stages (III/IV), in middle age (40–65 years) compared with data from an ageing non-epilepsy series (P < 0.01). There was no clear relationship between seizure type (generalized or complex partial), seizure frequency, age of onset and duration of epilepsy with Braak stage although higher Braak stages were noted with focal more than with generalized epilepsy syndromes (P < 0.01). In 30% of patients, there was pathological evidence of traumatic brain injury that was significantly associated with higher Braak stages (P < 0.001). Cerebrovascular disease present in 40.3% and cortical malformations in 11.3% were not significantly associated with Braak stage. Astrocytic-tau protein correlated with the presence of both traumatic brain injury (P < 0.01) and high Braak stage (P < 0.001). Hippocampal sclerosis, identified in 40% (bilateral in 48%), was not associated with higher Braak stages, but asymmetrical patterns of tau protein accumulation within the sclerotic hippocampus were noted. In over half of patients with cognitive decline, the Braak stage was low indicating causes other than Alzheimer's disease pathology. In summary, there is evidence of accelerated brain ageing in severe chronic epilepsy although progression to high Braak stages was infrequent. Traumatic brain injury, but not seizures, was associated with tau protein accumulation in this series. It is likely that Alzheimer's disease pathology is not the sole explanation for cognitive decline associated with epilepsy.

Hippocampal Sclerosis and Epilepsy in Elderly Population

“…Noteworthy, five of our 23 demented subjects had a final diagnosis of FTLD-TDP, and none of these subjects had displayed EP during life. Thus, our observations are in line with previous reports indicating that TDP43 pathology, even if being associated with HS, does not increase the risk for seizures [39,40].…”

Cell injury and Premature Neurodegeneration in Focal Malformations of Cortical Development

“…The increased expression of APP was, however, not associated with deposition of amyloid -b in our cohort. In a previous study (53), amyloid -b IR was detected in the dysplastic zone only in the oldest two FCD IIb patients (age > 50 years) and there was an absence of amyloid -b-positive plaques in the large majority (66%) of epilepsy cases in a large cohort of patients with hippocampal sclerosis (59).…”

Is phosphorylated tau unique to chronic traumatic encephalopathy? Phosphorylated tau in epileptic brain and chronic traumatic encephalopathy

“…An important caveat of all these studies is the fact that most if not all specimens derived from post mortem brain. This was true for samples from football players, blast TBI patients or epileptic subjects (3;9;10). Since a post mortem analysis is required for the evaluation of brain phosphorylated tau in CTE, a positive correlation with a given pathology has been difficult.…”