Do Patients With Temporal Lobe Epilepsy and Cognitive Decline Have Alzheimer's Disease or Chronic Traumatic Encephalopathy (CTE)?

Commentary

Hyperphosphorylated Tau in Patients With Refractory Epilepsy Correlates With Cognitive Decline: a Study of Temporal Lobe Resections.

Tai XY, Koepp M, Duncan JS, Fox N, Thompson P, Baxendale S, Liu JYW, Reeves C, Michalak Z, Thom M. Brain 2016;139pt 9:2441–2455. doi: 10.1093/brain/aww187.

Temporal lobe epilepsy, the most prevalent form of chronic focal epilepsy, is associated with a high prevalence of cognitive impairment but the responsible underlying pathological mechanisms are unknown. Tau, the microtubule-associated protein, is a hallmark of several neurodegenerative diseases including Alzheimer's disease and chronic traumatic encephalopathy. We hypothesized that hyperphosphorylated tau pathology is associated with cognitive decline in temporal lobe epilepsy and explored this through clinico-pathological study. We first performed pathological examination on tissue from 33 patients who had undergone temporal lobe resection between ages 50 and 65 years to treat drug-refractory temporal lobe epilepsy. We identified hyperphosphorylated tau protein using AT8 immunohistochemistry and compared this distribution to Braak patterns of Alzheimer's disease and patterns of chronic traumatic encephalopathy. We quantified tau pathology using a modified tau score created specifically for analysis of temporal lobectomy tissue and the Braak staging, which was limited without extra-temporal brain areas available. Next, we correlated tau pathology with pre- and postoperative cognitive test scores and clinical risk factors including age at time of surgery, duration of epilepsy, history of secondary generalized seizures, history of head injury, handedness and side of surgery. Thirty-one of 33 cases (94%) showed hyperphosphorylated tau pathology in the form of neuropil threads and neurofibrillary tangles and pre-tangles. Braak stage analysis showed 12% of our epilepsy cohort had a Braak staging III–IV compared to an age-matched non-epilepsy control group from the literature (8%). We identified a mixture of tau pathology patterns characteristic of Alzheimer's disease and chronic traumatic encephalopathy. We also found unusual patterns of subpial tau deposition, sparing of the hippocampus and co-localization with mossy fibre sprouting, a feature of temporal lobe epilepsy. We demonstrated that the more extensive the tau pathology, the greater the decline in verbal learning (Spearman correlation, r = −0.63), recall (r = −0.44) and graded naming test scores (r = −0.50) over 1-year post-temporal lobe resection (P < 0.05). This relationship with tau burden was also present when examining decline in verbal learning from 3 months to 1 year post-resection (r = −0.54). We found an association between modified tau score and history of secondary generalized seizures (likelihood-ratio χ², P < 0.05) however there was no clear relationship between tau pathology and other clinical risk factors assessed. Our findings suggest an epilepsy-related tauopathy in temporal lobe epilepsy, which contributes to accelerated cognitive decline and has diagnostic and treatment implications.

Results from an increasing number of studies have indicated that the trajectory of cognitive changes in patients with temporal lobe epilepsy (TLE) differs from the pattern observed in healthy aging. There are now descriptions of two forms of cognitive decline associated with TLE (1). One is characterized by a slow and gradual pattern of deterioration, which appears to be associated with seizures, treatment, and other related effects secondary to epilepsy. This constitutes what many have labeled as a form of “epileptic dementia.” The second form is characterized by cognitive changes observed in a stepwise fashion, occurring when seizures develop in an individual with reduced cognitive reserve secondary to age effects or a discrete neurologic event, such as a stroke or traumatic brain injury (TBI). While there has been increasing knowledge on the clinical manifestations of these two forms of cognitive decline in TLE, little is known about the underlying pathological mechanisms.

One approach to understanding the pathology underlying cognitive decline in TLE has been to make comparisons with other neurodegenerative disorders, Alzheimer's disease (AD) being the most prevalent and obvious candidate. It is known that unprovoked seizures develop in patients with AD at a higher rate than what is observed in the general population, raising questions about some inherent link between AD and epilepsy (2). As the underlying mechanism, it has been suggested that neuronal hyperexcitability increases synaptic release of amyloid beta (Aβ), which causes an accelerated cycle of cell death and cognitive decline in patients with AD (3). There have been suggestions that a similar process involving Aβ dysfunction or related mechanisms might be responsible for the progression of cognitive deficits and other behavioral features observed in patients with epilepsy (4).

Another approach has been to conceptualize the cognitive changes in TLE as a consequence of an underlying tauopathy. Increased focus on the study of cognitive changes associated with abnormal tau deposition has resulted from interest in cognitive changes reported to occur in athletes and others exposed to repetitive TBI. In fact, McKee and colleagues (5) included patients with epilepsy among their original series of patients confirmed to have chronic traumatic encephalopathy (CTE). Recent studies demonstrating abnormal tau deposition in the brains of patients with TLE (6) raise important questions about the specificity of abnormal tau findings in CTE and whether cognitive changes in patients with epilepsy can be attributed to the effects of abnormal tau deposition.

Results from studies analyzing surgically resected tissue in patients with TLE have provided support for both Aβ and tau pathology. In one study, the presence of senile amyloid plaques was observed in 10% of the sample of temporal lobe specimens, suggesting that the process underlying TLE has a positive influence on plaque formation (7). In another study, microtubule-associated proteins, including tau, were present in hippocampal tissue with a pattern of dispersion noted in the granular layer (8). However, attempts to relate these pathological findings to relevant clinical variables have yielded variable and inconclusive results.

In a study published recently in Brain, Tai et al. investigated the extent, nature, and significance of tau pathology from resected tissue obtained in subjects with TLE aged 50 to 65 years at the time of surgery. This study is a follow-up to a previously published investigation from this group, which had found neurofibrillary tangle pathology with age-accelerated changes in postmortem analysis of 138 patients with chronic refractory epilepsy in comparison to control subjects without epilepsy (9). The goal of the study by Tai et al. was to compare and contrast the findings to those reported for studies on AD and CTE and to determine the relationship of the pathological findings to the presence of postoperative cognitive decline.

The investigators performed pathological examination on surgically resected tissue from 33 subjects using AT8 (hyperphosphorylated tau) and Aβ-4 immunohistochemistry in association with semiquantitative methods. The presence and location of tau pathology were analyzed using modified Braak staging criteria, while the amyloid pathology was assessed through scores based on Consortium to Establish a Registry for Alzheimer's Disease methodology. The pathological data were analyzed in relation to a published series of postmortem data obtained from AD, CTE, and nonepilepsy control samples. Comparisons were made to clinical risk factors and neuropsychological test scores obtained before and after surgery.

Evidence of hyperphosphorylated tau pathology (e.g., neuropil threads, neurofibrillary tangles, and pre-tangles) was found in 31 of the 33 temporal lobe specimens. Ten of the specimens exhibited a Braak staging pattern of tau pathology within the transentorhinal and entorhinal regions compared with the temporal neocortex, similar to what is commonly seen in patients with AD. However, in contrast to what is typically seen in AD, this was observed in the absence of Aβ pathology. A “CTE-like” pattern of tau pathology was found in eight specimens, although there was a noted lack of perivascular and sulcal location of the pathology. The investigators identified a novel pattern of pathology in the remaining 18 specimens, resulting in an identified pattern that appears to be unique to TLE, characterized by subpial tau deposition, sparing the hippocampus and corresponding to a pattern of mossy fiber sprouting. The authors interpret this new pattern as representing a possible “axonal-tauopathy” resulting from a combination of seizure activity, neuronal loss, and a reorganization of temporal lobe networks.

The general pattern of tau pathology identified in this study was associated with a history of secondarily generalized seizures but was not found to be related to any other risk factors, including the duration of epilepsy or a history of TBI. The degree of tau pathology was not associated with neuropsychological test results obtained at the time of surgery. However, there was an association with an observed decline in verbal learning performance from 3 months to 1 year after resection, suggesting that the presence of tau pathology contributes to some form of accelerated cognitive decline in patients with TLE.

In response to the question raised by the title of this commentary, there is evidence from this study of substantial overlap in the pattern of abnormal tau deposition observed in patients with TLE compared with those with AD and CTE. The findings from this study raise intriguing questions about the presence of a possibly unique form of tauopathy associated with TLE while casting doubt on the proposed specificity of the pathological findings that have been attributed to AD and CTE (6, 10).

Returning to the two clinical profiles of cognitive decline observed in epilepsy (1), there is a possibility that the classic epileptic dementia could be differentiated from the pattern of stepwise decline on the basis of the differing patterns of tau deposition observed in this study. By any means, it is clear that studies focusing on the pathological mechanisms shared between dementia, TBI, and epilepsy have the potential to identify strategies for the treatment of cognitive decline resulting from TLE and a variety of other neurodegenerative disorders.