Hyperphosphorylated tau in patients with refractory epilepsy correlates with cognitive decline: a study of temporal lobe resections.
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SEE BERNASCONI DOI101093/AWW202 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: 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 χ(2), 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.
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Increased total and p-tau levels measured in surgically resected tissue from temporal lobe epilepsy patients are inversely correlated with cognitive scores.
“and increased total and p-tau levels measured in surgically resected tissue from TLE patients are inversely correlated with cognitive scores (Kandratavicius et al., 2013; Tai et al., 2016; Gourmaud et al., 2020).”
From Tauopathy and Epilepsy Comorbidities and Underlying Mechanisms (2022) · cites this paper as Tai et al., 2016
The Methods (Analysis of tau and amyloid pathology; page unavailable) describe a score of hyperphosphorylated-tau staining in resected temporal lobe tissue, not measurements of both total tau and p-tau levels. The Results (Modified tau score in relation to age and cognitive testing; page unavailable) report negative correlations with changes in verbal learning, recall, and naming scores over the year after surgery, but no significant correlation with preoperative scores. The claim is supported for p-tau burden and subsequent cognitive decline, not for total tau levels or cognitive scores generally. (LLM, conf=0.89)
Experimental — accuracy not yet measuredObservations of subpial bands formed by cortical p-tau depositions have been made across separate studies, providing evidence for a novel pattern of tau pathology in temporal lobe epilepsy that may result from seizure-induced reorganization of temporal lobe networks.
“Interestingly, observations of subpial bands formed by cortical p-tau depositions have been made across separate studies (Puvenna et al., 2016; Tai et al., 2016; Smith et al., 2019), providing evidence for a novel pattern of tau pathology in TLE that may result from seizure-induced reorganization of temporal lobe networks (Tai et al., 2018).”
From Tauopathy and Epilepsy Comorbidities and Underlying Mechanisms (2022) · cites this paper as Tai et al., 2016
Analysis of resected temporal lobe tissue by Tai et al. (2016) found pathological tau phosphorylation in the form of neuropil threads, neurofibrillary tangles, and pre-tangles in 31 of 33 temporal lobe epilepsy patients between 50 and 65 years of age.
“For instance, analysis of resected temporal lobe tissue by Tai et al. (2016) found pathological tau phosphorylation in the form of neuropil threads, NFTs, and pre-tangles in 31 of 33 TLE patients between 50 and 65 years of age.”
From Tauopathy and Epilepsy Comorbidities and Underlying Mechanisms (2022) · cites this paper as Tai et al., 2016
In humans with chronic epilepsy, elevated p-tau is present in post-mortem as well as surgically resected tissue.
“And in humans with chronic epilepsy, elevated p-tau is present in post-mortem (Thom et al., 2011) as well as surgically resected tissue (Puvenna et al., 2016; Tai et al., 2016; Liu C. et al., 2017; Prada Jardim et al., 2018; Smith et al., 2019; Gourmaud et al., 2020).”
From Tauopathy and Epilepsy Comorbidities and Underlying Mechanisms (2022) · cites this paper as Tai et al., 2016
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- Authors
- Tai, X. Y., Koepp, M., Duncan, J. S., Fox, N., Thompson, P., Baxendale, S., Liu, J. Y. W., Reeves, C., Michalak, Z., & Thom, M.
- Affiliations
- National Hospital for Neurology and Neurosurgery (GB)
- UCL Queen Square Institute of Neurology (GB)
- Corresponding author
- Thom, Maria
- ORCID
- Venue
- Brain
- Publisher
- Oxford University Press (OUP)
- Published
- 2016-08-07
- Volume
- 139
- Issue
- 9
- Pages
- 2441-2455
- ISSN
- 0006-8950 (ISSN-L)
- 1460-2156
- PMC
- PMC5926008
- OpenAlex
- W2513581974
- Cited by
- 291
- References
- 4
- Citations by year
- 2026: 25 · 2025: 35 · 2024: 40 · 2023: 31 · 2022: 29 · 2021: 35 · 2020: 30 · 2019: 32 · 2018: 21 · 2017: 9 · 2016: 4
- FWCI
- 19.55
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Brain (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- WestminsterResearch (University of Westminster) (acceptedVersion)
- UCL Discovery (University College London) (submittedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- National Institute for Health and Care Research (NF-SI-0513-10134, NF-SI-0509-10161, NF-SI-0508-10123, NF-SI-0515-10000)
- European Commission (2007–2013, 602102)
- University College London Hospitals NHS Foundation Trust
- Epilepsy Society
- Medical Research Council (MR/JO127OX/1, 602102, MR/J01270X/1)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- hyperphosphorylated tau, temporal lobe epilepsy, drug-resistant epilepsy, cognitive decline, temporal lobectomy, neuropil threads, neurofibrillary tangles, Braak staging, Alzheimer's disease, chronic traumatic encephalopathy, verbal learning, verbal memory, hippocampus, postoperative cognitive function, neurodegeneration
- MeSH terms
- Drug Resistant Epilepsy, Aged, Epilepsy, Temporal Lobe, Female, Humans, Male, Middle Aged, tau Proteins, Tauopathies, Cognitive Dysfunction
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