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Hyperphosphorylated Tau in Mesial Temporal Lobe Epilepsy: a Neuropathological and Cognitive Study

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Abstract

Temporal lobe epilepsy (TLE) often courses with cognitive deficits, but its underlying neuronal basis remains unclear. Confluent data suggest that epilepsy share pathophysiological mechanisms with neurodegenerative diseases. However, as most studies analyze subjects 60 years old and older, it is challenging to rule out that neurodegenerative changes arise from age-related mechanisms rather than epilepsy in these individuals. To fill this gap, we conducted a neuropathological investigation of the hippocampal formation of 22 adults with mesial TLE and 20 age- and sex-matched controls (both younger than 60 years). Moreover, we interrogated the relationship between these neuropathological metrics and cognitive performance. Hippocampal formation extracted from patients with drug-resistant mesial TLE undergoing surgery and postmortem non-sclerotic hippocampal formation of clinically and neuropathologically controls underwent immunohistochemistry against amyloid β (Aβ), hyperphosphorylated tau (p-tau), and TAR DNA-binding protein-43 (TDP-43) proteins, followed by quantitative analysis. Patients underwent a comprehensive neuropsychological evaluation prior to surgery. TLE hippocampi showed a significantly higher burden of p-tau than controls, whereas Aβ deposits and abnormal inclusions of TDP-43 were absent in both groups. Patients with hippocampal sclerosis (HS) type 2 had higher immunostaining for p-tau than patients with HS type 1. In addition, p-tau burden was associated with impairment in attention tasks and seizures frequency. In this series of adults younger than 60 years-old, the increase of p-tau burden associated with higher frequency of seizures and attention impairment suggests the involvement of tau pathology as a potential contributor to cognitive deficits in mesial TLE.

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Data Availability

The data that support the findings of this study are available from the corresponding author, upon reasonable request.

Abbreviations

Aβ:

Amyloid beta

AEDs:

Antiepileptic drugs

AD:

Alzheimer’s disease

β-APP:

Beta amyloid precursor protein

BNT:

Boston Naming Test

CA:

Cornus Ammonis

CDK5:

Cyclin-dependent kinase 5

CDR:

Clinical Dementia Rating Scale

CTE:

Chronic traumatic encephalopathy

DAB:

Diaminobenzidine

DG:

Dentate gyrus

EOAD:

Early-onset Alzheimer’s disease

FTLD:

Frontotemporal lobar degeneration

GSK3b:

Glycogen synthase kinase 3b

ILAE:

International League Against Epilepsy

MAPT :

Microtubule-associated protein tau

MTLE:

Mesial temporal lobe epilepsy

NFT:

Neurofibrillary tangles

p-tau:

Hyperphosphorylated tau

TDP-43:

TAR DNA-binding protein-43

TLE:

Temporal lobe epilepsy

WAIS:

Wechsler Adult Intelligence Scale

WMS:

Wechsler Memory Scale

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Acknowledgements

We are grateful to the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), and Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG), which funded this study. We also grateful to the patients with MTLE and the Biobank for Aging Studies for the sclerotic and control hippocampi, as well as to the Centro de Aquisição de Imagens (CAPI) da UFMG for the scanning of histological slides.

Author information

Authors and Affiliations

  1. Departamento de Patologia Geral, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil

    Eliana C. B. Toscano & Milene A. Rachid

  2. Departamento de Patologia, Faculdade de Medicina, Universidade Federal de Juiz de Fora, Av. Eugênio do Nascimento, s/no. - 36038-330 - Dom Bosco, Juiz de Fora, MG, Brazil

    Eliana C. B. Toscano

  3. Centre for Addiction and Mental Healthy (CAMH), Toronto, ON, Canada

    Érica L. M. Vieira

  4. Biobank for Aging Studies, Universidade de São Paulo, São Paulo, SP, Brazil

    Lea T. Grinberg, Regina S. Paradela, Claudia K. Suemoto, Renata E. P. Leite & Ricardo Nitrini

  5. Departments of Neurology and Pathology, University of California San Francisco, San Francisco, CA, USA

    Lea T. Grinberg

  6. The Mitchell Center for Alzheimer’s Disease and Related Brain Disorders, Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA

    Natalia P. Rocha

  7. Departamento de Neurocirurgia, Hospital das Clínicas da Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil

    Joseane A. S. Brant & Alexandre V. Giannetti

  8. Faculdade Santa Casa BH, Belo Horizonte, Brazil; Neuropsychiatry Program, Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA

    Antonio L. Teixeira

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  1. Eliana C. B. Toscano
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  2. Érica L. M. Vieira
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Contributions

Eliana Toscano and Érica Vieira designed this study, collected, analyzed, and interpreted clinical data. Eliana Toscano performed the histological examination, immunohistochemical reactions, morphometric evaluation, statistical analyses, and manuscript drafting. Lea Grinberg supported histopathological evaluation and data interpretation. Natalia Rocha and Regina Paradela supported statistical analysis and data interpretation. Joseane Brant applied the neuropsychologist tests. Alexandre Giannetti contributed for collection of sclerotic hippocampi. Claudia Suemoto, Renata Leite, and Ricardo Nitrini provided the control hippocampi. Milene Rachid and Antônio Teixeira coordinated the study and supported data interpretation. All authors contributed and approved the final manuscript.

Corresponding author

Correspondence to Eliana C. B. Toscano.

Ethics declarations

Ethics Approval

This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee in Research of the Universidade Federal de Minas Gerais (COEP-UFMG), protocol number 1.939.783.

Consent to Participate

All participants have given informed consent for this study. In the case of postmortem samples, the next of kin has given consent for each examination.

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The authors declare no competing interests.

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Key Points

• P-tau burden in hippocampal formation is significantly higher in young/middle age individuals with MTLE compared to matched controls.

• Patients with MTLE had both Alzheimer’s disease like- and divergent patterns of hyperphosphorylated tau deposits.

• Increased neuronal expression of p-tau was associated with impaired attention, but not with memory deficits in MTLE.

Supplementary Information

Supplementary Figure.

Neuronal expression of p-tau in sclerotic hippocampi of MTLE patients with and without cognitive impairment. The percentage of immunostained neurons for p-tau was associated with impairments in both BNT (language function) and digit span forward test (attention function) (E and F), but not with deficits in episodic memory (A-D). t-test was utilized in all the analyzes. Data are mean ± SD and are considered significant when p≤0.05. BNT: Boston naming test; MTLE: mesial temporal lobe epilepsy; SD: standard deviation of the mean. (PNG 231 kb)

High Resolution Image (TIF 616 kb)

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Toscano, E.C.B., Vieira, É.L.M., Grinberg, L.T. et al. Hyperphosphorylated Tau in Mesial Temporal Lobe Epilepsy: a Neuropathological and Cognitive Study. Mol Neurobiol 60, 2174–2185 (2023). https://doi.org/10.1007/s12035-022-03190-x

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