Pathological Tau Tangles Localize to Focal Cortical Dysplasia in Older Patients

Authors

  • Arjune Sen,

    1. Department of Clinical and Experimental Epilepsy, Institute of Neurology, University College London, Queen Square, London
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  • Maria Thom,

    1. Department of Clinical and Experimental Epilepsy, Institute of Neurology, University College London, Queen Square, London
    2. Division of Neuropathology, Institute of Neurology, University College London, Queen Square, London
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  • Lillian Martinian,

    1. Department of Clinical and Experimental Epilepsy, Institute of Neurology, University College London, Queen Square, London
    2. Division of Neuropathology, Institute of Neurology, University College London, Queen Square, London
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  • Brian Harding,

    1. Department of Histopathology, Great Ormond Street Hospital for Children, London
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  • J. Helen Cross,

    1. Neuroscience Unit, Institute of Child Health, London
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  • Margareta Nikolic,

    1. Department of Cellular and Molecular Neuroscience, Faculty of Medicine, Imperial College London, Charing Cross Campus, Fulham Palace Road, London, United Kingdom
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  • Sanjay M. Sisodiya

    1. Department of Clinical and Experimental Epilepsy, Institute of Neurology, University College London, Queen Square, London
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Address correspondence and reprint requests to Sanjay M. Sisodiya, Department of Clinical and Experimental Epilepsy, Box 29, The Institute of Neurology, UCL, Queen Square, London. WC1N 3BG. United Kingdom. E-mail: s.sisodiya@ion.ucl.ac.uk

Abstract

Summary: Purpose: Reactivation of neurodevelopmental processes may contribute to neurodegeneration. For example, the proteins cyclin dependent kinase 5 (cdk5) and glycogen synthase kinase 3 beta (GSK3β), which are essential to normal cortical development, can hyperphosphorylate tau and might contribute to the pathogenesis of Alzheimer's disease. Focal cortical dysplasia (FCD) is an important neurodevelopmental cause of refractory human epilepsy within which dysplastic neurons exhibit increased immunoreactivity for cdk5 and GSK3β as well as neurofilamentous accumulations. We therefore hypothesized that the developmentally abnormal cortex of FCD might be more susceptible to tau-mediated neurodegeneration than adjacent histologically normal cortex.

Materials and Methods: We examined a series of 15 cases of FCD, spanning a wide age range, for β-amyloid, pathologically phosphorylated tau and neurofibrillary tangles using silver staining, immunohistochemistry for tau, AT8, RD3, RD4 and two-dimensional cell counting.

Results:β-amyloid plaques, aberrantly phosphorylated tau and neurofibrillary tangles are only found in older patients. The hyperphosphorylated tau tangles are confined to dysplastic neurons. Immunoreactivity for 3- and 4-repeat tau was again only detected within regions of FCD in older patients. With increasing age, the dysplastic cortex became hypocellular and a higher proportion of dysplastic neurons exhibited pathological tau phosphorylation.

Conclusions: In older patients, FCD appears more susceptible to formation of pathologically phosphorylated tau neurofibrillary tangles than adjacent histologically normal cortex. Our results suggest a novel convergence of pathological neurodevelopment with pathological age-related neurodegeneration.

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