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Cell injury and Premature Neurodegeneration in Focal Malformations of Cortical Development

Authors

  • Anand Iyer,

    1. Department of (Neuro)Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
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  • Avanita Prabowo,

    1. Department of (Neuro)Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
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  • Jasper Anink,

    1. Department of (Neuro)Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
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  • Wim G. M. Spliet,

    1. Departments of Pathology, University Medical Center Utrecht, Utrecht, the Netherlands
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  • Peter C. van Rijen,

    1. Neurosurgery /Rudolf Magnus Institute for Neuroscience, University Medical Center Utrecht, Utrecht, the Netherlands
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  • Eleonora Aronica

    Corresponding author
    1. Department of (Neuro)Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
    2. SEIN—Stichting Epilepsie Instellingen Nederland, Heemstede, the Netherlands
    3. Swammerdam Institute for Life Sciences, Center for Neuroscience, University of Amsterdam, Amsterdam, the Netherlands
    • Corresponding author:

      Eleonora Aronica, MD, PhD, Dept. (Neuro) Pathology, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands (E-mail: e.aronica@amc.uva.nl)

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Abstract

Several lines of evidence suggest that cell injury may occur in malformations of cortical development associated with epilepsy. Moreover, recent studies support the link between neurodevelopmental and neurodegenerative mechanisms. We evaluated a series of focal cortical dysplasia (FCD, n = 26; type I and II) and tuberous sclerosis complex (TSC, n = 6) cases. Sections were processed for terminal deoxynucleotidyl transferase-mediated 2′-deoxyuridine 5′-triphosphate nick-end labeling (TUNEL) labeling and immunohistochemistry using markers for the evaluation of apoptosis signaling pathways and neurodegeneration-related proteins/pathways. In both FCD II and TSC specimens, we observed significant increases in both TUNEL-positive and caspase–3-positive cells compared with controls and FCD I. Expression of β-amyloid precursor protein was observed in neuronal soma and processes in FCD II and TSC. In these specimens, we also observed an abnormal expression of death receptor-6. Immunoreactivity for phosphorylated tau was only found in older patients with FCD II and TSC. In these cases, prominent nuclear/cytoplasmic p62 immunoreactivity was detected in both dysmorphic neurons and balloon/giant cells. Our data provide evidence of complex, but similar, mechanisms of cell injury in focal malformations of cortical development associated with mammalian target of rapamycin pathway hyperactivation, with prominent induction of apoptosis-signaling pathways and premature activation of mechanisms of neurodegeneration.

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