title: Early lipofuscin accumulation in frontal lobe epilepsy.
abstract: This study reports on a novel brain pathology in young patients with frontal lobe epilepsy (FLE) that is distinct from focal cortical dysplasia (FCD).
  
  
  
  Surgical specimens from 20 young adults with FLE (mean age, 30 years) were investigated with histological/immunohistochemical markers for cortical laminar architecture, mammalian target of (mTOR) pathway activation and inhibition, cellular autophagy, and synaptic vesicle-mediated trafficking as well as proteomics analysis. Findings were correlated with pre-/postoperative clinical, imaging, and electrophysiological data.
  
  
  
  Excessive lipofuscin accumulation was observed in abnormal dysmorphic neurones in 6 cases, but not in seven FCD type IIB and 7 pathology-negative cases, despite similar age and seizure histories. Abnormal dysmorphic neurones on proteomics analysis were comparable to aged human brains. The mTOR pathway was activated, as in cases with dysplasia, but the immunoreactivities of nucleoporin p62, DEP-domain containing protein 5, clathrin, and dynamin-1 were different between groups, suggesting that enhanced autophagy flux and abnormal synaptic vesicle trafficking contribute to early lipofuscin aggregation in these cases, compared to suppression of autophagy in cases with typical dysplasia. Cases with abnormal neuronal lipofuscin showed subtle magnetic resonance imaging cortical abnormalities that localized with seizure onset zone and were more likely to have a family history.
  
  
  
  We propose that excess neuronal lipofuscin accumulation in young patients with FLE represents a novel pathology underlying this epilepsy; the early accumulation of lipofuscin may be disease driven, secondary to as-yet unidentified drivers accelerating autophagic pathways, which may underpin the neuronal dysfunction in this condition. Ann Neurol 2016;80:882-895.
authors.affiliation: Division of Neuropathology, National Hospital for Neurology and Neurosurgery, London, United Kingdom.|Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, United Kingdom.
authors.forename: Joan Y W
authors.initials: JY
authors.lastname: Liu
authors.affiliation: Division of Neuropathology, National Hospital for Neurology and Neurosurgery, London, United Kingdom.|Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, United Kingdom.
authors.forename: Cheryl
authors.initials: C
authors.lastname: Reeves
authors.affiliation: Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, United Kingdom.|Department of Clinical Neurophysiology, National Hospital for Neurology and Neurosurgery, London, United Kingdom.
authors.forename: Beate
authors.initials: B
authors.lastname: Diehl
authors.affiliation: Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, United Kingdom.
authors.forename: Antonietta
authors.initials: A
authors.lastname: Coppola
authors.affiliation: The Lysholm Department of Neuroradiology in National Hospital for Neurology and Neurosurgery, London, United Kingdom and Department of Brain Repair and Rehabilitation, UCL Institute of Neurology, London, UK.
authors.forename: Aliya
authors.initials: A
authors.lastname: Al-Hajri
authors.affiliation: The Lysholm Department of Neuroradiology in National Hospital for Neurology and Neurosurgery, London, United Kingdom and Department of Brain Repair and Rehabilitation, UCL Institute of Neurology, London, UK.
authors.forename: Chandrashekar
authors.initials: C
authors.lastname: Hoskote
authors.affiliation: The Lysholm Department of Neuroradiology in National Hospital for Neurology and Neurosurgery, London, United Kingdom and Department of Brain Repair and Rehabilitation, UCL Institute of Neurology, London, UK.
authors.forename: Salim Al
authors.initials: SA
authors.lastname: Mughairy
authors.affiliation: The Lysholm Department of Neuroradiology in National Hospital for Neurology and Neurosurgery, London, United Kingdom and Department of Brain Repair and Rehabilitation, UCL Institute of Neurology, London, UK.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Tachrount
authors.affiliation: Division of Neuropathology, National Hospital for Neurology and Neurosurgery, London, United Kingdom.
authors.forename: Michael
authors.initials: M
authors.lastname: Groves
authors.affiliation: Division of Neuropathology, National Hospital for Neurology and Neurosurgery, London, United Kingdom.|Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, United Kingdom.
authors.forename: Zuzanna
authors.initials: Z
authors.lastname: Michalak
authors.affiliation: Biological Mass Spectrometry Centre, Institute of Child Health, University College London, London, United Kingdom.
authors.forename: Kevin
authors.initials: K
authors.lastname: Mills
authors.affiliation: Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, United Kingdom.|Victor Horsley Department of Neurosurgery, National Hospital for Neurology and Neurosurgery, London, United Kingdom.
authors.forename: Andrew W
authors.initials: AW
authors.lastname: McEvoy
authors.affiliation: Victor Horsley Department of Neurosurgery, National Hospital for Neurology and Neurosurgery, London, United Kingdom.
authors.forename: Anna
authors.initials: A
authors.lastname: Miserocchi
authors.affiliation: Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, United Kingdom.|Epilepsy Society, Chesham Lane, Chalfont St Peter, United Kingdom.
authors.forename: Sanjay M
authors.initials: SM
authors.lastname: Sisodiya
authors.affiliation: Division of Neuropathology, National Hospital for Neurology and Neurosurgery, London, United Kingdom.|Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, United Kingdom.
authors.forename: Maria
authors.initials: M
authors.lastname: Thom
mesh_terms: D001921:Brain / Q000378:metabolism*; D017034:Epilepsy, Frontal Lobe / Q000378:metabolism*; D006801:Humans; D008062:Lipofuscin / Q000378:metabolism*; D008279:Magnetic Resonance Imaging; D059906:Neuroimaging; D009474:Neurons / Q000378:metabolism / Q000648:ultrastructure; D040901:Proteomics; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D008062:Lipofuscin; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases