Liu, JY;
Reeves, C;
Diehl, B;
Coppola, A;
Al-Hajri, A;
Hoskote, C;
Al Mughairy, S;
... Thom, M; + view all
(2016)
Early lipofuscin accumulation in frontal lobe epilepsy.
Annals of Neurology
10.1002/ana.24803.
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Abstract
OBJECTIVE: This study reports on a novel brain pathology in young patients with Frontal Lobe Epilepsy that is distinct from Focal Cortical Dysplasia. METHODS: Surgical specimens from twenty young adults with frontal lobe epilepsy (mean age, 30 years) were investigated with histological/immunohistochemical markers for cortical laminar architecture, mammalian target of rapamycin pathway activation and inhibition, cellular autophagy, and synaptic vesicle-mediated trafficking as well as proteomics analysis. Findings were correlated with pre/post-operative clinical, imaging and electrophysiological data. RESULTS: Excessive lipofuscin accumulation was observed in abnormal dysmorphic neurones in six cases, but not in seven Focal Cortical Dysplasia type IIB and seven pathology-negative cases, despite similar age and seizure histories. Abnormal dysmorphic neurones on proteomics analysis were comparable to aged human brains. Mammalian target of rapamycin 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 MRI cortical abnormalities that localised with seizure onset zone, and were more likely to have a family history. INTERPRETATION: We propose that excess neuronal lipofuscin accumulation in young patients with frontal lobe epilepsy 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. This article is protected by copyright. All rights reserved.
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