Pathological tau tangles localize to focal cortical dysplasia in older patients.
OBJECTIVE
Reactivation of neurodevelopmental processes may contribute to neurodegeneration. For example, the proteins cyclin dependent kinase 5 (cdk5) and glycogen synthase kinase 3 beta (GSK3beta), 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 GSK3beta 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.


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


RESULTS
Beta-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.
Sen
Arjune
A
Department of Clinical and Experimental Epilepsy, Institute of Neurology, University College London, Queen Square, London, UK.
Thom
Maria
M
Martinian
Lillian
L
Harding
Brian
B
Cross
J Helen
JH
Nikolic
Margareta
M
Sisodiya
Sanjay M
SM
D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000369:Aged, 80 and over; D016229:Amyloid beta-Peptides / Q000378:metabolism; D002452:Cell Count / Q000379:methods; D002540:Cerebral Cortex / Q000002:abnormalities* / Q000473:pathology / Q000601:surgery; D002648:Child; D002675:Child, Preschool; D004396:Coloring Agents; D004828:Epilepsies, Partial / Q000378:metabolism / Q000473:pathology* / Q000601:surgery; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D008297:Male; D008875:Middle Aged; D009410:Nerve Degeneration / Q000473:pathology; D016874:Neurofibrillary Tangles / Q000378:metabolism / Q000473:pathology*; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D024801:Tauopathies / Q000378:metabolism / Q000473:pathology*; D016875:tau Proteins / Q000378:metabolism
D016229:Amyloid beta-Peptides; D004396:Coloring Agents; D016875:tau Proteins; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3