title: A comparative study of the dentate gyrus in hippocampal sclerosis in epilepsy and dementia.
abstract: OBJECTIVE
  Hippocampal sclerosis (HS) is long-recognized in association with epilepsy (HSE ) and more recently in the context of cognitive decline or dementia in the elderly (HSD ), in some cases as a component of neurodegenerative diseases, including Alzheimer's disease (AD) and fronto-temporal lobe dementia (FTLD). There is an increased risk of seizures in AD and spontaneous epileptiform discharges in the dentate gyrus of transgenic AD models; epilepsy can be associated with an age-accelerated increase in AD-type pathology and cognitive decline. The convergence between these disease processes could be related to hippocampal pathology. HSE typically shows re-organization of both excitatory and inhibitory neuronal networks in the dentate gyrus, and is considered to be relevant to hippocampal excitability. We sought to compare the pathology of HSE and HSD , focusing on re-organization in the dentate gyrus.
  
  
  METHODS
  In nine post mortem cases with HSE and bilateral damage, 18 HSD and 11 controls we carried out immunostaining for mossy fibres (dynorphin), and interneuronal networks (NPY, calbindin and calretinin) on sections from the mid-hippocampal body. Fibre sprouting (FS) or loss of expression in the dentate gyrus was semi-quantitatively graded from grade 0 (normal) to grade 3 (marked alteration).
  
  
  RESULTS
  Significantly more re-organization was seen with all four markers in the HSE than HSD group (P < 0.01). Mild alterations were noted in HSD group with dynorphin (FS in 3 cases), calretinin (FS in 6 cases), NPY (FS in 11 cases) and calbindin (loss in 10 cases). In eight HSD cases, alteration was seen with more than one antibody but in no cases were the highest grades seen. We also noted NPY and, to a lesser extent, calretinin labelling of Hirano bodies in CA1 of AD cases and some older controls, but not in HSE .
  
  
  CONCLUSIONS
  Reorganization of excitatory and inhibitory networks in the dentate gyrus is more typical of HSE . Subtle alterations in HSD may be a result of increased hippocampal excitability, including unrecognized seizure activity. An unexpected finding was the identification of NPY-positive Hirano bodies in HSD but not HSE , which may be a consequence of the relative vulnerabilities of interneurons in these conditions.
authors.affiliation: Department of Clinical and Experimental Epilepsy, UCL, Institute of Neurology and National Hospital for Neurology and Neurosurgery, London, UK.
authors.forename: R
authors.initials: R
authors.lastname: Bandopadhyay
authors.forename: J Y W
authors.initials: JY
authors.lastname: Liu
authors.forename: S M
authors.initials: SM
authors.lastname: Sisodiya
authors.forename: M
authors.initials: M
authors.lastname: Thom
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000473:pathology; D003704:Dementia / Q000473:pathology*; D018891:Dentate Gyrus / Q000473:pathology*; D004827:Epilepsy / Q000473:pathology*; D005260:Female; D057180:Frontotemporal Dementia / Q000473:pathology; D006624:Hippocampus / Q000473:pathology*; D006801:Humans; D008297:Male; D012598:Sclerosis
keywords: Hirano bodies; dementia; dentate gyrus; epilepsy; hippocampal sclerosis; synaptic reorganization
references.citation: Neuroscience. 2008 Jul 31;155(1):182-91
references.pmid: 18583063
references.citation: Curr Alzheimer Res. 2012 Jul;9(6):709-17
references.pmid: 22471863
references.citation: Curr Neurol Neurosci Rep. 2008 Sep;8(5):363-70
references.pmid: 18713571
references.citation: J Comp Neurol. 1986 Jun 15;248(3):376-94
references.pmid: 3522663
references.citation: Rom J Morphol Embryol. 2011;52(1):15-20
references.pmid: 21424027
references.citation: Neuropharmacology. 2002 Mar;42(4):444-58
references.pmid: 11955516
references.citation: Alzheimer Dis Assoc Disord. 2011 Oct-Dec;25(4):364-8
references.pmid: 21346515
references.citation: Neuroscience. 2000;96(1):7-25
references.pmid: 10683405
references.citation: J Physiol. 2005 Jan 1;562(Pt 1):73-80
references.pmid: 15498801
references.citation: Epilepsy Res. 2012 Nov;102(1-2):45-59
references.pmid: 22608064
references.citation: Neurobiol Aging. 2006 Nov;27(11):1658-72
references.pmid: 16271420
references.citation: Brain Res. 1990 Dec 10;535(2):195-204
references.pmid: 1705855
references.citation: Epilepsy Res. 2010 Mar;89(1):52-9
references.pmid: 20149961
references.citation: Brain Behav. 2012 Jul;2(4):435-42
references.pmid: 22950047
references.citation: Ann Neurol. 1989 Sep;26(3):321-30
references.pmid: 2508534
references.citation: Epilepsy Res. 2010 Aug;90(3):234-9
references.pmid: 20554432
references.citation: Eur J Neurol. 2005 Feb;12(2):103-7
references.pmid: 15679697
references.citation: Hippocampus. 2004;14(6):701-9
references.pmid: 15318329
references.citation: Acta Neuropathol. 1988;77(2):168-74
references.pmid: 3227813
references.citation: PLoS One. 2012;7(9):e44996
references.pmid: 23028730
references.citation: Neuropathol Appl Neurobiol. 2009 Aug;35(4):394-405
references.pmid: 19508443
references.citation: J Neurosci Methods. 2010 Jun 30;190(1):49-56
references.pmid: 20435066
references.citation: Acta Neuropathol. 2011 Sep;122(3):285-92
references.pmid: 21630115
references.citation: J Neurosci. 1995 May;15(5 Pt 2):3990-4004
references.pmid: 7751960
references.citation: Hippocampus. 2012 May;22(5):1107-20
references.pmid: 21630373
references.citation: Epilepsia. 2010 Sep;51(9):1801-8
references.pmid: 20738385
references.citation: Neurology. 1998 Nov;51(5):1256-62
references.pmid: 9818842
references.citation: Neuron. 2007 Sep 6;55(5):697-711
references.pmid: 17785178
references.citation: Neuroscience. 1997 Jan;76(2):377-85
references.pmid: 9015323
references.citation: Epilepsia. 2003 May;44(5):677-87
references.pmid: 12752467
references.citation: Neurology. 2009 Sep 29;73(13):1033-40
references.pmid: 19710404
references.citation: Epilepsy Res. 2012 Jan;98(1):14-24
references.pmid: 21920703
references.citation: Dement Geriatr Cogn Disord. 1999;10 Suppl 1:55-60
references.pmid: 10436342
references.citation: J Biomed Sci. 2012 Apr 10;19:41
references.pmid: 22489754
references.citation: Neuroscience. 2010 Aug 11;169(1):532-43
references.pmid: 20399254
references.citation: Neuropathology. 2010 Aug;30(4):408-19
references.pmid: 20102526
references.citation: Epilepsia. 2012 Jan;53(1):1-6
references.pmid: 22050314
references.citation: Neuroscience. 1998 Feb;82(4):979-91
references.pmid: 9466422
references.citation: Brain. 2011 May;134(Pt 5):1506-18
references.pmid: 21596774
references.citation: Brain Pathol. 2012 May;22(3):402-11
references.pmid: 22497612
references.citation: Neuroscience. 2000;97(1):47-58
references.pmid: 10771338
references.citation: Nat Rev Neurol. 2011 Apr;7(4):237-40
references.pmid: 21263461
references.citation: Exp Neurol. 2012 Dec;238(2):265-72
references.pmid: 23022456
references.citation: Acta Neuropathol. 2011 Jul;122(1):111-3
references.pmid: 21644037
references.citation: Acta Neuropathol. 2009 May;117(5):535-44
references.pmid: 19277686
references.citation: Epilepsia. 2012 Aug;53(8):1282-93
references.pmid: 22691064
references.citation: Acta Neuropathol. 2007 Oct;114(4):335-45
references.pmid: 17639426
references.citation: J Physiol. 2005 Jan 1;562(Pt 1):9-26
references.pmid: 15539390
references.citation: Proc Natl Acad Sci U S A. 2003 Aug 5;100(16):9572-7
references.pmid: 12881482
references.citation: Brain. 2012 Oct;135(Pt 10):3115-33
references.pmid: 22750659
references.citation: Neuropathology. 2013 Aug;33(4):442-58
references.pmid: 23530853
references.citation: Acta Neuropathol. 1994;88(3):212-21
references.pmid: 7810292
references.citation: Brain Pathol. 2009 Oct;19(4):565-72
references.pmid: 18761661
references.citation: Brain. 2011 Oct;134(Pt 10):2969-81
references.pmid: 21903728
references.citation: Acta Neuropathol. 2007 Mar;113(3):235-44
references.pmid: 17221203
references.citation: Epilepsy Curr. 2012 Sep;12(5):184-7
references.pmid: 23118603
references.citation: Acta Neuropathol. 2012 Jan;123(1):1-11
references.pmid: 22101365
references.citation: Int J Neurosci. 2011 Feb;121(2):69-85
references.pmid: 21142829
references.citation: Brain Struct Funct. 2010 Mar;214(2-3):145-60
references.pmid: 20213270
references.citation: Epilepsia. 2004 Jun;45(6):695-714
references.pmid: 15144438