title: Hippocampal sclerosis in Lewy body disease is a TDP-43 proteinopathy similar to FTLD-TDP Type A.
abstract: Hippocampal sclerosis (HpScl) is frequent in frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP), but it also occurs in dementia of the elderly with or without accompanying Alzheimer type pathology. HpScl has been hypothesized to be a neurodegenerative process given its association with TDP-43 pathology, but this is still controversial. TDP-43 pathology is found in Lewy body disease (LBD), but no study has focused on the pathologic and genetic characteristics of HpScl in LBD. We found HpScl in 5.2% of 669 LBD cases (289 transitional and 380 diffuse). Older age, higher Braak neurofibrillary tangle (NFT) stage, and presence of TDP-43 pathology were associated with HpScl. There was no difference in the frequency of HpScl between transitional and diffuse LBD, suggesting that Lewy-related pathology appears to have no direct association with HpScl. All HpScl cases had TDP-43 pathology consistent with Type A pattern. HpScl cases harbored genetic variation in TMEM106B that has been previously associated with FTLD-TDP. Interestingly, the severity of TDP-43-positive fine neurites in CA1 sector, a possible pathologic precursor of HpScl, was associated with the TMEM106B variant. These results demonstrate HpScl in LBD is a TDP-43 proteinopathy and is similar to FTLD-TDP Type A. Furthermore, a subset of LBD cases without HpScl ("pre-HpScl") had similar pathologic and genetic characteristics to typical HpScl, suggesting that the spectrum of HpScl pathology may be wider than previously thought. Some cases with many extracellular NFTs also had a similar profile. We suggest that HpScl is "masked" in these cases.
authors.affiliation: Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.
authors.forename: Naoya
authors.initials: N
authors.lastname: Aoki
authors.forename: Melissa E
authors.initials: ME
authors.lastname: Murray
authors.forename: Kotaro
authors.initials: K
authors.lastname: Ogaki
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Fujioka
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Rutherford
authors.forename: Rosa
authors.initials: R
authors.lastname: Rademakers
authors.forename: Owen A
authors.initials: OA
authors.lastname: Ross
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Dickson
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D053327:Apolipoprotein E4 / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D057174:Frontotemporal Lobar Degeneration / Q000453:epidemiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D020961:Lewy Body Disease / Q000453:epidemiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics; D016501:Neurites / Q000378:metabolism / Q000473:pathology; D000077153:Progranulins; D012598:Sclerosis / Q000453:epidemiology / Q000235:genetics / Q000378:metabolism; D057177:TDP-43 Proteinopathies / Q000453:epidemiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology*
chemical_list: D053327:Apolipoprotein E4; D004268:DNA-Binding Proteins; C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D000077153:Progranulins; C000598624:TARDBP protein, human; C556915:TMEM106B protein, human