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.
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Acknowledgments
We are grateful to all patients, family members, and caregivers who agreed to brain donation; without their donation these studies would have been impossible. We also acknowledge expert technical assistance of Linda Rousseau and Virginia Phillips for histology and Monica Castanedes-Casey for immunohistochemistry. This research was supported in part by a research Grant from the Uehara Memorial Foundation, The Mangurian Foundation, and NIH Grant P50NS72187, P50AG16574, and R01NS076471.
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Aoki, N., Murray, M.E., Ogaki, K. et al. Hippocampal sclerosis in Lewy body disease is a TDP-43 proteinopathy similar to FTLD-TDP Type A. Acta Neuropathol 129, 53–64 (2015). https://doi.org/10.1007/s00401-014-1358-z
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DOI: https://doi.org/10.1007/s00401-014-1358-z