Aoki Naoya, Murray Melissa E, Ogaki Kotaro, Fujioka Shinsuke, Rutherford Nicola J, Rademakers Rosa, Ross Owen A, Dickson Dennis W
Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.
Acta Neuropathol. 2015 Jan;129(1):53-64. doi: 10.1007/s00401-014-1358-z. Epub 2014 Nov 4.
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.
海马硬化（HpScl）在伴有TDP-43病理改变的额颞叶变性（FTLD-TDP）中很常见，但也见于伴有或不伴有阿尔茨海默病型病理改变的老年痴呆症。鉴于HpScl与TDP-43病理改变相关，有人推测它是一种神经退行性过程，但这仍存在争议。在路易体病（LBD）中发现了TDP-43病理改变，但尚无研究关注LBD中HpScl的病理和遗传特征。我们在669例LBD病例（289例过渡型和380例弥漫型）中发现5.2%存在HpScl。年龄较大、Braak神经原纤维缠结（NFT）分期较高以及存在TDP-43病理改变与HpScl相关。过渡型和弥漫型LBD中HpScl的发生率没有差异，这表明路易体相关病理改变似乎与HpScl没有直接关联。所有HpScl病例均有符合A型模式的TDP-43病理改变。HpScl病例在TMEM106B基因存在变异，该基因先前与FTLD-TDP相关。有趣的是，CA1区TDP-43阳性细神经突的严重程度，这可能是HpScl的一种病理前驱表现，与TMEM106B变异相关。这些结果表明，LBD中的HpScl是一种TDP-43蛋白病，与A型FTLD-TDP相似。此外，一部分无HpScl的LBD病例（“HpScl前期”）具有与典型HpScl相似的病理和遗传特征，这表明HpScl病理改变的范围可能比以前认为的更广。一些有许多细胞外NFTs的病例也有类似特征。我们认为在这些病例中HpScl被“掩盖”了。
