Abstract
Neurofibrillary tangles (NFTs), are shared between progressive supranuclear palsy (PSP) and Alzheimer disease (AD). Histological distinction of PSP and AD is possible based on the distribution of NFTs. However, neuropathologists may encounter diagnostic difficulty with comorbidity of PSP and AD. In this study, we tried to circumvent this difficulty by analyzing five autopsied brains harboring both PSP and AD pathology. Tau-positive lesions were sorted based on their cell type (neuron versus glia), and tau isoforms: three-repeat (3R) versus four-repeat (4R) tau. 16 regions were selected to map these lesions throughout the brain. 4R-tau lesions were present in all areas examined. Among them, 3R-tau lesions were absent in some areas. These 4R selective (4R+/3R-) areas dictate prototypic distribution of PSP, not usually found in AD, such as pontine nucleus, red nucleus, inferior olivary nucleus, dentate nucleus, globus pallidus and putamen, each contained both glial and neuronal lesions. In contrast, additional 3R-tau lesions were found in hippocampal formation to neocortex, where 3R immunoreactivity (IR) was predominant over the 4R counterpart mainly in neurons as found in AD but not in PSP. Although tau lesions in central grey matter, substantia nigra and locus coeruleus are found in both AD and PSP, 4R-selectivity with glial component suggests PSP origin. Even if the presence of 3 R IR in these areas suggests AD pathology, it does not exclude the involvement of PSP-type lesion because distinction of 4R IR into PSP or AD is not yet possible. Further demixing may be possible if biochemical difference of 4R tau between PSP and AD is identified.
Highlights
Alzheimer disease (AD) and progressive supranuclear palsy (PSP) are characterized by deposition of tau in the brain
Deparaffinized sections were treated for 15 min with 0.25% potassium permanganate (KMnO4), for 3 min with 2% oxalic acid (OA), for 30 min with > 99% formic acid (FA) and for 20 min autoclaved at 121 °C in 0.05 M citrate buffer [16, 38]
Neuron-selective involvement with preferential 3R tau over 4R tau may represent AD-type pathology [3, 23] even in this comorbid series, which replicated AD-type distribution of neurofibrillary tangle (NFT) (HF, insular cortex (IC), locus coeruleus (LC), Fig. 4, right upper rectangle labeled AD). This is in contrast with PSP-type pathology with 4R-selective tau in both tuft-shaped astrocytes (TAs) and NFTs (Fig. 4, left lower area in green) [11, 15], which replicated the PSP-type distribution. This operational sorting through our hybrid approach was powerful enough to distinguish origin of most of tau lesions into either AD-type or PSP-type (Fig. 4), suggesting that AD-type pathology and PSP-type pathology are independent even when these two processes are occurring in the same brain [7, 18, 19, 25, 27]
Summary
Alzheimer disease (AD) and progressive supranuclear palsy (PSP) are characterized by deposition of tau in the brain. Because clinicopathological spectra of PSP and of AD are still expanding [10, 30], accurate clinical diagnosis is more and more complex and difficult This diagnostic difficulty is much enhanced in aged population, where cormorbid pathologies, such as AD or Lewy pathology, may be encountered. Such comorbidity is challenging to neuropathologists; how to discriminate different types of pathology in the same brain This is problematic when a brain harbors AD-type pathology and PSP-type pathology because both are characterized by tau deposits [3, 11]. We tried to extract disease-specific features from these brains with AD and PSP for possible discrimination, based on the distribution of TAs and that of NFTs and immunohistochemistry for phosphorylated tau (AT8) [24], three-repeat (3R) and four-repeat (4R) tau [9]. This hybrid approach was quite successful in discriminating most, but Ebashi et al Acta Neuropathologica Communications
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