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We semiquantitatively compared the frequency and severity of cerebral amyloid angiopathy (CAA) in the cerebellum and CAA-positive occipital lobe of 60 subjects from routine autopsies. In the 60 subjects with a CAA-positive occipital lobe, cerebellar CAA was observed in 29 subjects (48.3%), and the severity of cerebellar CAA was relatively mild compared with occipital lobe CAA. Capillary CAA was observed in the occipital lobe of 12 subjects and the cerebellum of three subjects. CAA-related vasculopathies were observed in the occipital lobe of 15 subjects and the cerebellum of two subjects. The severity of CAA-related vasculopathy was mild in both of these subjects. Amyloid-β plaques were observed in the occipital lobe of 54 subjects (90%) and the cerebellum of 16 subjects (26.7%). The severity of amyloid-β plaques in the cerebellum was mild compared with the occipital lobe. In summary, we confirmed that cerebellar CAA is frequently observed in the cerebellum but with a lower severity than CAA in the occipital lobe., (© 2022 Japanese Society of Neuropathology.)

We examined 29 cases in which cerebral amyloid angiopathy (CAA) was detected among routine aged autopsies. Most cases with severe CAA had many amyloid-β (Aβ) plaques in the occipital cortex. Nonetheless, two cases had few Aβ plaques with many small vessels and capillaries with CAA. In the two cases, severe CAA was widely distributed, except in the frontal lobes. Aβ deposits in capillaries often showed the characteristic pattern of dysphoric amyloid angiopathy. A few naked plaques were present. Although Aβ plaques were sparse near small vessels with CAA, there were many Aβ plaques distant from small vessels with CAA. Some of the remaining plaques had a moth-eaten appearance. Based on Aβ-positive star-like appearance and results of double immunohistochemistry for glial fibrillary acidic protein and Aβ 1-42 , some astrocytes appeared to contain Aβ. Ionized calcium-binding adapter molecule 1 (Iba1)-positive microglia were scattered within the neuropil, with some present around small vessels with CAA. Iba1-positive microglia also seemed to phagocytose Aβ in several senile plaques by double immunostaining. Neurons and neurites identified with a monoclonal antibody against phosphorylated tau (clone AT8) were occasionally detected in sparse plaque areas, with AT8-identified dot-like structures present around capillaries with CAA. Accumulation of T lymphocytes was detected around vessels in the subarachnoid space in one case. The morphological changes detected in our two cases were similar to those of morphological markers of plaque clearance after Aβ immunotherapy. Nonetheless, our cases did not receive Aβ immunotherapy, but similar pathologies were observed. Overall, advanced CAA cases, including our two cases, may be examples of plaque clearance without Aβ immunotherapy. Further studies are needed to resolve the mechanism of Aβ plaque clearance using these cases., (© 2020 Japanese Society of Neuropathology.)

Argyrophilic and tau-positive abnormal structures in astrocytes are frequent in aged brains, with a new nomenclature of aging-related tau astrogliopathy (ARTAG) proposed. The two major cytomorphologies of ARTAG are thorn-shaped astrocytes (TSA) and granular or fuzzy tau immunoreactivity in processes of astrocytes (GFA). We selected 28 cases in which many AT8-identified astrocytic tauopathies were observed in the central nervous system from 330 routine aged autopsied cases, including Alzheimer's disease. AT8-identified and Gallyas silver staining-positive TSA were observed in subpial, subependymal, perivascular areas as well as white matter. These TSA were 4-repeat (4R) tau-positive. In contrast, 3-repeat (3R)-tau was negative in TSA, but positive in short thick cell processes, likely neuropil threads, in subpial and subependymal areas. The frequency of 3R-tau-positive processes was variable. Small dot-like AT8-identified astrocytic processes surrounding vessels in the neuropil were also positive for 4R-tau, but negative for 3R-tau. GFA in cerebral gray matter were AT8-identified and Gallyas-positive, and positive for 4R-tau but negative for 3R-tau. In this study, we did not identify 3R-tau+/4R-tau+ or 3R-tau+/4R-tau- astrocytes. Further studies are needed to clarify the nature and progression of glial tau-positive structures in ARTAG., (© 2019 Japanese Society of Neuropathology.)

We compared semiquantitatively AT8 immunoreactivity in the locus ceruleus (LC) and hippocampus of 154 brains from routine autopsies to investigate the initial sites of phosphorylated tau (phospho-tau) development. The numbers of AT8-positive neurons and the severity of AT8-positive neuropil threads (NTs) in the LC were strongly associated: there were no cases with AT8-positive neurons that lacked NTs and 20 cases (13%) had only NTs in the LC. Phospho-tau pathologies in the LC were almost equally on both sides, although some cases (7.8%) showed unilateral predominance. The numbers of AT8-positive neurons in the LC and the numbers of AT8-positive neurons and NTs in the hippocampus were also strongly associated. There were only two cases with AT8-positive neurons in the LC that lacked phospho-tau pathology in the hippocampus, and 21 cases (13.6%) with phospho-tau pathology in the hippocampus that lacked AT8-positive neurons in the LC. The numbers of AT8-positive NTs in the LC and AT8-positive neurons and NTs in the hippocampus were also strongly associated. There were seven cases (4.5%) with AT8-positive NTs in the LC that lacked phospho-tau pathology in the hippocampus, and five cases (3.2 %) with phospho-tau pathologies in the hippocampus that lacked AT8-positive NTs in the LC. In this study, we could not confirm that phospho-tau pathologies begin in the LC. We suspect their simultaneous occurrences in both hippocampal regions and in LC., (© 2017 Japanese Society of Neuropathology.)

The transactive response DNA-binding protein of 43 kDa (TDP-43) is normally located predominantly in the nucleus, whereas pathological TDP-43 is mostly found in the cytoplasm. Cytoplasmic TDP-43 accumulation has not yet been reported in normal general organs. In our preliminary study, paraffin sections of the general organs of individuals with or without amyotrophic lateral sclerosis (ALS) were immunostained with antibodies against TDP-43 and phosphorylated TDP-43 (pTDP-43). Diffuse and granular immunostaining pattern of TDP-43 and pTDP-43 were observed frequently in the cytoplasm of renal tubular cells, and less frequently in the cells of several organs; however, the majority of these immunoreactivities were nonspecific biotin reactions. Conversely, many TDP-43-positive and pTDP-43-negative cytoplasmic accumulations were observed in the adrenal medulla in every individual (with or without ALS). Skein-like or round inclusions were not observed. The cells in the adrenal medulla were well preserved, and the cytoplasmic TDP-43 accumulations were frequent in the cells of all routine autopsy cases without loss of nuclear TDP-43 immunostaining; therefore, we considered that this was a physiological phenomenon. This is the first study that demonstrated the cytoplasmic accumulation of TDP-43 in routinely autopsied cases., (© 2014 Japanese Society of Neuropathology.)

Little attention has been paid to the degeneration of small neurons in ALS spinal gray matter. The purpose of the present paper was to undertake morphometric and quantitative analysis of the spinal gray matter of 15 ALS patients and compare findings to those of five controls. A significant reduction of small neurons in the anteromedial and intermediate parts of the gray matter were detected in ALS spinal cords with diffuse myelin pallor in the ventral aspects of the anterolateral columns outside the corticospinal tracts, and the number of small neurons in these areas was decreased significantly depending on the intensity of the myelin pallor. There were no significant alterations in the number of small neurons in the corresponding areas of ALS spinal cords without diffuse myelin pallor or in those of controls. In the posterior parts of the gray matter, there were no significant differences in the number of small neurons among ALS patients and controls. These findings strongly suggest that diffuse myelin pallor in the ventral aspects of anterolateral columns in ALS spinal cords is derived from the degeneration of small neurons in the anteromedial and intermediate parts of the gray matter.

Semiquantitative morphological analysis of cerebral intraneuronal ubiquitin-positive tau-negative inclusions, a pathologic marker for motor neuron disease with dementia (MND-D), was performed in the dentate gyrus and parahippocampal gyrus of 20 clinicopathologically confirmed patients with MND-D. The forms of the inclusions were tentatively classified into three types: (i) C-type, consisting of relatively large and intensely stained crescent or circular structures; (ii) L-type, showing fine linear structures around the nuclei; and (iii) G-type, showing faintly stained granular structures. The frequencies of the C-type, L-type and G-type was 0.5-9.3%,0.2-6.5% and 0-6.6% of dentate granule cells, respectively. In contrast to the dentate gyrus, almost all inclusions showed either the C-type or L-type form in the parahippocampal gyrus. A positive correlation was noted only between incidences of C-type inclusion of the dentate gyrus and that of the parahippocampal gyrus (r = 0.69, P < 0.05). The morphological differences of the inclusions probably reflect different stages of their formation.