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We investigated the trends in dementia over the past 29 years in the town of Hisayama, Japan using 1266 autopsy specimens. The Hisayama study is a prospective cohort study of lifestyle-related diseases that was started in 1961. Clinical examination of dementia was started in 1985 with five detailed cross-sectional assessments conducted in 1985, 1992, 1998, 2005 and 2012. To examine the trends in dementia, we divided the 1266 autopsy samples into five groups according to the year of death: I (1986-1991, 257 cases), II (1992-1997, 268 cases), III (1998-2004, 318 cases), IV (2005-2011, 296 cases) and V (2012-2014, 127 cases). The prevalence of all-cause dementia significantly increased over time (28.4% in group I, 22.4% in group II, 32.1% in group III, 30.1% in group IV, 51.2% in group V; P for trend

The degree of polymerization of PrP has a close relationship with the pathological mechanisms of prion diseases. We examined, at the molecular level, the polymerization state of PrP in lysates of prion-infected cells using total internal reflection fluorescence microscopy (TIRFM). The crude lysates were fractionated by gel-filtration spin columns according to their molecular size. Both the oligomer-rich and the monomer-rich fractions were probed with fluorescein-labeled anti-PrP antibodies (mAb SAF70 and mAb 8G8). Fluorescent spots of varying intensity were detected, with the ratio of intense fluorescent spots being greater in the oligomer fraction samples with mAb SAF70 than those with 8G8, the specific epitope of which is thought to be buried in abnormal PrP molecules. The results indicated that PrP oligomers could be specifically detected and conformational changes of abnormal PrP molecules observed. Imaging by TIRFM may aid in determining the polymerization state and properties of PrP oligomers in pathological processes.

Intraventricular infusion of pentosan polysulfate (PPS) as a treatment for various human prion diseases has been applied in Japan. To evaluate the influence of PPS treatment we performed pathological examination and biochemical analyses of PrP molecules in autopsied brains treated with PPS (one case of sporadic Creutzfeldt-Jakob disease (sCJD, case 1), two cases of dura mater graft-associated CJD (dCJD, cases 2 and 4), and one case of Gerstmann-Straussler-Scheinker disease (GSS, case 3). Six cases of sCJD without PPS treatment were examined for comparison. Protease-resistant PrP (PrP(res) ) in the frontal lobe was evaluated by Western blotting after proteinase K digestion. Further, the degree of polymerization of PrP molecules was examined by the size-exclusion gel chromatography assay. PPS infusions were started 3-10 months after disease onset, but the treatment did not achieve any clinical improvements. Postmortem examinations of the treated cases revealed symmetrical brain lesions, including neuronal loss, spongiform change and gliosis. Noteworthy was GFAP in the cortical astrocytes reduced in all treated cases despite astrogliosis. Immunohistochemistry for PrP revealed abnormal synaptic deposits in all treated cases and further plaque-type PrP deposition in case 3 of GSS and case 4 of dCJD. Western blotting showed relatively low ratios of PrP(res) in case 2 of dCJD and case 3 of GSS, while in the treated sCJD (case 1), the ratio of PrP(res) was comparable with untreated cases. The indices of oligomeric PrP were reduced in one sCJD (case 1) and one dCJD (case 2). Although intraventricular PPS infusion might modify the accumulation of PrP oligomers in the brains of patients with prion diseases, the therapeutic effects are still uncertain.

Basophilic inclusions (BIs), which are characterized by their staining properties of being weakly argyrophilic, reactive with Nissl staining, and immunohistochemically negative for tau and transactive response (TAR) DNA-binding protein 43 (TDP-43), have been identified in patients with juvenile-onset amyotrophic lateral sclerosis (ALS) and adult-onset atypical ALS with ophthalmoplegia, autonomic dysfunction, cerebellar ataxia, or a frontal lobe syndrome. Mutations in the fused in sarcoma gene (FUS) have been reported in cases of familial and sporadic ALS, and FUS immunoreactivity has been demonstrated in basophilic inclusion body disease (BIBD), neuronal intermediate filament inclusion disease (NIFID), and atypical frontotemporal lobar degeneration with ubiquitin-positive and tau-negative inclusions (aFTLD-U). In the present study, we immunohistochemically and ultrastructurally studied an autopsy case of sporadic adult-onset ALS with numerous BIs. The patient presented with the classical clinical course of ALS since 75 years of age and died at age 79. Postmortem examination revealed that both Betz cells in the motor cortex and motor neurons in the spinal cord were affected. The substantia nigra was spared. Notably, BIs were frequently observed in the motor neurons of the anterior horns, the inferior olivary nuclei, and the basal nuclei of Meynert. BIs were immunopositive for p62, LC3, and FUS, but immunonegative for tau, TDP-43, and neurofilament. Ultrastructurally, BIs consisted of filamentous or granular structures associated with degenerated organelles with no limiting membrane. There were no Bunina bodies, skein-like inclusions, or Lewy-like inclusions. All exons and exon/intron boundaries of the FUS gene were sequenced but no mutations were identified.

Sekita A, Ninomiya T, Tanizaki Y, Doi Y, Hata J, Yonemoto K, Arima H, Sasaki K, Iida M, Iwaki T, Kanba S, Kiyohara Y. Trends in prevalence of Alzheimer’s disease and vascular dementia in a Japanese community: the Hisayama Study. Objective: To examine secular trends in the prevalence of Alzheimer’s disease (AD) and vascular dementia (VD) in a general Japanese population. Method: Four cross-sectional examinations were conducted among residents of a Japanese community aged ≥65 in 1985, 1992, 1998 and 2005. Results: The age- and sex-adjusted prevalence of all-cause dementia significantly increased with time (6.0% in 1985, 4.4% in 1992, 5.3% in 1998 and 8.3% in 2005; P for trend = 0.002). A similar trend was observed for AD (1.1%, 1.3%, 2.3% and 3.8% respectively; P for trend

Prion diseases are diagnosed by the detection of accumulation of abnormal prion protein (PrP) using immunohistochemistry or the detection of protease-resistant abnormal PrP (PrP(res)). Although the abnormal PrP is neurotoxic by forming aggregates, recent studies suggest that the most infectious units are smaller than the amyloid fibrils. In the present study, we developed a simplified method by applying size-exclusion gel-filtration chromatography to examine PrP oligomers without proteinase K digestion in Creutzfeldt-Jakob disease (CJD) samples, and evaluated the correlation between disease severity and the polymerization degree of PrP. Brain homogenates of human CJD and non-CJD cases were applied to the gel-filtration spin columns, and fractionated PrP molecules in each fraction were detected by western blot. We observed that PrP oligomers could be detected by the simple gel-filtration method and distinctly separated from monomeric cellular PrP (PrP(c)). PrP oligomers were increased according to the disease severity, accompanied by the depletion of PrP(c). The separated PrP oligomers were already protease-resistant in the case with short disease duration. In the cases with quite severe pathology the oligomeric PrP reached a plateau, which may indicate that PrP molecules could mostly develop into amyloid fibrils in the advanced stages. The increase of PrP oligomers correlated with the degree of histopathological changes such as spongiosis and gliosis. The decrease of monomeric PrP(c) was unexpectedly obvious in the diseased cases. Dynamic changes of both oligomerization of the human PrP and depletion of normal PrP(c) require further elucidation to develop a greater understanding of the pathogenesis of human prion diseases.

In prion diseases the normal cellular isoform of prion protein (PrP), denoted PrPC, is converted into an abnormal, pathogenic isoform of PrP (PrPSc). Diagnostic tools for prion diseases are conventionally based on the detection of protease-resistant PrP (PrPres) after proteinase K digestion. However, recent studies have revealed that protease-sensitive abnormal PrP (sPrPSc) also exists in significant amounts in brains suffering from prion diseases. Here, we designed a simplified size-exclusion gel chromatography assay, using disposable spin columns to examine PrP aggregates in the course of the disease, without proteinase K digestion. Brain homogenates of NZW mice, inoculated intracranially with Fukuoka-1 strain, and which died at around 120 days post-inoculation, were assayed by this gel-fractionation method and eluted PrP molecules in each fraction were detected by western blot analysis. Oligomeric PrP molecules were well separated from monomers, as predicted. A conventional protease-digestion assay was also performed to detect PrPres and revealed that the ratio of PrPres to total PrP increased drastically from 105 days. However, the increase of PrP oligomers became significant from 90 days. These PrP oligomers in the early disease stage would, therefore, be sPrPSc molecules that might affect the disease pathology, such as spongiform change and abnormal PrP deposition. We also observed that the resistance of PrP oligomers to proteinase K and insolubility in phosphotungstic acid precipitation increased with disease progression, which suggests that PrP oligomers are not clearly distinguished from cellular PrP or PrPres but may overlap in a continuous spectrum. Our study casts light on the ambiguity of the definition of PrPSc and indicates that the abnormality of PrP molecules should be determined from various perspectives, more than protease resistance. Copyright © 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

To explore the validity of the criteria for dementia with Lewy bodies (DLB) revised in 2005, we examined community based consecutive autopsy cases. 10.3% of the non-demented subjects and 31.2% of the demented subjects showed the Lewy body pathology. Applying the revised pathological criteria to the 205 demented subjects, the types of LB pathology of 11 cases (5.4%) were brainstem-predominant, 24 cases (11.7%) were limbic type and 24 cases (11.7%) were diffuse neocortical type, although there were many subjects not to fit the criteria exactly. The prevalence of Lewy bodies (LBs) was almost same regardless of gender; however, the extent of the LB pathology among females was more severe than that in males. The likelihood of DLB being modified by concomitant Alzheimer's pathology was as follows: 27 cases (13.2%) showed low likelihood, 16 cases (7.8%) showed intermediate likelihood and 16 cases (7.8%) showed high likelihood. Since the numbers of clinical features of DLB were significantly higher in the pathological intermediate and high likelihood DLB groups than in the low likelihood DLB group or no LB group, both the intermediate and high likelihood groups of DLB should be considered as pathological DLB.