Y Itoh

Tokyo Metropolitan Geriatric Medical Center, Edo, Tōkyō, Japan

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Publications (47)222.6 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: We recently demonstrated accumulation of α-synuclein aggregates of the cardiac sympathetic nerve in Parkinson's disease (PD) and a possible relationship between degeneration of the cardiac sympathetic nerve and α-synuclein aggregates. The aim of this study is to determine whether there is a difference in the degenerative process between unmyelinated and myelinated axons of the cardiac nerve. We immunohistochemically examined cardiac tissues from four pathologically verified PD patients, nine patients with incidental Lewy body disease (ILBD) and five control subjects, using antibodies against neurofilament, myelin basic protein (MBP) and α-synuclein. First, we counted the number of neurofilament-immunoreactive axons not surrounded by MBP (unmyelinated axons) and those surrounded by MBP (myelinated axons). Next, we counted the number of unmyelinated and myelinated axons with α-synuclein aggregates. (i) The percentage of unmyelinated axons in PD (77.5 ± 9.14%) was significantly lower compared to that in control subjects (92.2 ± 2.40%). (ii) The ratio of unmyelinated axons with α-synuclein aggregates to total axons with α-synuclein aggregates in ILBD ranged from 94.4 to 100 (98.2 ± 2.18%). Among axons with α-synuclein aggregates, unmyelinated axons were the overwhelming majority, comprising 98.2%. These findings suggest that in PD unmyelinated axons are more vulnerable to degeneration than myelinated axons of the cardiac nerve, because α-synuclein aggregates accumulate much more abundantly in unmyelinated axons.
    Neuropathology and Applied Neurobiology 06/2011; 37(7):791-802. · 4.84 Impact Factor
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    ABSTRACT: The aims of this study are to elucidate variations in the neuropathology of dementia of the Alzheimer's type (DAT) and related dementias in the elderly, and to delineate a senile dementia characterized by abundant neurofibrillary tangles (NFT) in the hippocampal region and by a scarcity of senile plaques (SP) throghout the brain (senile dementia of the NFT type; SD-NFT) in comparison with usual DAT cases. One hundred and five autopsied patients who developed dementia at age 70–100 years were investigated. The autopsy series included 57 cases of DAT, five of diffuse Lewy body disease (DLBD) with Alzheimer-tyupe neuropathological changes, and five of SD-NFT. The 57 DAT patients were classified into three subgroups depending onthe severity of the neocotical neuronal degeneration (NFT and neuronal loss): the diffuse, severe type (DAT-DS, extensive and severe involvement of the neocortex; n= 18); the diffuse, mild type (DAT-DM, mild involvement of the neocortex; n= 29); and the localized type (DAT-L, neuronal degeneration almost localized to the hippocampal region; DAT without neocortical NFT; n= 10). The frequencies of the DAT subgroups, DLBD, and SD-NFT in each age group at the onset were DAT-DS (41%) > DAT-DM (38%) > DLBD (16%) > DAT-L (6%) of patients in their 70s, DAT-DM (52%) > DAT-L (24%) > DAT-DS (16%) > SD-NFT (8%) of those in their 80s, and DAT-DS (40%) > SD-NFT (30%) > DAT-L (20%) > DAT-DS (10%) of those in their 90s and older. In a morphometric comparison with age-mathced DAT cases, the SD-NFT showed a significantly higher density of hippocampal NFT and a significant scarcity of SP and cerebral amyloid angiopathy in the brain. Analysis of genotypes of apolipoprotein E gene revealed that no patient with the SD-NFT had ε4 allele which was shown to be frequently associated with DAT. Our results have indicated (i) that the later onset of DAT and related dementias is linked with the milder neuronal degeneration in the neocortex, and (ii) that the SD-NFT is a common neuropathological condition that causes dementia in the very aged, in which the pathogenetic process may be different from that in DAT.
    Neuropathology 10/2007; 16(2):89 - 98. · 1.91 Impact Factor
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    ABSTRACT: The purposes of the study are to elucidate the ultimate stage of aging of the limbic system with observations of centenarian brains compared with dementia of the Alzheimer type (DAT), and to search for genetic factors that may influence formations of the senile changes in the limbic system. Neocortical as well as limbic regions of the brains from 13 centenarians were studied with younger control groups (average age about 80 years), that is 20 nondemented (ND) individuals and 20 patients with DAT. No centenarian subjects were clinically diagnosed as having DAT or satisfied neuropathological criteria for DAT. The densities of senile plaques (SP) in the centenarian brains tended to be higher than the ND subjects, but significantly lower than the DAT patients. The densities of neurofibrillary tangles (NFT) in the hippocampal region were significantly higher in the centenarians compared with the ND subjects. Five centenarian brains had an especially large number of NFT in the hippocampal region, which were comparable with DAT; however, NFT in the neocortical areas of the centenarians were scarce in contrast with DAT. The results suggest that DAT would not be an accelerated condition of the aging process represented by the centenarian brains, but a disease caused by a different pathological process. Further, a study was conducted to determine whether the polymorphisms of the apolipoprotein E (ApoE) and presenilin-1 (PS-1) genes were associated with SP and NFT in the limbic and neocortical areas of the brains from the 122 autopsy cases, including 36 DAT patients and 86 ND subjects. ApoEε4 allele frequency was significantly higher in the DAT patients (22.2%) compared with the ND subjects (7.6%) (P= 0.001), and individuals with the ε4 allele had higher densities of SP and NFT in the hippocampus. Further, ND elderly subjects without senile changes in the neocortical as well as limbic areas showed a significantly lower frequency of the ε4 allele and a significantly higher frequency of the ε2 allele compared with the other subjects. The PS-1 polymorphism was not associated with DAT, SP or NFT. The genetic polymorphisms of the other molecules may also contribute to expression of the age-related changes of the limbic system.
    Neuropathology 05/2007; 18(2):228 - 234. · 1.91 Impact Factor
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    ABSTRACT: We report a case of a right-handed 74-year-old man who showed semantic dementia with a disease duration of 19 years. He initially presented with excessive use of pronouns and semantic paraphasia at the age of 55 years. Impairment of object recognition developed 5 years after the onset. Face recognition impairment and stereotypic behaviors developed 11 years after onset, and pyramidal signs 2 years before death. Pathological examination disclosed circumscribed severe atrophy in not only the bilateral temporal tips but also in the left precentral gyrus and pars opercularis in a motor speech field. Pyramidal tract involvement and loss of Betz cells were also evident. On the other hand, neurons in the anterior horns and hypoglossal nuclei were spared in number, although astrocytes were mildly proliferated. Ubiquitin-positive lesions were observed in the hippocampus, and frontal and temporal cortices. Neither Bunina bodies nor Pick bodies were present. These features clinically fit the international diagnostic criteria of semantic dementia and, histopathologically, frontotemporal lobar degeneration with motor neuron disease (FTLD-MND). This case suggests that (1) the distribution of cortical lesions associated with language disturbance is not uniform in FTLD-MND. It may be that only some cases of FTLD with ubiquitin pathology develop semantic dementia despite the high incidence of language disturbance, and (2) the precentral gyrus can be severely affected in FTLD-MND. After reviewing previous cases of FTLD-MND with a clinical course of more than 10 years, we also noticed that (3) FTLD-MND cases with a long disease duration often show upper motor neuron-predominant involvement.
    Acta Neuropathologica 01/2007; 112(6):739-49. · 9.73 Impact Factor
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    ABSTRACT: Decreased cardiac uptake of meta-iodobenzylguanidine (MIBG) on [123I]MIBG myocardial scintigraphy has been reported in Parkinson's disease (PD) and dementia with Lewy bodies (DLB). We hypothesized that cardiac sympathetic denervation might account for the pathomechanism. To elucidate the extent, frequency and pattern of cardiac sympathetic nerve involvement in Lewy body disease and related neurodegenerative disorders, we immunohistochemically examined heart tissues from patients with PD (n=11), DLB (n=7), DLB with Alzheimer's disease (DLB/AD; n=4), multiple system atrophy (MSA; n=8), progressive supranuclear palsy (PSP; n=5), pure AD (n=10) and control subjects (n=5) together with sympathetic ganglia from patients with PD (n=5) and control subjects (n=4), using an antibody against tyrosine hydroxylase (TH). TH-immunoreactive nerve fibers in the hearts had almost entirely disappeared in nearly all the patients with PD, DLB and DLB/AD, whereas they were well preserved in all the patients with PSP and pure AD as well as in all except for one patient with MSA. In PD, neurons in the sympathetic ganglia were preserved in all except for one patient. Decreased cardiac uptake of MIBG in Lewy body disease reflects actual cardiac sympathetic denervation, which precedes the neuronal loss in the sympathetic ganglia.
    Acta Neuropathologica 07/2005; 109(6):583-8. · 9.73 Impact Factor
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    ABSTRACT: A recent study showed that transforming growth factor-beta1 (TGF-beta1) induces amyloid-beta deposition in cerebral blood vessels and meninges of a transgenic mouse model of Alzheimer's disease (AD), and that TGF-beta1 mRNA levels are correlated with cerebral amyloid angiopathy (CAA) in human AD brains. A T/C polymorphism at codon 10 in exon 1 of the TGF-beta1 gene has been reported to be associated with the serum TGF-beta1 concentration. We investigated whether the TGF-beta1 polymorphism is associated with the risk of CAA. The association between the severity of CAA and the T/C polymorphism at codon 10 in exon 1 of the TGF-beta1 was investigated in 167 elderly Japanese autopsy cases, including 73 patients with AD. The apolipoprotein E (APOE) genotype was also determined. The genotypes (TT/ TC/ CC) were associated with the severity of CAA significantly in all patients (p = 0.0026), in non-AD patients (p = 0.011), and APOE non-epsilon4 carriers (p = 0.0099), but not in AD patients or APOE epsilon4 carriers. The number of the T alleles positively correlated with the severity of CAA in all patients (p = 0.0011), non-AD patients (p = 0.0026), and APOE non-epsilon4 carriers (p = 0.0028), but not in AD patients or APOE epsilon4 carriers. The polymorphism was not significantly associated with AD. Our results suggest that the polymorphism in TGF-beta1 is associated with the severity of CAA, especially in non-AD patients and APOE non-epsilon4 carriers.
    Journal of Neurology Neurosurgery & Psychiatry 06/2005; 76(5):696-9. · 4.92 Impact Factor
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    ABSTRACT: In the last few years, cardiac sympathetic dysfunction in Parkinson disease (PD) has been postulated on the basis of decreased cardiac uptake of sympathoneural imaging tracers. However, the pathological substrate for the dysfunction remains to be established. We examined the left ventricular anterior wall from postmortem specimens with immunohistochemical staining for tyrosine hydroxylase (TH), neurofilament (NF) and S-100 protein in PD patients and control subjects, and quantified the immunoreactive areas. As TH-immunoreactive axons nearly disappeared and NF-immunoreactive axons drastically decreased in number, the morphological degeneration of the cardiac sympathetic nerves in PD was confirmed. Quantitative analysis showed that sympathetic nerves were preferentially involved. Triple immunofluorolabeling for NF, TH, and myelin basic protein showed clearly the profound involvement of sympathetic axons in PD. The extent of involvement of the cardiac sympathetic nerves seems likely to be equivalent to that in the central nervous system, including the nigrostriatal dopaminergic system. PD affects the cardiac sympathetic nervous system profoundly as well as nigrostriatal dopaminergic system.
    Brain Pathology 02/2005; 15(1):29-34. · 4.74 Impact Factor
  • Annals of Neurology 10/2004; 39(5):683 - 683. · 11.19 Impact Factor
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    ABSTRACT: The risk of sporadic cerebral amyloid angiopathy (CAA) may be associated with genetic polymorphisms of molecules related to anabolism or catabolism of amyloid beta protein (Abeta). The authors investigated whether a polymorphism of the gene (NEP) coding for neprilysin, an enzyme catabolising Abeta, is associated with CAA. The study analysed the GT repeat polymorphism in the enhancer/promoter region of NEP and severity of CAA in 164 necropsied elderly Japanese subjects. The subjects had NEP polymorphisms with 19 to 23 GT repeats and were classified into nine genotypes. CAA severity was significantly higher in the subjects with up to 40 repeats in total than those with more than 40 repeats (p=0.005). There was a significant correlation between the number of the shorter alleles (19 or 20 repeats) and CAA severity (p=0.024). In addition, there was no interaction between the NEP polymorphism and apolipoprotein E genotype. These results suggest the association between the NEP polymorphism and the risk of CAA. Further study using more samples from populations with different ethnic backgrounds is necessary.
    Journal of Neurology Neurosurgery & Psychiatry 07/2003; 74(6):749-51. · 4.92 Impact Factor
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    ABSTRACT: Both cerebral amyloid angiopathy (CAA) and paraoxonase have been reported to be related to lipid metabolism and atherosclerosis. We investigated whether the paraoxonase gene (PON1) polymorphism and atherosclerosis are associated with risk of CAA. Associations of the PON1 polymorphism and atherosclerosis of the aorta and coronary and cerebral arteries with the severity of CAA were investigated in 154 elderly Japanese individuals, including 47 patients with Alzheimer's disease. The PON1 polymorphism or severity of atherosclerosis of the arteries was not associated with the severity of CAA. The PON1 polymorphism and atherosclerosis would not appear to be associated with risk of CAA in the elderly, although further study with larger samples is necessary for confirmation.
    Stroke 05/2002; 33(4):896-900. · 6.16 Impact Factor
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    Journal of Neurology Neurosurgery & Psychiatry 01/2002; 71(6):817-8. · 4.92 Impact Factor
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    Journal of Neurology Neurosurgery & Psychiatry 11/2001; 71(4):556-7. · 4.92 Impact Factor
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    ABSTRACT: A subset of senile dementia, ‘senile dementia (SD) of the neurofibrillary tangle (NFT) type’ (SD-NFT), is characterized by numerous NFTs in the hippocampal region and absence or scarcity of senile plaques throughout the brain. To elucidate the pathogenesis of SD-NFT in comparison with Alzheimer’s disease (AD), we investigated the hippocampal lesions and analyzed the tau gene. The hippocampal regions from 5 patients with SD-NFT were neuropathologically evaluated in comparison with AD and nondemented control subjects. The tau gene was analyzed in 3 patients with SD-NFT. The densities of NFTs in the CA1/subiculum and entorhinal cortex of SD-NFT were significantly higher than those in AD. However, hippocampal atrophy, neuronal and synaptic loss, and astrocytic and microglial proliferation in SD-NFT were significantly mild compared with AD. There was no significant difference between SD-NFT and AD in the immunoreactivities of NFTs with different anti-tau antibodies. No mutation was found in the tau gene from the SD-NFT patients. Our results indicate that the neurodegenerative process with NFT formation of the hippocampal region in SD-NFT would be different from that in AD.
    Dementia and Geriatric Cognitive Disorders 01/2001; 12(2):117-126. · 2.79 Impact Factor
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    ABSTRACT: We conducted a retrospective study to elucidate clinical features of late onset dementia with Lewy bodies (DLB). Nineteen patients with DLB of neocortical category were neuropathologically diagnosed out of 500 consecutive autopsies at Yokufukai Hospital by using the pathological criteria of the consortium on DLB International Workshop. Medical history and clinical signs and symptoms were reviewed from the medical records. The age at onset was 55-88 years (mean 75.9 years), the age at death was 62-91 years, and duration of illness was 1-14 years. The initial symptoms were memory disturbance (10 cases), delirium (6 cases), gait disturbance (3 cases), visual hallucination (3 cases). We divided nineteen cases of DLB into two group: the age of onset was under 75 years (9 cases) and over 76 years (10 cases). The early onset group showed parkinsonism (67%), and visual hallucination (55%). The sensitivity of the clinical diagnosis of probable DLB based on DLB international workshop consensus criteria was 67%. On the other hand, the late onset group (10cases) presented with delirium (70%), parkinsonism (20%), and visual hallucination (30%). The sensitivity of a clinical diagnosis of probable DLB was 30%. Our results indicated considerable difficulty of the diagnosis of late onset DLB cases by the consensus criteria, requiring more sensitive criteria and diagnostic tests for DLB.
    Rinsho shinkeigaku = Clinical neurology 11/2000; 40(10):986-92.
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    ABSTRACT: alpha2-Macroglobulin (A2M) forms the complex with amyloid beta-protein (Abeta) and is associated with degradation of Abeta. It has been reported that the A2M gene (A2M) exon 18 splice acceptor deletion polymorphism influences the development of AD, regardless of apolipoprotein E-epsilon4 (APOE-epsilon4) status. To determine the effect of A2M polymorphism on the development of AD and AD-type neuropathologic changes. The authors examined the A2M and APOE genotypes, the densities of the senile plaques (SPs), SPs with dystrophic neurites (NPs), and neurofibrillary tangles (NFTs) in the brains of 62 postmortem-confirmed sporadic AD and 90 nondemented patients from an autopsy series of elderly Japanese subjects. There was no association of the A2M polymorphism with AD, age at onset, or duration of illness in AD. The A2M polymorphism was not associated with the SPs, NPs, or NFTs in AD or nondemented patients. The results remained insignificant, even when the A2M genotype groups were divided into subgroups by APOE-epsilon4 status. The A2M polymorphism does not affect the development of sporadic AD or formation of AD-type neuropathologic changes.
    Neurology 02/2000; 54(2):443-6. · 8.30 Impact Factor
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    Journal of Neurology Neurosurgery & Psychiatry 12/1999; 67(5):693-4. · 4.92 Impact Factor
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    ABSTRACT: alpha(2)-Macroglobulin may be implicated in amyloid beta protein deposition. A deletion in the exon 18 splice acceptor of the alpha(2)-macroglobulin gene (A2M) has been reported to be associated with risk for Alzheimer's disease (AD). In search of genetic risk factors for cerebral amyloid angiopathy (CAA), we investigated association of the A2M deletion polymorphism with CAA. The association between the severity of CAA and A2M deletion polymorphism was investigated in 178 autopsy cases of the elderly including 68 patients with AD. There was no significant difference in the severity of CAA between individuals with the A2M deletion allele and those without in the AD, non-AD, or total cases. Status for the epsilon4 allele of the apolipoprotein E gene did not influence the results. Our results suggest that the A2M deletion polymorphism may not be a definitive risk factor of CAA in the elderly, although further study with larger samples is necessary to confirm this.
    Stroke 12/1999; 30(11):2277-9. · 6.16 Impact Factor
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    ABSTRACT: Both AD and paraoxonase (PON) have been reported to be related to lipids and atherosclerosis, suggesting that the PON gene (PON) is a possible genetic risk factor for AD. We found no association of PON polymorphism with severity of atherosclerosis, densities of AD-type, neuropathologic change, or development of AD in 47 AD and 90 nondemented patients. Our study suggests that PON polymorphism does not play a causal role in the development of atherosclerosis or AD.
    Neurology 10/1999; 53(5):1146-8. · 8.30 Impact Factor
  • Neurology 08/1999; 53(1):236-7. · 8.30 Impact Factor
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    ABSTRACT: To clarify a clinical and neuropathologic phenotype of an inherited prion disease associated with a missense mutation at codon 105 in the prion protein (PrP) gene that was originally described as a variant of Gerstmann-Sträussler-Scheinker disease demonstrating spastic paraparesis. Two siblings from a Japanese family are described. PrP gene analyses, neuropathologic studies with immunohistochemistry, and Western blot analysis of the PrP were performed. Both patients showed a missense (proline-->leucine) mutation at codon 105 and a methionine/valine polymorphism at codon 129 of the PrP gene. Clinically, Patient 1 presented with progressive spastic paraparesis, ataxia, and dementia. Patient 2, the sister of Patient 1, showed prominent action myoclonus and dementia. Neuropathologically, multiple PrP-positive amyloid plaques and diffuse PrP deposition in the deep cortical layers were found in the cerebral cortex with primarily frontal dominant atrophy in both patients. Tau-positive pathologic structures including neurofibrillary tangles, neuropil threads, and dystrophic neurites around the plaques were abundant in the brain of Patient 2. In contrast, the tau pathology was scarce in Patient 1. Western blot analysis of the brain showed different patterns of detergent-insoluble PrP fragments between the patients. Despite the identical codon 105 mutation and codon 129 polymorphism of the PrP gene, remarkable clinical and neuropathologic differences, and PrP heterogeneity were present between the affected siblings. The phenotypic variability might be related to PrP heterogeneity.
    Neurology 07/1999; 53(1):181-8. · 8.30 Impact Factor

Publication Stats

840 Citations
222.60 Total Impact Points

Institutions

  • 1993–2011
    • Tokyo Metropolitan Geriatric Medical Center
      Edo, Tōkyō, Japan
  • 2007
    • The University of Tokyo
      • Department of Internal Medicine
      Tokyo, Tokyo-to, Japan
  • 2002
    • Kanazawa University
      • Department of Neurology and Neurobiology of Aging
      Kanazawa, Ishikawa, Japan
  • 2001
    • Kanazawa Medical University
      • Department of Neurology
      Kanazawa-shi, Ishikawa-ken, Japan
  • 1993–2000
    • Tokyo Medical and Dental University
      • Department of Neuropathology
      Edo, Tōkyō, Japan