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Kenji Kosaka

Publications and source records attributed to Kenji Kosaka.

At least 55 records · Page 3Linked to original sources
PubMed2003

Degeneration of tyrosine hydroxylase-immunoreactive neurons in the cerebral cortex and hippocampus of patients with dementia with Lewy bodies.

We immunohistochemically investigated the degeneration of tyrosine hydroxylase (TH)-positive neurons in the cerebral cortex and hippocampus of dementia with Lewy bodies (DLB) brains. TH-positive neurons in the cerebral cortex and hippocampus were decreased in number, and were rarely associated with Lewy bodies (LB) or neurofibrillary tangles (NFT). A mild to moderate loss of TH-positive neurons was observed in both the cerebral cortex and substantia nigra. In addition, most brains showing low NFT stages and lacking amyloid deposits (AM), corresponding to pure-form DLB brains, demonstrated a moderate to severe loss of TH-positive neurons. These findings suggest that TH-positive neurons in the cerebral cortex degenerate by a pathomechanism similar to that in the substantia nigra, and that the degeneration of these neurons is partly related to LB or NFT formation in either the substantia nigra or cerebral cortex.

Aged↗
PubMed2003

Neuronal accumulation of alpha- and beta-synucleins in the brain of a GM2 gangliosidosis mouse model.

Sandhoff disease (SD) is a heritable lysosomal storage disease resulting from impaired degradation of GM2 ganglioside. The hallmark pathology of the SD model mouse brain is GM2 ganglioside accumulation in neurons. In the present study, we immunohistochemically investigated the neuronal pathology in SD mouse brains, and demonstrated neuronal accumulation of alpha- and beta-synucleins in addition to GM2 ganglioside. Synuclein-positive neurons were extensively observed throughout SD mouse brains, although the distribution of beta-synuclein was less extensive than that of alpha-synuclein. Synuclein-positive neurons were negative to ubiquitin and PHF-tau. These findings suggest that neuronal synucleins may accumulate secondarily to GM2 ganglioside in SD mouse brains, and that neuronal accumulation of synucleins may be more critical than that of GM2 ganglioside for SD mice.

Animals↗
PubMed2003

Reversible conformational change of tau2 epitope on exposure to detergent in glial cytoplasmic inclusions of multiple system atrophy.

Tau-like immunoreactivity (IR) on glial cytoplasmic inclusions (GCIs) of multiple system atrophy (MSA) was investigated with a panel of anti-tau antibodies and we found that tau2, one of the phosphorylation-independent antibodies, preferentially immunolabeled GCIs. Co-presence (0.03%) of polyethyleneglycol- p-isooctylphenyl ether (Triton X-100, TX) with tau2, however, abolished this IR on GCIs, but did not abolish tau2 IR on neurofibrillary tangles (NFTs). Tau2-immunoreactive bands on immunoblot of brain homogenates from MSA brains were retrieved mainly in a TRIS-saline-soluble fraction, as reported in normal brains. This was in contrast to SDS-soluble fractions from brain with Down's syndrome, which contained tau2-immunoreactive bands of higher molecular weight. It indicates that the appearance of tau2 IR on GCIs is not related to hyperphosphorylation of tau. These tau2-immunoreactive bands, except those from bovine brain, were similarly abolished in the presence of TX (0.06%), and repeated washing after exposure to TX restored the tau2 IR on immunohistochemistry and on immunoblot. These findings can be explained if the modified tau2 epitope undergoes a reversible conformational change on exposure to TX, which is reversible after washing. Because the conformation centered at Ser101 of bovine tau is crucial for its affinity to tau2, the Ser-like conformation mimicked by its human counterpart Pro may represent pathological modification of tau shared by GCIs and NFTs. The relative resistance of tau2 epitope on NFTs on exposure to TX suggests that tau woven into NFTs confers additional stability to the pathological conformation of tau2 epitope. The conformation of the tau2 epitope in GCIs is not as stable as in NFTs, suggesting that tau proteins are not the principal constituents of the fibrillary structures of GCIs, even though they were immunodecorated with tau2. The difference in the susceptibility of the tau2 epitope to TX may distinguish its conformational states, which are variously represented according to disease conditions.

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PubMed2003

Plasmid-based gene transfer ameliorates visceral storage in a mouse model of Sandhoff disease.

Sandhoff disease is a severe neurodegenerative disorder with visceral involvement caused by mutations in the HEXB gene coding for the beta subunit of the lysosomal hexosaminidases A and B. HEXB mutations result in the accumulation of undegraded substrates such as GM2 and GA2 in lysosomes. We evaluated the efficacy of cationic liposome-mediated plasmid gene therapy using the Sandhoff disease mouse, an animal model of a human lysosomal storage disease. The mice received a single intravenous injection of two plasmids, encoding the human alpha and beta subunits of hexosaminidase cDNAs. As a result, 10-35% of normal levels of hexosaminidase expression, theoretically therapeutic levels, were achieved in most visceral organs, but not in the brain, 3 days after injection with decreased levels by day 7. Histochemical staining confirmed widespread enzyme activity in visceral organs. Both GA2 and GM2 were reduced by almost 10% and 50%, respectively, on day 3, and by 60% and 70% on day 7 compared with untreated age-matched Sandhoff disease mice. Consistent with the biochemical results, a reduction in GM2 was observed in liver cells histologically as well. These initial findings support further development of the plasmid gene therapy against lysosomal diseases with visceral pathology.

Animals↗
PubMed2003

Autonomic dysfunctions in dementia with Lewy bodies.

Twenty-nine cases of both clinically and neuropathologically diagnosed dementia with Lewy bodies (DLB) were retrospectively examined for autonomic symptoms. Twenty-eight cases showed some kind of autonomic dysfunction. Urinary incontinence (97 %) and constipation (83 %) were the two most common. Although urinary retention and episodic hypotension causing syncopal attacks were less common, the frequency was still high (28 % each). There were 18 cases (62 %) with severe autonomic failure. These 28 cases showed similar tendencies, with no significant differences between the subtypes of DLB (brainstem, limbic, and neocortical types or common and pure forms). We found that DLB of all pathological subtypes exhibits some kind and level of autonomic symptoms.

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PubMed2003

Immunohistochemical study of the expression of cytokines and nitric oxide synthases in brains of patients with dementia with Lewy bodies.

Regional expression of cytokines (IL-1alpha, TNF-alpha), inducible nitric oxide synthase (iNOS) and neuronal NOS (nNOS) was immunohistochemically investigated in the brains of patients with dementia with Lewy bodies (DLB), compared with those of patients with Alzheimer's disease (AD) and non-demented elderly persons. It has been reported that inflammatory responses by cytokines and oxygen free radicals such as nitric oxide (NO) are associated with damaged neurons, degenerative neurites or amyloid deposits in AD brains. In the present study, overexpression of IL-1alpha, TNF-alpha and iNOS was demonstrated in the amygdala, hippocampus, entorhinal and insular cortices of DLB brains, which are pathologically the most vulnerable regions in DLB brains as well as AD brains. In addition, some Lewy body (LB)-bearing neurons were involved by the processes of IL-1alpha- and TNF-alpha-positive microglia, and most extracellular LB were associated with the processes of TNF-alpha- and iNOS-positive astroglia. Glial involvement was also found around neuritic plaques and extracellular neurofibrillary tangles. In contrast, the expression of nNOS was reduced in the amygdala of DLB brains showing severe Lewy pathology. These findings suggest that cytokines and NO are significantly implicated in neuronal damage and death including LB formation in DLB brains.

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PubMed2003

Efficacy of open-system social skills training in inpatients with mood, neurotic and eating disorders.

Open-system social skills training (SST) was performed in an open psychiatric ward of the hospital of Yokohama City University. Between June 1998 and March 2000, 223 patients were being treated for various mental disorders and 136 of these patients voluntarily participated in the open-system SST at least once. The SST participants' ages were 37.2 +/- 16.9 years and the admission period was 102.6 +/- 61.4 days, while non-participants' ages were 49.8 +/- 18.8 years and the admission period was 71.8 +/- 55.6 days. The correlation between participation time and the admission period showed a ratio of approximately 0.5. As for diagnoses, schizophrenia, eating disorder and personality disorder patients tended to participate in SST, while organic mental disorder patients tended to be non-participants. After October 1998 there were 26 patients continuing to attend SST who participated in the evaluation study that compared social skills estimation before SST with that after SST by self-evaluation and by the staff using a social skills questionnaire. After SST sessions, the average staff evaluation score was 43.9% in schizophrenia, 64.4% in mood disorder, 64.9% in neurotic disorder and 55.3% in eating disorders, while they were 29.1%, 33.8%, 44.4% and 34.5% before the sessions, respectively. After the SST sessions, mood disorder patients showed a 25-30% increase of both self-estimation and staff estimation in all subcategories of social skills. These findings suggest that SST was effective for all patients motivated to improve their social skills despite diagnoses and that the SST program had different effects in each diagnosis group.

Adolescent↗
PubMed2003

Lack of association in Japanese patients between neuroleptic malignant syndrome and the TaqI A polymorphism of the dopamine D2 receptor gene.

OBJECTIVE: The molecular basis of neuroleptic malignant syndrome (NMS) is unclear, but clinical studies have noted a genetic predisposition. A recent genetic study suggested an association between NMS and the I A polymorphism in the dopamine D2 receptor (DRD2 ) gene. We further examined the association in a larger number of subjects. METHODS: We studied 49 Japanese patients previously diagnosed with NMS, and 123 schizophrenic patients treated with neuroleptics without occurrence of NMS. PCR and RFLP analyses were performed to screen the I A polymorphism. RESULTS: The I A1 allele frequency was 0.408 in NMS patients and 0.415 in patients without NMS. No significant differences in allelic or genotypic frequencies were observed between the two groups. CONCLUSIONS: We cannot conclude that the I A polymorphism is associated with development of NMS.

Antipsychotic Agents↗
PubMed2003

Clinicopathological study of two subtypes of Pick's disease in Japan.

We examined the clinical and neuropathological findings in 3 cases of Pick's disease with Pick bodies (PiD) and 7 cases of atypical Pick's disease without Pick bodies (aPiD). PiD and aPiD cases corresponded clinically to frontotemporal dementia and semantic dementia, respectively, based on the clinical diagnostic criteria of frontotemporal lobar degeneration. Brain CT showed that cerebral atrophy was accentuated at an early stage of the illness in the anterior portion of the frontal lobes in PiD cases and in the anterior portion of the temporal lobes in aPiD cases. Neuropathologically, PiD cases showed more circumscribed lobar atrophy than aPiD cases. Both PiD and aPiD cases revealed moderate to severe degeneration with neuronal loss and gliosis in the affected cerebral cortex and subcortical nuclei, but only aPiD cases had pyramidal tract degeneration. Immunohistochemical analyses demonstrated that tauopathy with phosphorylated tau accumulation in the Pick bodies in PiD cases, while aPiD cases showed ubiquitinopathy with ubiquitin accumulation in the intraneuronal and dendritic inclusions. These findings suggested that two subtypes of Pick's disease in Japan can be distinguished not only neuropathologically but also clinically based on differences in pathogenesis.

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PubMed2003

Prolactin levels in schizophrenic patients receiving perospirone in comparison to risperidone.

Serum prolactin levels were investigated in 41 patients with schizophrenia who were receiving clinically effective doses of perospirone or risperidone for more than 4 weeks. In order to determine baseline prolactin levels, blood samples were obtained in the morning, 10 - 14 h after antipsychotic medication. Median levels were within normal limits in both female and male patients receiving perospirone, while risperidone induced significant elevation. These results suggest that in contrast to risperidone, where baseline prolactin levels were elevated 5.3-fold in female and 4.2-fold in male patients, baseline prolactin levels are not elevated after treatment with perospirone. However, these results should be cautiously interpreted, because drug-by-time interaction has previously been reported in antipsychotic-induced hyperprolactinemia.

Antipsychotic Agents↗
PubMed2003

[A Japanese family with familial Alzheimer's disease associated with presenilin 1 mutation: relationship between younger age of onset and ApoE gene polymorphism].

We previously reported a Japanese family with early-onset familial Alzheimer's disease associated with G 209 R presenilin 1(PS 1) mutation. There have been six patients across three generations in this family. In the present report, we described the clinical course, findings with neuroimaging and results of genetic examination of PS 1 and apolipoprotein E(ApoE) in three of six patients(II-1, III-1 and 2). The clinical course was common to all three patients. Memory disturbance, disorientation, amnestic aphasia, personality changes and perseveration appeared at early stages, whereas Gerstmann's syndrome, myoclonus and general convulsion were recognized at advanced stages. CT disclosed mild brain atrophy in the temporal lobes at early stages and diffuse brain atrophy predominantly in the fronto--temporal lobes at advanced stages. SPECT exhibited hypoperfusion in the fronto-temporal areas at early stages and hypoperfusion in the fronto-temporal and parieto-occipital areas at advanced stages. The age of onset in six patients demonstrated two clusters at age 53-55(I-1, II-1, 2 and 5) and age 46-48(III-1 and 2). PS 1 genotyping demonstrated that the heterozygous exonic missense mutation G 209 R was confirmed in all three patients. Regarding the ApoE genotyping, II-1(mother) was epsilon 3/epsilon 3, whereas III-1 and 2(children) were epsilon 3/epsilon 4. These findings suggest the possibility that there might be a gene dose effect, since the age of onset ranged from 5 to 7 years younger in patients who received epsilon 4 alleles from the father.

Age Factors↗
PubMed2003

[Natural killer cell activity among patients with atopic dermatitis].

We examined natural killer (NK) activity in 128 patients with atopic dermatitis (AD) to investigate the relationships between NK activity and severity of dermatitis, duration of disease, and mental states. The results showed the following: 1) No relationship was shown between severity of dermatitis and NK activity, neither between NK activity nor eosinophilic counts nor serum IgE. 2) Patients with longer duration of AD lesions showed significantly lower NK activity (P=0.036). The significant relationship was recognized between severity of dermatitis and the duration of disease (P=0.014). 3) No relationships were recognized between NK activity and mental states evaluated using the Profile Of Mood States (POMS) questionnaire, as tension-anxiety, depression-dejection, anger-hostility, vigor, fatigue and confusion. From a psychoneuroimmunological viewpoint, chronic stress as having AD might influence the lower NK activity of patients with longer duration of AD.

Adolescent↗
PubMed2002

Dementia with Lewy bodies from the perspective of tauopathy.

We immunohistochemically investigated the prevalence and pattern of phosphorylated tau accumulation in neurons and glia in 46 cases of dementia with Lewy bodies (DLB). Tau-positive neurons composed of neurofibrillary tangles (NFT) and pretangle neurons were found in the hippocampal area in all 46 cases, although the ratio of pretangle neurons in tau-positive neurons was higher in the cases showing low NFT stages. Tau-positive astrocytes were found in the periventricular area in 18 of 46 cases, and partly represented argyrophilic thorn-shaped astrocytes. In contrast, tau-positive oligodendroglia were found in the subcortical white matter in 9 of 46 cases, and represented argyrophilic coiled bodies. Tau-positive argyrophilic grains were found in the hippocampal area in the same cases as those with coiled bodies. The 9 cases with tau-positive coiled bodies and grains were included in the 18 cases with tau-positive astrocytes, and showed larger proportions in the low NFT stages than the 46 cases with tau-positive neurons. Tau-positive neurons were positive both to anti-three-repeat (3R) and -4R tau-specific antibodies, while tau-positive astrocytes, coiled bodies and grains were predominantly positive to anti-4R tau-specific antibody. These tau-positive structures were negative to anti-alpha-synuclein antibody. These findings suggest that the tau accumulation in DLB represents both tau-positive neurons with all six tau isoforms and tau-positive astrocytes, coiled bodies and grains with the 4R tau isoform, and that the different cytoskeletal abnormalities form a link between some neurodegenerative dementing disorders including DLB.

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PubMed2002

Post-traumatic stress disorder associated with suspected lung cancer and bereavement: 4-year follow-up and review of the literature.

We report here a patient who developed post-traumatic stress disorder (PTSD) after being given a diagnosis of suspected lung cancer. The symptoms of PTSD continued even after it had been confirmed that the lesion was benign after all. A 73-year-old man was referred to our psychiatric outpatient clinic for depressed mood, appetite loss and difficulty in sleeping. On examination the patient explained that he had become preoccupied with intrusive thoughts and memories since his diagnosis of suspected lung cancer and that although he had been told the lesion was not malignant, he had distressing memories of that period and was experiencing severe psychological distress. The patient also explained that he had experienced the death of a close friend through lung cancer and he had a deep fear of developing lung cancer himself. In this patient, the psychological distress evoked by the diagnosis of suspected cancer was severe enough to induce the symptoms of PTSD even though the tumor was benign. From the clinical point of view, it could provide useful information if liaison psychiatrists were to ask patients about any experience of losing significant others to the same disease and this might be helpful in gaining an understanding of the disease process.

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