Risk factors for delusion of theft in patients with Alzheimer's disease showing mild dementia in Japan.

The mechanism underlying delusion in Alzheimer's disease patients has not been fully clarified; however, the occurrence of delusion is a critical issue for dementia patients and their caregivers. In Japan, delusion of theft is the most frequent delusion in AD patients. We examined the risk factors for delusion of theft in AD patients showing mild dementia. Fifty-six AD patients were administered HDS-R, MMSE and COGNISTAT, including the 'speech sample', to assess their neuropsychological and social cognitive functions. The age, years of education, presence of cohabiting family members and premorbid personality traits were obtained from family members. About 25.0% of AD patients showed delusion of theft (D-group), and 75% did not (non-D-group). About 33.3% of female patients and 5.9% of male patients were included in the D-group (p < 0.05). About 13.6% of patients who were cohabiting with family members and 66.7% of patients who were living alone were included in the D-group (p < 0.05). About 35.1% of patients who had a neurotic personality and 5.3% of patients who did not were included in the D-group (p < 0.05). There were no significant differences in scores on HDS-R, MMSE and COGNISTAT sub-scales, except for 'speech sample', between the two groups. In the 'speech sample', 38.7% of patients who understood a relationship between two boys and 12.0% of patients who did not were included in the D-group (p < 0.05). These results indicated that delusion of theft in AD patients was related to female gender, absence of cohabiting family members, neurotic personality and retained social cognitive function.

Comparison of extent of tau pathology in patients with frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17), frontotemporal lobar degeneration with Pick bodies and early onset Alzheimer's disease.

In order to gain insight into the pathogenesis of frontotemporal lobar degeneration (FTLD), the mean tau load in frontal cortex was compared in 34 patients with frontotemporal dementia linked to chromosome 17 (FTDP-17) with 12 different mutations in the tau gene (MAPT), 11 patients with sporadic FTLD with Pick bodies and 25 patients with early onset Alzheimer's disease (EOAD). Tau load was determined, as percentage of tissue occupied by stained product, by image analysis of immunohistochemically stained sections using the phospho-dependent antibodies AT8, AT100 and AT180. With AT8 and AT180 antibodies, the amount of tau was significantly (P < 0.001 in each instance) less than that in EOAD for both FTDP-17 (8.5% and 10.0% respectively) and sporadic FTLD with Pick bodies (16.1% and 10.0% respectively). With AT100, the amount of tau detected in FTDP-17 was 54% (P < 0.001) of that detected in EOAD, but no tau was detected in sporadic FTLD with Pick bodies using this particular antibody. The amount of insoluble tau deposited within the brain in FTDP-17 did not depend in any systematic way upon where the MAPT mutation was topographically located within the gene, or on the physiological or structural change generated by the mutation, regardless of which anti-tau antibody was used. Not only does the amount of tau deposited in the brain differ between the three disorders, but the pattern of phosphorylation of tau also varies according to disease. These findings raise important questions relating to the role of aggregated tau in neurodegeneration - whether this represents an adaptive response which promotes the survival of neurones, or whether it is a detrimental change that directly, or indirectly, brings about the demize of the affected cell.

Alterations of muscarinic acetylcholine receptors in atypical Pick's disease without Pick bodies.

BACKGROUND: Atypical Pick's disease without Pick bodies is a type of frontotemporal dementia characterised by semantic dementia and temporal dominant lobar atrophy with ubiquitinopathy. No neurochemical analyses have ever been reported in this condition. OBJECTIVE: To investigate muscarinic acetylcholine receptors (mAchR) and their subtypes (M1-M4) in atypical Pick's disease. SUBJECTS: Five cases of atypical Pick's disease were studied. They were compared with nine control cases, 11 cases of Alzheimer's disease, and seven cases of dementia with Lewy bodies. METHODS: A [(3)H]quinuclidinyl benzilate (QNB) binding assay and an immunoprecipitation assay using subtype specific antisera were used. RESULTS: The total amount of mAchR in the temporal cortex was lower in atypical Pick's disease than in controls or Alzheimer's disease cases, but there were no significant differences between the three groups in the frontal cortex. In the temporal cortex, there was a smaller proportion of M1 receptors in atypical Pick's disease than in the controls or in the patients with Alzheimer's disease and dementia with Lewy bodies. In contrast, the proportion of M2 receptor was higher in atypical Pick's disease than in the other three groups. CONCLUSIONS: Depletion of postsynaptic cholinoreceptive neurones in the temporal cortex is more severe in atypical Pick's disease than in other neurodegenerative dementing disorders.

Dementia with Lewy bodies showing advanced Lewy pathology but minimal Alzheimer pathology--Lewy pathology causes neuronal loss inducing progressive dementia.

The present study concerns an autopsied case of dementia with Lewy bodies (DLB) showing advanced Lewy pathology but minimal Alzheimer pathology. The patient was a 50-year-old Japanese male without inheritance. His initial symptoms at the age of 43 suggested the diagnosis ofjuvenile idiopathic Parkinson's disease (PD), but were followed by memory disturbance 1 year later. He showed parkinsonism, dementia, personality change, fluctuating cognition and visual hallucinations 3 years later. Neuroradiological examination revealed moderate brain atrophy, predominantly in the frontal and temporal lobes. Neuropathological examination demonstrated a widespread occurrence of Lewy bodies (LB) with LB-related neurites not only in the brainstem but also in the cerebrum. The present case showed Lewy pathology which corresponded to stage IV by our staging and was parallel to neuronal loss. There was marked neuronal loss with many LB-related neurites in the CA2 of the hippocampus. Neurofibrillary tangles (NFT) were almost restricted to the entorhinal cortex, while senile plaques were absent. Consequently, the present case was pathologically diagnosed as having DLB of the neocortical type, pure form. In the present study, we suggest that Lewy pathology in the cerebral cortex could be responsible for progressive dementia.

Distribution of m1 muscarinic acetylcholine receptors in the hippocampus of patients with Alzheimer's disease and dementia with Lewy bodies-an immunohistochemical study.

Of the five subtypes (m1-m5) of muscarinic acetylcholine receptors (mAChR), the m1 subtype is the most abundant in the human cerebral cortex and hippocampus. Impairment of the muscarinic cholinergic system in the brain may cause cognitive dysfunction in patients with Alzheimer's disease (AD), and choline esterase inhibitors (ChE-I) are used to improve cognitive dysfunction. Severe impairment of the cholinergic system has also been reported in the brains of subjects with dementia with Lewy bodies (DLB). There have been a few reports about the distribution of mAChR subtypes in the human brain. In the present study, we investigated the distribution of m1 mAChR in the human hippocampus using an antibody against the m1 subtype. In the control brains, m1 immunoreactivity was observed in the apical dendrites and cell bodies of granular neurons of the dentate gyrus and pyramidal neurons of CA1-3 and the subiculum. The dendrites and the cell bodies of the pyramidal neurons in layers III and V of the parahippocampal cortex and other temporal cortices were also positive for m1 immunoreactivity. This m1 immunoreactivity was markedly reduced in AD and DLB brains.

Familial frontotemporal dementia and parkinsonism with a novel N296H mutation in exon 10 of the tau gene and a widespread tau accumulation in the glial cells.

We report a 62-year-old Japanese man with familial frontotemporal dementia and a novel missense mutation (N296H) in exon 10 of the tau gene. The patient presented with frontal signs followed by temporal signs and parkinsonism. The brain showed localized frontotemporal lobe atrophy including the precentral gyrus and discoloration of the substantia nigra, and revealed severe neuronal loss with proliferation of tau-positive protoplasmic astroglia in the affected cerebral cortex, tau-positive coiled bodies and threads in the subcortical white matter, and tau-positive pretangle neurons in the subcortical and brain stem nuclei. There were no tau-positive neurofibrillary tangles, Pick bodies, tuft-shaped astrocytes or astrocytic plaques in the cerebral cortex. Immunoelectron microscopically, phosphorylated tau accumulated in both neurons and glial cells in different modalities, such as glial filaments in protoplasmic astroglia, straight tubules in coiled bodies, and free ribosomes in pretangle neurons. These findings suggest that tau proteins are not always assembled in abnormal filaments such as twisted ribbons, paired helical filaments and straight tubules in neurons and glial cells, which have been shown in previous cases with frontotemporal dementia and parkinsonism linked to chromosome 17. Immunoblotting of sarkosyl-insoluble tau exhibited accumulation of four-repeat tau isoforms in the brain. The N296H mutation may interfere with the ability of mutated tau to bind with microtubules and lead to tau aggregation. Further study is necessary to determine whether this mutation can account for the characteristic tau pathology of this case.

A neuropathological study of the disturbance of the nigro-amygdaloid connections in brains from patients with dementia with Lewy bodies.

We neuropathologically and immunohistochemically investigated characteristics of the central amygdaloid nucleus lesion and its relationship with the substantia nigra lesion in dementia with Lewy bodies (DLB) brains. Nine DLB, four Parkinson's disease (PD) and four Alzheimer-type dementia (ATD) cases were examined. The degree of neuronal loss in the substantia nigra was (+)-(+++) in DLB cases, (+++) in PD cases and (+) in ATD cases. All DLB cases showed spongy change and ubiquitin-positive spheroids in the central nucleus. The degree of spongy change was (+)-(+++) in DLB cases, (+) in PD cases and (-)-(+) in ATD cases, which was correlated with the degree of neuronal loss in the substantia nigra in DLB cases. The number of ubiquitin-positive spheroids was parallel to the degree of spongy change. The central nucleus receives dense dopaminergic fibers from the substantia nigra. Many ubiquitin-positive spheroids were also positive to alpha-synuclein and tyrosine-hydroxylase, suggesting that they derive from the degeneration of terminal or distal axons of Lewy body-bearing dopaminergic neurons in the substantia nigra. The disturbance of the dopaminergic connections from the substantia nigra to the central nucleus may be responsible for psychotic symptoms in DLB patients.

No evidence of an association between CYP2D6 polymorphisms among Japanese and dementia with Lewy bodies.

Dementia with Lewy bodies (DLB) is the second most frequent degenerative dementia among the elderly, following Alzheimer-type dementia (ATD). An association of DLB with CYP2D6*4, one of the cytochrome P450IID6 (debrisoquine 4-hydroxylase; CYP2D6) gene polymorphisms, was reported previously, but this is controversial. Moreover, these reports have been restricted to Caucasian populations. Therefore, we compared frequencies of CYP2D6*3, *4, and *10 mutant alleles in 17 Japanese DLB patients to those among Alzheimer-type dementia (ATD) patients and healthy controls. Polymerase chain reaction amplification and restriction fragment length polymorphism analyses were used for genotyping. No significant difference of genotype or mutant allele frequencies was detected between DLB, ATD, and healthy controls. The present results do not support the suggestion that the CYP2D6 gene is related to DLB susceptibility, at least in the Japanese population.

Glial involvement in the degeneration process of Lewy body-bearing neurons and the degradation process of Lewy bodies in brains of dementia with Lewy bodies.

Glial involvement in the degeneration process of Lewy body (LB)-bearing neurons and the degradation process of LBs in the cerebral cortex and amygdala in brains of dementia with Lewy bodies was investigated immunohistochemically. HLA-DR-positive microglia frequently extended their processes to degenerated neurons with alpha-synuclein-positive LBs, while some GFAP-positive astroglial processes attached to weakly alpha-synuclein-positive extracellular LBs. Some intracellular LBs were immunoreactive to anti-C4d antibody, and these LB-bearing neurons were involved by activated microglia. About half of the intracellular LBs were immunoreactive to anti-chromogranin-A (CGA) antibody, and most of CGA-positive LB-bearing neurons were surrounded by microglia. Although we could find no evident participation of TNF-alpha, a candidate cytokine that is up-regulated by microglia following CGA stimulation, in the degeneration process of LB-bearing neurons, some intracellular LBs were immunoreactive to the antibody to NF-kappaB, a transcriptional factor activated by cytokines. These findings suggest that microglia participate in the degeneration process of LB-bearing neurons via varying immunogenic elements including complement proteins, CGA and probably some cytokines, and that astroglia participate in the degradation process of LBs.

Immunohistochemical localization of plasminogen activator inhibitor-1 in rat and human brain tissues.

We investigated immunohistochemically the localization of type 1 plasminogen activator inhibitor (PAI-1) in rat and human brain tissues. In rat, neurons and astrocytes were stained positively for PAI-1 after colchicine treatment. In post-mortem human brain, neurons were stained for PAI-1 but the number of positive neurons varied greatly from case to case. PAI-1 positive astrocytes occurred in the white matter lesions of some patients. In Alzheimer's disease, weak PAI-1 labeling was seen in association with senile plaques and ghost tangles. The present results support a notion that PAI-1 and its target proteases such as plasminogen activators and thrombin are involved in a variety of physiological and pathological processes in brain.

Frequency and distribution of TUNEL-positive neurons in brains of dementia with Lewy bodies: comparison with those in brains of Alzheimer's disease.

The present study investigated the frequency and distribution of TUNEL-positive neurons in brains of dementia with Lewy bodies (DLB) in comparison with those in brains of Alzheimer's disease (AD), Down syndrome (DS) and non-demented elderly persons. In DLB brains, TUNEL-positive neurons were increased in frequency compared with those in non-demented elderly brains, and showed a distribution similar to those in AD and DS brains. DLB cases with TUNEL-positive neurons showing severe Lewy pathology were all neocortical type, while DLB cases of the limbic type showing mild Lewy pathology did not demonstrate TUNEL-positive neurons. In addition, we investigated the relationships between TUNEL-positive neurons and pathological hallmarks of DLB or AD brains. TUNEL-positive neurons had no Lewy bodies or neurofibrillary tangles, and were not located within amyloid deposits. These findings suggest that neuronal damage showing DNA fragmentations occurs in DLB brains as well as in AD and DS brains, and that it is accelerated by progression of Lewy pathology as well as Alzheimer pathology, although it is not directly related to their pathological hallmarks.

Expression of CD40 in the brain of Alzheimer's disease and other neurological diseases.

We have investigated immunohistochemically the expression of CD40 in post-mortem human brain tissues. In control brain, the blood vessels were stained weakly for CD40. Vascular expression of CD40 was enhanced in the lesions of Alzheimer's disease and some other neurological diseases. In such diseases, reactive microglia were also positive for CD40. The results of this study suggest that CD40 expression by microglia is up-regulated upon a variety of brain insults and is not limited to lesions with amyloid beta-protein deposits.

Accumulation of human alpha-synuclein in different cytoskeletons in Lewy bodies in brains of dementia with Lewy bodies.

We investigated the origin of alpha-synuclein-immunoreactive components in Lewy bodies (LB) in brains of dementia with Lewy bodies (DLB) using immunohistochemistry and immunoelectron microscopy with anti-alpha-synuclein antibodies and anti-cytoskeleton antibodies. alpha-Synuclein-positive LB light microscopically consisted of phosphorylated neurofilament (PN)-positive LB, tubulin-positive LB and LB that were negative for both stains. Immunoelectron microscopically, PN-positive LB were composed of PN-positive and alpha-synuclein-positive filamentous components, suggesting that these filamentous components originate from neurofilaments with partially reduced immunoreactivity and alpha-synuclein accumulation. However, tubulin-positive LB were composed of tubulin-positive and alpha-synuclein-positive tubular components, suggesting that these tubular components originate from microtubules with diffusely reduced immunoreactivity and alpha-synuclein accumulation. The results of the present study suggest that alpha-synuclein accumulates in different cytoskeletons in the LB in DLB brains presumably due to a blockage of axonal transport.

Clinicopathological studies on diffuse Lewy body disease.

With reports of dementia cases with numerous cortical Lewy bodies and our proposal that this be named 'diffuse Lewy body disease' (DLBD), this condition has received a great deal of attention, first in Japan and subsequently in Europe and North America. In the early 1990s, similar types of nomenclature were considered, and at the First International Workshop in 1995, it was proposed that 'dementia with Lewy bodies' be used as a generic term for Lewy body dementia, including the DLBD form. We review our previous clinicopathological findings and describe our recent immunohistochemical studies on DLBD.

Familial frontotemporal dementia with a P301L tau mutation in Japan.

We have reported the family line with frontotemporal dementia (FTD) in Japan. This family line has so far included four patients. Patient II-1 (man) had a 10 year history of slowly progressive personality and behavioral changes and died at the age of 56. His neuropathological examination showed severe atrophy of the bilateral frontal and temporal cortices with neuronal loss, gliosis and superficial spongiosis. Pick bodies were not found. The neuropathological diagnosis was atypical Pick's disease without Pick bodies or Pick-type in FTD. Patient III-2 is patient II-1's oldest daughter and was taken ill with personality change at the age of 52. She died at the age of 68. Patient III-4 is patient II-1's second daughter. Her onset with strange speech and behavior was at the age of 59. Patient III-5 is patient II-1's oldest son. He also had onset with personality change at the age of 54 and had the P301L mutation in tau. In all III generation cases CT/MRI revealed circumscribed frontotemporal atrophy. Patient III-5's PET/SPECT showed signs of hypoperfusion or hypometabolism in the bilateral frontotemporal areas. This is the first report of familial FTD with the P301L mutation in Japan.

Cyclin-dependent kinase 5 (Cdk5) associated with Lewy bodies in diffuse Lewy body disease.

We investigated the cyclin-dependent kinase (Cdk) 5 distribution pattern in diffuse Lewy body disease brains using immunohistochemistry. Cdk5 immunoreactivity was detected in both brainstem-type Lewy bodies (LBs) and cortical LBs. The number of Cdk5-positive LBs was less than that of ubiquitin- or alpha-synuclein-positive LBs, and more than that of phosphorylated neurofilament-positive LBs. Immunoelectron microscopy revealed Cdk5-immunolabeled granulo-filamentous components in LBs and LB-related neurites. These data suggest that Cdk5 may be associated with LB formation.

Degeneration process of Lewy bodies in the brains of patients with dementia with Lewy bodies using alpha-synuclein-immunohistochemistry.

We investigated the degeneration process of Lewy bodies (LB) in the brains of dementia with Lewy bodies, using alpha-synuclein-immunohistochemistry. Intracellular LB, LB-related neurites and some extracellular LB were positively immunostained with anti-alpha-synuclein antibodies. Concentric LB-bearing neurons had no microglial involvement, while degenerated neurons with ill-defined LB displayed intense microglial involvement. The late stage of extracellular LB were immunoelectron-microscopically composed of loose aggregates of filamentous components with lost alpha-synuclein-immunoreactivity and penetrated astroglial processes. These findings suggest that microglias are involved during the stages from degenerated LB-bearing neurons to extracellular LB, while astroglias are involved during the stage of extracellular LB. Some intracellular LB were positive for anti-C3d and -C4d antibodies, suggesting that the classical complement pathway is activated in degenerated LB-bearing neurons, inducing microglial activation and neuronal death.

Occurrence of human alpha-synuclein immunoreactive neurons with neurofibrillary tangle formation in the limbic areas of patients with Alzheimer's disease.

We examined alpha-synuclein immunoreactivity in the brains from 23 patients with Alzheimer's disease (AD) and two patients with Down's syndrome. In ten of the 23 AD cases and both the two Down's syndrome cases, alpha-synuclein immunoreactivities were observed in the neurons of the limbic areas, predominantly of the amygdala. Nearly all alpha-synuclein-positive neurons had tau-positive neurofibrillary tangles (NFT) in the same neurons, and these consisted of intermingled-type and superimposed-type. By immunoelectron microscopy, the intermingled-type revealed aggregations of alpha-synuclein-positive filamentous components, which were in continuity with paired helical filaments (PHF), while the superimposed-type revealed accumulations of alpha-synuclein-positive non-filamentous components in PHF bundles. These findings suggest that alpha-synuclein can accumulate in PHF and form filamentous aggregations in neurons of the limbic areas in AD cases.

Cdk5 and munc-18/p67 co-localization in early stage neurofibrillary tangles-bearing neurons in Alzheimer type dementia brains.

Hyperphosphorylation of tau protein occurs during the formation of paired helical filament (PHF) in the brain with Alzheimer's disease. As previously reported, cyclin-dependent kinase (cdk) 5 can phosphorylate tau at the site of abnormally phosphorylated in PHF. To characterize the relationship between cdk5 and PHF-tau, we investigated the localization of cdk5 and its regulator, p67 (munc 18), in the hippocampus and temporal lobes from 12 Alzheimer type dementia (ATD) patients and 5 controls using immunohistochemical procedures. The specificity of antibodies was confirmed with Western blot analysis. Anti-cdk5 antibody diffusely stained the perikarya of some tau2-positive or neurofibrillary tangle (NFT)-bearing neurons in ATD brains, while cdk5-positive staining was scarcely found in control brains. Anti-p67 antibody also showed stronger immunoreactivity of pyramidal neurons in ATD brains than in control brains. Double immunostaining with anti-cdk5 and anti-p67 antibodies revealed co-localization of both molecules in some pyramidal neurons. These findings suggest that cdk5 is activated by p67 at the early stage of NFT formation and accelerates NFT formation. In cdk5-positive and p67-negative neurons, cdk5 may be activated by other regulator molecules such as p35. In addition, cdk5-positive reactive astrocytes were found close to cdk5-positive NFT-bearing neurons m ATD brains but not in control brains, suggesting a correlation between NFT and reactive astrocytes.