Yuken Fukutani

Neurons, intracellular and extracellular neurofibrillary tangles in subdivisions of the hippocampal cortex in normal ageing and Alzheimer's disease

Unaffected neurons, intracellular neurofibrillary tangles (I-NFTs) and extracellular NFTs (E-NFTs) in six normal subjects and six patients with Alzheimers disease (AD) were morphometrically evaluated in eight subdivisions of the hippocampal cortex, using the Gallyas silver impregnation technique modified by the application of hematoxylin and eosin. The subdivisions examined included CA1-4, prosubiculum (PRO), subiculum and presubiculum (PRE), parasubiculum (PARA) and the entorhinal cortex (ENT). In the AD patients, the number of unaffected neurons in ENT, CA1, PRO and PARA was significantly decreased to one-quarter to two-thirds of that of the normal aged subjects. These four subdivisions in the AD patients had a greater number of both I- and E-NFTs. There were no significant differences in the total number of unaffected neurons, I- and ENTs between the AD patients and normal aged subjects for all the subdivisions. These findings suggest that neuronal loss in the hippocampal cortex in AD is almost entirely due to NFT formation. Furthermore, with regards to neuronal loss and NFT formation, there were two different subdivision groups in the AD patients. One group was composed of severely affected subdivisions (ENT, CA1, PRO and Para) and was distinct from the other group which was composed of mildly affected subdivisions (CA4, CA3, CA2 and PRE). Each subdivision in the normal aged subjects belonged to the mildly affected group as seen in the AD patients. These findings indicate that both neuronal loss and NFT formation associated with normal ageing and with AD are not only quantitatively but also qualitatively different.

Purkinje cell loss and astrocytosis in the cerebellum in familial and sporadic Alzheimer's disease

In order to elucidate further the pathological differences between familial Alzheimers disease (FAD) and sporadic Alzheimers disease (SAD), Purkinje cells and astrocytosis in the cerebellum of 10 FAD patients including two cases with the beta-amyloid precursor protein (APP) gene mutation in codon 717 (APP717 Val-->Ile), 10 SAD patients and 10 non-demented, age-matched controls were morphometrically investigated using immunohistochemistry. The regions examined included the molecular, Purkinje cell and granular cell layers, and the cerebellar white matter. This is the first report of a significantly decreased Purkinje cell density in FAD when compared to SAD. The density in SAD was also significantly decreased when compared to controls. In addition, the astrocyte density in FAD was significantly greater than that of SAD in the Purkinje cell layer, granular cell layer, and white matter. The density in SAD was also greater than that in controls, but not significantly in the granular cell layer and white matter. In the cases with the APP717 (Val-->Ile) mutation, Purkinje cell loss in the cerebellum was greater than the mean for FAD and SAD cases, while the astrocyte density was lower than the mean of all FAD cases, but higher than the mean of SAD cases. This study demonstrates that Purkinje cell loss and astrocytosis in FAD in the cerebellum are greater than in SAD, indicating that the cerebellum is more affected in FAD than in SAD.

Association of phosphorylation site of tau protein with neuronal apoptosis in Alzheimer's disease

In addition to neuritic changes and amyloid deposits, neuronal and glial cell apoptosis is an important pathological feature of Alzheimers disease (AD). Several factors have been postulated as causes or triggers of cellular apoptotic change. This study focused on a quantifiable relationship between phosphorylation sites of tau protein in the neurofibrillary tangles (NFT) and neuronal apoptosis. Five monoclonal anti-tau antibodies (AT180, AT8, HT7, Tau2 and Tau5) for NFT labeling and TdT-mediated UTP nick-end labeling (TUNEL) for localizing apoptotic change were employed. TUNEL-stained neuronal nuclei showed significantly high density in the entorhinal cortex, cornu ammonis (CA) and the parietal cortex. In all regions, density of TUNEL-stained neuronal nuclei showed significantly direct correlation with that of AT8-, AT180- and Tau2-positive neurons. Correlation of TUNEL-stained neuronal nuclei with tau-positive neurons differed depending on the cerebral regions. Density of TUNEL-stained neuronal nuclei showed inverse correlation with that of both AT8-positive and Gallyas-stained NFT in the CA and showed significantly direct correlation with AT8- and HT7-positive neurons in the frontal cortex. Density of tau-positive and Gallyas-stained NFT was higher than that of TUNEL-stained nuclei. We conclude that phosphorylation sites of tau, 159-163 and 202-205, are probably associated with neuronal apoptosis and apoptotic change follows abnormal phosphorylation of tau.

Neuronal loss and neurofibrillary degeneration in the hippocampal cortex in late-onset sporadic Alzheimer's disease

Abstract To explore more fully the relationship between neuronal death and neurofibrillary degeneration, unaffected neurons, intracellular neurofibrillary tangles (i‐NFT) and extracellular NFT (e‐NFT) in 22 patients with late‐onset sporadic Alzheimers disease (AD) were morphometrically evaluated in eight subdivisions of the hippocampal cortex, using the Gallyas hematoxylin‐eosin stain. The subdivisions examined included CA4, CA3, CA2, CA1 (CA: cornu ammonis), prosubiculum (PRO), subiculum and presubiculum (PRE), parasubiculum (PARA) and the entorhinal cortex (ENT). The unaffected neuron density was significantly lower and both i‐NFT and e‐NFT densities were significantly higher in subdivisions other than CA4 and CA3 in AD patients compared with those in the aged controls. Unaffected neuron density was significantly, inversely correlated with e‐NFT density and with total NFT density in all subdivisions except for PRE in AD patients. Especially in CA2, CA1, PRO and ENT, there were strong correlations between the neuron density and these NFT densities. Both unaffected neuron and e‐NFT densities in CA1 and ENT were significantly correlated with the disease duration. The i/e‐NFT ratio, an index of the degree and/or rate of progress of neuronal death via neurofibrillary degeneration, showed the lowest value in ENT in AD patients. The findings suggest that neuronal death via neurofibrillary degeneration starts earliest and/or most rapidly progresses in ENT. Furthermore, the i/e‐NFT ratios in both ENT and CA1 were significantly correlated with the disease duration, suggesting that the neuronal death pattern in the two subdivisions parallels disease progression.

Cerebellar pathology in sporadic and familial Alzheimer's disease including APP 717 (Val-->Ile) mutation cases: a morphometric investigation.

Familial Alzheimers disease (FAD) tends to present with more prominent neurological symptoms including cerebellar signs than sporadic Alzheimers disease (SAD). In order to elucidate the pathological differences in the cerebellum, which may be associated with the cerebellar symptoms, we have investigated morphometrically beta-amyloid deposits, atrocytosis, Purkinje cells and dentate neurons in the cerebellum of 10 FAD patients including two cases with the beta-amyloid precursor protein (APP) gene mutation (APP717 Val-->Ile), 10 SAD patients and 10 non-demented age-matched controls. The regions examined included the molecular, Purkinje cell and granular cell layers, the cerebellar white matter and the dentate nucleus. Purkinje cell density in FAD was significantly lower than in SAD. There were no significant differences in the density of dentate neurons among the three groups. The density of astrocytes in FAD was significantly greater than that in SAD in the granular cell and Purkinje cell layers and in the white matter. There were no significant differences in the amount and subtypes of beta-amyloid deposits (extracellular, vascular and perivascular) between FAD and SAD in all the regions investigated. In two cases with the APP mutation, both Purkinje cell loss and beta-amyloid deposition in the cerebellum were greater than the mean for FAD and SAD cases. Astrocytosis in the mutation cases was not greater than the mean for FAD cases except for the dentate nucleus in one case. Extracellular beta-amyloid deposits were not seen in any of the control cases although amyloid angiopathy was observed in one case. This study demonstrates for the first time that Purkinje cell loss and reactive astrocytosis of the cerebellum in FAD are more severe than in SAD, but that beta-amyloid deposition in the cerebellum in both FAD and SAD are similar. The more prominent neurological signs observed in FAD may be explained by more severe neurodegeneration than are found in sporadic cases.

CT Findings of the Interval Form of Carbon Monoxide Poisoning Compared with Neuropathological Findings

Cerebral computed tomography findings were described in 2 clinical cases of the interval form of carbon monoxide poisoning and comparison with postmortem CT finding of an autopsy case was made. There was low density in the bilateral frontal region, centrum semiovale and pallidal parts. In the course of the disease, the degree of low density in the white matter showed a tendency to diminish but it became more apparent in the pallidal parts. Myelinopathic white matter lesion in an autopsy material was recognized as a low density area in CT, which is identical with that seen in clinical cases.

KP-1 Is a Marker for Extraneuronal Neurofibrillary Tangles and Senile Plaques in Alzheimer Diseased Brains

KP-1 immunostaining with microwave pretreatment in formalin-fixed, paraffin-embedded sections enhanced its immunoreactivity revealing extraneuronal neurofibrillary tangles (NFTs) called ghost tangles, senile plaques (SPs) and perivascular deposits as well as microglial labelling in Alzheimer-diseased brains. KP-1 stained cored and uncored SPs, granules within the SPs, perivascular β-amyloid protein (βAP) and star-like βAP deposits in cortical layer I, which was confirmed in comparison to silver-impregnated structures in the Reusche-stained or Gallyas-Schiff-stained sections. On double immunostaining with KP-1 and ubiquitin, ghost tangles were labelled by KP-1 and intraneuronal NFTs were positive for ubiquitin. A few KP-1-positive granules deposits different from amyloid core were found within the SPs and the outer margin of amyloid cores of SPs were stained by KP-1. KP-1-positive microglia were attached to the ubiquitin-positive intraneuronal NFTs. Microglia were more numerously labelled by CR3/43 than by KP-1, and CR3/43-positive microglia were found to be preferentially attached to SPs. As KP-1 recognizes lysosome-associated antigen CD68, similarities between KP-1 positivity and Reusche-stained structures suggested that lysosomal activity was associated with βAP deposits and ghost tangles were involved in lysosome-associated processes. It is speculated that lysosomes play a role in the process of ghost tangle formation and in βAP deposits leading to SP formation.

Adult-type metachromatic leukodystrophy with a compound heterozygote mutation showing character change and dementia

A 26‐year‐old Japanese woman slowly developed a change of character such as hypospontaneity and blunted affect, followed by obvious mental deterioration. She was diagnosed as having a disorganized type of schizophrenia at the first examination. Brain magnetic resonance imaging demonstrated diffuse high intensity in the cerebral white matter, particularly in the frontal lobes. The single photon emission computed tomography images using 123I‐IMP disclosed diffuse cerebral hypofusion, especially in the frontal lobes. Electroencephalogram showed a moderate amount of 5–6 Hz θ waves on the background of α activity. Nerve conduction velocities in the extremities were delayed. The level of leucocyte arylsulphatase was low. In the arylsulphatase A gene analysis, a compound heterozygote having the 99Gly→Asp and 409Thr→Ile mutations was confirmed. The patient was diagnosed as having metachromatic leukodystrophy. She gradually showed obvious dementing symptoms such as memory disturbance and disorientation. The characteristics of the psychiatric symptoms in the leukodystrophy are discussed.

A case of diffuse neurofibrillary tangles with calcification

Abstract We report a 79‐year‐old female with atypical senile dementia with Fahr‐type calcification. The patient started to show memory disturbance at the age of 75 years, followed by visual hallucination, stereotypy, personality changes such as irritability, aggression and disinhibition. Brain computed tomography (CT) demonstrated bilateral and symmetric calcification of the basal ganglia and thalamus. Magnetic resonance imaging (MRI) revealed diffuse cortical atrophy pronounced in the fronto‐temporal areas. On MRI T1‐weighted images the calcified areas showed a mixture of low‐ and high‐intensity signals. Based on the overlapping clinical symptoms of Alzheimers disease and Picks disease, together with the brain CT and MRI findings, we clinically diagnosed the patient as having ‘diffuse neurofibrillary tangles with calcification’ (DNTC). The characteristics of psychiatric symptoms and neuroradiological findings in DNTC are discussed.

Glyceraldehyde 3-phosphate dehydrogenase and endothelin-1 immunoreactivity is associated with cerebral white matter damage in dentatorubral–pallidoluysian atrophy

DRPLA is a rare neurodegenerative disorder caused by CAG triplet elongation on chromosome 12p. In addition to neurodegeneration of both the dentatorubral and pallidoluysian systems, there is cerebral white matter damage, especially in older cases. Intracellular accumulation of DRPLA protein is widespread in the central nervous system, and DRPLA protein has been shown to immobilize glyceraldehyde 3‐phosphate dehydrogenase (GAPDH), which regulates glycolysis and controls mRNA of tissue‐type plasminogen activator (tPA) in tissue restoration. However, little is known about the pathogenesis regarding the formation of cerebral white matter damage in DRPLA. Therefore, the pathology of this damage was investigated by examining markers of glycolysis and related processes. Nine clinically and pathologically confirmed DRPLA cases were used in the present study. CAG triplet elongation on chromosome 12p was confirmed in all cases where tissue was available for genotyping (seven cases). PAS and immunohistochemistry with antibodies to GFAP, GAPDH and endothelin‐1 were used to demonstrate astrocytosis. The polysaccharides storage state with PAS‐positive astrocytes was detected in seven cases. GAPDH‐ and endothelin‐1‐positive endothelium and astrocytes were observed in two cases with GFAP‐positivity. Based on the biochemical process together with the present results, GAPDH and endothelin‐1 immunoreactivity is associated with this damage and the mismetabolism of polysaccharides caused by CAG triplet elongation on chromosome 12p may contribute to the formation of the cerebral white matter damage in DRPLA.