[Show abstract][Hide abstract] ABSTRACT: Tangle-predominant dementia (TPD) is characterized neuropathologically by numerous neurofibrillary tangles in the limbic areas with no or occasional senile plaques throughout the brain. TPD is an under-recognized disease, while it is a common cause of dementia in those over 80 years of age. In the present study, we describe hyperphosphorylated tau (tau) accumulation in the nucleus accumbens (Acb) in patients with TPD.
We investigated immunohistochemically the brain tissues from 7 patients with TPD, 22 with Alzheimer disease (AD) and 11 non-demented aged subjects. In the Acb of all 7 TPD patients, a considerable number of tau positive neurons were found together with many neuropil threads. The tau deposits in the Acb were labeled with all the anti-tau antibodies used in the present study. They included conformational change-specific, phosphorylation-specific and phosphorylation-independent antibodies. The Acb consists of the predominant medium-sized neurons with a small number of large neurons. Both the cell types were affected by tau pathology in TPD. Tau accumulation in the majority of such neurons appeared to be pretangle-like, diffuse deposits with only occasional paired helical filament formation. Tau positive neurons were also found in the Acb in some AD and non-demented aged subjects but much fewer in the majority of cases. The immunoblot analyses of fresh frozen samples of the Acb and parahippocampal cortex from 3 TPD and 3 AD patients revealed that the insoluble tau in the Acb was a mixture of the 3- and 4-repeat isoforms.
To our knowledge, this is the first report on the occurrence of tau accumulation in the Acb in TPD. The Acb receives direct and massive projections from the hippocampal CA1 and subiculum where neurofibrillary tangles are known to occur more frequently in TPD than in AD. The prevalence of abnormal tau accumulation in the Acb in TPD may support the idea that abnormal tau aggregation propagates via neural circuits. In all but one TPD cases used in this study, delusion was a consistent clinical feature. Whether the Acb tau accumulation is related to the psychiatric symptoms in TPD may be an issue for further investigation.
[Show abstract][Hide abstract] ABSTRACT: Accumulating evidence suggests that advanced glycation end products, generated as a consequence of facilitated carbonyl stress, are implicated in the development of a variety of diseases. These diseases include neurodegenerative illnesses, such as Alzheimer disease. Pyridoxamine is one of the 3 forms of vitamin B6, and it acts by combating carbonyl stress and inhibiting the formation of AGEs. Depletion of pyridoxamine due to enhanced carbonyl stress eventually leads to a decrease in the other forms of vitamin B6, namely pyridoxal and pyridoxine. We previously reported that higher levels of plasma pentosidine, a well-known biomarker for advanced glycation end products, and decreased serum pyridoxal levels were found in a subpopulation of schizophrenic patients. However, there is as yet no clinical characterization of this subset of schizophrenia. In this study, we found that these patients shared many clinical features with treatment-resistant schizophrenia. These include a higher proportion of inpatients, low educational status, longer durations of hospitalization, and higher doses of antipsychotic medication, compared with patients without carbonyl stress. Interestingly, psychopathological symptoms showed a tendency towards negative association with serum vitamin B6 levels. Our results support the idea that treatment regimes reducing carbonyl stress, such as supplementation of pyridoxamine, could provide novel therapeutic benefits for this subgroup of patients.
[Show abstract][Hide abstract] ABSTRACT: We investigated the pathological features of frontotemporal lobar degeneration (FTLD) with fused in sarcoma protein (FUS) accumulation (FTLD-FUS) in the Japanese population. Only one out of nine FTLD-FUS cases showed pathology that corresponds to atypical FTLD with ubiquitin-positive inclusions (aFTLD-U). Five were basophilic inclusion body disease (BIBD) and two were neuronal intermediate filament inclusion disease. The last case was unclassifiable and was associated with dystrophic neurites (DNs) as the predominant FUS pathology. The results of this study indicate an ethnic difference from western countries. In Japan, BIBD is the most common subtype of FTLD-FUS and aFTLD-U is rare, a finding which contrasts with aFTLD-U being the most common form in western countries. Immunohistochemical analyses of these FTLD-FUS cases reveal that FUS abnormally accumulated in neuronal cytoplasmic inclusions (NCIs) and DNs has an immunohistochemical profile distinct from that of normal, nuclear FUS. NCIs and DNs are more readily stained than the nuclei by antibodies to the middle portion of FUS. Antibodies to the carboxyl terminal portion, on the other hand, stain the nuclei more readily than NCIs and DNs. Such an immunohistochemical profile of NCIs and DNs was similar to that of cytoplasmic granular FUS staining which we previously reported to be associated with dendrites and synapses. Redistribution of FUS from the nucleus to the cytoplasm could be associated with the formation of abnormal FUS aggregates in FTLD-FUS.
Journal of the neurological sciences 09/2013; · 2.32 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Corticobasal degeneration (CBD) is a disorder affecting cognition and movement due to a progressive neurodegeneration associated with distinctive neuropathologic features, including abnormal phosphorylated tau protein in neurons and glia in cortex, basal ganglia, diencephalon, and brainstem, as well as ballooned neurons and astrocytic plaques. We identified three cases of CBD with olivopontocerebellar atrophy (CBD-OPCA) that did not have α-synuclein-positive glial cytoplasmic inclusions of multiple system atrophy (MSA). Two patients had clinical features suggestive of progressive supranuclear palsy (PSP), and the third case had cerebellar ataxia thought to be due to idiopathic OPCA. Neuropathologic features of CBD-OPCA are compared to typical CBD, as well as MSA and PSP. CBD-OPCA and MSA had marked neuronal loss in pontine nuclei, inferior olivary nucleus, and Purkinje cell layer. Neuronal loss and grumose degeneration in the cerebellar dentate nucleus were comparable in CBD-OPCA and PSP. Image analysis of tau pathology showed greater infratentorial tau burden, especially in pontine base, in CBD-OPCA compared with typical CBD. In addition, CBD-OPCA had TDP-43 immunoreactive neuronal and glial cytoplasmic inclusions and threads throughout the basal ganglia and in olivopontocerebellar system. CBD-OPCA met neuropathologic research diagnostic criteria for CBD and shared tau biochemical characteristics with typical CBD. These results suggest that CBD-OPCA is a distinct clinicopathologic variant of CBD with olivopontocerebellar TDP-43 pathology.
[Show abstract][Hide abstract] ABSTRACT: A 30-year-old Japanese woman without relevant family history presented with a behavioral abnormality followed by motor weakness about 14 years later. The patient died at age 45. Post mortem examination revealed degeneration of the frontal and temporal lobes, as well as lower motor neurons in the brainstem and spinal cord. These features were reported previously as being consistent with a diagnosis of frontotemporal lobar degeneration (FTLD) with amyotrophic lateral sclerosis (ALS). In the present study, we show abundant fused in sarcoma (FUS)-positive dystrophic neurites but only a few neuronal cytoplasmic inclusions in the frontal and temporal cortices. TAR DNA-binding protein 43 (TDP-43)-positive inclusions were absent in the cerebrum. However, TDP-43-positive inclusions were present in the lower motor neurons of the brainstem and spinal cord. To our knowledge, this is the first report of a case in which FTLD-FUS pathology is of a dystrophic neurites-predominant type and FTLD-FUS is associated with ALS-TDP.
[Show abstract][Hide abstract] ABSTRACT: Role of mitochondrial pathology in schizophrenia has not been fully clarified. We searched for distinctive variants in mtDNA extracted from the gray matter of postmortem brains and from peripheral blood samples. We screened mtDNA region containing 5 genes encoding subunits of cytochrome c oxidase and ATPases. Polymorphisms not already reported in databases are recorded as unregistered rare variants. Four unregistered, non-synonymous rare variants were detected in 4 schizophrenic samples. Seven registered non-synonymous variants were not previously detected in non-psychotic Japanese samples registered in the mtSNP database. These variants may contribute to disease pathophysiology. In one family, compound mutations showed co-segregation with schizophrenia. MtDNA mutations could confer a risk for schizophrenia in the Japanese population, although further analyses are needed.
Molecular Genetics and Metabolism 01/2012; 105(1):103-9. · 2.83 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Alzheimer disease (AD) is characterized by numerous senile plaques (SP) in addition to widespread neocortical neurofibrillary tangles (NFT). Some elderly have pathologic aging (PA), which is characterized by numerous SP composed of diffuse amyloid deposits with few or no NFT confined to the limbic lobe. Both AD and PA represent a range of Alzheimer type pathology (ATP). Some cases of progressive supranuclear palsy (PSP) have concurrent ATP, but the relationship between ATP and PSP has not been addressed. In this study, a consecutive series of PSP cases were divided into three groups according to the degree of concurrent ATP - pure PSP, PSP/PA and PSP/AD. Braak NFT stage was significantly greater in PSP/AD compared with both PSP/PA and PSP. Among the pathologic variables studied in middle frontal, superior temporal and motor cortices, there were no differences between PSP and PSP/PA except for SP. In PSP/AD, there was greater neuronal tau pathology (pretangles, NFT and neuropil threads) in middle frontal and superior temporal cortices, probably a reflection of ATP since there was no comparable increase in PSP-related glial tau pathology in these regions. The APOEvarepsilon4 allele frequency was significantly higher in PSP/PA and PSP/AD than in PSP. These results strongly argue that ATP in PSP represents independent disease processes even when present in the same brain.
International journal of clinical and experimental pathology 02/2009; 2(4):399-406. · 2.24 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A 58-year-old Japanese man developed psychomotor excitement and hallucinatory paranoia at age 53, which gradually developed to residual schizophrenia. He was administered various common tranquilizers until death. Myelodysplastic syndrome was noted 10 months before death. A routine autopsy was performed. The brain weighed 1365 g, and macroscopic observation revealed no remarkable findings. However, microscopic examination disclosed cells with enlarged and basophilic nuclei, and unusual astrocytes in the demyelinated foci, especially at the corticomedullary junctions in the temporal and occipital lobes. On the other hand, the white matter was relatively intact. Immunohistochemical analysis using anti-JC virus protein, VP-1 antibody, demonstrated JC virus-infected cells in not only abnormal glial cells and neurons but also normal-looking cells, which are suggestive of progressive multifocal leukoencephalopathy (PML). Immunostaining for GFAP revealed severe gliosis and some scattered abnormal enlarged nuclear cells in the lesions. Some clusters of CD8-positive lymphocytes were seen, which kill infected cells. PML could be considered a short-term disease preceding death, as "incidental PML" in this case. This is a rare autopsy case of early PML occurring in a schizophrenia patient with PML.
[Show abstract][Hide abstract] ABSTRACT: Cerebral amyloid angiopathy (CAA) affects both leptomeningeal and parenchymal blood vessels and is common in Alzheimer's disease (AD). In some vessels, CAA is accompanied by localized neuritic dystrophy around the affected blood vessel. The aim of this study was to assess the distribution and severity of perivascular neuritic dystrophy in primary visual and visual association cortices. The severity of perivascular neuritic dystrophy and Abeta deposition was scored in an association cortex (Brodmann area 18) and a primary cortex (Brodmann area 17) with double labeling immunohistochemistry for tau and Abeta in 31 cases of AD with severe CAA. The perivascular tau neuritic dystrophy score was significantly worse in visual association cortex than in primary visual cortex. On the other hand, there was no difference in the perivascular Abeta score between the two cortices. There were positive correlations between the severity of perivascular tau and perivascular Abeta scores for both primary and association cortices. The results suggest that the local neuronal environment determines the severity and nature of the perivascular neuritic pathology more than the severity of the intrinsic vascular disease and suggest a close association between perivascular amyloid deposits, so-called dyshoric angiopathy, and perivascular neuritic dystrophy.
International journal of clinical and experimental pathology 02/2008; 1(5):403-8. · 2.24 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Alcoholic cerebellar degeneration (ACD) is one of the most common neurological complications in alcoholics. As far as we know, however, only four Japanese autopsy cases of ACD have been reported, and only limited clinicopathological data on this disease are now available in Japan. The aims of this study were: (i) to examine the clinicopathological correlation of six Japanese autopsy cases of ACD, including three asymptomatic cases; and (ii) to elucidate the pattern of progression of the cerebellar lesion in ACD. All six alcoholics were histopathologically diagnosed as having "pure" ACD without Wernicke's encephalopathy. The characteristics of the topographical distribution of the cerebellar lesion were as follows. Symptomatic cases (cases 1-3) showed more severe and widespread change than asymptomatic cases (cases 4-6). Even in case 6, which had the mildest lesion, the anterior vermis developed a moderate change (Purkinje cell loss and narrowing of the molecular layer). In cases 4 and 5 with more severe and widespread lesions, the superior and posterior vermis and the adjacent regions of the superior hemisphere, including the anterior lobe and simple lobule, were involved. In all symptomatic cases, the anterior superior hemisphere had severe lesions involving the granular cell layer. In contrast to asymptomatic cases, all symptomatic cases also had severe to moderate lesions in the anterior inferior hemisphere. In cases 1 and 2 with the most severe lesions, the moderate to severe changes were distributed in the posterior and inferior portions of both the vermis and hemisphere. These findings suggest that in ACD, severe lesions successively develop: (i) in the anterior superior vermis; (ii) anterior superior hemisphere; (iii) anterior inferior hemisphere; and (iv) anterior inferior vermis. In addition, cerebellar symptoms may frequently occur if the anterior superior hemisphere and anterior inferior hemisphere, in addition to the anterior superior vermis, are involved.
[Show abstract][Hide abstract] ABSTRACT: Alcoholic cerebellar degeneration (ACD) is a pivotal neurological complication in alcoholics. However, although there are a few autopsy reports and some data on its frequency, it is considered very rare in Japan. The aims of this study were (1) to estimate the frequency of the disease in Japanese autopsy cases, and (2) to examine the clinicopathological features of symptomatic and asymptomatic cases of ACD. We reviewed the records of 1,509 Japanese autopsies obtained from three autopsy series in Japan, and selected all 55 cases (3.6%) with alcoholism. On neuropathological reexamination, ACD was confirmed in six male alcoholics [0.4% of all subjects; 10.9% of all alcoholics; mean age at death 59.3+/-13.4 years (+/- SD)], including three asymptomatic cases. These frequencies were much lower than some previous Western findings, but more common than that has been expected in Japan. The frequencies of memory impairment and ataxia in ACD cases were significantly higher than those in alcoholics without any alcohol-related pathologies. In ACD cases, loss of Purkinje cells, narrowing of the width of the molecular layer, and tissue rarefaction in the granular layer were observed in the anterior and superior portions of the vermis of the cerebellum. In adjacent regions, the Purkinje cell and molecular layers were more mildly affected. The distribution of severely affected regions was more restricted in the asymptomatic cases than in the symptomatic cases. This study confirmed the frequency of asymptomatic cerebellar degeneration in alcoholics, suggesting that early intervention in alcoholism in the subclinical phase is important to prevent the development of cerebellar symptoms.
[Show abstract][Hide abstract] ABSTRACT: Cerebral amyloid angiopathy (CAA) is a manifestation of amyloid beta-protein (Abeta) accumulation in the elderly as well as in patients with Alzheimer's disease (AD). Two types of CAA have been noted, based on the type of vasculature in which Abeta is deposited: cerebral capillary amyloid angiopathy (capCAA) and non-capCAA. Non-capCAA is a common form of CAA that consists of Abeta deposited in arteries and arterioles. Recent information on Abeta metabolism in the brain suggests that non-capCAA is associated with Abeta secretion into the cerebrospinal fluid via the perivascular space, whereas capCAA is associated with Abeta removal to blood plasma via the capillary endothelium. Abeta40, a major and relatively soluble Abeta isoform, is deposited predominantly in non-capCAA, and Abeta42, which is insoluble and associated more closely than Abeta40 with AD, is deposited predominantly in capCAA. Studying small areas of microscopic size within a given cortical region, we found an inverse association of capCAA and senile plaques. We also found a relative paucity of tau pathology in the small areas with abundant capCAA compared with the small areas with abundant senile plaques within a cortical region with the same cytoarchitecture. We suppose that both capCAA and senile plaques indicate high Abeta42 in the neuropil but that only Abeta42 in the form of insoluble deposits in senile plaques promotes tau abnormality.
[Show abstract][Hide abstract] ABSTRACT: A male residual schizophrenic out-patient of 65 years old had presented "heat stroke" and died in progressive course of 7 months. His mental condition had been stable and he had kept good drug compliance. In some summer day, he presented high fever and confusion, followed by convulsion. He showed over 40 degrees C high temperature (max 42 degrees C) for about 6 hours. After 10 day's high serum CPK, he gradually presented severe muscle atrophy (proximal dominant), flaccid quadriplegia and brain atrophy (especially in cerebellum). He died from pneumonia. His brain weight was 1,350g. Neuropathological study showed severe loss of Purkinje cell with gliosis. Neurons in dentate nucleus ware entirely lost and a great amount of fatty macrophages were present around the dentate nucleus. Fatty macrophages were observed from cerebellum to red nucleus through superior cerebellar peduncle. These findings have been known as findings of heat stroke. Addition to these findings, this case presented a neuronal loss in the substantita nigra and in the anterior horn of spinal cord and the degeneration of bilateral pyramidal tract. These findings have not been thus far reported, so this case is thought to be the valuable case on considering the variation of neuropathology of "heat stroke".
Nō to shinkei = Brain and nerve 06/2006; 58(5):418-24.
[Show abstract][Hide abstract] ABSTRACT: We report an autopsy case showing neuropathologically abundant Lewy bodies and argyrophilic grains. A Japanese woman without hereditary burden developed parkinsonian gait at the age of 74, following by insomnia, memory disturbance, delirium, resting tremor, rigidity, and retropulsion. About 8 months later, a visual hallucination, concerning small worms, children, and so on, became obvious. About 16 months later, malignant lymphoma was detected. About 17 months later, she died of pneumonia. The total duration of illness was approximately one year and five months. The weight of the brain was 1153 g before fixation. Depigmentation of the substantia nigra and locusceruleus was prominent. Many argyrophilic grains were seen in the temporal lobe (T3, T4), amygdala, and hippocampal CA1. Some ballooned neurons were found in the amygdala. Many Lewy bodies were encountered in the transentorhinal region and cingulated gyrus. A few Lewy bodies were seen in the temporal, frontal, and parietal lobes. In this case, neuropathological examination is compatible for dementia of Lewy bodies and argyrophilic grain dementia, and clinical course is consistent with dementia of Lewy bodies. This report may contribute to the elucidation of the clinicopathological hallmarks of argyrophilic grain dementia and dementia with Lewy bodies.
Nō to shinkei = Brain and nerve 09/2005; 57(8):695-700.
[Show abstract][Hide abstract] ABSTRACT: We investigated clinicopathologically four Japanese autopsy cases of diffuse neurofibrillary tangles with calcification (DNTC), which has been believed to be characterized by temporal or temporofrontal circumscribed lobar atrophy, and examined the distribution of their cerebral cortical lesions using hemisphere specimens. The lesions were classified into three categories (slight, moderate, and severe). Severe lesions were present in the temporal lobes and insular gyri of all four cases, consistent with the studies reported to date. In contrast, severe lesions were encountered in the parietal lobe of case 1 and moderate lesions were found in the parietal lobes of cases 2-4. Furthermore, moderate lesions of the precentral gyrus were present in cases 2-4, and moderate lesions of the postcentral gyrus were encountered in all four cases. We postulate that the distribution of cerebral cortical lesions in DNTC is more widespread than previously assumed. Our data also indicate that the unusual clinical signs of DNTC reported by several Japanese researchers, including parietal signs such as apraxia and agnosia, are roughly consistent with the topographic distribution of cerebral cortical lesions in DNTC elucidated in this study.
[Show abstract][Hide abstract] ABSTRACT: Argyrophilic grain disease (AGD) is a neurodegenerative dementia, which is neuropathologically characterized by the spindle-or comma-shaped argyrophilic grains scattered in the neuropil of hippocampal area. Several research reports have disclosed the pathological, biochemical and genetic characteristics of AGD, whereas the clinical aspects have not been fully investigated. Here we report an autopsy case of AGD. She developed tremor at age 63, and then developed dyskinesia, rigidity and gait disturbance. Thereafter, she had cognitive impairment and emotional disturbance at age 71, and died of pneumonia at age 76. She was clinically diagnosed as Parkinson's disease with dementia due to the presence of parkinsonism and dementia. Macroscopically, the brain demonstrated mild atrophy, and the weight was 1,240 g. Many argyrophilic grains were found in the hippocampus and amygdala. Coiled bodies and ballooned neurons were also present, while Alzheimer-type neurofibrillary changes were mild, consistent with stage 2 of Braak's classification. This case was neuropathologically diagnosed as AGD. In contrast, no remarkable pathological changes, including neuronal loss and Lewy bodies, were found in the nigra, locus ceruleus and basal nuclei. On the basis of the above-mentioned clinicopathological findings, parkinsonism with dementia is considered to be one of the clinical manifestations of AGD.
Nō to shinkei = Brain and nerve 10/2004; 56(9):785-8.
[Show abstract][Hide abstract] ABSTRACT: We report an autopsy case of Parkinson's disease mimicking senile dementia of the Alzheimer type. A Japanese man developed memory disturbance and visual hallucination at age 70. Although he died from pneumonia at age of 74, he had no neurological signs throughout the clinical course. The weight of his brain was 1,420 g. Macroscopic examination of the brain revealed prominent depigmentation of the substantia nigra and locus ceruleus. Histological examination disclosed neuronal loss with astrocytosis and the appearance of the Lewy bodies in the nucleus basalis of Meynert, substantia nigra, locus ceruleus, and dorsal vagal nucleus. There were widespread senile plaques in the brain, including the precentral gyrus, which was compatible with Braak stage C. A small number of neurofibrillary changes were present in the limbic areas, consistent with Braak stage III. This case is consistent with brain stem dominance with the pathological diagnosis of the Consortium on Dementia with Lewy Bodies International Workshop. That is, it is compatible with Parkinson's disease. We postulate that the clinical features of Parkinson's disease are more widespread than previously considered.
Nō to shinkei = Brain and nerve 08/2004; 56(7):603-6.
[Show abstract][Hide abstract] ABSTRACT: We report an autopsy case of a Japanese man with "progressive supranuclear palsy (PSP)" who showed neither neurological nor psychiatric signs. Although he died by heart failure at the age of 84 years, he had neither neurological nor psychiatric signs throughout the clinical course. Neuropathological examination revealed neuronal loss of the substantia nigra and pallidum. Neurofibrillary tangles were observed in the caudate nucleus, subthalamic nucleus, pallidum, putamen, substantia nigra, locus ceruleus, pontine nucleus, inferior olivary nucleus, and dentate nucleus, compatible with the NINDS pathological diagnosis of PSP reported in 1994. Staining by Gallyas-Braak methods disclosed tuft-shaped astrocytes in the caudate nucleus, putamen, and thalamus. To our knowledge, this is the first report of "PSP" without psychiatric or neurological signs.
Nō to shinkei = Brain and nerve 03/2004; 56(2):157-61.
[Show abstract][Hide abstract] ABSTRACT: Background: To date, there have been few studies about elderly psychiatric patients using psychiatric emergency services. In the present study, we analyze data from the Tokyo metropolitan psychiatric emergency system and the Tokyo Metropolitan Matsuzawa Hospital to examine the clinical features and social factors of elderly psychiatric patients hospitalized in psychiatric emergency units.Methods: Over a 4 year period, from April 1998 to March 2001, there were 7971 patients (4520 men, 3451 women) who used the Tokyo Metropolitan Government's psychiatric emergency system. Of these 584 patients (337 men, 247 women) were elderly, over 60 years. Of these geriatric patients, 72 (45 men, average age 74.4 years; 27 women, average age 76.0 years) were received at Tokyo Metropolitan Matsuzawa Hospital from January 1999 to December 2001. The present study examines the reasons for hospitalization, legally mandated admission, diagnosis, psychiatric symptoms at admission, inappropriate behaviors, family status and disease complications.Results: Epidemiological data showed that the number of geriatric patients has increased annually and the distribution of elderly patients’ diagnoses is entirely different from that of younger or middle-aged patients’. Almost all geriatric patients were under mandatory hospitalization by Law Related to Mental Health and Welfare of the Person with Mental Disorder. Psychiatric symptoms and inappropriate behaviors were considered to be highly severe, like those of younger patients.Conclusion: The importance of psychiatric emergency care for geriatric patients is strongly recognized by the present study. It is necessary to improve the present psychiatric medical system to develop a suitable and desirable system to care for geriatric patients.