High-resolution copy number variation analysis of schizophrenia in Japan.

Recent schizophrenia (SCZ) studies have reported an increased burden of de novo copy number variants (CNVs) and identified specific high-risk CNVs, although with variable phenotype expressivity. However, the pathogenesis of SCZ has not been fully elucidated. Using array comparative genomic hybridization, we performed a high-resolution genome-wide CNV analysis on a mainly (92%) Japanese population (1699 SCZ cases and 824 controls) and identified 7066 rare CNVs, 70.0% of which were small (<100 kb). Clinically significant CNVs were significantly more frequent in cases than in controls (odds ratio=3.04, P=9.3 × 10-9, 9.0% of cases). We confirmed a significant association of X-chromosome aneuploidies with SCZ and identified 11 de novo CNVs (e.g., MBD5 deletion) in cases. In patients with clinically significant CNVs, 41.7% had a history of congenital/developmental phenotypes, and the rate of treatment resistance was significantly higher (odds ratio=2.79, P=0.0036). We found more severe clinical manifestations in patients with two clinically significant CNVs. Gene set analysis replicated previous findings (e.g., synapse, calcium signaling) and identified novel biological pathways including oxidative stress response, genomic integrity, kinase and small GTPase signaling. Furthermore, involvement of multiple SCZ candidate genes and biological pathways in the pathogenesis of SCZ was suggested in established SCZ-associated CNV loci. Our study shows the high genetic heterogeneity of SCZ and its clinical features and raises the possibility that genomic instability is involved in its pathogenesis, which may be related to the increased burden of de novo CNVs and variable expressivity of CNVs.

Autopsy study of Alzheimer's disease brain pathology in schizophrenia.

The brains of 125 schizophrenic patients (DSM-IV criteria) without other major diseases likely to affect brain morphology were examined at autopsy in our hospital for an evaluation of the number of neurofibrillary tangles (NFT) and senile plaques (SP) as indicators of the incidence of Alzheimer's disease (AD) brain pathology. The clinical degree of dementia and the presence or absence of delirium and Parkinsonism were determined in a review of the patients' charts. No significant difference in the degree of AD brain pathology between the 12 schizophrenics more than 75 years old and 12 age-matched normal controls was present. We conclude that AD pathology seems to be no more frequent among schizophrenic patients than in the normal population, and that the severe cognitive impairment observed in schizophrenics is based on neither neuronal degeneration nor neuronal loss like that occurring in AD. We believe that future morphological studies of cognitive impairments in schizophrenics will require a more detailed investigation at the receptor level.

Immunohistochemical localization of the P2Y1 purinergic receptor in Alzheimer's disease.

The biological actions of extracellular nucleotides are mediated by two distinct classes of P2 receptor, P2X and P2Y. The G protein-coupled P2Y receptors comprise five mammalian subtypes, P2Y(1-11). The P2Y1 subtype is expressed abundantly throughout the human brain and is specifically localized to neuronal structures. In the present study, the distribution of the P2Y1 receptor was investigated in Alzheimer's disease (AD) brains. In contrast to control human brain, the P2Y1 receptor was localized to a number of characteristic AD structures such as neurofibrillary tangles, neuritic plaques and neuropil threads. Immunoblot analysis showed that this specific immunostaining observed over tangles was not a result of cross-reactivity between the anti-P2Y1 antiserum and abnormal tau protein, the major constituent of tangles. The significance of this altered P2Y1 cellular distribution in AD brains is at present unclear.

Astroglial function of schizophrenic brain: a study using lobotomized brain.

The neurodevelopmental hypothesis is now being recognized as one of the most useful hypothesis for schizophrenia, and by using it, abnormalities in protein associated with neuron growth or neuronal migration have been reported. From neuron-glia interrelations in the neural development, it is important to study the function of astroglia in the schizophrenic brain. In this study, we examined the neuropathological reaction of astroglia using lobotomized brains, and a significant decrease of astroglia after artificial histological damage was observed in schizophrenic brains. We speculated that this may be due to the latent vulnerability of the dynamic function of astroglia in schizophrenia. Astroglia plays a guidance role on migration and if astroglia has latent vulnerability, we speculate that younger neurons may not sufficiently migrate during development. In further investigation of the neurodevelopmental hypothesis of schizophrenia, it will be necessary to examine the function of astroglia.

The distribution of neuropeptide Y and brain-derived neurotrophic factor immunoreactivity in hippocampal formation of the monkey and rat.

The distribution of neuropeptide Y (NPY) and Brain-Derived Neurotrophic Factor (BDNF) in the hippocampal formation of monkey and rat brains was studied immunohistochemically. The NPY-neuronal system is more highly developed in the monkey compared to that in the rat. The distribution of NPY-positive products was coincident with that of abundant BDNF-positive deposits. These observations suggest that the role of BDNF and the interaction of BDNF-NPY may differ between species.

Ultrastructural and immunohistochemical study of degenerate neurite-bearing ghost tangles.

Some ghost tangles in the brains of Alzheimer patients were accompanied by many small argyrophilic structures which were electron microscopically confirmed to be degenerate neurites. In these ghost tangles, roughly dispersed 15 nm straight and occasional twisted tubules were penetrated by proliferated astrocytic processes. Immunohistochemically, these ghost tangles lost immunoreactivities to anti-NFT, -tau and -ubiquitin antibodies, but were thioflavine-S fluorescent, though antigenicity to beta-protein was not proved. This similarity in composition of degenerate neurite-bearing ghost tangles to senile plaques might be induced by the amyloid nature of tubules, which probably provokes the reaction of neuropils.

Coexistence of paired helical filaments and glial filaments in astrocytic processes within ghost tangles.

Ultrastructural examination of ghost tangles in an autopsy case of long-term Alzheimer's disease revealed, in addition to degenerate neurites containing paired helical filaments (PHF), astrocytic processes which included PHF. This finding suggests either that astrocytes in ghost tangles possess the capacity to produce PHF or that PHF are incorporated into astrocytes by endocytosis.

Immunohistochemical localization of gamma-aminobutyric acid(B) receptor in the hippocampus of subjects with schizophrenia.

Recent studies have demonstrated the involvements of gamma-aminobutyric acid (GABA) neurotransmitter systems in the schizophrenic brain. In order to further elucidate the alterations of this system in schizophrenia, we employed immunohistochemical techniques and examined the expression and anatomical distribution of the GABA(B) receptor in the hippocampus of five subjects with schizophrenia and three age-matched controls. In the control hippocampus, the most intense immunoreactivity was observed in the soma and processes of multipolar interneurons throughout the hippocampus. Pyramidal cells too were intensely labeled in their soma and proximal portion of dendrites, although the labeling intensity was varied in each subregion. For example, in the CA1 subfield, the labeling intensity of pyramidal cells was much less intense than that in the CA3 and CA2 subfields. In the subjects with schizophrenia, GABA(B) immunoreactivity was markedly reduced in granule cells as well as in pyramidal cells throughout the CA fields. In interneurons, GABA(B) labeling was relatively preserved compared to that in pyramidal cells. Our findings suggest that in the hippocampus of schizophrenic patients the expression of the GABA(B) receptor is reduced, and raise the possibility that this reduction contributes to the pathophysiological process in the schizophrenic brain.

Alz-50/Gallyas-positive lysosome-like intraneuronal granules in Alzheimer's disease and control brains.

The Gallyas-Braak silver impregnation method revealed neurons containing well-defined intraneuronal granules in both Alzheimer's disease and normal control brains. The granules were immunostained prominently with the Alz-50 antibody and, to a lesser degree, with the tau-2 antibody, but not with other anti-tau antibodies examined. The areas of distribution of granule-containing neurons detected by the Gallyas-Braak method appeared to overlap with the reported main sites of subcortical distribution of neurofibrillary tangles. They, however, were not observed in the cerebral cortex, including the hippocampal region. The Alz-50 immunoreactive granules showed ultrastructural features similar to those of lysosomes or lipofuscin. These findings suggest that denatured tau might be degraded in lysosomes.

Argyrophilic glial inclusions in the midbrain of patients with Parkinson's disease and diffuse Lewy body disease are immunopositive for NACP/alpha-synuclein.

Argyrophilic glial inclusions occur in the midbrain of patients with Parkinson's disease (PD) and diffuse Lewy body disease (DLBD). These inclusions are immunohistochemically positive for NACP/alpha-synuclein but negative for tau protein. The results of the present study suggest that a primary degenerative process involves NACP/alpha-synuclein in PD and DLBD and that the process takes place not only in neurons but also in glial cells. Argyrophilic cytoplasmic inclusions, both glial and neuronal, in a variety of degenerative diseases may be grouped into two major categories; one related to aggregates of abnormally phosphorylated tau protein and the other to unusual accumulations of NACP/alpha-synuclein.

A quantitative study on the expression of synapsin II and N-ethylmaleimide-sensitive fusion protein in schizophrenic patients.

The application of DNA array technology to schizophrenic studies enabled us to assess molecular features of this disease. The expression of synapsin II and N-ethylmaleimide-sensitive fusion protein (NSF) mRNAs is reported to decrease in the prefrontal cortex of these patients. We attempted to reproduce this result with two distinct approaches. With high quality samples, mRNA and protein levels for synapsin II and NSF were measured by real-time polymerase chain reaction and by immunoblotting. Both experiments led to the same conclusion: The expression of these presynaptic markers is not altered significantly in the prefrontal cortex of our schizophrenic samples, compared to that in control subjects. These observations suggest that the neurochemical impairments of synapses reported in schizophrenia are not evident for all presynaptic markers and needs to be re-evaluated at molecular levels.

Morphological changes in neuropeptide Y-positive fiber in the hippocampal formation of schizophrenics.

1. The authors observed NPY-positive fibers in the CA4 area of the hippocampus from schizophrenics and normal controls using immunohistochemical techniques. 2. Positive fibers followed a straight course and were oriented to exit the CA4 region of hippocampus in normal controls. 3. Many NPY-positive fibers in the CA4 area appeared coiled or helix-like or appeared wasted and thread-like in schizophrenic brains, compared to those of normal controls. 4. These findings may indicate a dysfunction of the interneuron in the schizophrenic brain and support the hypothesis of developmental impairments of the CNS in schizophrenia, and these morphological changes in fibers may relate to schizophrenic symptoms such as memory or/and learning deterioration.

Calbindin immunoreactivity in the hippocampal formation and neocortex of schizophrenics.

1. The authors studied the morphology of CalbindinD28K (CaBp) immunoreactive cells and processes in the hippocampal formation and the prefrontal cortex of schizophrenics using the immunohistochemical technique of avidin-biotin-complex method (ABC method), and the results were compared with those from normal human brains. 2. In the hippocampal formation area CA2 of schizophrenics, many CaBp-immunopositive cell bodies and fibers were disordered in their arrangement compared to normal control brains. 3. In the prefrontal cortex (Brodmann area 9) of schizophrenics, many immunopositive cell bodies were exhibited irregular axis arrangement and fiber disarray. 4. The altered distribution pattern of CaBp-immunopositive structures in the hippocampal formation and the prefrontal cortex might indicate the existence of GABA(gamma-aminobutyric acid)ergic dysfunction in the brain of schizophrenic patients.

Cognitive decline in schizophrenics with Alzheimer's disease: a mini-review of neuropsychological and neuropathological studies.

Cognitive decline in elderly schizophrenic patients is an important clinical symptom, but it is often difficult to analyze in detail due to the patient's original residual psychotic symptoms. In this article, the authors provide neuropsychological and neuropathological research information about cognitive decline in elderly schizophrenic patients, especially with reference to Alzheimer's disease (AD). Neuropsychological and neuropathological reports about cognitive impairments are reviewed. The effect of long-term antipsychotic medication upon cognitive function is also discussed. As a result, it is apparent that elderly schizophrenic patients often show cognitive impairments, however, such impairments do not have the characteristics of progressive degenerative illnesses such as AD, and the speed of their progress is very slow. Neuropathological studies have shown that AD brain pathology appears no more frequently among schizophrenic patients than in the normal population. Since making a diagnosis of AD means that the progressive deterioration not only of cognitive function, but also of physical ability, paralleling the degeneration of the central nervous system, can be expected within a few years and appropriate care will be required. One should be very cautious in adding a diagnosis of AD to elderly schizophrenic patients with cognitive impairments.

The distribution of substance P in the cerebral cortex and hippocampal formation: an immunohistochemical study in the monkey and rat.

The distribution of substance P-containing fibers in the cerebral cortex and the hippocampal formation of the Japanese monkey (Macaca fuscata fuscata) was studied by immunohistochemistry using a monoclonal antibody raised against substance P. The results were compared with the distribution in homologous regions of the rat brain. Substance P-containing fibers and cell bodies were observed in all regions of the cerebral cortex. In deep layers of the neocortex (IV-VI), substance P-immunoreactive fibers formed arrays that ran perpendicular to the surface. These immunoreactive fibers tended to branch as they approached the cortical surface in layers II and III, at which point they were oriented in many directions. The molecular layer (I) of the monkey neocortex contained many granular, substance P-immunoreactive structures, resembling terminal boutons. In contrast to the monkey, rat cortical areas contained substantially fewer substance P-containing fibers. The immunoreactive profiles, mostly fine dot-like structures, were seen uniformly in layers II and IV of the rat neocortex, although in the medial prefrontal cortex many thick, varicose fibers were also observed. Substance P-containing fibers were seen throughout the hippocampal formation of the monkey, including the subiculum and the parahippocampal regions. The regional distribution of immunoreactive fibers was most dense in the molecular layers of dentate gyrus, in the stratum moleculare of the CA1 region, and in the stratum pyramidalis of the CA2 region. In the rat, the hippocampus and dentate gyrus contained fewer immunoreactive fibers. Moderate densities were observed in the rat subiculum and entorhinal cortex.(ABSTRACT TRUNCATED AT 250 WORDS)

Atypical late-onset dementia characterized by limbic degeneration with coiled bodies and argyrophilic threads.

This report concerns an autopsy case of late-onset dementia with atypical neuropathological features. The patient was a Japanese man who was 83 years old at the age of death. At 73 years, he developed behavioral disorders, including emotional changes, and dementia. He died at the age of 83. A neuropathological study revealed largely confined involvement of the limbic regions, characterized by degeneration consisting of neuronal loss with a spongy state and gliosis. Massive tau-positive oligodendroglial coiled bodies and argyrophilic threads were also observed mainly in these regions. Although the clinicopathological findings of the present case showed some similarities to those of a unique subtype of frontotemporal dementia, including mesolimbocortical dementia, argyrophilic grain disease, corticobasal degeneration and dementia with tangles, there seems to be no suitable category of neurodegenerative disease into which our case can be classified. Further study is needed to determine whether the present case could be classified as an atypical case of these diseases or represents a new entity.

Language production in Parkinson's disease: acoustic and linguistic considerations.

The hypokinetic dysarthria of Parkinson's disease (PD) has been described extensively. In contrast, patterns of hesitation and the language structure in spontaneous speech of the PD patient have not been investigated, although several studies have shown language-related abnormalities in word naming, word generation, and verbal recall. In the present study, 10 male Parkinson's patients and 10 normal male speakers were compared in a reading and spontaneous speaking paradigm for acoustic and linguistic features. Among acoustic measures, fundamental frequency and relative intensity differentiated PD from control subjects, consistent with reported features of hypokinetic dysarthria. The striking observations among linguistic measures differentiating PD from control subjects were an increase in the number of (a) silent hesitations per minute, (b) abnormally long silent hesitations, (c) words per silent hesitation, (d) open class phrases, and (e) optional open phrases per speech sample, and a decrease in the number of modalizations and interjections. An increase in the number of filled hesitations occurring per minute, as well as a decrease in syntactic complexity separated moderate from mild Parkinson's patients. Our interpretation of the data favors the hypothesis that changes in the structure of spontaneous language production with increasing severity of dysarthria reflect PD patients' adaptation to their disease.

[An autopsy case of "diffuse neurofibrillary tangles with calcification", multiple infarctions and hyaline arteriosclerosis].

"Diffuse neurofibrillary tangles with calcification (DNTC)" is a slowly progressive form of presenile dementia characterized by localized temporal atrophy, pronounced calcareous deposits and numerous neurofibrillary tangles (NFTs) without senile plaques. We report a 70-year-old woman with DNTC, multiple infarctions and hyaline arteriosclerosis. This case was clinically characterized by persistent delusional ideas and personality changes. Intellectual deterioration was mild, and no focal manifestations were noted. Neuropathologically, numerous NFTs were seen distributed primarily in the hippocampal region, and massive calcareous deposits were observed in the cerebrum, basal ganglia and cerebellum. There were no senile plaques. Although the findings in this case were compatible with a diagnosis of DNTC, certain additional findings were also noted. The first was the presence of multiple infarctions in the basal ganglia and hyaline arteriosclerosis. Although these lesions may have been induced by hypertension, our review of previous reports of DNTC revealed a high incidence of arteriosclerosis. The second was the absence of lobar atrophy, which may have been due to the cerebral edema caused by the subdural hemorrhage or related to the relatively short duration of the illness. The dilatation of the temporal horn of the lateral ventricle and prominent NFTs in the hippocampal region indicate the initial occurrence of the disease in this region.

[An elderly patient with progressive supranuclear palsy without neurological signs].

We report an elderly patient with progressive supranuclear palsy (PSP) who showed no neurological signs clinically. A 70-year-old man presented with irritation and poor hygiene, thereafter he showed excitement and violence. A cranial CT scan revealed bilateral moderate atrophy of the temporal lobes and slight enlargement of the lateral ventricle. The brain stem was slightly atrophic. Although he died at the age of 80 years, he had no neurological signs throughout the clinical course. Neuropathological study showed typical findings of PSP, neuronal loss with gliosis and neurofibrillary tangles in the basal ganglia, amygdala, midbrain, pons, dentate nucleus and inferior olivary nucleus. Staining by Gallyas-Braak methods revealed argyrophilic and tau-positive glial fibrillary tangles in the cerebral cortex. Neurofibrillary tangles showed greater frequency than usual for the physiological level in that age group in the hippocampus regions as well as in the amygdala. The possibility that the psychotic symptoms, mainly personality change, are connected with the degeneration of limbic system is indicated. Since there have not been any previous reports of PSP without neurological signs, this case represents an important in terms of clinico-pathological variation of PSP. We suggest that there is discrepancy between symptomatic and neuropathological aspects in elderly patients with PSP.