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Globular glial tauopathy (GGT) is a recently proposed tauopathy characterized by the globular accumulation of four-repeat (4R) tau in the oligodendroglia (globular oligodendroglial inclusion (GOI)) and astrocytes (globular astrocytic inclusion (GAI)), in addition to deposition in neurons. Although it is proposed that GGT should be classified into three different neuropathological subtypes, previous reports have indicated that subclassification might be difficult in some cases. We report an autopy case of a 79-year-old man with behavioral variant frontotemporal dementia (bvFTD). He developed behavioral changes at 67 years of age and had auditory hallucinations and persecutory delusions at admission to a psychiatric hospital at 69 years of age. Neuropathologically, marked atrophy of the frontotemporal lobes and severe degeneration of the white matter and frontopontine tract were observed. The present case corresponded to GGT Type I, as numerous GOIs were observed, predominantly in the frontotemporal region. However, concurrent degeneration of the motor cortex and corticospinal tract suggest characteristics of Type II. Although the relationship between psychotic symptoms and GGT remains unclear, the present case demonstrates heterogeneity of GGT subtypes.

We aimed to determine the similarities and differences in the roles of genic and regulatory copy number variations (CNVs) in bipolar disorder (BD), schizophrenia (SCZ), and autism spectrum disorder (ASD).Based on high-resolution CNV data from 8708 Japanese samples, we performed to our knowledge the largest cross-disorder analysis of genic and regulatory CNVs in BD, SCZ, and ASD.In genic CNVs, we found an increased burden of smaller (100 kb) exonic deletions in BD, which contrasted with the highest burden of larger (500 kb) exonic CNVs in SCZ/ASD. Pathogenic CNVs linked to neurodevelopmental disorders were significantly associated with the risk for each disorder, but BD and SCZ/ASD differed in terms of the effect size (smaller in BD) and subtype distribution of CNVs linked to neurodevelopmental disorders. We identified 3 synaptic genes (DLG2, PCDH15, and ASTN2) as risk factors for BD. Whereas gene set analysis showed that BD-associated pathways were restricted to chromatin biology, SCZ and ASD involved more extensive and similar pathways. Nevertheless, a correlation analysis of gene set results indicated weak but significant pathway similarities between BD and SCZ or ASD (r = 0.25-0.31). In SCZ and ASD, but not BD, CNVs were significantly enriched in enhancers and promoters in brain tissue.BD and SCZ/ASD differ in terms of CNV burden, characteristics of CNVs linked to neurodevelopmental disorders, and regulatory CNVs. On the other hand, they have shared molecular mechanisms, including chromatin biology. The BD risk genes identified here could provide insight into the pathogenesis of BD.

Piccolo, a presynaptic cytomatrix protein, plays a role in synaptic vesicle trafficking in the presynaptic active zone. Certain single-nucleotide polymorphisms of the Piccolo-encoding gene PCLO are reported to be associated with mental disorders. However, a few studies have evaluated the relationship between Piccolo dysfunction and psychotic symptoms. Therefore, we investigated the neurophysiological and behavioral phenotypes in mice with Piccolo suppression in the medial prefrontal cortex (mPFC). Downregulation of Piccolo in the mPFC reduced regional synaptic proteins, accompanied with electrophysiological impairments. The Piccolo-suppressed mice showed an enhanced locomotor activity, impaired auditory prepulse inhibition, and cognitive dysfunction. These abnormal behaviors were partially ameliorated by the antipsychotic drug risperidone. Piccolo-suppressed mice received mild social defeat stress showed additional behavioral despair. Furthermore, the responses of these mice to extracellular glutamate and dopamine levels induced by the optical activation of mPFC projection in the dorsal striatum (dSTR) were inhibited. Similarly, the Piccolo-suppressed mice showed decreased depolarization-evoked glutamate and -aminobutyric acid elevations and increased depolarization-evoked dopamine elevation in the dSTR. These suggest that Piccolo regulates neurotransmission at the synaptic terminal of the projection site. Reduced neuronal connectivity in the mPFC-dSTR pathway via suppression of Piccolo in the mPFC may induce behavioral impairments observed in schizophrenia.

Brain blood vessels constitute a micrometer-scale vascular network responsible for supply of oxygen and nutrition. In this study, we analyzed cerebral tissues of the anterior cingulate cortex and superior temporal gyrus of schizophrenia cases and age/gender-matched controls by using synchrotron radiation microtomography or micro-CT in order to examine the three-dimensional structure of cerebral vessels. Over 1 m of cerebral blood vessels was traced to build Cartesian-coordinate models, which were then used for calculating structural parameters including the diameter and curvature of the vessels. The distribution of vessel outer diameters showed a peak at 7–9 μm, corresponding to the diameter of the capillaries. Mean curvatures of the capillary vessels showed a significant correlation to the mean curvatures of neurites, while the mean capillary diameter was almost constant, independent of the cases. Our previous studies indicated that the neurites of schizophrenia cases are thin and tortuous compared to controls. The curved capillaries with a constant diameter should occupy a nearly constant volume, while neurons suffering from neurite thinning should have reduced volumes, resulting in a volumetric imbalance between the neurons and the vessels. We suggest that the observed structural correlation between neurons and blood vessels is related to neurovascular abnormalities in schizophrenia.

Huntington's disease (HD) is an autosomal-dominant neurodegenerative disorder characterized by the presence of chorea, psychiatric symptoms, and dementia. Although motor symptoms are thought to be correlated with the degeneration of the striatum, there is little information regarding the neuropathological basis of psychiatric symptoms. The ventral part of the striatum is known as the nucleus accumbens (Acb) and is a region of interest as a responsible focus of psychiatric symptoms. The purpose of this study was to investigate the neuronal changes in the Acb and its relevance to psychiatric symptoms in HD. We investigated the brains of 16 HD patients (three patients presented psychiatric symptoms as the onset phenotype (HD-P), 13 patients presented motor symptoms as the onset phenotype (HD-M)) and four control subjects. The numerical cell densities for each of the large and small striatal neurons in the Acb, caudate nucleus and putamen were measured at three levels from the caudal to rostral region. As the result, the median small neuronal densities in all striatal regions in the HD brains were significantly lower than controls. Regarding the median small neuronal density in the caudate nucleus and putamen among the three levels, there were significant differences in the HD brains, but not in controls. The median large neuronal density in the Acb was significantly higher in the HD-P than in the HD-M, but there was no difference in the median small neuronal density between them. In the present study, we revealed that the Acb as well as the caudate nucleus were affected in HD brains. In terms of neuronal size and caudal to rostral levels, non-uniform neurodegeneration was observed in the striatum of the HD brains. The pathological difference in the Acb between HD-P and HD-M may be one of the factors involved in the development of psychiatric symptoms.

The cerebral cortex is composed of multiple cortical areas that exert a wide variety of brain functions. Although human brain neurons are genetically and areally mosaic, the three-dimensional structural differences between neurons in different brain areas or between the neurons of different individuals have not been delineated. Here, we report a nanometer-scale geometric analysis of brain tissues of the superior temporal gyrus of 4 schizophrenia and 4 control cases by using synchrotron radiation nanotomography. The results of the analysis and a comparison with results for the anterior cingulate cortex indicated that 1) neuron structures are dissimilar between brain areas and that 2) the dissimilarity varies from case to case. The structural diverseness was mainly observed in terms of the neurite curvature that inversely correlates with the diameters of the neurites and spines. The analysis also revealed the geometric differences between the neurons of the schizophrenia and control cases, suggesting that neuron structure is associated with brain function. The area dependency of the neuron structure and its diverseness between individuals should represent the individuality of brain functions., 3 figures

Objective:We have often observed dementia symptoms or severe neurocognitive decline in the long-term course of schizophrenia. While there are epidemiological reports that patients with schizophrenia are at an increased risk of developing dementia, there are also neuropathological reports that the prevalence of Alzheimer’s disease (AD) in schizophrenia is similar to that in normal controls. It is difficult to distinguish, based solely on the clinical symptoms, whether the remarkable dementia symptoms and cognitive decline seen in elderly schizophrenia are due to the course of the disease itself or a concomitant neurocognitive disease. Neuropathological observation is needed for discrimination.Methods:We conducted a neuropathological search on three cases of schizophrenia that developed cognitive decline or dementia symptoms after a long illness course of schizophrenia. The clinical symptoms of total disease course were confirmed retrospectively in the medical record. We have evaluated neuropathological diagnosis based on not only Hematoxylin–Eosin and Klüver–Barrera staining specimens but also immunohistochemical stained specimens including tau, β-amyloid, pTDP-43 and α-synuclein protein throughout clinicopathological conference with multiple neuropathologists and psychiatrists.Results:The three cases showed no significant pathological findings or preclinical degenerative findings, and poor findings consistent with symptoms of dementia were noted.Conclusion:Although the biological background of dementia symptoms in elderly schizophrenic patients is still unclear, regarding the brain capacity/cognitive reserve ability, preclinical neurodegeneration changes in combination with certain brain vulnerabilities due to schizophrenia itself are thought to induce dementia syndrome and severe cognitive decline.

The precise biological etiology of autism spectrum disorder (ASD) remains unknown. In this study, we investigated the neuropathology of a monkey model of autism Human ABCA13 is the largest ABC transporter protein, with a length of 5058 amino acids and a predicted molecular weight of >450 kDa. However, the function of this protein remains to be elucidated. This protein is thought to be associated with major psychiatric disease. Using this monkey model of autism with an ABCA13 deletion and a mutation of 5HT2c, we neuropathologically investigated the changes in the neuronal formation in the frontal cortex. As a result, the neuronal formation in the cortex was found to be disorganized with regard to the neuronal size and laminal distribution in the ABCA13 deletion monkey. The catecholaminergic and GABAergic neuronal systems, serotoninergic neuronal formation (5HT2c) were also found to be impaired by an immunohistochemical evaluation. This study suggested that ABCA13 deficit induces the impairment of neuronal maturation or migration, and the function of the neuronal network. This protein might thus play a role in the neurodevelopmental function of the central nervous system and the dysfunction of this protein may be a pathophysiological cause of mental disorders including autism.

Summary: Compelling evidence in Caucasian populations suggests a role for copy-number variations (CNVs) in autism spectrum disorder (ASD) and schizophrenia (SCZ). We analyzed 1,108 ASD cases, 2,458 SCZ cases, and 2,095 controls in a Japanese population and confirmed an increased burden of rare exonic CNVs in both disorders. Clinically significant (or pathogenic) CNVs, including those at 29 loci common to both disorders, were found in about 8% of ASD and SCZ cases, which was significantly higher than in controls. Phenotypic analysis revealed an association between clinically significant CNVs and intellectual disability. Gene set analysis showed significant overlap of biological pathways in both disorders including oxidative stress response, lipid metabolism/modification, and genomic integrity. Finally, based on bioinformatics analysis, we identified multiple disease-relevant genes in eight well-known ASD/SCZ-associated CNV loci (e.g., 22q11.2, 3q29). Our findings suggest an etiological overlap of ASD and SCZ and provide biological insights into these disorders. : Kushima et al. perform comparative analyses of CNVs in ASD and SCZ in a Japanese population. They identify pathogenic CNVs and biological pathways in each disorder with significant overlap. Patients with pathogenic CNVs have a higher prevalence of intellectual disability. Disease-relevant genes are detected in eight well-known ASD/SCZ-associated CNV loci. Keywords: autism spectrum disorder, schizophrenia, copy-number variation, array comparative genomic hybridization, genetic overlap, Japanese population, oxidative stress response, genome integrity, lipid metabolism, gene ontology

Aim Rapid eye movement sleep behavior disorder (RBD) and psychiatric symptoms often antedate the clinical diagnosis of Parkinson's disease or dementia with Lewy bodies. The purpose of this study was to investigate RBD and its relevance to Lewy body disease (LBD) in patients with late-onset psychiatric disorders. Methods Study subjects included 19 patients with late-onset psychiatric disorders who exhibited REM sleep without atonia (RWA), which is a hallmark of RBD on polysomnography, at our psychiatric ward. Clinical profiles and radiological findings by cardiac [123 I]-metaiodobenzylguanidine ([123 I]-MIBG) scintigraphy and imaging for the dopamine transporter (DAT) were compared between patients with and without RBD symptoms. The correlations between the percentage of RWA in the total rapid eye movement sleep (%RWA) and radiological findings were also investigated. Results Nine patients reported RBD symptoms only on specific questioning, but clinical profiles, including the prevalence of antipsychotropic usage, did not differ when compared to the remaining 10 patients without RBD (incidental RWA group). The median %RWA was significantly higher in the definite RBD group than in the incidental RWA group. Although the cardiac [123 I]-MIBG uptake was significantly lower in the definite RBD group than in the incidental RWA group, there was overlap in the specific binding ratio on DAT scan. Conclusion The severity of %RWA was highly correlated with the value of cardiac [123 I]-MIBG uptake, but not with specific binding ratio on DAT scan. Clinical history of RBD and cardiac [123 I]-MIBG scintigraphy are helpful for an early differential diagnosis of LBD from late-onset psychiatric disorders, even before parkinsonism or dementia appears.

We herein report the neuropathological findings of a schizophrenic patient who showed cognitive decline and deterioration of psychiatric symptoms in his elderly years. In the neuropathological investigation in this case, Alzheimer-type pathology and argyrophilic grain pathology were observed. Schizophrenic patients can sometimes show cognitive decline in later life as an intrinsic symptom. However, they may also be complicated with dementia in later life, although these complications in a clinical setting have not been well examined. Few reports have investigated whether or not schizophrenic patients are likely to be complicated with dementia, and the findings remain controversial. We confirmed relatively mild ageing changes neuropathologically in the present case. How much these pathological changes influenced his psychiatric symptoms is unclear, but these changes were thought to have some degree of relevance. We also discuss the relationship between schizophrenia and dementia. We should remain alert to the fact that even schizophrenic patients can contract neurodegenerative diseases as a dual diagnosis in their clinical course and that they can show complicated symptoms. Further investigations of the clinical-pathological relationship between schizophrenia and dementia are thus needed.

Rapid eye movement (REM) sleep without atonia (RWA), which is a hallmark of REM sleep behavior disorder (RBD) on polysomnography (PSG), may represent specific characteristics of prodromal Parkinson's disease (PD)/dementia with Lewy bodies (DLB), even when dream-enactment behavior is absent. We investigated the clinical profiles associated with PD/DLB in late-onset psychiatric patients exhibiting incidental RWA. Among patients who underwent PSG in our psychiatric ward, eight with incidental RWA, nine with idiopathic RBD, and seven with PD or DLB who had preceding RBD were included. Clinical variables, including the percentage of RWA in the total REM sleep (%RWA), were compared among the three groups. The frequency of depressive disorders as a primary psychiatric diagnosis and antidepressant usage were significantly higher in the incidental RWA group than in the other groups. There were no differences in the prevalence of supportive features of DLB among the three groups. The median %RWA was significantly lower in the incidental RWA group than in the other groups. Although the cardiac 123I-metaiodobenzylguanidine uptake was significantly higher in the incidental RWA group compared with the other groups, the groups showed overlap in the specific binding ratios on dopamine transporter imaging. All patients in the three groups exhibited cingulate island sign ratios on brain perfusion single-photon emission computed tomography within a threshold of 0.281, which is the optimal cut-off value for a diagnosis of DLB. In this series, late-onset psychiatric patients with incidental RWA partially shared common clinical profiles with idiopathic RBD and PD/DLB.

The etiology of schizophrenia remains unknown. However, using molecular biological techniques, some candidate genes have been identified that might be associated with the disease. One of these candidate genes, disrupted-in-schizophrenia 1 (DISC1), was found in a large Scottish family with multiple mental illnesses. The function of DISC1 is considered to be associated with axon elongation and neuron migration in the central nervous system, but the functional consequences of defects in this gene have not been fully clarified in brain neuronal systems. Dysfunction of the gamma-aminobutyric acid (GABA)ergic neuronal system is also considered to contribute to the pathogenesis of schizophrenia. Thus, to clarify the neuropathological changes associated with DISC1 dysfunction, we investigated the number and distribution of GABAergic neurons in the prefrontal cortex of DISC1 knockout mice. We immunohistochemically quantified the laminar density of GABAergic neurons using anti-parvalbumin and anti-calbindin D28k antibodies (markers of GABAergic neuronal subpopulations). We found that the densities of both parvalbumin- and calbindin-immunoreactive neurons in the anterior cingulate, medial prefrontal, and orbitofrontal cortices were markedly lower in DISC1 knockout mice than in wild-type mice. In addition, reductions in cell density were observed in layers II and III and the deep layers of the cortex. This reduction in GABAergic neuronal density was not associated with alterations in neuronal size. These findings suggest that disrupted GABAergic neuronal network formation due to a DISC1 deficit might be involved in the pathophysiology of schizophrenia.

In recent years, MRI has revealed cortical superficial siderosis (cSS), which exhibits hemosiderin deposition in only the cortical surface. However, the associations between the histological findings and clinical symptoms of cSS remain unclear. We herein report an autopsy case of a 75-year-old Japanese man with cSS with persistent abnormal behavior according to cognitive impairment, hallucination and delusion. At 73 years of age, the patient presented with unusual behavior that indicated auditory hallucination and delusion. One year later, he was admitted to the hospital for malignant lymphoma. On admission, cognitive impairment was detected by a screening test. Soon after hospitalization, he presented with active delirium including visual hallucination and delusion. The patient's excited behavior was improved by the administration of a major tranquilizer. However, the abnormal behavior and cognitive impairment persisted. At 75 years of age, he died of heart failure. A neuropathological investigation revealed hemosiderin depositions in the superficial layer of the cortex in the medial and lateral frontal lobe, the lateral temporal lobe, the parietal lobe, and the medial and lateral occipital lobe. Neuritic plaques and diffuse plaques were extensively observed, which corresponded to Braak stage C and CERAD B, although NFTs were observed that corresponded to Braak stage II. Cortical amyloid angiopathy was not observed in any regions. Ischemic change of brain was also mild. Our report suggests that localized deposition of hemosiderin in the cortex might affect the manifestation of cognitive impairments and hallucination. Further clinicopathological studies are needed to clarify the clinical manifestations of patients with cSS.

Background Lewy body disease (LBD), including Parkinson's disease (PD) and dementia with Lewy bodies (DLB), is defined pathologically as degeneration in the central and peripheral nervous system associated with Lewy bodies. Somatic symptom disorder often predates the clinical diagnosis of PD and DLB. It is crucial to make an initial diagnosis of LBD in patients with psychiatric symptoms because administering psychotropic drugs often causes or exacerbates extrapyramidal signs. Given the close association between rapid eye movement (REM) sleep behaviour disorder and LBD, REM sleep without atonia on polysomnography may help to diagnose LBD in middle-aged and older patients with somatic symptom disorder. Methods We reviewed the clinical profiles of five patients with an initial diagnosis of somatic symptom disorder who exhibited REM sleep without atonia on polysomnography. There were three men and two women, with a mean age of 68.4 years (range: 55.0–78.0 years). The mean Mini-Mental State Examination score was 26 (range: 22–30). Results Only two patients had a clinical history of dream-enacting behaviour and fulfilled the clinical criteria for REM sleep behaviour disorder, but clinical conditions in the other three patients corresponded to subclinical REM sleep behaviour disorder. Final clinical diagnoses were made as probable DLB in three patients; two patients did not meet the clinical criteria for PD or DLB. Neurological examinations revealed mild extrapyramidal signs in these two patients, and their scores on the motor component of the Unified Parkinson's Disease Rating Scale were 8 and 5 points, and their Mini-Mental State Examination scores were 30 points. Neither patient exhibited dream-enacting behaviour, but both had constipation. Cardiac 123I-metaiodobenzylguanidine scintigraphy revealed mild increased washout rates. Discussion REM sleep without atonia may provide an opportunity to identify LBD in patients with somatic symptom disorder, even before they fulfil the clinical criteria for PD or DLB. Continued follow-up will be needed to determine whether these psychiatric patients are in the prodromal stage of PD or DLB.

The Japan Agency of Medical Research and Development (AMED) has approved the budget for the 5-year project called Establishment of the JAPAN Brain Bank Network, which commenced in 2016. This project was established with the aim of storing brain tissue samples to enable research on the etiologies and mechanisms of psychiatric diseases, which would eventually improve standards of clinical treatment for these diseases. Japanese researchers in the field of biological psychiatry have historically depended on Western brain banks, particularly from Europe and the United States, which is regrettable. To remedy this situation and improve the Japanese research standards, attempts for establishing an autonomous Japanese brain bank are ongoing. Reviews of the previous attempts on elucidating the etiopathology of neuropsychiatric diseases reveal that rapid advances result from studies on tissue samples from diseased brains. For example, in the Kraepelin era, i.e. in 1900 years before and after, long-term, resolute research on diseased brain specimens ultimately led to the discoveries of entities such as Alzheimer disease and Lewy body disease. The recent advances in techniques of neuroimaging and molecular biology have resulted in a shift of interest from brain tissue analysis. However, the integration of findings of all these techniques is recommended going forward, with a shift in focus back to brain tissue analysis. The JAPAN Brain Bank Network project was launched under this setting. The success of this project largely depends on the will of patients and family members (for donating samples) as well as cooperation among many clinicians. In this paper, we provide a brief overview of the history of biological psychiatric research and related perspectives, which will hopefully encourage further studies that will help bridge the gap between clinical and biological research on psychiatric diseases.

ObjectiveRecent studies based on the neuroimaging analysis, genomic analysis and transcriptome analysis of the postmortem brain suggest that the pathogenesis of schizophrenia is related to myelin-oligodendrocyte abnormalities. However, no serious neuropathological investigation of this protein in the schizophrenic brain has yet been performed. In this study, to confirm the change in neuropathological findings due to the pathogenesis of this disease, we observed the expression of myelin-oligodendrocyte directly in the brain tissue of schizophrenia patients.MethodsMyelin oligodendrocyte glycoprotein (MOG) was evaluated in the cortex of the superior temporal gyrus (STG) and the hippocampus in 10 schizophrenic and nine age- and sex-matched normal control postmortem brains.ResultsThe expression of MOG was significantly lower in the middle layer of the neocortex of the STG and stratum lucidum of CA3 in the hippocampus in the long-term schizophrenic brains (patients with ≥30 years of illness duration) than in the age-matched controls. Furthermore, the thickness of MOG-positive fibre-like structures was significantly lower in both regions of the long-term schizophrenic brains than in the age-matched controls.ConclusionThese findings suggest that a long duration of illness has a marked effect on the expression of MOG in these regions, and that myelin-oligodendrocyte abnormalities in these regions may be related to the progressive pathophysiology of schizophrenia.

Rapid eye movement sleep behavior disorder (RBD) and psychiatric symptoms often antedate the clinical diagnosis of Parkinson's disease or dementia with Lewy bodies. The purpose of this study was to investigate RBD and its relevance to Lewy body disease (LBD) in patients with late-onset psychiatric disorders.Study subjects included 19 patients with late-onset psychiatric disorders who exhibited REM sleep without atonia (RWA), which is a hallmark of RBD on polysomnography, at our psychiatric ward. Clinical profiles and radiological findings by cardiac [Nine patients reported RBD symptoms only on specific questioning, but clinical profiles, including the prevalence of antipsychotropic usage, did not differ when compared to the remaining 10 patients without RBD (incidental RWA group). The median %RWA was significantly higher in the definite RBD group than in the incidental RWA group. Although the cardiac [The severity of %RWA was highly correlated with the value of cardiac [

Discrepancies between clinical and pathological diagnoses of dementia with Lewy bodies (DLB) may occur because the full disease progression remains unclear, especially during the early stage. Herein, we report the case of a 78-year-old Japanese man with hypochondriasis who had autopsy-confirmed limbic-type DLB pathology. He exhibited no core clinical features of DLB. We attempted to identify the clinicopathological correlations in the early stages of DLB. At the age of 77, he became hypochondriacal and exhibited progressive cognitive decline after the death of his wife. He was concerned about his poor physical condition, but hospital examinations did not identify any overtly abnormal findings. At 78 years of age, he consulted a neurologist with complaints of facial numbness and irritability. Neurological examination revealed no overt abnormality, and he scored 21 points on the Mini-Mental State Examination. Magnetic resonance imaging of the brain showed mild bilateral ventricular enlargement. The patient was clinically diagnosed as having possible Alzheimer's disease. Approximately 1 month after his consult, he died of acute pneumonia in a psychiatric hospital to which he had been admitted for severe aggressive behaviour. He exhibited no core clinical features pointing towards a clinical diagnosis of DLB. Neuropathological investigation revealed limbic-type Lewy body disease with concurrent minimum Alzheimer-type pathology, which corresponds to high-likelihood DLB pathology based on the Third Consortium DLB pathological criteria. The patient had minimum nigral degeneration, which is consistent with the absence of parkinsonism. This autopsied case suggests that some DLB patients exhibit hypochondriasis in the early stage of the disease, even if they lack the core clinical features of DLB.

Alzheimer's disease (AD) is clinically characterized by gradual onset over years with worsening of cognition. The initial and most prominent cognitive deficit is commonly memory dysfunction. However, a subset of AD cases has less hippocampal atrophy than would be expected relative to the predominance of cortical atrophy. These hippocampal-sparing cases have distinctive clinical features, including the presence of focal cortical clinical syndromes. Given that previous studies have indicated that severe hippocampal atrophy corresponds to prominent loss of episodic memory, it is likely that memory impairment is initially absent in hippocampal-sparing AD cases. Here, we report on a patient with an 8-year history of delusional jealousy with insidious onset who was clinically diagnosed as possible AD and pathologically confirmed to have AD with relatively preserved neurons in the hippocampus. This patient had delusional jealousy with a long pre-dementia stage, which initially was characterized by lack of memory impairment. Head magnetic resonance imaging findings showed preserved hippocampal volume with bilateral enlarged ventricles and mild-to-moderate cortical atrophy. Head single-photon emission computed tomography revealed severely decreased regional cerebral blood flow in the right temporal lobe. The resolution of the delusion was attributed to pharmacotherapy by an acetylcholinesterase inhibitor, suggesting that the occurrence of delusional jealousy was due to the disease process of AD. Although the neural basis of delusional jealousy remains unclear, this hippocampal-sparing AD case may be classified as an atypical presentation of AD.

Neuropeptide Y (NPY) has been found to play a critical role in various mental functions as a neurotransmitter and is involved in the development of schizophrenia, a particularly intractable psychiatric disease whose precise etiology remains unknown. Recent molecular biological investigations have identified several candidate genes which may be associated with this disease, including disrupted-in-schizophrenia 1 (DISC1). The role of DISC1 would involve neurogenesis and neuronal migration. However, the functional consequences of this gene defect have not yet been fully clarified in neuronal systems. In the present study, to clarify the neuropathological changes associated with the function of DISC1, we explored how DISC1 dysfunction can induce abnormalities in the NPY neuronal network in the central nervous system. We performed immunohistochemical analyses (including the observation of the distribution and density) of prefrontal cortex specimens from DISC1-knockout (KO) mice, which are considered to be a novel animal model of schizophrenia. We then evaluated the number and size of NPY-immunoreactive (NPY-IR) neurons and the length of NPY-IR fibers. The number of NPY-IR neurons and the length of the fibers were decreased in the prefrontal cortex of DISC1-KO mice. The decrease was particularly prominent in the superficial regions, and the distribution of NPY-IR neurons differed between wild-type and DISC1-KO mice. However, the size of the neurons in the cortices of the DISC1-KO and wild-type mice did not differ markedly. Our findings suggest that dysfunction of DISC1 may lead to the alteration of NPY neurons and neurotransmission issues in NPY-containing neuron systems, which seem to play important roles in both the mental function and neuronal development. DISC1 dysfunction may be involved in the pathogenesis of schizophrenia through the impairment of the NPY neuronal network.

The etiology of schizophrenia remains unknown. However, using molecular biological techniques, some candidate genes have been identified that might be associated with the disease. One of these candidate genes, disrupted-in-schizophrenia 1 (DISC1), was found in a large Scottish family with multiple mental illnesses. The function of DISC1 is considered to be associated with axon elongation and neuron migration in the central nervous system, but the functional consequences of defects in this gene have not been fully clarified in brain neuronal systems. Dysfunction of the gamma-aminobutyric acid (GABA)ergic neuronal system is also considered to contribute to the pathogenesis of schizophrenia. Thus, to clarify the neuropathological changes associated with DISC1 dysfunction, we investigated the number and distribution of GABAergic neurons in the prefrontal cortex of DISC1 knockout mice. We immunohistochemically quantified the laminar density of GABAergic neurons using anti-parvalbumin and anti-calbindin D28k antibodies (markers of GABAergic neuronal subpopulations). We found that the densities of both parvalbumin- and calbindin-immunoreactive neurons in the anterior cingulate, medial prefrontal, and orbitofrontal cortices were markedly lower in DISC1 knockout mice than in wild-type mice. In addition, reductions in cell density were observed in layers II and III and the deep layers of the cortex. This reduction in GABAergic neuronal density was not associated with alterations in neuronal size. These findings suggest that disrupted GABAergic neuronal network formation due to a DISC1 deficit might be involved in the pathophysiology of schizophrenia.

Diffuse neurofibrillary tangles with calcification (DNTC) is a relatively rare presenile dementia that clinically shows overlapping symptoms of Alzheimer's disease and frontotemporal lobar degeneration (FTLD). DNTC is pathologically characterized by localized temporal or frontotemporal atrophy with massive neurofibrillary tangles, neuropil threads and Fahr's-type calcification without senile plaques. We tried to clarify the molecular basis of DNTC by immunohistochemically examining the appearance and distribution of accumulated alpha-synuclein (aSyn) and TAR DNA-binding protein of 43 kDa (TDP-43) in the brains of 10 Japanese autopsy cases. We also investigated the clinically characteristic symptoms from the clinical charts and previous reports, and the correlations with neuropathological findings. The characteristic symptoms were evaluated using the Neuropsychiatric Inventory Questionnaire (NPI-Q). As a result, we confirmed the high frequency of neuronal cytoplasmic accumulation of aSyn (80%) and phosphorylated TDP-43 (90%) in DNTC cases. There was a significant correlation between some selected items of NPI-Q scores and the severity of the limbic TDP-43 pathology. The pathology of DNTC included TDP-43 and aSyn pathology with high frequency. These abnormal accumulations of TDP-43 might be involved in the pathological process of DNTC, having a close relationship to the FTLD-like psychiatric symptoms during the clinical course.

BackgroundThe precise aetiology of schizophrenia remains unclear. The neurodevelopmental hypothesis of schizophrenia has been proposed based on the accumulation of genomic or neuroimaging studies.ObjectiveIn this study, we examined the catecholaminergic neuronal networks in the frontal cortices of disrupted-in-schizophrenia 1 (DISC1) knockout (KO) mice, which are considered to be a useful model of schizophrenia.MethodsSix DISC1 homozygous KO mice and six age-matched littermates were used. The animals’ brains were cut into 20-μm-thick slices, which were then immunohistochemically stained using an anti-tyrosine hydroxylase (TH) monoclonal antibody.ResultsThe TH-immunopositive fibres detected in the orbitofrontal cortices of the DISC1 KO mice were significantly shorter than those seen in the wild-type mice.ConclusionThese neuropathological findings indicate that the hypofrontal symptoms of schizophrenia are associated with higher mental function deficiencies or cognitive dysfunction such as a loss of working memory.

Discrepancies between clinical and pathological diagnoses of dementia with Lewy bodies (DLB) may occur because the full disease progression remains unclear, especially during the early stage. Herein, we report the case of a 78-year-old Japanese man with hypochondriasis who had autopsy-confirmed limbic-type DLB pathology. He exhibited no core clinical features of DLB. We attempted to identify the clinicopathological correlations in the early stages of DLB. At the age of 77, he became hypochondriacal and exhibited progressive cognitive decline after the death of his wife. He was concerned about his poor physical condition, but hospital examinations did not identify any overtly abnormal findings. At 78 years of age, he consulted a neurologist with complaints of facial numbness and irritability. Neurological examination revealed no overt abnormality, and he scored 21 points on the Mini-Mental State Examination. Magnetic resonance imaging of the brain showed mild bilateral ventricular enlargement. The patient was clinically diagnosed as having possible Alzheimer's disease. Approximately 1 month after his consult, he died of acute pneumonia in a psychiatric hospital to which he had been admitted for severe aggressive behaviour. He exhibited no core clinical features pointing towards a clinical diagnosis of DLB. Neuropathological investigation revealed limbic-type Lewy body disease with concurrent minimum Alzheimer-type pathology, which corresponds to high-likelihood DLB pathology based on the Third Consortium DLB pathological criteria. The patient had minimum nigral degeneration, which is consistent with the absence of parkinsonism. This autopsied case suggests that some DLB patients exhibit hypochondriasis in the early stage of the disease, even if they lack the core clinical features of DLB.

Alzheimer's disease (AD) is clinically characterized by gradual onset over years with worsening of cognition. The initial and most prominent cognitive deficit is commonly memory dysfunction. However, a subset of AD cases has less hippocampal atrophy than would be expected relative to the predominance of cortical atrophy. These hippocampal-sparing cases have distinctive clinical features, including the presence of focal cortical clinical syndromes. Given that previous studies have indicated that severe hippocampal atrophy corresponds to prominent loss of episodic memory, it is likely that memory impairment is initially absent in hippocampal-sparing AD cases. Here, we report on a patient with an 8-year history of delusional jealousy with insidious onset who was clinically diagnosed as possible AD and pathologically confirmed to have AD with relatively preserved neurons in the hippocampus. This patient had delusional jealousy with a long pre-dementia stage, which initially was characterized by lack of memory impairment. Head magnetic resonance imaging findings showed preserved hippocampal volume with bilateral enlarged ventricles and mild-to-moderate cortical atrophy. Head single-photon emission computed tomography revealed severely decreased regional cerebral blood flow in the right temporal lobe. The resolution of the delusion was attributed to pharmacotherapy by an acetylcholinesterase inhibitor, suggesting that the occurrence of delusional jealousy was due to the disease process of AD. Although the neural basis of delusional jealousy remains unclear, this hippocampal-sparing AD case may be classified as an atypical presentation of AD.

The etiology of schizophrenia has been proposed to be neurodevelopmental based on neuroimaging and molecular biological studies. If there is neuronal vulnerability based on neurodevelopment failures in schizophrenic brains, then the impact of aging may have a greater effect on schizophrenic brains than on normal brains. To determine the impact of aging on schizophrenic brains, we investigated the age-related morphological changes of the cross-sectional area of the gray matter (GM) in the left Heschl's gyrus (HG) and the left superior gyrus (STG) in 22 schizophrenic and 24 age- and sex-matched normal control postmortem brains two-dimensionally. The subject groups were divided into younger groups (30–54 years of age) and older groups (65–84 years of age) on the basis of age at death. Both in schizophrenic and control subjects, the GM area in HG and the STG was significantly smaller in the older group than in the younger group, however, no significant differences were observed between the schizophrenic and control subjects. In the STG, the cross-sectional area of the white matter (WM) was also measured. In the older group, the ratio of the GM area to the WM area in the STG was significantly larger in schizophrenic subjects than controls, although there was no significant difference between the schizophrenic and control subjects in the younger group. These findings indicate that the impact of aging has a greater effect on the WM in the STG in schizophrenic subjects than in normal individuals, although the pathological basis is still unclear.

The exact pathophysiology of schizophrenia is unknown despite intensive scientific studies using molecular biology, psychopharmacology, neuropathology, etc. It is thought that neurodevelopmental failures such as neuronal network incompetence and the inappropriate formation of neurons affect the neurotransmitters. Several animal models have been created to investigate the etiology of this disease. In this study, we investigated the expression of vesicle monoamine transporter 2 (VMAT2), which has a significant role in neurotransmission, in the hippocampal formation in 1-phenylcyclohexylpiperazine (PCP)-treated mice using immunohistochemical staining technique to clarify neuronal abnormalities. PCP-treated mice are thought to be one of novel animal models for schizophrenia. The expression of VMAT2 in the hippocampal formation was significantly reduced overall in the PCP-treated mice compared to that in control (saline-treated) mice, also these reductions were observed throughout the brain. These facts implied that the pathophysiology of this disease involves abnormal monoaminergic transmission through VMAT2, despite PCP was the N-methyl-d-aspartate (NMDA) receptor antagonist that might induce glutamatergic abnormality. Since insufficient or excess release of neurotransmitter might alter neurochemical function and neurotransmission, VMAT2 might be an important target for biological research in psychiatric disease including schizophrenia.