Neuropathological substrate of incident dementia in older patients with schizophrenia: A clinicopathological study.

AIM: Clinical studies reported that patients with schizophrenia are at a higher risk of developing dementia than people without schizophrenia. However, early neuropathological studies have shown that the incidence of Alzheimer's disease (AD) in schizophrenia patients does not differ from that in controls. These inconsistent results may be attributable to the inclusion of non-AD dementia, but there have been few clinicopathological studies in older patients with schizophrenia based on the current neuropathological classification. This study aimed to investigate the neuropathological basis of incident dementia in older patients with schizophrenia. METHODS: We systematically examined 32 brains of old patients with schizophrenia using standardized pathological methods. The severity of dementia-related neuropathologies was analyzed using standardized semiquantitative assessments. After excluding patients who fulfilled the neuropathological criteria, clinicopathological variables were compared between patients with and without incident dementia to identify potential differences. RESULTS: Seven patients fulfilled the pathological criteria for AD (n = 3), argyrophilic grain disease (AGD) (n = 2), dementia with Lewy bodies (n = 1), and AGD/progressive supranuclear palsy (n = 1). Among 25 patients for whom a neuropathological diagnosis was not obtained, 10 had dementia, but the clinicopathological findings did not differ from the remaining 15 patients without dementia. CONCLUSION: Two types of older schizophrenia patient present dementia: patients with co-existing neurodegenerative disease and patients who do not meet pathological criteria based on the current classification. To understand the neurobiological aspects of incident dementia in older patients with schizophrenia, further clinicopathological studies are needed that do not simply analyze incident dementia as a comorbidity of conventional dementia-related neuropathologies.

Copy number variations in RNF216 and postsynaptic membrane-associated genes are associated with bipolar disorder: a case-control study in the Japanese population.

AIM: Bipolar disorder (BD) is a common psychiatric disorder characterized by alterations between manic/hypomanic and depressive states. Rare pathogenic copy number variations (CNVs) that overlap with exons of synaptic genes have been associated with BD. However, no study has comprehensively explored CNVs in synaptic genes associated with BD. Here, we evaluated the relationship between BD and rare CNVs that overlap with synaptic genes, not limited to exons, in the Japanese population. METHODS: Using array comparative genome hybridization, we detected CNVs in 1839 patients with BD and 2760 controls. We used the Synaptic Gene Ontology database to identify rare CNVs that overlap with synaptic genes. Using gene-based analysis, we compared their frequencies between the BD and control groups. We also searched for synaptic gene sets related to BD. The significance level was set to a false discovery rate of 10%. RESULTS: The RNF216 gene was significantly associated with BD (odds ratio, 4.51 [95% confidence interval, 1.66-14.89], false discovery rate < 10%). The BD-associated CNV that corresponded with RNF216 also partially overlapped with the minimal critical region of the 7p22.1 microduplication syndrome. The integral component of the postsynaptic membrane (Gene Ontology:0099055) was significantly associated with BD. The CNV overlapping with the intron region of GRM5 in this gene set showed a nominal significant association between cases and controls (P < 0.05). CONCLUSION: We provide evidence that CNVs in RNF216 and postsynaptic membrane-related genes confer a risk of BD, contributing to a better understanding of the pathogenesis of BD.

Clinicopathological investigation of the background of cognitive decline in elderly schizophrenia.

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, ß-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.

Globular glial tauopathy Type I presenting with behavioral variant frontotemporal dementia.

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.

Background of the neuropathological site in neurocognitive decline in elderly schizophrenic patients.

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.

Clinical profiles of late-onset psychiatric patients exhibiting incidental REM sleep without atonia.

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.

Clinicopathological differences between the motor onset and psychiatric onset of Huntington's disease, focusing on the nucleus accumbens.

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.

Early diagnosis of Lewy body disease in patients with late-onset psychiatric disorders using clinical history of rapid eye movement sleep behavior disorder and [123 I]-metaiodobenzylguanidine cardiac scintigraphy.

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.

The neuropathological study of myelin oligodendrocyte glycoprotein in the temporal lobe of schizophrenia patients.

OBJECTIVE: Recent 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. METHODS: Myelin 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. RESULTS: The 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. CONCLUSION: These 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.

An autopsy case of dementia with Lewy bodies clinically diagnosed to have a behavioral variant of frontotemporal dementia.

We herein report the case of a 75-year-old male who had shown many psychiatric symptoms, but whose autopsy disclosed the presence of dementia with Lewy bodies (DLB). When he was 70 years old, the patient had presented with stereotyped behavior, dietary changes, and a decline in social interpersonal conduct in clinical settings, and it was thought that these symptoms were consistent with a behavioral variant of frontotemporal dementia (bvFTD), and he lacked the core features of DLB. Nevertheless, this case was pathologically defined as the limbic type of DLB after he died at the age of 75 years. Looking retrospectively at the clinical course, it was considered that the following features were suggestive or supportive of DLB: neuroleptic sensitivity, autonomic symptoms, and psychiatric symptoms. It can be presumed that the bvFTD-like behavioral disturbances were caused by the severe Lewy pathology of the locus ceruleus (LC) and left anterior temporal region. The clinical symptoms of DLB might be more multifarious than has conventionally been thought, because the symptoms can be modified by the pathological spread of DLB within the brain. It is important to be aware of these possible symptoms of DLB so as not to overlook the diagnosis in the clinical setting.
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Rapid eye movement sleep without atonia may help diagnose Lewy body disease in middle-aged and older patients with somatic symptom disorder.

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 123 I-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.

Immunohistochemical evaluation of the GABAergic neuronal system in the prefrontal cortex of a DISC1 knockout mouse model of schizophrenia.

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.

An autopsy case of cortical superficial siderosis with persistent abnormal behavior.

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.