Language：Japanese   Publisher：(株)ワールドプランニング  

Other Link： https://search.jamas.or.jp/default/link?pub_year=2024&ichushi_jid=J02464&link_issn=&doc_id=20240516020009&doc_link_id=%2Faj2rsizd%2F2024%2F003504%2F010%2F0385-0394%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Faj2rsizd%2F2024%2F003504%2F010%2F0385-0394%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Authorship：Lead author   Language：Japanese   Publisher：(株)医学書院  

＜文献概要＞クレペリンが統合失調症(早発性痴呆;dementia praecox)の疾患単位を提唱して以来,その生物学的な病態解明は主として神経病理学的手法によっていた。その後認知症をはじめとする変性疾患の神経病理学的な理解は,顕微鏡の性能の向上や組織染色法の開発とあいまって目覚ましく進歩した。一方でいわゆる内因性精神疾患の病態解明は,従前の方法では限界があり,「統合失調症に神経病理変化はない」とまで結論付けられた時代が長く続いた。しかし,画像研究やゲノム精神医学の病態解明研究が進み,それらの研究成果を脳組織の器質的な変化に収斂させることで病因にアプローチできるようになってきている。そして,過去の神経病理観察所見も意味を持たせることができうる可能性が出てきた。また,精神疾患の器質的背景を研究するうえで,精神疾患死後脳(精神科ブレインバンク)は必須であり,われわれの精神科ブレインバンク活動も紹介した。

Language：Japanese   Publisher：(株)医学書院  

＜文献概要＞クレペリンが統合失調症(早発性痴呆;dementia praecox)の疾患単位を提唱して以来,その生物学的な病態解明は主として神経病理学的手法によっていた。その後認知症をはじめとする変性疾患の神経病理学的な理解は,顕微鏡の性能の向上や組織染色法の開発とあいまって目覚ましく進歩した。一方でいわゆる内因性精神疾患の病態解明は,従前の方法では限界があり,「統合失調症に神経病理変化はない」とまで結論付けられた時代が長く続いた。しかし,画像研究やゲノム精神医学の病態解明研究が進み,それらの研究成果を脳組織の器質的な変化に収斂させることで病因にアプローチできるようになってきている。そして,過去の神経病理観察所見も意味を持たせることができうる可能性が出てきた。また,精神疾患の器質的背景を研究するうえで,精神疾患死後脳(精神科ブレインバンク)は必須であり,われわれの精神科ブレインバンク活動も紹介した。

Other Link： https://search.jamas.or.jp/default/link?pub_year=2024&ichushi_jid=J00749&link_issn=&doc_id=20240430030008&doc_link_id=10.11477%2Fmf.1405207235&url=https%3A%2F%2Fdoi.org%2F10.11477%2Fmf.1405207235&type=%E5%8C%BB%E6%9B%B8.jp_%E3%82%AA%E3%83%BC%E3%83%AB%E3%82%A2%E3%82%AF%E3%82%BB%E3%82%B9&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00024_2.gif

Language：English   Publishing type：Research paper (scientific journal)  

Indoleamine 2,3-dioxygenase 2 (IDO2) is an enzyme of the tryptophan-kynurenine pathway that is constitutively expressed in the brain. To provide insight into the physiological role of IDO2 in the brain, behavioral and neurochemical analyses in IDO2 knockout (KO) mice were performed. IDO2 KO mice showed stereotyped behavior, restricted interest and social deficits, traits that are associated with behavioral endophenotypes of autism spectrum disorder (ASD). IDO2 was colocalized immunohistochemically with tyrosine-hydroxylase-positive cells in dopaminergic neurons. In the striatum and amygdala of IDO2 KO mice, decreased dopamine turnover was associated with increased α-synuclein level. Correspondingly, levels of downstream dopamine D1 receptor signaling molecules such as brain-derived neurotrophic factor and c-Fos positive proteins were decreased. Furthermore, decreased abundance of ramified-type microglia resulted in increased dendritic spine density in the striatum of IDO2 KO mice. Both chemogenetic activation of dopaminergic neurons and treatment with methylphenidate, a dopamine reuptake inhibitor, ameliorated the ASD-like behavior of IDO2 KO mice. Sequencing analysis of exon regions in IDO2 from 309 ASD samples identified a rare canonical splice site variant in one ASD case. These results suggest that the IDO2 gene is, at least in part, a factor closely related to the development of psychiatric disorders.

DOI： 10.1111/febs.17019

Open Access

Web of Science

PubMed

Language：Japanese   Publisher：(株)ワールドプランニング  

Language：English   Publishing type：Research paper (scientific journal)  

AIM: The present study aimed to examine the association between copy number variations (CNVs) in parkin (PRKN) and schizophrenia (SCZ) and autism spectrum disorder (ASD) in a large case-control sample. METHOD: Array comparative genomic hybridization was performed on 3111 cases with SCZ, 1236 cases with ASD, and 2713 controls. We systematically prioritized likely pathogenic CNVs (LP-CNVs) in PRKN and examined their association with SCZ and ASD. RESULTS: In total, 3014 SCZ cases (96.9%), 1205 ASD cases (97.5%), and 2671 controls (98.5%) passed quality control. We found that monoallelic carriers of LP-CNVs in PRKN were common (70/6890, 1.02%) and were not at higher risk of SCZ (p = 0.29) or ASD (p = 0.72). We observed that the distribution pattern of LP-CNVs in the Japanese population was consistent with those in other populations. We also identified a patient diagnosed with SCZ and early-onset Parkinson's disease carrying biallelic pathogenic CNVs in PRKN. The absence of Parkinson's symptoms in 10 other monoallelic carriers of the same pathogenic CNV further reflects the lack of effect of monoallelic pathogenic variants in PRKN in the absence of a second hit. CONCLUSION: The present findings suggest that monoallelic CNVs in PRKN do not confer a significant risk for SCZ or ASD. However, further studies to investigate the association between biallelic CNVs in PRKN and SCZ and ASD are warranted.

DOI： 10.1002/npr2.12370

Open Access

Web of Science

PubMed

Language：Japanese   Publisher：(公社)日本生化学会  

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

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.

DOI： 10.1111/pcn.13597

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PubMed

Language：Japanese   Publisher：(一社)日本自殺予防学会  

高齢発症うつ病では、若年発症と比較して、焦燥、心気症、身体症状、認知機能障害などを伴うことが多く、加齢による脳器質的変化の影響が一要因と推測されるが、その背景病理は不明である。加齢に伴い、レビー病理は高齢者剖検脳に認められ、パーキンソン病やレビー小体型認知症(DLB)を含むレビー小体病の背景病理であり、その前駆(初期)症状として、しばしば抑うつ状態が出現する。症候学的にうつ病と重複することから、両者の鑑別診断に注意が必要であり、レム睡眠行動障害、嗅覚障害、視覚認知障害、自律神経障害に着目することが重要である。Prodromal DLBの研究目的の臨床診断基準が公表され、Psychiatric-onset DLBとして前駆・病初期の抑うつ状態に関心が向けられているが、65歳未満における認知症告知後の自殺リスクに留意しつつ、治療方法の確立が課題となっている。(著者抄録)

DOI： 10.51098/spcijasp.43.2_81

Open Access

Language：Japanese   Publisher：(有)科学評論社  

Language：Japanese   Publisher：(株)ワールドプランニング  

DSM-5によるレビー小体型認知症(DLB)診断について,国際会議に基づくDLB診断基準の変遷を踏まえて概説し,2020年のProdromal DLB診断基準を示しつつ,軽度認知障害の診断について述べた.また,精神症状が前景化し,認知機能障害の評価に苦慮したPsychiatric-onset prodromal DLBの症例を呈示し,DSM-5診断基準に照らし合わせ,レビー小体病の臨床像について再考した.(著者抄録)

Language：Japanese   Publisher：日本生物学的精神医学会  

統合失調症の神経病理学的研究は100年以上前からなされてきた古典的な手法である。その観察所見は統合失調症における神経細胞の分化・遊走,神経突起の分枝・伸長,シナプス形成などの発達段階における異常を示唆し,統合失調症の病態解明に寄与してきた。一方で,統合失調症における神経病理学的研究では,統合失調症という臨床診断に伴う生物学的な異質性や生涯にわたるさまざまなイベントの影響から,得られた所見が実際の疾患に特異的であることを明確化することに度々困難が生じることがあった。そのため,筆者らはまれなゲノム変異を有する統合失調症に着目して観察を行い,遺伝学的な情報も加味することによって,より疾患特異的な神経病理学的所見を見いだすことを戦略の一つとして行っている。統合失調症の病態の解明のためには,単に死後脳を集積するのみならず,ゲノム解析情報も備わったブレインバンクの拡充が望ましいと考えられる。(著者抄録)

DOI： 10.11249/jsbpjjpp.34.2_47

Open Access

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/psyg.12935

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PubMed

Language：English  

DOI： 10.1111/psyg.12948

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PubMed

Language：English  

DOI： 10.1111/pcn.13532

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PubMed

Language：English  

DOI： 10.1002/gps.5863

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PubMed

Language：English  

DOI： 10.1111/psyg.12922

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PubMed

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Public Library of Science (PLoS)  

Human mentality develops with age and is altered in psychiatric disorders, though their underlying mechanism is unknown. In this study, we analyzed nanometer-scale three-dimensional structures of brain tissues of the anterior cingulate cortex from eight schizophrenia and eight control cases. The distribution profiles of neurite curvature of the control cases showed a trend depending on their age, resulting in an age-correlated decrease in the standard deviation of neurite curvature (Pearson's r = -0.80, p = 0.018). In contrast to the control cases, the schizophrenia cases deviate upward from this correlation, exhibiting a 60% higher neurite curvature compared with the controls (p = 7.8 × 10-4). The neurite curvature also showed a correlation with a hallucination score (Pearson's r = 0.80, p = 1.8 × 10-4), indicating that neurite structure is relevant to brain function. This report is based on our 3D analysis of human brain tissues over a decade and is unprecedented in terms of the number of cases. We suggest that neurite curvature plays a pivotal role in brain aging and can be used as a hallmark to exploit a novel treatment of schizophrenia.

DOI： 10.1371/journal.pone.0287646

Open Access

Web of Science

PubMed

Language：Japanese   Publisher：(株)ワールドプランニング  

統合失調症の病態解明には死後脳における検証が欠かせず,疾患特異的な所見を見いだすためには,ゲノム情報を背景にした検証が有用と考えられる.また,海外では,脳組織から得たゲノムデータが分析・公開されており,本邦でもブレインバンクとゲノム研究とのさらなる連携が期待される.老年期精神医学の観点からも,統合失調症に晩年生じる認知症状態などについて,精神科ブレインバンクを用いた多面的なアプローチが期待される.(著者抄録)

Language：Japanese   Publisher：(公社)日本精神神経学会  

統合失調症研究にとって脳は中心的な標的器官である.脳は重量比にして体重の50分の1程度の小さな臓器だが,膨大なエネルギー(全グルコースの5分の1,酸素の4分の1)を必要とする.膨大な酸素とグルコースは,ミトコンドリアの酸化的リン酸化という代謝過程を経てATPにエネルギー転換され,これは神経細胞の静止膜電位の維持に消費される.脳は高度に機能分化した局所の集合体でもあり,血管系と神経系が緻密に連携することで,エネルギーを細部へ効果的に届けることができている.この脳の特徴-グルコース酸化と神経血管カップリング-から,統合失調症の代謝と構造について概説し,統合失調症研究の再現性問題を解決する方策の1例として,症候群から抽出した糖化ストレスを伴う小亜種を紹介した.脳構造を個人差レベルまで識別できる解像度をもつ放射光ナノCT法により,脳血管と神経細胞の構造アンバランスを同定した自験例を,統合失調症のエネルギー代謝研究への応用例として紹介した.(著者抄録)

Other Link： https://search.jamas.or.jp/default/link?pub_year=2022&ichushi_jid=J00755&link_issn=&doc_id=20221031250002&doc_link_id=vol%3D124%26year%3D2022%26mag%3D0%26number%3D10%26start%3D688&url=https%3A%2F%2Fjournal.jspn.or.jp%2FDisp%3Fstyle%3Dabst%26vol%3D124%26year%3D2022%26mag%3D0%26number%3D10%26start%3D688&type=%E7%B2%BE%E7%A5%9E%E7%A5%9E%E7%B5%8C%E5%AD%A6%E9%9B%91%E8%AA%8C&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00022_2.gif

Language：English  

DOI： 10.1111/psyg.12842

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PubMed

Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.biopsych.2022.04.003

Open Access

Web of Science

PubMed

Language：Japanese   Publisher：(有)科学評論社  

Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：Japanese   Publisher：(株)ワールドプランニング  

レビー小体型認知症(DLB)は、その診断基準の成立を契機として、アルツハイマー病に次いで2番目に頻度の高い神経変性性認知症疾患として周知されるようになった。一方、レム睡眠行動障害などを手がかりにDLBの早期診断が現実的となり、2020年にprodromal DLB診断基準が作成された。DLBを包含する臨床病理学的概念であるレビー小体病は、認知症の鑑別診断のみならず、脳病理を意識した診断・治療が期待される精神神経疾患である。(著者抄録)

Other Link： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2021&ichushi_jid=J02464&link_issn=&doc_id=20211124160006&doc_link_id=%2Faj2rsizd%2F2021%2F003210%2F007%2F1058-1067%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Faj2rsizd%2F2021%2F003210%2F007%2F1058-1067%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/psyg.12701

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Scopus

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

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.

DOI： 10.3390/jpm11070607

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Scopus

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

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.

DOI： 10.1038/s41598-021-91233-z

Open Access

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Scopus

PubMed

Language：Japanese  

CiNii Books

J-GLOBAL

Language：English   Publishing type：Research paper (scientific journal)  

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.

DOI： 10.1017/neu.2020.40

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PubMed

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/pcn.13187

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PubMed

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/pcn.13181

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PubMed

Language：English   Publishing type：Research paper (scientific journal)  

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 schizophrenia and control cases. The results of the analysis and a comparison with results for the anterior cingulate cortex indicated that (1) neuron structures are significantly 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. The schizophrenia cases showed a thin and tortuous neuronal network compared with the controls, suggesting that the neuron structure is associated with the disorder. The area dependency of the neuron structure and its diverseness between individuals should represent the individuality of brain functions.

DOI： 10.1038/s41398-020-01173-x

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PubMed

arXiv

Other Link： http://arxiv.org/pdf/2007.00212v1

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/psyg.12626

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PubMed

Language：English   Publishing type：Research paper (scientific journal)  

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.

DOI： 10.1111/neup.12668

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PubMed

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.schres.2020.07.003

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PubMed

Language：English  

DOI： 10.1016/j.schres.2020.09.012

PubMed

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

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Language：English   Publishing type：Research paper (scientific journal)  

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.

DOI： 10.1111/psyg.12522

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Language：Japanese   Publisher：(株)ワールドプランニング  

本稿では、レビー小体型認知症(DLB)の前駆状態(prodromal DLB)の診断について、「背景病理の同定」と「進展予測」の2つの側面から、指標的バイオマーカーと脳画像の現状を概説した。Prodromal DLB診断では、レム睡眠行動障害(RBD)の的確な把握が中心的な役割を担うため、睡眠医学と老年精神医学の連携が重要となる。DLBにおいて脳内βアミロイド(Aβ)蓄積と認知機能低下の関係が報告され、prodromal DLBを対象としたアミロイドイメージングの経時的変化の解明が期待される。(著者抄録)

Other Link： https://search.jamas.or.jp/default/link?pub_year=2020&ichushi_jid=J02464&link_issn=&doc_id=20200420130003&doc_link_id=%2Faj2rsizd%2F2020%2F003103%2F004%2F0233-0244%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Faj2rsizd%2F2020%2F003103%2F004%2F0233-0244%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：Japanese   Publisher：(公社)日本精神神経学会  

Kraepelin, E.が早発性痴呆の概念を提案したとき,彼は将来に神経病理学的所見が発見されることを期待した.その後120年の間にさまざまな神経病理学的な特徴が発表されたが,いまだ確定した所見は得られていない.われわれは,ホルマリン固定された統合失調症4例,これらと年齢・性別の一致した対照4例の前部帯状回ゴルジ染色標本について放射光ナノトモグラフィ法を用いて三次元構造をナノメータースケールで解析した.測定は,大型放射光施設SPring-8と,米国アルゴンヌ国立研究所Advanced Photon Sourceにおいて行った.得られた三次元像から,専用のアルゴリズムを用いて広い意味でのいわゆるAIにより神経ネットワークを自動トレースさせ,神経細胞の構造をデカルト座標に変換して構造変化を幾何学的に検討し,統合失調症例の2,592本と対照例の2,069本の神経突起を解析した.その結果,対照4例と比較して統合失調症4例の神経突起で,有意に大きな曲率を見出した(1.5倍:P=0.020).興味深いことに,最も高い曲率の症例では,カルボニルストレスの除去酵素であるグリオキサラーゼ1遺伝子にフレームシフト変異が見出され,治療抵抗性の臨床像が同定されていた.これまで統合失調症での神経細胞の構造変化について,長年にわたって困難な検討が続けられてきた.放射光ナノトモグラフィ法による組織構造の幾何学的解析は,この長く続いてきた懸案に光明を与える可能性が期待できると考える.(著者抄録)

Other Link： https://search.jamas.or.jp/default/link?pub_year=2019&ichushi_jid=J00755&link_issn=&doc_id=20191227140003&doc_link_id=vol%3D121%26year%3D2019%26mag%3D0%26number%3D12%26start%3D926&url=https%3A%2F%2Fjournal.jspn.or.jp%2FDisp%3Fstyle%3Dabst%26vol%3D121%26year%3D2019%26mag%3D0%26number%3D12%26start%3D926&type=%E7%B2%BE%E7%A5%9E%E7%A5%9E%E7%B5%8C%E5%AD%A6%E9%9B%91%E8%AA%8C&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00022_2.gif

Language：English   Publishing type：Research paper (scientific journal)  

Kraepelin expected that the neuropathological hallmark of schizophrenia would be identified when he proposed the concept of dementia praecox 120 years ago. Although a variety of neuropathological findings have been reported since then, a consensus regarding the pathology of schizophrenia has not been established. The discrepancies have mainly been ascribed to limitations in the disease definition of schizophrenia that accompanies etiological heterogeneity and to the incompleteness of the visualization methodology and technology for biochemical analyses. However, macroscopic structural changes in the schizophrenia brain, such as volumetric changes of brain regions, must entail structural changes to cells composing the brain. This paper overviews neuropathology of schizophrenia and also summarizes recent application of synchrotron radiation nanotomography (nano-CT) to schizophrenia brain tissues. Geometric parameters of neurites determined from the 3-D nano-CT images of brain tissues indicated that the curvature of neurites in schizophrenia cases is significantly higher than that of controls. The schizophrenia case with the highest curvature carried a frameshift mutation in the glyoxalase 1 gene and exhibited treatment resistance. Controversies in the neuropathology of schizophrenia are mainly due to the difficulty in reproducing histological findings reported for schizophrenia. Nano-CT visualization using synchrotron radiation and subsequent geometric analysis should shed light on this long-standing question about the neuropathology of schizophrenia.

DOI： 10.1111/pcn.12957

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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.

DOI： 10.1111/neup.12578

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Language：Japanese   Publisher：(株)星和書店  

Language：English   Publishing type：Research paper (scientific journal)  

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.

DOI： 10.1007/s00702-019-02035-7

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DOI： 10.1111/psyg.12425

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DOI： 10.1017/S1431927619007451

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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.

DOI： 10.1016/j.celrep.2018.08.022

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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.

DOI： 10.1016/j.ijdevneu.2018.09.002

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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.

DOI： 10.1017/neu.2018.6

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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.

DOI： 10.18999/nagjms.80.3.309

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Language：English   Publishing type：Research paper (scientific journal)  

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.

DOI： 10.1111/pcn.12651

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Language：Japanese   Publisher：(株)ワールドプランニング  

Other Link： https://search.jamas.or.jp/default/link?pub_year=2018&ichushi_jid=J02464&link_issn=&doc_id=20180517070010&doc_link_id=%2Faj2rsizd%2F2018%2F002904%2F011%2F0429-0434%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Faj2rsizd%2F2018%2F002904%2F011%2F0429-0434%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：English   Publishing type：Research paper (scientific journal)   Publisher：CHURCHILL LIVINGSTONE  

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 (DISCI). The role of DISCI 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 DISCI, we explored how DISCI 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 DISCI-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 DISCI-KO mice. The decrease was particularly prominent in the superficial regions, and the distribution of NPY-IR neurons differed between wild-type and DISCI-KO mice. However, the size of the neurons in the cortices of the DISCI-KO and wild-type mice did not differ markedly. Our findings suggest that dysfunction of DISCI 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. DISCI dysfunction may be involved in the pathogenesis of schizophrenia through the impairment of the NPY neuronal network. (C) 2017 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.npep.2016.12.010

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY  

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 I-123-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.

DOI： 10.1111/psyg.12181

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：DUSTRI-VERLAG DR KARL FEISTLE  

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.

DOI： 10.5414/NP300869

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY  

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.

DOI： 10.1002/syn.21924

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY  

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. Aneuropathological 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.

DOI： 10.1111/neup.12301

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Language：Japanese  

CiNii Books

J-GLOBAL

Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2016&ichushi_jid=J03168&link_issn=&doc_id=20160502030006&doc_link_id=issn%3D1343-3474%26volume%3D19%26issue%3D5%26spage%3D573&url=http%3A%2F%2Fwww.pieronline.jp%2Fopenurl%3Fissn%3D1343-3474%26volume%3D19%26issue%3D5%26spage%3D573&type=PierOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00005_2.gif

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Cambridge University Press  

Background: The precise aetiology of schizophrenia remains unclear. The neurodevelopmental hypothesis of schizophrenia has been proposed based on the accumulation of genomic or neuroimaging studies. Objective: In 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. Methods: Six 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. Results: The TH-immunopositive fibres detected in the orbitofrontal cortices of the DISC1 KO mice were significantly shorter than those seen in the wild-type mice. Conclusion: These 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.

DOI： 10.1017/neu.2015.51

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

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.

DOI： 10.1111/psyg.12128

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

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.

DOI： 10.1111/psyg.12105

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PubMed

DOI： 10.1111/eje.12093

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PubMed

Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

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. (C) 2011 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.schres.2011.10.024

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

Important genes have been identified that are associated with susceptibility to schizophrenia. DISCI is one of these candidate genes. The protein 14-3-3 epsilon is a DISC1-interacting molecule and is associated with axon elongation. The genetically modified 14-3-3 epsilon heterozygous knockout mice are considered to be an animal model of schizophrenia because they present endophenotypes of schizophrenia including working memory impairment. This study investigated the immunohistochemical expression of tyrosine hydroxylase (TH) to reveal the alterations in the functional structure of the axon elongation caused by the deficit of 14-3-3 epsilon. The study focused on the orbitofrontal cortex in the prefrontal cortex which is a region of interest in schizophrenia research. The investigation used eight 15-week-old knockout mice and six age-matched wild-type mice. The TH immunopositive fibers were linear and dense in the wild-type mice. These fibers were serpentine, thin and short in the knockout mice. Although it appeared that dendritic spine-like immunopositive varices were strung tightly in the fibers of wild-type mice, these were few and sparse in those of the of the knockout mice. Quantitative analysis showed a significant decrease in the total extent of the TH-immunopositive fibers in the orbital cortex of the knockout mouse. There is thought to be a dysfunction of a neurotransmitter such as dopamine and noradrenalin in the prefrontal cortex of these knockout mice. (C) 2011 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.brainres.2011.03.058

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

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. (C) 2010 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.jns.2010.10.021

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DOI： 10.1016/j.neures.2011.07.1721

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER IRELAND LTD  

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. (C) 2010 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.

DOI： 10.1016/j.neures.2010.06.005

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Authorship：Lead author   Language：Japanese  

Language：Japanese   Publisher：(株)文光堂  

J-GLOBAL

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