RESUMEN
Tauopathies, including Alzheimer's disease and primary age-related tauopathy (PART), present heterogeneous clinico-pathological phenotypes that include dementia, aphasia, motor neuron diseases, and psychiatric symptoms. PART is neuropathologically characterized by the presence of neurofibrillary tangles in limbic regions without significant Aß deposition, but its clinical features have not yet been fully established. Here, we present two patients with distinct psychosis and behavioral symptoms. At autopsy, these patients showed tau pathologies that could not be classified as typical PART, although PART-like neurofibrillary tangles were present in limbic regions. Clinically, both patients were admitted to mental hospitals due to severe delusions or other neuropsychiatric/behavioral symptoms. The first case presented with hallucination, delusion, and apathy at age 70, and died of pancreatic cancer at age 75. He had neuronal cytoplasmic inclusions with selective accumulation of 3Rtau in the striatum and thorn-shaped astrocytes in the amygdala. The second case, who presented with abnormal behaviors such as wandering, agitation and disinhibition, exhibited limbic neurodegeneration with massive 4R tau-positive oligodendroglial inclusions in the medial temporal white matter. His age at onset was 73, and the duration of disease was 15 years. These findings support the notion that distinct limbic tau pathology with concomitant degeneration of the related neural circuits might induce specific psychosis and behavioral symptoms. This underlines the importance of neuropathological evaluation for both clinical education and practice in the fields of neuropathology and neuropsychiatry.
Asunto(s)
Enfermedad de Alzheimer , Trastornos Psicóticos , Tauopatías , Masculino , Humanos , Proteínas tau , Autopsia , Tauopatías/complicaciones , Tauopatías/patología , Enfermedad de Alzheimer/patología , Ovillos Neurofibrilares/patología , Trastornos Psicóticos/patologíaRESUMEN
Several studies have reported a high prevalence of missed and delayed mild cognitive impairment (MCI) or mild dementia diagnosis, which could lead to delayed treatment and increased patient and caregiver burden. OBJECTIVES: This study aimed to develop a new questionnaire for nonprofessionals to help detect early signs of MCI and dementia. Respondents included patients, family caregivers, or health professionals. Scores are calculated based on the respondent type and age of subject. METHODS: This study consisted of four steps and included 461 respondents. Steps 1-3 were conducted by a working group, and step 4, by 67 specialist members of the Japanese Society of Geriatric Psychiatry. A scoring algorithm was created and predictive diagnostic probability was analyzed using misdiscrimination rate and cross-validation after item selection to establish a cut-off value for MCI or dementia symptoms. Alzheimer's disease, Lewy body dementia, and frontotemporal dementia were diagnosed. RESULTS: The prediction error rate for patient or informant respondents was confirmed from the evaluation results of 13 items. Sensitivity and specificity were 90.6% and 56.6%, respectively, with a cut-off score of 2. Overall, 82% (61 pairs) of respondents received a definitive diagnosis following a diagnosis from the questionnaire. CONCLUSIONS: This questionnaire could promote earlier presentation to clinical settings for treatment. The high sensitivity indicates the utility of this instrument, but it is not meant as a definitive diagnostic tool and should be followed with a professional assessment.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Demencia , Anciano , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/psicología , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/psicología , Demencia/diagnóstico , Demencia/psicología , Humanos , Autoinforme , Encuestas y CuestionariosRESUMEN
OBJECTIVES: Recent neuroimaging studies have indicated that the mesolimbic pathway, known to work as reward neuronal circuitry, regulates cognitive-behavioral flexibility in prolonged anorexia nervosa (AN). Although AN is associated with the highest mortality rate among psychiatric disorders, there have been few neuropathological studies on this topic. This study aims to identify alterations of the reward circuitry regions, especially in the nucleus accumbens (NAcc), using AN brain tissues. METHODS: The neuronal networks in AN cases and controls were examined by immunohistochemistry directed at tyrosine hydroxylase (TH; dopaminergic neuron marker) and glial fibrillary acidic protein (GFAP; astrocyte marker). We also immunochemically analyzed frozen samples presenting astrogliosis, especially in the NAcc and striatum. RESULTS: Histologically, neuronal deformation with cytoplasmic shrinkage was seen in reward-related brain regions, such as the orbitofrontal cortex/anterior cingulate cortex. The NAcc showed massive GFAP-positive astrocytes and dot-like protrusions of astrocytes in the shell compartment. In the shell, TH and GFAP immunoreactivities revealed prominent astrogliosis within striosomes, which receive projection from the ventral tegmental area (VTA). The numbers of GFAP-positive astrocytes in the NAcc (P = 0.0079) and VTA (P = 0.0025) of AN cases were significantly higher than those of controls. Strongly immunoreactive 18 to 25 kDa bands, which might represent degradation products, were detected only in the NAcc of AN cases. Clinically, all cases presented cognitive rigidity, which might reflect a deficit of the reward pathway. CONCLUSION: Our findings suggest impaired dopaminergic innervation between the NAcc and VTA in AN. Functional dysconnectivity in the reward-related network might induce neuropsychiatric symptoms associated with AN.
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Anorexia Nerviosa , Anorexia Nerviosa/metabolismo , Gliosis/metabolismo , Humanos , Núcleo Accumbens/diagnóstico por imagen , Núcleo Accumbens/metabolismo , Recompensa , Área Tegmental Ventral/fisiologíaRESUMEN
OBJECTIVES: Frontotemporal lobar degeneration (FTLD) is associated with accumulation of neurodegeneration-related protein, such as tau, TAR DNA-binding protein 43 (TDP-43), or fused in sarcoma protein (FUS). There have been very few systematic studies of the early symptoms of clinical phenotypes: behavioral variant frontotemporal dementia (bvFTD), semantic variant primary progressive aphasia (svPPA). Clinical subtypes and the patterns of atrophy reflect protein-accumulation patterns, but the relationship between early symptoms and pathological findings remains unclear. METHODS: We retrospectively investigated the clinical records and examined the neuropathology of 39 bvFTD and 6 svPPA patients to identify symptoms appearing within 2 years of the first clinically apparent changes. RESULTS: The bvFTD group consisted of 13 FTLD-tau, 18 FTLD-TDP, and 8 FTLD-FUS, and the svPPA group consisted of 6 FTLD-TDP. Age at death is significantly younger in FTLD-FUS (52.8 ± 12.6; P = 0.0104 < 0.05). Over 50% of bvFTD patients show apathy or inertia, and distinct language features appear early in svPPA. Interestingly, bvFTD and svPPA frequently present additional symptoms, not included in the diagnostic criteria, such as physical signs, reticence, dazed condition, and delusions. Stereotyped behaviors, hyperorality and dietary changes are prominent in FTLD-FUS, while linguistic deficits are greater in FTLD-TDP. CONCLUSIONS: Specific symptoms tend to appear in the early stage of FTLD in each pathological background. They might reflect the morphological features and pathological progression, and should be helpful in the stratification of patients for future therapeutic trials based on the proteinopathies.
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Demencia Frontotemporal , Degeneración Lobar Frontotemporal , Proteínas de Unión al ADN , Humanos , Fenotipo , Proteína FUS de Unión a ARN , Estudios Retrospectivos , Proteínas tauRESUMEN
Anorexia nervosa (AN) is a serious eating disorder characterized by self-starvation and extreme weight loss. It has the highest mortality rate among all psychiatric disorders. Recent research indicates that malnutrition in AN patients induces various kinds of functional brain damage, but the pathophysiology of AN remains unclear. We report here the neuropathological findings of a 31-year-old Japanese woman. At age 24, she had a fear of gaining weight and reduced her dietary intake; she had extremely low body weight associated with overeating then self-induced vomiting. She was clinically diagnosed as having AN and was admitted to a psychiatric hospital with severe depression and suicidal thoughts. At age 31, she died despite intensive physical care and psychotherapy. Neuropathological examination revealed increased capillary blood vessels and slight fibrillary gliosis in the mammillary bodies, with similarities to Wernicke encephalopathy. The brainstem exhibited the characteristic features of central pontine myelinolysis, characterized by a sharply demarcated region of myelin pallor and relative sparing of axons. Senile changes, including neurofibrillary tangles/senile plaques, were not significant. Severe fibrillary gliosis was prominent around periventricular regions, including the caudate nucleus and nucleus accumbens, which are associated with cognition, emotion, and emotional behaviors via the dopaminergic pathways. These findings indicate that prolonged malnutrition in AN patients may induce brain damage, leading to dysfunction of the reward-related dopaminergic pathways. Furthermore, they represent the first pathological evidence that dysfunction of the cortico-limbic-striatal circuitry is involved in the pathophysiology of psychiatric symptoms in AN patients.
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Anorexia Nerviosa/patología , Autopsia , Gliosis/patología , Ovillos Neurofibrilares/patología , Adulto , Anorexia Nerviosa/complicaciones , Anorexia Nerviosa/diagnóstico , Autopsia/métodos , Núcleo Caudado/patología , Femenino , Gliosis/diagnóstico , Humanos , Placa Amiloide/complicaciones , Placa Amiloide/patologíaRESUMEN
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.
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Vaina de Mielina/metabolismo , Glicoproteína Mielina-Oligodendrócito/metabolismo , Esquizofrenia/metabolismo , Lóbulo Temporal/metabolismo , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Vaina de Mielina/patología , Esquizofrenia/patología , Lóbulo Temporal/patologíaRESUMEN
BACKGROUND: The behavioural variant of frontotemporal dementia (bvFTD) is the most common phenotype of frontotemporal lobar degeneration (FTLD). FTLD is divided into three main pathological subtypes: tau-positive FTLD (FTLD-tau), FTLD-TAR DNA-binding protein (TDP), and FTLD-Fused in sarcoma (FUS). At present, it is difficult to predict the underlying pathological subtypes of sporadic bvFTD before a patient's death. METHODS: We retrospectively investigated the clinical features of 34 Japanese patients with sporadic bvFTD, with or without motor neuron disease (MND), who had been pathologically diagnosed with FTLD. We examined whether, and how, the clinical features differed among Pick's disease, FTLD-TDP, and FTLD-FUS patients. RESULTS: Six of the 34 patients developed MND during the course of bvFTD. These six bvFTD-MND patients were all pathologically diagnosed with FTLD-TDP. The other 28 patients were composed of 12 FTLD-tau patients including 11 Pick's disease patients, 8 FTLD-TDP patients, and 8 FTLD-FUS patients. A comparison of the clinical features of the three pathological subtypes of the 33 patients demonstrated that the age at onset was significantly younger in FTLD-FUS patients than in Pick's disease or FTLD-TDP patients. Furthermore, while hyperorality and dietary changes in the early stage of the disease were present in approximately 40% of Pick's disease and FTLD-FUS patients, they were absent in FTLD-TDP patients. CONCLUSION: The comorbidity of MND, a younger age at onset, and hyperorality and dietary changes in the early stage may be useful clinical features for predicting underlying pathological subtypes of sporadic bvFTD. The results of our study should be confirmed by prospective studies employing a larger number of cases.
Asunto(s)
Encéfalo/patología , Demencia Frontotemporal/patología , Degeneración Lobar Frontotemporal/patología , Enfermedad de la Neurona Motora/patología , Enfermedad de Pick/patología , Adulto , Anciano , Femenino , Demencia Frontotemporal/epidemiología , Demencia Frontotemporal/psicología , Degeneración Lobar Frontotemporal/clasificación , Degeneración Lobar Frontotemporal/epidemiología , Degeneración Lobar Frontotemporal/psicología , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de la Neurona Motora/epidemiología , Enfermedad de Pick/epidemiología , Enfermedad de Pick/psicología , Estudios RetrospectivosRESUMEN
Although delirium shares clinical characteristics with dementia with Lewy bodies (DLB), there is limited information regarding the relationship between delirium and Lewy body pathology. Here, we report an 89-year-old Japanese woman with an episode of delirium who was pathologically confirmed to have limbic-type Lewy body disease (LBD). Although she exhibited transient visual hallucinations during the delirium, she had no overt dementia. She developed no core clinical features of DLB and died of pneumonia at the age of 90 years. This autopsied case suggests that delirium may be one of the clinical phenotypes of LBD prior to the onset of dementia.
Asunto(s)
Delirio/etiología , Cuerpos de Lewy/patología , Enfermedad por Cuerpos de Lewy/patología , Anciano de 80 o más Años , Autopsia , Femenino , Alucinaciones/etiología , Humanos , FenotipoRESUMEN
A 30-year-old Japanese woman without relevant family history presented with a behavioral abnormality followed by motor weakness about 14 years later. The patient died at age 45. Post mortem examination revealed degeneration of the frontal and temporal lobes, as well as lower motor neurons in the brainstem and spinal cord. These features were reported previously as being consistent with a diagnosis of frontotemporal lobar degeneration (FTLD) with amyotrophic lateral sclerosis (ALS). In the present study, we show abundant fused in sarcoma (FUS)-positive dystrophic neurites but only a few neuronal cytoplasmic inclusions in the frontal and temporal cortices. TAR DNA-binding protein 43 (TDP-43)-positive inclusions were absent in the cerebrum. However, TDP-43-positive inclusions were present in the lower motor neurons of the brainstem and spinal cord. To our knowledge, this is the first report of a case in which FTLD-FUS pathology is of a dystrophic neurites-predominant type and FTLD-FUS is associated with ALS-TDP.
Asunto(s)
Esclerosis Amiotrófica Lateral/patología , Proteínas de Unión al ADN/metabolismo , Degeneración Lobar Frontotemporal/patología , Proteína FUS de Unión a ARN/metabolismo , Adulto , Esclerosis Amiotrófica Lateral/metabolismo , Femenino , Lóbulo Frontal/metabolismo , Lóbulo Frontal/patología , Humanos , Cuerpos de Inclusión/metabolismo , Cuerpos de Inclusión/patología , Persona de Mediana Edad , Neuronas Motoras/metabolismo , Neuronas Motoras/patología , Médula Espinal/metabolismo , Médula Espinal/patología , Lóbulo Temporal/metabolismo , Lóbulo Temporal/patologíaRESUMEN
The function of each organ including the brain tends to decline with aging. This influences on the appearance of psychotic symptoms in the elderly. A manic state in the elderly is often atypical and different from that in younger and middle aged patients. Manic pseudodementia is an important symptom, which means that elderly manic patients easily show dementia-like behavior because of their Tatendrang(pressured action) or hyperkinesis, so they are misdiagnosed as having dementia. On medication, as the response to drugs is different to that in younger patients, side effects easily appear in the elderly. However, we have very few clinical-pharmacological data on the use of major tranquilizers including anti-manic drugs for elderly patients.
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Trastorno Bipolar/diagnóstico , Trastornos Fingidos/diagnóstico , Anciano de 80 o más Años , Trastorno Bipolar/terapia , Femenino , Humanos , MasculinoRESUMEN
Role of mitochondrial pathology in schizophrenia has not been fully clarified. We searched for distinctive variants in mtDNA extracted from the gray matter of postmortem brains and from peripheral blood samples. We screened mtDNA region containing 5 genes encoding subunits of cytochrome c oxidase and ATPases. Polymorphisms not already reported in databases are recorded as unregistered rare variants. Four unregistered, non-synonymous rare variants were detected in 4 schizophrenic samples. Seven registered non-synonymous variants were not previously detected in non-psychotic Japanese samples registered in the mtSNP database. These variants may contribute to disease pathophysiology. In one family, compound mutations showed co-segregation with schizophrenia. MtDNA mutations could confer a risk for schizophrenia in the Japanese population, although further analyses are needed.
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ADN Mitocondrial/genética , Patrón de Herencia/genética , Madres , Mutación/genética , Esquizofrenia/genética , Adulto , Anciano , Anciano de 80 o más Años , Secuencia de Aminoácidos , Secuencia de Bases , Estudios de Casos y Controles , Análisis Mutacional de ADN , Femenino , Humanos , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Linaje , Esquizofrenia/sangre , Adulto JovenRESUMEN
Glutamate is one of the key molecules involved in signal transduction in the brain, and dysfunction of glutamate signaling could be linked to schizophrenia. The SLC1A1 gene located at 9p24 encodes the glutamate transporter EAAT3/EAAC1. To investigate the association between the SLC1A1 gene and schizophrenia in the Japanese population, we genotyped 19 tagging single nucleotide polymorphisms (tagSNPs) in the SLC1A1 gene in 576 unrelated individuals with schizophrenia and 576 control subjects followed by replication in an independent case-control study of 1,344 individuals with schizophrenia and 1,344 control subjects. In addition, we determined the boundaries of the copy number variation (CNV) region in the first intron (Database of Genomic Variants, chr9:4516796-4520549) and directly genotyped the CNV because of significant deviation from the Hardy-Weinberg equilibrium. The CNV was not associated with schizophrenia. Four SNPs showed a possible association with schizophrenia in the screening subjects and the associations were replicated in the same direction (nominal allelic P < 0.05), and, among them, an association with rs7022369 was replicated even after Bonferroni correction (allelic nominal P = 5 × 10(-5) , allelic corrected P = 2.5 × 10(-4) , allelic odds ratio, 1.30; 95% CI: 1.14-1.47 in the combined subjects). Expression analysis quantified by the real-time quantitative polymerase chain reaction in the postmortem prefrontal cortex of 43 Japanese individuals with schizophrenia and 11 Japanese control subjects revealed increased SLC1A1 expression levels in individuals homozygous for the rs7022369 risk allele (P = 0.003). Our findings suggest the involvement of SLC1A1 in the pathogenesis of schizophrenia.
Asunto(s)
Transportador 3 de Aminoácidos Excitadores/genética , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple/genética , Esquizofrenia/genética , Alelos , Encéfalo/patología , Variaciones en el Número de Copia de ADN/genética , Transportador 3 de Aminoácidos Excitadores/metabolismo , Femenino , Pruebas Genéticas , Humanos , Masculino , Persona de Mediana Edad , Cambios Post Mortem , Reproducibilidad de los ResultadosRESUMEN
Chromatin remodeling may play a role in the neurobiology of schizophrenia and the process, therefore, may be considered as a therapeutic target. The SMARCA2 gene encodes BRM in the SWI/SNF chromatin-remodeling complex, and associations of single nucleotide polymorphisms (SNPs) to schizophrenia were found in two linkage disequilibrium blocks in the SMARCA2 gene after screening of 11 883 SNPs (rs2296212; overall allelic P = 5.8 x 10(-5)) and subsequent screening of 22 genes involved in chromatin remodeling (rs3793490; overall allelic P = 2.0 x 10(-6)) in a Japanese population. A risk allele of a missense polymorphism (rs2296212) induced a lower nuclear localization efficiency of BRM, and risk alleles of intronic polymorphisms (rs3763627 and rs3793490) were associated with low SMARCA2 expression levels in the postmortem prefrontal cortex. A significant correlation in the fold changes of gene expression from schizophrenic prefrontal cortex (from the Stanley Medical Research Institute online genomics database) was seen with suppression of SMARCA2 in transfected human cells by specific siRNA, and of orthologous genes in the prefrontal cortex of Smarca2 knockout mice. Smarca2 knockout mice showed impaired social interaction and prepulse inhibition. Psychotogenic drugs lowered Smarca2 expression while antipsychotic drugs increased it in the mouse brain. These findings support the existence of a role for BRM in the pathophysiology of schizophrenia.
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Ensamble y Desensamble de Cromatina , Proteínas de Unión al ADN/metabolismo , Esquizofrenia/metabolismo , Factores de Transcripción/metabolismo , Adulto , Anciano , Secuencia de Aminoácidos , Animales , Pueblo Asiatico , Estudios de Casos y Controles , Línea Celular , Núcleo Celular/química , Núcleo Celular/metabolismo , Estudios de Cohortes , Proteínas de Unión al ADN/genética , Femenino , Expresión Génica , Humanos , Relaciones Interpersonales , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Persona de Mediana Edad , Datos de Secuencia Molecular , Polimorfismo de Nucleótido Simple , Corteza Prefrontal/química , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Transporte de Proteínas , Psicotrópicos/administración & dosificación , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/genética , Esquizofrenia/fisiopatología , Alineación de Secuencia , Factores de Transcripción/química , Factores de Transcripción/genéticaRESUMEN
Advanced glycation end products play a key role in the pathophysiology of schizophrenia. Cognitive impairment is one of the central features of schizophrenia; however, the association between advanced glycation end products and cognitive impairment remains unknown. This study investigated whether advanced glycation end products affect the cognitive domain in patients with schizophrenia. A total of 58 patients with chronic schizophrenia were included in this cross-sectional study. Plasma advanced glycation end products were measured using high-performance liquid chromatography (HPLC). Neuropsychological and cognitive functions were assessed using the Wechsler Adult Intelligence Scale, Third Version, and the Wisconsin Card Sorting Test Keio-FS version. Multiple regression analysis adjusted for age, sex, body mass index, educational years, daily dose of antipsychotics, and psychotic symptoms revealed that processing speed was significantly associated with plasma pentosidine, a representative advanced glycation end product (standardized ß = -0.425; p = 0.009). Processing speed is the cognitive domain affected by advanced glycation end products. Considering preceding evidence that impaired processing speed is related to poor functional outcome, interventions targeted at reducing advanced glycation end products may contribute to promoting recovery of patients with schizophrenia as well as cognitive function improvement.
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Disfunción Cognitiva/metabolismo , Productos Finales de Glicación Avanzada/metabolismo , Esquizofrenia/metabolismo , Arginina/análogos & derivados , Arginina/metabolismo , Cognición/fisiología , Estudios Transversales , Femenino , Humanos , Lisina/análogos & derivados , Lisina/metabolismo , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Receptor para Productos Finales de Glicación Avanzada/metabolismoRESUMEN
Schizophrenia is a heterogeneous psychiatric disorder characterized by positive symptoms such as hallucinations and delusions, negative symptoms such as anhedonia and flat affect, and cognitive impairment. Recently, glucuronate (GlucA) levels were reported to be significantly higher in serum of patients with schizophrenia than those in healthy controls. The accumulation of GlucA is known to be related to treatment-resistant schizophrenia, since GlucA is known to promote drug excretion by forming conjugates with drugs. However, the cause of GlucA accumulation remains unclear. Aldo-keto reductase family one member A1 (AKR1A1) is an oxidoreductase that catalyzes the reduction of GlucA. Genetic loss of AKR1A1 function is known to result in the accumulation of GlucA in rodents. Here, we aimed to explore genetic defects in AKR1A1 in patients with schizophrenia, which may result in the accumulation of GlucA. We identified 28 variants of AKR1A1 in patients with schizophrenia and control subjects. In particular, we identified a silent c.753G > A (rs745484618, p. Arg251Arg) variant located at the first position of exon 8 to be associated with schizophrenia. Using a minigene assay, we found that the c.753G > A variant induced exon 8 skipping in AKR1A1, resulting in a frameshift mutation, which in turn led to truncation of the AKR1A1 protein. Using the recombinant protein, we demonstrated that the truncated AKR1A1 completely lost its activity. Furthermore, we showed that AKR1A1 mRNA expression in the whole blood cells of individuals with the c.753G > A variant tended to be lower than that in those without the variants, leading to lower AKR activity. Our findings suggest that AKR1A1 carrying the c.753G > A variant induces exon skipping, leading to a loss of gene expression and enzymatic activity. Thus, GlucA patients with schizophrenia with the c.753G > A variant may show higher GlucA levels, leading to drug-resistant schizophrenia, since drug excretion by GlucA is enhanced.
RESUMEN
Transactivation response (TAR) DNA-binding protein of Mr 43 kDa (TDP-43) is a major component of the tau-negative and ubiquitin-positive inclusions that characterize amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration which is now referred to as FTLD-TDP. Concurrent TDP-43 pathology has been reported in a variety of other neurodegenerative disorders such as Alzheimer's disease, forming a group of TDP-43 proteinopathy. Accumulated TDP-43 is characterized by phosphorylation and fragmentation. There is a close relationship between the pathological subtypes of FTLD-TDP and the immunoblot pattern of the C-terminal fragments of phosphorylated TDP-43. These results suggest that proteolytic processing of accumulated TDP-43 may play an important role for the pathological process. In cultured cells, transfected C-terminal fragments of TDP-43 are more prone to form aggregates than full-length TDP-43. Transfecting the C-terminal fragment of TDP-43 harboring pathogenic mutations of TDP-43 gene identified in familial and sporadic ALS cases into cells enhanced the aggregate formation. Furthermore, we found that methylene blue and dimebon inhibit aggregation of TDP-43 in these cellular models. Understanding the mechanism of phosphorylation and truncation of TDP-43 and aggregate formation may be crucial for clarifying the pathogenesis of TDP-43 proteinopathy and for developing useful therapeutics.
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Esclerosis Amiotrófica Lateral/metabolismo , Encéfalo/metabolismo , Proteínas de Unión al ADN/metabolismo , Degeneración Lobar Frontotemporal/metabolismo , Esclerosis Amiotrófica Lateral/patología , Encéfalo/patología , Degeneración Lobar Frontotemporal/patología , Humanos , Cuerpos de Inclusión/metabolismo , Cuerpos de Inclusión/patología , Fosforilación , alfa-Sinucleína/metabolismoRESUMEN
In elderly patients with so-called psychogenic physical symptoms, changes with age of the symptoms were discussed from the standpoint of geriatric psychiatry. In recent years, the diagnostic criteria for psychogenic physical symptoms have been revised and are closer to the definition of psychosomatic disorders. In aging, the aging phenomenon of each body organ progresses, and the brain is no exception. Clinical findings suggest that conventional physical and mental symptoms are alleviated as brain function declines in general. If dementia is added, the speed of relief will increase. In Japan, where super-aging is advancing, the need to focus on the positive aspects of aging is discussed.
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Envejecimiento/fisiología , Encéfalo/fisiopatología , Psiquiatría Geriátrica , Trastornos Psicofisiológicos/fisiopatología , Trastornos Psicofisiológicos/psicología , Anciano , Anciano de 80 o más Años , Ansiedad , Trastornos de Ansiedad/fisiopatología , Trastornos de Ansiedad/psicología , Femenino , Humanos , Masculino , Trastornos Psicofisiológicos/diagnósticoRESUMEN
TAR DNA-binding protein of 43 kDa (TDP-43) is a major component of intracellular aggregates formed in brains of the patients with frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS), which are correctively referred to as TDP-43 proteinopathies. A link between Ataxin-2 (ATXN2) and TDP-43 proteinopathies was established when intermediate CAG repeat expansions of ATXN2 gene were found to be associated with ALS and it was shown that ATXN2 modifies TDP-43 toxicity. Although ATXN2's contribution to TDP-43 proteinopathies has been mostly studied in ALS, recent studies have shown that intermediate repeat expansions of ATXN2 also influence the phenotype of FTLD by an unknown mechanism. To address this issue, we immunohistochemically and biochemically analyzed the intracellular dynamics of ATXN2 in brains of normal controls and FTLD-TDP cases. The immunohistochemical studies revealed that ATXN2 localized in the neuronal cytoplasm and proximal dendrites, and expressed widely and uniformly in normal human brains. A semi-quantitative immunofluorescent analysis of normal brains revealed that the cytoplasmic ATXN2 strongly associates with ribosomal protein S6 and poly-A binding protein 1 and partially overlaps with the endoplasmic reticulum marker Calnexin, suggesting a major role of ATXN2 in protein synthesis. The results of immunohistochemical and biochemical analyses of brains from FTLD-TDP cases showed the colocalization of ATXN2 and phosphorylated TDP-43 in the dystrophic neurites and the neuronal cytoplasmic inclusions in the hippocampal region, and a significant reduction of ATXN2 protein compared to controls. These results suggest that ATXN2 is involved in the pathological process of FTLD-TDP. It remains to be clarified whether reduced ATXN2 expression induces neurodegeneration by impairing protein synthesis or plays a neuroprotective role by attenuating the toxicity of TDP-43 aggregates in FTLD-TDP and other TDP-43 proteinopathies.
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Ataxina-2/metabolismo , Encéfalo/metabolismo , Proteínas de Unión al ADN/metabolismo , Degeneración Lobar Frontotemporal/metabolismo , Agregación Patológica de Proteínas/metabolismo , Anciano , Anciano de 80 o más Años , Esclerosis Amiotrófica Lateral/metabolismo , Esclerosis Amiotrófica Lateral/patología , Animales , Encéfalo/patología , Estudios de Casos y Controles , Femenino , Degeneración Lobar Frontotemporal/patología , Humanos , Masculino , Ratones , Persona de Mediana Edad , Agregación Patológica de Proteínas/patologíaRESUMEN
Narcolepsy with cataplexy is a sleep disorder caused by a deficiency in hypocretin neurons in the lateral hypothalamus (LH). Here we performed an epigenome-wide association study (EWAS) of DNA methylation for narcolepsy and replication analyses using DNA samples extracted from two brain regions: LH (Cases: N = 4; Controls: N = 4) and temporal cortex (Cases: N = 7; Controls: N = 7). Seventy-seven differentially methylated regions (DMRs) were identified in the LH analysis, with the top association of a DMR in the myelin basic protein (MBP) region. Only five DMRs were detected in the temporal cortex analysis. Genes annotated to LH DMRs were significantly associated with pathways related to fatty acid response or metabolism. Two additional analyses applying the EWAS data were performed: (1) investigation of methylation profiles shared between narcolepsy and other disorders and (2) an integrative analysis of DNA methylation data and a genome-wide association study for narcolepsy. The results of the two approaches, which included significant overlap of methylated positions associated with narcolepsy and multiple sclerosis, indicated that the two diseases may partly share their pathogenesis. In conclusion, DNA methylation in LH where loss of orexin-producing neurons occurs may play a role in the pathophysiology of the disease.
Asunto(s)
Cataplejía/genética , Metilación de ADN/genética , Área Hipotalámica Lateral/metabolismo , Esclerosis Múltiple/genética , Narcolepsia/genética , Lóbulo Temporal/metabolismo , Cataplejía/fisiopatología , ADN/metabolismo , Epigenoma , Femenino , Estudio de Asociación del Genoma Completo/métodos , Humanos , Masculino , Narcolepsia/fisiopatología , Neuronas/metabolismo , Orexinas/genética , Orexinas/metabolismoRESUMEN
A 58-year-old Japanese man developed psychomotor excitement and hallucinatory paranoia at age 53, which gradually developed to residual schizophrenia. He was administered various common tranquilizers until death. Myelodysplastic syndrome was noted 10 months before death. A routine autopsy was performed. The brain weighed 1365 g, and macroscopic observation revealed no remarkable findings. However, microscopic examination disclosed cells with enlarged and basophilic nuclei, and unusual astrocytes in the demyelinated foci, especially at the corticomedullary junctions in the temporal and occipital lobes. On the other hand, the white matter was relatively intact. Immunohistochemical analysis using anti-JC virus protein, VP-1 antibody, demonstrated JC virus-infected cells in not only abnormal glial cells and neurons but also normal-looking cells, which are suggestive of progressive multifocal leukoencephalopathy (PML). Immunostaining for GFAP revealed severe gliosis and some scattered abnormal enlarged nuclear cells in the lesions. Some clusters of CD8-positive lymphocytes were seen, which kill infected cells. PML could be considered a short-term disease preceding death, as "incidental PML" in this case. This is a rare autopsy case of early PML occurring in a schizophrenia patient with PML.