A case report of late-onset schizophrenia differentiated from a dementing disorder.

We report a case of late-onset schizophrenia that required differentiation from a dementing disorder. The patient was an 83-year-old woman who had experienced auditory hallucinations since she was 67 years old. The patient had slightly elevated total tau and slightly decreased amyloid ß1-42, cerebrospinal fluid biomarkers. This case was identified as late-onset schizophrenia. However, the results of cerebrospinal fluid biomarkers indicated that neurofibrillary tangles and neuronal death, which are characteristic of Alzheimer 's disease, may also have been present. Late-onset schizophrenia should be treated based on an appropriate differential diagnosis, including neuropathological consideration of dementing disorders.

Intelligence decline across major depressive disorder, bipolar disorder, and schizophrenia.

BACKGROUND: Major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SCZ) are associated with impaired intelligence that predicts poor functional outcomes. However, little is known regarding the extent and severity of intelligence decline, that is, decreased present intelligence quotient (IQ) relative to premorbid levels, across psychiatric disorders and which clinical characteristics affect the decline. METHODS: Premorbid IQ, present IQ, and intelligence decline were compared across patients with MDD (n = 45), BD (n = 30), and SCZ (n = 139), and healthy controls (HCs; n = 135). Furthermore, we investigated which factors contribute to the intelligence decline in each diagnostic group. RESULTS: Significant differences were observed in premorbid IQ, present IQ, and intelligence decline across the diagnostic groups. Patients with each psychiatric disorder displayed lower premorbid and present IQ and more intelligence decline than HCs. Patients with SCZ displayed lower premorbid and present IQ and more intelligence decline than patients with MDD and BD, while there were no significant differences between patients with MDD and BD. When patients with BD were divided based on bipolar I disorder (BD-I) and bipolar II disorder (BD-II), degrees of intelligence decline were similar between MDD and BD-II and between BD-I and SCZ. Lower educational attainment was correlated with a greater degree of intelligence decline in patients with SCZ and BD but not MDD. CONCLUSIONS: These findings confirm that although all psychiatric disorders display intelligence decline, the severity of intelligence decline differs across psychiatric disorders (SCZ, BD-I > BD-II, MDD > HCs). Higher educational attainment as cognitive reserve contributes to protection against intelligence decline in BD and SCZ.

Differences in executive function among patients with schizophrenia, their unaffected first-degree relatives and healthy participants.

BACKGROUND: Patients with schizophrenia (SCZ) display impaired executive functions compared with healthy controls (HCs). Furthermore, unaffected first-degree relatives (FRs) of patients with SCZ independently perform worse executive functions than do HCs. However, few studies have investigated the differences in executive functions assessed among patients with SCZ, FRs, and HCs, and the findings are inconsistent. METHODS: We investigated diagnostic differences in executive functions, namely, (i) numbers of categories achieved (CA), (ii) total errors (TE) and (iii) %perseverative errors of Nelson types (%PEN), using the Wisconsin card sorting test (WCST) among patients with SCZ (n=116), unaffected FRs (n=62) and HCs (n=146) at a single institute. Correlations between these executive functions and clinical variables were investigated. RESULTS: Significant differences existed in all executive functions among diagnostic groups (CA, F2,319=15.5, p=3.71×10-7; TE, F2,319=16.2, p=2.06×10-7; and %PEN, F2,319=21.3, p=2.15×10-9). Patients with SCZ had fewer CA and more TE and %PEN than those of HCs (CA, Cohen's d=-0.70, p=5.49×10-8; TE, d=0.70, p=5.62×10-8; and %PEN, d=0.82, p=2.85×10-10) and FRs (TE, d=0.46, p=3.73×10-3 and %PEN, d=0.38, p=0.017). Of the three executive functions, CA and %PEN of FRs were intermediately impaired between patients with SCZ and HCs (CA, d=-0.41, p=0.011 and %PEN, d=0.41, p=0.012). In contrast, no significant difference in TE existed between FRs and HCs (d=0.22, p=0.18). Although CA and TE were affected by the duration of illness (p<0.017), %PEN was not affected by any clinical variable in patients with SCZ (p>0.017). CONCLUSIONS: Executive function, particularly %PEN, could be a useful intermediate phenotype for understanding the genetic mechanisms implicated in SCZ pathophysiology.

Polygenetic Risk Scores for Major Psychiatric Disorders Among Schizophrenia Patients, Their First-Degree Relatives, and Healthy Participants.

BACKGROUND: The genetic etiology of schizophrenia (SCZ) overlaps with that of other major psychiatric disorders in samples of European ancestry. The present study investigated transethnic polygenetic features shared between Japanese SCZ or their unaffected first-degree relatives and European patients with major psychiatric disorders by conducting polygenic risk score (PRS) analyses. METHODS: To calculate PRSs for 5 psychiatric disorders (SCZ, bipolar disorder [BIP], major depressive disorder, autism spectrum disorder, and attention-deficit/hyperactivity disorder) and PRSs differentiating SCZ from BIP, we utilized large-scale European genome-wide association study (GWAS) datasets as discovery samples. PRSs derived from these GWASs were calculated for 335 Japanese target participants [SCZ patients, FRs, and healthy controls (HCs)]. We took these PRSs based on GWASs of European psychiatric disorders and investigated their effect on risk in Japanese SCZ patients and unaffected first-degree relatives. RESULTS: The PRSs obtained from European SCZ and BIP patients were higher in Japanese SCZ patients than in HCs. Furthermore, PRSs differentiating SCZ patients from European BIP patients were higher in Japanese SCZ patients than in HCs. Interestingly, PRSs related to European autism spectrum disorder were lower in Japanese first-degree relatives than in HCs or SCZ patients. The PRSs of autism spectrum disorder were positively correlated with a young onset age of SCZ. CONCLUSIONS: These findings suggest that polygenic factors related to European SCZ and BIP and the polygenic components differentiating SCZ from BIP can transethnically contribute to SCZ risk in Japanese people. Furthermore, we suggest that reduced levels of an ASD-related genetic factor in unaffected first-degree relatives may help protect against SCZ development.

Genetic correlations between subcortical brain volumes and psychiatric disorders.

Psychiatric disorders as well as subcortical brain volumes are highly heritable. Large-scale genome-wide association studies (GWASs) for these traits have been performed. We investigated the genetic correlations between five psychiatric disorders and the seven subcortical brain volumes and the intracranial volume from large-scale GWASs by linkage disequilibrium score regression. We revealed weak overlaps between the genetic variants associated with psychiatric disorders and subcortical brain and intracranial volumes, such as in schizophrenia and the hippocampus and bipolar disorder and the accumbens. We confirmed shared aetiology and polygenic architecture across the psychiatric disorders and the specific subcortical brain and intracranial volume.

Smoking Rates and Number of Cigarettes Smoked per Day in Schizophrenia: A Large Cohort Meta-Analysis in a Japanese Population.

Background: Cigarette smoking is consistently more common among schizophrenia patients than the general population worldwide; however, the findings of studies in Japan are inconsistent. Recently, the smoking rate has gradually decreased among the general population. Methods: We performed a meta-analysis of smoking status in a large Japanese cohort of (1) 1845 schizophrenia patients and 196845 general population and (2) 842 schizophrenia patients and 766 psychiatrically healthy controls from 12 studies over a 25-year period, including 301 patients and 131 controls from our study. Results: In our case-control sample, schizophrenia patients had a significantly higher smoking rate than healthy controls (P=.031). The proportion of heavy smokers (P=.027) and the number of cigarettes smoked per day (P=8.20×10-3) were significantly higher among schizophrenia patients than healthy controls. For the smokers in the schizophrenia group, atypical antipsychotics dosage was positively correlated with cigarettes per day (P=1.00×10-3). A meta-analysis found that schizophrenia patients had a higher smoking rate than the general population for both men (OR=1.53, P=.035; schizophrenia patients, 52.9%; general population, 40.1%) and women (OR=2.40, P=1.08×10-5; schizophrenia patients, 24.4%; general population, 11.8%). In addition, male schizophrenia patients had a higher smoking rate than male healthy controls (OR=2.84, P=9.48×10-3; schizophrenia patients, 53.6%; healthy controls, 32.9%), but the difference was not significant for women (OR=1.36, P=.53; schizophrenia patients, 17.0%; healthy controls,14.1%). Among both males and females, schizophrenia patients had a higher smoking rate than both the general population (OR=1.88, P=2.60×10-5) and healthy controls (OR=2.05, P=.018). These rates were not affected by the patients' recruitment year (P>.05). The cigarettes per day values of schizophrenia patients and the general population were 22.0 and 18.8, respectively. Conclusions: Schizophrenia patients are approximately 2 times more likely to smoke than the general population and healthy controls based on data collected over a decade in Japan.

Meta-analysis of physical activity and effects of social function and quality of life on the physical activity in patients with schizophrenia.

Schizophrenia patients have increased mortality and morbidity, mainly due to premature cardiovascular disease resulting from decreased physical activity (PA). However, which PA intensity is impaired in the patients and how factors such as social function and quality of life (QoL) are related to decreased PA is unknown. To assess PA, social function and QoL, the International Physical Activity Questionnaire (IPAQ), Social Functioning Scale (SFS) and Schizophrenia Quality of Life Scale (SQLS), respectively, were used in 109 schizophrenia patients and 69 healthy subjects. A meta-analysis comparing PA intensities (vigorous, moderate and light) assessed by the single PA measurement between schizophrenia patients and healthy subjects after including our case-control sample was performed. Furthermore, the effects of social function and QoL on each level of PA intensity were investigated in patients and controls. The meta-analysis in 212 schizophrenia patients and 132 healthy subjects revealed that patients showed lower total PA, particularly vigorous PA, than controls (I2 = 0, Hedges' g = - 0.41, P = 2.80 × 10-4). The decreased total PA was correlated with impaired total SFS scores (ß = 0.24, P = 2.86 × 10-3), withdrawal (ß = 0.23, P = 3.74 × 10-3) and recreation (ß = 0.23, P = 3.49 × 10-3) without significant heterogeneity between patients and controls. In contrast, the decreased total PA was affected by low independence-performance (ß = 0.22, P = 0.034), employment/occupation (ß = 0.27, P = 8.74 × 10-3), psychosocial (ß = - 0.24, P = 0.021) and motivation/energy (ß = - 0.26, P = 0.013), but only in patients. Similar findings were obtained for vigorous PA but not moderate or light PA. Our findings suggest that the impaired vigorous PA in schizophrenia patients may be mediated by schizophrenia-specific factors of social functioning and QoL. Understanding these factors has important implications for increasing PA participation in schizophrenia patients.

The Role of Family Variables in the Length of Stay of Psychiatric In-patients.

BACKGROUND: In Japan, the number of beds and average length of stay in a psychiatric ward are greater than in other developed countries. OBJECTIVE: The present study aimed to investigate the association between family variables and the length of stay of patients with mental and behavioural disorders in a private psychiatric hospital in Japan. METHODS: The medical records of patients discharged during a one-year period (n=56: men 50.0% excepting 27 patients discharged due to death were re-examined regarding age, laundry type (self-washing of clothes, family washing or supplier washing), number of family visits per one month while hospitalised, and family structure prior to hospitalisation. A length of stay greater than six months was considered the cut-off point for a long hospital stay. Bivariate logistic regression analyses were conducted to identify factors independently associated with the length of stay, adjusted for sex, age, and mental and/or behavioural disorders according to the criteria of the International Statistical Classification of Diseases and Related Health Problems. RESULTS: The bivariate-adjusted odds ratio (95% confidence intervals) for in-patients hospitalised for more than six months was 0.08 (0.01, 0.48) for those who used family washing (p = 0.006) compared with those who used supplier washing. The number of visits per month and family structures before hospitalisation were not significantly associated. CONCLUSION: These results suggest that within a private psychiatric hospital in Japan, family washing is associated with shortened stays and frequency of family visits, while family structure is not associated with these factors.

Generation of resonance-dependent oscillation by mGluR-I activation switches single spiking to bursting in mesencephalic trigeminal sensory neurons.

The primary sensory neurons supplying muscle spindles of jaw-closing muscles are unique in that they have their somata in the mesencephalic trigeminal nucleus (MTN) in the brainstem, thereby receiving various synaptic inputs. MTN neurons display bursting upon activation of glutamatergic synaptic inputs while they faithfully relay respective impulses arising from peripheral sensory organs. The persistent sodium current (IN aP ) is reported to be responsible for both the generation of bursts and the relay of impulses. We addressed how IN aP is controlled either to trigger bursts or to relay respective impulses as single spikes in MTN neurons. Protein kinase C (PKC) activation enhanced IN aP only at low voltages. Spike generation was facilitated by PKC activation at membrane potentials more depolarized than the resting potential. By injection of a ramp current pulse, a burst of spikes was triggered from a depolarized membrane potential whereas its instantaneous spike frequency remained almost constant despite the ramp increases in the current intensity beyond the threshold. A puff application of glutamate preceding the ramp pulse lowered the threshold for evoking bursts by ramp pulses while chelerythrine abolished such effects of glutamate. Dihydroxyphenylglycine, an agonist of mGluR1/5, also caused similar effects, and increased both the frequency and impedance of membrane resonance. Immunohistochemistry revealed that glutamatergic synapses are made onto the stem axons, and that mGluR1/5 and Nav1.6 are co-localized in the stem axon. Taken together, glutamatergic synaptic inputs onto the stem axon may be able to switch the relaying to the bursting mode.

Increased pituitary volume in subjects at risk for psychosis and patients with first-episode schizophrenia.

AIM: Enlarged pituitary gland has been reported in schizophrenia, possibly reflecting hypothalamic-pituitary-adrenal hyperactivity. The aim of the present study was to examine whether individuals at risk of psychosis also have similar changes. METHODS: Magnetic resonance imaging was used to examine the pituitary volume in 22 individuals with at-risk mental state (ARMS; 11 male, 11 female), 64 first-episode patients with schizophrenia (FESz; 37 male, 27 female), and 86 healthy controls. The control subjects were divided into age- and gender-matched controls for ARMS (11 male, 11 female) and FESz (37 male, 27 female). RESULTS: Both the ARMS and FESz groups had a larger pituitary volume compared with matched controls, but no difference was found between the ARMS and FESz subjects. There was no association between the pituitary volume and clinical variables (symptommeasures at scanning, daily dosage or duration of antipsychotic medication) in either clinical group. The pituitary volume did not differ significantly between the ARMS individuals who later developed schizophrenia (n = 5) and those who did not (n = 17). The pituitary volume was larger in women than in men for all diagnostic groups. CONCLUSION: The finding of increased pituitary volume in both ARMS and FESz subjects may reflect a common vulnerability to stress in early psychosis. Further work in a larger ARMS sample is required to examine the possible relationship between pituitary volume and emergence of psychosis.

Reduced white matter fractional anisotropy and clinical symptoms in schizophrenia: a voxel-based diffusion tensor imaging study.

Although not consistently replicated, diffusion tensor imaging (DTI) studies in schizophrenia have revealed lower fractional anisotropy (FA) in various white matter regions, a finding consistent with the disruption of white matter integrity. In this study, we used voxel-based DTI to investigate possible whole-brain differences in the white matter FA values between 58 schizophrenia patients and 58 healthy controls. We also explored the association between FA values and clinical symptoms in schizophrenia. Compared with the controls, the schizophrenia patients showed significant FA reductions in bilateral superior longitudinal fasciculus, bilateral inferior fronto-occipital fasciculus, and genu of right internal capsule. Furthermore, in the patient group, the FA value of the anterior part of the corpus callosum was negatively correlated with the avolition score on the Scale for the Assessment of Negative Symptoms. These findings suggest widespread disruption of white matter integrity in schizophrenia, which could partly explain the severity of negative symptomatology.

Longitudinal MRI study of the pituitary volume in chronic schizophrenia: a preliminary report.

This longitudinal MRI study investigated the pituitary volume in 17 patients with chronic schizophrenia and 17 matched controls. In contrast to previous findings of pituitary expansion during the first episode of schizophrenia, the chronic patients showed non-significant mild pituitary atrophy, suggesting that the pituitary volume changes differently at different illness stages.

[Structural MRI-based classification: possible contributions to clinical diagnosis of schizophrenia].

Magnetic resonance imaging (MRI) is a non-invasive technique which provides with stable and reliable information of brain structure. Although utilizing MRI as an objective biological marker adjunct to clinical information would be useful for better early detection and treatment of schizophrenia, it has not been applied to the clinical diagnosis because of a considerable between-group overlap in each anatomical variable. However a combination of brain anatomical variables or a pattern of disease-related anatomical changes would possibly differentiate patients with schizophrenia from healthy subjects or patients with other psychiatric disorders. In this article, we review several MRI-based classification studies that showed favorable classification accuracy using measures of multiple regions of interest, voxel-based morphometry, and automatically parcellated cortical regions of the entire cerebral cortex.

A Retrospective Study on the Relationship Between Cognitive Function and Social Function in Patients With Schizophrenia.

Background: Social dysfunction is associated with decreased activity, employment difficulties, and poor prognosis in patients with schizophrenia. Cognitive functions, such as attention and processing speed, have been implicated in the social functions of schizophrenia patients; however, the relationship between cognitive functions and social functions remains unclear. Thus, understanding the factors that influence social functioning can aid the development of therapeutic strategies for schizophrenia. Herein, we retrospectively analyzed factors that influence social functioning in patients with schizophrenia. Methods: Patient background, intelligence quotient (IQ) scores, Japanese version of the Brief Assessment of Cognition in Schizophrenia (BACS-J) scores, the dose of antipsychotic drugs, Positive and Negative Syndrome Scale (PANSS) scores, and the factors influencing each subscale of the Japanese version of the Social Functioning Scale (SFS-J) were evaluated using univariate and multivariate analyses. The Bonferroni correction was applied to evaluate the correlation between each factor in the univariate analysis. In multivariate analysis, independent variables were selected using a stepwise method. In each model, considering the sample size, the maximum number of variables extracted using the stepwise method was set to three. We then calculated the standard partial regression coefficient (standard ß) between the SFS-J subscale scores and each factor. Results: Data from 36 patients were analyzed. The average age, illness duration, and total length of hospitalization were 57.8 years, 34.8 years, and 196.7 months, respectively. Of the seven significant correlations with the SFS-J subscale in the univariate analysis, only three were significant in the multivariate analysis model. According to the multivariable model, BACS-J verbal fluency positively correlated with SFS-J withdrawal, interpersonal communication, and employment/occupation. Moreover, BACS-J token motor and educational history were positively correlated with SFS-J recreation and SFS-J employment/occupation, respectively. PANSS scores, IQ scores, and doses of antipsychotic drugs did not show clear associations with SFS-J scores. Conclusions: In conclusion, there were significant correlations between BACS-J subscale scores for cognitive functioning and SFS-J subscale scores for social functioning in patients with schizophrenia.

Alterations in hippocampal subfield volumes among schizophrenia patients, their first-degree relatives and healthy subjects.

Reduced hippocampal volumes feature prominently in schizophrenia patients (SCZ). Although several studies have investigated hippocampal volume alterations between unaffected first-degree relatives (FR) of SCZ and healthy controls (HC), the results were inconsistent. Furthermore, it remains unclear whether FR have specific alterations in hippocampal subfield volumes. Three-Tesla T1-weighted MP-RAGE brain scans were collected from 347 subjects (138 SCZ, 47 FR and 162 HC) and processed using the hippocampal subfields algorithm in FreeSurfer v6.0. We investigated volumetric differences in the twelve hippocampal subfields bilaterally among SCZ, FR and HC. SCZ displayed bilateral reductions in whole hippocampal volume compared with FR and HC. The hippocampal volumes of FR did not differ from those of HC but exceeded those observed in SCZ. We found volumetric differences in specific hippocampal subfields, including the CA1, hippocampal fissure, presubiculum, molecular layer, fimbria and hippocampal-amygdala transitional area, among diagnostic groups. These alterations arose from differences in the hippocampal subfield volumes between SCZ and the other two diagnostic groups. However, right hippocampal fissure volumes linearly increased among the groups. In contrast, no significant volumetric differences were found in other hippocampal subfields between HC and FR. There were no significant intergroup differences in laterality in any hippocampal subfield volumes and no significant correlations between hippocampal subfield volumes and illness duration, psychiatric symptoms, antipsychotics or premorbid IQ in SCZ. Our findings suggest that volumetric alterations in hippocampal subfields (except the hippocampal fissure) in SCZ could be stable phenomena that are present at illness onset and minimally affected by antipsychotics.

Effects of genome-wide neuroticism-associated variants on five-factor model personality traits in schizophrenia.

Patients with schizophrenia (SCZ) have characteristic personality traits compared with healthy subjects. Genome-wide significant variants for neuroticism have been reported in healthy subjects. However, the associations of these genome-wide neuroticism-associated variants with five-factor personality traits in patients with SCZ are less clear. We investigated the influences of nine independent genome-wide significant variants for neuroticism on five-factor personality traits (neuroticism, extraversion, openness, agreeableness, and conscientiousness) assessed by the NEO Five-Factor Inventory (NEO-FFI) in 107 patients with SCZ and 119 healthy controls (HCs). As expected, patients with SCZ scored significantly higher for neuroticism and lower for extraversion, openness, agreeableness and conscientiousness than HCs (p < 0.05). Of nine neuroticism-associated variants, the T allele at rs4653663 related to lower neuroticism was only significantly associated with lower neuroticism in patients with SCZ (ß = -0.27, p = 3.88 × 10-3) and in combined subjects (ß = -0.15, p = 0.026). Furthermore, of other personality traits, the genetic variant was significantly associated with higher agreeableness in combined subjects (ß = 0.17, p = 9.41×10-3), higher conscientiousness in patients with SCZ (ß = 0.21, p = 0.031) and lower conscientiousness in HCs (ß = -0.20, p = 0.034), and nominally associated with higher extraversion in patients with SCZ (ß = 0.18, p = 0.056) and in combined subjects (ß = 0.13, p = 0.051). These outcomes were not affected by clinical variables. We suggest that genome-wide neuroticism-associated variant could be associated with neuroticism as well as other personality traits in schizophrenia.

Superior temporal gyrus volume in antipsychotic-naive people at risk of psychosis.

BACKGROUND: Morphological abnormalities of the superior temporal gyrus have been consistently reported in schizophrenia, but the timing of their occurrence remains unclear. AIMS: To determine whether individuals exhibit superior temporal gyral changes before the onset of psychosis. METHOD: We used magnetic resonance imaging to examine grey matter volumes of the superior temporal gyrus and its subregions (planum polare, Heschl's gyrus, planum temporale, and rostral and caudal regions) in 97 antipsychotic-naive individuals at ultra-high risk of psychosis, of whom 31 subsequently developed psychosis and 66 did not, and 42 controls. RESULTS: Those at risk of psychosis had significantly smaller superior temporal gyri at baseline compared with controls bilaterally, without any prominent subregional effect; however, there was no difference between those who did and did not subsequently develop psychosis. CONCLUSIONS: Our findings indicate that grey matter reductions of the superior temporal gyrus are present before psychosis onset, and are not due to medication, but these baseline changes are not predictive of transition to psychosis.

Superior temporal gyrus volume in teenagers with first-presentation borderline personality disorder.

This magnetic resonance imaging study investigated the superior temporal gyrus (STG) subregion volumes in 20 teenagers with first-presentation borderline personality disorder (BPD) and 20 healthy controls. While the STG volume early in the course of BPD did not differ from that of healthy controls, the BPD participants with violent episodes had a smaller left caudal STG volume compared with those without such episodes during the previous 6 months. Our preliminary findings might reflect the neurobiological heterogeneity of the disorder.

The First Report of Macrolide-Resistant Bordetella pertussis Isolation in Japan.

We report the first detection of a macrolide-resistant Bordetella pertussis strain in Japan. The isolate was highly resistant to the macrolides (minimum inhibitory concentrations for erythromycin and clarithromycin: > 256 µg/ml, for azithromycin: 32 µg/ml) and A2047G mutation was identified in the 23S rRNA. The Multilocus Sequence Typing and Multilocus Variable Number of Tandem Repeat Analysis genotypes of this isolate were MT195 and ptxP1/ptxA1/prn1/fim3A/fhaB3, respectively, suggesting a relationship with the macrolide-resistant B. pertussis lineage currently found in China. This raises the possibility that macrolide-resistant B. pertussis has already fully spread in Japan. For a better control of B. pertussis infections, the surveillance for macrolide-resistant B. pertussis is essential in not only Japan, but also other Asian countries.