Prevalence of possible idiopathic normal pressure hydrocephalus in older inpatients with schizophrenia: a replication study.

BACKGROUND: We recently reported that older patients with schizophrenia (SZ) show possible idiopathic normal pressure hydrocephalus (iNPH) more frequently than the general population. In this study, we estimated the prevalence of iNPH in a larger number of older SZ patients and explored useful examination values for diagnosis in the SZ population. METHODS: We enrolled older inpatients with SZ (n = 39, mean age = 68.6 ± 7.7 years) from several psychiatric hospitals in Ehime, Japan and acquired brain imaging data using computed tomography. We evaluated three iNPH symptoms (dementia, gait disturbance, and urinary incontinence). In addition, we combined these data with our previous data to elucidate the relationship between iNPH and characteristics of SZ symptoms. RESULTS: In total, five (12.8%) patients were diagnosed with possible iNPH. Evans' index for patients with iNPH was significantly higher than for those without iNPH (p = 0.002). The number of disproportionately enlarged subarachnoid space hydrocephalus (DESH) findings was significantly higher in patients with iNPH than in those without iNPH (p <  0.001). Using combined data, Drug-Induced Extra-pyramidal Symptoms Scale (DIEPSS) subscales of gait and bradykinesia showed an increasing trend in the SZ with iNPH group. CONCLUSIONS: We reconfirmed that older inpatients with SZ experienced possible iNPH more frequently than the general population. We should pay attention to the DIEPSS subscales of gait and bradykinesia and DESH findings in addition to the three main symptoms of iNPH and Evans' index so as to not miss SZ patients with iNPH.

Distribution of D-3-aminoisobutyrate-pyruvate aminotransferase in the rat brain.

BACKGROUND: D-3-aminoisobutyrate, an intermediary product of thymine, is converted to 2-methyl-3-oxopropanoate using pyruvate as an amino acceptor by D-3-aminoisobutyrate-pyruvate aminotransferase (D-AIB AT; EC 2.6.1.40). A large amount of D-AIB AT is distributed in the kidney and liver; however, small amounts are found in the brain. Recently, D-AIB AT was reported to metabolize asymmetric dimethylarginine (ADMA) in vivo and was suggested to be an important enzyme for nitric oxide metabolism because ADMA is a competitive inhibitor for nitric oxide synthase. In this study, we examined the distribution of D-AIB AT in the rat brain further to understand its role. We measured D-AIB AT mRNA and protein expression using quantitative RT-PCR and Western blotting, and monitored its distribution using immunohistochemical staining. RESULTS: D-AIB AT was distributed throughout the brain, with high expression in the cortex and hippocampus. Immunohistochemical staining revealed that D-AIB AT was highly expressed in the retrosplenial cortex and in hippocampal neurons. CONCLUSION: Our results suggest that D-AIB AT is distributed in the examined- just the regions and may play an important role there.

Linking lifestyle factors and insulin resistance, based on fasting plasma insulin and HOMA-IR in middle-aged Japanese men: a cross-sectional study.

OBJECTIVE: Insulin resistance (IR) is regarded as one of the earliest features of many metabolic diseases, and major efforts are aimed at improving insulin function to confront this issue. The aim of this study was to investigate the relationship of body mass index (BMI), cigarette smoking, alcohol intake, physical activity, green tea and coffee consumption to IR. METHODS: We performed a cross-sectional study of 1542 male self defense officials. IR was defined as the highest quartile of the fasting plasma insulin (≥ 50 pmol/L) or the homeostasis model assessment-estimated IR (HOMA-IR ≥ 1.81). An unconditional logistic model was used to estimate the odds ratio (OR) and 95% confidence interval (CI) for the association between IR and influential factors. Stratified analysis by obesity status (BMI < 25 kg/m(2), non-obese; ≥ 25 kg/m(2), obese) was performed. RESULTS: IR was significantly positively related to BMI and glucose tolerance, negatively related to alcohol use. Independent of obesity status, significant trends were observed between IR and alcohol use. Drinking 30 mL or more of ethanol per day reduced IR by less than 40%. Strong physical activity was associated with decreased risk of IR based on fasting plasma insulin only in the obese. Coffee consumption was inversely associated with the risk of IR based on HOMA-IR in the non-obese group. CONCLUSION: Higher coffee consumption may be protective against IR among only the non-obese. Further studies are warranted to examine the effect modification of the obesity status on the coffee-IR association.

[A case report of early-onset Alzheimer's disease with multiple psychotic symptoms, finally diagnosed as APPV717I mutation by genetic testing].

It is difficult to confirm a diagnosis of early-onset Alzheimer's disease (EOAD) because patients sometimes have non-specific cortical features, such as psychiatric symptoms, executive functional impairment, and pyramidal symptoms, along with typical symptoms, such as recent memory impairment and disorientation. We encountered a patient with multiple psychotic symptoms, finally diagnosed with EOAD on genetic testing. A right-handed sixty-year-old man, whose mother was suspected of having dementia, developed memory impairment at the age of fifty, disorientation at the age of fifty-six, and both visual hallucination and dressing apraxia at the age of fifty-nine. After admission to a psychiatric hospital for treatment, his symptoms disappeared with antipsychotic medication. However, his ADL were declining and so he was referred to our university hospital. He had frontal lobe symptoms, pyramidal signs, and extrapyramidal signs with severe dementia. Neuropsychological examinations were not possible because of sedation. On brain MRI, he showed diffuse atrophy of the cerebral cortex and hippocampus. HMPO-SPECT showed hypoperfusion of cerebral cortices diffusely. We decided to perform genetic testing because he had both family and alcohol abuse histories. He showed EOAD with V717I mutation of the amyloid precursor protein gene. After the discontinuation of antipsychotics, excessive sedation and extrapyramidal signs disappeared. A dose of 10 mg of donepezil was effective to improve motivation and activity, and his mini mental examination score was calculable after recovery. The case supports usefulness of applying genetic testing for Alzheimer's disease to patients with early onset dementia, even when they do not have a family history.

Phenotypical difference of amyloid precursor protein (APP) V717L mutation in Japanese family.

BACKGROUND: Alzheimer's disease (AD) is the most common form of dementia. Mutations in genes such as those encoding amyloid precursor protein (APP), presenilin 1 and presenilin 2, are responsible for early-onset familial AD. CASE PRESENTATION: In this study, we report a 275341 G > C (Val717Leu) mutation in the APP gene in a Japanese family with early onset AD by genetic screening. This mutation has previously been detected in European families. In the Japanese family we screened, the age at onset of AD was 47.1 ± 3.1 years old (n = 9; range, 42-52). The symptoms in the affected members included psychiatric vulnerability and focal signs such as pyramidal signs, epileptic seizures, and myoclonic discharges. An MR imaging study showed relatively mild atrophic changes in the bilateral hippocampus and cerebral cortices in all affected members compared with their clinical presentations. CONCLUSION: We conclude that the clinical features of Alzheimer's disease can be different even when caused by the same mutation in the APP gene. Further clinical and genetic studies are required to clarify the relationship between phenotypes and genotypes.

Antidepressant action via the nitric oxide system: A pilot study in an acute depressive model induced by arginin.

Nitric oxide (NO) may be a neurotransmitter related to major depressive disorder (MDD) because the selective neuronal NO synthase (NOS) inhibitor, 7-nitroindazole, induces dose-dependent antidepressant-like effects. However, its role in MDD is not yet known. The purpose of our study was to determine if antidepressants improve depression via the NO pathway using an acute depressive rat model induced by L-arginine (AR). Three types of antidepressants were examined, fluoxetine (FLX, 10 mg/kg), milnacipran (MIL, 30 mg/kg), and mirtazapine (MIR, 10 mg/kg), in a depressive model that used AR (750 mg/kg) pretreatment. mRNA expression levels of three NOS subtypes were analyzed by real-time PCR, as well as serum NO levels. Significant increases in iNOS mRNA expression levels were found in brain regions after AR treatment, although the eNOS gene tended to decrease with AR injection. After antidepressant treatment, there were no mRNA expression changes in either nNOS or iNOS. However, eNOS mRNA expression significantly increased with FLX (cerebellum, P=0.011; hippocampus, P=0.011; midbrain, P=0.011; pons, P=0.013; striatum, P=0.011; and thalamus, P<0.001). There was a statistically significant increase in serum NO levels with MIL treatment (P=0.011). We conclude that changes in eNOS mRNA levels in the brain with FLX treatment, and amount of serum NO with MIL treatment may be related to antidepressant effects of both agents, but further experiments are needed to confirm involvement of the NO system in MDD.

TREM2 mRNA Expression in Leukocytes Is Increased in Alzheimer's Disease and Schizophrenia.

UNLABELLED: TREM2 and TYROBP are causal genes for Nasu-Hakola disease (NHD), a rare autosomal recessive disease characterized by bone lesions and early-onset progressive dementia. TREM2 forms a receptor signaling complex with TYROBP, which triggers the activation of immune responses in macrophages and dendritic cells, and the functional polymorphism of TREM2 is reported to be associated with neurodegenerative disorders such as Alzheimer's disease (AD). The objective of this study was to reveal the involvement of TYROBP and TREM2 in the pathophysiology of AD and schizophrenia. METHODS: We investigated the mRNA expression level of the 2 genes in leukocytes of 26 patients with AD and 24 with schizophrenia in comparison with age-matched controls. Moreover, we performed gene association analysis between these 2 genes and schizophrenia. RESULTS: No differences were found in TYROBP mRNA expression in patients with AD and schizophrenia; however, TREM2 mRNA expression was increased in patients with AD and schizophrenia compared with controls (P < 0.001). There were no genetic associations of either gene with schizophrenia in Japanese patients. CONCLUSION: TREM2 expression in leukocytes is elevated not only in AD but also in schizophrenia. Inflammatory processes involving TREM2 may occur in schizophrenia, as observed in neurocognitive disorders such as AD. TREM2 expression in leukocytes may be a novel biomarker for neurological and psychiatric disorders.

[Preliminary study on measurement of human fecundity applicability of time to pregnancy with Japanese subjects].

BACKGROUND: Debate has been continuing whether endocrine disrupting chemicals (EDC) in the environment affect human reproduction. We are planning to use time to pregnancy (TTP) as a measure of human fecundity to relate EDC exposure in a future research. TTP is expressed as the number of non-contracepting menstrual cycles or months required for a couple to conceive. An extended TTP might be considered to reflect an injury to reproductive processes. Since this parameter has never been measured in Japan. the present preliminary study aimed at establishing a Japanese version of the TTP questionnaire and determining if TTP could be reliably measured in Japan. METHODS: We prepared a self-administered questionnaire that consisted of questions on TTP, sexual life and dietary habits. Women who visited a gynecology clinic in Tokyo for confirmation of pregnancy during the period October 2000 to March 2001 were the subjects asked to fill in the questionnaire. The results were statistically analyzed by chi-square test, t-test and binorminal logistic model after classifying the subjects into two groups: (a) Group I (TTP < or = 6 months; n = 53) (b) Group II (TTP > 6 months; n = 16) RESULTS: Of the 92 women approached, 69 (75.0%) could report TTP. The distribution of TTP, the mode being around 1-2 months with a positive skew toward longer value, was similar to those reported so far in Western countries. There were statistically significantly more smokers in Group II (smoker 62.5%) than in I (15.6%). Logistic regression analysis indicated prior gravidity and fish and milk consumption, in addition to cigarette smoking, to be related to TTP. CONCLUSIONS: The present preliminary study indicated that TTP surveys are feasible with Japanese based on the high response rate and plausible distribution of reported value. It also indicated that TTP was related to cigarette smoking, gravidity and dietary habits, again consistent with previous studies.

Missense variants of the alanine:glyoxylate aminotransferase 2 gene are not associated with Japanese schizophrenia patients.

Alanine:glyoxylate aminotransferase 2 (AGXT2) is the only enzyme that degrades D-3-aminoisobutyrate (D-AIB), which is an intermediate product of thymine, and 30-40% of Japanese lack AGXT2 activity genetically and excrete high amounts of D-AIB in their urine. Recently, AGXT2 is reported to metabolize asymmetric dimethyl arginine (ADMA), a competitive inhibitor of nitric oxide (NO) synthase. Since AGXT2 is expressed in the central nervous system, the loss of AGXT2 activity will be related to the vulnerability for neuropsychiatric disorders related to the NO system. In this study, we recruited 85 Japanese subjects to discover loss variants of the AGXT2 gene with the amount of D-AIB excretion in their urine. From the statistical relevance between them, we found three missense polymorphisms (rs37370, rs37369, and rs180749) independently related to AGXT2 activity (P<0.0001). Then, we performed a case-control association analysis of its missense polymorphisms with 1136 schizophrenia and 1908 control subjects because the NO system may be involved in the vulnerability of schizophrenia processes. We could not find any associations of three functional SNPs with schizophrenia pathogenesis in the analyses of either genotypic or allelic models. We concluded that the AGXT2 gene is not associated with schizophrenia in Japanese subjects.

The nicotinic cholinergic system is affected in rats with delayed carbon monoxide encephalopathy.

Delayed carbon monoxide (CO) encephalopathy may occur following recovery from acute CO poisoning. However, the mechanism of delayed neuronal injury remains unknown. The nicotinic acetylcholine receptors (nAChRs) have been suggested to play a role in cognitive status in neurodegenerative diseases, including Alzheimer's disease. Therefore, in the current study, we investigated the effect of delayed neuronal CO poisoning on gene expression of nAChRs in the hippocampus of Wistar rats. Behavioral effects (measured by the passive-avoidance test) and histological analyses (hematoxylin-eosin-stained hippocampal cell counts and cell death observations) were also investigated, 21 days after CO exposure for 1h (1000ppm for 40min+3000ppm for 20min). Our findings show cognitive impairment and hippocampal cell death, suggesting our rat model is suitable for studying delayed CO encephalopathy. Expression of nAChR (Chrna3, Chrna4, Chnra7, and Chrnb2) mRNA was assessed using quantitative real-time polymerase chain reaction. Hippocampal Chrna3 expression was significantly decreased, and cerebellar Chrna7 expression significantly increased, in the delayed CO encephalopathy rat model. Thus, the nicotinic cholinergic system may be affected in delayed CO encephalopathy.

Different actions for acute and chronic administration of mirtazapine on serotonergic transmission associated with raphe nuclei and their innervation cortical regions.

The atypical antidepressant, mirtazapine enhances noradrenergic transmission, but its effects on serotonergic transmission remain to be clarified. The present study determined the effects of acute and chronic administration of mirtazapine on serotonergic transmissions in raphe nuclei and their innervation regions, frontal and entorhinal cortex, using multiple-probes microdialysis with real-time PCR and western blotting. Acute administration of mirtazapine did not affect extracellular serotonin level in raphe nuclei or cortex; however, chronic administration increased extracellular serotonin level in raphe nuclei without affecting that in cortex. Blockade of 5-HT1A receptor, but not that of the 5-HT2A/2C receptor, enhanced the effects of acute administration of mirtazapine on extracellular serotonin level in raphe nuclei. Chronic mirtazapine administration reduced the inhibitory function associated with somatodendritic 5-HT1A receptor in raphe nuclei, but enhanced postsynaptic 5-HT1A receptor in serotonergic innervated cortical regions. Chronic administration reduced the expression of mRNA and protein of serotonin transporter and 5-HT1A receptor in raphe nuclei, but not in the cortices. These results suggested that acute administration of mirtazapine probably activated serotonergic transmission, but its stimulatory action was abolished by activated inhibitory 5-HT1A receptor. Chronic administration of mirtazapine resulted in increased extracellular serotonin level via reduction of serotonin transporter with reduction of somatodendritic 5-HT1A autoreceptor function in raphe nuclei. These pharmacological actions of mirtazapine include its serotonergic profiles as noradrenergic and specific serotonergic antidepressant (NaSSA).

A case study: neuroleptic malignant syndrome with risperidone and CYP2D6 gene variation.

We present a schizophrenic patient who experienced neuroleptic malignant syndrome with risperidone treatment due to variants of the CYP2D6 gene with reduced function. Clinicians need to be aware of this potential complication.