Hiroyasu Shiraishi

Central nervous system changes in mitochondrial encephalomyopathy: light and electron microscopic study

SummaryAn autopsy case of mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) is reported. It presented with generalized muscle atrophy, stroke-like episodes, schizophrenia-like mental disorder and progressive dementia. Serum lactate and pyruvate levels were high. In the biopsied muscles, ragged-red fibers were observed by light microscopy and aggregation of abnormal mitochondria with paracrystaline formation by electron microscopy. The most characteristic neuropathological findings were infarct-like lesions widespread in the cerebral cortex. In addition, this case showed some unusual pathological features: (1) diffuse moderate fibrillary gliosis in the whole cerebral and cerebellar white matter, which might have been due to metabolic disturbances; (2) several focal lesions with demyelination and numerous spheroids in the pontocerebellar fibers; and (3) marked degeneration of the posterior columns and spinocerebellar tracts. Electron microscopic examination revealed that abnormal mitochondria were markedly aggregated in smooth muscle cells and endothelium of the cerebral and cerebellar blood vessels. These fine structural findings suggest a “mitochondrial angiopathy”.

Signal Hyperintensities on Brain Magnetic Resonance Imaging in Elderly Depressed Patients

In a retrospective brain magnetic resonance imaging study, we evaluated the prevalence and severity of signal hyperintensities in 30 elderly depressed patients and 30 controls matched for age, sex and cerebrovascular risk factors. A semiquantitative scoring method was used to grade findings in T2-weighted and proton density images. The elderly depressed patients had more extended periventricular hyperintensities, especially in the frontal region (depressed vs. control, 87 vs. 57%, p < 0.05), pons (33 vs. 7%, p < 0.05) as well as hyperintensities in the putamen and globus pallidus (57 vs. 27%, p < 0.05). The third ventricle was more dilated in depressed patients than controls after adjustment for age and cerebrovascular risk factors. The global index for ventricular enlargement was correlated significantly (r = 0.36, p < 0.05) with the severity of the hyperintensity in depressed patients. Our results indicate that these hyperintensities, especially in the frontal region, pons and lenticular nuclei, and the dilatation of the third ventricle play an important role, through the frontal-subcortical circuits, in mood regulation of elderly depressed patients.

Immunohistochemical localization of γ-aminobutyric acidB receptor in the hippocampus of subjects with schizophrenia

Recent studies have demonstrated the involvements of gamma-aminobutyric acid (GABA) neurotransmitter systems in the schizophrenic brain. In order to further elucidate the alterations of this system in schizophrenia, we employed immunohistochemical techniques and examined the expression and anatomical distribution of the GABA(B) receptor in the hippocampus of five subjects with schizophrenia and three age-matched controls. In the control hippocampus, the most intense immunoreactivity was observed in the soma and processes of multipolar interneurons throughout the hippocampus. Pyramidal cells too were intensely labeled in their soma and proximal portion of dendrites, although the labeling intensity was varied in each subregion. For example, in the CA1 subfield, the labeling intensity of pyramidal cells was much less intense than that in the CA3 and CA2 subfields. In the subjects with schizophrenia, GABA(B) immunoreactivity was markedly reduced in granule cells as well as in pyramidal cells throughout the CA fields. In interneurons, GABA(B) labeling was relatively preserved compared to that in pyramidal cells. Our findings suggest that in the hippocampus of schizophrenic patients the expression of the GABA(B) receptor is reduced, and raise the possibility that this reduction contributes to the pathophysiological process in the schizophrenic brain.

Effects of chronic administration of interferon α A/D on serotonergic receptors in rat brain

The effects of chronic administration of interferon (IFN; recombinant human IFN -αA/D) on serotonergic binding sites in rat brain were investigated. IFN was injected daily for 2 weeks at a dose of 100000 I.U./kg, (i.p.) in male Wistar rats. IFN did not alter either [3H]ketanserin binding to 5-HT2A receptors or [3H]paroxetine binding to 5-HT transporters. Scatchard analysis of [3H]8-hydroxy-dipropylaminotetraline (8-OH-DPAT) binding to 5-HT1A receptors demonstrated the presence of high- and low-affinity binding sites in both treatment and control groups. IFN significantly increased both Kd and Bmax measures of [3H]8-OH-DPAT binding at low-affinity binding sites, but not at the high-affinity sites. These results suggest that IFN affects the low-affinity 5-HT1A receptors sites and may be involved in the development of IFN-induced psychiatric disturbances.

Quantitative regional cerebral blood flow measured by Tc-99m HMPAO SPECT in mood disorder

Abstract Depressed (n = 14) and remitted (n = 9) patients with mood disorder, patients with depressive disorder not otherwise specified (NOS; n = 10) and normal subjects (n = 8) underwent non-invasive and quantitative measurement of cerebral blood flow using HMPAO and SPECT in a resting state. The mean and regional cerebral blood flow (CBF) in twelve ROIs were compared among the four groups and correlations between CBF and the depressive symptoms were studied. The CBF was computed using graphical analysis on the SPECT console after a bolus injection of Tc-99m HMPAO and radionuclide angiography. The depressed group had significantly lower mCBF in the bilateral hemisphere and rCBF in all except one of the ROIs that the NOS and normal group. Significant negative correlations were found between the Hamilton scale for depression and rCBF in the bilateral lower frontal cortex after correcting for age in the mood disorder. Parallel analysis using both the quantitative and semiquantitative methods revealed that the former provided more global reduction of CBF in mood disorder. These results indicate that mean and regional CBF measured by this non-invasive method contributes to the objective evaluation of depressive symptoms. Negative correlations between HRSD and rCBF in the frontal regions indicate that frontal hypoactivity is closely related to depressive symptoms.

Parental representation in eating disorder patients with suicide

OBJECTIVE We examined parental, personality, and symptomatological characteristics in relation to suicide attempts among eating disorder patients. METHODS Fifty-one eating disorder inpatients, divided into two groups according to lifetime suicide attempts, and 107 non-psychiatric subjects were compared on the following variables: Parental Bonding Instrument (PBI), Global Clinical Score (GCS), Eating Disorder Inventory-91 (EDI-91), Eating Attitudes Test-26 (EAT), clinical and personality characteristics, and family backgrounds. RESULTS Suicidal patients reported significantly higher overprotection by both parents than non-suicidal patients and non-psychiatric subjects. Suicidal patients had a more prevalent history of child abuse, affective instability, unstable self-image, avoidance of abandonment, maladaptive perfectionism, personality disorder, and mood disorder. There were no differences in symptomatological factors or the severity of the eating disorders. CONCLUSION The results suggest that high overprotection is associated with suicidal behaviour in eating disorder patients. The association between overprotective parenting and personality characteristics, and methods of suicide prevention are discussed briefly.

European Pentoxifylline Multi-Infarct Dementia Study

A double-blind, placebo-controlled, parallel-group, multicentre study was conducted to evaluate the efficacy of pentoxifylline (Trental) in patients with multi-infarct dementia (MID) according to DSM-III-R criteria. Men and women aged 45 years or older, with a Hachinski Ischemia Scale score > or = 7 and a Mini Mental State Examination (MMSE) score of 10-25 at entry, and computed tomographic evidence of vascular disease were enrolled. A total of 289 patients were randomised to receive either oral pentoxifylline 400 mg t.i.d. or placebo for 9 months, and efficacy was assessed every 3 months. The primary outcome variable was the difference in scores between the two treatment groups, as measured on the Gottfries, Bråne, Steen (GBS) scale. Secondary outcome variables included the scores achieved on the Sandoz Clinical Assessment Geriatric (SCAG) scale and MMSE, and a battery of psychological and other tests. The intention-to-treat analysis for patients completing the study (n = 239) showed a statistically significant difference in the total GBS score in favour of pentoxifylline (improvement of 3.5 points, p = 0.028). A significant difference in the total GBS score in favour of pentoxifylline was even almost achieved in the intention-to-treat analysis for all evaluable patients (n = 269, improvement of 2.1 points, p = 0.065). It is concluded that treatment with pentoxifylline is beneficial for patients with MID, the global results of the GBS and SCAG scales being reinforced by significant improvements in those subscales specific for intellectual and cognitive function.

Mitochondrial encephalomyopathy (MELAS) with mental disorder

SummaryA case of mitochondrial encephalomyopathy (MELAS) with mental disorder is reported. The SPECT study using123I-iodoamphetamine (IMP) and MRI study revealed abnormality in the left parieto-occipital areas without abnormality in the brain CT or brain scintigram. These findings suggest a localized dysfunction of the brain capillary endothelium in association with the cerebral involvement of mitochondrial encephalomyopathy.

Effects of cocaine administration on receptor binding and subunits mRNA of GABAA‐benzodiazepine receptor complexes

The effects of intermittent intraperitoneal (i.p.) administration of cocaine (20 mg/kg) on GABAA‐benzodiazepine (BZD) receptors labeled by t‐[35S]butylbicyclophosphorothionate (TBPS), and on several types of mRNA subunits were investigated in rat brain by in vitro quantitative receptor autoradiography and in situ hybridization. Phosphor screen imaging with high sensitivity and a wide linear range of response was utilized for imaging analysis. There was a significant decrease in the level of α1, α6, β2, β3, and γ2 subunits mRNA, with no alteration of [35S]TBPS binding in any regions in the brain of rats at 1 h following a single injection of cocaine. In chronically treated animals, the mean scores of stereotyped behavior were increased with the number of injections. The level of β3 subunit mRNA was decreased in the cortices and caudate putamen, at 24 h after a final injection of chronic administrations for 14 days. In the withdrawal from cocaine, the frontal cortex and hippocampal complexes showed a significant increase in [35S]TBPS binding and α1 and β3 subunit mRNA in the rats 1 week after a cessation of chronic administration of cocaine. These findings suggest that the disruption of GABAA‐BZD receptor formation is closely involved in the development of cocaine‐related behavioral disturbances. Further studies on the physiological functions on GABAA‐BZD receptor complex will be necessary for an explanation of the precise mechanisms underlying the acute effects, development of hypersensitization, and withdrawal state of cocaine. Synapse 38:198–215, 2000.

Novel variants in the promoter region of the CREB gene in schizophrenic patients

AbstractCyclic AMP-responsive element-binding protein (CREB) is one of the messenger molecules involved in intracellular signal transduction pathways used by most dopamine and serotonin receptor subtypes. In addition, CREB stimulates the expression of a number of genes, alterations in the expression of which may be associated with schizophrenia. The promoter region of the human CREB gene was therefore analyzed to identify genetic variants that may lead to the modification of CREB expression and contribute to schizophrenia. Eighty unrelated schizophrenics and 100 healthy controls were screened for genetic variants of the CREB gene by SSCP analysis, followed by direct sequencing of PCR products. Two novel variants (−933T→C and −413G→A) were found only in schizophrenics. A patient with the −933T→C variant had unusual clinical characteristics in addition to typical schizophrenic symptoms.