Yoshifumi Koshino

Apoptosis of astrocytes with enhanced lysosomal activity and oligodendrocytes in white matter lesions in Alzheimer's disease.

Cerebral white matter lesions in Alzheimers disease (AD) consist of subcortical degeneration and ischaemic–hypoxic changes. Glial changes are intimately associated with the white matter lesions, and regressive changes in astrocytes and loss of oligodendroglial cells have been reported. We quantitatively compared glial changes including apoptosis and enhanced lysosomal activity in the frontal and temporal white matter by using terminal dUTP nick end labelling (TUNEL) and immunohistochemistry for glial markers, lysosomes and apoptosis‐regulating proteins in non‐familial AD brains. The degree of myelin pallor and axonal loss varied considerably in both the frontal and temporal white matter but fibrillary gliosis in demyelinated lesions tended to be less prominent in the temporal white matter in AD cases. A morphometric study with planimetric methods for cross‐sectional areas of frontal and temporal white matter revealed that the white matter of AD cases manifested atrophy with significant reduction in frontal (11.9%) and temporal (29.4%) white matter compared to normal controls. Double immunolabelling for glial fibrillary acidic protein (GFAP) and KP1 (CD68) revealed KP1‐positive fragmented structures within the weakly GFAP‐labelled astrocytes. These KP1‐positive structures correspond to process fragmentation and cytoplasmic vacuoles, which in turn indicate enhanced lysosomal activity during regressive changes in astrocytes. The KP1‐modified astrocytes were not found in Picks disease and corticobasal degeneration. The density of apoptotic glial cells, largely oligodendroglial, was significantly higher in the temporal than in the frontal white matter, and most GFAP‐positive astrocytes with regressive changes were apoptotic. GFAP‐positive astrocyte density was statistically the same in the frontal and temporal white matter, but the density of KP1‐modified astrocytes was higher in the temporal than in the frontal white matter. The rate of white matter shrinkage was significantly correlated with the density of apoptotic glial cells and the density of KP1‐modified astrocytes in the temporal lobe in AD cases. An increase in apoptotic glial cell density was found to contribute to GFAP‐positive astrocytes with regressive changes in temporal white matter, while apoptosis of vascular smooth muscle cells did not show topographical accentuation. Astrocytes labelled with beta amyloid protein were not apoptotic, and the density of apoptotic cells labelled with CD95 and caspase‐3 was too low in both types of white matter to be statistically evaluated. Our results imply that regressive changes in astrocytes and glial apoptosis are, to some extent, associated with white matter lesions, particularly of the temporal lobe in AD brains. The presence of apoptotic astrocytes with evidence of regressive change could therefore be a histological hallmark for white matter degeneration in AD.

Reduced Interhemispheric EEG Coherence in Alzheimer Disease: Analysis During Rest and Photic Stimulation

The present study was conducted to examine interhemispheric electroencephalogram (EEG) coherence at rest and during photic stimulation (5, 10, and 15 Hz) in 10 patients with presenile dementia of the Alzheimer type (AD; mean age at onset, 56 years) and 10 sex- and age-matched control subjects. Compared with the control subjects, the AD patients had significantly lower interhemispheric coherence in the resting EEG for the delta, theta-2, alpha, and beta-1 frequency bands. EEG analysis during photic stimulation also showed that the patients had significantly lower coherence, irrespective of the stimulus frequency. In addition, when we examined the changes in coherence from the resting state to the stimulus condition (i.e., coherence reactivity), significant group differences were found at the brain region primarily involved in visual functioning; the patients had significantly smaller coherence reactivity to photic stimulation at 5 and 15 Hz over the posterior regions. These findings suggest that AD patients have an impairment of interhemispheric functional connectivity in both nonstimulus and stimulus conditions. The findings also suggest a failure of normal stimulation-related brain activation in AD.

P300 and the thought disorder factor extracted by factor-analytic procedures in schizophrenia

BACKGROUND In order to clarify the clinical significance of P300 as a biologic marker that can reflect schizophrenic symptomatology, many previous studies have evaluated the relationship of P300 with the symptoms on the basis of a positive/negative dichotomy, but yielded inconsistent conclusions. Such a dichotomy has been criticized as being too reductionistic. Recently, most studies with factor-analytic procedures have extracted some symptom factors outside this dichotomy. Therefore, it is important to examine associations of P300 with the symptom factors extracted by these statistical analyses. METHODS In the present study, the amplitudes of P300 were measured by using an auditory oddball paradigm for 73 schizophrenics whose psychopathology was assessed with the Positive and Negative Syndrome Scale (PANSS). RESULTS The principal component analysis of the PANSS items revealed five factors labeled the thought disorder, negative, hostile/excitable, delusional/hallucinatory, and depressive factors. The score for the thought disorder factor correlated negatively with the amplitude of P300 recorded at Pz T5, and T6, but that for the other factors did not. CONCLUSIONS These findings suggest that the reduction of P300 amplitudes recorded at the midline parietal and bilateral temporoparietal regions may be one of the electrophysiologic indices representing the thought disorder clinically observed in schizophrenia.

Quantitative EEG in never-treated schizophrenic patients

To clarify whether patients with schizophrenia still show EEG slowing in the absence of psychopharmacological treatment, EEG was analyzed in 20 acute never-treated schizophrenics and 20 age-matched healthy controls using the computerized wave-form recognition method. Compared to controls, schizophrenics had more fast theta (6-8 Hz) and slow alpha (8-9 Hz) activity, and less fast alpha activity (9-13 Hz). The average EEG frequency at O1 correlated negatively with total and positive symptom scores on the BPRS in the schizophrenic group. These findings confirm that the frequency of alpha rhythm is slowed in schizophrenia and that this slowing is possibly related to the expression of psychopathology in this disorder.

Role of serotonin receptor subtypes in the development of amygdaloid kindling in rats.

The present study was conducted to identify serotonin (5-HT) receptor subtypes involved in the development of amygdala (AM) kindling. We used 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), a 5-HT1A agonist, and 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), a 5-HT2 agonist, both of which were injected subcutaneously 15 min prior to each daily electrical stimulation to the rat AM. Treatment with 8-OH-DPAT (1 mg/kg) slightly suppressed behavioral and electrographic seizure development during the course of kindling. In contrast, DOI (1 mg/kg) strongly facilitated kindling development and reduced the number of stimulations needed to produce generalized seizures. These facilitatory effects of DOI were completely blocked by pretreatment with a 5-HT2 antagonist ketanserin. The present results suggest that the activation of 5-HT1A receptors can retard the development of AM kindling, whereas 5-HT2 receptors play a facilitatory role in this developmental seizure process.

Reduced auditory P300 amplitude, medial temporal volume reduction and psychopathology in schizophrenia

Twenty-five schizophrenic patients diagnosed by DSM-III-R underwent event-related potentials and magnetic resonance imaging scans. Latency and amplitude of P300 waveform were measured using an auditory odd-ball paradigm. Anterior and posterior volumes of the superior temporal gyrus and medial temporal structure were measured from contiguous coronal images using the level of the mammillary body as an anatomical landmark. Principal component analysis of P300 latency and amplitude disclosed two orthogonal independent factors each: overall latency and residual, and amplitudes from posterior and anterior recordings, respectively. Structural volumes consisted of four orthogonally independent factors: left superior temporal volume, anterior medial temporal volume, right superior temporal volume, and posterior medial temporal volume. The factor score of the P300 amplitude from posterior recordings correlated with the factor score of volumetric changes in the anterior medial temporal structures. The present study failed to replicate a previously reported association between auditory P300 amplitude and superior temporal volume. Furthermore, the factor score of the P300 amplitude was correlated with the severity of clinical ratings of attentional impairments and positive thought disorder. These findings demonstrate that the information processing dysfunction of schizophrenia indicated by reduced P300 amplitude is associated with structural abnormality in the medial temporal lobe.

Native EEG and treatment effects in neuroleptic-naïve schizophrenic patients: time and frequency domain approaches.

Time domain analysis of electroencephalography (EEG) can identify subsecond periods of quasi-stable brain states. These so-called microstates assumingly correspond to basic units of cognition and emotion. On the other hand, Global Field Synchronization (GFS) is a frequency domain measure to estimate functional synchronization of brain processes on a global level for each EEG frequency band [Koenig, T., Lehmann, D., Saito, N., Kuginuki, T., Kinoshita, T., Koukkou, M., 2001. Decreased functional connectivity of EEG theta-frequency activity in first-episode, neuroleptic-naive patients with schizophrenia: preliminary results. Schizophr Res. 50, 55-60.]. Using these time and frequency domain analyzes, several previous studies reported shortened microstate duration in specific microstate classes and decreased GFS in theta band in drug naïve schizophrenia compared to controls. The purpose of this study was to investigate changes of these EEG parameters after drug treatment in drug naïve schizophrenia. EEG analysis was performed in 21 drug-naive patients and 21 healthy controls. 14 patients were reevaluated 2-8 weeks (mean 4.3) after the initiation of drug administration. The results extended findings of treatment effect on brain functions in schizophrenia, and imply that shortened duration of specific microstate classes seems a state marker especially in patients with later neuroleptic responsive, while lower theta GFS seems a state-related phenomenon and that higher gamma GFS is a trait like phenomenon.

Abnormal functional connectivity in Alzheimer's disease: intrahemispheric EEG coherence during rest and photic stimulation.

Abstract Electroencephalography (EEG) coherence provides a measure of functional correlations between two EEG signals. The present study was conducted to examine intrahemispheric EEG coherence at rest and during photic stimulation (PS; 5, 10 and 15 Hz) in ten unmedicated patients with presenile dementia of the Alzheimer type (AD; mean age at onset 56 years). In the resting EEG, the AD patients had significantly lower coherence than gender- and age-matched control subjects in the alpha-1, alpha-2 and beta-1 frequency bands. The EEG analysis during PS also showed that the patients had significantly lower coherence in the frequency corresponding to PS at 10 and 15 Hz. In this study, the changes in coherence from the resting state to the stimulus condition (i.e. PS-related coherence reactivity) were examined. The patients were found to show significantly smaller coherence reactivity to PS at 5 and 15 Hz. These findings suggest that, in addition to the resting state, AD patients have an impairment of intrahemispheric functional connectivity during PS. They also suggest that AD shows a failure of PS-related functional reorganization.

EPWORTH SLEEPINESS SCALE AND SLEEP STUDIES IN PATIENTS WITH OBSTRUCTIVE SLEEP APNEA SYNDROME

Excessive daytime sleepiness (EDS) is the major symptom of patients with obstructive sleep apnea syndrome (OSAS). In this study, we examined the relationship between subjective EDS scored with the Epworth Sleepiness Scale (ESS), objective EDS measured with the multiple sleep latency test (MSLT) and sleep variables evaluated with polysomnography for patients with OSAS. Subjects were 10 patients (51.7 ± 19.0 years old). The average ESS and MSLT scores were 10.6 ± 5.6 and 7.7 ± 5.6, respectively. There was no significant relationship between ESS and MSLT. The Multiple Sleep Latency Test had a significant negative relationship with the number of awakenings and the apnea/hypopnea index. No relationship was found between nocturnal hypoxia and either ESS or MSLT. Our findings suggest that objective EDS in OSAS is related with fragmentation of sleep, and that several patients are not aware of their EDS.

Association of phosphorylation site of tau protein with neuronal apoptosis in Alzheimer's disease

In addition to neuritic changes and amyloid deposits, neuronal and glial cell apoptosis is an important pathological feature of Alzheimers disease (AD). Several factors have been postulated as causes or triggers of cellular apoptotic change. This study focused on a quantifiable relationship between phosphorylation sites of tau protein in the neurofibrillary tangles (NFT) and neuronal apoptosis. Five monoclonal anti-tau antibodies (AT180, AT8, HT7, Tau2 and Tau5) for NFT labeling and TdT-mediated UTP nick-end labeling (TUNEL) for localizing apoptotic change were employed. TUNEL-stained neuronal nuclei showed significantly high density in the entorhinal cortex, cornu ammonis (CA) and the parietal cortex. In all regions, density of TUNEL-stained neuronal nuclei showed significantly direct correlation with that of AT8-, AT180- and Tau2-positive neurons. Correlation of TUNEL-stained neuronal nuclei with tau-positive neurons differed depending on the cerebral regions. Density of TUNEL-stained neuronal nuclei showed inverse correlation with that of both AT8-positive and Gallyas-stained NFT in the CA and showed significantly direct correlation with AT8- and HT7-positive neurons in the frontal cortex. Density of tau-positive and Gallyas-stained NFT was higher than that of TUNEL-stained nuclei. We conclude that phosphorylation sites of tau, 159-163 and 202-205, are probably associated with neuronal apoptosis and apoptotic change follows abnormal phosphorylation of tau.