Kiminori Isaki

Neurons, intracellular and extracellular neurofibrillary tangles in subdivisions of the hippocampal cortex in normal ageing and Alzheimer's disease

Unaffected neurons, intracellular neurofibrillary tangles (I-NFTs) and extracellular NFTs (E-NFTs) in six normal subjects and six patients with Alzheimers disease (AD) were morphometrically evaluated in eight subdivisions of the hippocampal cortex, using the Gallyas silver impregnation technique modified by the application of hematoxylin and eosin. The subdivisions examined included CA1-4, prosubiculum (PRO), subiculum and presubiculum (PRE), parasubiculum (PARA) and the entorhinal cortex (ENT). In the AD patients, the number of unaffected neurons in ENT, CA1, PRO and PARA was significantly decreased to one-quarter to two-thirds of that of the normal aged subjects. These four subdivisions in the AD patients had a greater number of both I- and E-NFTs. There were no significant differences in the total number of unaffected neurons, I- and ENTs between the AD patients and normal aged subjects for all the subdivisions. These findings suggest that neuronal loss in the hippocampal cortex in AD is almost entirely due to NFT formation. Furthermore, with regards to neuronal loss and NFT formation, there were two different subdivision groups in the AD patients. One group was composed of severely affected subdivisions (ENT, CA1, PRO and Para) and was distinct from the other group which was composed of mildly affected subdivisions (CA4, CA3, CA2 and PRE). Each subdivision in the normal aged subjects belonged to the mildly affected group as seen in the AD patients. These findings indicate that both neuronal loss and NFT formation associated with normal ageing and with AD are not only quantitatively but also qualitatively different.

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.

Neuronal loss and neurofibrillary degeneration in the hippocampal cortex in late-onset sporadic Alzheimer's disease

Abstract To explore more fully the relationship between neuronal death and neurofibrillary degeneration, unaffected neurons, intracellular neurofibrillary tangles (i‐NFT) and extracellular NFT (e‐NFT) in 22 patients with late‐onset sporadic Alzheimers disease (AD) were morphometrically evaluated in eight subdivisions of the hippocampal cortex, using the Gallyas hematoxylin‐eosin stain. The subdivisions examined included CA4, CA3, CA2, CA1 (CA: cornu ammonis), prosubiculum (PRO), subiculum and presubiculum (PRE), parasubiculum (PARA) and the entorhinal cortex (ENT). The unaffected neuron density was significantly lower and both i‐NFT and e‐NFT densities were significantly higher in subdivisions other than CA4 and CA3 in AD patients compared with those in the aged controls. Unaffected neuron density was significantly, inversely correlated with e‐NFT density and with total NFT density in all subdivisions except for PRE in AD patients. Especially in CA2, CA1, PRO and ENT, there were strong correlations between the neuron density and these NFT densities. Both unaffected neuron and e‐NFT densities in CA1 and ENT were significantly correlated with the disease duration. The i/e‐NFT ratio, an index of the degree and/or rate of progress of neuronal death via neurofibrillary degeneration, showed the lowest value in ENT in AD patients. The findings suggest that neuronal death via neurofibrillary degeneration starts earliest and/or most rapidly progresses in ENT. Furthermore, the i/e‐NFT ratios in both ENT and CA1 were significantly correlated with the disease duration, suggesting that the neuronal death pattern in the two subdivisions parallels disease progression.

In vivo proton magnetic resonance spectroscopy study on premature aging in adult Down's syndrome

Proton magnetic resonance spectroscopy (1H-MRS) was performed in a group of 18 adult patients with Downs syndrome (DS) aged 20-46 years, and the peak area ratios (NAA/Cr, Cho/Cr, NAA/Cho) of N-acetylaspartate (NAA), total creatine (Cr), and choline-containing compounds (Cho) calculated separately in the patients in their 20s, 30s, and 40s. In age-matched healthy control groups, there were no significant age-related changes in any of the peak area ratios. In contrast, in the DS group, although the relative amount of NAA (NAA/Cr) showed no significant change with increasing age, the relative amount of Cho (Cho/Cr and NAA/Cho) was significantly increased in the 40s group. At least as judged by MRI, few age-related general morphological changes such as brain atrophy were apparent in the third, fourth, and fifth decade groups. However, the MRI findings considered together with the age-related changes in the peak area ratios suggest that in DS patients in the fifth decade metabolic abnormalities such as degradation and/or rapid synthesis of brain cell membrane may occur prior to neuronal loss and degeneration.

Neuronal substrates participating in attentional set-shifting of rules for visually guided motor selection: a functional magnetic resonance imaging investigation.

To investigate the neuronal substrates participating in attentional set-shifting for motor selection rules, a functional magnetic resonance imaging study was performed during hand-shape selection tasks. During the session, six right-handed subjects were required to make one of three hand-shapes using their right hands, in response to the hand-shape images on a video screen, following one of the three predefined rules of win, lose, and tie. The selection rules were consistently applied in three conditions (win, tie, and lose), and changed alternately in one condition (alternate win-lose). Thus the alternate win-lose condition requires the shift of rules for motor selection. This alternate condition compared with the win, tie, and lose conditions showed activation in the left middle frontal gyrus, the bilateral inferior frontal gyri, and the left posterior fusiform and lingual gyri. These activation patterns in the prefrontal cortex were similar to those observed during the performance of the Wisconsin Card Sorting Test (WCST), which requires a typical set-shifting ability from one perceptual dimension to another (Berman et al., 1995. Neuropsychologia 33, 1027-1046; Nagahama et al., 1996. Brain 119, 1667-1675; Konishi et al., 1998. Nature Neuroscience 1, 80-84.). Our data may indicate that the dorsolateral prefrontal cortex including the middle and inferior frontal gyri are important in attentional set-shifting of both perceptual and non-perceptual characteristics. Another activation in the fusiform and lingual gyri may have reflected the increased attentional demand for visual processing in the light of a current rule for motor selection.

Non‐linear analysis of the sleep EEG

A sleep electroencephalogram was analyzed by non‐linear analysis. The polysomnography of a healthy male subject was analyzed and the correlation dimensions calculated. The correlation dimensions decreased from the ‘awake’ stage to sleep stages 1–3 and increased during rapid eye movement (REM) sleep. These results were seen during each sleep cycle. In each sleep cycle, the correlation dimensions decrease for slow wave sleep, and increase for REM sleep.

Dynamic changes in glucose metabolism by lactate loading as revealed by a positron autoradiography technique using rat living brain slices

To demonstrate the preference of lactate over glucose as an energy substrate in normal brain tissue under normoxic condition, the dynamic changes in glucose uptake by lactate loading were investigated in living rat brain slices using a positron autoradiography technique. Fresh rat brain slices were incubated with [18F]2-fluoro-2-deoxy-D-glucose ([18F]FDG) in oxygenated Krebs-Ringer solution containing 10 mM glucose at 36 degrees C. During incubation, serial two-dimensional imaging of [18F]FDG uptake in the slices was constructed on the imaging plates. Lactate loading (20 mM) reversibly suppressed the [18F]FDG accumulation up to 80 min. Compared with the pre-loading and the unloaded control values, [18F]FDG uptake was suppressed to 25-45% in cerebral regions and 6-7% in cerebellum. The lactate concentration in the surrounding medium decreased after lactate loading. Hence brain tissue preferentially uses lactate over glucose under normoxic and euglycemic condition.

EEG Analysis in Patients with Senile Dementia and Alzheimer's Disease

Abstract: An EEG frequency analysis using the wave‐form recognition method was performed in different stages of senile dementia (SD), evaluated according to the Hasegawa Dementia Rating Scale (HDS), and the differences in EEG changes between patients with Alzheimers disease (AD) and patients with SD were studied.

The influence of light drowsiness on the latency and amplitude of P300

Light drowsiness affected the P300 obtained with a standard auditory oddball paradigm. A simple two-tone discrimination paradigm was used. The frequent nontarget stimuli were 1000 Hz pure tones and the infrequent target stimuli were 2000 Hz pure tones. The subjects were required to press a button whenever infrequent target tones were presented. With light drowsiness, P300 increased in latency and decreased in amplitude, but the counts of infrequent tones remained correct nevertheless. It was concluded that electrophysiological brain function differs in the light drowsy and awake states. In studies on P300, it is essential to rule out light drowsiness to obtain valid P300 amplitudes and latencies.

Adult-type metachromatic leukodystrophy with a compound heterozygote mutation showing character change and dementia

A 26‐year‐old Japanese woman slowly developed a change of character such as hypospontaneity and blunted affect, followed by obvious mental deterioration. She was diagnosed as having a disorganized type of schizophrenia at the first examination. Brain magnetic resonance imaging demonstrated diffuse high intensity in the cerebral white matter, particularly in the frontal lobes. The single photon emission computed tomography images using 123I‐IMP disclosed diffuse cerebral hypofusion, especially in the frontal lobes. Electroencephalogram showed a moderate amount of 5–6 Hz θ waves on the background of α activity. Nerve conduction velocities in the extremities were delayed. The level of leucocyte arylsulphatase was low. In the arylsulphatase A gene analysis, a compound heterozygote having the 99Gly→Asp and 409Thr→Ile mutations was confirmed. The patient was diagnosed as having metachromatic leukodystrophy. She gradually showed obvious dementing symptoms such as memory disturbance and disorientation. The characteristics of the psychiatric symptoms in the leukodystrophy are discussed.