Osamu Muramoto

Central noradrenaline metabolism in cerebellar ataxic mice.

Central noradrenaline (NA) metabolism was investigated in 4 types of ataxic mutant mice, weaver, reeler, staggerer and rolling mouse Nagoya (RMN) and hypocerebellar mice experimentally produced by neonatal treatment with cytosine arabinoside (ara-C). As neurochemical markers for synthesis, steady-state level and turnover of NA, we measured tyrosine hydroxylase (TH) activity, NA and total (free + conjugated) 3-methoxy-4-hydroxyphenylethyleneglycol (total MHPG) concentrations in the cerebellum, cerebral cortex and spinal cord. In the weaver and staggerer whose cerebellar weight loss was severe (40 and 21% of controls, respectively), the 3 neurochemical markers were all increased in the cerebellum, and a similar increase was observed in other regions. In the reeler, the 3 markers were also markedly increased in the cerebellum, but no similar pattern of increase was observed in other regions. In the RMN whose cerebellum showed the least weight loss (76% of control), only TH activity and MHPG concentration were increased in the cerebellum and spinal cord but not in the cerebral cortex. In ara-C-treated mice, the neurochemical markers were also increased in the cerebellum, but to a lesser extent in other regions. These results suggest that, although total contents and total activity of these markers per whole cerebellum were significantly decreased, the central NA metabolism was basically enhanced throughout the CNS of the cerebellar ataxic mice irrespective of their cause. The degree and extent of this enhancement appeared to be correlated with the degree of the cerebellar weight loss.

Neurotransmitter abnormality in rolling mouse Nagoya, an ataxic mutant mouse

An extensive neurochemical study has been performed on the CNS of Rolling mouse Nagoya (RMN), an ataxic mutant mouse. Although the symptoms observed are as severe as those found in Weaver mutants, little is known of the pathogenesis of the ataxia, except for a slight hypoplasia of the anterior part of the cerebellum. The present study revealed two major neurotransmitter-related abnormalities in the CNS. The first is a reduced concentration of glutamate, a putative transmitter of granule cells, and an increased concentration of glycine and taurine in the cerebellum of the RMN. The second is an increased activity of tyrosine hydroxylase, the rate-limiting enzyme in catecholamine synthesis, not only in the cerebellum but also in spinal cord, medulla oblongata, thalamus and hypothalamus. These results, together with previous data obtained from other ataxic mutant mice or experimentally-induced ataxic animals suggest that the cerebellum is the most severely affected part of the CNS in the RMN with the number of granule cells being reduced. The increase in the concentration of inhibitory amino acids and the widespread increase in tyrosine hydroxylase activity are probably not specific to the RMN but seem to be common to other ataxic animals with hypoplastic cerebellum and granule cell loss.

Studies on neurotransmitter markers and neuronal cell density in the cerebellar system in olivopontocerebellar atrophy and cortical cerebellar atrophy

Glutamate, aspartate and gamma-aminobutyrate (GABA) concentrations and choline acetyltransferase (ChAT) activity were measured in postmortem cerebellar cortical areas and brainstem nuclei of 10 normal controls, 5 patients of olivopontocerebellar atrophy (OPCA) with multiple system atrophy (MSA) and 2 patients of cortical cerebellar atrophy (CCA). In addition, the neuronal cell density in the cerebellar cortex and the brainstem nuclei was determined, and the correlation between neurotransmitter markers and the neuronal cell densities were investigated. Glutamate and aspartate concentrations in the cerebellar cortical tissues were markedly varied from case to case of MSA (OPCA) and CCA patients. However, glutamate concentration in the anterior vermis showed a positive correlation coefficient with the density of granule cells (r = 0.554, 0.05 less than P less than 0.10) and, those in the posterior vermis and in the cerebellar hemisphere were positively correlated with cells in the inferior olive (r = 0.707 and 0.607, P less than 0.05, respectively). Aspartate concentration in the anterior vermis also has a positive correlation coefficient (r = 0.571, 0.05 less than P less than 0.10) with the density of cells in the inferior olive. GABA concentrations in the dentate nucleus were decreased in all cases of MSA (OPCA) and CCA, and were positively correlated with the degree of loss of Purkinje cells (r = 0.765, P less than 0.01). ChAT activities were decreased in certain cases of MSA (OPCA), but conversely, increased in CCA patients. ChAT activity in the posterior vermis has a positive correlation coefficient (r = 0.613, 0.05 less than P0.10) with the cell density in the pontine nucleus. A possibility of a compensatory increase of ChAT activity in CCA patients was discussed.

Selective reminding in normal and demented aged people: auditory verbal versus visual spatial task.

A new test of visual spatial learning (VS) which uses the rationale of selective reminding and evaluates memory and learning of spatial positions of objects was presented. This was compared with the auditory verbal selective reminding (AV) in regard to normal aging and dementia. The results showed that the performance of VS declines with age more steeply than those of AV. Factor analyses showed that the performance of VS to be factorially independent of that of AV, and showed that VS can account for most of the decline in performance of normal aged people. The performance on VS of demented patients correlated well with the serverity of dementia. The comparison between multi-infarct dementia and Alzheimer type dementia indicated that severe impairment of VS with relative preservation of AV is a distinctive pattern of Alzheimer type. These results suggest that VS is a useful tool to evaluate memory decline with aging and that it can be useful in the clinical diagnosis of dementia.

Cross-Cultural and Multi-Ethnic Dementia Evaluation by Mental Status and Memory Testing

Two studies investigated aspects of cross-cultural dementia evaluation. The first explored consequences of using different mental status tests; the second compared mental status and memory assessments for normal individuals aged 70-79 and 80-89 in Japan and in America. In a dementia screening clinic, scores from the Hasegawa mental status test could be converted to the Blessed scale without influencing patient classification (impaired vs. unimpaired). Younger subjects were slightly superior to older subjects in mental status in both comparison groups. Both Japanese groups performed better on the memory test than even the younger American group.

Studies on neurotransmitter markers of the basal ganglia in Pick's disease, with special reference to dopamine reduction

gamma-Aminobutyric acid (GABA), substance P and dopamine concentrations and choline acetyltransferase (ChAT) activity were measured in post-mortem cerebrocortical and basal ganglial areas of 14 controls and 4 patients with pathologically verified Picks disease (1 classic case and 3 cases of the generalized form). GABA and substance P levels in the substantia nigra and the globus pallidus were generally decreased, corresponding to the moderate to severe loss of small neurones in the striatum. ChAT activities in the striatum varied from case to case, in proportion to various degrees of loss of large neurones in the striatum. These neurotransmitter abnormalities in Picks disease were exactly the same as those in Huntingtons disease. However, dopamine concentrations were markedly reduced in the striatum in Picks disease, whereas striatal dopamine in Huntingtons disease is reported to be increased. A dopamine reduction in the striatum of Picks disease was more disproportionately prominent than expected for various degrees of nigral cell loss. This may be one of the important factors which prevents the generation of choreic movements in Picks disease in spite of definite striatal atrophy similar to Huntingtons disease.

Developmental profiles of substance P and GABA contents in the substantia nigra of rat

The developmental changes of concentrations of substance P and GABA in the substantia nigra at various postnatal ages of the rat were investigated. Both substance P and GABA were present in measurable amount at birth and continuously increased with age thereafter. When the two curves were compared, GABA seemed to develop slightly faster than substance P in the substantia nigra. Therefore, in contrast to previous reports, there was no discontinuously rapid increase in the concentrations of these transmitter candidates during normal postnatal development of the rat substantia nigra.