Akitsugu Okada

Lipoprotein(a) Phenotypes in Patients with Vascular Dementia

We tried to examine if there is a particular distribution pattern of lipoprotein(a) [Lp(a)] phenotypes specific for patients with vascular dementia (VD). Fourteen cases of VD (9 males and 5 females), 18 cases of dementia of the Alzheimer type (DAT)(7 males and 11 females), 29 cases of cerebrovascular disease (CVD) in the chronic phase (18 males and 11 females) and 47 healthy individuals as controls (25 males and 22 females) were examined for serum Lp(a). Serum concentrations and phenotypes of Lp(a) were assessed by ELISA and a test kit for the Lp(a) phenotype, respectively. Serum concentrations of Lp(a) were significantly higher in patients with VD (p < 0.05) as well as patients with CVD (p < 0.01) compared with those in healthy individuals. Serum concentrations of Lp(a) did not significantly differ between patients with DAT and healthy individuals. The incidences of Lp(a) phenotypes containing relatively low-molecular-weight apolipoprotein(a) isoforms were significantly higher in patients with CVD in the chronic phase (p < 0.05) or those with VD (p < 0.01) compared with those in healthy individuals. Distribution patterns of Lp(a) phenotypes did not differ between patients with DAT and healthy individuals. Thus, high serum levels of Lp(a) could be considered a clinical hallmark to distinguish VD from DAT. Abnormally high serum levels of Lp(a) in patients with CVD and VD seemed to be due to specific increases in low-molecular-weight apolipoprotein(a) isoforms in Lp(a).

Amyloid βprotein precursors with kunitz-type inhibitor domains and acetyl-cholinesterase in cerebrospinal fluid from patients with dementia of the Alzheimer type

We used the ELISA to measure the concentration of amyloid protein precursor with Kunitz type trypsin inhibitor domains (APPI) in CSF of dementia of the Alzheimer type (DAT) and examined the correlation of APPI with acetylcholinesterase (AChE) and somatostatin (SRIF). We found the APPI concentration in CSF of DAT to be significantly elevated compared with that of multi‐infarct dementia and controls. We could significantly correlate APPI with AChE, but not correlate APPI with SRIF. The present results suggest that measurement of CSF APPI levels may be useful for diagnosis of DAT and the change of APPI may closely be associated with abnormality of acetylcholine system in DAT that has been reported.

Cu, Zn superoxide dismutase in patients with dementia of the Alzheimer type

Cu, Zn superoxide dismutase (SOD) levels in the serum, cerebrospinal fluid (CSF) and skin fibroblasts of patients with dementia of the Alzheimer type (DAT) were estimated using enzyme immunoassay. The SOD mRNA level in the skin fibroblasts was also determined by the Northern blot analysis. As compared with the age‐matched control groups of neurological patients without dementia, the AD group consisting of patients with DAT at ages under 65 years of age as well as the SDAT group of patients with DAT at ages over 65 years of age showed no significant changes in serum or CSF SOD levels. However, the skin fibroblast SOD‐ and SOD mRNA levels, which were correlate each other, were significantly higher in the AD group (p<0.05), while lower in the SDAT group (p<0.05). These results suggest that the determination of the SOD level of skin fibroblast may be useful for diagnosis of DAT and that the abnormality of SOD may play an important role in developing DAT.

The Expression of Presenilin 1 mRNA in Skin Fibroblasts and Brains from Sporadic Alzheimer’s Disease

We examined the expression of presenilin 1 (PS-1) mRNA in cultured skin fibroblasts taken from living patients with Alzheimer’s disease (AD) and human brains taken postmortem from AD patients by RT-PCR analysis. The donors of fibroblasts consisted of 28 cases with AD and 19 neurological patient without dementia (CTL). The brains came from 17 cases with AD and 23 cases with CTL. We found that PS-1 mRNA levels in skin fibroblasts of AD patients were significantly higher than those of CTL patients (p < 0.0001). Moreover, we found that PS-1 mRNA levels in human brains with AD were significantly higher than in those with CTL (p < 0.0001). These findings suggest that high levels of PS-1 mRNA in AD may play an important role in developing AD and that the examination of PS-1 mRNA in skin fibroblasts may be helpful for the diagnosis of AD.

Electrically induced blink reflex and clinical blinking ability in patients with amyotrophic lateral sclerosis

A study of the electrically induced blink reflex was performed on 17 patients with amyotrophic lateral sclerosis (ALS), graded according to the voluntary and reflexive blinking ability. In the early stage, delay of bilateral R2 latencies, decrease of bilateral R2 amplitudes and disappearance of the contralateral R2 component occurred. Then, the ipsilateral R2 component vanished when the voluntary blinking was incomplete. In cases with the remaining R2 component, the recovery curves of R2 amplitude revealed the weakened influence of the central nervous system to the interneurons that constructed the R2 component. In highly impaired patients who had lost the reflexive blinking ability, the R1 component had disappeared. Electrically induced blink reflex is useful in assessing the degree of disability in the upper facial muscles.

Analysis of amyloid precursor protein mRNAs in skin fibroblasts in Down's syndrome.

We examined amyloid precursor protein (APP) mRNAs expression in skin fibroblasts from Downs syndrome (DS) patients of different ages to determine the time of occurrence of abnormal splicing. The ratio of APP770 + 751 mRNA to APP695 mRNA (APP770 + 751/695) was significantly increased in the young DS group and adult DS group compared with the age-matched control groups (p < 0.01, p < 0.05), but no significant increase was observed in the aged DS group compared with the age-matched control group. These findings suggest that metabolic abnormalities of the APP gene occur at a very early stage of DS, at a mean age of about 5 years. Therefore, metabolic abnormalities of the APP gene are considered to appear at a very young age also Alzheimers disease (AD). In this study, we confirmed that examination of the APP gene in skin fibroblasts might be useful for early diagnosis of AD.

Clinical effect of WEB 1881 (nebracetam fumarate) on patients with dementia of the Alzheimer type and study of its clinical pharmacology.

We administrated WEB 1881, 800 mg/day (400 mg twice a day), nine patients with dementia of the Alzheimer type for 8 weeks, and undertook an open study to investigate the clinical effects of the distribution into the cerebrospinal fluid (CSF) as well as the influence on the neurotransmitter-related substances in the CSF. These were outpatients living at home with caregivers. Significant clinical improvement was shown by means of the Gottfries, Bråne, and Steen Scale and by Hasegawas dementia scale. Unchanged WEB 1881 was identified in the CSF. The mean concentration of which was 198.7 ng/ml, this corresponded to 19.0% of the plasma concentration. Of several neurotransmitter-related substances measured in the CSF, a marked rise of AChE activity was observed. Adverse effects consisted of a slight skin eruption in one case and alterations in a clinical laboratory test in another case. These were, however, not significant from a clinical viewpoint. It is suggested that the mechanisms of action of WEB 1881 are based on its transit into the CSF as well as the activation of intracerebral acetylcholinergic systems.