Masakuni Kameyama

Lp(a) lipoprotein as a risk factor for coronary heart disease and cerebral infarction

Attempts were made to prepare antisera monospecific for Lp(a) lipoprotein and to investigate the distribution of subjects according to plasma levels of Lp(a) in Japanese controls and patients with coronary heart disease or cerebral infarction. Positive plasma reactions to the double diffusion test for Lp(a) (Ouchterlony) were observed in 32.3% of the healthy Japanese subjects, which is similar to results previously reported in western countries. The plasma threshold level of 17 mg/dl was considered an appropriate point for dividing subjects into positive and negative groups depending on reactions to the double diffusion test. When subjects were divided into two groups at 17 mg/dl, a significant association was found between a high plasma level of Lp(a) and either coronary heart disease or cerebral infarction in the distribution of the cortical artery. These results suggest that Lp(a) may play an important part as a risk factor for coronary heart disease and cerebral infarction.

Changes in nicotinic and muscarinic cholinergic receptors in Alzheimer-type dementia.

Abstract: Nicotinic and muscarinic cholinergic receptors were studied in autopsied brains from four histologically normal controls and five histopathologically verified cases of Alzheimer‐type dementia (ATD), using ligand binding techniques. Nicotinic and muscarinic cholinergic receptors were assessed by (–)‐[3H]nicotine and [3H]quinuclidinyl benzilate ([3H]QNB), respectively. Compared with the controls, (–)‐[3H]nicotine binding sites in the ATD brain regions examined were significantly reduced in the putamen and the nucleus basalis of Meynert (NbM). [3H]QNB binding was significantly reduced in the hippocampus and NbM. These findings suggest that there are significant changes of nicotinic and muscarinic cholinergic receptors in selected regions of ATD brains.

Importance of the hematocrit as a risk factor in cerebral infarction.

The relationship between the incidence of cerebral infarction and the hematocrit was studied using 432 consecutive autopsied patients with the average age of 77.1 years. The incidence of cerebral infarction was higher in patients with hematocrit values of more than 46%, (the average in younger adult subjects). The increase in the frequency of cerebral infarction with highhematocrit values was more conspicuous in patients with severe cerebral atherosclerosis than in those with slight cerebral atherosclerosis. High blood pressure per se did not influence the relationship between the hematocrit value and the incidence of cerebral infarction. With hematocrit values of more than 41%, cerebral infarction occurred more frequently in patients over 78 years of age than in the younger patients, but the difference was not significant statistically. High hematocrit values are associated with a higher risk of cerebral infarction in deep subcortical structures of the brain than for cortical infarctions. The pathogenetic and preventive implications of these results are discussed in the light of blood rheology.

Clinical efficacy and safety of donepezil on cognitive and global function in patients with Alzheimer's disease. A 24-week, multicenter, double-blind, placebo-controlled study in Japan. E2020 Study Group

This study evaluated efficacy and safety of donepezil hydrochloride (donepezil) at 5 mg/day in patients with mild to moderately severe Alzheimer’s disease for 24 weeks in a double-blind, placebo-controlled comparative trial. In this study, 268 patients were enrolled and 39 of these (15%) were withdrawn. In the evaluable population of efficacy, Protocol-Compatible (PC) analyzed patients (n = 228), better effects than that of placebo were confirmed using two primary efficacy measures: a cognitive performance test, the Japanese version of the Alzheimer’s Disease Assessment Scale – cognitive subscale (ADAS-J cog, p = 0.003) and a clinical global assessment, the Japanese version of the Clinical Global Impression of Change (J-CGIC, p = 0.000). The superiority of donepezil was also shown by secondary measures: the Sum of the Boxes of the Clinical Dementia Rating (CDR-SB), the Mental Function Impairment Scale (MENFIS) and the caregiver-rated modified Crichton scale (CMCS). The same results were obtained in the intention-to-treat (ITT) analysis (n = 263). The incidence of drug-related adverse events was 10% (14/136) in the donepezil and 8% (10/131) in the placebo group; no significant difference was seen between the two groups. The main adverse events were gastrointestinal symptoms, and these were almost all mild, and they all disappeared with continued administration or temporary discontinuation of donepezil. These results indicate that the donepezil appears to be effective and well tolerated in patients with mild to moderately severe Alzheimer’s disease.

Tissue-specific expression of three types of β-protein precursor mRNA: Enhancement of protease inhibitor-harboring types in Alzheimer's disease brain

Abstract Expression of three types of mRNA encoding amyloid β-protein precursor (APP) in various tissues was analysed, using a ribonuclease protection assay, with special reference to Alzheimers disease (AD). The total content and the proportion of APP mRNAs were specific to each tissue. Among eight tissues examined, the brain was distinct in that the expression level was highest and APP695 mRNA was expressed in abundance. The ratio of APP770/APP751/APP695 mRNAs was approximately 1:10:20 in the cerebral cortex of control brain. The proportions of APP770 mRNA and APP770-plus-APP751 mRNAs increased up to 2.6- and 1.4-fold, respectively, in various regions of AD brain compared with control. The enhanced expression of protease inhibitor-haboring types (APP770 and APP751) may disturb the balance between biosynthesis and degradation of APPs and ultimately lead to accumulation of β-protein as amyloid.

Expression of monoamine oxidase B activity in astrocytes of senile plaques

SummaryMonoamine oxidase (MAO) histochemistry has been performed in brains from patients with dementia of Alzheimer type (DAT) and aged controls. Conspicuous MAO-positive cell clusters were frequently observed in the amygdala, hippocampus, and insular cortex in the brains of DAT. Double staining with glial fibrillary acidic protein immunohistochemistry revealed that the clusterforming MAO-positive cells were astrocytes. Using Bielschowskys method, Congo red and thioflavin S counterstaining, this astrocytic mass was shown to be associated with senile plaques. By the enzyme inhibition experiment, MAO activity in senile plaques was revealed to be of type B. The present results clearly indicate that MAO-B activity is expressed in fibrillary astrocytes in or around senile plaques, suggesting that these astrocytes metabolize exogenous amines in senile plaques.

Regional cerebral blood flow in Parkinson disease with nonpsychotic visual hallucinations

Background: Patients with Parkinson disease (PD) often experience visual hallucinations (VH) with retained insight (nonpsychotic) but the precise mechanism remains unclear. Objective: To clarify which neural substrates participate in nonpsychotic VH in PD, the authors evaluated regional cerebral blood flow (rCBF) changes in patients with PD and VH. Methods: The authors compared 24 patients with PD who had nonpsychotic VH (hallucinators) and 41 patients with PD who had never experienced VH (non-hallucinators) using SPECT images with N-isopropyl-p-[123I]iodoamphetamine. There were no significant differences in age, sex, duration of disease, doses of PD medications, Hoehn and Yahr scale, or Mini-Mental State Examination (MMSE) scores between the two groups. The rCBF data were analyzed using statistical parametric mapping (SPM). Results: The rCBF in the right fusiform gyrus was lower in the hallucinators than in the non-hallucinators (corrected p < 0.05 at cluster levels). The hallucinators revealed higher rCBF in the right superior and middle temporal gyri than the non-hallucinators (uncorrected p < 0.001). These significant differences were demonstrated after MMSE scores and duration of disease, which are the relevant factors associated with VH, were covariated out. Conclusions: Nonpsychotic visual hallucinations in Parkinson disease (PD) may be associated with hypoperfusion in the right fusiform gyrus and hyperperfusion in the right superior and middle temporal gyri. These temporal regions are important for visual object recognition and these regional cerebral blood flow changes are associated with inappropriate visual processing and are responsible for nonpsychotic visual hallucinations in PD.

Age-related changes of pyramidal cell basal dendrites in layers III and V of human motor cortex: A quantitative Golgi study

SummaryAge-related changes of pyramidal cell basal dendrites in layers III and V of human motor cortex (area 4) were analyzed quantitatively in Golgiimpregnated sections by Sholls method of concentric cireles (Sholl 1953). The present data suggested that basal dendrites of the pyramidal cells were decreased in number with advancing age, and that the decrease was more prominent in basal dendrites of layer V pyramidal cells than in those of layer III pyramidal cells.

Hemodynamics in internal carotid artery occlusion examined by positron emission tomography.

Using positron emission tomography in nine patients with minor strokes, unilateral internal carotid artery occlusion, and good collateral circulation through the anterior portion of the circle of Willis, we analyzed regional cerebral blood flow, cerebral metabolic rate of oxygen, oxygen extraction fraction, and cerebral blood volume. These studies allowed quantification of the regional hemodynamic status, especially in relation to watershed areas. Compared with eight normal controls, the patients had significantly (p less than 0.01) decreased regional cerebral blood flow in the middle cerebral artery territory and the surrounding watershed areas of the occluded hemisphere. The oxygen extraction fraction rose with the distance from the anterior portion of the circle of Willis, attaining the highest value in the superior parietal and posterior temporo-occipital watershed area. A concomitant decrease in the cerebral blood flow/cerebral blood volume ratio suggested reduction in the mean blood flow velocity, whereby elevated blood viscosity would be more liable to reduce cerebral blood flow. These findings suggest hemodynamic vulnerability of the watershed areas after internal carotid artery occlusion in persons with good collateral circulation through the anterior portion of the circle of Willis. Our results also emphasize the importance of systemic hemodynamic factors such as blood pressure and circulating blood volume in the genesis of watershed infarction.

Biochemical Characterization of the Nicotinic Cholinergic Receptors in Human Brain: Binding of (—)-[3H]Nicotine

Abstract: (−)‐[3H]Nicotine was found to bind specifically to membranes of human brains obtained at autopsy. The binding was stereospecific, (−)‐nicotine being 40 times more potent than (+)‐nicotine in displacing labeled (−)‐nicotine. Saturation binding studies revealed the presence of two binding sites with dissociation constant (KD) values of 8.1 and 86 nM, and maximum binding capacity (Bmax) values of 36 and 90 fmol/mg protein, respectively. In competition studies, nicotinic agonists were 1,000 times more potent than ganglionic, neuromuscular, and muscarinic blocking drugs in displacing labeled (−)nicotine. IC50 values for cholinergic drugs of (−)[3H]nicotine binding were as follows: (−)‐nicotine, 0.51 nM; acetylcholine, 12.6 nM; (+)‐nicotine, 19.9 nM; cytisine, 27.3 nM; and carbachol, 527 nM. IC50 values of α‐bungarotoxin, hexamethonium, d‐tubocurarine, and atropine were larger than 50 μM. (−)‐[3H]Nicotine binding was highest in the nucleus basalis of Meynert and thalamus and lowest in the cerebral cortex and caudate in the brain regions tested. These results suggest that nicotinic cholinergic receptors are present in human brain and that there are regional differences in the density of these receptors.