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Biomedical subjects

J Ogata

Publications and source records attributed to J Ogata.

At least 19 recordsLinked to original sources

The effect of intrathecal fentanyl added to hyperbaric bupivacaine on maternal respiratory function during Cesarean section.

BACKGROUND: Subarachnoid blockade with local anesthetics induces respiratory depression. Although the addition of fentanyl to bupivacaine has become popular in subarachnoid blockade for Cesarean section, there is no information on the effect of intrathecal fentanyl on maternal spirometric respiratory function in parturients undergoing Cesarean section. METHODS: We tested the effect of the addition of intrathecal fentanyl to hyperbaric bupivacaine on maternal spirometric performance in 40 consenting parturients undergoing Cesarean section. The parturients were randomized into two groups: those receiving 2.0 ml of hyperbaric bupivacaine 0.5% and 0.4 ml of saline intrathecally and those receiving 2.0 ml of hyperbaric bupivacaine and 0.4 ml of fentanyl (20 microg) intrathecally. We performed spirometry on arriving at the operation room and 15 min after subarachnoid blockade. RESULTS: Subarachnoid blockade with bupivacaine significantly decreased the peak expiratory flow rate, but did not induce significant changes in vital capacity and forced vital capacity. The addition of intrathecal fentanyl to bupivacaine improved the quality of subarachnoid blockade, but did not lead to a deterioration in respiratory function compared with intrathecal bupivacaine alone. CONCLUSIONS: The addition of intrathecal fentanyl to hyperbaric bupivacaine did not lead to a deterioration in maternal spirometric respiratory function in parturients undergoing Cesarean section.

Adult↗

Preoperative stellate ganglion blockade prevents tourniquet-induced hypertension during general anesthesia.

BACKGROUND: Prolonged and excessive inflation of pneumatic tourniquets leads to a hyperdynamic circulatory response. Sympathomimetic activity is an important factor in tourniquet-induced hypertension. Stellate ganglion block specifically blunts sympathetic efferent nerves and prevents hypertension induced by sympathomimetic stimulation. The present study was performed to investigate the effects of stellate ganglion block (SGB) on arterial pressure and heart rate during prolonged tourniquet use under general anesthesia. METHODS: Twenty patients scheduled for knee arthroscopy were either treated with 10 ml of 1% lidocaine for SGB (SGB group; n = 10), or intramuscular injection (IM group; n = 10) before tourniquet inflation. Comparisons of systolic and diastolic arterial pressure and heart rate were made before and after the induction of anesthesia, 10 min after the lidocaine treatment, every 5 min during the first 60 min after tourniquet inflation, and immediately before and 5 min following deflation. The maximum values of the circulatory variables were compared. RESULTS: Tourniquet inflation caused increases in the circulatory variables in both groups. Systolic arterial pressure in the SGB group was significantly lower than that in the IM group after 55 min of tourniquet inflation. Diastolic arterial pressure also was significantly lower in the SGB group immediately before the deflation. The maximum values of the three hemodynamic variables were significantly lower in the SGB group. Arterial pressure significantly decreased after tourniquet deflation in the IM group. CONCLUSION: Ipsilateral SGB attenuated the hyperdynamic response mediated by prolonged tourniquet inflation during knee arthroscopy.

Adult↗

The influence of the laryngeal mask airway on the shape of the submandibular gland.

UNLABELLED: Although transient sialadenopathy of the submandibular gland associated with insertion of the laryngeal mask airway (LMA) has been described, the influence of the LMA on the submandibular gland is unknown. We measured the width and length of the submandibular glands by using ultrasonography in patients in whom the LMA was used. An increased intracuff pressure of the LMA, up to 150 cm H2O, was used in a prospective study of adult patients scheduled for elective surgery. The width of the gland increased with an increasing intracuff pressure from 50 to 100 cm H2O (P < 0.01) and 100 to 150 cm H2O (P < 0.01) but did not change from 0 to 50 cm H2O. There was no change in the length of the gland. We conclude that the submandibular gland was deformed by the insertion of the LMA. IMPLICATIONS: The findings in our study show that the submandibular triangle can be easily compressed by the insertion of the laryngeal mask airway (LMA). When inserting the LMA, it is important to consider that the LMA cuff may alter these tissues, which are situated between the lingual root and the submandibular triangle.

Adult↗

Association analyses between genetic polymorphisms of endothelial nitric oxide synthase gene and hypertension in Japanese: The Suita Study.

OBJECTIVES: Endothelium-derived nitric oxide plays a key role in the regulation of vascular tone. Recently, endothelial nitric oxide synthase (eNOS) gene polymorphisms were reported to be associated with hypertension or coronary spasm. We investigated the association between the eNOS gene polymorphisms and hypertension in a large population-based sample of 4055 Japanese. DESIGN AND METHODS: We investigated two polymorphisms of the eNOS gene, Glu298Asp polymorphism of exon 7 and T(-786)C polymorphism of the promoter region. The genotype distribution in hypertensive subjects was compared to that in the other subjects. The influence of the genotype on blood pressure values was analyzed in the subjects not taking hypertensive medication. The promoter activities of the eNOS gene with the (-786)T or (-786)C allele were measured by a luciferase reporter gene assay. RESULTS: There was significant linkage disequilibrium between the two polymorphisms (P < 0.0001). The genotype distribution of the Glu298Asp or T(-786)C polymorphism did not differ between the hypertensive and the other subjects. No significant differences in the blood pressure of subjects not taking hypertensive medication were observed among the three genotypes of Glu298Asp or T(-786)C polymorphisms. No significant differences in the promoter activity were observed between bovine endothelial cells transfected with the (-786)T and (-786)C alleles. CONCLUSIONS: Our data suggested that these polymorphisms of the eNOS gene are unlikely to be major factors in the susceptibility to hypertension in the Japanese population studied.

Adult↗

T+31C polymorphism of angiotensinogen gene and essential hypertension.

A common variant at codon 235 of the angiotensinogen gene with methionine to threonine amino acid substitution (AGT M235T) has been reported as a genetic risk for essential hypertension. However, the frequency of AGT T235 was heterogeneous among races, and a positive association between AGT M235T and hypertension was not settled. To examine the association in a general population of Japanese (n=4013), we introduced the TaqMan polymerase chain reaction method and examined the relation between hypertension and T+31C polymorphism, which was in absolute linkage disequilibrium with AGT M235T. The C+31 allele of AGT was significantly associated with the positive family history of hypertension (FH) but not with the presence of hypertension or blood pressure. The subjects with CC tended to have hypertensive relatives, especially a hypertensive father or siblings, and its statistical significance was stronger in men. Adjustment of confounding factor did not alter the results of simple association study, suggesting that this positive association with FH is independent and significant. Our findings revealed that the TaqMan polymerase chain reaction method is a powerful tool for genetic association study with a large number of subjects and that AGT T+31C is significantly associated with paternal FH.

Aged↗

Association of sodium channel gamma-subunit promoter variant with blood pressure.

The SCNN1G gene, located on human chromosome 16p12, encodes the gamma subunit of the amiloride-sensitive epithelial sodium channel, and mutations in SCNN1G can result in Liddle's syndrome or pseudohypoaldosteronism type I. We identified sequence variations in the promoter region of SCNN1G and examined the association between this polymorphism and blood pressure in a large cohort (n=4075) representing the general population in Japan. We found T(-1290)C, T(-501)G, G(-173)A, and G(-104)T polymorphisms in the promoter region of SCNN1G and confirmed the existence of T387C and T474C polymorphisms in exon 3 and the C1947G polymorphism in exon 13. Because the genotypes of the T(-1290)C, T(-501)G, G(-104)T, and T474C polymorphisms were in tight linkage disequilibrium, we selected the T474C and G(-173)A polymorphisms for an association study. The G(-173)A polymorphism of SCNN1G had a significant effect on systolic pressure (P=0.0050) and pulse pressure (P=0.0050). The AA genotype was associated with an 11 mm Hg drop in systolic pressure and an 8 mm Hg drop in pulse pressure and with a higher prevalence of hypotension (P=0.0195). A transient transfection assay using MDCK cells and human renal epithelial cells indicated that the promoter activity of the G(-173) allele was higher than that of the A(-173) allele. Although the effects of the A(-173) allele were recessive and although the AA genotype was found in just 0.7% of our study population, we observed that this variation of human SCNN1G had significant effects on blood pressure.

Adult↗

Low potentiality of angiotensin-converting enzyme gene insertion/deletion polymorphism as a useful predictive marker for carotid atherogenesis in a large general population of a Japanese city: the Suita study.

BACKGROUND AND PURPOSE: Some previous studies, almost all western, have investigated whether there is a relationship between the insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) and carotid atherosclerosis. The results, however, have not been consistently positive. Further, there have been few investigations based on a large, general population. Therefore, the present study aimed to clarify whether ACE gene deletion polymorphism was associated with carotid atherosclerosis in a large Japanese general population with a more homogeneous genetic background than Caucasian populations. METHODS: Subjects aged 30 to 86 years were randomly selected from Suita City, located in Osaka, the second largest urban area of Japan, and included 1894 men and 2137 women. With the aid of high-resolution ultrasonography, carotid atherosclerosis was evaluated using our atherosclerotic indexes of intimal-medial thickness (IMT), plaque number (PN), plaque score (PS), and percentage of stenosis of the carotid artery assessed using high-resolution B-mode ultrasonography. ACE gene I/D polymorphism was detected by polymerase chain reaction. RESULTS: There were no significant differences among the ACE genotypes for age and conventional cardiovascular risk factors, except for systolic blood pressure (SBP) and the percentage of hypertension in men. The values of IMT, PN, and PS as carotid atherosclerotic indexes were not significantly different among genotypes for either sex. After adjusting for age, body mass index, smoking habit, high-density lipoprotein cholesterol, triglycerides, presence of hypertension, presence of diabetes mellitus, and presence of hyperlipidemia, the estimated ORs for the presence of IMT >/=1.10 mm (defined as thickened IMT), according to ACE genotype (DD versus II, DD+ID versus II, and DD versus ID+II), for men were 0.80 (95% CI 0.60 to 1.23), 0.89 (0.62 to 1.29), and 0.89 (0.70 to 1.28), respectively. On the other hand, the ORs for women after the same adjustment were 0.92 (95% CI 0.58 to 1.35), 0.93 (0.59 to 1.45), and 0.91 (0.59 to 1.27), respectively. CONCLUSIONS: Our present data suggest that ACE I/D polymorphism is not potentially a useful predictive marker for carotid atherogenesis when investigated in a large and homogeneous general Japanese population of 4031 subjects, a finding similar to that in a Caucasian population study, the Perth Carotid Ultrasound Disease Assessment Study, an Australian study based on a general population using 1111 subjects.

Adult↗

Adrenomedullin inhibits the pressor effects and decrease in renal blood flow induced by norepinephrine or angiotensin II in anesthetized rats.

Adrenomedullin (AM), a hypotensive peptide originally isolated from human pheochromocytoma, has been reported to regulate renal functions. In patients with glomerulonephritis, the serum levels of AM are elevated as well as hypertensive agents norepinephrine (NE) and angiotensin II (AII). The effects of AM on the NE- or AII-induced pressor effects and renal blood flow responses, however, are not well clarified. We examined the effects of AM on blood pressure and renal blood flow induced by NE or AII in anesthetized rats. Arterial blood pressure and renal blood flow were measured using a calibrated pressure transducer and a laser Doppler flowmeter, respectively. Drugs were injected into the tail vein with a syringe. Intravenous administration of AM (1-3 nmol/kg) decreased the arterial blood pressure in anesthetized rats in a dose-dependent manner, whereas it did not affect the renal blood flow. NE or AII administration in anesthetized rats caused both increases in blood pressure and decreases in renal blood flow. Simultaneous administration of AM with NE or All prevented the increasing effects of blood pressure and inhibited the decreases in renal blood flow caused by NE or AII. These findings suggest that AM may have a protective role against the pressor effects and decrease in renal blood flow caused by NE or AII.

Adrenomedullin↗

Lack of association between genetic polymorphism of CYP11B2 and hypertension in Japanese: the Suita Study.

Aldosterone synthase (CYP11B2) is a key enzyme in the biosynthesis of aldosterone. Recently, a polymorphism in the 5'-flanking region of the CYP11B2 gene [T(-344)C] has been reported to be associated with blood pressure and plasma aldosterone levels. We investigated the association between this polymorphism and hypertension in a large population-based sample of 4,000 Japanese. The genotype distribution in hypertensive subjects (n=1,535) was compared to that in normotensive subjects (n=2,514). In subjects not receiving antihypertensive medication, the influence of the genotype on blood pressure values adjusted for clinical covariates was analyzed. All analyses were performed separately for men and women. The genotype distribution did not differ between hypertensive and normotensive subjects in either men (frequency of C allele: 30.3% vs. 31.4%, p=0.48) or women (31.5% vs. 31.7%, p=0.93). There were no significant differences in systolic blood pressure, diastolic blood pressure, or pulse pressure among the three genotypes in either men or women who had not received hypertensive medication. Our data suggest that the T(-344)C polymorphism of CYP11B2 is unlikely to influence blood pressure status in the Japanese population.

Aged↗

The aldehyde dehydrogenase 2 gene is a risk factor for hypertension in Japanese but does not alter the sensitivity to pressor effects of alcohol: the Suita study.

Excessive alcohol consumption is a potent risk factor for high blood pressure. About half of Japanese show an extremely high sensitivity to alcohol, which is due to a genetic deficiency in an isoenzyme of aldehydede-hydrogenase with a low Km (ALDH2). It is possible that the effects of alcohol consumption on blood pressure differ according to the ALDH2 genotype. The purpose of the present study was to assess the influence of the ALDH2 genotype on the pressor effects of alcohol. The influence of the ALDH2 genotype on blood pressure was investigated in a large cohort (4,000 subjects) representing the general population in Japan. The genotype was determined by the TaqMan method. The genotype was significantly associated with alcohol consumption, gamma-GTP level, and HDL cholesterol level in both males and females. The odds ratio for the presence of hypertension for the Glu/Glu genotype in comparison to other genotypes was 1.67 (p< 0.0001, odds ratio=1.37-2.08, 95% confidence interval) among males. In contrast, the ALDH2 genotype had no significant effects on blood pressure among females. To investigate whether the ALDH2 genotype affected the sensitivity to the pressor effects of alcohol, we analyzed the effects of the ALDH2 genotype (Lys/Lys+Lys/Glu=0, Glu/Glu=1) and the level of alcohol consumption on blood pressure values after adjusting for age and BMI (residuals after adjusting for age and BMI). Among males, while the level of alcohol consumption significantly affected systolic, diastolic and pulse pressure, no significant interaction was observed between the ALDH2 genotype and the level of alcohol consumption in determining blood pressure levels. These results suggest that the Glu/Glu genotype is a potent risk factor for hypertension among males mainly through its association with the level of alcohol consumption, and that the ALDH2 genotype does not affect the sensitivity to the pressor effects of alcohol.

Adult↗

Massive pontine hemorrhagic infarction associated with embolic basilar artery occlusion.

We report here an autopsy case of massive pontine hemorrhagic infarction secondary to embolic basilar artery occlusion. A large embolus appeared to have traversed the vertebral artery into the basilar artery as a result of basilarization of the vertebral artery due to severe stenosis of the contralateral vertebral artery. Extensive ischemia due to embolic occlusion of the entire length of the basilar artery, and migration of the embolus are assumed to have resulted in a massive pontine hemorrhagic infarction.

Aged↗

Deletion allele of angiotensin-converting enzyme gene increases risk of essential hypertension in Japanese men : the Suita Study.

BACKGROUND: The Framingham Study recently revealed that the homozygous deletion polymorphism of the angiotensin-converting enzyme gene (ACE DD) is associated with increased risk for essential hypertension in a male-specific manner. However, this association has not been confirmed in races other than whites. METHODS AND RESULTS: Using a large number of Japanese subjects (n=5014) that were randomly selected from the general population (the Suita Study), we examined the association between ACE DD and hypertension. The frequency of DD (17.1%) in hypertensive men was significantly higher (P<0.0015) than that (11.8%) in other mildly hypertensive or normotensive men, and the estimated odds prevalence for hypertension (DD vs II) was 1.75 (95% CI 1.21 to 2.53). In contrast, no significant association was confirmed in women (OR 1.17, 95% CI 0.79 to 1.72). CONCLUSIONS: Despite the lower frequency of the DD genotype in Japanese than in whites, the ACE gene polymorphism was associated with increased risk for hypertension, suggesting that this polymorphism is a mild but certain genetic risk factor for essential hypertension in men.

Age Factors↗

Linkage between alpha(1) adrenergic receptor and the Jak/STAT signaling pathway in vascular smooth muscle cells.

The Jak/STAT pathway is activated following stimulation of the type I angiotensin II receptor. To examine whether this pathway is shared among other G-protein-coupled receptors, we studied the linkage between the alpha(1) adrenergic receptor and this pathway. The alpha(1) agonist phenylephrine induced tyrosine phosphorylation of Jak2, Tyk2, and STAT1 in vascular smooth muscle cells. The phosphorylation of Jak2 was prevented by the alpha(1) receptor antagonists prazosin and chloroethylclonidine, but not by WB4101, and that of STAT1 was inhibited by prazosin and the Jak2 inhibitor AG490. After stimulation with phenylephrine, Jak2 and STAT1 were found to associate with alpha(1B) receptor. Phenylephrine stimulated the DNA binding activity of STAT1. Protein synthesis promoted by phenylephrine was inhibited by prazosin, AG490, and the introduction of a decoy oligonucleotide for STAT1. These results suggested that alpha(1) receptor is linked to the Jak/STAT pathway and that this pathway mediates alpha(1) agonist-induced smooth muscle hypertrophy.

Adrenergic alpha-Agonists↗

Differential expression of proteoglycans biglycan and decorin during neointima formation after stent implantation in normal and atherosclerotic rabbit aortas.

Proteoglycans decorin and biglycan, which bind to TGF-beta, are thought to participate in regulation of extracellular matrix accumulation in arterial intimal hyperplasia. To investigate the correlation of these proteoglycans with the cellular localization and phenotypic modulation of smooth muscle cells (SMCs), we analyzed the spatial and chronological distribution of these proteoglycans and two cytokines, TGF-beta and IL-1beta, in the process of neointima formation after stent implantation in the aortas of rabbits fed a high-cholesterol diet (atherosclerotic group) or a regular diet (control group). We implanted metallic stents in the rabbit aortas and harvested the aortas 4-56 days later for immunohistochemical and mRNA in situ hybridization analyses. In the control group, TGF-beta and biglycan expression was in correspondence with the chronology and localization of embryonic SMCs. In the atherosclerotic group, TGF-beta and biglycan expression was sustained throughout the experimental period, which was in accord with the prolonged expression of embryonic SMCs. Decorin, which did not occur in neointima in the control group, appeared in the atherosclerotic aortas in the confined area of vascular SMCs surrounding the macrophages around the stent wire. These results indicate that biglycan and decorin kinetics during neointima formation after arterial injury are distinct, despite their similar construction; biglycan synthesis correlates with embryonic SMCs.

Animals↗

Does hypertension confer a hypercoagulable state in stroke-prone spontaneously hypertensive rats?

OBJECTIVE: To verify whether hypertension confers a hypercoagulable state in a hypertensive animal model. DESIGN: The parameters of blood coagulation were compared between stroke-prone spontaneously hypertensive rats (SHR-SP) and Wistar-Kyoto (WKY) rats. Each rat group consisted of a younger subgroup at 8-12 weeks old (n = 12) and an older subgroup at 16-20 weeks old (n = 12). METHODS: Prothrombin time (PT), activated partial thromboplastin time (APTT), fluorogenic PT, fibrinogen, fibrin/fibrinogen degradation products (FDP), thrombin-anti-thrombin III complex (TAT), factor Xa activity, anti-thrombin III (AT-III), tissue factor pathway inhibitor (TFPI), protein C and C1 inhibitor were measured in both rat groups. RESULTS: There was no significant difference in FDP and TAT levels between SHR-SP and WKY rats even at 16-20 weeks when SHR-SP developed severe hypertensive vascular lesions. Contrary to expectations, fluorogenic PT and factor Xa activity were significantly lower in SHR-SP than in WKY rats. While there was no significant difference in AT-III, TFPI and protein C activities between SHR-SP and WKY rats, C1 inhibitor activity was significantly higher in SHR-SP than in WKY rats. The elevated C1 inhibitor activity was inversely correlated with the reduced factor Xa activity. Gel-filtered fractionated plasma with C1 inhibitor activity had an inhibitory effect on the purified rat factor Xa, and immunodepletion of C1 inhibitor from the fractionated plasma attenuated the inhibitory effect CONCLUSION: These results suggest that SHR-SP get into a hypocoagulable state rather than a hypercoagulable state, and that the reduction of factor Xa activity in SHR-SP may be related to the elevation of C1 inhibitor activity.

Animals↗

Potential of carotid enlargement as a useful indicator affected by high blood pressure in a large general population of a Japanese city: the Suita study.

BACKGROUND AND PURPOSE: Few studies have examined whether there is a relationship between carotid arterial diameter and cardiovascular risk factors in a large general population. The aim of this study was to investigate cross-sectionally whether, in a randomly selected general large population of a Japanese city, there is a relationship between common carotid artery (CCA) diameter and conventional cardiovascular risk factors. METHODS: The subjects of the present study were randomly selected from the residents of the city of Suita, located in the second largest urban area of Japan, and consisted of 2284 men and 2568 women aged 30 to 89 years. The outer and inner CCA diameters and intima-media thickness (IMT) of CCA were detected and measured by a single physician with high-resolution ultrasonography. We assessed cross-sectionally by age/sex group the relationships between IMT or CCA diameters and cardiovascular risk factors, especially blood pressure levels divided into 3 groups: the normal group of subjects had a diastolic blood pressure (DBP) <85 mm Hg and systolic blood pressure (SBP) <130 mm Hg and were not taking antihypertensive medication; the high group of subjects had DBP >/=90 mm Hg and/or SBP >/=140 mm Hg and/or were taking antihypertensive medication; and the moderate group consisted of all other subjects. RESULTS: The outer and inner CCA diameters for the high group were significantly (P:<0.05) enlarged in comparison with those for the moderate and normal groups in all age/sex groups of both sexes after adjustment for body mass index, pack-years of smoking, alcohol consumption, and total serum cholesterol. Multiple regression analysis showed that age, body mass index, SBP, pack-years of smoking, alcohol consumption, and IMT were positively and significantly (P:<0.005) related to both outer and inner CCA diameters in both sexes except for between alcohol consumption and outer CCA diameter in women and showed that only serum total cholesterol level was negatively and significantly (P:<0.01) related to inner CCA diameter in both sexes. CONCLUSIONS: Our present study showed that the outer and inner CCA diameters correlated with conventional cardiovascular risk factors, including high blood pressure and IMT. These findings suggest that the outer and inner CCA diameters may be a useful indicator of carotid atherosclerosis, particularly in relation to high blood pressure.

Adult↗

[An autopsy case of dementia with Lewy bodies who showed the typical parkinsonism in the initial five years].

A 76-year-old man with parkinsonism and dementia was reported. He developed resting tremor at age 69 followed by hypokinesia, rigidity and small step gait. L-dopa ameliorated his symptoms with no hallucinations for the initial 5 years. His mental level did not decrease during that period. He was admitted to our hospital because of dehydration and fever at age 74. Subsequently, his cognitive function deteriorated, with visual hallucination. Serial brain CT studies displayed a progressive cerebral cortical atrophy without focal lesions. He died of respiratory distress syndrome and disseminated coagulopathy resulting from pneumonia, dehydration and syndrome malin. Postmortem examination revealed a marked bilateral loss of melanin-containing neurons with Lewy bodies in the substantia nigra and locus ceruleus. Lewy bodies were also in the basal nucleus of Meynert, with moderate neuronal cell loss. The distribution of Lewy bodies was widespread in the cerebral cortical areas, corresponding to the neocortical subtype according to the consensus guideline for the pathologic diagnosis of dementia with Lewy bodies. According to the criteria of the Consortium to Establish a Registry for Alzheimer's Disease, the age-related plaque score in the present case suggested Alzheimer's disease, although cortical neurofibrillary changes corresponded to stage II by the criteria of Braak and Braak. These pathological findings established the diagnosis of dementia with Lewy bodies from the quantitative and distributional viewpoints. Based on recent neuropathological evidence, a spectral theory, which presents idiopathic Alzheimer's disease and Parkinson's disease as the two extremes of a spectrum of neurodegeneration, has been proposed. Dementia with Lewy bodies is located in the middle of this spectrum. Pathological evaluation based on quantitative consensus guidelines is important to establish the diagnosis in patients with parkinsonism and dementia, since neuropathological changes of Alzheimer's disease, Parkinson's disease and dementia with Lewy bodies are often observed in a mixed manner in these patients.

Aged↗