Background: The purpose of the present paper was to elucidate the influence of an elevated serum lipoprotein (a) (Lp(a)) concentration on the incidence of ischemic heart disease (IHD) and perforating artery occlusion‐type cerebral infarction (CI) in elderly patients with type‐2 diabetes. Methods: The serum Lp(a) levels in type‐2 diabetic subjects aged ≥60 years ( n = 158; 81 male, 77 female) were measured. At the commencement of the study, subjects were allocated on the basis of past history of CI to a CI– or CI+ group, and on the basis of past history of angina pectoris or myocardial infarction to an IHD– or IHD+ group. They were followed up prospectively for 4 years and the incidences of IHD and CI were monitored. Diagnoses of CI were confirmed by computed tomography (CT), and of myocardial infarction by electrocardiography and blood chemistry. Serum Lp(a) levels of ≥ 20 mg/dL were considered elevated, and < 20 mg/dL as normal. Kaplan–Meier survival analysis (log–rank test) was used to assess the time to event rate stratified by an Lp(a) cut‐off of 20 mg/dL. The predictive value for CI or IHD events was assessed by multiple logistic regression analysis. Results: The probability of IHD events was significantly higher in the elevated Lp(a) group than in the normal Lp(a) group without a history of IHD ( P < 0.001; log–rank test), but was similar in the two subgroups of subjects with a history of IHD. No significant difference was seen between the elevated Lp(a) and normal Lp(a) groups in the probability of CI events, with or without a history of CI. On multiple logistic regression analysis, Lp(a), hyperlipidemia and a history of IHD were significant predictors of IHD, whereas hypertension, hyperlipidemia and a history of CI were significant predictors of CI. Conclusion: These results indicate that an elevated serum Lp(a) concentration is an independent risk factor for IHD, but not for perforating artery occlusion‐type CI, in elderly patients with type‐2 diabetes.
Background: An anion exchange resin has been reported to lower blood glucose levels in patients with type 2 diabetes. Aim: To examine, in comparison with an α-glucosidase inhibitor, the usefulness of colestimide in lowering blood glucose levels in patients with type 2 diabetes and hypercholesterolemia. Methods: Thirty-three patients with type 2 diabetes and hypercholesterolemia were more or less randomly assigned to receive either colestimide (17 patients) or acarbose (16 patients). At 10 time points before and after administration, plasma glucose levels and serum lipid concentrations were measured in all subjects, and the J-index and M-value were calculated. Results: Patients receiving colestimide showed significant decreases in glucose levels 2 hours after breakfast (from 216.9 ± 37.2 mg/dl before treatment to 191.1 ± 40.9 mg/dl after treatment; p=0.008), in the J-index (from 42.6 ± 14.5 to 32.6 ± 9.8; p<0.001), and in the M-value (from 23.1 ± 12.1 to 14.6 ± 7.1; p<0.001). Conclusion: In patients with type 2 diabetes and hyperlipidemia, colestimide was suggested to have blood glucose-lowering activity as does acarbose.
The aim of this study was to clarify the relationship between apolipoprotein (a) (apo (a) ) phenotypes and diabetic retinopathy in elderly type 2 diabetes. Serum Lp (a) concentrations and apo (a) phenotypes were analyzed in 250 diabetic patients aged 60 to 88 years old. Apo (a) phenotypes were classified into 7 subtypes (F, B, S1, S2, S3, S4, O (Null) ) by the method SDS electrophoresis with Western blotting. Patients were divided into two groups according to their apo (a) phenotypes:a low molecular weight (LMW) Lp (a) group, and a high molecular weight (HML) Lp (a) group. Patients were classified as having one of 4 types of diabetic retinopathy: no retinopathy (R0), simple retinopathy (R1), pre-proliferative retinopathy (R2), and proliferative retinopathy (R3). There was a significant association between serum Lp (a) levels and severity of diabetic retinopathy (p<0.001). A gradual trend toward increasing serum Lp (a) levels was observed across the groups (from R0 to R3). A significantly greater percentage of LMW Lp (a) was observed in the R1, R2, and R3 groups than in the R0 group (42.9% (p<0.001), 27.0% (p<0.01), and 27.3% (p<0.05) vs. 10.4%). Multiple logistic regression analysis revealed that duration of diabetes and LMW Lp (a) are independent risk factors for diabetic retinopathy. These results provide significant evidence that LMW Lp (a) contributes to an increased risk of diabetic retinopathy in elderly type 2 diabetes.
To the Editor: In Europe and the United States, a movement has emerged in recent years to reevaluate traditional herbal medicine and apply it to the treatment of Alzheimer's disease.1 A double-blind, randomized, placebo-controlled study was conducted to examine the effects of two Chinese herbal medicines used in Japanese traditional medicine (choto-san (CS), Tsumura & Co., Tokyo, Japan) and (gosya-jinki-gan (GJG), Tsumura & Co.) on cognitive function of Japanese inpatients diagnosed with dementia according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. At the onset of this study, a history was taken, and physical and neurological examinations and computed tomography of the head were conducted. Mini-Mental State Examination (MMSE), Barthel Index (BI), and Zarit Caregiver Burden Scale assessed cognitive function, activities of daily living (ADLs), and caregiver burden (Z score), respectively. Patients taking cholinesterase inhibitors were excluded. This study, initiated on October 26, 2004, and completed on January 10, 2005, enrolled 30 Japanese inpatients (mean age±standard deviation 84.4±6.3), 13 of whom had mild to moderate dementia of the Alzheimer type (MMSE score: 14–25) and 17 of whom had Alzheimer's disease (AD) (MMSE score: 10–21) and cerebrovascular disease (CVD); they were randomly assigned to the CS, GJG, or placebo (lactose) group. The study drugs were administered orally for 8 weeks, and MMSE, BI, and Z scores of the three groups were compared before and after administration. The numbers of patients were as follows: 10 in the CS group (M:F=3:7, mean age: 85.1±5.7), 10 in the GJG group (M:F=2:8, mean age: 85.2±6.6), and 10 in the placebo group (M:F=2:8, mean age: 83.0±6.9). Each patient ingested 2.5 g of CS, GJG, or placebo (which had been chosen by the controller and wrapped in white paper) 30 minutes before every meal. The physician and others were blinded to the study drug being ingested by the patient. The local ethics committee approved this study, and written informed consent was obtained from all families. No significant difference was found in characteristics among the three groups. After 8 weeks of administration, MMSE scores increased significantly compared with baseline values (repeated measures analysis of variance (ANOVA); P<.01) (from 15.5±4.0 to 17.5±4.9 points, 95% confidence interval (CI)=−2.8 to −0.57) in the CS group but not in the GJG and placebo groups. BI scores increased significantly compared with baseline values (repeated measures ANOVA; P<.05) (from 67.5±34.6 to 73.5±35.8 points, 95% CI=−5.4 to −0.1; P=.046) in the CS group but not in the GJG and placebo groups (Figure 1). No significant difference was found in Z score among the three groups.An earlier randomized study described positive effects of CS in patients with cerebrovascular dementia,2 and another showed that CS improves electrophysiological function of patients with poststroke mild cognitive impairment.3 The current study suggests that CS improves cognitive function and ADL in patients with dementia of the Alzheimer type and with AD and CVD. This may reflect effects on frontal lobe regional blood flow because CVD and AD present with decreased regional blood flow in the frontal lobe. Donepezil hydrochloride has been reported to increase cerebral blood flow mainly in the temporal to occipital lobes.4 Therefore, CS is conjectured to exert its synergic effects with donepezil hydrochloride in the relevant patients. Another study enrolling a greater number of patients will be required to further investigate the mechanism of CS's action. Compared with baseline values, the choto-san (CS) group showed significant increases in Mini-Mental State Examination (MMSE) and Barthel Index scores at 8 weeks of administration (from 15.5±4.0 points to 17.5±4.9 points (P<.01) and from 67.5±34.6 points to 73.5±35.8 points (P<.05)), respectively. The gosya-jinki-gan (GJG) and placebo (P) groups showed no significant increases in these scores after 8 weeks of administration. Values are expressed as the mean±standard deviation. *P<.05; †P<.01. Financial Disclosure: None of the authors had any financial conflicts. Author Contributions: Tatsuya Suzuki contributed toward study concept and design, acquisition of subjects and/or data, analysis and interpretation of the data, and preparation of manuscript. Shoko Futami, Yoshimasa Igari, Noriaki Matsumura, Kentaro Watanabe, Hiroshi Nakano, Kenzo Oba, Yuichi Murata, Hitoshi Koibuchi, and Yoshiaki Kigawa all equally contributed to the acquisition of subjects, data, or both and to analysis and interpretation of the data. Sponsor's Role: None.
Dear Editor, Alzheimer's disease (AD) and Creutzfeldt–Jakob disease (CJD) are both characterized by the accumulation in the brain of abnormally folded proteins, a process leading to neurodegeneration.1 In AD, amyloid-β (Abeta) peptide aggregates in extracellular formations known as senile plaques, while in CJD a protease-resistant prion protein (PrP) accumulates in neurons and extracellular amyloid-like aggregates. Co-localizations in the same neuropathological structures of both proteins have been reported in patients affected by CJD,2–5 raising speculation about a possible pathogenic overlap between AD and CJD.6–8 Although codon 129 polymorphism of the prion protein gene (PRNP) represents a major genetic risk factor for CJD,9 there has been a growing interest both in the role of PRNP 129 polymorphism in the elderly and in the neurodegenerative processes, including AD.10–12 A recent meta-analysis in white patients also revealed that PRNP 129 is associated with a significantly higher risk of AD.13 In contrast to these studies, other studies could not find any association between this polymorphism and AD.14–16 Similar results have been reported in AD subjects of non-white ethnicity in Japan17 and South Korea.18 These contradictory results may be due to the different sizes of the population analyzed or to the differences in the distribution of PRNP genotypes between different ethnic groups. Other possible explanations include lack of examination of senile plaque in autopsy findings and premature death prior to the development of AD lesions. We encountered a 79-year-old Japanese man with CJD with the causative point mutation of valine to isoleucine at codon 180 (CJD V180I).19 His polymorphic codons showed methionine/valine heterozygosity at codon 129 and glutamine homozygosity at codon 219. His status progressed rapidly to akinetic mutism, and he died of a lung abscess 12 months after the symptoms of dementia appeared. In magnetic resonance imaging (MRI) of the brain, the cerebral cortex was depicted as high-intensity lesion by T2-weighted, diffusion-weighted (DWI) and fluid-attenuated inversion recovery (FLAIR) imaging, except a portion of the right parietal lobe and both temporal lobes. These MRI findings were highly suggestive of CJD and led us to a premortem diagnosis. Although the abnormal lesions of sporadic CJD (sCJD) seen in MRI are varied, those of CJD V180I are rather uniform. There were no visual or cerebellar symptoms in the early stage, and the medial occipital and cerebellar cortices were not involved until the terminal stage.20 The high-intensity area was depicted along the cortical ribbon by DWI, but not in the optical area of the occipital lobe or cerebellum in the present case. At autopsy, the brain weighed 1180 g. Macroscopically, mild cerebral atrophy was present and the cerebral cortex was clearly thinned in coronal sections. Histopathologically, the cerebral cortex showed severe spongiform change, and neuronal atrophy and loss. However, neurons were relatively preserved compared with those of typical sCJD. Both cerebral cortex and white matter showed gliosis, which tended to be weak in the severest spot of spongiform change. Immunohistochemical staining with anti-PrP monoclonal antibody 3F4 showed a moderate synaptic type of diffuse deposition in the cerebral cortex (Fig. 1). Using an Abeta stain, many senile plaques (Braak stage II) were found extensively, together with spongiform changes and amyloid angiopathy in the cerebral cortex (Fig. 2). There were only a few neurofibrillary tangles. There was no CJD pathology in the cerebellum. Immunohistochemistry with anti-prion protein monoclonal antibody 3F4 showing a moderate synaptic type of diffuse deposition in the cerebral cortex. Using an amyloid-β stain, many senile plaques (Braak stage II) were found extensively in the cerebral cortex. Point mutations in the PRNP gene vary significantly in frequency between countries.21 A V180I mutation is extremely rare in European and North American countries, but it is more common in Japan than anywhere else, where it is restricted to a solely Japanese population.20 Jin et al.20 clarified the clinical characteristics of 9 Japanese CJD V180I patients by comparing them with those of 123 patients with genetically verified sCJD. CJD V180I showed an older onset age (mean, 72.8 years; range, 58–81), slower progression of the diseases, unique clinical symptoms such as frequent higher cortical dysfunction, which was less frequent in sCJD, no visual or cerebellar symptoms, which were important in the diagnosis of sCJD, rare myoclonic jerk, rather than the generalized one in sCJD, no periodic sharp wave complexes (PSWC) in electroencephalogram and no family history. Given the clinical feature of CJD V180I, characterized by older onset age and higher cortical dysfunction, it is reasonable to search carefully for the Alzheimer-type changes in these cases. As far as we know, in each CJD V180I case, the degree of senile plaque formation is variable (Table 1). Matsumura et al.22 reported on a 79-year-old Japanese woman with CJD V180I with sparse senile plaques, and Iwasaki et al.23 described an 80 year-old Japanese man with CJD V180I without senile plaque.19 Numerous sites of senile plaque formation were found only in our case. The significance of the many senile plaques seen in this case is uncertain. These plaques appeared to be related to various factors, such as APOE 4/4, other genetic effects, unknown environmental factors, and merely representing age-related changes. From a review of the published work, Tsuchiya et al. found that the coexistence of pathological features of CJD and AD in the same patient occurs in a very small number of patients, and that there are two forms of this combination in the same patients.6 The first is one in which AD cases develop CJD in the late period of AD and neurofibrillary changes predominate in the brain, in addition to widespread appearance of senile plaques. The second form is CJD cases having AD pathological features without any clinical features typical of AD, in which neurofibrillary changes are usually scarce in the brain, despite the many senile plaques. Our case corresponds to the second form. However, the present case is limited by the fact that we did not examine the APOE genotype of the patient although it is the most important factor for AD. It is felt that our experience in this issue should be made available for further large-scale studies to identify a possible pathogenic overlap between AD and CJD.
Postprandial hyperglycemia is an independent risk factor for cardiovascular disease-related morbidity and mortality, not only in diabetes mellitus (DM) but also in impaired glucose tolerance.Postprandial glycemic levels have been difficult to monitor, but recently 1,5-anhydroglucitol (1,5-AG) levels have proven to be beneficial for this purpose.
