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Possible mechanisms of Alzheimer's disease-related cognitive impairment in patients with diabetes mellitus are shown in this figure. DPP-4i may modulate Aβ accumulation in the process of AD-related cognitive impairment.

ObjectiveCerebral microbleeds (CMBs) are a magnetic resonance imaging (MRI) marker for cerebral small vessel disease. Existing CMBs and those that newly develop are associated with the risks of stroke incidence and recurrence. The purpose of the present study was to investigate the association of oral anticoagulant (OAC) use and the development of new CMBs in cardioembolic stroke patients with atrial fibrillation.Subjects and methodsWe prospectively followed cardioembolic stroke patients with atrial fibrillation who had been hospitalized in the stroke center of our hospital, had been prescribed anticoagulants at discharge, and underwent repeated brain MRI with an interval of at least one year from the baseline MRI. Assessing the presence, number and location of CMBs using T2*-weighted gradient-recalled echo MRI, we used logistic regression models to investigate the associations between OAC use and the incidence of new CMBs. We also examined associations of subsequent stroke with OACs and CMBs during the follow-up.ResultsA total of 81 patients, consisting of 45 patients receiving direct oral anticoagulants (DOACs) and 36 patients receiving warfarin (WF), were analyzed in the present study. Baseline CMBs were observed in 19/81 patients (23.5%) and new CMBs in 18/81 patients (22.2%) on follow-up MRI (median interval, 34 months). Of the 31 new CMBs, 25 (80.6%) developed in the lobar location and 6 (19.4%) in the deep or infratentorial location. New CMBs occurred in 4 patients (10.0%) taking DOACs alone, in 10 patients (35.7%) taking WF alone, in 3 patients (37.5%) taking WF plus antiplatelet agents and in 1 patient (20.0%) taking DOAC plus antiplatelet agent. Regarding location, the new CMBs were the lobar type in 7 of the 10 patients taking WF alone, as well as in 3 of the 4 patients taking DOACs alone. In multivariate analysis, the presence of CMBs at baseline and WF use (vs. DOAC use) were associated with new CMBs (CMB presence at baseline: OR 4.16, 95% CI 1.19-14.44; WF use: OR 3.38, 95% CI 1.02-11.42). The presence of ≥ 2 CMBs at baseline was related to a higher risk of subsequent stroke (OR 7.25, 95% CI 1.01-52.35, P = 0.048).ConclusionOur findings suggest that DOAC compared with WF use at discharge is associated with a lower incidence of new CMBs in cardioembolic stroke patients with atrial fibrillation. Further prospective studies in the clinical setting are needed to confirm our exploratory data.

Aims We investigated the effect of re-coaching on self-injection of insulin and impact of cognitive function in 100 older diabetic patients. Methods We examined patients on a variety of skills and knowledge regarding self-injection of insulin and evaluated the effect of re-coaching the patients after 3 months and 4 years. We also investigated the influence of cognitive impairment (CI) on coaching. Results Skills scores for self-injection of insulin and HbA1c improved significantly 3 months after re-coaching. In 51 patients followed-up for 4 years, skills scores were maintained during the 4 years, while knowledge scores improved after 3 months but then returned to the baseline level. In the group of patients with CI as determined by the Mini-Mental Status Examination, skills scores were similar to those in the group without CI, while knowledge scores were significantly lower as compared with those in the group without CI at any time point. Skills scores were maintained during the 4 years regardless of CI. Conclusion The present study showed that re-coaching in skills for self-injection of insulin was effective in improving and maintaining insulin treatment in older diabetic patients, even if patients had CI.

Background: Large artery atherosclerosis is a major cause of ischemic stroke worldwide. Differential biomarker profiles associated with extra- and intracranial atherosclerosis are a topic of considerable interest. Cystatin C (CysC), a marker of renal function, is a risk factor for cardiovascular disease. Aim: We sought to determine whether CysC levels were associated with extra- and intracranial large artery stenosis (LAS) in patients with acute ischemic stroke. Methods: We retrospectively analyzed data of acute noncardioembolic ischemic stroke patients who were admitted to our stroke center within 5 days from symptom onset. Serum CysC levels were measured using latex agglutination turbidimetric immunoassay. Extra- and intracranial LAS were defined as ≥50% diameter stenosis or occlusion of the relevant internal carotid artery (ICA) and/or middle cerebral artery (MCA) using carotid echography and volume rendering on magnetic resonance angiography. Multivariate logistic analyses were used to assess the association between CysC levels and LAS after adjustment for potential confounders. Results: Of 205 patients (mean age 70.2 years), 76 (37.1%) had LAS. The distribution of LAS was 29 extracranial ICA, 34 intracranial ICA/MCA (8 ICA only, 25 MCA only, 1 ICA+MCA) and 13 tandem stenosis (both extracranial ICA and intracranial ICA/MCA). Levels of CysC were higher in patients with extracranial ICA stenosis than in those with intracranial ICA/MCA stenosis (1.23 ± 0.33 vs. 0.97 ± 0.21 mg/l, p < 0.001). In multivariate analysis, the highest CysC tertile (>1.04 mg/l) was significantly associated with extracranial ICA stenosis (adjusted odds ratio [OR] 5.01, 95% confidence interval [CI] 1.51-16.63, p = 0.009) after adjustment for age, sex, diabetes, chronic kidney disease, current smoking, systolic blood pressure, HDL cholesterol, high-sensitivity C-reactive protein (hs-CRP) and premorbid lipid-lowering drugs use. When CysC was considered as a continuous variable, 1 SD increase in CysC was significantly associated with extracranial ICA stenosis (adjusted OR 3.01, 95% CI 1.58-5.72, p = 0.001). However, there were no significant associations between CysC levels and intracranial ICA/MCA stenosis. In addition, CysC levels showed a weak but statistically significant correlation with hs-CRP levels (r = 0.195, p = 0.021). Using receiver operating characteristic curve analysis, CysC value displayed good performance in discriminating extracranial ICA stenosis (c-statistic 0.79, 95% CI 0.69-0.89, p < 0.001). Conclusions: This preliminary study suggests that higher levels of CysC were independently associated with symptomatic extracranial ICA stenosis, but not with intracranial ICA/MCA stenosis in patients with noncardioembolic stroke. Our findings provide new insights into the link between serum CysC and carotid atherosclerosis.

Aims Type 2 diabetes mellitus (T2DM) is a risk for cognitive decline in older adults. The current study was carried out to determine the factors associated with cognitive decline. Methods The older T2DM patients (aged ≥65 years, mean age 79.2 ± 5.1 years) were observed for 6 years, and the mean values in clinical indicators of participants with and without cognitive decline over a 6-year period were compared. Then, multiple logistic analysis was carried out to determine the factors associated with cognitive decline. Separate analyses were also carried out for each of five cognitive assessments (Mini-Mental State Examination, word immediate and delayed recall, Stroop test, digit symbol substitution). Results In the composite of several cognitive assessments, higher age and a lower level of high-density lipoprotein cholesterol were associated with cognitive decline in older T2DM patients. Lower systolic blood pressure was associated with a decline in delayed word list recall. Higher plasma insulin level was associated with a decline in the Stroop test performance. Conclusion Lower high-density lipoprotein cholesterol was significantly associated with general cognitive decline in older T2DM patients during our 6-year observation. Several other factors were also associated with cognitive assessments of various cognitive domains. Geriatr Gerontol Int 2015; 15: 302–310.

Background and Purpose— Albuminuria, a marker of chronic kidney disease, is associated with an increased risk of incident stroke and unfavorable long-term outcomes. However, the association of albuminuria with short-term outcomes and change in infarct volume in patients with acute small subcortical infarction remains unknown. Methods— We retrospectively reviewed 85 consecutive patients with acute small subcortical infarcts in the lenticulostriate artery territory who were admitted to our stroke center within 24 hours of symptom onset and underwent serial diffusion-weighted imaging (DWI). Albuminuria was determined based on the urinary albumin-to-creatinine ratio obtained from a first morning spot urine after admission. Infarct volume was measured on axial sections of the initial and follow-up DWI. Early neurological deterioration (END) was defined as an increase of ≥2 points in the National Institutes of Health Stroke Scale score during the first 5 days after admission. Results— Albuminuria (UACR ≥30 mg/g creatinine) was observed in 14 of 18 patients with END (77.8%) and in 25 of 67 patients without END (37.3%), P =0.002. Multivariate logistic regression analysis revealed that albuminuria was associated with END after adjustment for age, low estimated glomerular filtration rate (2 ), and infarct volume on initial DWI (odds ratio, 6.64; 95% confidence interval, 1.62–27.21; P =0.009). In addition, albuminuria was an independent predictor of increase in infarct volume using multivariate linear regression analysis ( β coefficient=0.217; P =0.038). Conclusions— Our findings suggest that albuminuria is associated with END and infarct volume expansion in patients with small subcortical infarcts in the lenticulostriate artery territory.

Background/Aims: In recent years, the relationship between chronic kidney disease (CKD) and cognitive impairment has been attracting attention. Cerebral small vessel disease (SVD) is also associated with an increased risk of cognitive impairment. However, it is still unknown whether CKD markers are associated with cognitive impairment independently of SVD in elderly diabetic patients. Methods: Seventy-nine type 2 diabetic patients (mean age, 76.0 years) were enrolled in the present study. CKD was defined as the presence of albuminuria and/or a low estimated glomerular filtration rate (eGFR 2). SVD was evaluated by the presence and severity of silent brain infarcts (SBIs) and white matter lesions (WMLs) on brain magnetic resonance imaging. Neuropsychological tests were assessed using four validated cognitive instruments. Results: In multiple linear regression analyses, albuminuria was associated with worse modified Stroop Color Word scores (β = 0.284, p = 0.017) and low eGFR was associated with reduced Digit Symbol Substitution scores (β = -0.224, p = 0.026) after adjustment for age, sex, education years, diabetes duration, hypertension, multiple SBIs, and advanced WMLs. In contrast, there were no significant associations between CKD markers and Mini-Mental State Examination or Word Recall scores. Conclusion: Our findings suggest that albuminuria and low eGFR are associated with frontal lobe dysfunction independently of SVD in elderly type 2 diabetic patients.

Retinal microvascular abnormalities may be useful predictive imaging marker for cerebral small vessel disease. Learning from retinal signs may provide clues to understanding pathophysiology of lacunar stroke and subclinical cerebrovascular diseases in diabetic patients.

Background/Aims: We conducted a 3-year longitudinal study concerning factors associated with changes in brain atrophy in elderly diabetic patients. Methods: We evaluated hippocampal and global brain atrophy using automatic voxel-based morphometry of structural magnetic resonance images, 4 cognitive function tests, and cerebral small vessel disease (SVD) in 66 diabetic patients. Results: During the 3-year follow-up, hippocampal and global brain atrophy advanced, and cognitive functions worsened. For changes in hippocampal atrophy, changes in estimated glomerular filtration rate (eGFR), albuminuria, and being an ApoE ε4 carrier were independent factors; change in the number of silent brain infarctions was an independent factor for changes in global brain atrophy. A significant association of changes in eGFR and albuminuria with hippocampal atrophy remained after adjusting for confounders including SVD. Both types of brain atrophy at baseline were significantly correlated with cognitive impairment at baseline and especially associated with changes in delayed word recall during the follow-up after adjusting for confounders. Conclusion: Changes in eGFR and albuminuria during follow-up were independent risk factors for hippocampal atrophy, which was associated with decline in delayed word recall, suggesting that management of chronic kidney disease may prevent the progression of hippocampal atrophy.

Diabetes patients have more than double the risk of ischemic stroke compared with non‐diabetic individuals, and its neuroimaging characteristics have important clinical implications. To understand the pathophysiology of ischemic stroke in diabetes, it is important to focus not only on the stroke subtype, but also on the size and location of the occlusive vessels. Specifically, ischemic stroke in diabetes patients might be attributed to both large and small vessels, and intracranial internal carotid artery disease and small infarcts of the posterior circulation often occur. An additional feature is that asymptomatic lacunar infarctions are often seen in the basal ganglia and brain stem on brain magnetic resonance imaging. In particular, cerebral small vessel disease (SVD), including lacunar infarctions, white matter lesions and cerebral microbleeds, has been shown to be associated not only with stroke incidence, but also with the development and progression of dementia and diabetic microangiopathy. However, the pathogenesis of cerebral SVD is not fully understood. In addition, data on the association between neuroimaging findings of the cerebral SVD and diabetes are limited. Recently, the clinical importance of the link between cerebral SVD and retinal microvascular abnormalities has been a topic of considerable interest. Several clinical studies have shown that retinal microvascular abnormalities are closely related to cerebral SVD, suggesting that retinal microvascular abnormalities might be pathophysiologically linked to ischemic cerebral SVD. We review the literature relating to the pathophysiology and neuroimaging of cerebrovascular disease in diabetes, and discuss the problems based on the concept of cerebral large and small vessel disease.

It is well recognized that the prevalence of dementia is higher in diabetic patients than non‐diabetic subjects. The incidence of diabetes has been increasing because of dramatic changes in lifestyles, and combined with longer lifespans as a result of advances in medical technology, this has brought about an increase in the number of elderly diabetic patients. Together, aging and diabetes have contributed to dementia becoming a serious problem. Progression to dementia reduces quality of life, and imposes a burden on both patients themselves and the families supporting them. Therefore, preventing the complication of dementia will become more and more important in the future. Although many mechanisms have been considered for an association between diabetes and cognitive dysfunction, glucose metabolism abnormalities such as hyperglycemia and hypoglycemia, and insulin action abnormalities such as insulin deficiency and insulin resistance can be causes of cognitive impairment. Recent large‐scale longitudinal studies have found an association between glycemic control and cognitive decline, although it is still unclear how cognitive decline might be prevented by good glycemic control. However, at an early stage, it is necessary to detect moderate cognitive dysfunction and try to reduce the risk factors for it, which should result in prevention of dementia, as well as vascular events. In the present review, in addition to outlining an association between diabetes and cognitive function, we discuss how glycemic control and cognitive decline are related.

BACKGROUND: Brain microbleeds (BMBs) detected on gradient echo T2*-weighted magnetic resonance imaging (GE-MRI) may be pathophysiologically linked to ischemic cerebral small-vessel disease (SVD) and increased risk of future hemorrhagic stroke. Chronic kidney disease (CKD) has been associated with the presence of BMBs in stroke patients. However, the relationship between CKD markers and BMBs in stroke-free populations is unknown. METHODS: Two hundred and eighty-five hypertensive subjects (mean age 68.6 years) without neurological symptoms were enrolled from a hospital-based outpatient clinic and all participants underwent GE-MRI. We calculated urinary albumin/creatinine ratio (UACR) from morning spot urine and the estimated glomerular filtration rate (eGFR) in serum samples. Multivariate logistic regression analysis was used to evaluate the association between these kidney biomarkers and the presence and location of BMBs, controlling for age, sex, use of antihypertensive or antithrombotic drugs, and MRI findings. RESULTS: BMBs were observed in 48 (16.8%) patients. Median UACRs were significantly higher in patients with deep or infratentorial BMBs than in patients with pure lobar BMBs (54 vs. 17 mg/g creatinine, P = 0.04). No significant differences were found between eGFR levels and the location of BMBs. Microalbuminuria (UACR >30- ≤300 mg/g creatinine), but not low eGFR level was significantly associated with higher prevalence of deep or infratentorial BMBs (odds ratio (OR): 3.16, 95% confidence interval (CI): 1.34-7.44, P = 0.009) even after adjustment for potential confounding factors. CONCLUSIONS: Microalbuminuria is closely associated with the prevalence of deep or infratentorial BMBs in hypertensive patients. Our findings provide new insights into the association between risk factors and the distribution of BMBs.

Aims We conducted a 3-year longitudinal study concerning an association between cognitive function and cerebral small vessel disease (SVD) seen on magnetic resonance imaging (MRI) in elderly type 2 diabetic patients. Methods Four cognitive function tests – MMSE, word recall, Digit Symbol Substitution (DSS), and Stroop Color Word (Stroop) – were performed in 67 diabetic patients twice in 2006 and 2009. SVD was diagnosed as silent brain infarct (SBI) and white matter lesions (WMLs) according to MRI. Results Number of SBI was significantly correlated with a decline in DSS and Stroop tests, while WMLs grade was only associated with it in DSS tests after adjustment for age, gender, education years, the presence of hypertension and dyslipidemia, and smoking. Severity of SVD at baseline was stronger associated with cognitive function after the 3-year follow-up than at baseline. WMLs progression was associated with more rapid decline of DSS tests compared to a group without progression. Conclusions SVD seen on MRI is a good marker for predicting future cognitive decline, and monitoring of treatment through the use of such markers is expected to maintain a good quality of life for elderly diabetic patients.

The aim of this study was to examine whether additional repeated counselling further improves the health effects of limited, highly individualized lifestyle guidance in metabolic syndrome. One hundred and nine previously untreated metabolic syndrome patients received highly standardized and individualized lifestyle guidance for weight loss. A tentative goal of 5% weight reduction over the course of 2 months was set. Patients were then randomly assigned to either the multiple guidance group who received further counselling every 2 months (n = 52) or the single guidance group who received no further guidance until the final assessment 6 months later (n = 57). Baseline data between the multiple guidance and single guidance groups were similar. Body weight and waist circumference were significantly reduced, and liver function, lipid profiles and glucose metabolism were significantly improved in both groups. After adjustment for baseline data, the multiple guidance group showed considerably higher reduction in waist circumference and fasting blood sugar concentration than the single guidance group. These data suggest that additional counselling further improved the antidiabetic effects of limited individualized lifestyle guidance in metabolic syndrome.

The average life expectancy of diabetic patients has been increasing year-by-year in Japan as a result of tremendous advances in medical technology, although it remains shorter than that of people without diabetes. However, their healthy life expectancy does not always keep pace. One of the most important reasons for healthy diabetic patients' life expectancy not being as long is thought to be the complication of dementia, and previous large-scale epidemiological studies have found that the incidence of dementia in diabetic patients is two- to threefold higher than in non-diabetic people. Therefore, prevention of dementia in an increasing population of elderly people with diabetes is an important issue in diabetes treatment. Many underlying mechanisms of cognitive impairment have been studied, but they are still yet to be fully clarified. Up until now, those involving hyperglycemia, hypoglycemia and insulin disorders, such as insulin deficiency and insulin resistance, have been considered to be the main mechanisms1. First, hyperglycemia might be directly involved in nerve degeneration in the brain through advanced glycation end-products and oxidative stress, and vascular risk factors concomitant with hyperglycemia cause cerebrovascular disease, leading to cognitive dysfunction. Second, a consensus is being reached that severe hypoglycemia is associated with cognitive decline. Third, deficiency in insulin secretion impairs brain metabolism, resulting in a decline in cognitive functions, such as memory. Accumulation of amyloid-β peptide (Aβ) in the brain is the characteristic pathology for Alzheimer's disease, but insulin induces the release of Aβ to the brain exterior. Insulin also promotes the expression of insulin-degrading enzyme (IDE), which degrades Aβ. In contrast, in the case of hyperinsulinemia, IDE is consumed, resulting in accumulation of Aβ. In addition, insulin resistance in the brain has recently drawn considerable attention as a potent mechanism of Alzheimer's disease. An association between diabetic microvascular disease (in particular retinopathy and nephropathy) and cognitive impairment has been reported. Therefore, evaluation of the retina and kidney could be a way to screen for an underlying vascular etiology in people with cognitive impairment. It is thought that this association is based on the same metabolic abnormality rather than cause and effect, as organs such as the retina and kidney and cerebral small vessels are considered to have a similar embryological origin and structures, and share common physiological characteristics. However, it cannot be said that an association between microvessel damage in the retina and kidney is necessarily confined to diabetics, though it is likely that hyperglycemia and insulin resistance in diabetic patients impair microvessels through endothelial dysfunction as a result of glycation, oxidative stress and increased activity of the polyol pathway as compared with non-diabetic people. In the brain, these factors might affect the incidence and progression of cerebral small vessel disease (SVD), such as asymptomatic brain infarction, white matter lesions and microbreeds, which are also reported to be associated with cognitive impairment, in addition to the incidence of ischemic stroke2. As a mechanism, it is thought that endothelial dysfunction in brain microvessels might cause disruption of the blood–brain barrier, leading to impaired Aβ clearance as well as incidence of SVD. Therefore, from the standpoint of diabetic vascular disease, endothelial dysfunction could play a central role in cognitive impairment through microvessel disease (Figure​(Figure11). Figure 1 Possible mechanism for the incidence of cognitive impairment in people with type 2 diabetes from the standpoint of diabetic vascular disease. Although an increased risk of cognitive impairment in patients with diabetic retinopathy was found in the reviewed studies, a relationship between severity of diabetic retinopathy and cognitive impairment has not been established3. Also, in Diabetes Care, Crosby-Nwaobi et al.4 recently published findings opposite to those that had previously been reported. They stated that cognitive impairment was not associated with the degree and severity of diabetic retinopathy, and on the contrary, that cognitive decline was greater in patients with no and mild retinopathy as compared with those with advanced retinopathy. In their study, diabetic patients with advanced retinopathy, as compared with those with no and mild retinopathy, had a comparably longer duration of diabetes, higher levels of glycosylated hemoglobin A1c, frequent nephropathy and cardiovascular disease, which are reportedly associated with cognitive impairment. In contrast, education levels were lower in patients with no and mild retinopathy. Naturally enough, the effects of such confounders cannot be disregarded, although the study was adjusted for them. Another issue of their study was that they evaluated patients with no and mild retinopathy together, as the number of patients with no retinopathy was limited, and they also excluded severe retinopathy. It is likely that subtle changes in endothelial cells have already occurred in mild retinopathy and, therefore, differences between no and mild retinopathy should be compared. Also, as it has recently been reported that flow disturbances within the ocular blood vessels of patients with type 2 diabetes were atherogenic changes of coronary arteries, further studies on a relationship between ocular blood vessel flow and cognitive function are desirable. In contrast, it is generally agreed that chronic kidney disease might be associated with cognitive impairment. However, chronic kidney disease involves albuminuria and estimate glomerular filtration rate (eGFR) decline, and it is still controversial as to which of these markers is more strongly associated with cognitive function. It has been reported that blockers of the renin–angiotensin system decreased albuminuria and protected against cognitive decline as well. In addition, parallel changes in severity and improvement of chronic kidney disease and some cognitive functions have been reported in the recent subanalysis of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial5. In this regard, we reported that changes in albuminuria, but not eGFR, were strongly correlated with changes in word recall during a 3-year follow up in elderly diabetic patients6. However, in that study, a cross-sectional evaluation of an association between cognitive functions and albuminuria or eGFR produced different results from those of a longitudinal evaluation. Results appear to differ depending on which parameter, eGFR or albuminuria, is used and whether it is a cross-sectional or a longitudinal study. Such disagreement could also be seen in an association between retinopathy and cognitive function. Unfortunately, regarding an association with retinopathy, there have been few longitudinal studies, and to our knowledge there has been no study on an association between changes in cognitive function and retinopathy as a result of therapy. If the findings of Crosby-Nwaobi et al.4 are verified, it is likely that other factors might be present in the relationship with retinopathy, unlike nephropathy. As retinal abnormalities could have a more direct influence in brain damage through disruption of the blood–brain barrier in the retina, there might be some differences in the effect on cognition between retinopathy and nephropathy. There have been a few reports regarding an association between peripheral neuropathy and cognitive impairment. However, interestingly, it has been reported that progression of diabetic nephropathy and retinopathy depended on the final severity of diabetic neuropathy7. Therefore, it is likely that diabetic neuropathy is also associated with cognitive decline. In any case, further prospective studies on these associations will be required. Recently, many studies have been carried out on the early detection of cognitive impairment, but, unfortunately, they have produced hardly any useful and simple clinical tools. Most clinicians will agree that preventing the incidence or advance of microangiopathy can play an important role in maintaining quality of life and reducing mortality in patients with diabetes mellitus. Also, as microangiopathy is routinely evaluated in the clinical setting, if an association between cognitive impairment and microangiopahy is clarified, and a reduction of microangiopathy reduces the rate of cognitive decline, the monitoring and treatment of microangiopathy could possibly be a tool for preventing cognitive decline in people with diabetes.

We investigated the influence of the reciprocal association between serum levels of high-sensitivity C-reactive protein (hs-CRP) and intercellular adhesion molecule-1 (sICAM-1) on the risk of brain infarction in type 2 diabetic patients. One hundred seventy nine middle-aged and elderly diabetic patients without histories of cardiovascular events were followed up for an average of 8 years. Fourteen patients developed symptomatic brain infarction (BI) during follow-up. These patients had significantly higher blood pressure, longer duration of diabetes, silent brain infarction, microvascular complications such as macroalbuminuria, and higher creatinine, sICAM-1 and hs-CRP levels at baseline as compared with those without BI. A high risk of stroke was observed in patients with high levels of sICAM-1 (260microg/L) and hs-CRP (0.83mg/L) at baseline, respectively, and patients with high levels of both were more likely to develop BI. In addition, sICAM-1 levels were significantly correlated with systolic blood pressure and glycemic control index, whereas hs-CRP levels were correlated with fasting insulin levels, HDL-cholesterol, triglycerides, and uric acid. Consequently, sICAM-1 and hs-CRP levels were, respectively, reflected in different cardiovascular risk factors. This study suggests that both measurements of hs-CRP and sICAM-1 levels are useful as a predictor of future stroke in diabetic subjects.

Background: We investigated what factors were associated with brain atrophy in elderly patients with type 2 diabetes. Methods: We evaluated hippocampal and whole brain atrophy with automatic voxel-based morphometry of structural magnetic resonance image (MRI), voxel-based specific analysis regional analysis for Alzheimer’s disease (VSRAD), in 70 diabetic subjects and 35 non-diabetic subjects. Cognitive function tests – MMSE, word recall (immediate and delayed), Digit Symbol Substitution test (DSST), and Stroop Color Word (Stroop) test were performed. Cerebral small vessel disease (SVD) was diagnosed as silent brain infarct and white matter lesions (WMLs) according to MRI. Results: Significantly stronger hippocampal and whole brain atrophy were observed in diabetic patients than non-diabetic subjects. The levels of glycosylated hemoglobin A1c were significantly correlated with indices of hippocampal and whole brain atrophy. In diabetic subjects, hippocampal atrophy was independently associated with age, albuminuria, serum intercellular adhesion molecules -1 levels and lower diastolic blood pressure, while whole brain atrophy was associated with age and subcortical WMLs grade. Regarding an association between albuminuria and brain atrophy, significant hippocampal and whole brain atrophy were found in patients with albuminuria after adjusting for confounders. Hippocampal atrophy was independently associated with word recall and Stroop test after adjustment, while whole brain atrophy was also associated with word recall, DSST, and Stroop test, although the association weakened after adding degree of SVD to the variables. Conclusions: Albuminuria was an independent risk factor for brain atrophy, especially hippocampal atrophy, which was associated with cognitive impairment, suggesting that the management of albuminuria may prevent progression of brain atrophy resulting in cognitive decline. In addition, the usefulness of VSRAD to support diagnosis of cognitive decline associated with brain atrophy was shown in daily clinical setting.

The purpose of this study was to investigate the association between the progression of silent cerebral infarction (SCI) and levels of soluble adhesion molecules and high-sensitivity C-reactive protein (hs-CRP) in type 2 diabetic patients. One hundred twenty middle-aged and elderly diabetic patients without histories of vascular events were followed up for a period of 3 years. We measured levels of soluble intercellular adhesion molecule 1 (sICAM-1), vascular cell adhesion molecule 1, E-selectin, and hs-CRP and assessed brain ischemic lesions by magnetic resonance imaging at baseline and 3 years later. Silent cerebral infarction was observed in 13% of the patients at baseline, and these patients were significantly older and had significantly higher blood pressure than those without SCI. Thirty-two patients had newly diagnosed SCI after 3 years. There were no significant differences in factors such as age, blood pressure, and diabetic control between patients without SCI and those in whom it was newly diagnosed. However, only sICAM-1 levels, but not the other soluble adhesion molecules or hs-CRP, were associated with the progression of SCI, and this relationship remains after adjustment for risk factors. On the other hand, higher levels of sICAM-1 and hs-CRP at baseline were observed in 7 patients who were excluded from the present study because of the onset of symptomatic cerebral infarction during follow-up. Our present study suggests that sICAM-1 levels may be a potential marker for SCI, which may lead to future stroke and vascular dementia, and that this marker could be useful in monitoring disease progression and as a surrogate marker in treatment studies.

Diabetes is rapidly increasing worldwide. In 2011, approximately 366 million people had diabetes, with a prevalence of approximately 8.3%, according to a report by the International Diabetes Federation. Approximately half of the diabetic population is concentrated in Asian countries, and there has been a particularly rapid increase in China and India, where diabetes is a major public health burden. As diabetes‐related mortality rapidly increases from the age of 40 years onwards, to maintain quality of life, it is important to prevent not only microvascular complications, but also macrovascular complications from the early stage. Needless to say, it is important to prevent cardiovascular events in diabetics, and this is particularly so for Asian populations in whom the prevalence of stroke is higher than in Western populations. Many epidemiological studies have shown that diabetic patients have an approximately two to threefold higher risk of incident stroke compared with non‐diabetic subjects. Prevention of stroke will raise quality of life and promote longevity. For clinicians, an in depth knowledge of the relationship between diabetes and stroke is very important from the aspect of preventive medicine.

Recent progress in medical technology has markedly improved the prognosis for people with diabetic mellitus. In contrast, rapid changes in lifestyles have increased the number of people with impaired glucose metabolism, resulting in greater numbers of elderly diabetic patients. It is generally accepted that impaired cognitive function is more common in patients with diabetes than those without, regardless of whether the diabetes is type 1 or type 21. Future progression to dementia reduces quality of life and imposes a burden on both patients themselves and the families supporting them. Therefore, preventing the complication of dementia will become even more important than it is now. Although many factors are thought to be involved in impaired cognitive function, the mechanisms are very complex and have not been fully resolved1,2. We have to discuss mechanisms separately for patients with type 1 and type 2 diabetes mellitus, because of the different backgrounds. In particular, evaluation of the contribution of various factors to cognitive dysfunction, which include concomitant hypertension, dyslipidemia and complicated cerebral vascular disease, as well as changes in the brain and other organs as a result of aging, is difficult for elderly type 2 diabetes because they are very intricate in nature. Also, the two major types of dementia – cerebral vascular dementia and Alzheimer’s disease, and a mixed type including aspects of both – should be taken into consideration in middle‐aged and elderly subjects. However, in adolescent and middle‐aged type 1 diabetic patients, a consideration of the complications of Alzheimer’s disease might be excluded and only the direct effects as a result of hyperglycemia and hypoglycemia might be investigated. However, it is noteworthy that cognitive impairment observed in type 1 diabetes is generally subtle and it is unknown whether it will actually lead to future dementia. In addition, few large‐scale, longstanding longitudinal studies have been carried out. The DCCT/EDIC study, in which 1144 patients with type 1 diabetes were followed up for an average of 18 years and a variety of cognitive function tests were carried out, is a very interesting and significant study. It did not find evidence for a substantial long‐term decline in cognitive function in the large group of patients who were carefully followed up, despite relatively high rates of recurrent severe hypoglycemia. Higher glycated hemoglobin levels were associated with moderate declines in motor speed and psychomotor efficiency, but not other domains3. Recently, an association of other biomedical risk factors and decreased cognitive functioning has been reported in Diabetologia4. Although a modest association between cognitive impairment and smoking or hypertension was found by carrying out univariate analysis on the study results, retinal and renal complications, as well as glycemic control, were each independently associated with a decline in cognitive function, specifically affecting measures of psychomotor efficiency. These findings might indicate that long‐term hyperglycemia has an adverse effect not only on the microvasculature of the retina and kidney, but also on the small vessels in the brain. In fact, it has been previously reported that retinopathy was related to cognitive impairment in both type 1 and type 2 diabetes, and recently an association between the brain and kidney has been focused on, because of their similar microvasculature structures1,2. Several mechanisms that mediate the toxic effects of hyperglycemia, such as oxidative stress, accumulation of advanced glycation end‐products and increased activity in the polyol pathway, have been implicated in damage to the brain, leading to cognitive dysfunction. However, most of the respective studies were carried out in animal models and such an association remains unclear. Interestingly, recent research using functional magnetic resonance imaging and positron emission tomography has detected elevated levels of brain glucose and glutamate, an excitatory neurotransmitter that can cause neuronal damage in high concentrations, in prefrontal regions in type 1 diabetic patients as compared with non‐diabetic controls. In addition, poorer metabolic control has been seen to be inversely correlated with levels of N‐acetylasparate and choline‐containing compounds in white matter and deep grey matter. These findings of study suggest that axonal injury, demyelination and increased membrane proliferation have occurred and might be a consequence of glucose neurotoxicity. This non‐vascular pathway could explain, at least in part, the recent observation that adults with a long history of type 1 diabetes manifest psychomotor slowing associated with microstructure damage to white matter fiber tracts1,4. In agreement with the present article, psychomotor efficiency, which reflects frontal lobe function, has been identified in other studies as the cognitive domain most often affected in patients with diabetes. Although the reason why frontal function is impaired in diabetic patients has not been clarified fully, it is thought to be a possible mechanism for prefrontal loop impairment as a result of silent brain infarct (SBI) in basal ganglia of the brain and hyperglycemia‐induced white matter lesions, which are likely to be found in diabetic patients. In addition to hyperglycemia, an association between hypoglycemia attacks and decline in cognitive function has also been previously debated. Many studies on this theme have supported such a relationship, regardless of whether subjects have had type 1 or type 2 diabetes mellitus. However, clear evidence showing that frequent hypoglycemic episodes will lead to a longstanding decline in cognitive function in type 1 diabetes was not produced. In the DCCT/EDIC study, no associations between recurrent severe hypoglycemic attacks and a decline in cognitive function were observed. It might be because patients recruited for the DCCT/EDIC study were well controlled. Namely, if patients were carefully followed up, persistent hyperglycemia might have had a greater adverse effect on cognitive function than hypoglycemia. The relationship between cognitive function and hypoglycemic attacks is also discussed in a commentary in Diabetologia5. As aforementioned, it seems reasonable to suppose that brain damage based on hyperglycemia is associated with a decline in cognitive function. Therefore, exaggerating things a bit, we could say that cognitive impairment is the fourth diabetic microvascular disease. If this is so, a hypothesis might be developed. Impaired endothelial function is known to contribute to the progression of diabetic vascular complications. Also, damage to the brain has been reported to be associated with impairment of the blood–brain barrier and such endothelial dysfunction might cause focal neural damage or ischemic changes through small vascular vessels, leading to cognitive impairment in type 1 diabetic patients. A partially similar phenomenon was found in type 2 diabetic patients. We have reported that levels of soluble adhesion molecules reflect endothelial function, especially intercellular adhesion molecule‐1, and there were associations with progression of cerebral small vessel disease and cognitive function in our cross‐sectional and longitudinal studies in middle‐aged and elderly type 2 diabetic patients6. It is unlikely that there would be visual findings in magnetic resonance imaging indicating SBI and white matter lesions in relatively young type 1 diabetic patients. However, one could easily suppose that longstanding endothelial dysfunction would cause progression in cerebral small vessel lesions. Endothelial function is impaired by not only hyperglycemia, but also many other factors, such as hypertension, dyslipidemia and smoking, and it has been reported that such impairment in middle‐aged people will lead to a future decline in cognitive function. Therefore, the early inhibition of such risk factors is important in the prevention of dementia7. However, in contrast with young type 1 diabetes patients, the complications of Alzheimer’s disease should be always taken into account in elderly people. Although an association between Alzheimer’s disease and diabetes is becoming clearer, much still remains to be discovered. It has been suggested that the weakened action of insulin as a result of hyperinsulinemia or lack of insulin might interfere with Aβ metabolism by stimulating its secretion and inhibiting its breakdown. In fact, impaired cognition has been reported in patients with hyperinsulinemia and hypertension, and poorly controlled diabetic patients1,2,8. Last, the effect of genetic factors should also be considered. The APOE e4 allele is a representative genetic factor for Alzheimer’s disease. However, having this genetic factor is not necessarily associated with incidence of Alzheimer’s disease and it is thought that daily habits have a great impact in this regard. Recently, a variety of interesting studies have been carried out on modification of diabetes by this genotype. In summary, many factors, as shown in Figure 1, contribute to cognitive dysfunction in type 1 and type 2 diabetes mellitus. Therefore, one might say that better control of hyperglycemia, hypertension and dyslipidemia, in addition to improvement of daily lifestyle – with respect to such aspects as smoking, exercise and diet – will prevent not only the progression of diabetic vascular disease, but also a future decline in cognitive function. Further examination of the results of large scale, longstanding research, such as the DCCT/EDIC study, is expected to clarify the respective mechanisms and help the prevention of dementia in people with diabetes mellitus. Figure 1 Summary of possible mechanistic contributors to cognitive dysfunction seen in diabetes mellitus.

In 1999, the Japan Diabetes Society (JDS) launched the previous version of the diagnostic criteria of diabetes mellitus, in which JDS took initiative in adopting glycated hemoglobin (HbA1c) as an adjunct to the diagnosis of diabetes. In contrast, in 2009 the International Expert Committee composed of the members of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) manifested the recommendation regarding the use of HbA1c in diagnosing diabetes mellitus as an alternative to glucose measurements based on the updated evidence showing that HbA1c has several advantages as a marker of chronic hyperglycemia2–4. The JDS extensively evaluated the usefulness and feasibility of more extended use of HbA1c in the diagnosis of diabetes based on Japanese epidemiological data, and then the ‘Report of the Committee on the Classification and Diagnostic Criteria of Diabetes Mellitus’ was published in the Journal of Diabetes Investigation5 and Diabetology International6. The new diagnostic criterion in Japan came into effect on 1 July 2010. According to the new version of the criteria, HbA1c (JDS) ≥6.1% is now considered to indicate a diabetic type, but the previous diagnosis criteria of high plasma glucose (PG) levels to diagnose diabetes mellitus also need to be confirmed. Those are as follows: (i) FPG ≥126 mg/dL (7.0 mmol/L); (ii) 2‐h PG ≥200 mg/dL (11.1 mmol/L) during an oral glucose tolerance test; or (iii) casual PG ≥200 mg/dL (11.1 mmol/L). If both PG criteria and HbA1c in patients have met the diabetic type, those patients are immediately diagnosed to have diabetes mellitus5,6.

Type 2 diabetes mellitus (T2DM) is a risk for cognitive decline in older adults. The current study was carried out to determine the factors associated with cognitive decline.The older T2DM patients (aged ≥65 years, mean age 79.2 ± 5.1 years) were observed for 6 years, and the mean values in clinical indicators of participants with and without cognitive decline over a 6-year period were compared. Then, multiple logistic analysis was carried out to determine the factors associated with cognitive decline. Separate analyses were also carried out for each of five cognitive assessments (Mini-Mental State Examination, word immediate and delayed recall, Stroop test, digit symbol substitution).In the composite of several cognitive assessments, higher age and a lower level of high-density lipoprotein cholesterol were associated with cognitive decline in older T2DM patients. Lower systolic blood pressure was associated with a decline in delayed word list recall. Higher plasma insulin level was associated with a decline in the Stroop test performance.Lower high-density lipoprotein cholesterol was significantly associated with general cognitive decline in older T2DM patients during our 6-year observation. Several other factors were also associated with cognitive assessments of various cognitive domains.

Aims/Introduction We investigated the effect of renal impairment on cognitive function during a 3-year follow up in elderly type 2 diabetic patients, and an association with microinflammation. Materials and Methods Four cognitive function tests – Mini-Mental State Examination (MMSE), word recall, Digit Symbol Substitution (DSS) and Stroop Color Word – were carried out in 67 patients. Renal impairment was defined as the presence of albuminuria and a decline in estimated glomerular filtration (eGFR)

OBJECTIVE To determine whether long-term treatment with an angiotensinconverting enzyme (ACE) inhibitor has a beneficial effect on the urinary microalbumin excretion and renal function in non-insulin-dependent diabetes mellitus (NIDDM) patients, enalapril (5 mg/day) was administered for 48 months. RESEARCH DESIGN AND METHODS Fifty-two patients with NIDDM who had persistent microalbuminuria in the range of 20–300 mg/24 h, serum creatinine < 106.1 μM 1.2 mg/dl), supine systolic blood pressure (BP) RESULTS After 48 months, urinary albumin excretion (UAE) was markedly reduced in group NE from 102.4 ×/÷ 1.3 to 55.5 ×/÷ 1.3 mg/24 h (P < 0.005), whereas no significant change occurred in group NC. In the well-controlled hypertensive groups, a significant reduction in UAE occurred in group HE (P < 0.05), whereas no significant change occurred in group HC. No changes in creatinine clearance, BP, or blood glucose control were seen during the study. CONCLUSIONS Treatment with enalapril for 48 months may have a beneficial effect on the decline of microalbumin excretion in NIDDM patients.

グルコオリゴ糖および生菌剤(S. faecalis, C. butyricum及びB. mesentericusを含む)が盲腸内細菌叢をはじめとする腸管内容物の修飾や産卵成績にどの様な影響を及ぼすかを明らかにするために,84週齢の産卵鶏を用い2つの実験を行った。実験1はグルコオリゴ糖の効果を,また実験2ではグルコオリゴ糖と生菌剤の協同作用について検討を加えた。実験1および2において,産卵率及び盲腸内細菌叢には対照区に比して有意な変化が認められなかった。両実験において新鮮糞中の酢酸含量に変化は認められなかったが,乳酸含量はグルコオリゴ糖の添加で高まり,実験1においては有意な差が認められた。実験2において,投与した生菌は盲腸内で生存することが確認されたが,グルコオリゴ糖の添加により生菌数が増加することはなかった。グルコオリゴ糖により高められた乳酸は,他の有害菌の増殖を抑制する効果が期待でき,腸内環境改善因子になりうることが示唆された。

Background/Aims: Although recent evidence has indicated that type 2 diabetes mellitus (T2DM) in the elderly is a risk factor for cognitive dysfunction or dementia, few studies have prospectively observed this potential cognitive decline. In the current study, we performed cognitive assessments at baseline and after 3 years in the same patient group in an attempt to reveal the contributions of diabetes-related factors to the increased decline in cognitive function in elderly patients with T2DM. Methods: We recruited 55 consecutive T2DM patients with a Mini-Mental State Examination (MMSE) score ≧24 from the Diabetic Center at the Chubu Rosai Hospital. These patients ranged in age from 65 to 85 years. Cognitive and clinical assessments, including brain MRI, were performed at baseline and at the 3-year follow-up. Results: The higher plasma insulin and HbA1c levels observed at baseline were significantly associated with a worse cognitive performance at baseline and a more neurocognitive decline at the follow-up visit. Conclusion: The current prospective study suggests that higher insulin and glycohemoglobin levels may be associated with diabetes-related cognitive dysfunction.

The pathophysiology underlying the high incidence of post-stroke infectious complications has not been fully understood. We measured the respiratory burst of neutrophils as an index of their bactericidal function in patients with haemorrhagic stroke, and we also measured the plasma concentrations of noradrenalin, cortisol and neutrophil function-related amino acids. Blood samples were obtained from patients who underwent emergency craniotomies for haemorrhagic stroke (n=11) or CT-guided stereotaxic aspiration of intracerebral haematomas (n=6). Neutrophils were isolated, and their chemiluminescence response to N-formyl-methionyl-leucyl-phenylalanine was measured. Healthy volunteers served as controls (n=15). In patients with stroke, the chemiluminescence response of the isolated neutrophils was significantly lower than in the controls, and it was significantly inversely correlated with the plasma noradrenalin concentration. By Day 30, this value approached control levels. Other parameters measured were not significantly correlated with the chemiluminescence response. Stroke-induced suppression of the neutrophil respiratory burst may be responsible for frequent post-stroke infectious complications.

Silent brain infarction (SBI) is often detected on MR imaging, however the pathogenesis is still unclear. We aimed to investigate and compare the association of soluble adhesion molecules and C-reactive protein levels with the prevalence of SBI in patients with and without diabetes mellitus. We recruited 130 patients (mean age 59.6 +/- 7.6 yrs) with type 2 diabetes and 130 age- and sex-matched non-diabetic subjects. All subjects underwent head MRI to determine SBI. We measured levels of soluble intercellular adhesion molecule 1(sICAM-1), vascular cell adhesion molecule 1(sVCAM-1), and high sensitivity C-reactive protein (hs-CRP) and evaluated intima-media complex thickness (IMT) in common carotid arteries by ultrasound B-mode imaging. SBI was present in 36 (27.7%) of the diabetic patients and 31 ( 23.8%) of the non-diabetic subjects. Levels of sICAM-1, sVCAM-1 and IMT were all significantly higher in diabetic patients than in non-diabetic subjects, and were significantly increased in both subjects with SBI. IMT was only positively correlated with sVCAM-1 levels in diabetic and non-diabetic subjects. On the other hand, hs-CRP levels were not significantly different in both subjects with and without SBI. In addition, sICAM-1 levels were associated with a significantly higher relative risk for the prevalence of SBI in diabetic patients after multivariate adjustment. Our study suggests that the associations between endothelial dysfunction and presence of SBI may be stronger in diabetic patients than in nondiabetic subjects. In particular, sICAM-1 may play an important role for the pathogenesis of SBI in patients with diabetes mellitus.

採卵鶏の育成用ケージについて,異なる大きさのケージを用いて検討した。間口を90cm, 67.5cm,45cm,奥行を60cm, 45cm, 30cmとした高さ45cmの9種類のケージを使い,飼育密度を450cm2/羽に一定として,1ケージ当たり3～12羽を収容した。7週齢より19週齢まで育成したが,10週齢からは飼料を自由摂取するものと制限給餌するものに2分した。なお,90cm×60cmのケージに8羽を収容し,従来の飼育密度675cm2/羽として育成した鶏を対照とした。その結果,雛の発育はケージの間口よりも奥行によって生じる影響の大きいことが知られた。自由摂取により奥行30cmのケージで育成した鶏の20週齢体重は60cmケージの場合より大きく,制限給餌による育成ではケージ奥行による平均体重の差は認められなかったが,個体差が小さくなり斉一化された。悪癖による被害も奥行30cmのケージにおける発生が少なかった。育成した鶏の産卵,卵重,飼料摂取量,飼料要求率,体重及び生存率を60週齢まで調べたが,育成方式による差は認められなかった。

Diabetic patients have a higher incidence of stroke, especially cerebral infarction. Hypertension as well as aging and sex differences are recognized as a major factor for stroke. In addition, diabetes is likely to be accompanied by hypertension. Recently, many mega studies have reported that aggressive blood pressure reduction significantly reduced stroke. Therefore, the tighter control of blood pressure is required to prevent stroke in diabetic patients as compared with non-diabetic subjects. Desirable target pressure is less than 130/80 mmHg and the treatment in older patients should be almost the same as in younger patients, although blood reduction should be attempted safely and by a step. The use of ACE-inhibitor and/or Ca antagonist is recommended as first-line drugs for achieving it.