Neuroprotective properties of DPP-4i: A therapeutic target for dementia prevention in elderly diabetic patients?

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

[A case of Fisher syndrome presented by rapidly progressing bilateral palatoplegia after cytomegalovirus infection].

A 35-year-old male developed sensory abnormality of peripheral limbs and oral cavity after prior infection with diarrhea and cold symptoms. Hyperrhinolalia, nasopharyngeal reflux, double vision, and wobbling in walking rapidly progressed. Neurological examination revealed palatoplegia, omnidirectional ophthalmoplegia, hyperreflexia, sensory disturbance of extremities, and truncal and limb ataxia due to decreased deep sensation. A peripheral nerve conduction study found a slight decrease in sensory nerve action potential of the median nerve and a decrease in F wave frequency of the median nerve. Serum IgM-CMV antibody was positive on admission. After IVIg therapy, palatoplegia and ataxia markedly improved. In this case, GalNAc-GD1a and GM2 antibodies, which are often detected after CMV infection, were positive in addition to the GT1a and GQ1b antibodies, and it was assumed that these findings were associated with the palatoplegia, which is included in cranial nerve palsy. Pathophysiologically, the present case is considered to be an overlap with acute oropharyngeal palsy (AOP), which is a rare subtype of Guillain-Barre syndrome, and Fisher syndrome (FS). The clinical aspects of the present case suggest a continuous spectrum between AOP and FS.

Oral anticoagulant use and the development of new cerebral microbleeds in cardioembolic stroke patients with atrial fibrillation.

OBJECTIVE: Cerebral 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 METHODS: We 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. RESULTS: A 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). CONCLUSION: Our 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.

Effect of re-coaching on self-injection of insulin in older diabetic patients - Impact of cognitive impairment.

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 3months and 4years. We also investigated the influence of cognitive impairment (CI) on coaching. RESULTS: Skills scores for self-injection of insulin and HbA1c improved significantly 3months after re-coaching. In 51 patients followed-up for 4years, skills scores were maintained during the 4years, while knowledge scores improved after 3months 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 4years 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.

Pathogenesis and neuroimaging of cerebral large and small vessel disease in type 2 diabetes: A possible link between cerebral and retinal microvascular abnormalities.

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.

Retinopathy: A sign of cerebral small vessel disease in diabetes?

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.

Factors Associated with Changes in Brain Atrophy during a Three-Year Observation in Elderly Diabetic Patients: Effect of Renal Impairment on Hippocampal Atrophy.

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.

Higher Levels of Cystatin C Are Associated with Extracranial Carotid Artery Steno-Occlusive Disease in Patients with Noncardioembolic Ischemic Stroke.

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.

Factors associated with cognitive decline in older adults with type 2 diabetes mellitus during a 6-year observation.

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.

Effect of renal impairment on cognitive function during a 3-year follow up in elderly patients with type 2 diabetes: Association with microinflammation.

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) <60 mL/min/1.73 m(2). Inflammatory markers, such as highly sensitive C-reactive protein (hs-CRP), tumor necrotizing factor-α (TNF-α), interleukin (IL)-1ß and IL-6, were measured at baseline. RESULTS: At baseline, cognitive decline was found in patients with renal impairment. The DSS test was independently associated with eGFR decline, whereas MMSE tended to be associated with albuminuria after adjusting for confounding factors. Regarding changes in cognitive function and renal impairment, changes in urinary albumin to creatinine ratios were strongly and independently associated with changes in word recall scores. In patients with persistent eGFR decline, there was a tendency toward a greater decrease in MMSE and DSS scores, whereas in those with newly detected albuminuria, there was a tendency toward a greater decrease in word recall scores. Increased baseline levels of hs-CRP, TNF-α and IL-6 were associated with renal impairment and cognitive function, especially DSS tests, respectively. However, the increased levels were not independent predictors for cognitive decline. CONCLUSIONS: The present study showed a reciprocal relationship between cognitive decline and renal impairment, especially progression of albuminuria. Thus, monitoring treatment using renal biomarkers will be important for preserving both renal and cognitive function.

Impact of albuminuria on early neurological deterioration and lesion volume expansion in lenticulostriate small infarcts.

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 (<60 mL/min per 1.73 m2), 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 (ß 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.

Association of chronic kidney disease and cerebral small vessel disease with cognitive impairment in elderly patients with type 2 diabetes.

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 <60 ml/min/1.73 m(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 (ß = 0.284, p = 0.017) and low eGFR was associated with reduced Digit Symbol Substitution scores (ß = -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.

[Following sensory neuropathy, anti-Hu antibody-positive paraneoplastic neurological syndrome presenting with limbic encephalitis occurs after complete remission].

Paraneoplastic limbic encephalitis is a rare neurological disorder that frequently precedes the detection of malignancy. We report the case of a 68-year-old male with small-cell lung cancer who developed paraneoplastic limbic encephalitis associated with presence of the anti-Hu antibody, after achieving complete remission of the tumor by chemotherapy. The patient visited our hospital because of progressive sensory disturbance of the distal extremities at 65 years of age. Though paraneoplastic sensory neuropathy was suspected, we could not find any tumor and he did not improve with steroids or immunoglobulin therapy. Chest computed tomography (CT) revealed large mediastinal lymphadenopathy. He was subsequently diagnosed with small cell lung cancer at one year and three months after the neurological symptoms occurred. As his serum analysis was positive for the anti-Hu antibody, we diagnosed paraneoplastic sensory neuropathy. The lung cancer disappeared with chemotherapy, but he had developed short-term memory loss six months later. Brain fluid attenuated inversion recovery (FLAIR) imaging showed an abnormal high-intensity lesion in the left medial temporal lobe including the hippocampus. We therefore made the diagnosis of paraneoplastic limbic encephalitis following subacute sensory neuropathy associated with the anti-Hu antibody. To our knowledge, this is the first report of a patient presenting with paraneoplastic neurological syndrome in which limbic encephalitis developed after tumor disappearance. So we must recognize the possibility of neurological symptoms occurring during remission. As the mechanism of pathogenesis, delayed neuronal cell damage due to immune responses against the tumor is implicated.

Microalbuminuria is independently associated with deep or infratentorial brain microbleeds in hypertensive adults.

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.

Cognitive impairment in diabetic patients: Can diabetic control prevent cognitive decline?

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.