Usefulness of 18F‐fluorodeoxyglucose positron emission tomography for diagnosis of asymptomatic giant cell arteritis in a patient with Alzheimer's disease

It is often difficult to diagnose disease in elderly patients, in particular those with dementia, who do not present with typical symptoms. This report describes our experience of an elderly patient (an 83‐year‐old woman) who presented with a chief complaint of memory loss, showed a marked inflammatory response, and was diagnosed with large‐vessel giant cell arteritis (GCA) on the basis of ¹⁸F‐fluorodeoxyglucose positron emission tomography (FDG‐PET) findings. She had no symptoms typical of GCA including jaw claudication, visual field defect and heavy headed feeling. Corticosteroid therapy resulted in a trend toward improvement in the inflammatory response and then she first recognized that she might have experienced slight dull headache before treatment of GCA. This was probably because this patient had large‐vessel GCA, which produces a few symptoms in the head and neck, and because she had Alzheimer's disease and could not accurately describe her symptoms. Our experience suggests the usefulness of FDG‐PET for the diagnosis of GCA, particularly in elderly patients without typical symptoms. Geriatr Gerontol Int 2011; 11: 114–118.     

Peripheral T cell receptors αβ and γδ in patients with Hodgkin's lymphoma

Antigen recognition by T cells is determined by an antigen specific T cell receptor (TCR). Two heterodimeric TCR structures associated with CD3 have been defined: TCR αβ and TCR γδ. TCR αβ and its function are well described but the role of TCR γδ in normal and lymphoproliferative disorders is not well established. In newly diagnosed or relapsed/refractory Hodgkin's disease (HD), a disease associated with defective T cell functions and increased sIL-2R, We determined levels of seven TCR αβ variable regions [βV5(a), βV5(b), βV6(a), βV12(a), αβV(a), αV2(a)] and TCR γδ by using monoclonal antibodies (MCA). TCR γδ levels did not show any difference, but several variable regions of the TCR αβ differed when groups are compared with each other and the control group.     

Amyloid‐β neurotoxicity in organotypic culture is attenuated by melatonin: involvement of GSK‐3β, tau and neuroinflammation

Abstract: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder marked by accumulation of extracellular deposits of amyloid‐β (Aβ) peptide in brain regions that are important for memory and cognition. The buildup of Aβ aggregates in the AD is followed by the formation of intracellular neurofibrillary tangles and activation of neuroinflammatory reactions. The present study investigated whether melatonin possesses a neuroprotective effect against Aβ‐induced toxicity. For this purpose, organotypic hippocampal slices were cultured and exposed to 25 μm of Aβ_25–35 in the absence or in the presence of melatonin (25, 50, or 100 μm ). In addition, the authors have investigated the involvement of GSK‐3β, tau protein, astroglial, and microglial activation, and cytokine levels in the melatonin protection against Aβ‐induced neurotoxicity. Melatonin prevented the cell damage in hippocampus induced by the exposure to Aβ_25–35. In addition, melatonin significantly reduced the activation of GSK‐3β, the phosphorylation of tau protein, the glial activation and the Aβ‐induced increase of TNF‐α and IL‐6 levels. On the basis of these findings, we speculate that melatonin may provide an effective therapeutic strategy for AD, by attenuating Aβ‐induced phosphorylation of tau protein, and preventing GSK‐3β activation and neuroinflammation.     

Comparison of three α‐glucosidase inhibitors for glycemic control and bodyweight reduction in Japanese patients with obese type 2 diabetes

Aims/Introduction

α‐Glucosidase inhibitors (αGIs) are widely used for the primary treatment of type 2 diabetes. We compared the clinical effects of three αGIs (miglitol, acarbose and voglibose) in patients with obese type 2 diabetes.

Materials and Methods

Japanese patients (n = 81) with obese type 2 diabetes (body mass index [BMI] ≥25 kg/m²) were enrolled in this multicenter, open‐label study. The participants were randomized into the miglitol (n = 18), acarbose (n = 22), voglibose (n = 19) or control (n = 22) groups. Glycemic control (fasting blood glucose and glycated hemoglobin [HbA1c]), bodyweight, BMI, serum insulin, serum lipids (low‐density lipoprotein and high‐density lipoprotein cholesterol, and triacylglycerols) and adipocytokines (leptin and adiponectin) were evaluated every 4 weeks for 12 weeks.

Results

In the miglitol group, HbA1c was improved significantly from the baseline at all points. The changes in HbA1c at 8 and 12 weeks from baseline were greater in the miglitol group than the control group. The voglibose group showed significant improvements in HbA1c at 12 weeks. Bodyweight and BMI were decreased significantly in the miglitol group. In addition, significant correlations were observed between the decrements in HbA1c and bodyweights over 12 weeks in the miglitol (r = 0.759, P < 0.001) and voglibose groups (r = 0.667, P = 0.002). Serum lipid and adipocytokine levels were not altered in any groups.

Conclusions

αGIs, especially miglitol, can effectively control blood glucose and bodyweight in obese type 2 diabetes. This study was registered with UMIN (no. UMIN000006465).     

An association between Type 2 diabetes and α1‐antitrypsin deficiency

Aims α₁‐Antitrypsin (AAT) is a serine protease inhibitor which recently has been shown to prevent Type 1 diabetes development, to prolong islet allograft survival and to inhibit pancreatic B‐cell apoptosis in vivo. It has also been reported that Type 1 diabetic patients have significantly lower plasma concentrations of AAT, suggesting the potential role of AAT in the pathogenesis of Type 1 diabetes. We have investigated whether plasma AAT levels are altered in Type 2 diabetes. Methods The study included patients with Type 2 diabetes (n = 163) and non‐diabetic control subjects matched for age, sex and smoking habits (n = 158) derived from the population‐based Malmö Diet and Cancer study. Plasma samples were analysed for AAT concentration and phenotype and serum glucose, insulin, C‐reactive protein and lipid levels were measured. Glycated haemoglobin was also measured. Results In the diabetic group, the women had higher mean plasma AAT levels than men (P < 0.05). The mean plasma AAT levels did not differ between diabetic and control subjects. However, the number of individuals with low AAT levels (< 1.0 mg/ml) was 50% higher in the diabetic group (P < 0.05) and the frequency of AAT deficiency genotypes was 50% higher (NS) in diabetic compared with control subjects. In the group of diabetic patients with AAT < 1 mg/ml, AAT directly correlated with systolic blood pressure (P = 0.048) and inversely correlated with waist–hip ratio (P = 0.031). Conclusions Our results provide evidence that deficiency of AAT may be associated with an increased risk of developing Type 2 diabetes.     

Melatonin ameliorates Aβ42‐induced alteration of βAPP‐processing secretases via the melatonin receptor through the Pin1/GSK3β/NF‐κB pathway in SH‐SY5Y cells

Melatonin is involved in the physiological regulation of the β‐amyloid precursor protein (βAPP)‐cleaving secretases which are responsible for generation of the neurotoxic amyloid beta (Aβ) peptide, one of the hallmarks of Alzheimer's disease (AD) pathology. In this study, we aimed to determine the underlying mechanisms of this regulation under pathological conditions. We establish that melatonin prevents Aβ₄₂‐induced downregulation of a disintegrin and metalloproteinase domain‐containing protein 10 (ADAM10) as well as upregulation of β‐site APP‐cleaving enzyme 1 (BACE1) and presenilin 1 (PS1) in SH‐SY5Y cell cultures. We also demonstrate that the intrinsic mechanisms of the observed effects occurred via regulation of nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NF‐κB) and glycogen synthase kinase (GSK)‐3β as melatonin reversed Aβ₄₂‐induced upregulation and nuclear translocation of NF‐κBp65 as well as activation of GSK3β via its receptor activation. Furthermore, specific blocking of the NF‐κB and GSK3β pathways partially abrogated the Aβ₄₂‐induced reduction in the BACE1 and PS1 levels. In addition, GSK3β blockage affected α‐secretase cleavage and modulated nuclear translocation of NF‐κB. Importantly, our study for the first time shows that peptidyl‐prolyl cis‐trans isomerase NIMA‐interacting 1 (Pin1) is a crucial target of melatonin. The compromised levels and/or genetic variation of Pin1 are associated with age‐dependent tau and Aβ pathologies and neuronal degeneration. Interestingly, melatonin alleviated the Aβ₄₂‐induced reduction of nuclear Pin1 levels and preserved the functional integrity of this isomerase. Our findings illustrate that melatonin attenuates Aβ₄₂‐induced alterations of βAPP‐cleaving secretases possibly via the Pin1/GSK3β/NF‐κB pathway.     

Difference between old and young adults in contribution of β‐cell function and sarcopenia in developing diabetes mellitus

Aims/Introduction

To investigate the difference in contributing factors in developing diabetes between old and young adults.

Materials and Methods

Subjects with recent‐onset diabetes were selected from a nationwide survey data and classified according to age: elderly (age ≥75 years), middle‐age (age 45–64 years) and young (age 25–39 years). The homeostasis model assessment of insulin resistance and β‐cell function were calculated. Sarcopenia was assessed using dual‐energy X‐ray absorptiometry.

Results

The prevalence of recent‐onset diabetes was 13.5%, 8.0%, and 1.4% in patients aged ≥75 years (unweighted n = 1,082), 45–64 years (unweighted n = 6,532), and 25–39 years (unweighted n = 5,178), respectively. Homeostasis model assessment of β‐cell function along with homeostasis model assessment of insulin resistance showed increasing trends as onset age increased in recent‐onset diabetes (P for trend < 0.001 in both). Elderly‐onset diabetic patients had significantly higher homeostasis model assessment of β‐cell function and homeostasis model assessment of insulin resistance compared with the middle‐age‐onset group (P < 0.001 and 0.014, respectively). Multivariate analysis showed that sarcopenia was significantly associated with recent‐onset diabetes only in patients aged ≥75 years (odds ratio [OR] 2.478, 95% confidence interval [CI] 1.379–4.452) but not in patients aged 45–64 years. In the middle‐age group, abdominal obesity (OR 2.933, 95% CI 2.086–4.122), hypertriglyceridemia (OR 1.529, 95% CI 1.078–2.169]) and low high‐density lipoprotein cholesterolemia (OR 1.930, 95% CI 1.383–2.695) were associated with recent‐onset diabetes.

Conclusions

Elderly‐onset diabetic patients had higher insulin resistance and relatively preserved β‐cell function compared with middle‐age‐onset patients. Sarcopenia might play a more important role in developing diabetes in the elderly population.     

Amyloid‐ß‐directed immunotherapy for Alzheimer's disease

Current treatment options for Alzheimer's disease (AD) are limited to medications that reduce dementia symptoms. Given the rapidly ageing populations in most areas of the world, new therapeutic interventions for AD are urgently needed. In recent years, a number of drug candidates targeting the amyloid‐ß (Aß) peptide have advanced into clinical trials; however, most have failed because of safety issues or lack of efficacy. The Aß peptide is central to the pathogenesis, and immunotherapy against Aß has attracted considerable interest. It offers the possibility to reach the target with highly specific drugs. Active immunization and passive immunization have been the most widely studied approaches to immunotherapy of AD. A favourable aspect of active immunization is the capacity for a small number of vaccinations to generate a prolonged antibody response. A potential disadvantage is the variability in the antibody response across patients. The potential advantages of passive immunotherapy include the reproducible delivery of a known amount of therapeutic antibodies to the patient and rapid clearance of those antibodies if side effects develop. A disadvantage is the requirement for repeated infusions of antibodies over time. After more than a decade of research, anti‐amyloid immunotherapy remains one of the most promising emerging strategies for developing disease‐modifying treatments for AD. In this review, we examine the presently ongoing Aß‐directed immunotherapies that have passed clinical development Phase IIa.     

TNF‐α polymorphisms in Korean adult‐onset Still's disease patients

Aim: To investigate the role of TNF‐α promoter polymorphisms in the pathogenesis of Korean adult‐onset Still's disease (AOSD) patients. Methods: DNA was isolated from blood samples collected from 58 patients with AOSD meeting Yamaguchi's criteria and 105 healthy controls. TNF‐αpromoter polymorphisms at positions –1013, –863, –857, –308 were analysed by polymerase chain reaction‐restriction fragment length polymorphism method. Genotype, allele, and estimated haplotype frequencies were compared between the AOSD group and controls. Results: The genotype, allele distributions, and estimated haplotype frequencies of the TNF‐αpolymorphism between AOSD patients and controls were not significantly different. In addition, TNF‐αpolymorphisms did not appear to have an effect on the disease course of the Korean AOSD patients. Conclusion: Genetic polymorphisms of TNF‐αdo not play a significant role in the development or in their course of Korean AOSD patients.     

β‐cell mass in people with type 2 diabetes

The early occurrence of β‐cell dysfunction has been broadly recognized as a critical determinant of the development and progression of type 2 diabetes. β‐cell dysfunction might be induced by insufficient β‐cell mass, by a dysfunction of the β‐cells, or both. Whether or not β‐cell dysfunction constitutes a cause of reduced β‐cells or vice‐versa currently remains unclear. The results of some studies have measured the loss of β‐cells in type 2 diabetic patients at between 22 and 63% by planimetric measurements. Because β‐cell hypertrophy has been noted in type 2 diabetic patients, the loss of β‐cell number should prove more profound than what has thus far been reported. Furthermore, β‐cell volumes are reduced even in patients with impaired fasting glucose. Such defects in β‐cell mass are associated with increased apoptosis rather than insufficient replication or neogenesis of β‐cells. With these results, although they still require clarification, the peak β‐cell mass might be determined at quite an early stage of life, and then might decline progressively over time as the result of exposure to harmful environmental influences over one’s lifetime. In this review, we have summarized the relevant studies regarding β‐cell mass in patients with type 2 diabetes, and then presented a review of the various causes of β‐cell loss in adults. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2010.00072.x, 2010)