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

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          Abstract

          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)‐1β 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.

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          Most cited references30

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          The role of inflammatory cytokines in diabetic nephropathy.

          Cytokines act as pleiotropic polypeptides regulating inflammatory and immune responses through actions on cells. They provide important signals in the pathophysiology of a range of diseases, including diabetes mellitus. Chronic low-grade inflammation and activation of the innate immune system are closely involved in the pathogenesis of diabetes and its microvascular complications. Inflammatory cytokines, mainly IL-1, IL-6, and IL-18, as well as TNF-alpha, are involved in the development and progression of diabetic nephropathy. In this context, cytokine genetics is of special interest to combinatorial polymorphisms among cytokine genes, their functional variations, and general susceptibility to diabetic nephropathy. Finally, the recognition of these molecules as significant pathogenic mediators in diabetic nephropathy leaves open the possibility of new potential therapeutic targets.
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            Glucose tolerance status and risk of dementia in the community: the Hisayama study.

            We investigated the association between glucose tolerance status defined by a 75-g oral glucose tolerance test (OGTT) and the development of dementia. A total of 1,017 community-dwelling dementia-free subjects aged ≥60 years who underwent the OGTT were followed up for 15 years. Outcome measure was clinically diagnosed dementia. The age- and sex-adjusted incidence of all-cause dementia, Alzheimer disease (AD), and vascular dementia (VaD) were significantly higher in subjects with diabetes than in those with normal glucose tolerance. These associations remained robust even after adjustment for confounding factors for all-cause dementia and AD, but not for VaD (all-cause dementia: adjusted hazard ratio [HR] = 1.74, 95% confidence interval [CI] = 1.19 to 2.53, p = 0.004; AD: adjusted HR = 2.05, 95% CI = 1.18 to 3.57, p = 0.01; VaD: adjusted HR = 1.82, 95% CI = 0.89 to 3.71, p = 0.09). Moreover, the risks of developing all-cause dementia, AD, and VaD significantly increased with elevated 2-hour postload glucose (PG) levels even after adjustment for covariates, but no such associations were observed for fasting plasma glucose (FPG) levels: compared with those with 2-hour PG levels of <6.7 mmol/L, the multivariable-adjusted HRs of all-cause dementia and AD significantly increased in subjects with 2-hour PG levels of 7.8 to 11.0 mmol/L or over, and the risk of VaD was significantly higher in subjects with levels of ≥11.1 mmol/L. Our findings suggest that diabetes is a significant risk factor for all-cause dementia, AD, and probably VaD. Moreover, 2-hour PG levels, but not FPG levels, are closely associated with increased risk of all-cause dementia, AD, and VaD.
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              Inflammatory markers and the risk of Alzheimer disease: the Framingham Study.

              To examine whether serum cytokines and spontaneous production of peripheral blood mononuclear cell (PBMC) cytokines are associated with the risk of incident Alzheimer disease (AD). We followed 691 cognitively intact community-dwelling participants (mean age 79 years, 62% women) and related PBMC cytokine production (tertiles of spontaneous production of interleukin 1 [IL-1], IL-1 receptor antagonist, and tumor necrosis factor alpha [TNF-alpha]) and serum C-reactive protein and interleukin 6 (IL-6) to the risk of incident AD. Adjusting for clinical covariates, individuals in the top two tertiles (T2 and T3) of PBMC production of IL-1 or the top tertile (T3) of PBMC production of TNF-alpha were at increased risk of developing AD (multivariable-adjusted hazard ratio [HR] for IL-1 T2 = 2.84, 95% CI 1.09 to 7.43; p = 0.03 and T3 = 2.61, 95% CI 0.96 to 7.07; p = 0.06; for TNF-alpha, adjusted HR for T2 = 1.30, 95% CI 0.53 to 3.17; p = 0.57 and T3 = 2.59, 95% CI 1.09 to 6.12; p = 0.031]) compared with those in the lowest tertile (T1). Higher spontaneous production of interleukin 1 or tumor necrosis factor alpha by peripheral blood mononuclear cells may be a marker of future risk of Alzheimer disease (AD) in older individuals. These data strengthen the evidence for a pathophysiologic role of inflammation in the development of clinical AD.
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                Author and article information

                Journal
                J Diabetes Investig
                J Diabetes Investig
                10.1111/(ISSN)2040-1124
                JDI
                Journal of Diabetes Investigation
                Wiley-Blackwell
                2040-1116
                2040-1124
                04 February 2014
                September 2014
                : 5
                : 5 ( doiID: 10.1111/jdi.2014.5.issue-5 )
                : 597-605
                Affiliations
                [ 1 ] Department of Diabetes and Endocrine Internal MedicineNagoya University Graduate School of Medicine NagoyaJapan
                [ 2 ] Center for Preventive MedicineNagoya University Graduate School of Medicine NagoyaJapan
                [ 3 ] Department of NeurologyChubu Rosai Hospital Nagoya University Graduate School of Medicine NagoyaJapan
                [ 4 ] Department of GeriatricsNagoya University Graduate School of Medicine NagoyaJapan
                [ 5 ] Department of PsychiatryNagoya University Graduate School of Medicine NagoyaJapan
                [ 6 ] Diabetic CenterAichi Medical University NagakuteJapan
                Author notes
                [*] [* ]Corresponding author. Takahiko Kawamura Tel.: +81‐52‐652‐5511 Fax: +81‐52‐651‐5567 E‐mail address: kawamura.hsc@ 123456chubuh.rofuku.go.jp
                Article
                JDI12190
                10.1111/jdi.12190
                4188119
                3f93da8b-79ef-4f35-b2cf-9b6d27a7d8ea
                © 2014 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and Wiley Publishing Asia Pty Ltd

                This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                History
                : 12 July 2013
                : 12 November 2013
                : 14 November 2013
                Page count
                Pages: 9
                Funding
                Funded by: Japan Labor Health and Welfare Organization
                Categories
                Original Article
                Articles
                Clinical Science and Care
                Custom metadata
                2.0
                jdi12190
                September 2014
                Converter:WILEY_ML3GV2_TO_NLM version:4.1.1 mode:remove_FC converted:08.09.2014

                cognitive impairment,microinflammation,renal impairment

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