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    Age-related hypoxia in CNS pathology. Bădescu George Mihai,Fîlfan Mădălina,Ciobanu Ovidiu,Dumbravă DănuŢ Adrian,Popa-Wagner Aurel Romanian journal of morphology and embryology = Revue roumaine de morphologie et embryologie Although neuropathological conditions differ in the etiology of the inflammatory response, cellular and molecular mechanisms of neuroinflammation are probably similar in aging, hypertension, depression and cognitive impairment. Moreover, a number of common risk factors such as obesity, hypertension, diabetes and atherosclerosis are increasingly understood to act as "silent contributors" to neuroinflammation and can underlie the development of disorders such as cerebral small vessel disease (cSVD) and subsequent dementia. On the other hand, acute neuroinflammation, such as in response to traumatic or cerebral ischemia, aggravates the acute damage and can lead to a number of pathological such as depression, post-stroke dementia and potentially neurodegeneration. All of those sequelae impair recovery and most of them provide the ground for further cerebrovascular events and a vicious cycle develops. Therefore, understanding the mechanisms associated with vascular dementia, stroke and related complications is of paramount importance in improving current preventive and therapeutic interventions. Likewise, understanding of molecular factors and pathways associated with neuroinflammation will eventually enable the discovery and implementation of new diagnostic and therapeutic strategies indicated in a wide range of neurological conditions.
    Diabetes impairs spatial learning and memory and hippocampal neurogenesis via BDNF in rats with transient global ischemia. Han Hui,Wu Li-Min,Han Ming-Xiang,Yang Wen-Ming,Wang Yan-Xin,Fang Zhao-Hui Brain research bulletin Diabetic conditions worsen the prognosis of stroke. The molecular mechanism underlying the impairment of post-stroke recovery is not very clear. Here, we establish a rat model resembling human cerebral infarction with or without diabetes to determine how diabetes impairs cognitive recovery. Our data show that diabetes inhibits hippocampal BDNF expression and impairs the survival and differentiation of the newborn neural cells in rats with ischemia. Consequently, the rats of diabetic ischemia have a significantly lower score in spatial learning and memory in the Morris water maze test than the non-diabetic ischemia model rats. On the other hand, treatment with BDNF effectively improves hippocampal neurogenesis and the spatial learning and memory in rat with diabetic ischemia. All together, our data suggest that diabetes impaired spatial learning and memory and hippocampal neurogenesis in rats with ischemia by inhibition of the BDNF expression in the hippocampus. 10.1016/j.brainresbull.2016.05.011
    Multidomain intervention for the prevention of cognitive decline after stroke - a pooled patient-level data analysis. Teuschl Y,Ihle-Hansen H,Matz K,Dachenhausen A,Ratajczak P,Tuomilehto J,Ursin M H,Hagberg G,Thommessen B,Øksengård A R,Brainin M, European journal of neurology BACKGROUND AND PURPOSE:The aim of this pooled patient-level data analysis was to test if multidomain interventions, addressing several modifiable vascular risk factors simultaneously, are more effective than usual post-stroke care for the prevention of cognitive decline after stroke. METHODS:This pooled patient-level data analysis included two randomized controlled trials using a multidomain approach to target vascular risk factors in stroke patients and cognition as primary outcome. Changes from baseline to 12 months in the trail making test (TMT)-A, TMT-B and 10-words test were analysed using stepwise backward linear mixed models with study as random factor. Two analyses were based on the intention-to-treat (ITT) principle using different imputation approaches and one was based on complete cases. RESULTS:Data from 322 patients (157 assigned to multidomain intervention and 165 to standard care) were analysed. Differences between randomization groups for TMT-A scores were found in one ITT model (P = 0.014) and approached significance in the second ITT model (P = 0.087) and for complete cases (P = 0.091). No significant intervention effects were found for any of the other cognitive variables. CONCLUSION:We found indications that multidomain interventions compared with standard care can improve the scores in TMT-A at 1 year after stroke but not those for TMT-B or the 10-words test. These results have to be interpreted with caution due to the small number of patients. 10.1111/ene.13684
    Recurrent Hypoglycemia Exacerbates Cerebral Ischemic Damage in Diabetic Rats via Enhanced Post-Ischemic Mitochondrial Dysfunction. Shukla Vibha,Fuchs Perry,Liu Allen,Cohan Charles H,Dong Chuanhui,Wright Clinton B,Perez-Pinzon Miguel A,Dave Kunjan R Translational stroke research Diabetes significantly increases the risk of stroke and post-stroke mortality. Recurrent hypoglycemia (RH) is common among diabetes patients owing to glucose-lowering therapies. Earlier, we showed that RH in a rat model of insulin-dependent diabetes exacerbates cerebral ischemic damage. Impaired mitochondrial function has been implicated as a central player in the development of cerebral ischemic damage. Hypoglycemia is also known to affect mitochondrial functioning. The present study tested the hypothesis that prior exposure of insulin-treated diabetic (ITD) rats to RH exacerbates brain damage via enhanced post-ischemic mitochondrial dysfunction. In a rat model of streptozotocin-induced diabetes, we evaluated post-ischemic mitochondrial function in RH-exposed ITD rats. Rats were exposed to five episodes of moderate hypoglycemia prior to the induction of cerebral ischemia. We also evaluated the impact of RH, both alone and in combination with cerebral ischemia, on cognitive function using the Barnes circular platform maze test. We observed that RH exposure to ITD rats leads to increased cerebral ischemic damage and decreased mitochondrial complex I activity. Exposure of ITD rats to RH impaired spatial learning and memory. Our results demonstrate that RH exposure to ITD rats potentially increases post-ischemic damage via enhanced post-ischemic mitochondrial dysfunction. 10.1007/s12975-018-0622-2
    Determinants of post-stroke cognitive impairment: analysis from VISTA. Arba F,Quinn T,Hankey G J,Inzitari D,Ali M,Lees K R, Acta neurologica Scandinavica BACKGROUND:Post-stroke cognitive impairment (PSCI) occurs commonly and is linked with development of dementia. We investigated the relationship between demographic, clinical and stroke symptoms at stroke onset and the presence of PSCI at 1 and 3 years after stroke. METHODS:We accessed anonymized data from the Virtual International Stroke Trial Archive (VISTA), including demographic and clinical variables. Post-stroke cognitive impairment was defined as a Mini-Mental State Examination (MMSE) score of ≤26. We assessed univariate relationships between baseline stroke symptoms and PSCI at 1 and 3 years following stroke, retaining the significant and relevant clinical factors as covariates in a final adjusted logistic regression model. RESULTS:We analysed data on 5435 patients with recent (median 33 days) stroke or transient ischaemic attack (TIA). Mean (±SD) age was 62.6 (±12.6) years; 3476 (65%) patients were male. Follow-up data were available for 2270 and 1294 patients at 1 and 3 years, respectively. At 1 year, 781 (34%) patients had MMSE≤26; at 3 years, 391 (30%) had MMSE≤26. After adjusting for age, stroke severity, hypertension, diabetes and type of qualifying event, initial stroke impairment (leg paralysis) was associated with increased rate of PSCI at 1 year (OR=1.62; 95% CI=1.20-2.20) and at 3 years (OR=1.95; 95% CI=1.23-3.09). Associations were consistent on subgroup analysis restricted to ischaemic stroke and transient ischaemic attack (N=4992). CONCLUSIONS:Besides well-known determinants of PSCI such as age, stroke severity and the presence of vascular risk factors, also leg paralysis is associated with subsequent of PSCI up to 3 years after stroke. 10.1111/ane.12637
    Cerebral small vessel disease, medial temporal lobe atrophy and cognitive status in patients with ischaemic stroke and transient ischaemic attack. Arba F,Quinn T,Hankey G J,Ali M,Lees K R,Inzitari D, European journal of neurology BACKGROUND AND PURPOSE:Small vessel disease (SVD) and Alzheimer's disease (AD) are two common causes of cognitive impairment and dementia, traditionally considered as distinct processes. The relationship between radiological features suggestive of AD and SVD was explored, and the association of each of these features with cognitive status at 1 year was investigated in patients with stroke or transient ischaemic attack. METHODS:Anonymized data were accessed from the Virtual International Stroke Trials Archive (VISTA). Medial temporal lobe atrophy (MTA; a marker of AD) and markers of SVD were rated using validated ordinal visual scales. Cognitive status was evaluated with the Mini Mental State Examination (MMSE) 1 year after the index stroke. Logistic regression models were used to investigate independent associations between (i) baseline SVD features and MTA and (ii) all baseline neuroimaging features and cognitive status 1 year post-stroke. RESULTS:In all, 234 patients were included, mean (±SD) age 65.7 ± 13.1 years, 145 (62%) male. Moderate to severe MTA was present in 104 (44%) patients. SVD features were independently associated with MTA (P < 0.001). After adjusting for age, sex, disability after stroke, hypertension and diabetes mellitus, MTA was the only radiological feature independently associated with cognitive impairment, defined using thresholds of MMSE ≤ 26 (odds ratio 1.94; 95% confidence interval 1.28-2.94) and MMSE ≤ 23 (odds ratio 2.31; 95% confidence interval 1.48-3.62). CONCLUSION:In patients with ischaemic cerebrovascular disease, SVD features are associated with MTA, which is a common finding in stroke survivors. SVD and AD type neurodegeneration coexist, but the AD marker MTA, rather than SVD markers, is associated with post-stroke cognitive impairment. 10.1111/ene.13191
    Post-stroke neovascularization and functional outcomes differ in diabetes depending on severity of injury and sex: Potential link to hemorrhagic transformation. Li Weiguo,Valenzuela John Paul,Ward Rebecca,Abdelbary Mahmoud,Dong Guangkuo,Fagan Susan C,Ergul Adviye Experimental neurology Diabetes is associated with increased risk and worsened outcome of stroke. Previous studies showed that male diabetic animals had greater hemorrhagic transformation (HT), profound loss of cerebral vasculature, and poor behavioral outcomes after ischemic stroke induced by suture or embolic middle cerebral artery occlusion (MCAO). Females are protected from stroke until reaching the menopause age, but young females with diabetes have a higher risk of stroke and women account for the majority of stroke mortality. The current study postulated that diabetes is associated with greater vascular injury and exacerbated sensorimotor and cognitive outcome after stroke even in young female animals. Male and female control and diabetic animals were subjected to transient MCAO and followed for 3 or 14 days to assess the neurovascular injury and repair. The vascularization indices after stroke were lower in male diabetic animals with 90-min but not 60-min ischemia/reperfusion injury, while there was no change in female groups. Cognitive deficits were exacerbated in both male and female groups regardless of the injury period, while the sensorimotor dysfunction was worsened in male diabetic animals with longer ischemia time. These results suggest that diabetes negates the protection afforded by sex in young female animals, and post-stroke vascularization pattern is influenced by the degree of injury and correlates with functional outcome in both sexes. Vasculoprotection after acute ischemic stroke may provide a novel therapeutic strategy in diabetes. 10.1016/j.expneurol.2018.09.013
    Cognitive impairment one year after ischemic stroke: predictorsand dynamics of significant determinants. Alexandrova Margarita Lubomirova,Danovska Maya Penkova Turkish journal of medical sciences BACKGROUND/AIM:Evidence suggests that the risk for dementia increases after stroke. This study investigated the dynamics of the neurological and cognitive status of patients with no baseline dementia over a 1-year period after ischemic stroke. MATERIALS AND METHODS:We examined 47 ischemic stroke patients admitted within 48 h of ictus. Their neurological and cognitive statuses, blood biochemical parameters, and microalbuminuria levels were prospectively evaluated over a 1-year period post-stroke. RESULTS:A more severe neurological deficit was found in the cognitively impaired patients (P = 0.003). The NIHSS score over a 1-year follow-up period improved only in patients with normal cognition (P = 0.000). Time-varying dynamics of the MMSE score were observed in both patient groups (P = 0.000). Age (Р = 0.000), education (Р = 0.004), sex (Р = 0.041), history of diabetes (Р = 0.045), and serum high sensitive C-reactive protein (hs-CRP) on admission (Р = 0.003) were significant determinants of cognitive decline 1 year after a stroke. The albumin-to-creatinine ratio was high during the whole follow-up period in the cognitively impaired group after adjusting for sex and age (P = 0.010). Binary logistic regression showed that hs-CRP (Р = 0.013) and age (Р = 0.010) were independent predictors of patients' cognitive status 1 year after stroke. CONCLUSION:The level of inflammatory markers could be considered as an additional criterion of long-term cognitive impairment. 10.3906/sag-1403-29
    Prediabetes is associated with post-stroke cognitive impairment in ischaemic stroke patients. Wang Qiongzhang,Zhao Kai,Cai Yan,Tu Xinjie,Liu Yuntao,He Jincai Brain research AIM:Diabetes mellitus is associated with post-stroke cognitive impairment. To the best of our knowledge, no study has explored the relationship between prediabetes and post-stroke cognitive impairment. The purpose of this study is to explore the association between prediabetes and cognitive impairment in ischaemic stroke patients at 1 month. METHODS:Two hundred one acute ischaemic stroke patients were consecutively recruited within the first 24 h after admission and were followed up for 1 month. Patients were divided into a diabetes mellitus group, prediabetes group and non-diabetes mellitus group by fasting glucose levels, 2-h postprandial blood glucose levels and glycosylated haemoglobin levels at admission. Cognitive function was evaluated by the Mini-Mental State Examination at 1 month after stroke. RESULTS:The prediabetes group had a higher risk of post-stroke cognitive impairment than the non-diabetes group (35.7% vs. 18.1%, χ = 4.252, P = .039). In logistical analyses, prediabetes was associated with post-stroke cognitive impairment after adjusting for potential confounding factors (odds ratio 3.062, 95% confidence interval 1.130-8.299, P = .028). CONCLUSIONS:Our findings show that prediabetes is associated with post-stroke cognitive impairment and may predict its development at 1 month post-stroke. 10.1016/j.brainres.2017.12.034
    Validation of the RCHADS and CHADS Scores for Predicting Post-stroke Cognitive Impairment. Washida Kazuo,Kowa Hisatomo,Hamaguchi Hirotoshi,Kanda Fumio,Toda Tatsushi Internal medicine (Tokyo, Japan) Objective Post-stroke cognitive impairment often afflicts stroke survivors and is a major obstacle both for cognitive and physical rehabilitation. Stroke risk scores ["Congestive heart failure, Hypertension, Age ≥75 years, Diabetes mellitus, Stroke" (CHADS) and "CHADS + creatinine clearance <60 mL/min" (RCHADS)] are used to assess the future risk of cardioembolic stroke in patients with atrial fibrillation (AF). However, congestive heart failure, hypertension, aging, diabetes mellitus, stroke, and renal dysfunction are also risk factors for cognitive impairment. Methods Sixty-two patients with nonvalvular AF-induced cardioembolic stroke underwent cognitive testing, including the Japanese version of the Montreal Cognitive Assessment (MoCA-J), Mini-Mental State Examination (MMSE), and Apathy Scale. The correlations between the MoCA-J/MMSE/Apathy Scale scores and stroke risk scores were examined. Results The average CHADS and RCHADS scores were 4.1±1.0 and 5.6±1.6, respectively. The average MoCA-J, MMSE, and Apathy Scale scores were 17.4±6.2, 22.0±5.3, and 20.0±8.9, respectively. The CHADS and RCHADS scores were negatively correlated with the MoCA-J/MMSE and positively correlated with the Apathy Scale. The RCHADS score was more sensitive to poststroke cognitive impairment than the CHADS score. This correlation was stronger for MoCA-J than for MMSE, as the MMSE scores were skewed toward the higher end of the range. The results for individual MoCA-J and MMSE subtests indicated that the visuoexecutive, calculation, abstraction, and remote recall functions were significantly decreased after cardioembolic stroke. Conclusion These results suggest that the RCHADS and CHADS scores are useful for predicting post-stroke cognitive impairment. 10.2169/internalmedicine.6651-15
    Predictors of Cognitive Impairment After Stroke: A Prospective Stroke Cohort Study. Ding Meng-Yuan,Xu Yi,Wang Ying-Zhe,Li Pei-Xi,Mao Yi-Ting,Yu Jin-Tai,Cui Mei,Dong Qiang Journal of Alzheimer's disease : JAD BACKGROUND:Post-stroke cognitive impairment (PSCI) significantly affects stroke survivors' quality of life and rehabilitation. A risk model identifying cognitive decline at admission would help to improve early detection and management of post-stroke patients. OBJECTIVE:To develop a new clinical risk score for ischemic stroke survivors in predicting 6-12 months PSCI. METHODS:We prospectively enrolled 179 patients diagnosed with acute ischemic stroke within a 7-day onset. Data were analyzed based on baseline demographics, clinical risk factors, and radiological parameters. Logistic regression and area under the receiver operating curve (AUROC) were used to evaluate model efficiency. RESULTS:One hundred forty-five subjects completed a 6-12-month follow-up visit, and 77 patients (53.1%) were diagnosed with PSCI. Age (β= 0.065, OR = 1.067, 95% CI = 1.016-1.120), years of education (β= -0.346, OR = 0.707, 95% CI = 0.607-0.824), periventricular hyperintensity grading (β= 1.253, OR = 3.501, 95% CI = 1.652-7.417), diabetes mellitus (β= 1.762, OR = 5.825, 95% CI = 2.068-16.412), and the number of acute nonlacunar infarcts (β= 0.569, OR = 1.766, 95% CI = 1.243-2.510) were independently associated with 6-12 month PSCI, constituting a model with optimal predictive efficiency (AUC = 0.884, 95% CI = 0.832-0.935). CONCLUSIONS:The optimized risk model was effective in screening stroke survivors at high risk of developing 6-12 months PSCI in a simple and pragmatic way. It could be a potential tool to identify patients with a high risk of PSCI at an early stage in clinical practice after further independent external cohort validation. 10.3233/JAD-190382
    Altered Insulin/Insulin-Like Growth Factor Signaling in a Comorbid Rat model of Ischemia and β-Amyloid Toxicity. Amtul Zareen,Hill David J,Arany Edith J,Cechetto David F Scientific reports Ischemic stroke and diabetes are vascular risk factors for the development of impaired memory such as dementia and/or Alzheimer's disease. Clinical studies have demonstrated that minor striatal ischemic lesions in combination with β-amyloid (Aβ) load are critical in generating cognitive deficits. These cognitive deficits are likely to be associated with impaired insulin signaling. In this study, we examined the histological presence of insulin-like growth factor-I (IGF-1) and insulin receptor substrate (IRS-1) in anatomically distinct brain circuits compared with morphological brain damage in a co-morbid rat model of striatal ischemia (ET1) and Aβ toxicity. The results demonstrated a rapid increase in the presence of IGF-1 and IRS-1 immunoreactive cells in Aβ + ET1 rats, mainly in the ipsilateral striatum and distant regions with synaptic links to the striatal lesion. These regions included subcortical white matter, motor cortex, thalamus, dentate gyrus, septohippocampal nucleus, periventricular region and horizontal diagonal band of Broca in the basal forebrain. The alteration in IGF-1 and IRS-1 presence induced by ET1 or Aβ rats alone was not severe enough to affect the entire brain circuit. Understanding the causal or etiologic interaction between insulin and IGF signaling and co-morbidity after ischemia and Aβ toxicity will help design more effective therapeutics. 10.1038/s41598-018-22985-4
    Influence of glucose metabolism on cognitive function of patients with acute small-artery occlusion. Zhai L P,Zhang X L,Guan Q B,Yu B,Wang Y P,Shen H P,Yu X X,Wang D D,Zhu Y Journal of biological regulators and homeostatic agents The aim of this study was to evaluate the influence of abnormal glucose metabolism on cognitive function of patients with acute small-arterial occlusion (SAO). The present study included 1,211 patients, with small-artery occlusion according to the Trial of Org 10172 in acute stroke treatment (TOAST) classification, admitted between March 2014 and December 2016 to The Second Hospital of Jiaxing. According to cognitive function, the patients were divided into a group of normal cognitive function, a mild cognitive impairment group (MCI group) and a dementia group. The patients were also divided into normal a blood sugar group, an impaired glucose regulation group (IGR group) and a diabetes mellitus (DM) group based on glucose metabolism. Cognitive functions of patients in the different glucose metabolism groups were compared based on Mini-mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA). General data, medical history, neuropsychological assessment and haematological index of the patients in each group were analyzed. Logistic regression analysis was used to study independent risk factors influencing cognitive impairment. When comparing the group of normal cognitive function with the MCI group, there were no statistical significant differences between the MMSEs scores of patients among the three groups, but the difference in MoCAs scores had statistical significance. Hypertension history, hyperhomocysteinemia (Hhcy) and sedentariness were independent risk factors for SAO patients with MCI. When comparing the group of normal cognitive function with the dementia group, there were statistically significant differences (P<0.05) between the MMSE and MoCA scores of patients among the three groups. Abnormal glucose metabolism, old age, female, high blood pressure, Hhcy, family stroke history and sedentariness were independent risk factors for SAO patients with dementia. In conclusion, abnormal glucose metabolism impairing cognitive function is not an independent risk factor for SAO patients with MCI, but is an independent risk factor for SAO patients with dementia.
    The GLP-1 receptor agonists exendin-4 and liraglutide alleviate oxidative stress and cognitive and micturition deficits induced by middle cerebral artery occlusion in diabetic mice. Li Ping-Chia,Liu Li-Fen,Jou Ming-Jia,Wang Hao-Kuang BMC neuroscience BACKGROUND:Glucagon-like peptide 1 (GLP-1) analogs protect a variety of cell types against oxidative damage and vascular and neuronal injury via binding to GLP-1 receptors. This study aimed to investigate the effects of the GLP-1 analogs exendin-4 and liraglutide on cerebral blood flow, reactive oxygen species production, expression of oxidative stress-related proteins, cognition, and pelvic sympathetic nerve-mediated bladder contraction after middle cerebral artery occlusion (MCAO) injury in the db/db mouse model of diabetes. RESULTS:Sixty minutes of MCAO increased blood and brain reactive oxygen species counts in male db/db mice, as revealed by dihydroethidium staining. MCAO also increased nuclear factor-κB and intercellular adhesion molecule-1 expression and decreased cerebral microcirculation. These effects were attenuated by treatment with exendin-4 or liraglutide. MCAO did not affect basal levels of phosphorylated Akt (p-Akt) or endothelial nitric oxide synthase (p-eNOS); however, exendin-4 and liraglutide treatments significantly enhanced p-Akt and p-eNOS levels, indicating activation of the p-Akt/p-eNOS signaling pathway. MCAO-induced motor and cognitive deficits and micturition dysfunction, indicated by reduced pelvic nerve-mediated voiding contractions and increased nonvoiding contractions, were also partially attenuated by exendin-4 treatment. CONCLUSIONS:The above data indicate that treatment with GLP-1 agonists exerts protective effects against oxidative, inflammatory, and apoptotic damage in brain areas that control parasympathetic/pelvic nerve-mediated voiding contractions and cognitive and motor behaviors in a diabetic mouse model. 10.1186/s12868-016-0272-9
    Peripheral glucose levels and cognitive outcome after ischemic stroke-Results from the Munich Stroke Cohort. Zietemann Vera,Wollenweber Frank Arne,Bayer-Karpinska Anna,Biessels Geert Jan,Dichgans Martin European stroke journal Introduction:The relationship between glucose metabolism and stroke outcome is likely to be complex. We examined whether there is a linear or non-linear relationship between glucose measures in the acute phase of stroke and post-stroke cognition, and whether altered glucose metabolism at different time intervals (long- and short-term before stroke, acute phase) is associated with cognitive outcome. Patients and methods:In all, 664 consecutively recruited patients with acute ischemic stroke and without pre-stroke dementia were included in this prospective observational study. Blood samples were taken at admission and fasting on the first morning after stroke. Duration of diabetes was assessed by interview. Cognitive outcome was assessed by the Telephone Interview for Cognitive Status 3 months post-stroke. Dose-response analyses were used to investigate non-linearity. Regression analyses were stratified by diabetes status and adjusted for relevant confounders. Results:Cognitive status was testable in 422 patients (81 with diabetes). There was a non-linear relationship between both admission and fasting glucose levels and cognitive outcome. Lower glucose values were significantly associated with lower Telephone Interview for Cognitive Status scores 3 months post-stroke in patients without diabetes with a similar trend in diabetic patients. There was an inverse association between duration of diabetes and Telephone Interview for Cognitive Status scores (linear regression: -0.10 (95% confidence interval: -0.17 to -0.02) per year increase of diabetes duration), whereas HbA was not related to cognitive outcome. Results were supported by sensitivity analyses accounting for attrition. Conclusion:Lower glucose levels in the acute phase of stroke are associated with worse cognitive outcome but the relationship is non-linear. Long-term abnormalities in glucose metabolism are also related to poor outcome but this is not the case for shorter term abnormalities. Altered glucose levels at different stages of stroke may affect stroke outcome through different pathways. 10.1177/2396987316631674
    Linagliptin treatment improves cerebrovascular function and remodeling and restores reduced cerebral perfusion in Type 2 diabetes. Hardigan Trevor,Yasir Abdul,Abdelsaid Mohammed,Coucha Maha,El-Shaffey Sally,Li Weiguo,Johnson Maribeth H,Ergul Adviye American journal of physiology. Regulatory, integrative and comparative physiology The antihyperglycemic agent linagliptin, a dipeptidyl peptidase-4 (DPP-IV) inhibitor, has been shown to reduce inflammation and improve endothelial cell function. In this study, we hypothesized that DPP-IV inhibition with linagliptin would improve impaired cerebral perfusion in diabetic rats, as well as improve insulin-induced cerebrovascular relaxation and reverse pathological cerebrovascular remodeling. We further postulated that these changes would lead to a subsequent improvement of cognitive function. Male Type-2 diabetic and nondiabetic Goto-Kakizaki rats were treated with linagliptin for 4 wk, and blood glucose and DPP-IV plasma levels were assessed. Cerebral perfusion was assessed after treatment using laser-Doppler imaging, and dose response to insulin (10(-13) M-10(-6) M) in middle cerebral arteries was tested on a pressurized arteriograph. The impact of DPP-IV inhibition on diabetic cerebrovascular remodeling was assessed over a physiologically relevant pressure range, and changes in short-term hippocampus-dependent learning were observed using a novel object recognition test. Linagliptin lowered DPP-IV activity but did not change blood glucose or insulin levels in diabetes. Insulin-mediated vascular relaxation and cerebral perfusion were improved in the diabetic rats with linagliptin treatment. Indices of diabetic vascular remodeling, such as increased cross-sectional area, media thickness, and wall-to-lumen ratio, were also ameliorated; however, improvements in short-term hippocampal-dependent learning were not observed. The present study provides evidence that linagliptin treatment improves cerebrovascular dysfunction and remodeling in a Type 2 model of diabetes independent of glycemic control. This has important implications in diabetic patients who are predisposed to the development of cerebrovascular complications, such as stroke and cognitive impairment. 10.1152/ajpregu.00057.2016
    Plasma homocysteine and cerebral small vessel disease as possible mediators between kidney and cognitive functions in patients with diabetes mellitus. Sonoda Mika,Shoji Tetsuo,Kuwamura Yukinobu,Okute Yujiro,Naganuma Toshihide,Shima Hideaki,Motoyama Koka,Morioka Tomoaki,Mori Katsuhito,Fukumoto Shinya,Shioi Atsushi,Shimono Taro,Fujii Hisako,Kabata Daijiro,Shintani Ayumi,Emoto Masanori,Inaba Masaaki Scientific reports Cognitive impairment is more prevalent in those with decreased kidney function. We tested a hypothesis that an increased homocysteine and/or cerebral small vessel diseases (SVDs) mediate the link between kidney and cognitive functions in a cross-sectional study in 143 type 2 diabetes patients without diagnosis of dementia or prior stroke. The exposure and outcome variables were estimated glomerular filtration rate (eGFR) and cognitive performance evaluated with Modified Mini-Mental State (3 MS) examination, respectively. The candidate mediators were plasma homocysteine concentration, and SVDs including silent cerebral infarction, cerebral microbleed, periventricular hyperintensity, and deep and subcortical white matter hyperintensity by magnetic resonance imaging. In multiple regression models adjusted for 12 potential confounders, eGFR was positively associated with 3 MS score, inversely with homocysteine, but not significantly with the presence of any type of SVD. The association of eGFR with 3 MS remained significant when each of the SVDs was added to the model, whereas it disappeared when homocysteine was included in place of SVD. Mediation analysis indicated nearly significant mediation of homocysteine (P = 0.062) but no meaningful mediations of SVDs (P = 0.842-0.930). Thus, homocysteine, not SVDs, was shown to be the possible mediator between kidney and cognitive functions in patients with type 2 diabetes mellitus. 10.1038/s41598-017-04515-w
    Early Onset of Diabetes Mellitus Accelerates Cognitive Decline in Japanese Patients with Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis, and Stroke-Like Episodes. Murakami Takaaki,Shinoto Yuya,Yonemitsu Shin,Muro Seiji,Oki Shogo,Koga Yasutoshi,Goto Yu-Ichi,Kaneda Daita The Tohoku journal of experimental medicine Approximately 80% of patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) carry the A3243G mutation in the mitochondrial tRNALeu (UUR) gene. Conversely, this mutation has also been identified as one of the most prevalent genetic abnormalities in patients with diabetes mellitus. Mitochondrial diabetes mellitus complicated with MELAS is relatively common, and 12.5% of patients with the A3243G mutation develop MELAS after being diagnosed with diabetes mellitus. However, the clinical impact of diabetes mellitus in MELAS patients remains unclear. Therefore, we retrospectively studied 14 Japanese MELAS patients with the A3243G mutation: three men and eleven women, with the mean age of 48.0 (± 15.4) years. Eight patients had been diagnosed with diabetes mellitus prior to the diagnosis of mitochondrial disease, and all of them were treated with insulin. The other six included four patients with concurrent diagnosis of diabetes and mitochondrial disease, one patient diagnosed with diabetes after the diagnosis of mitochondrial disease, and one patient without developing diabetes currently. We thus compared the patients' characteristics between those with and without early onset of diabetes mellitus. Cognitive decline (75.0% vs. 0%; p = 0.03) and poor glycemic control with severe hypoglycemic events (75.0% vs. 16.7%; p = 0.05) were more common in MELAS patients with a prior diagnosis of diabetes than in those without the prior diagnosis of diabetes. Our data suggest that the latent progress of cognitive decline is accelerated because of early onset of diabetes mellitus in MELAS patients. 10.1620/tjem.238.311
    Potentials of incretin-based therapies in dementia and stroke in type 2 diabetes mellitus. Groeneveld Onno N,Kappelle L Jaap,Biessels Geert Jan Journal of diabetes investigation Patients with type 2 diabetes mellitus are at risk for accelerated cognitive decline and dementia. Furthermore, their risk of stroke is increased and their outcome after stroke is worse than in those without diabetes. Incretin-based therapies are a class of antidiabetic agents that are of interest in relation to these cerebral complications of diabetes. Two classes of incretin-based therapies are currently available: the glucagon-like-peptide-1 agonists and the dipeptidyl peptidase-4 -inhibitors. Independent of their glucose-lowering effects, incretin-based therapies might also have direct or indirect beneficial effects on the brain. In the present review, we discuss the potential of incretin-based therapies in relation to dementia, in particular Alzheimer's disease, and stroke in patients with type 2 diabetes. Experimental studies on Alzheimer's disease have found beneficial effects of incretin-based therapies on cognition, synaptic plasticity and metabolism of amyloid-β and microtubule-associated protein tau. Preclinical studies on incretin-based therapies in stroke have shown an improved functional outcome, a reduction of infarct volume as well as neuroprotective and neurotrophic properties. Both with regard to the treatment of Alzheimer's disease, and with regard to prevention and treatment of stroke, randomized controlled trials in patients with or without diabetes are underway. In conclusion, experimental studies show promising results of incretin-based therapies at improving the outcome of Alzheimer's disease and stroke through glucose-independent pleiotropic effects on the brain. If these findings would indeed be confirmed in large clinical randomized controlled trials, this would have substantial impact. 10.1111/jdi.12420
    Intravenous Administration of Human Adipose Derived-Mesenchymal Stem Cells Is Not Efficient in Diabetic or Hypertensive Mice Subjected to Focal Cerebral Ischemia. Mangin Gabrielle,Cogo Adrien,Moisan Anaïck,Bonnin Philippe,Maïer Benjamin,Kubis Nathalie, Frontiers in neuroscience As the second cause of death and cognitive decline in industrialized countries, stroke is a major burden for society. Vascular risks factors such as hypertension and diabetes are involved in most stroke patients, aggravate stroke severity, but are still poorly taken into account in preclinical studies. Microangiopathy and sustained inflammation are exacerbated, likely explaining the severity of stroke in those patients. We sought to demonstrate that intravenous administration of human adipose derived-mesenchymal stem cells (hADMSC) that have immunomodulatory properties, could accelerate sensorimotor recovery, prevent long-term spatial memory impairment and promote neurogenesis, in diabetic or hypertensive mice, subjected to permanent middle cerebral artery occlusion (pMCAo). Diabetic (streptozotocin IP) or hypertensive (L-NAME in drinking water) male C57Bl6 mice subjected to pMCAo, were treated by hADMSC (500,000 cells IV) 2 days after cerebral ischemia induction. Infarct volume, neurogenesis, microglial/macrophage density, T-lymphocytes density, astrocytes density, and vessel density were monitored 7 days after cells injection and at 6 weeks. Neurological sensorimotor deficit and spatial memory were assessed until 6 weeks post-stroke. Whatever the vascular risk factor, hADMSC showed no effect on functional sensorimotor recovery or cognitive decline prevention at short or long-term assessment, nor significantly modified neurogenesis, microglial/macrophage, T-lymphocytes, astrocytes, and vessel density. This work is part of a European program (H2020, RESSTORE). We discuss the discrepancy of our results with those obtained in rats and the optimal cell injection time frame, source and type of cells according to the species stroke model. A comprehensive understanding of the mechanisms preventing recovery should help for successful clinical translation, but first could allow identifying good and bad responders to cell therapy in stroke. 10.3389/fnins.2019.00718
    Genetics of cerebral small vessel disease. Choi Jay Chol Journal of stroke Cerebral small vessel disease (SVD) is an important cause of stroke and cognitive impairment among the elderly and is a more frequent cause of stroke in Asia than in the US or Europe. Although traditional risk factors such as hypertension or diabetes mellitus are important in the development of cerebral SVD, the exact pathogenesis is still uncertain. Both, twin and family history studies suggest heritability of sporadic cerebral SVD, while the candidate gene study and the genome-wide association study (GWAS) are mainly used in genetic research. Robust associations between the candidate genes and occurrence of various features of sporadic cerebral SVD, such as lacunar infarction, intracerebral hemorrhage, or white matter hyperintensities, have not yet been elucidated. GWAS, a relatively new technique, overcomes several shortcomings of previous genetic techniques, enabling the detection of several important genetic loci associated with cerebral SVD. In addition to the more common, sporadic cerebral SVD, several single-gene disorders causing cerebral SVD have been identified. The number of reported cases is increasing as the clinical features become clear and diagnostic examinations are more readily available. These include cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy, COL4A1-related cerebral SVD, autosomal dominant retinal vasculopathy with cerebral leukodystrophy, and Fabry disease. These rare single-gene disorders are expected to play a crucial role in our understanding of cerebral SVD pathogenesis by providing animal models for the identification of cellular, molecular, and biochemical changes underlying cerebral small vessel damage. 10.5853/jos.2015.17.1.7
    Diabetic Stroke Promotes a Sexually Dimorphic Expansion of T Cells. Jackson Ladonya,Li Weiguo,Abdul Yasir,Dong Guangkuo,Baban Babak,Ergul Adviye Neuromolecular medicine We recently reported that diabetes negates the cerebrovascular protection typically seen in adult female rats resulting in cognitive impairment, which is worsened by increased parenchymal bleeding and edema after ischemic stroke. Although women experience more severe diabetes and suffer from a higher rate of diabetic complications, including stroke and cognitive impairment, underlying mechanisms contributing to sex differences are limited. Emerging evidence suggests interleukin (IL)-17 contributes to cerebrovascular pathologies: (1) high salt diet-mediated expansion of IL-17-producing T cells (Th17) in the gut microbiome promotes cerebrovascular dysfunction and cognitive impairment in male mice, (2) increased IL-17-producing γδTCR cells exacerbates stroke injury in male mice, and (3) IL-17 promotes rupture of cerebral aneurysms in female mice. Based on these premises, we investigated the potential involvement of IL-17-producing inflammatory cells in cerebrovascular dysfunction and post-stroke vascular injury in diabetes by measuring intestinal, circulating, or cerebral T cell profiles as well as in plasma IL-17 in both sexes. Cell suspensions prepared from naive or stroked (3 days after stroke) diabetic and control rats were analyzed by flow cytometry, and IL-17 levels were measured in plasma using ELISA. Diabetes deferentially promoted the expansion of cerebral Th17 cells in females. In response to stroke, diabetes had a sexually dimorphic effect on the expansion of numerous T cell profiles. These results suggest that a better understanding of the role of IL-17-producing cells in diabetes may identify potential avenues in which the molecular mechanisms contributing to these sex differences can be further elucidated. 10.1007/s12017-019-08554-6
    Effects of glycemic variability and hyperglycemia in acute ischemic stroke on post-stroke cognitive impairments. Lim Jae-Sung,Kim Chulho,Oh Mi Sun,Lee Ju-Hun,Jung San,Jang Min Uk,Lee Sang-Hwa,Kim Yeo Jin,Kim Yerim,Suh Sang Won,Lee Byung-Chul,Yu Kyung-Ho Journal of diabetes and its complications AIMS:We aimed to investigate the effect of glycemic variability in the acute stage of stroke on the development of post-stroke cognitive impairment (PSCI). METHODS:Patients who underwent blood glucose tests at least five times within 7 days after acute ischemic stroke were included. Factors related to glycemic variability (standard deviation (SD), coefficient of variance (CV), and mean absolute glucose (MAG)) were calculated; neuropsychological assessments were administered 3 months after stroke. PSCI was defined as a score of less than -2 SDs for age-, sex-, and education-adjusted means in at least one cognitive domain. RESULTS:A total of 354 patients were enrolled. PSCI was identified in 74 (20.9%) subjects. In the diabetic group (n = 87), MAG was a significant predictor for PSCI (adjusted OR, 1.94; 95% CI, 1.11-3.42); however, it was not significant in the non-diabetic group, although PSCI exhibited an increasing tendency within higher SD and MAG tertiles. Moreover, hyperglycemia demonstrated a detrimental effect on PSCI, regardless of diabetes status; this effect did not appear in poorly-controlled diabetic patients with HbA1c ≥ 8.0%. CONCLUSIONS:Glycemic variability and hyperglycemia during acute ischemic stroke were identified as novel predictors for PSCI. Although this result is not evidence of a causal relationship, our study suggests that monitoring glycemic index and controlling its variability during the acute phase of ischemic stroke may help to prevent poor cognitive outcomes. 10.1016/j.jdiacomp.2018.02.006
    NLRP3 inflammasome inhibition with MCC950 improves diabetes-mediated cognitive impairment and vasoneuronal remodeling after ischemia. Ward Rebecca,Li Weiguo,Abdul Yasir,Jackson LaDonya,Dong Guangkuo,Jamil Sarah,Filosa Jessica,Fagan Susan C,Ergul Adviye Pharmacological research Diabetes increases the risk and worsens the progression of cognitive impairment via the greater occurrence of small vessel disease and stroke. Yet, the underlying mechanisms are not fully understood. It is now accepted that cardiovascular health is critical for brain health and any neurorestorative approaches to prevent/delay cognitive deficits should target the conceptual neurovascular unit (NVU) rather than neurons alone. We have recently shown that there is augmented hippocampal NVU remodeling after a remote ischemic injury in diabetes. NLRP3 inflammasome signaling has been implicated in the development of diabetes and neurodegenerative diseases, but little is known about the impact of NLRP3 activation on functional and structural interaction within the NVU of hippocampus, a critical part of the brain that is involved in forming, organizing, and storing memories. Endothelial cells are at the center of the NVU and produce trophic factors such as brain derived neurotrophic factor (BDNF) contributing to neuronal survival, known as vasotrophic coupling. Therefore, the aims of this study focused on two hypotheses: 1) diabetes negatively impacts hippocampal NVU remodeling and worsens cognitive outcome after stroke, and 2) NLRP3 inhibition with MCC950 will improve NVU remodeling and cognitive outcome following stroke via vasotrophic (un)coupling between endothelial cells and hippocampal neurons. Stroke was induced through a 90-min transient middle cerebral artery occlusion (MCAO) in control and high-fat diet/streptozotocin-induced (HFD/STZ) diabetic male Wistar rats. Saline or MCC950 (3 mg/kg), an inhibitor of NLRP3, was injected at 1 and 3 h after reperfusion. Cognition was assessed over time and neuronal density, blood-brain barrier (BBB) permeability as well as NVU remodeling (aquaporin-4 [AQP4] polarity) was measured on day 14 after stroke. BDNF was measured in endothelial and hippocampal neuronal cultures under hypoxic and diabetes-mimicking condition with and without NLRP3 inhibition. Diabetes increased neuronal degeneration and BBB permeability, disrupted AQP4 polarity, impaired cognitive function and amplified NLRP3 activation after ischemia. Inhibition with MCC950 improved cognitive function and vascular integrity after stroke in diabetic animals and prevented hypoxia-mediated decrease in BDNF secretion. These results are the first to provide essential data showing MCC950 has the potential to become a therapeutic to prevent neurovascular remodeling and worsened cognitive decline in diabetic patients following stroke. 10.1016/j.phrs.2019.01.035
    Diabetes Mellitus Impairs Cognitive Function in Middle-Aged Rats and Neurological Recovery in Middle-Aged Rats After Stroke. Zhang Li,Chopp Michael,Zhang Yanlu,Xiong Ye,Li Chao,Sadry Neema,Rhaleb Imane,Lu Mei,Zhang Zheng Gang Stroke BACKGROUND AND PURPOSE:Diabetes mellitus (DM) is a common metabolic disease among the middle-aged and older population, which leads to an increase of stroke incidence and poor stroke recovery. The present study was designed to investigate the impact of DM on brain damage and on ischemic brain repair after stroke in aging animals. METHODS:DM was induced in middle-aged rats (13 months) by administration of nicotinamide and streptozotocin. Rats with confirmed hyperglycemia status 30 days after nicotinamide-streptozotocin injection and age-matched non-DM rats were subjected to embolic middle cerebral artery occlusion. RESULTS:Middle-aged rats subjected to nicotinamide-streptozotocin injection became hyperglycemic and developed cognitive deficits 2 months after induction of DM. Histopathologic analysis revealed that there was sporadic vascular disruption, including cerebral microvascular thrombosis, blood-brain barrier leakage, and loss of paravascular aquaporin-4 in the hippocampi. Importantly, middle-aged DM rats subjected to stroke had exacerbated sensorimotor and cognitive deficits compared with age-matched non-DM ischemic rats during stroke recovery. Compared with age-matched non-DM ischemic rats, DM ischemic rats exhibited aggravated neurovascular disruption in the bilateral hippocampi and white matter, suppressed stroke-induced neurogenesis and oligodendrogenesis, and impaired dendritic/spine plasticity. However, DM did not enlarge infarct volume. CONCLUSIONS:Our data suggest that DM exacerbates neurovascular damage and hinders brain repair processes, which likely contribute to the impairment of stroke recovery. 10.1161/STROKEAHA.115.012578
    Type 2 Diabetes Mellitus and Impaired Renal Function Are Associated With Brain Alterations and Poststroke Cognitive Decline. Ben Assayag Einor,Eldor Roy,Korczyn Amos D,Kliper Efrat,Shenhar-Tsarfaty Shani,Tene Oren,Molad Jeremy,Shapira Itzhak,Berliner Shlomo,Volfson Viki,Shopin Ludmila,Strauss Yehuda,Hallevi Hen,Bornstein Natan M,Auriel Eitan Stroke BACKGROUND AND PURPOSE:Type 2 diabetes mellitus (T2DM) is associated with diseases of the brain, kidney, and vasculature. However, the relationship between T2DM, chronic kidney disease, brain alterations, and cognitive function after stroke is unknown. We aimed to evaluate the inter-relationship between T2DM, impaired renal function, brain pathology on imaging, and cognitive decline in a longitudinal poststroke cohort. METHODS:The TABASCO (Tel Aviv brain acute stroke cohort) is a prospective cohort of stroke/transient ischemic attack survivors. The volume and white matter integrity, ischemic lesions, and brain and hippocampal volumes were measured at baseline using 3-T MRI. Cognitive tests were performed on 507 patients, who were diagnosed as having mild cognitive impairment, dementia, or being cognitively intact after 24 months. RESULTS:At baseline, T2DM and impaired renal function (estimated creatinine clearance [eCCl] <60 mL/min) were associated with smaller brain and hippocampal volumes, reduced cortical thickness, and worse white matter microstructural integrity. Two years later, both T2DM and eCCl <60 mL/min were associated with poorer cognitive scores, and 19.7% of the participants developed cognitive decline (mild cognitive impairment or dementia). Multiple analysis, controlling for age, sex, education, and apolipoprotein E4, showed a significant association of both T2DM and eCCl <60 mL/min with cognitive decline. Having both conditions doubled the risk compared with patients with T2DM or eCCl <60 mL/min alone and almost quadrupled the risk compared with patients without either abnormality. CONCLUSIONS:T2DM and impaired renal function are independently associated with abnormal brain structure, as well as poorer performance in cognitive tests, 2 years after stroke. The presence of both conditions quadruples the risk for cognitive decline. T2DM and lower eCCl have an independent and additive effect on brain atrophy and the risk of cognitive decline. CLINICAL TRIAL REGISTRATION:URL: http://www.clinicaltrials.gov. Unique identifier: NCT01926691. 10.1161/STROKEAHA.117.017709
    Metabolic/inflammatory/vascular comorbidity in psychiatric disorders; soluble epoxide hydrolase (sEH) as a possible new target. Swardfager W,Hennebelle M,Yu D,Hammock B D,Levitt A J,Hashimoto K,Taha A Y Neuroscience and biobehavioral reviews The common and severe psychiatric disorders, including major depressive disorder (MDD) and bipolar disorder (BD), are associated with inflammation, oxidative stress and changes in peripheral and brain lipid metabolism. Those pathways are implicated in the premature development of vascular and metabolic comorbidities, which account for considerable morbidity and mortality, including increased dementia risk. During endoplasmic reticulum stress, the soluble epoxide hydrolase (sEH) enzyme converts anti-inflammatory fatty acid epoxides generated by cytochrome p450 enzymes into their corresponding and generally less anti-inflammatory, or even pro-inflammatory, diols, slowing the resolution of inflammation. The sEH enzyme and its oxylipin products are elevated post-mortem in MDD, BD and schizophrenia. Preliminary clinical data suggest that oxylipins increase with symptoms in seasonal MDD and anorexia nervosa, requiring confirmation in larger studies and other cohorts. In rats, a soluble sEH inhibitor mitigated the development of depressive-like behaviors. We discuss sEH inhibitors under development for cardiovascular diseases, post-ischemic brain injury, neuropathic pain and diabetes, suggesting new possibilities to address the mood and cognitive symptoms of psychiatric disorders, and their most common comorbidities. 10.1016/j.neubiorev.2018.01.010
    Type 2 diabetes mellitus and biomarkers of neurodegeneration. Moran Chris,Beare Richard,Phan Thanh G,Bruce David G,Callisaya Michele L,Srikanth Velandai, Neurology OBJECTIVE:Our objective was to investigate whether type 2 diabetes mellitus (T2DM) influences neurodegeneration in a manner similar to Alzheimer disease (AD), by promoting brain β-amyloid (Aβ) or tau. METHODS:We studied the cross-sectional associations of T2DM with cortical thickness, brain Aβ load, and CSF levels of Aβ and tau in a sample of people from the Alzheimer's Disease Neuroimaging Initiative with diagnoses of AD dementia, mild cognitive impairment, and normal cognition. All (n=816) received MRI, and a subsample underwent brain amyloid imaging (n=102) and CSF Aβ and tau measurements (n=415). Analyses were performed across and within cognitive diagnostic strata. RESULTS:There were 124 people with T2DM (mean age 75.5 years) and 692 without T2DM (mean age 74.1 years). After adjusting for age, sex, total intracranial volume, APO ε4 status, and cognitive diagnosis, T2DM was associated with lower bilateral frontal and parietal cortical thickness (mL) (β=-0.03, p=0.01). T2DM was not associated with 11C Pittsburgh compound B standardized uptake value ratio (AU) in any brain region or with CSF Aβ42 levels (pg/mL). T2DM was associated with greater CSF total tau (pg/mL) (β=16.06, p=0.04) and phosphorylated tau (β=5.84, p=0.02). The association between T2DM and cortical thickness was attenuated by 15% by the inclusion of phosphorylated tau. CONCLUSIONS:T2DM may promote neurodegeneration independent of AD dementia diagnosis, and its effect may be driven by tau phosphorylation. The mechanisms through which T2DM may promote tau phosphorylation deserve further study. 10.1212/WNL.0000000000001982
    Increased risk of cognitive impairment in patients with diabetes is associated with metformin. Moore Eileen M,Mander Alastair G,Ames David,Kotowicz Mark A,Carne Ross P,Brodaty Henry,Woodward Michael,Boundy Karyn,Ellis Kathryn A,Bush Ashley I,Faux Noel G,Martins Ralph,Szoeke Cassandra,Rowe Christopher,Watters David A, Diabetes care OBJECTIVE:To investigate the associations of metformin, serum vitamin B12, calcium supplements, and cognitive impairment in patients with diabetes. RESEARCH DESIGN AND METHODS:Participants were recruited from the Primary Research in Memory (PRIME) clinics study, the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging, and the Barwon region of southeastern Australia. Patients with Alzheimer disease (AD) (n=480) or mild cognitive impairment (n=187) and those who were cognitively intact (n=687) were included; patients with stroke or with neurodegenerative diseases other than AD were excluded. Subgroup analyses were performed for participants who had either type 2 diabetes (n=104) or impaired glucose tolerance (n=22). RESULTS:Participants with diabetes (n=126) had worse cognitive performance than participants who did not have diabetes (n=1,228; adjusted odds ratio 1.51 [95% CI 1.03-2.21]). Among participants with diabetes, worse cognitive performance was associated with metformin use (2.23 [1.05-4.75]). After adjusting for age, sex, level of education, history of depression, serum vitamin B12, and metformin use, participants with diabetes who were taking calcium supplements had better cognitive performance (0.41 [0.19-0.92]). CONCLUSIONS:Metformin use was associated with impaired cognitive performance. Vitamin B12 and calcium supplements may alleviate metformin-induced vitamin B12 deficiency and were associated with better cognitive outcomes. Prospective trials are warranted to assess the beneficial effects of vitamin B12 and calcium use on cognition in older people with diabetes who are taking metformin. 10.2337/dc13-0229
    Risk factors for incident dementia after stroke and transient ischemic attack. Yang Jie,Wong Adrian,Wang Zhaolu,Liu Wenyan,Au Lisa,Xiong Yunyun,Chu Winnie W C,Leung Eric Y L,Chen Sirong,Lau Christine,Chan Anne Y Y,Lau Alexander Y L,Fan Florence,Ip Vincent,Soo Yannie,Leung Thomas,Ho Chi L,Wong Lawrence K S,Mok Vincent C T Alzheimer's & dementia : the journal of the Alzheimer's Association BACKGROUND:We hypothesized that chronic brain changes are important substrates for incident dementia after stroke and transient ischemic attack (TIA). METHODS:We compared clinical and imaging features between patients with consecutive stroke/TIA with (n = 88) and without (n = 925) incident dementia at 3 to 6 months after a stroke/TIA. Pittsburg compound B (PiB) positron emission tomography was performed in 50 patients, including those with (n = 37) and without (n = 13) incident dementia. RESULTS:Age, history of diabetes mellitus, severity of white matter changes (WMCs), and medial temporal lobe atrophy (MTLA) were associated with incident dementia. Alzheimer's disease (AD)--like PiB retention was found in 29.7% and 7.7% (P = .032) of patients with and without incident dementia, respectively. CONCLUSIONS:Chronic brain changes including WMCs, MTLA, and AD pathology are associated with incident dementia after stroke/TIA. Interventions targeting these chronic brain changes may reduce burden of vascular cognitive impairment. 10.1016/j.jalz.2014.01.003
    Diabetes is associated with cerebrovascular but not Alzheimer's disease neuropathology. Abner Erin L,Nelson Peter T,Kryscio Richard J,Schmitt Frederick A,Fardo David W,Woltjer Randall L,Cairns Nigel J,Yu Lei,Dodge Hiroko H,Xiong Chengjie,Masaki Kamal,Tyas Suzanne L,Bennett David A,Schneider Julie A,Arvanitakis Zoe Alzheimer's & dementia : the journal of the Alzheimer's Association INTRODUCTION:The relationship of diabetes to specific neuropathologic causes of dementia is incompletely understood. METHODS:We used logistic regression to evaluate the association between diabetes and infarcts, Braak neurofibrillary tangle stage, and neuritic plaque score in 2365 autopsied persons. In a subset of >1300 persons with available cognitive data, we examined the association between diabetes and cognition using Poisson regression. RESULTS:Diabetes increased odds of brain infarcts (odds ratio [OR] = 1.57, P < .0001), specifically lacunes (OR = 1.71, P < .0001), but not Alzheimer's disease neuropathology. Diabetes plus infarcts was associated with lower cognitive scores at end of life than infarcts or diabetes alone, and diabetes plus high level of Alzheimer's neuropathologic changes was associated with lower mini-mental state examination scores than the pathology alone. DISCUSSION:This study supports the conclusions that diabetes increases the risk of cerebrovascular but not Alzheimer's disease pathology, and at least some of diabetes' relationship to cognitive impairment may be modified by neuropathology. 10.1016/j.jalz.2015.12.006