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    Longitudinal Brain Atrophy Rates in Transient Ischemic Attack and Minor Ischemic Stroke Patients and Cognitive Profiles. Munir Muhammad,Ursenbach Jake,Reid Meaghan,Gupta Sah Rani,Wang Meng,Sitaram Amith,Aftab Arooj,Tariq Sana,Zamboni Giovanna,Griffanti Ludovica,Smith Eric E,Frayne Richard,Sajobi Tolulope T,Coutts Shelagh B,d'Esterre Christopher D,Barber Philip A, Frontiers in neurology Patients with transient ischemic attack (TIA) and minor stroke demonstrate cognitive impairment, and a four-fold risk of late-life dementia. To study the extent to which the rates of brain volume loss in TIA patients differ from healthy controls and how they are correlated with cognitive impairment. TIA or minor stroke patients were tested with a neuropsychological battery and underwent T1 weighted volumetric magnetic resonance imaging scans at fixed intervals over a 3 years period. Linear mixed effects regression models were used to compare brain atrophy rates between groups, and to determine the relationship between atrophy rates and cognitive function in TIA and minor stroke patients. Whole brain atrophy rates were calculated for the TIA and minor stroke patients; = 38 between 24 h and 18 months, and = 68 participants between 18 and 36 months, and were compared to healthy controls. TIA and minor stroke patients demonstrated a significantly higher whole brain atrophy rate than healthy controls over a 3 years interval ( = 0.043). Diabetes ( = 0.012) independently predicted higher atrophy rate across groups. There was a relationship between higher rates of brain atrophy and processing speed (composite = 0.047 and digit symbol coding = 0.02), but there was no relationship with brain atrophy rates and memory or executive composite scores or individual cognitive tests for language (Boston naming, memory recall, verbal fluency or Trails A or B score). TIA and minor stroke patients experience a significantly higher rate of whole brain atrophy. In this cohort of TIA and minor stroke patients changes in brain volume over time precede cognitive decline. 10.3389/fneur.2019.00018
    Insulin resistance and cognitive test performance in elderly adults: National health and nutrition examination survey (NHANES). Sherzai Ayesha Z,Shaheen Magda,Yu Jeffrey J,Talbot Konrad,Sherzai Dean Journal of the neurological sciences OBJECTIVES:To examine the relationship between homeostatic model of insulin resistance (HOMA-IR) and cognitive test performance among population≥60years in a national database. HYPOTHESIS:Higher insulin resistance is associated with lower cognitive test performance score in the population≥60years. PARTICIPANTS:We analyzed data from the National Health and Nutrition Examination Survey (NHANES) 1999-2000 and 2001-2002. MEASUREMENTS:Cognitive test performance was measured by the Digit Symbol Substitution (DSS) exercise score. The main independent variable was the homeostasis model assessment of insulin resistance (HOMA-IR). We used bivariate analysis and generalized linear model adjusting for age, gender, race, education, body mass index, and systolic and diastolic blood pressures; total cholesterol, low density lipoprotein (LDL), high density lipoprotein (HDL) and triglyceride levels; and physical activity, diabetes mellitus, stroke, and congestive heart failure. STATA 14 was used to analyze the data taking into consideration the design, strata and weight. RESULTS:Of the 1028 participants, 44% were male and 85% were white. The mean age was 70.0±0.28 (SE) years. Their average HOMA-IR was 3.6±0.14 and they had a mean of 49.2±0.8 correct DSS score in the cognitive test. Adjusting for the confounding variables, HOMA-IR was associated with decline in DSS score (B=-0.30, 95% confidence interval=-0.54 and -0.05, p=0.01). The model explained 44% of the variability of the DSS score (R=0.44). Significant predictors of decline in DSS score were age, gender, race, and education (p=0.01). CONCLUSION:Insulin resistance as measured by HOMA-IR was independently associated with lower cognitive test performance score among elderly participants aged ≥60years. Longitudinal studies are needed to test the mechanism and the causal relationship. 10.1016/j.jns.2017.11.031
    Insulin Resistance and Future Cognitive Performance and Cognitive Decline in Elderly Patients with Cardiovascular Disease. Lutski Miri,Weinstein Galit,Goldbourt Uri,Tanne David Journal of Alzheimer's disease : JAD BACKGROUND:The role of insulin resistance (IR) in the pathogenesis of cognitive performance is not yet clear. OBJECTIVE:To examine the associations between IR and cognitive performance and change in cognitive functions two decades later in individuals with cardiovascular disease with and without diabetes. METHODS:A subset of 489 surviving patients (mean age at baseline 57.7±6.5 y) with coronary heart disease who previously participated in the secondary prevention Bezafibrate Infarction Prevention (BIP trial; 1990-1997), were included in the current neurocognitive study. Biochemical parameters including IR (using the homeostasis model of assessment; HOMA-IR) were measured at baseline. During 2004-2008, computerized cognitive assessment and atherosclerosis parameters were measured (T1; n = 558; mean age 72.6±6.4 years). A second cognitive assessment was performed during 2011-2013 (T2; n = 351; mean age 77.2±6.4 years). Cognitive function, overall and in specific domains, was assessed. We used linear regression models and linear mixed models to evaluate the differences in cognitive performance and decline, respectively. RESULTS:Controlling for potential confounders, IR (top HOMA-IR quartile versus others) was associated with subsequent poorer cognitive performance overall (β= -4.45±Standard Error (SE) 1.54; p = 0.004) and on tests of memory and executive function among non-diabetic patients (β= -7.16±2.38; p = 0.003 and β= -3.33±1.84; p = 0.073, respectively). Moreover, among non-diabetic patients, IR was related to a greater decline overall (β= -0.17±0.06; p = 0.008), and in memory (β= -0.22±0.10; p = 0.024) and executive function (β= -0.19±0.08; p = 0.012). The observed associations did not differ after excluding subjects with prevalent stroke or dementia. CONCLUSION:IR is related to subsequent poorer cognitive performance and greater cognitive decline among patients with cardiovascular disease with and without diabetes. 10.3233/JAD-161016
    Effects of butylphthalide on cognitive decline in diabetic rats. Tian Zhiyan,Wang Jinhua,Wang Yan,Zhang Miao,Zhou Yuying Molecular medicine reports Butylphthalide, a component extracted from seeds of Chinese celery, is an effective neuroprotective agent used for the treatment of ischemic stroke and dementia. Diabetes may cause central nervous system damage, and diabetes is closely associated with dementia. The aim of the present study was to investigate the effects of butylphthalide on cognitive impairment in a streptozotocin‑induced diabetic rat model, and the underlying mechanisms of action. A total of 30 healthy male Sprague Dawley rats were randomly divided into the following 2 groups: Normal control (NC; n=10) and diabetes model (DM) groups (n=20). Diabetes was induced in rats in the DM group by intraperitoneal injection of streptozotocin, and these rats were further subdivided into the following 2 groups: Diabetic control (n=10) and butylphthalide‑treated groups (n=10). Following 8 consecutive weeks of treatment, a Morris water maze test was performed and the levels of blood fasting plasma glucose (FPG), superoxide dismutase (SOD), malondialdehyde (MDA) and tumor necrosis factor‑α (TNF‑α), interleukin (IL)‑1β, and IL‑6 inflammatory cytokines in the hippocampus were measured. FPG levels were significantly decreased in the butylphthalide‑treated group when compared with the DM group. In addition, cognitive deficits in diabetic rats were improved following butylphthalide treatment. Furthermore, butylphthalide significantly increased the level of SOD, reduced MDA levels, and reduced TNF‑α, IL‑1β, and IL‑6 levels in the hippocampus when compared with the DM group. The results of the present study suggest that butylphthalide may be an effective neuroprotective agent to improve cognitive dysfunction during diabetes. 10.3892/mmr.2017.7700
    Cognitive impairment and stroke in elderly patients. Lo Coco Daniele,Lopez Gianluca,Corrao Salvatore Vascular health and risk management We reviewed current knowledge about the interaction between stroke and vascular risk factors and the development of cognitive impairment and dementia. Stroke is increasingly recognized as an important cause of cognitive problems and has been implicated in the development of both Alzheimer's disease and vascular dementia. The prevalence of cognitive impairment after stroke is high, and their combined effects significantly increase the cost of care and health resource utilization, with reflections on hospital readmissions and increased mortality rates. There is also substantial evidence that vascular risk factors (such as hypertension, diabetes, obesity, dyslipidemia, and tobacco smoking) are independently associated with an increased risk of cognitive decline and dementia. Thus, a successful management of these factors, as well as optimal acute stroke management, might have a great impact on the development of cognitive impairment. Notwithstanding, the pathological link between cognitive impairment, stroke, and vascular risk factors is complex and still partially unclear so that further studies are needed to better elucidate the boundaries of this relationship. Many specific pharmacological treatments, including anticholinergic drugs and antihypertensive medications, and nonpharmacological approaches, such as diet, cognitive rehabilitation, and physical activity, have been studied for patients with vascular cognitive impairment, but the optimal care is still far away. Meanwhile, according to the most recent knowledge, optimal stroke care should also include cognitive assessment in the short and long term, and great efforts should be oriented toward a multidisciplinary approach, including quality-of-life assessment and support of caregivers. 10.2147/VHRM.S75306
    Diabetes and the link between neuroplasticity and glutamate in the aging human motor cortex. Fried Peter J,Pascual-Leone Alvaro,Bolo Nicolas R Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology OBJECTIVES:In older adults, type-2 diabetes mellitus (T2DM) impacts cognition and increases dementia risk. Prior studies suggest that impaired neuroplasticity may contribute to the cognitive decline in T2DM, but the underlying mechanisms of altered neuroplasticity are unclear. We investigated the relationship of the concentration of glutamatergic metabolites with measures of cortical plasticity in older adults across the spectrum of glucose intolerance/insulin resistance. METHODS:Forty adults (50-87 years: 17-T2DM, 14-pre-diabetes, 9-controls) underwent magnetic resonance spectroscopy to quantify glutamate and other key metabolites within a 2 cm region around the hand knob of the left primary motor cortex. Thirty-six also underwent a separate transcranial magnetic stimulation (TMS) assessment of cortical excitability and plasticity using single-pulse TMS and intermittent theta-burst stimulation targeting the same brain region. RESULTS:Group differences were observed in relative concentrations of glutamine (p = .028), glucose (p = .008), total cholines (p = .048), and the glutamine/glutamate ratio (p = .024). Cortical plasticity was reduced in both T2DM and pre-diabetes groups relative to controls (p-values < .05). Only the T2DM group showed a significant positive association between glutamate concentration and plasticity (r = .56, p = .030). CONCLUSIONS:Neuroplastic mechanisms are already impaired in pre-diabetes. In T2DM, reduced cortico-motor plasticity is associated with lower cortical glutamate concentration. SIGNIFICANCE:Impaired plasticity in T2DM is associated with low glutamatergic metabolite levels. The glutamatergic neurotransmission system constitutes a potential therapeutic target for cognitive problems linked to plasticity-related deficiencies in T2DM. 10.1016/j.clinph.2019.04.721
    Early Cognitive Deficits in Type 2 Diabetes: A Population-Based Study. Marseglia Anna,Fratiglioni Laura,Laukka Erika J,Santoni Giola,Pedersen Nancy L,Bäckman Lars,Xu Weili Journal of Alzheimer's disease : JAD Evidence links type 2 diabetes to dementia risk. However, our knowledge on the initial cognitive deficits in diabetic individuals and the factors that might promote such deficits is still limited. This study aimed to identify the cognitive domains initially impaired by diabetes and the factors that play a role in this first stage. Within the population-based Swedish National Study on Aging and Care-Kungsholmen, 2305 cognitively intact participants aged ≥60 y were identified. Attention/working memory, perceptual speed, category fluency, letter fluency, semantic memory, and episodic memory were assessed. Diabetes (controlled and uncontrolled) and prediabetes were ascertained by clinicians, who also collected information on vascular disorders (hypertension, heart diseases, and stroke) and vascular risk factors (VRFs, including smoking and overweight/obesity). Data were analyzed with linear regression models. Overall, 196 participants (8.5%) had diabetes, of which 144 (73.5%) had elevated glycaemia (uncontrolled diabetes); 571 (24.8%) persons had prediabetes. In addition, diabetes, mainly uncontrolled, was related to lower performance in perceptual speed (β - 1.10 [95% CI - 1.98, - 0.23]), category fluency (β - 1.27 [95% CI - 2.52, - 0.03]), and digit span forward (β - 0.35 [95% CI - 0.54, - 0.17]). Critically, these associations were present only among APOEɛ4 non-carriers. The associations of diabetes with perceptual speed and category fluency were present only among participants with VRFs or vascular disorders. Diabetes, especially uncontrolled diabetes, is associated with poorer performance in perceptual speed, category fluency, and attention/primary memory. VRFs, vascular disorders, and APOE status play a role in these associations. 10.3233/JAD-160266
    Arterial stiffness, endothelial and cognitive function in subjects with type 2 diabetes in accordance with absence or presence of diabetic foot syndrome. Tuttolomondo Antonino,Casuccio Alessandra,Guercio Giovanni,Maida Carlo,Del Cuore Alessandro,Di Raimondo Domenico,Simonetta Irene,Di Bona Danilo,Pecoraro Rosaria,Della Corte Vittoriano,Gulotta Eliana,Gulotta Gaspare,Pinto Antonio Cardiovascular diabetology BACKGROUND:Endothelial dysfunction is an early marker of cardiovascular disease so endothelial and arterial stiffness indexes are good indicators of vascular health. We aimed to assess whether the presence of diabetic foot is associated with arterial stiffness and endothelial function impairment. METHODS:We studied 50 subjects with type 2 diabetes mellitus and diabetic foot syndrome (DFS) compared to 50 diabetic subjects without diabetic foot, and 53 patients without diabetes mellitus, by means of the mini mental state examination (MMSE) administered to evaluate cognitive performance. Carotid-femoral pulse wave velocity (PWV) and augmentation index (Aix) were also evaluated by Applanation tonometry (SphygmoCor version 7.1), and the RH-PAT data were digitally analyzed online by Endo-PAT2000 using reactive hyperemia index (RHI) values. RESULTS:In comparison to diabetic subjects without diabetic foot the subjects with diabetic foot had higher mean values of PWV, lower mean values of RHI, and lower mean MMSE. At multinomial logistic regression PWV and RHI were significantly associated with diabetic foot presence, whereas ROC curve analysis had good sensitivity and specificity in arterial PWV and RHI for diabetic foot presence. CONCLUSIONS:Pulse wave velocity and augmentation index, mean RHI values, and mean MMSE were effective indicators of diabetic foot. Future research could address these issues by means of longitudinal studies to evaluate cardiovascular event incidence in relation to arterial stiffness, endothelial and cognitive markers. 10.1186/s12933-016-0483-5
    Role of the glymphatic system in ageing and diabetes mellitus impaired cognitive function. Zhang Li,Chopp Michael,Jiang Quan,Zhang Zhenggang Stroke and vascular neurology Diabetes mellitus (DM) is a common metabolic disease in the middle-aged and older population, and is associated with cognitive impairment and an increased risk of developing dementia. The glymphatic system is a recently characterised brain-wide cerebrospinal fluid and interstitial fluid drainage pathway that enables the clearance of interstitial metabolic waste from the brain parenchyma. Emerging data suggest that DM and ageing impair the glymphatic system, leading to accumulation of metabolic wastes including amyloid-β within the brain parenchyma, and consequently provoking cognitive dysfunction. In this review, we concisely discuss recent findings regarding the role of the glymphatic system in DM and ageing associated cognitive impairment. 10.1136/svn-2018-000203
    Poststroke cognitive impairment and hippocampal neurovascular remodeling: the impact of diabetes and sex. Ward Rebecca,Valenzuela John Paul,Li Weiguo,Dong Guangkuo,Fagan Susan C,Ergul Adviye American journal of physiology. Heart and circulatory physiology Diabetes increases the risk and severity of cognitive impairment, especially after ischemic stroke. Pathological remodeling of the cerebrovasculature has been postulated to contribute to poor neuronal repair and worsened cognitive deficits in diabetes. However, little is known about the effect of diabetes on the vascularization of hippocampus, a domain critical to memory and learning. Therefore, we had two aims for this study: 1) to determine the impact of diabetes on hippocampal neurovascular remodeling and the resulting cognitive impairment after stroke using two models with varying disease severity, and 2) to compare the effects of ischemia on hippocampal neurovascular injury in diabetic male and female animals. Stroke was induced by middle cerebral artery occlusion (MCAO) by either the suture or embolic method in control and diabetic age-matched male and female Wistar rats. Hippocampal neuronal density, vascular architecture, and microglial activation as well as cognitive outcomes were measured. Embolic MCAO induced greater neuronal degeneration, pathological vascularization, microglial activation, and cognitive impairment in diabetes as compared with control animals or 60-min MCAO. Although diabetic males had lower neuronal density at baseline, diabetic females had more neurodegeneration after stroke. Control animals recovered cognitive function by day 14 after stroke; diabetic animals showed deficits regardless of sex. These results suggest that mechanisms underlying cognitive decline in diabetes may differ in males and females and provide further insight to the impact of diabetes on stroke severity and poststroke cognitive impairment. NEW & NOTEWORTHY The present study is the first to provide comparative information on the effects of diabetes and ischemia on cognitive outcomes in both sexes while also evaluating the neurovascular structure in the hippocampus, a critical region for cognitive and memory-related tasks. 10.1152/ajpheart.00390.2018
    Low intakes of carotene, vitamin B , pantothenate and calcium predict cognitive decline among elderly patients with diabetes mellitus: The Japanese Elderly Diabetes Intervention Trial. Araki Atsushi,Yoshimura Yukio,Sakurai Takashi,Umegaki Hiroyuki,Kamada Chiemi,Iimuro Satoshi,Ohashi Yasuo,Ito Hideki, Geriatrics & gerontology international AIM:The present study aimed to examine whether nutrient intakes predicted cognitive decline among elderly patients with diabetes mellitus. METHODS:This study evaluated data from a 6-year prospective follow up of 237 elderly patients (aged ≥65 years) with diabetes mellitus, and the associations of baseline nutrient intakes with cognitive decline. Cognitive decline was defined as a ≥2-point decrease in the Mini-Mental State Examination (MMSE) score. Intakes of food and nutrients were assessed using a validated food frequency questionnaire, and were compared between patients with cognitive decline and intact cognition. Analysis of covariance and logistic regression analysis were used to compare the changes in the MMSE score during the follow up among intake tertile groups for each nutrient. RESULTS:Compared with men with intact cognition, the men with cognitive decline had lower baseline intakes of calcium, vitamin A, vitamin B , pantothenate, soluble fiber, green vegetables and milk. However, no significant associations between cognitive decline and nutrient intakes were observed among women. After adjusting for age, body mass index, glycated hemoglobin levels, history of severe hypoglycemia, previous stroke and baseline MMSE score, we found that cognitive decline was significantly associated with low intakes of carotene, vitamin B , pantothenate, calcium and green vegetables. Multiple logistic regression analysis showed that intakes of nutrients and green vegetables predicted cognitive decline after adjusting for age, body mass index, glycated hemoglobin levels, baseline MMSE score, and incident stroke during the follow up. CONCLUSIONS:These findings suggest that sufficient intakes of carotene, vitamin B , pantothenate, calcium and vegetables could help prevent cognitive decline among elderly men with diabetes mellitus. Geriatr Gerontol Int 2017; 17: 1168-1175. 10.1111/ggi.12843
    Inhibition of Ephrin-B2 in brain pericytes decreases cerebral pathological neovascularization in diabetic rats. Coucha Maha,Barrett Amy C,Elgebaly Mostafa,Ergul Adviye,Abdelsaid Mohammed PloS one We have previously shown that diabetes causes dysfunctional cerebral neovascularization that increases the risk for cerebrovascular disorders such as stroke and cognitive impairment. Pericytes (PCs) play a pivotal role in the angiogenic process through their interaction with the endothelial cells (EC). Yet, the role of PCs in dysfunctional cerebral neovascularization in diabetes is unclear. In the present study, we tested the hypothesis that the increased proangiogenic Ephrin-B2 signaling in PCs contributes to the dysfunctional cerebral neovascularization in diabetes. Type-II diabetes was induced by a combination of high fat diet and low dose streptozotocin injection in male Wistar rats. Selective in vivo Ephrin-B2 silencing in brain PCs was achieved using the stereotactic injection of adeno-associated virus (AAV) with NG2-promoter that expresses Ephrin-B2 shRNA. Neovascularization was assessed using vascular fluorescent dye stain. Novel object recognition (NOR) test was used to determine cognitive functions. Human brain microvascular pericytes HBMVPCs were grown in high glucose 25 mM and palmitate 200 uM (HG/Pal) to mimic diabetic conditions. Scratch migration and tube formation assays were conducted to evaluate PC/EC interaction and angiogenic functions in PC/EC co-culture. Diabetes increased the expression of Ephrin-B2 in the cerebrovasculature and pericytes. Concomitant increases in cerebral neovascularization parameters including vascular density, tortuosity and branching density in diabetic rats were accompanied by deterioration of cognitive function. Inhibition of Ephrin-B2 expression in PCs significantly restored cerebral vascularization and improved cognitive functions. HG/Pal increased PC/EC angiogenic properties in co-culture. Silencing Ephrin-B2 in PCs significantly reduced PC migration and PC/EC co-culture angiogenic properties. This study emphasizes the significant contribution of PCs to the pathological neovascularization in diabetes. Our findings introduce Ephrin-B2 signaling as a promising therapeutic target to improve cerebrovascular integrity in diabetes. 10.1371/journal.pone.0210523
    Central nervous system involvement in diabetes mellitus. Selvarajah Dinesh,Tesfaye Solomon Current diabetes reports Diabetic complications result in much morbidity and mortality and considerable consumption of scarce medical resources. Thus, elucidation of the risk factors and pathophysiologic mechanisms underlying diabetic complications is important. The effects of diabetes on the central nervous system (CNS) result in cognitive dysfunction and cerebrovascular disease. Treatment-related hypoglycemia also has CNS consequences. Advances in neuroimaging now provide greater insights into the structural and functional impact of diabetes on the CNS. Greater understanding of CNS involvement could lead to new strategies to prevent or reverse the damage caused by diabetes mellitus. 10.1007/s11892-006-0075-y
    White matter changes and diabetes predict cognitive decline in the elderly: the LADIS study. Verdelho A,Madureira S,Moleiro C,Ferro J M,Santos C O,Erkinjuntti T,Pantoni L,Fazekas F,Visser M,Waldemar G,Wallin A,Hennerici M,Inzitari D, Neurology OBJECTIVE:We aimed to study if age-related white matter changes (WMC) and vascular risk factors were predictors of cognitive decline in elderly subjects with WMC living independently. METHODS:The Leukoaraiosis and Disability prospective multinational European study (LADIS) evaluates the impact of WMC on the transition of independent elderly subjects into disability. Independent elderly were enrolled due to the presence of WMC. Subjects were evaluated yearly during 3 years with a comprehensive clinical protocol and a neuropsychological battery. Additionally, dementia, subtypes of dementia, and cognitive decline without dementia were classified according to usual clinical criteria. MRI was performed at entry and at the end of the study. RESULTS:A total of 639 subjects were included (74.1 +/- 5 years, 55% women, 9.6 +/- 3.8 years of schooling). At end of follow-up, 90 patients had dementia and 147 had cognitive impairment no dementia. Using Cox regression analysis, WMC severity independently predicted cognitive decline (dementia and not dementia), independently of age, education, and medial temporal atrophy (MTA). Diabetes at baseline was the only vascular risk factor that independently predicted cognitive decline during follow-up, controlling for age, education, WMC severity, and temporal atrophy. Considering subtypes of dementia, Alzheimer disease (AD) was predicted only by MTA, while vascular dementia was predicted by previous stroke, WMC severity, and MTA. CONCLUSION:WMC severity and diabetes are independent predictors of cognitive decline in an initially nondisabled elderly population. Vascular dementia is predicted by previous stroke and WMC, while AD is predicted only by MTA. 10.1212/WNL.0b013e3181e7ca05
    Macro- and microstructural magnetic resonance imaging indices associated with diabetes among community-dwelling older adults. Falvey Cherie M,Rosano Caterina,Simonsick Eleanor M,Harris Tamara,Strotmeyer Elsa S,Satterfield Suzanne,Yaffe Kristine, Diabetes care OBJECTIVE:To better understand the association between diabetes and cognitive impairment, we evaluated macro- and microstructural brain MRI measures for the total brain and regions of interest (ROIs) in a group of community-dwelling elders with and without diabetes. RESEARCH DESIGN AND METHODS:MRI measures were obtained on 308 elders (mean age 83.3 years; n = 85 with diabetes) from the Health ABC Healthy Brain Substudy. We performed a series of linear regressions and used standardized β values to estimate the cross-sectional association between diabetes and macrostructural (gray matter volume [GMV] and white matter hyperintensities [WMHs]) and microstructural (mean diffusivity [MD] and fractional anisotropy [FA]) measures for the total brain and ROIs. Models were adjusted for age, race, and sex; GMV values for ROIs were also adjusted for total brain volume (TBV). RESULTS:In multivariate-adjusted models, diabetes was associated with lower total GMV (P = 0.0006), GMV in the putamen (P = 0.02 for left and right), and TBV (P = 0.04) and greater cerebral atrophy (P = 0.02). There was no association with WMHs. On microstructural measures, diabetes was associated with reduced FA for total white matter (P = 0.006) and greater MD for the hippocampus (P = 0.006 left; P = 0.01 right), dorsolateral prefrontal cortex (P = 0.0007, left; P = 0.002, right), left posterior cingulate (P = 0.02), and right putamen (P = 0.02). Further adjustment for stroke, hypertension, and myocardial infarction produced similar results. CONCLUSIONS:In this cross-sectional study, elders with diabetes compared with those without had greater brain atrophy and early signs of neurodegeneration. Further studies are needed to determine whether these structural changes associated with diabetes predict risk of cognitive decline. 10.2337/dc12-0814
    Diabetes and cognitive outcomes in a nationally representative sample: the National Health and Aging Trends Study. Wennberg Alexandra M V,Gottesman Rebecca F,Kaufmann Christopher N,Albert Marilyn S,Chen-Edinboro Lenis P,Rebok George W,Kasper Judith D,Spira Adam P International psychogeriatrics BACKGROUND:The prevalence of both type II diabetes mellitus (DM) and cognitive impairment is high and increasing in older adults. We examined the extent to which DM diagnosis was associated with poorer cognitive performance and dementia diagnosis in a population-based cohort of US older adults. METHODS:We studied 7,606 participants in the National Health and Aging Trends Study, a nationally representative cohort of Medicare beneficiaries aged 65 years and older. DM and dementia diagnosis were based on self-report from participants or proxy respondents, and participants completed a word-list memory test, the Clock Drawing Test, and gave a subjective assessment of their own memory. RESULTS:In unadjusted analyses, self-reported DM diagnosis was associated with poorer immediate and delayed word recall, worse performance on the Clock Drawing Test, and poorer self-rated memory. After adjusting for demographic characteristics, body mass index, depression and anxiety symptoms, and medical conditions, DM was associated with poorer immediate and delayed word recall and poorer self-rated memory, but not with the Clock Drawing Test performance or self-reported dementia diagnosis. After excluding participants with a history of stroke, DM diagnosis was associated with poorer immediate and delayed word recall and the Clock Drawing Test performance, and poorer self-rated memory, but not with self-reported dementia diagnosis. CONCLUSIONS:In this recent representative sample of older Medicare enrollees, self-reported DM was associated with poorer cognitive test performance. Findings provide further support for DM as a potential risk factor for poor cognitive outcomes. Studies are needed that investigate whether DM treatment prevents cognitive decline. 10.1017/S1041610214001380
    Disruption of the hippocampal and hypothalamic blood-brain barrier in a diet-induced obese model of type II diabetes: prevention and treatment by the mitochondrial carbonic anhydrase inhibitor, topiramate. Salameh Therese S,Mortell William G,Logsdon Aric F,Butterfield D Allan,Banks William A Fluids and barriers of the CNS BACKGROUND:Type II diabetes is a vascular risk factor for cognitive impairment and increased risk of dementia. Disruption of the blood-retinal barrier (BRB) and blood-brain barrier (BBB) are hallmarks of subsequent retinal edema and central nervous system dysfunction. However, the mechanisms by which diet or metabolic syndrome induces dysfunction are not understood. A proposed mechanism is an increase in reactive oxygen species (ROS) and oxidative stress. Inhibition of mitochondrial carbonic anhydrase (mCA) decreases ROS and oxidative stress. In this study, topiramate, a mCA inhibitor, was examined for its ability to protect the BRB and BBB in diet-induced obese type II diabetic mice. METHODS:BBB and BRB permeability were assessed using C-sucrose and Tc-albumin in CD-1 mice fed a low-fat (control) or a high-fat diet. Topiramate administration was compared to saline controls in both preventative and efficacy arms examining BRB and BBB disruption. Body weight and blood glucose were measured weekly and body composition was assessed using EchoMRI. Metabolic activity was measured using a comprehensive laboratory animal monitoring system. Brain tissues collected from the mice were assessed for changes in oxidative stress and tight junction proteins. RESULTS:High-fat feeding caused increased entry of C-sucrose and Tc-albumin into the brains of diet-induced obese type II diabetic mice. Increased permeability to C-sucrose was observed in the hypothalamus and hippocampus, and attenuated by topiramate treatment, while increased permeability to Tc-albumin occurred in the whole brain and was also attenuated by topiramate. Treatment with topiramate decreased measures of oxidative stress and increased expression of the tight junction proteins ZO-1 and claudin-12. In the retina, we observed increased entry of Tc-albumin simultaneously with increased entry into the whole brain during the preventative arm. This occurred prior to increased entry to the retina for C-sucrose which occurred during the efficacy arm. Treatment with topiramate had no effect on the retina. CONCLUSIONS:Blood-brain barrier and blood-retinal barrier dysfunction were examined in a mouse model of diet-induced obese type II diabetes. These studies demonstrate that there are spatial and temporal differences in C-sucrose and Tc-albumin permeability in the brain and retina of diet-induced obese type II diabetic mice. Topiramate, a mitochondrial carbonic anhydrase inhibitor, is efficacious at both preventing and treating BBB disruption in this diet-induced obese type II diabetic mouse model. 10.1186/s12987-018-0121-6
    Blood Pressure, Aortic Stiffness, Hemodynamics, and Cognition in Twin Pairs Discordant for Type 2 Diabetes. Karayiannis Christopher,Moran Chris,Sharman James E,Beare Richard,Quinn Stephen J,Phan Thanh G,Wood Amanda G,Thrift Amanda G,Wang Wei C,Srikanth Velandai Journal of Alzheimer's disease : JAD BACKGROUND:Type 2 diabetes (T2D) is associated with an increased risk of cognitive impairment and dementia with poorly understood underlying mechanisms. OBJECTIVE:We examined the role of blood pressure (BP), aortic stiffness, and hemodynamics in this association. METHODS:Cross-sectional sample of late middle-aged twins discordant for T2D from the Australian Twin Registry. Measurements included neuropsychological battery and brain MRI including arterial spin labelling (ASL) to measure cerebral perfusion. Mobil-o-Graph devices were used to non-invasively obtain 24-hour BP, aortic stiffness, and hemodynamic measures. Using mixed modelling, we studied associations of T2D with cognition, MRI measures, BP, aortic stiffness, and hemodynamics. RESULTS:There were 23 twin pairs with mean age 63.7 (SD = 6.1) years. T2D (β=-0.45, p < 0.001) and age (β=-0.05, p = 0.022) were independently associated with poorer attention but not with memory or perceptual speed. T2D was associated with reduced nocturnal central systolic BP dipping (β=-3.79, p = 0.027), but not with BP, aortic stiffness, cerebral perfusion, or other hemodynamic measures. There was a statistically significant interaction between T2D and central systolic BP dipping in predicting attention scores (both p < 0.05 for the interaction term) whereby there was a positive association between BP dipping and attention scores in those with T2D, but not in those without T2D. CONCLUSION:We found an association between T2D and reduced nocturnal central systolic dipping, but not with any other measures of BP, stiffness or hemodynamic measures. Further study of the role of nocturnal central BP dipping in the association between T2D and cognitive impairment may help identify potential mechanisms. 10.3233/JAD-190319
    Diabetes Mellitus and Blood-Brain Barrier Dysfunction: An Overview. Prasad Shikha,Sajja Ravi K,Naik Pooja,Cucullo Luca Journal of pharmacovigilance A host of diabetes-related insults to the central nervous system (CNS) have been clearly documented in type-1 and -2 diabetic patients as well as experimental animal models. These host of neurological disorders encompass hemodynamic impairments (e.g., stroke), vascular dementia, cognitive deficits (mild to moderate), as well as a number of neurochemical, electrophysiological and behavioral alterations. The underlying causes of diabetes-induced CNS complications are multifactorial and are relatively little understood although it is now evident that blood-brain barrier (BBB) damage plays a significant role in diabetes-dependent CNS disorders. Changes in plasma glucose levels (hyper- or hypoglycemia) have been associated with altered BBB transport functions (e.g., glucose, insulin, choline, amino acids, etc.), integrity (tight junction disruption), and oxidative stress in the CNS microcapillaries. Last two implicating a potential causal role for upregulation and activation of the receptor for advanced glycation end products (RAGE). This type I membrane-protein also transports amyloid-beta (Aβ) from the blood into the brain across the BBB thus, establishing a link between type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD, also referred to as "type 3 diabetes"). Hyperglycemia has been associated with progression of cerebral ischemia and the consequent enhancement of secondary brain injury. Difficulty in detecting vascular impairments in the large, heterogeneous brain microvascular bed and dissecting out the impact of hyper- and hypoglycemia has led to controversial results especially with regard to the effects of diabetes on BBB. In this article, we review the major findings and current knowledge with regard to the impact of diabetes on BBB integrity and function as well as specific brain microvascular effects of hyper- and hypoglycemia. 10.4172/2329-6887.1000125
    Brain Activation during Memory Encoding in Type 2 Diabetes Mellitus: A Discordant Twin Pair Study. Wood Amanda G,Chen Jian,Moran Christopher,Phan Thanh,Beare Richard,Cooper Kimberley,Litras Stacey,Srikanth Velandai Journal of diabetes research Type 2 diabetes mellitus increases the risk of dementia and neuronal dysfunction may occur years before perceptible cognitive decline. We aimed to study the impact of type 2 diabetes on brain activation during memory encoding in middle-aged people, controlling for age, sex, genes, and early-shared environment. Twenty-two twin pairs discordant for type 2 diabetes mellitus (mean age 60.9 years) without neurological disease were recruited from the Australian Twin Registry (ATR) and underwent functional magnetic resonance imaging (fMRI) during a memory encoding task, cognitive tests, and structural MRI. Type 2 diabetes was associated with significantly reduced activation in left hemisphere temporoparietal regions including angular gyrus, supramarginal gyrus, and middle temporal gyrus and significantly increased activation in bilateral posteriorly distributed regions. These findings were present in the absence of within-pair differences in standard cognitive test scores, brain volumes, or vascular lesion load. Differences in activation were more pronounced among monozygotic (MZ) pairs, with MZ individuals with diabetes also displaying greater frontal activation. These results provide evidence for preclinical memory-related neuronal dysfunction in type 2 diabetes. They support the search for modifiable later-life environmental factors or epigenetic mechanisms linking type 2 diabetes and cognitive decline. 10.1155/2016/3978428
    Diabetes and the brain: issues and unmet needs. Bornstein Natan M,Brainin Michael,Guekht Alla,Skoog Ingmar,Korczyn Amos D Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology Diabetes mellitus (DM) is associated with an increased risk of mild cognitive impairment, dementia and stroke. The association between DM and dementia appears to be stronger for vascular cognitive impairment than for Alzheimer's disease, suggesting cerebrovascular disease may be an important factor in cognitive impairment in DM. Although the exact mechanisms by which DM affects the brain remain unclear, changes to brain vasculature, disturbances of cerebral insulin signaling, insulin resistance, glucose toxicity, oxidative stress, accumulation of advanced glycation end products, hypoglycemic episodes, and alterations in amyloid metabolism may all be involved. Cognitive impairment and dementia associated with DM may also be mediated via vascular risk factors, in particular brain ischemia, the occurrence of which can have an additive or synergistic effect with concomitant neurodegenerative processes. To date, no drug has been approved for the treatment of vascular dementia and there are no specific pharmacological treatments for preventing or reducing cognitive decline in patients with DM. Most focus has been on tighter management of vascular risk factors, although evidence of reduced cognitive decline through reducing blood pressure, lipid-lowering or tighter glycemic control is inconclusive. Tailored, multimodal therapies may be required to reduce the risk of cognitive dysfunction and decline in patients with DM. The use of pleiotropic drugs with multimodal mechanisms of action (e.g., cerebrolysin, Actovegin) may have a role in the treatment of cognitive dysfunction and their use may warrant further investigation in diabetic populations. 10.1007/s10072-014-1797-2
    Hyperglycemia-Driven Neuroinflammation Compromises BBB Leading to Memory Loss in Both Diabetes Mellitus (DM) Type 1 and Type 2 Mouse Models. Rom Slava,Zuluaga-Ramirez Viviana,Gajghate Sachin,Seliga Alecia,Winfield Malika,Heldt Nathan A,Kolpakov Mikhail A,Bashkirova Yulia V,Sabri Abdel Karim,Persidsky Yuri Molecular neurobiology End organ injury in diabetes mellitus (DM) is driven by microvascular compromise (including diabetic retinopathy and nephropathy). Cognitive impairment is a well-known complication of DM types 1 and 2; however, its mechanism(s) is(are) not known. We hypothesized that blood-brain barrier (BBB) compromise plays a key role in cognitive decline in DM. Using a DM type 1 model (streptozotocin injected C57BL/6 mice) and type 2 model (leptin knockout obese db/db mice), we showed enhanced BBB permeability and memory loss (Y maze, water maze) that are associated with hyperglycemia. Gene profiling in isolated microvessels from DM type 1 animals demonstrated deregulated expression of 54 genes related to angiogenesis, inflammation, vasoconstriction/vasodilation, and platelet activation pathways by at least 2-fold (including eNOS, TNFα, TGFβ1, VCAM-1, E-selectin, several chemokines, and MMP9). Further, the magnitude of gene expression was linked to degree of cognitive decline in DM type 1 animals. Gene analysis in brain microvessels of DM type 2 db/db animals showed alterations of similar genes as in DM 1 model, some to an even greater extent. Neuropathologic analyses of brain tissue derived from DM mice showed microglial activation, expression of ICAM-1, and attenuated coverage of pericytes compared to controls. There was a significant upregulation of inflammatory genes in brain tissue in both DM models. Taken together, our findings indicate that BBB compromise in DM in vivo models and its association with memory deficits, gene alterations in brain endothelium, and neuroinflammation. Prevention of BBB injury may be a new therapeutic approach to prevent cognitive demise in DM. 10.1007/s12035-018-1195-5
    Different risk factors for cognitive impairment among community-dwelling elderly, with impaired fasting glucose or diabetes. Xiu Shuangling,Zheng Zheng,Liao Qiuju,Chan Piu Diabetes, metabolic syndrome and obesity : targets and therapy Aim:The aim of this study was to investigate whether elderly people with impaired fasting glucose (IFG) or diabetes mellitus (DM) share the common risk factors for cognitive impairment as compared to normal blood glucose population. Methods:This cross-sectional study assessed 10,039 community-dwelling participants aged ≥ 55 years in Beijing, China. According to the glycemic status, subjects were classified into three groups: normal fasting plasma glucose (NG, n=6399), impaired fasting glucose (IFG, n=873) and DM (n=2626). The Mini-Mental State Examination (MMSE) was applied to evaluate the cognitive function status of the study population. Potential demographic, clinical, and genetic risk factors for cognitive impairment were collected and compared across the three groups. Multivariate logistic regression model was performed to explore the risk factors associated with cognitive impairment. Results:Education-modified MMSE scores in the participants with NG, IFG, and DM were 26.91±3.94, 26.67±4.00, and 26.58±4.11, respectively (=0.0008). In the age- and sex-adjusted comparisons, the MMSE scores in subjects with DM and IFG were significantly lower than that in subjects with normal glucose (=0.01 and =0.02, respectively). The logistic regression analysis showed that risk factors only in the NG population were older age, female, apoEε4 carrier, normal or lower uric acid (UA) levels. Hypertension was an independent risk factor only in IFG group, and the history of stroke and depression were the risk factors associated with cognitive impairment only in the DM group. Conclusion:Subjects with DM or IFG had a lower performance on the MMSE test compared with subjects who had normal blood glucose. The elderly with diabetes and IFG have some different risk factors for cognitive impairment as compared to those with normal blood glucose. 10.2147/DMSO.S180781
    The Clinical Phenotype of Vascular Cognitive Impairment in Patients with Type 2 Diabetes Mellitus. Groeneveld Onno N,Moneti Costanza,Heinen Rutger,de Bresser Jeroen,Kuijf Hugo J,Exalto Lieza G,Boomsma Jooske M F,Kappelle L Jaap,Barkhof Frederik,Prins Niels D,Scheltens Philip,van der Flier Wiesje M,Biessels Geert Jan, Journal of Alzheimer's disease : JAD BACKGROUND:Type 2 diabetes mellitus (T2DM) increases the risk of vascular cognitive impairment (VCI). It is unknown which type of vascular lesions and co-morbid etiologies, in particular Alzheimer's disease pathology, are associated with T2DM in patients with VCI, and how this relates to cognition and prognosis. OBJECTIVE:To compare brain MRI and cerebrospinal fluid (CSF) markers, cognition, and prognosis in patients with possible VCI with and without T2DM. METHODS:We included 851 memory clinic patients with vascular brain injury on MRI (i.e., possible VCI) from a prospective cohort study (T2DM: n = 147, 68.4±7.9 years, 63% men; no T2DM: n = 704, 67.6±8.5 years, 52% men). At baseline, we assessed between-group differences in brain MRI abnormalities, CSF markers of Alzheimer's disease, and cognitive profile. After two years follow-up, we compared occurrence of cognitive decline, stroke, and death. RESULTS:The distribution of clinical diagnoses did not differ between patients with and without T2DM. T2DM patients had more pronounced brain atrophy (total and white matter volume), and more lacunar infarcts, whereas microbleeds were less common (all p < 0.05). CSF amyloid-β levels were similar between the groups. T2DM patients performed worse on working memory (effect size: - 0.17, p = 0.03) than those without, whereas performance on other domains was similar. During follow-up, risk of further cognitive decline was not increased in T2DM.∥Conclusion: In patients with possible VCI, presence of T2DM is related to more pronounced brain atrophy and a higher burden of lacunar infarcts, but T2DM does not have a major impact on cognitive profile or prognosis.∥. 10.3233/JAD-180914
    Disrupted White Matter Network and Cognitive Decline in Type 2 Diabetes Patients. Zhang Junying,Liu Zhen,Li Zixiao,Wang Yunxia,Chen Yaojing,Li Xin,Chen Kewei,Shu Ni,Zhang Zhanjun Journal of Alzheimer's disease : JAD Type 2 diabetes mellitus is accompanied by cognitive impairment and is associated with an increased risk of dementia. Damage to brain structures such as white matter network disruption may underlie this cognitive disturbance. In the present study, 886 non-diabetic and 163 type 2 diabetic participants completed a battery of neuropsychological tests. Among them, 38 diabetic patients and 34 non-diabetic participants that matched the patients for age/sex/education received a magnetic resonance imaging-based diffusion tensor imaging. Then we calculated the topological properties of the white matter network using a graph theoretical method to investigate network efficiency differences between groups. We found that type 2 diabetic patients had inferior performances compared to the non-diabetic controls, in several cognitive domains involving executive function, spatial processing, memory, and attention. We also found that diabetic patients exhibited a disrupted topological organization of the white matter network (including the global network properties, i.e., network strength, global efficiency, local efficiency and shortest path length, and the nodal efficiency of the right rolandic operculum) in the brain. Moreover, those global network properties and the nodal efficiency of the right rolandic operculum both had positive correlations with executive function in the patient group. The results suggest that type 2 diabetes mellitus leads to an alteration in the topological organization of the cortical white matter network and this alteration may account for the observed cognitive decline. 10.3233/JAD-160111
    Serum levels of inflammatory markers in depressed elderly patients with diabetes and mild cognitive impairment. Gorska-Ciebiada Malgorzata,Saryusz-Wolska Malgorzata,Borkowska Anna,Ciebiada Maciej,Loba Jerzy PloS one OBJECTIVE:The aim of the study was to determine the serum levels of CRP, IL-6 and TNF-α in elderly diabetic patients with depressive syndrome alone or with coexisting mild cognitive impairment (MCI). METHODS:276 diabetics elders were screened for depressive symptoms (using Geriatric Depression Scale: GDS-30) and MCI (using the Montreal Cognitive Assessment: MoCA score). Data of HbA1c, blood lipids and inflammatory markers levels were collected. RESULTS:In all groups of patients levels of CRP, IL-6 and TNF-α were significantly higher as compared to controls. The highest level of inflammatory markers was detected in group with depressive mood and coexisting MCI, however IL-6 level didn't significantly differ as compared to MCI group. We founded correlations between all inflammatory markers in group of patients with depressive mood and in group of subjects with depressive symptoms and coexisting MCI. GDS-30 score was correlated with levels of inflammatory markers in group with depressive mood, and with levels of CRP and TNF-α in group with depressive mood and coexisting MCI. In the group with depressive mood and coexisting MCI we founded that MoCA score was negatively correlated with CRP and TNF-α levels; and HbA1c level was positively correlated with all inflammatory markers. The univariate logistic regression models revealed that variables which increased the likelihood of having been diagnosed with MCI in depressed patients were: higher levels of HbA1c, CRP, IL-6 and TNF-α, previous CVD or stroke, increased number of co-morbidities and microvascular complications, older age, less years of formal education. The multivariable model showed that previous CVD, higher HbA1c and IL-6 levels are significant factors. CONCLUSIONS:We demonstrated that the presence of depressive syndrome is associated with higher levels of inflammatory markers in elderly patients with diabetes. The presence of MCI in these depressed subjects has additive effect on levels of inflammatory mediators. 10.1371/journal.pone.0120433
    Neuroimaging and its Relevance to Understanding Pathways Linking Diabetes and Cognitive Dysfunction. Moran Chris,Beare Richard,Phan Thanh,Starkstein Sergio,Bruce David,Romina Mizrahi,Srikanth Velandai Journal of Alzheimer's disease : JAD Diabetes mellitus is associated with an elevated risk of cognitive impairment and dementia. Cerebrovascular disease and neurodegeneration are two major pathways that may explain the effect of diabetes on the brain and therefore deserve investigation. Neuroimaging provides an effective way to investigate the contribution of these pathways in vivo, guiding further mechanistic research and providing biomarkers for clinical correlation or interventional studies. In this paper, we present a narrative review of the state of play with neuroimaging evidence in studies of people with diabetes mellitus, how these data are useful in understanding mechanistic links between diabetes and brain impairment, and possible ways that the field may develop in the future. 10.3233/JAD-161166
    Effects of Exercise on Type 2 Diabetes Mellitus-Related Cognitive Impairment and Dementia. Callisaya Michele,Nosaka Kazunori Journal of Alzheimer's disease : JAD Cognitive impairment and dementia are common contributors to institutionalization and loss of quality of life in older people. Both type 2 diabetes mellitus (T2DM) and physical inactivity are prevalent and important modifiable risk factors for developing dementia. Physical activity is recommended in the management of T2DM, and there is growing evidence that exercise, a subgroup of physical activity, is also beneficial for maintaining and improving brain structure and function. This paper reviews the evidence for a benefit of exercise on T2DM related cognitive impairment and dementia. In addition, the type (e.g., aerobic, resistance), intensity, duration, and frequency of exercise are discussed. This review shows that although exercise has known benefits on the mechanisms linking T2DM to dementia, there are very few randomized controlled trials examining whether this is the case. It is concluded that the uptake of exercise for the brain has great potential to improve quality of life and provide significant cost savings, but further research is warranted to clarify the effects of exercise on T2DM and those on dementia. 10.3233/JAD-161154
    The Relationship Between the Score on a Simple Measure of Cognitive Function and Incident CVD in People With Diabetes: A Post Hoc Epidemiological Analysis From the ACCORD-MIND Study. Cukierman-Yaffe Tali,Gerstein Hertzel C,Miller Michael E,Launer Lenore J,Williamson Jeff D,Horowitz Karen R,Ismail-Beigi Faramarz,Lazar Ronald M The Journal of clinical endocrinology and metabolism Context and Objective:Diabetes is associated with a greater risk for incident cardiovascular disease and cognitive dysfunction. This study aimed to investigate, in people with type 2 diabetes, the association of a simple measure of cognitive function to cardiovascular disease events and mortality. Design, Setting, Participants, Measurements, and Outcomes:The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial included persons with longstanding type 2 diabetes. A substudy of 2977 (Memory in Diabetes) participants aged 55 years or older aimed to test the effect of the interventions on brain structure and function. At baseline, participants were administered a cognitive battery that included the digit symbol substitution test (DSST). The associations of the DSST and the ACCORD primary outcome (the first occurrence of nonfatal myocardial infarction or nonfatal stroke or death from cardiovascular causes) and all-cause mortality were investigated with Cox proportional hazard models adjusting for several demographic and clinical variables. Results:Median follow-up time was 4.27 years. An inverse relationship between the incidence of the ACCORD primary outcome and baseline cognitive score was demonstrated. A 1-point higher DSST score was associated with a lower incidence of the primary outcome (hazard ratio, 0.987; 95% confidence interval, 0.977 to 0.998; P = 0.019), after adjustment for demographic and clinical trial factors, additional baseline cardiovascular risk factors, and self-reported need for assistance to follow the protocol. Conclusion:Lower scores on the DSST, a simple, sensitive neuropsychological instrument, are associated with a higher incidence of cardiovascular events in persons >55 years old with longstanding diabetes. 10.1210/jc.2016-3480
    Type 2 diabetes, skin autofluorescence, and brain atrophy. Moran Chris,Münch Gerald,Forbes Josephine M,Beare Richard,Blizzard Leigh,Venn Alison J,Phan Thanh G,Chen Jian,Srikanth Velandai Diabetes Type 2 diabetes mellitus (T2DM) is associated with brain atrophy, but the mechanisms underlying this link are unknown. Advanced glycation end products (AGEs) accumulate in T2DM, resulting in inflammation, oxidative stress, and protein cross-linking, which are known contributors to neurodegeneration. We aimed to study whether tissue AGE accumulation is associated with T2DM-related brain atrophy. We performed brain magnetic resonance imaging, cognitive tests, and noninvasive skin autofluorescence (SAF; a measure of tissue AGE levels) on people aged >55 years with and without T2DM. Multivariable linear regression was used to study the relationships among T2DM, SAF, and gray matter volume (GMV). There were 486 people included in the study. T2DM was associated with greater SAF. Greater SAF, T2DM, and cognitive impairment were each associated with lower GMV independently of age, sex, and total intracranial volume. SAF partially mediated the association between T2DM and GMV. Longitudinal studies may help confirm whether tissue AGE accumulation is associated with brain atrophy in T2DM. 10.2337/db14-0506
    HbA, diabetes and cognitive decline: the English Longitudinal Study of Ageing. Zheng Fanfan,Yan Li,Yang Zhenchun,Zhong Baoliang,Xie Wuxiang Diabetologia AIMS/HYPOTHESIS:The aim of the study was to evaluate longitudinal associations between HbA levels, diabetes status and subsequent cognitive decline over a 10 year follow-up period. METHODS:Data from wave 2 (2004-2005) to wave 7 (2014-2015) of the English Longitudinal Study of Ageing (ELSA) were analysed. Cognitive function was assessed at baseline (wave 2) and reassessed every 2 years at waves 3-7. Linear mixed models were used to evaluate longitudinal associations. RESULTS:The study comprised 5189 participants (55.1% women, mean age 65.6 ± 9.4 years) with baseline HbA levels ranging from 15.9 to 126.3 mmol/mol (3.6-13.7%). The mean follow-up duration was 8.1 ± 2.8 years and the mean number of cognitive assessments was 4.9 ± 1.5. A 1 mmol/mol increment in HbA was significantly associated with an increased rate of decline in global cognitive z scores (-0.0009 SD/year, 95% CI -0.0014, -0.0003), memory z scores (-0.0005 SD/year, 95% CI -0.0009, -0.0001) and executive function z scores (-0.0008 SD/year, 95% CI -0.0013, -0.0004) after adjustment for baseline age, sex, total cholesterol, HDL-cholesterol, triacylglycerol, high-sensitivity C-reactive protein, BMI, education, marital status, depressive symptoms, current smoking, alcohol consumption, hypertension, CHD, stroke, chronic lung disease and cancer. Compared with participants with normoglycaemia, the multivariable-adjusted rate of global cognitive decline associated with prediabetes and diabetes was increased by -0.012 SD/year (95% CI -0.022, -0.002) and -0.031 SD/year (95% CI -0.046, -0.015), respectively (p for trend <0.001). Similarly, memory, executive function and orientation z scores showed an increased rate of cognitive decline with diabetes. CONCLUSIONS/INTERPRETATION:Significant longitudinal associations between HbA levels, diabetes status and long-term cognitive decline were observed in this study. Future studies are required to determine the effects of maintaining optimal glucose control on the rate of cognitive decline in people with diabetes. 10.1007/s00125-017-4541-7
    Brain changes underlying cognitive dysfunction in diabetes: what can we learn from MRI? Biessels Geert Jan,Reijmer Yael D Diabetes Diabetes is associated with cognitive dysfunction and an increased risk of dementia. This article addresses findings with brain MRI that may underlie cognitive dysfunction in diabetes. Studies in adults with type 1 diabetes show regional reductions in brain volume. In those with a diabetes onset in childhood, these volume reductions are likely to reflect the sum of changes that occur during brain development and changes that occur later in life due to exposure to diabetes-related factors. Type 2 diabetes is associated with global brain atrophy and an increased burden of small-vessel disease. These brain changes occur in the context of aging and often also in relation to an adverse vascular risk factor profile. Advanced imaging techniques detect microstructural lesions in the cerebral gray and white matter of patients with diabetes that affect structural and functional connectivity. Challenges are to further unravel the etiology of these cerebral complications by integrating findings from different imaging modalities and detailed clinical phenotyping and by linking structural MRI abnormalities to histology. A better understanding of the underlying mechanisms is necessary to establish interventions that will improve long-term cognitive outcomes for patients with type 1 and type 2 diabetes. 10.2337/db14-0348
    Type 2 diabetes mellitus, brain atrophy and cognitive decline in older people: a longitudinal study. Callisaya Michele L,Beare Richard,Moran Chris,Phan Thanh,Wang Wei,Srikanth Velandai K Diabetologia AIMS/HYPOTHESIS:The aims of the study were to examine whether type 2 diabetes mellitus is associated with greater brain atrophy and cognitive decline, and whether brain atrophy mediates associations between type 2 diabetes and cognitive decline. METHODS:Participants without dementia aged 55-90 years from the Cognition and Diabetes in Older Tasmanians (CDOT) study underwent brain MRI (ventricular and total brain volume) and neuropsychological measures (global function and seven cognitive domains) at three time points over 4.6 years. Mixed models were used to examine longitudinal associations of type 2 diabetes with cognitive and MRI measures, adjusting for covariates. A test of mediation was used to determine whether brain atrophy explained associations between type 2 diabetes and cognitive decline. RESULTS:A total of 705 participants (diabetes: n = 348, mean age 68.2 years [SD 7.0]; no diabetes: n = 357, mean age 72.5 years [SD 7.1]) were available at baseline. Adjusting for age, sex, education and vascular risk factors, there were significant diabetes × time interactions for verbal memory (β -0.06; 95% CI -0.09, -0.02) and verbal fluency (β -0.03; 95% CI -0.06, -0.00). Although people with diabetes had lower brain (β -14.273; 95% CI -21.197, -6.580) and greater ventricular (β 2.672; 95% CI 0.152, 5.193) volumes at baseline, there were no significant diabetes × time interactions (p > 0.05) or evidence of mediation of the diabetes-cognition relationship by brain atrophy. CONCLUSIONS/INTERPRETATION:In older community-dwelling people, type 2 diabetes is associated with decline in verbal memory and fluency over ~5 years. The effect of diabetes on brain atrophy may begin earlier (midlife). 10.1007/s00125-018-4778-9