Eelco van Duinkerken

Resting-State Brain Networks in Type 1 Diabetic Patients With and Without Microangiopathy and Their Relation to Cognitive Functions and Disease Variables

Cognitive functioning depends on intact brain networks that can be assessed with functional magnetic resonance imaging (fMRI) techniques. We hypothesized that cognitive decrements in type 1 diabetes mellitus (T1DM) are associated with alterations in resting-state neural connectivity and that these changes vary according to the degree of microangiopathy. T1DM patients with (MA+: n = 49) and without (MA−: n = 52) microangiopathy were compared with 48 healthy control subjects. All completed a neuropsychological assessment and resting-state fMRI. Networks were identified using multisubject independent component analysis; specific group differences within each network were analyzed using the dual-regression method, corrected for confounding factors and multiple comparisons. Relative to control subjects, MA− patients showed increased connectivity in networks involved in motor and visual processes, whereas MA+ patients showed decreased connectivity in networks involving attention, working memory, auditory and language processing, and motor and visual processes. Better information-processing speed and general cognitive ability were related to increased degree of connectivity. T1DM is associated with a functional reorganization of neural networks that varies, dependent on the presence or absence of microangiopathy.

Functional Brain Connectivity and Neurocognitive Functioning in Patients With Long-Standing Type 1 Diabetes With and Without Microvascular Complications: A Magnetoencephalography Study

OBJECTIVE Hyperglycemia-associated microvascular disease may underlie changes in cerebral functioning and cognitive performance in patients with type 1 diabetes. Functional connectivity, an indicator of functional interactions and information exchange between brain regions, provides a measure of cerebral functioning. This study addresses functional connectivity and cognition in type 1 diabetic patients with and without proliferative retinopathy, relative to healthy control subjects, using magnetoencephalography. RESEARCH DESIGN AND METHODS Fluctuations in magnetic field at scalp for Δ, θ, lower and upper α, β, and lower and upper γ frequency bands were measured using magnetoencephalography. Synchronization likelihood, a measure of functional connectivity, was computed. Using neuropsychological tests, cognitive functioning was assessed and its associations with functional connectivity were determined. RESULTS Compared with control subjects, type 1 diabetic patients performed poorer on general cognitive ability, information processing speed, and motor speed, irrespective of their microvascular complication status. Functional connectivity, however, was lowest for type 1 diabetic patients with retinopathy, compared with type 1 diabetic patients without microvascular complications and control subjects, whereas type 1 diabetic patients without microvascular complications showed an increase relative to control subjects. Positive associations were found between functional connectivity and executive functioning, memory, information processing speed, motor speed, and attention. CONCLUSIONS Compared with healthy control subjects, functional connectivity and cognition differed in type 1 diabetic patients irrespective of microvascular complication status, indicating that chronic hyperglycemia, among other factors, may negatively affect brain functioning even before microvascular damage becomes manifest. The association found between synchronization likelihood and cognition suggests functional connectivity plays a significant role in cognitive functioning.

Association of plasma osteoprotegerin and adiponectin with arterial function, cardiac function and metabolism in asymptomatic type 2 diabetic men

BackgroundOsteoprotegerin (OPG), a soluble member of the tumor necrosis factor receptor superfamily, is linked to cardiovascular disease. Negative associations exist between circulating OPG and cardiac function. The adipocytokine adiponectin (ADPN) is downregulated in type 2 diabetes mellitus (T2DM) and coronary artery disease and shows an inverse correlation with insulin sensitivity and cardiovascular disease risk. We assessed the relationship of plasma OPG and ADPN and arterial function, cardiac function and myocardial glucose metabolism in T2DM.MethodsWe included 78 asymptomatic men with uncomplicated, well-controlled T2DM, without inducible ischemia, assessed by dobutamine-stress echocardiography, and 14 age-matched controls. Cardiac function was measured by magnetic resonance imaging, myocardial glucose metabolism (MMRglu) by 18F-2-fluoro-2-deoxy-D-glucose positron emission tomography. OPG and ADPN levels were measured in plasma.ResultsT2DM patients vs. controls showed lower aortic distensibility, left ventricular (LV) volumes, impaired LV diastolic function and MMRglu (all P < 0.05). In T2DM men vs. controls, OPG levels were higher (P = 0.02), whereas ADPN concentrations were decreased (P = 0.04). OPG correlated inversely with aortic distensibility, LV volumes and E/A ratio (diastolic function), and positively with LV mass/volume ratio (all P < 0.05). Regression analyses showed the associations with aortic distensibility and LV mass/volume ratio to be independent of age-, blood pressure- and glycated hemoglobin (HbA1c). However, the associations with LV volumes and E/A ratio were dependent of these parameters. ADPN correlated positively with MMRglu (P < 0.05), which, in multiple regression analysis, was dependent of whole-body insulin sensitivity, HbA1c and waist.ConclusionsOPG was inversely associated with aortic distensibility, LV volumes and LV diastolic function, while ADPN was positively associated with MMRglu. These findings indicate that in asymptomatic men with uncomplicated T2DM, OPG and ADPN may be markers of underlying mechanisms linking the diabetic state to cardiac abnormalities.Trial registrationCurrent Controlled Trials ISRCTN53177482

Cognition in Older Patients with Type 1 Diabetes Mellitus: A Longitudinal Study

reasoning 0.06 ( 0.19 to 0.30) 0.24 ( 0.14 to 0.62) .08 Memory 0.001 ( 0.11 to 0.11) 0.05 ( 0.25 to 0.14) .01 Information processing speed 0.12 ( 0.25 to 0.02) 0.38 ( 0.711 to 0.050) .54 Attention and executive function 0.17 ( 0.40 to 0.06) 0.10 ( 0.35 to 0.14) .93 Visuoconstruction 0.20 ( 0.45 to 0.04) 0.40 (0.13 to 0.67) .44 Cardiovascular events§,k Overall cognitive functioning 0.11 ( 0.28 to 0.05) 0.10 ( 0.24 to 0.45) .04 Information processing speed 0.34 ( 0.65 to 0.03) 0.05 ( 0.77 to 0.88) .05 Severe hypoglycemic events Overall cognitive functioning 0.01 ( 0.12 to 0.24) 0.38 ( 0.70 to 0.05) .87 Information processing speed 0.19 ( 0.40 to 0.01) 0.67 ( 1.21 to 0.14) .04 Mean change in z-scores over time for the whole group. Negative values indicate poorer performance at follow-up than at baseline. Mean difference in z-scores between people with type 1 diabetes mellitus (T1DM) and controls (upper half table) or patients with and without events (lower half table). Negative values indicate poorer performance for the people with T1DM than controls or for participants with events than for those without. zInteraction represent the P-value of the time group interaction. The analyses of cardiovascular and hypoglycemic events only concern the group with T1DM and reflect the differences between patients with and without these events. k Cardiovascular events (7 events in 6 patients) between baseline and follow-up were self-reported stroke (n 5 1), myocardial infarction (n 5 1), percutaneous angioplasty treatment (n 5 1), and angina pectoris (n 5 4). Severe hypoglycemic events (17 events in 12 patients) were self-reported between baseline and follow-up and were defined as events needing assistance to treat loss of consciousness or coma. 564 LETTERS TO THE EDITOR MARCH 2011–VOL. 59, NO. 3 JAGS

Disrupted subject-specific gray matter network properties and cognitive dysfunction in type 1 diabetes patients with and without proliferative retinopathy

Type 1 diabetes mellitus (T1DM) patients, especially with concomitant microvascular disease, such as proliferative retinopathy, have an increased risk of cognitive deficits. Local cortical gray matter volume reductions only partially explain these cognitive dysfunctions, possibly because volume reductions do not take into account the complex connectivity structure of the brain. This study aimed to identify gray matter network alterations in relation to cognition in T1DM. Methods: We investigated if subject‐specific structural gray matter network properties, constructed from T1‐weighted MRI scans, were different between T1DM patients with (n = 51) and without (n = 53) proliferative retinopathy versus controls (n = 49), and were associated to cognitive decrements and fractional anisotropy, as measured by voxel‐based TBSS. Global normalized and local (45 bilateral anatomical regions) clustering coefficient and path length were assessed. These network properties measure how the organization of connections in a network differs from that of randomly connected networks. Results: Global gray matter network topology was more randomly organized in both T1DM patient groups versus controls, with the largest effects seen in patients with proliferative retinopathy. Lower local path length values were widely distributed throughout the brain. Lower local clustering was observed in the middle frontal, postcentral, and occipital areas. Complex network topology explained up to 20% of the variance of cognitive decrements, beyond other predictors. Exploratory analyses showed that lower fractional anisotropy was associated with a more random gray matter network organization. Conclusion: T1DM and proliferative retinopathy affect cortical network organization that may consequently contribute to clinically relevant changes in cognitive functioning in these patients. Hum Brain Mapp 37:1194–1208, 2016.

Subgenual Cingulate Cortex Functional Connectivity in Relation to Depressive Symptoms and Cognitive Functioning in Type 1 Diabetes Mellitus Patients

Objectives Patients with Type 1 diabetes mellitus (T1DM) are at an increased risk for major depression, but its underlying mechanisms are still poorly understood. In nondiabetic participants, mood disturbances are related to altered subgenual cingulate cortex (SGC) resting-state functional connectivity. We tested for SGC connectivity alterations in T1DM, whether these alterations were related to depressive symptoms, and if depressive symptoms were associated with cognition. Methods A bilateral SGC seed-based resting-state functional magnetic resonance imaging analysis was performed in 104 T1DM patients and 49 controls without known psychiatric diagnosis or treatment. Depressive symptoms were self-reported using the Center for Epidemiological Studies Depression scale. Cognition was assessed with a battery of standardized tests. Results In patients versus controls, SGC to right inferior frontal gyrus and frontal pole connectivity was decreased (52 voxels, z valuepeak = 3.56, pcluster-FWE = .002), whereas SGC to bilateral precuneus (33 voxels, z valuepeak = 3.34, pcluster-FWE = .04) and left inferior parietal lobule (50 voxels, z valuepeak = 3.50, pcluster-FWE = .003) connectivity was increased. In all participants, increased depressive symptoms was related to lower SGC to inferior frontal gyrus and frontal pole connectivity (&bgr; = −0.156, p = .053), and poorer general cognitive ability (&bgr; = −0.194, p = .023), information processing speed (&bgr; = −0.222, p = .008), and motor speed (&bgr; = −0.180, p = .035). Conclusions T1DM patients showed a pattern of SGC connectivity that is characterized by lower executive control and higher default mode network connectivity. Depressive symptoms are partially related to these alterations and seem to exacerbate T1DM-related cognitive dysfunction. Future studies should detail the effect of diagnosed major depressive disorder in this population and establish what alterations are diabetes specific.

Differential impact of subclinical carotid artery disease on cerebral structure and functioning in type 1 diabetes patients with versus those without proliferative retinopathy

BackgroundType 1 diabetes mellitus (T1DM) is associated with cerebral compromise, typically found in patients with microangiopathy. Associations between subclinical macroangiopathy and the brain, whether or not in the presence of microangiopathy, have not been fully explored in T1DM. We hypothesized that subclinical macroangiopathy in adult T1DM may affect the brain and interacts with microangiopathy.MethodsIn 51 asymptomatic T1DM patients with, 53 without proliferative retinopathy and 51 controls, right common carotid artery ultrasound was used to assess intima media thickness (cIMT) and distensibility (cD). Neuropsychological tests for cognitive functions, and magnetic resonance imagining for white matter integrity and functional connectivity, i.e. neuronal communication, were used.ResultsAfter correction for confounders, cIMT was borderline significantly increased in all T1DM patients (P = 0.071), whereas cD was not statistically significantly altered (P = 0.45). Patients with proliferative retinopathy showed the largest increase in cIMT and decrease in cD. In all participants, after adjustment for confounders, increased cIMT was related to decreased white matter integrity (β = −0.198 P = 0.041) and decreased functional connectivity in visual areas (β = −0.195 P = 0.046). For cognition, there was a significant interaction between cIMT and the presence of proliferative retinopathy after adjustment for confounding factors (all P < 0.05). Increased cIMT was associated with lower general cognitive ability (β = −0.334; P = 0.018), information processing speed (β = −0.361; P = 0.010) and attention (β = −0.394; P = 0.005) scores in patients without, but not in patients with proliferative retinopathy.ConclusionsThese findings suggest that subclinical macroangiopathy may be a factor in the development of diabetes-related cognitive changes in uncomplicated T1DM, whereas in patients with advanced T1DM, proliferative retinopathy may rather be the driving force of cerebral compromise.

Cortical and subcortical gray matter structural alterations in normoglycemic obese and type 2 diabetes patients: relationship with adiposity, glucose, and insulin

Type 2 diabetes (T2DM) is associated with structural cortical and subcortical alterations, although it is insufficiently clear if these alterations are driven by obesity or by diabetes and its associated complications. We used FreeSurfer5.3 and FSL-FIRST to determine cortical thickness, volume and surface area, and subcortical gray matter volume in a group of 16 normoglycemic obese subjects and 28 obese T2DM patients without clinically manifest micro- and marcoangiopathy, and compared them to 31 lean normoglycemic controls. Forward regression analysis was used to determine demographic and clinical correlates of altered (sub)cortical structure. Exploratively, vertex-wise correlations between cortical structure and fasting glucose and insulin were calculated. Compared with controls, obese T2DM patients showed lower right insula thickness and lower left lateral occipital surface area (PFWE < 0.05). Normoglycemic obese versus controls had lower thickness (PFWE < 0.05) in the right insula and inferior frontal gyrus, and higher amygdala and thalamus volume. Thalamus volume and left paracentral surface area were also higher in this group compared with obese T2DM patients. Age, sex, BMI, fasting glucose, and cholesterol were related to these (sub)cortical alterations in the whole group (all P < 0.05). Insulin were related to temporal and frontal structural deficits (all PFWE < 0.05). Parietal/occipital structural deficits may constitute early T2DM-related cerebral alterations, whereas in normoglycemic obese subjects, regions involved in emotion, appetite, satiety regulation, and inhibition were affected. Central adiposity and elevated fasting glucose may constitute risk factors.

Preserving Cognition in Children With Diabetes: Do Alterations in Functional Network Connectivity Play a Role?

Whether, and to what extent, type 1 diabetes (T1D) affects the brains of children and adolescents has been debated for more than 30 years. Early studies found that children and adolescents with T1D were more likely to perform somewhat poorer than their healthy peers on tasks of mental efficiency that required rapid responses and sustained attention, as well as on measures of executive functioning that required problem-solving and planning (1). It was assumed, but not proven, that these between-group differences were a consequence of differences in brain integrity. Only when researchers began using MRI techniques was there unequivocal evidence that diabetes in childhood is accompanied by gross structural changes to the brain, including relative reductions in gray matter density in multiple cortical regions and microstructural abnormalities in major white matter tracts (2,3). Furthermore, these effects were most pronounced in those who developed diabetes early in life and were evident within 2–4 years of disease onset (4–7). One might expect that a significant loss of neurons, accompanied by axonal damage relatively early in life, would lead to increasingly serious cognitive impairment over time in people with diabetes. Interestingly, that does not appear to be the case. Cross-sectional studies of children and young adults with T1D do not show a significant worsening of performance with increasing age or disease duration (8), nor were marked declines in cognition seen in the adolescents and adults participating in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions …

PS9 - 5. Proliferative retinopathy in type 1 diabetes is associated with cerebral microbleeds and decreased skin capillary density

Small vessel disease (SVD) accounts for most of the strokes in type 1 diabetes mellitus (T1DM). Retinal microvascular changes appear to reflect cerebral SVD, but whether diabetic proliferative retinopathy (PDR) is associated with cerebral SVD is unknown. Moreover, it is unclear whether SVD is limited to the brain or part of a generalized microvascular disorder.