Intranasal Insulin Enhanced Resting-State Functional Connectivity of Hippocampal Regions in Type 2 Diabetes

Type 2 diabetes mellitus (T2DM) alters brain function and manifests as brain atrophy. Intranasal insulin has emerged as a promising intervention for treatment of cognitive impairment. We evaluated the acute effects of intranasal insulin on resting-state brain functional connectivity in older adults with T2DM. This proof-of-concept, randomized, double-blind, placebo-controlled study evaluated the effects of a single 40 IU dose of insulin or saline in 14 diabetic and 14 control subjects. Resting-state functional connectivity between the hippocampal region and default mode network (DMN) was quantified using functional MRI (fMRI) at 3Tesla. Following insulin administration, diabetic patients demonstrated increased resting-state connectivity between the hippocampal regions and the medial frontal cortex (MFC) as compared with placebo (cluster size: right, P = 0.03) and other DMN regions. On placebo, the diabetes group had lower connectivity between the hippocampal region and the MFC as compared with control subjects (cluster size: right, P = 0.02), but on insulin, MFC connectivity was similar to control subjects. Resting-state connectivity correlated with cognitive performance. A single dose of intranasal insulin increases resting-state functional connectivity between the hippocampal regions and multiple DMN regions in older adults with T2DM. Intranasal insulin administration may modify functional connectivity among brain regions regulating memory and complex cognitive behaviors.     

Resting-state brain functional connectivity is altered in type 2 diabetes

Type 2 diabetes mellitus (T2DM) is a risk factor for Alzheimer disease (AD). Populations at risk for AD show altered brain activity in the default mode network (DMN) before cognitive dysfunction. We evaluated this brain pattern in T2DM patients. We compared T2DM patients (n = 10, age = 56 ± 2.2 years, fasting plasma glucose [FPG] = 8.4 ± 1.3 mmol/L, HbA(1c) = 7.5 ± 0.54%) with nondiabetic age-matched control subjects (n = 11, age = 54 ± 1.8 years, FPG = 4.8 ± 0.2 mmol/L) using resting-state functional magnetic resonance imaging to evaluate functional connectivity strength among DMN regions. We also evaluated hippocampal volume, cognition, and insulin sensitivity by homeostasis model assessment of insulin resistance (HOMA-IR). Control subjects showed stronger correlations versus T2DM patients in the DMN between the seed (posterior cingulate) and bilateral middle temporal gyrus (β = 0.67 vs. 0.43), the right inferior and left medial frontal gyri (β = 0.75 vs. 0.54), and the left thalamus (β = 0.59 vs. 0.37), respectively, with no group differences in cognition or hippocampal size. In T2DM patients, HOMA-IR was inversely correlated with functional connectivity in the right inferior frontal gyrus and precuneus. T2DM patients showed reduced functional connectivity in the DMN compared with control subjects, which was associated with insulin resistance in selected brain regions, but there were no group effects of brain structure or cognition.     

Impaired Macromolecular Protein Pools in Fronto-Striato-Thalamic Circuits in Type 2 Diabetes Revealed by Magnetization Transfer Imaging

Previous research has shown that type 2 diabetes mellitus (T2DM) is associated with white matter microstructural changes, cognitive impairment, and decreased resting-state functional connectivity and spontaneous brain activity. This study used magnetization transfer imaging to examine, for the first time, the integrity of macromolecular protein pools in fronto-striato-thalamic circuits and its clinical and cognitive correlates in patients with T2DM. T2DM patients without mood disorders (n = 20, aged 65.05 ± 11.95 years) and healthy control subjects (HCs; n = 26, aged 62.92 ± 12.71 years) were recruited. Nodes of fronto-striato-thalamic circuits—head of the caudate nucleus (hCaud), putamen, globus pallidus, thalamus—and four cortical regions—rostral and dorsal anterior cingulate cortex, dorsolateral prefrontal cortex, and lateral orbitofrontal cortex—were examined. Compared with HCs, patients with T2DM had significantly lower magnetization transfer ratio (MTR) in bilateral anterior cingulate and hCaud. Reduced MTRs in the above regions showed correlations with T2DM-related clinical measures, including hemoglobin A_1c level and vascular risk factors, and neuropsychological task performance in the domains of learning and memory, executive function, and attention and information processing. The impaired biophysical integrity of brain macromolecular protein pools and their local microenvironments in T2DM patients may provide insights into the neurological pathophysiology underlying diabetes-associated clinical and cognitive deficits.     

Changes in fMRI activation following rehabilitation of reading and visual processing deficits in subjects with traumatic brain injury

In this case series fMRI was used to examine activation patterns during presentation of a reading comprehension (RC) task in three adult subjects with a history of severe traumatic brain injury (TBI). These subjects received cognitive rehabilitation therapy (CRT) for visual processing and acquired reading deficits. fMRI and neuropsychological testing occurred pre- and post-rehabilitation. The study's objective was to evaluate the neurobiological changes using fMRI occurring with CRT and to compare these results to repeat fMRI in matched control subjects. While improvements in neuropsychological testing occurred post-CRT, diffuse and variable activation patterns in the subjects with TBI were still demonstrated when compared to the control subjects repeat imaging. Multiple networks exist to accomplish the complex task of sentence reading and rehabilitation of the cognitive components of reading, such as visual processing; in subjects with TBI, can alter the activation pattern demonstrated during reading comprehension in subjects many years post-injury. This is the first demonstration of changes in network activation patterns post-CRT in patients with severe, chronic TBI on an fMRI task shown to have imaging stability in a normal control sample.     

Changes in fMRI activation following rehabilitation of reading and visual processing deficits in subjects with traumatic brain injury

In this case series fMRI was used to examine activation patterns during presentation of a reading comprehension (RC) task in three adult subjects with a history of severe traumatic brain injury (TBI). These subjects received cognitive rehabilitation therapy (CRT) for visual processing and acquired reading deficits. fMRI and neuropsychological testing occurred pre- and post-rehabilitation. The study's objective was to evaluate the neurobiological changes using fMRI occurring with CRT and to compare these results to repeat fMRI in matched controlsubjects. While improvements in neuropsychologicaltesting occurred post-CRT, diffuse and variable activation patterns in the subjects with TBI were still demonstrated when compared to the control subjects repeat imaging. Multiple networks exist to accomplish the complex task of sentence reading and rehabilitation of the cognitive components of reading, such as visual processing; in subjects with TBI, can alter the activation pattern demonstrated during reading comprehension in subjects many years post-injury. This is the first demonstration of changes in network activation patterns post-CRT in patients with severe, chronic TBI on an fMRI task shown to have imaging stability in a normal control sample.     

Resting-state functional connectivity reflects structural connectivity in the default mode network

Resting-state functional connectivity magnetic resonance imaging(fcMRI) studies constitute a growing proportion of functionalbrain imaging publications. This approach detects temporal correlationsin spontaneous blood oxygen level–dependent (BOLD) signaloscillations while subjects rest quietly in the scanner. Althoughdistinct resting-state networks related to vision, language,executive processing, and other sensory and cognitive domainshave been identified, considerable skepticism remains as towhether resting-state functional connectivity maps reflect neuralconnectivity or simply track BOLD signal correlations drivenby nonneural artifact. Here we combine diffusion tensor imaging(DTI) tractography with resting-state fcMRI to test the hypothesisthat resting-state functional connectivity reflects structuralconnectivity. These 2 modalities were used to investigate connectivitywithin the default mode network, a set of brain regions—includingmedial prefrontal cortex (MPFC), medial temporal lobes (MTLs),and posterior cingulate cortex (PCC)/retropslenial cortex (RSC)—implicatedin episodic memory processing. Using seed regions from the functionalconnectivity maps, the DTI analysis revealed robust structuralconnections between the MTLs and the retrosplenial cortex whereastracts from the MPFC contacted the PCC (just rostral to theRSC). The results demonstrate that resting-state functionalconnectivity reflects structural connectivity and that combiningmodalities can enrich our understanding of these canonical brainnetworks.     

Hemispheric asymmetry of visual scene processing in the human brain: evidence from repetition priming and intrinsic activity

Asymmetrical specialization of cognitive processes across the cerebral hemispheres is a hallmark of healthy brain development and an important evolutionary trait underlying higher cognition in humans. While previous research, including studies of priming, divided visual field presentation, and split-brain patients, demonstrates a general pattern of right/left asymmetry of form-specific versus form-abstract visual processing, little is known about brain organization underlying this dissociation. Here, using repetition priming of complex visual scenes and high-resolution functional magnetic resonance imaging (MRI), we demonstrate asymmetrical form specificity of visual processing between the right and left hemispheres within a region known to be critical for processing of visual spatial scenes (parahippocampal place area [PPA]). Next, we use resting-state functional connectivity MRI analyses to demonstrate that this functional asymmetry is associated with differential intrinsic activity correlations of the right versus left PPA with regions critically involved in perceptual versus conceptual processing, respectively. Our results demonstrate that the PPA comprises lateralized subregions across the cerebral hemispheres that are engaged in functionally dissociable yet complementary components of visual scene analysis. Furthermore, this functional asymmetry is associated with differential intrinsic functional connectivity of the PPA with distinct brain areas known to mediate dissociable cognitive processes.     

Association between functional connectivity hubs and brain networks

Functional networks are usually accessed with "resting-state" functional magnetic resonance imaging using preselected "seeds" regions. Frequently, however, the selection of the seed locations is arbitrary. Recently, we proposed local functional connectivity density mapping (FCDM), an ultrafast data-driven to locate highly connected brain regions (functional hubs). Here, we used the functional hubs obtained from local FCDM to determine the functional networks of the resting state in 979 healthy subjects without a priori hypotheses on seed locations. In addition, we computed the global functional connectivity hubs. Seven networks covering 80% of the gray matter volume were identified. Four major cortical hubs (ventral precuneus/posterior cingulate, inferior parietal cortex, cuneus, and postcentral gyrus) were linked to 4 cortical networks (default mode, dorsal attention, visual, and somatosensory). Three subcortical networks were associated to the major subcortical hubs (cerebellum, thalamus, and amygdala). The networks differed in their resting activity and topology. The higher coupling and overlap of subcortical networks was associated to higher contribution of short-range functional connectivity in thalamus and cerebellum. Whereas cortical local FCD hubs were also hubs of long-range connectivity, which corroborates the key role of cortical hubs in network architecture, subcortical hubs had minimal long-range connectivity. The significant variability among functional networks may underlie their sensitivity/resilience to neuropathology.     

Fine modulation in network activation during motor execution and motor imagery

Motor imagery, the 'mental rehearsal of motor acts without overt movements', involves either a visual representation (visual imagery, VI) or mental simulation of movement, associated with a kinesthetic feeling (kinetic imagery, KI). Previous brain imaging work suggests that patterns of brain activation differ when comparing execution (E) with either type of imagery but the functional connectivity of the participating networks has not been studied. Using functional magnetic resonance imaging (fMRI) and structural equation modeling, this study elucidates the inter-relationships among the relevant areas for each of the three motor behaviors. Our results suggest that networks underlying these behaviors are not identical, despite the extensive overlap between E and KI. Inputs to M1, which are facilitatory during E, have the opposite effect during KI, suggesting a physiological mechanism whereby the system prevents overt movements. Finally, this study highlights the role of the connection of superior parietal lobule to the supplementary motor area in both types of motor imagery.     

Functional Connectivity during Modulation of Tinnitus with Orofacial Maneuvers

Objective To determine changes in cortical neural networks as defined by resting-state functional connectivity magnetic resonance imaging during voluntary modulation of tinnitus with orofacial maneuvers. Study Design Cross-sectional study. Setting Academic medical center. Subjects and Methods Participants were scanned during the maneuver and also at baseline to serve as their own control. The authors chose, a priori, 58 seed regions to evaluate previously described cortical neural networks by computing temporal correlations between all seed region pairs. Seed regions whose correlations significantly differed between rest and maneuver (P < .05, uncorrected) entered into a second-stage analysis of computing the correlation coefficient between the seed region and time courses in each of the remaining brain voxels. A threshold-free cluster enhancement permutation analysis evaluated the distribution of these correlation coefficients after transformation to Fisher z scores and registration to a surface-based reconstruction using Freesurfer. Results The median age for the 16 subjects was 54 years (range, 27-72 years), and all had subjective, unilateral or bilateral, nonpulsatile tinnitus for 6 months or longer. In 9 subjects who could voluntarily increase the loudness of their tinnitus, there were no significant differences in functional connectivity in any cortical networks. A separate analysis evaluated results from 3 patients who decreased the loudness of their tinnitus. Four subjects were excluded because of excessive motion in the scanner. Conclusion The absence of significant differences in functional connectivity due to voluntary orofacial maneuvers that increased tinnitus loudness failed to confirm prior reports of altered cerebral blood flows during somatomotor behaviors.     

Changes of cortico-striatal effective connectivity during visuomotor learning

It has been suggested that the cortico-striatal system might play a crucial role in learning behavioural plans of action. We have tested this hypothesis by studying the dynamics of functional coupling among the neural elements of cortico-striatal circuitry. Human cerebral activity was measured with functional magnetic resonance imaging (fMRI) during the learning of an associative visuomotor task. Structural equation modelling of regional fMRI time-series was used to characterize learning-related changes in effective connectivity. We report that learning to associate visual instructions with motor responses significantly altered cortico-striatal functional couplings. Specific learning-related increases of effective connectivity were found in temporo-striatal and fronto-striatal circuits. Connectivity among portions of the frontal cortex decreased as a function of learning. Temporo-frontal and parieto-frontal couplings were not altered during learning. We infer that novel visuomotor associations are established through the enhancement of specific cortico-striatal circuits, rather than through the alteration of direct temporo-frontal or parieto-frontal connectivity.     

Decoding subject-driven cognitive states with whole-brain connectivity patterns

Decoding specific cognitive states from brain activity constitutes a major goal of neuroscience. Previous studies of brain-state classification have focused largely on decoding brief, discrete events and have required the timing of these events to be known. To date, methods for decoding more continuous and purely subject-driven cognitive states have not been available. Here, we demonstrate that free-streaming subject-driven cognitive states can be decoded using a novel whole-brain functional connectivity analysis. Ninety functional regions of interest (ROIs) were defined across 14 large-scale resting-state brain networks to generate a 3960 cell matrix reflecting whole-brain connectivity. We trained a classifier to identify specific patterns of whole-brain connectivity as subjects rested quietly, remembered the events of their day, subtracted numbers, or (silently) sang lyrics. In a leave-one-out cross-validation, the classifier identified these 4 cognitive states with 84% accuracy. More critically, the classifier achieved 85% accuracy when identifying these states in a second, independent cohort of subjects. Classification accuracy remained high with imaging runs as short as 30-60 s. At all temporal intervals assessed, the 90 functionally defined ROIs outperformed a set of 112 commonly used structural ROIs in classifying cognitive states. This approach should enable decoding a myriad of subject-driven cognitive states from brief imaging data samples.     

Cerebral White Matter Integrity and Resting-State Functional Connectivity in Middle-aged Patients With Type 2 Diabetes

Early detection of brain abnormalities at the preclinical stage can be useful for developing preventive interventions to abate cognitive decline. We examined whether middle-aged type 2 diabetic patients show reduced white matter integrity in fiber tracts important for cognition and whether this abnormality is related to preestablished altered resting-state functional connectivity in the default mode network (DMN). Diabetic and nondiabetic participants underwent diffusion tensor imaging, functional magnetic resonance imaging, and cognitive assessment. Multiple diffusion measures were calculated using streamline tractography, and correlations with DMN functional connectivity were determined. Diabetic patients showed lower fractional anisotropy (FA) (a measure of white matter integrity) in the cingulum bundle and uncinate fasciculus. Control subjects showed stronger functional connectivity than patients between the posterior cingulate and both left fusiform and medial frontal gyri. FA of the cingulum bundle was correlated with functional connectivity between the posterior cingulate and medial frontal gyrus for combined groups. Thus, middle-aged patients with type 2 diabetes show white matter abnormalities that correlate with disrupted functional connectivity in the DMN, suggesting that common mechanisms may underlie structural and functional connectivity. Detecting brain abnormalities in middle age enables implementation of therapies to slow progression of neuropathology.     

Effect of dopamine transporter genotype on intrinsic functional connectivity depends on cognitive state

Functional connectivity between brain regions can define large-scale neural networks and provide information about relationships between those networks. We examined how relationships within and across intrinsic connectivity networks were 1) sensitive to individual differences in dopaminergic function, 2) modulated by cognitive state, and 3) associated with executive behavioral traits. We found that regardless of cognitive state, connections between frontal, parietal, and striatal nodes of Task-Positive networks (TPNs) and Task-Negative networks (TNNs) showed higher functional connectivity in 10/10 homozygotes of the dopamine transporter gene, a polymorphism influencing synaptic dopamine, than in 9/10 heterozygotes. However, performance of a working memory task (a state requiring dopamine release) modulated genotype differences selectively, such that cross-network connectivity between TPNs and TNNs was higher in 10/10 than 9/10 subjects during working memory but not during rest. This increased cross-network connectivity was associated with increased self-reported measures of impulsivity and inattention traits. By linking a gene regulating synaptic dopamine to a phenotype characterized by inefficient executive function, these findings validate cross-network connectivity as an endophenotype of executive dysfunction.     

Reduced resting-state brain activity in the "default network" in normal aging

Normal aging is associated with cognitive decline. Functions such as attention, information processing, and working memory are compromised. It has been hypothesized that not only regional changes, but also alterations in the integration of regional brain activity (functional brain connectivity) underlie the observed age-related deficits. Here, we examined the functional properties of brain networks based on spontaneous fluctuations within brain systems using functional magnetic resonance imaging. We hypothesized that functional connectivity of intrinsic brain activity in the "default-mode" network (DMN) is affected by normal aging and that this relates to cognitive function. Ten younger and 22 older subjects were scanned at "rest," that is, lying awake with eyes closed. Our results show decreased activity in older versus younger subjects in 2 resting-state networks (RSNs) resembling the previously described DMN, containing the superior and middle frontal gyrus, posterior cingulate, middle temporal gyrus, and the superior parietal region. These results remain significant after correction for RSN-specific gray matter volume. The relevance of these findings is illustrated by the correlation between reduced activity of one of these RSNs and less effective executive functioning/processing speed in the older group.     

Sensorimotor cortical activity in patients with complete spinal cord injury: a functional magnetic resonance imaging study

Residual activation of the cortex was investigated in nine patients with complete spinal cord injury between T6 and L1 by functional magnetic resonance imaging (fMRI). Brain activations were recorded under four conditions: (1) a patient attempting to move his toes with flexion-extension, (2) a patient imagining the same movement, (3) passive proprio-somesthesic stimulation of the big toes without visual control, and (4) passive proprio-somesthesic stimulation of the big toes with visual control by the patient. Passive proprio-somesthesic stimulation of the toes generated activation posterior to the central sulcus in the three patients who also showed a somesthesic evoked potential response to somesthesic stimulation. When performed under visual control, activations were observed in two more patients. In all patients, activations were found in the cortical areas involved in motor control (i.e., primary sensorimotor cortex, premotor regions and supplementary motor area [SMA]) during attempts to move or mental imagery of these tasks. It is concluded that even several years after injury with some local cortical reorganization, activation of lower limb cortical networks can be generated either by the attempt to move, the mental evocation of the action, or the visual feedback of a passive proprio-somesthesic stimulation.     

Dissociation of verbal working memory system components using a delayed serial recall task

Functional magnetic resonance imaging (fMRI) was used to investigate the neural substrates of component processes in verbal working memory. Based on behavioral research using manipulations of verbal stimulus type to dissociate storage, rehearsal, and executive components of verbal working memory, we designed a delayed serial recall task requiring subjects to encode, maintain, and overtly recall sets of verbal items for which phonological similarity, articulatory length, and lexical status were manipulated. By using a task with temporally extended trials, we were able to exploit the temporal resolution afforded by fMRI to partially isolate neural contributions to encoding, maintenance, and retrieval stages of task performance. Several regions commonly associated with maintenance, including supplementary motor, premotor, and inferior frontal areas, were found to be active across all three trial stages. Additionally, we found that left inferior frontal and supplementary motor regions showed patterns of stimulus and temporal sensitivity implicating them in distinct aspects of articulatory rehearsal, while no regions showed a pattern of sensitivity consistent with a role in phonological storage. Regional modulation by task difficulty was further investigated as a measure of executive processing. We interpret our findings as they relate to notions about the cognitive architecture underlying verbal working memory performance.     

Renal functional reserve in patients with recently diagnosed Type 2 diabetes mellitus with and without microalbuminuria

BACKGROUND/AIMS: During the first 10 years, two thirds of the patients with type 2 diabetes mellitus (DM) have microalbuminuria (MA). Functional renal reserve (FRR) and its relationship with proteinuria and metabolic control are unknown at the early phases of disease. We investigated the frequency of MA in recently diagnosed type 2 DM patients, and its association with FRR. METHODS: We studied 181 type 2 DM patients with less than 6 months since diagnosis. Renal volume, MA, glomerular filtration rate (GFR) and renal plasma flow (ERPF) were evaluated before and after an acute oral protein load in 28 type 2 DM patients (14 with, and 14 without MA), and in 7 healthy subjects. RESULTS: A total of 10.6% of the patients had MA. MA patients had higher cholesterol and triglyceride levels than those normoalbuminuric. Twenty recently diagnosed type 2 diabetic patients showed high basal GFR. Twelve of them had MA and insulin resistance. After the acute oral protein load, the control subjects and the patients without MA increased their GFR and their ERPF. The group with MA did not. CONCLUSIONS: Seventy-five percent of the patients were hyperfiltering. Normoalbuminuric patients had larger increase in GFR and ERRPF than MB patients. We conclude that FRR measurement can be an important tool for the diagnosis of latent diabetic nephropathy.     

Nonenzymatic Glycation and Degree of Mineralization Are Higher in Bone From Fractured Patients With Type 1 Diabetes Mellitus

Low‐energy fractures are frequent complications in type 1 diabetes mellitus patients (T1DM). Modifications of bone intrinsic composition might be a potential cause of fragility observed in diabetic subjects. Advanced glycation end products (AGEs) were found in numerous connective tissues from T1DM patients. However, whether AGEs are present at high levels in bone matrix from diabetic subjects is unknown. Moreover, whether elevated AGEs in the bone matrix impair mineralization has not been addressed in humans. The purposes of this study were 1) to determine whether bone matrix from fracturing and nonfracturing T1DM contained more AGEs than bone from healthy patients (CTL), and 2) to compare the degree of mineralization of bone and hardness between fracturing and nonfracturing T1DM versus CTL. We analyzed iliac crest bone biopsies from 5 fracturing T1DM patients, 5 nonfracturing T1DM patients, and 5 healthy subjects, all age‐ and sex‐matched. AGEs (pentosidine) in bone matrix was measured by high‐performance liquid chromatography separately in trabecular and cortical bone. The degree of mineralization of bone (DMB) was assessed by digitized microradiography, and mechanical properties by micro‐ and nanohardness tests. Trabecular bone from fracturing T1DM exhibited significantly higher levels of pentosidine than CTL (p = 0.04) and was more mineralized than nonfracturing T1DM (p = 0.04) and CTL (p = 0.04). Trabecular bone was not significantly different in pentosidine between nonfracturing T1DM and CTL. Cortical bone from nonfracturing T1DM was not significantly different from CTL. Positive correlations were found between HbA1c and pentosidine (r' = 0.79, p < 0.003) and between HbA1c and DMB (r' = 0.64, p < 0.02). Both modifications could lead to less flexible bone (reduced modulus of elasticity) and a tendency toward low‐energy fractures in T1DM patients. © 2015 American Society for Bone and Mineral Research.     

Microalbuminuria and left ventricular function in type 2 diabetes: a quantitative assessment by stress echocardiography in the Myocardial Doppler in Diabetes (MYDID) Study III

BACKGROUND: Left ventricular (LV) function might be altered in type 2 diabetes (DM) and microalbuminuria (MA) may accentuate the abnormalities. We sought to investigate whether additional LV dysfunction could be unmasked using tissue Doppler (TVE)-enhanced dobutamine stress echocardiography (TVE-DSE) in patients with DM + MA. METHODS: Twenty seven DM subjects with MA, (DM + MA), 31 DM subjects without MA (DM - MA), and 13 Controls were evaluated using TVE-DSE. LV basal peak systolic (PSV), early (E') and late (A') diastolic velocities (cm/sec) at rest and peak stress were post-processed. LV filling pressure was assessed using E/E'ratio. RESULTS: PSV and E'velocity at peak stress in the respective three groups were 13.7 +/- 1.0, 10.1 +/- 1.1, 10.0 +/- 1.2 for PSV; and 10.0 +/- 1.6, 5.0 +/- 1.4, 4.8 +/- 1.4 for E' (p < 0.001 for controls vs. both groups). E/E' at rest was 7.9 +/- 0.7 in the controls, 10.8 +/- 2.4 in DM - MA, and 11.0 +/- 2.2 in DM + MA (p < 0.01 Controls vs. both the DM groups). CONCLUSIONS: Patients with DM + MA do not have additional LV regional systolic and diastolic dysfunctions compared with DM -MA, as revealed by TVE-DSE, when controlled for glycemia levels, lipids, and treatment strategies.