Faculty Bibliography

OBJECTIVE: We set out to ascertain the relationship between insulin resistance, fitness, and brain structure and function in adolescents. DESIGN AND METHODS: We studied 79 obese and 51 non-obese participants who were recruited from the community, all without type 2 diabetes mellitus. All participants received medical, endocrine, neuropsychological, and MRI evaluations as well as a 6-minute walk test that was used to estimate fitness (maximal oxygen consumption). RESULTS: Obese adolescents had significantly thinner orbitofrontal cortices and performed significantly worse on Visual Working Memory tasks and the Digit Vigilance task. Insulin sensitivity and maximal oxygen consumption (VO2 max) were both highly correlated with central obesity and orbitofrontal cortical thickness, although insulin sensitivity was the stronger predictor for orbitofrontal cortical thickness. We also found that VO2 max was the only significant physiological variable related to visual working memory. CONCLUSIONS: This is the first study to report positive associations between insulin resistance, VO2 max, and frontal lobe brain integrity in adolescents. Given the importance of brain health for learning and school performance, we conclude that schools should also emphasize physical fitness in order to maintain structural and functional brain integrity and facilitate academic achievement.

Cerebral perfusion was evaluated in 87 subjects prospectively enrolled in three study groups-healthy controls (HC), patients with insulin resistance (IR) but not with diabetes, and type 2 diabetes mellitus (T2DM). Participants received a comprehensive 8-hour clinical evaluation and arterial spin labeling magnetic resonance imaging (MRI). In order of decreasing significance, an association was found between cerebral blood flow (CBF) and sex, waist circumference, diastolic blood pressure (BP), end tidal CO2, and verbal fluency score (R2=0.27, F=5.89, P<0.001). Mean gray-matter CBF in IR was 4.4 mL/100 g per minute lower than in control subjects (P=0.005), with no hypoperfusion in T2DM (P=0.312). Subjects with IR also showed no CO2 relationship (slope=-0.012) in the normocapnic range, in contrast to a strong relationship in healthy brains (slope=0.800) and intermediate response (slope=0.445) in diabetic patients. Since the majority of T2DM but few IR subjects were aggressively treated with blood glucose, cholesterol, and BP lowering medications, our finding could be attributed to the beneficial effect of these drugs.Journal of Cerebral Blood Flow & Metabolism advance online publication, 15 October 2014; doi:10.1038/jcbfm.2014.173.

IMPORTANCE: Cerebral white matter (WM) damage has been reported in childhood obesity and in metabolic syndrome (MetS) but mechanisms remain unclear. OBJECTIVES: To ascertain whether adolescents with MetS have retinal vessel alterations and if the anticipated reductions in retinal arteriolar diameter are associated with diminished cerebral WM microstructural integrity and to test a model for vascular etiology of the WM abnormalities. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional study of the brain correlates of obesity and related metabolic disease in youths. This study was conducted at the Brain, Obesity, and Diabetes Laboratory, New York University School of Medicine, New York. Thirty-nine obese adolescents with MetS and 51 matched adolescents without MetS received comprehensive endocrine, neuropsychological, retinal vessel, and diffusion tensor imaging-based cerebral WM evaluations. MAIN OUTCOMES AND MEASURES: Retinal arteriolar diameter, cerebral WM microstructural integrity, waist circumference, and insulin resistance. RESULTS: Obese adolescents with MetS had significant reductions in retinal arteriolar diameter relative to adolescents without MetS (mean [SD] central retinal arteriolar equivalent, 182.35 [16.10] vs 198.62 [19.03] mum, respectively; P < .001). The greater the number of MetS criteria present, the greater the reduction was in retinal arteriolar diameter (beta = -8.61; r2 = 0.335; F1,83 = 70.79; P < .001). We found that abdominal obesity (waist circumference) was the strongest MetS component related to reductions in retinal arteriolar diameter (rp[85] = -0.661; P < .001), and importantly, for the first time to our knowledge, we demonstrated that its effect was partially mediated by comorbid insulin resistance (indirect effect = -0.1355 [95% CI, -0.2471 to -0.0593]; Z = -2.56; P = .01). Consistent with our prior report of nondiabetic adolescents with MetS, we also uncovered cerebral WM microstructural damage. These subtle WM changes were associated with reductions in retinal arteriolar diameter, a proxy for cerebral microvascular health (3150 voxels or 3.15 cm3; P < .001). Importantly, some of the WM regions showing lower microstructural integrity also demonstrated associations with retinal arteriolar diameter, suggesting that the observed WM pathology is likely vascular in nature. CONCLUSIONS AND RELEVANCE: We document, for the first time to our knowledge, the associations between retinal vessel alterations and subclinical WM pathology among obese adolescents with MetS. This suggests that the subtle WM pathology in adolescents with MetS may have a vascular origin. Future work should include direct assessments of cerebral microvascular health.

OBJECTIVE: To ascertain whether pediatric obesity without clinically significant insulin resistance (IR) impacts brain structure and function. METHODS: Thirty obese and 30 matched lean adolescents, all without clinically significant IR or a diagnosis of metabolic syndrome (MetS), received comprehensive endocrine, neuropsychological, and MRI evaluations. RESULTS: Relative to lean adolescents, obese non-IR adolescents had significantly lower academic achievement (i.e., arithmetic and spelling) and tended to score lower on working memory, attention, psychomotor efficiency, and mental flexibility. In line with our prior work on adolescent MetS, memory was unaffected in uncomplicated obesity. Reductions in the thickness of the orbitofrontal and anterior cingulate cortices as well as reductions of microstructural integrity in major white matter tracts without gross volume changes were also uncovered. CONCLUSIONS: It was documented, for the first time, that adolescents with uncomplicated obesity already have subtle brain alterations and lower performance in selective cognitive domains. When interpreting these preliminary data in the context of our prior reports of similar, but more extensive brain findings in obese adolescents with MetS and T2DM, it was concluded that "uncomplicated" obesity may also result in subtle brain alterations, suggesting a possible dose effect with more severe metabolic dysregulation giving rise to greater abnormalities.

Adolescent overweight/obesity (OW/O) has reached epidemic proportions. The Youth Self-Report (YSR) was administered to 514 primarily Hispanic urban high school students to examine the relationship between weight and psychological distress. YSR and study population-specific norms were used to assess risk on Anxious/Depressed, Withdrawn/Depressed, Somatic Complaints, and Social Problems scales. OW/O status increased Social Problems regardless of norms. OW/O students endorsed greater Withdrawn/Depressed symptoms with YSR norms; greater Anxious/Depressed and Somatic Complaints were endorsed with population-specific norms. Females drive results. Findings suggest norms need to incorporate minority and economically disadvantaged groups.

Background: Verbal memory impairment is well documented in type 2 diabetes mellitus (T2DM) but, to date, the neural substrates remain unclear. The present study evaluated verbal memory and ascertained the degree of frontal and temporal lobe involvement in the anticipated verbal memory impairment among adults with T2DM. Method: Forty-six late-middle-aged and elderly adults with T2DM and 50 age-, sex-, and education-matched adults without T2DM underwent medical evaluation, verbal memory assessment, and brain magnetic resonance imaging (MRI) evaluations. Results: As anticipated, participants with T2DM had clear verbal memory impairments. Consistent with prior reports, we found volume reductions restricted to the hippocampus. Our diffusion tensor imaging analysis revealed that participants with T2DM had extensive cerebral gray and white matter microstructural abnormalities predominantly in the left hemisphere, with a larger concentration present in the temporal lobe. In contrast, we uncovered mostly nonspecific microstructural abnormalities in the absence of tissue loss in the frontal lobe. Of great importance, we present the first evidence among participants with T2DM linking verbal memory impairment and compromised microstructural integrity of the left parahippocampal gyrus, a key memory-relevant structure. Conclusions: Our results suggest that the hippocampus and parahippocampal gyrus may be particularly vulnerable to the deleterious effects of T2DM. The parahippocampal gyrus in particular may play a crucial role in the verbal memory impairments frequently reported in T2DM. Future studies should employ methods such as resting state functional magnetic resonance imaging and diffusion tensor imaging tractography to better characterize network connectivity, which may help further characterize the verbal memory impairment frequently reported in T2DM.

OBJECTIVE: Dopamine mediates the rewarding effects of food that can lead to overeating and obesity, which then trigger metabolic neuroadaptations that further perpetuate excessive food consumption. We tested the hypothesis that the dopamine response to calorie intake (independent of palatability) in striatal brain regions is attenuated with increases in weight. METHOD: We used positron emission tomography with [11C]raclopride to measure dopamine changes triggered by calorie intake by contrasting the effects of an artificial sweetener (sucralose) devoid of calories to that of glucose to assess their association with body mass index (BMI) in nineteen healthy participants (BMI range 21-35). RESULTS: Neither the measured blood glucose concentrations prior to the sucralose and the glucose challenge days, nor the glucose concentrations following the glucose challenge vary as a function of BMI. In contrast the dopamine changes in ventral striatum (assessed as changes in non-displaceable binding potential of [11C]raclopride) triggered by calorie intake (contrast glucose - sucralose) were significantly correlated with BMI (r = 0.68) indicating opposite responses in lean than in obese individuals. Specifically whereas in normal weight individuals (BMI <25) consumption of calories was associated with increases in dopamine in the ventral striatum in obese individuals it was associated with decreases in dopamine. CONCLUSION: These findings show reduced dopamine release in ventral striatum with calorie consumption in obese subjects, which might contribute to their excessive food intake to compensate for the deficit between the expected and the actual response to food consumption.

Objective: Endothelial dysfunction in childhood obesity may precede cerebrovascular damage and cognitive impairment in adulthood. A noninvasive proxy of microvascular health is required to identify the risk for microvascular damage in obese children. DESIGN AND METHODS: The associations of hippocampal volumes and global cerebral atrophy were assessed with retinal vessel caliber in 40 normal BMI controls and 62 obese age-matched nondiabetic adolescents and the contribution of inflammation, obesity, and insulin resistance to retinal vessel caliber was evaluated. RESULTS: Compared to controls, obese adolescents had smaller retinal arterioles (8.3% decrease, P < 0.05) and wider venules (5.4% increase, P < 0.01). Larger retinal arteriole diameters were associated with less global cerebral atrophy (B = -0.24 [95% confidence interval, CI: -0.48, -0.002]) and larger hippocampal volumes (B = 0.01 [95% CI: 0, 0.02]). Venule diameters (B = 84.2 [95% CI: 30.3, 138.1]) were predicted by inflammation (fibrinogen). Arteriolar diameters were predicted by insulin resistance, indicated by logHOMA (homeostatic model assessment, HOMA) values (B = -17.03 [95% CI: -28.25, -5.81)] and body mass index (BMI) (B = -.67 [95% CI: -1.09, -0.24)]. All analyses were adjusted for mean arterial pressure, sleep apnea, and vessel diameter. CONCLUSIONS: Measures of brain health, BMI, and insulin resistance are associated with retinal vessel caliber. If confirmed in larger studies, retinal arteriolar caliber may serve as a possible noninvasive proxy for brain atrophy in obese adolescents, and the identification of elevated risk for cerebral microvascular disease in adulthood.

Phosphorus ((31) P) magnetization transfer (MT) techniques enable the non-invasive measurement of metabolic turnover rates of important enzyme-catalyzed reactions, such as the creatine kinase reaction (CK), a major transducing reaction involving adenosine triphosphate and phosphocreatine. Alteration in the kinetics of the CK reaction rate appears to play a central role in many disease states. In this study, we developed and implemented at ultra-high field (7T) a novel three-dimensional (31) P-MT imaging sequence that maps the kinetics of CK in the entire volume of the lower leg at relatively high resolution (0.52 mL voxel size), and within acquisition times that can be tolerated by patients (below 60 min). We tested the sequence on five healthy and two clinically diagnosed type 2 diabetic subjects. Overall, we obtained measurements that are in close agreement with measurements reported previously using spectroscopic methods. Importantly, our spatially resolved method allowed us to measure local CK reaction rate constants and metabolic fluxes in individual muscles in a non-invasive manner. Furthermore, it allowed us to detect variations of the CK rates of different muscles, which would not have been possible using unlocalized MRS methods. The results of this work suggest that 3D mapping of the CK reaction rates and metabolic fluxes can be achieved in the skeletal muscle in vivo at relatively high spatial resolution and with acquisition times well tolerated by patients. The ability to measure bioenergetics simultaneously in large areas of muscles will bring new insights into possible heterogeneous patterns of muscle metabolism associated with several diseases and serve as a valuable tool for monitoring the efficacy of interventions