Faculty Bibliography

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.

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.

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: 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

Glucose obtained from unprocessed blood samples can decrease by 5%-7% per hour due to glycolysis. This study compared the impact of glucose degradation on measured glucose values by examining two different collection methods. For the first method, blood samples were collected in tubes containing sodium fluoride (NaF), a glycolysis inhibitor. For the second method, blood samples were collected in tubes containing a clot activator and serum gel separator and were centrifuged to separate the serum and plasma 20 minutes after sample collection. The samples used in the two methods were collected during the same blood draw and were assayed by the clinical laboratory 2-4 hours after the samples were obtained. A total of 256 pairs of samples were analyzed. The average glucose reading for the centrifuged tubes was significantly higher than the NaF tubes by 0.196 +/- 0.159 mmol/L (P < 0.01) or 4.2%. This study demonstrates the important role collection methods play in accurately assessing glucose levels of blood samples collected in the field, where working environment may be suboptimal. Therefore, blood samples collected in the field should be promptly centrifuged before being transported to clinical labs to ensure accurate glucose level measurements.

We examined 33 hypertensive (22 with comorbid type 2 diabetes mellitus (T2DM)) and 29 normotensive (8 with T2DM) middle-aged and elderly adults, comparable in age and education. Relative to normotensive participants, those with hypertension, in addition to a higher prevalence of periventricular white matter (WM) lesions, had significantly lower WM microstructural integrity of major fiber tracts as seen with MRI-based diffusion tensor imaging. Among participants with hypertension, those with co-morbid T2DM (n = 22) had more widespread WM pathology than those without T2DM (n = 11). Furthermore and consistent with previous research, both hypertension and T2DM were related to decreased retinal arterial diameter. Further exploratory analysis demonstrated that the observed retinal arteriolar narrowing among individual with hypertension was associated with widespread subclinical losses in WM microstructural integrity and these associations were present predominantly in the frontal lobe. We found that T2DM adds to the damaging effects of hypertension on cerebral WM, and notably these effects were independent of age and body mass index. Given that the decrease in retinal arteriolar diameter may be a biomarker for parallel pathology in cerebral arterioles, our data suggest that the frontal lobe may be particularly vulnerable to microvascular damage in the presence of hypertension and T2DM.