Asian Adolescents with Excess Weight are at Higher Risk for Insulin Resistance than Non-Asian Peers.

OBJECTIVE: The purpose of this study was to evaluate whether Asian American adolescents have higher metabolic risk from excess weight than non-Asians. METHODS: Seven hundred thirty-three students, aged 14 to 19 years old, completed a school-based health screening. The 427 Asian and 306 non-Asian students were overall equivalent on age, sex, and family income. Height, weight, waist circumference, percent body fat, and blood pressure were measured. Fasting triglycerides, high- and low-density lipoproteins, glucose, and insulin levels were measured. Asian and non-Asians in lean or overweight/obesity groups were contrasted on the five factors that make up the metabolic syndrome. RESULTS: Asian adolescents carrying excess weight had significantly higher insulin resistance (IR), triglyceride levels, and waist-height ratios (W/H), despite a significantly lower overall BMI than corresponding non-Asians. Similarly, Asians had a stronger relationship between W/H and the degree of IR than non-Asian counterparts; 35% and 18% of the variances were explained (R2 = 0.35, R2 = 0.18) respectively, resulting in a significant W/H by racial group interaction (Fchange [1,236] = 11.56, P < 0.01). CONCLUSIONS: Despite lower overall BMI, Asians have higher IR and triglyceride levels from excess weight than their non-Asian counterparts. One-size-fits-all public health policies targeting youth should be reconsidered and attention paid to Asian adolescents, including those with mild degrees of excess weight.

Insulin resistance among obese middle-aged is associated with decreased cerebrovascular reactivity.

OBJECTIVE: To evaluate differences in cerebrovascular reactivity (CVR) to mild hypercapnia in obese/overweight individuals with and without insulin resistance (IR) compared to comparable lean controls. METHODS: A total of 60 cognitively normal participants (20 lean controls and 24 obese/overweight individuals with and 16 without IR) were evaluated using a high spatial resolution arterial spin labeling MRI technique at rest and during mild hypercapnia. We analyzed group differences in CVR in cerebral cortex and ascertained the relationships between CVR, IR, and body mass index (BMI). RESULTS: Obese/overweight participants with and without IR had significantly lower CVR to hypercapnia than lean controls after controlling for age, sex, and the presence of hypertension (F2,53 = 5.578, p = 0.006 [Formula: see text] = 0.174). In the obese/overweight participants with IR, there was a significant correlation between higher CVR and a measure of insulin sensitivity, even after accounting for BMI (rp = 0.575, p = 0.004). In contrast, there was no relationship between CVR and BMI when controlling for IR. No such relationships existed for the other 2 groups. CONCLUSIONS: IR is associated with impaired CVR; the relationship appears to be driven by the degree of IR and not by obesity. These rarely reported results suggest that early forms of cerebrovascular dysfunction exist among obese middle-aged individuals with significant IR but without type 2 diabetes mellitus. These functional vascular abnormalities may help explain the associations among IR, diabetes, and dementia, and suggest that interventions aiming to improve IR or CVR may help prevent cognitive decline later in life.

Insulin Sensitivity and Inflammation Mediate the Impact of Fitness on Cerebrovascular Health in Adolescents.

BACKGROUND/OBJECTIVES: To investigate in adolescents the relationships between retinal vessel diameter, physical fitness, insulin sensitivity, and systemic inflammation. METHODS: We evaluated 157 adolescents, 112 with excessive weight and 45 lean, all without type 2 diabetes mellitus. All received detailed evaluations, including measurements of retinal vessel diameter, insulin sensitivity, levels of inflammation, and physical fitness. RESULTS: Overweight/obese adolescents had significantly narrower retinal arteriolar and wider venular diameters, significantly lower insulin sensitivity, and physical fitness. They also had decreased levels of anti-inflammatory and increased levels of proinflammatory markers as well as an overall higher inflammation balance score. Fitness was associated with larger retinal arteriolar and narrower venular diameters and these relationships were mediated by insulin sensitivity. We demonstrate that inflammation also mediates the relationship between fitness and retinal venular, but not arterial diameter; insulin sensitivity and inflammation balance score jointly mediate this relationship with little overlap in their effects. CONCLUSIONS: Increasing fitness and insulin sensitivity and reducing inflammation among adolescents carrying excess weight may improve microvascular integrity. Interventions to improve physical fitness and insulin function and reduce inflammation in adolescents, a group likely to benefit from such interventions, may reduce not only cardiovascular disease in middle age, but also improve cerebrovascular function later in life.

Effects of aging on slow-wave sleep dynamics and human spatial navigational memory consolidation.

The consolidation of spatial navigational memory during sleep is supported by electrophysiological and behavioral evidence. The features of sleep that mediate this ability may change with aging, as percentage of slow-wave sleep is canonically thought to decrease with age, and slow waves are thought to help orchestrate hippocampal-neocortical dialog that supports systems level consolidation. In this study, groups of younger and older subjects performed timed trials before and after polysomnographically recorded sleep on a 3D spatial maze navigational task. Although younger subjects performed better than older subjects at baseline, both groups showed similar improvement across presleep trials. However, younger subjects experienced significant improvement in maze performance during sleep that was not observed in older subjects, without differences in morning psychomotor vigilance between groups. Older subjects had sleep quality marked by decreased amount of slow-wave sleep and increased fragmentation of slow-wave sleep, resulting in decreased slow-wave activity. Across all subjects, frontal slow-wave activity was positively correlated with both overnight change in maze performance and medial prefrontal cortical volume, illuminating a potential neuroanatomical substrate for slow-wave activity changes with aging and underscoring the importance of slow-wave activity in sleep-dependent spatial navigational memory consolidation.

Fitness, insulin sensitivity, and frontal lobe integrity in adults with overweight and obesity.

OBJECTIVE: To formally test whether insulin sensitivity mediates the relationship between fitness and brain integrity. METHODS: Eighty-four middle-aged participants without diabetes received a 6-min walk test from which maximal oxygen uptake (VO2 max) was derived, a structural magnetic resonance scan, and a medical evaluation including fasting glucose and insulin levels. RESULTS: This study showed significant associations between fitness, abdominal obesity, and insulin sensitivity and anterior cingulate cortex (ACC) volume as well as between ACC thickness and quantitative insulin-sensitivity check index (QUICKI). The relationship between ACC volume and VO2 max was completely mediated through QUICKI. Further, this strong association was confirmed by a single and very significant cluster on the ACC linking gray matter volume and QUICKI in a voxel-based morphometry analysis. CONCLUSIONS: As expected, increased abdominal obesity was associated with reductions in fitness, ACC volumes, and insulin sensitivity. Importantly, this study demonstrated a significant mediation of the relationship between VO2 max and ACC volume by QUICKI. This suggests that the links between impaired insulin sensitivity and brain abnormalities in adults carrying excess weight could be alleviated through increased physical activity and fitness.

Obesity, fitness, and brain integrity in adolescence.

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 in insulin resistance and type 2 diabetes.

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 (R(2)=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.

Retinal vessel alterations and cerebral white matter microstructural damage in obese adolescents with metabolic syndrome.

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] µm, respectively; P < .001). The greater the number of MetS criteria present, the greater the reduction was in retinal arteriolar diameter (ß = -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.

Preliminary evidence of cognitive and brain abnormalities in uncomplicated adolescent obesity.

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.

Neural substrates of verbal memory impairments in adults with type 2 diabetes mellitus.

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.

Obesity and metabolic syndrome and functional and structural brain impairments in adolescence.

BACKGROUND: The prevalence of metabolic syndrome (MetS) parallels the rise in childhood obesity. MetS is associated with neurocognitive impairments in adults, but this is thought to be a long-term effect of poor metabolism. It would be important to ascertain whether these brain complications are also present among adolescents with MetS, a group without clinically manifest vascular disease and relatively short duration of poor metabolism. METHODS: Forty-nine adolescents with and 62 without MetS, matched on age, socioeconomic status, school grade, gender, and ethnicity, received endocrine, MRI, and neuropsychological evaluations. RESULTS: Adolescents with MetS showed significantly lower arithmetic, spelling, attention, and mental flexibility and a trend for lower overall intelligence. They also had, in a MetS-dose-related fashion, smaller hippocampal volumes, increased brain cerebrospinal fluid, and reductions of microstructural integrity in major white matter tracts. CONCLUSIONS: We document lower cognitive performance and reductions in brain structural integrity among adolescents with MetS, thus suggesting that even relatively short-term impairments in metabolism, in the absence of clinically manifest vascular disease, may give rise to brain complications. In view of these alarming results, it is plausible that obesity-associated metabolic disease, short of type 2 diabetes mellitus, may be mechanistically linked to lower the academic and professional potential of adolescents. Although obesity may not be enough to stir clinicians or even parents into action, these results in adolescents strongly argue for an early and comprehensive intervention. We propose that brain function be introduced among the parameters that need to be evaluated when considering early treatment of childhood obesity.

Impact of metabolic syndrome on cognition and brain: a selected review of the literature.

Metabolic syndrome (MetS), a clustering of risk factors for type 2 diabetes mellitus and cardiovascular disease, has been associated with cognitive dysfunction and brain abnormalities. This review describes the literature on the impact of MetS on brain and cognition and suggests directions for future research. A literature search for reports of MetS and cognition and brain imaging was conducted for both nonelderly adults and adolescents. No studies were found describing MetS and brain or cognition among adolescents; therefore, we also included studies investigating individual components of MetS in this age group. Most studies found associations between MetS and cognitive dysfunction. Multiple cognitive domains were affected by MetS in adults. In adolescents, the majority of findings were in executive functioning. Brain imaging literature in adults implicated MetS in ischemic stroke, white matter alterations, and altered brain metabolism. For adolescents, individual MetS factors were linked to volume losses in the hippocampus and frontal lobes. MetS negatively impacts cognitive performance and brain structure. Potential explanatory models include impaired vascular reactivity, neuroinflammation, oxidative stress, and abnormal brain lipid metabolism. We posit that insulin resistance-associated impairment in cerebrovascular reactivity is an important mechanism underlying brain deficits seen in MetS.

Obesity-mediated inflammation may damage the brain circuit that regulates food intake.

Adiposity is associated with chronic low-grade systemic inflammation and increased inflammation in the hypothalamus, a key structure in feeding behavior. It remains unknown whether inflammation impacts other brain structures that regulate feeding behavior. We studied 44 overweight/obese and 19 lean individuals with MRI and plasma fibrinogen levels (marker of inflammation). We performed MRI-based segmentations of the medial and lateral orbitofrontal cortex (OFC) and hippocampal volumes. Gray matter (GM) volumes were adjusted for head size variability. We conducted logistic and hierarchical regressions to assess the association between fibrinogen levels and brain volumetric data. Using diffusion tensor imaging (DTI), we created apparent diffusion coefficient (ADC) maps and conducted voxelwise correlational analyses. Fibrinogen concentrations were higher among the overweight/obese (t[61] = -2.33, P = 0.023). Lateral OFC associated together with fibrinogen correctly classified those with excess of weight (accuracy = 76.2%, sensitivity = 95.5%, and specificity=31.6%). The lateral OFC volumes of overweight/obese were negatively associated with fibrinogen (r = -0.37, P = 0.016) and after accounting for age, hypertension, waist/hip ratio and lipid and sugar levels, fibrinogen significantly explained an additional 9% of the variance in the lateral OFC volume (ß = -0.348, ΔR(2) = 0.093, ΔF P = 0.046). Among overweight/obese the associations between GM ADC and fibrinogen were significantly positive (P < 0.001) in the left and right amygdala and the right parietal region. Among lean individuals these associations were negative and located in the left prefrontal, the right parietal and the left occipital lobes. This is the first study to report that adiposity-related inflammation may reduce the integrity of some of the brain structures involved in reward and feeding behaviors.

Neuroimaging supports central pathology in familial dysautonomia.

Familial dysautonomia (FD) is a hereditary peripheral and central nervous system disorder with poorly defined central neuropathology. This prospective pilot study aimed to determine if MRI would provide objective parameters of central neuropathology. There were 14 study subjects, seven FD individuals (18.6 +/- 4.2 years, 3 female) and seven controls (19.1 +/- 5.8 years, 3 female). All subjects had standardized brain MRI evaluation including quantitative regional volume measurements, diffusion tensor imaging (DTI) for assessment of white matter (WM) microstructural integrity by calculation of fractional anisotropy (FA), and proton MR spectroscopy ((1)H MRS) to assess neuronal health. The FD patients had significantly decreased FA in optic radiation (p = 0.009) and middle cerebellar peduncle (p = 0.004). Voxel-wise analysis identified both GM and WM microstructural damage among FD subjects as there were nine clusters of WM FA reductions and 16 clusters of GM apparent diffusion coefficient (ADC) elevations. Their WM proportion was significantly decreased (p = 0.003) as was the WM proportion in the frontal region (p = 0.007). (1)H MRS showed no significant abnormalities. The findings of WM abnormalities and decreased optic radiation and middle cerebellar peduncle FA in the FD study group, suggest compromised myelination and WM micro-structural integrity in FD brains. These neuroimaging results are consistent with clinical visual abnormalities and gait disturbance. Furthermore the frontal lobe atrophy is consistent with previously reported neuropsychological deficits.

Emotional and neutral declarative memory impairments and associated white matter microstructural abnormalities in adults with type 2 diabetes.

Declarative memory impairment is frequently reported among adults with type 2 diabetes mellitus (T2DM), who also demonstrate hippocampal volume reduction. Our goals were to ascertain whether emotional memory, which is mediated by neural circuits overlapping those of declarative memory, is also affected. In addition we wanted to characterize cerebral white matter (WM) involvement in T2DM. We studied 24 middle-aged and elderly patients with T2DM who were free of obvious vascular pathology or a psychiatric disorder, and 17 age- and education-matched healthy individuals with no evidence of insulin resistance. We examined emotional and neutral memory and performed a whole-brain voxelwise WM assessment utilizing diffusion tensor imaging (DTI). We found clear evidence of impairment in declarative memory among diabetic subjects and in addition found some preliminary support to suggest a possible blunting of the memory facilitation by emotional material among female but not male diabetics. This report is also the first DTI assessment among individuals with T2DM, which after accounting for overt WM damage, revealed diffuse but predominantly frontal and temporal WM microstructural abnormalities, with extensive involvement of the temporal stem. Hierarchical regression analyses demonstrated that immediate, but not delayed, emotional memory performance was explained by temporal stem FA, independent of age, poor metabolic regulation, and systolic blood pressure. Given that the temporal lobe memory networks appear to be particularly vulnerable to the deleterious effects of T2DM, this may help explain the observed memory impairments among diabetics. Future efforts should better clarify, with a larger sample, whether emotional memory is affected in adults with T2DM and whether there are clear gender effects.