Faculty Bibliography

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.

BACKGROUND: Hippocampus (HC) atrophy is a hallmark of early Alzheimer's disease (AD). Atrophy rates can be measured by high-resolution structural MRI. Longitudinal studies have previously shown sex differences in the progression of functional and cognitive deficits and rates of brain atrophy in early AD dementia. It is important to corroborate these findings on independent datasets. OBJECTIVE: To study temporal rates of HC atrophy over a one-year period in probable AD patients and cognitively normal (CN) subjects by longitudinal MRI scans obtained from the Minimal Interval Resonance Imaging in AD (MIRIAD) database. METHODS: We used a novel algorithm to compute an index of hippocampal (structural) integrity (HI) at baseline and one-year follow-up in 43 mild-moderate probable AD patients and 22 CN subjects in MIRIAD. The diagnostic power of longitudinal HI measurement was assessed using a support vector machines (SVM) classifier. RESULTS: The HI was significantly reduced in the AD group (p < 10-20). In addition, the annualized percentage rate of reduction in HI was significantly greater in the AD group (p < 10-13). Within the AD group, the annual reduction of HI in women was significantly greater than in men (p = 0.008). The accuracy of SVM classification between AD and CN subjects was estimated to be 97% by 10-fold cross-validation. CONCLUSION: In the MIRIAD patients with probable AD, the HC atrophies at a significantly faster rate in women as compared to men. Female sex is a risk factor for faster descent into AD. The HI measure has potential for AD diagnosis, as a biomarker of AD progression and a therapeutic target in clinical trials.

Adolescent obesity continues to be a major public health issue with a third of American adolescents being overweight or obese. Excess weight is associated with cardiovascular risk factors and pre-diabetes. High school students identified as carrying excess weight [body mass index (BMI) >/=25 kg/m2, or BMI percentile >/=85 %] were invited to participate in The BODY Project, an intervention that included a medical evaluation and a personalized medical report of the results of that evaluation sent to the parent/guardian at home. The medical evaluation and report was repeated 12 months later. The reports also contained advice on how the individual student could modify their lifestyle to improve the specific medical parameters showing abnormalities. Outcomes were change in BMI, blood pressure, high-density lipoprotein (HDL), low-density lipoprotein (LDL), fasting glucose, and fasting insulin. Students participating in The BODY Project intervention demonstrated modest, yet significant, reductions in BMI (p < 0.001) 1 year later, and also had significant improvements in systolic blood pressure (p < 0.001) and cholesterol profile (HDL p = 0.002; LDL p < 0.001) at follow-up. The BODY Project, by means of a minimal educational program anchored on the principle of teachable moments around the students' increased perception of their own risk for disease from the medical abnormalities uncovered, demonstrates evidence of potential effectiveness in addressing adolescent obesity.

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.