Faculty Bibliography

OBJECTIVE:To investigate the effects of lifestyle and vascular-related risk factors for Alzheimer's disease (AD) on in vivo MRI-based brain atrophy in asymptomatic young to middle-aged adults. DESIGN:Cross-sectional, observational. SETTING:Broader New York City area. Two research centres affiliated with the Alzheimer's disease Core Center at New York University School of Medicine. PARTICIPANTS:We studied 116 cognitively normal healthy research participants aged 30-60 years, who completed a three-dimensional T1-weighted volumetric MRI and had lifestyle (diet, physical activity and intellectual enrichment), vascular risk (overweight, hypertension, insulin resistance, elevated cholesterol and homocysteine) and cognition (memory, executive function, language) data. Estimates of cortical thickness for entorhinal (EC), posterior cingulate, orbitofrontal, inferior and middle temporal cortex were obtained by use of automated segmentation tools. We applied confirmatory factor analysis and structural equation modelling to evaluate the associations between lifestyle, vascular risk, brain and cognition. RESULTS:≥-0.22, P≤0.01). CONCLUSIONS:In cognitively normal middle-aged adults, MeDi and insulin sensitivity explained cortical thickness in key brain regions for AD, and EC thickness predicted memory performance in turn. Intellectual activity and overweight were associated with cognitive performance through different pathways. Our findings support further investigation of lifestyle and vascular risk factor modification against brain ageing and AD. More studies with larger samples are needed to replicate these research findings in more diverse, community-based settings.

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.

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 eta2p = 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.

BACKGROUND: Childhood obesity and obesity-associated diabetes and metabolic syndrome (MetS) continue to rise. Obesity has been linked to structural and functional brain abnormalities, particularly in the frontal lobe. METHODS: One hundred sixty-two adolescents (aged 19.53 +/- 1.53 years) underwent medical, neurocognitive, and brain magnetic resonance imaging assessments. Participants were either healthy weight (BMI <25.0 kg/m2 or BMI percentile <85%) or obese (BMI >/=30.0 kg/m2 or BMI percentile >/=95%). We evaluated frontal lobe cognitive functions and the size of the corpus callosum (CC). RESULTS: Groups differed on four measures of processing speed contained in four different cognitive tests, but not on executive function. A confirmatory factor analysis verified that the significant processing speed variables loaded on the same factor. We also found differences between the weight groups on the area of the anterior portion of the CC, but not the overall CC. Only the Controlled Oral Word Association Test (COWAT) was significantly correlated with the area of the anterior portion of the CC. In the obese group, 32.4% met criteria for MetS. No differences were found between obese participants with or without MetS and none of the MetS factors contributed consistently to cognitive performance. CONCLUSIONS: Obese adolescents show slower cognitive processing speed while maintaining equivalent performance on executive functioning compared with their healthy weight peers. The group differences in the anterior portion of the CC, responsible for frontal lobe interhemispheric communication, may in part explain our processing speed findings. Future studies should include a longitudinal design and diffusion tensor imaging to examine the integrity of white matter.

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.

In adult obesity, low-grade systemic inflammation is considered an important step in the pathogenesis of insulin resistance (IR). The association between obesity and inflammation is less well established in adolescents. Here, we ascertain the importance of inflammation in IR among obese adolescents by utilizing either random forest (RF) classification or mediation analysis approaches. The inflammation balance score, composed of eight pro- and anti-inflammatory makers, as well as most of the individual inflammatory markers differed significantly between lean and overweight/obese. In contrast, adiponectin was the only individual marker selected as a predictor of IR by RF, and the balance score only revealed a medium-to-low importance score. Neither adiponectin nor the inflammation balance score was found to mediate the relationship between obesity and IR. These findings do not support the premise that low-grade systemic inflammation is a key for the expression of IR in the human. Prospective longitudinal studies should confirm these findings.

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.

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.