Predictors of visceral and subcutaneous adipose tissue and muscle density: The ShapeUp! Kids study.

BACKGROUND AND AIMS: Body fat distribution, i.e., visceral (VAT), subcutaneous adipose tissue (SAT) and intramuscular fat, is important for disease prevention, but sex and ethnic differences are not well understood. Our aim was to identify anthropometric, demographic, and lifestyle predictors for these outcomes. METHODS AND RESULTS: The cross-sectional ShapeUp!Kids study was conducted among five ethnic groups aged 5-18 years. All participants completed questionnaires, anthropometric measurements, and abdominal MRI scans. VAT and SAT areas at four lumbar levels and muscle density were assessed manually. General linear models were applied to estimate coefficients of determination (R2) and to compare the fit of VAT and SAT prediction models. After exclusions, the study population had 133 male and 170 female participants. Girls had higher BMI-z scores, waist circumference (WC), and SAT than boys but lower VAT/SAT and muscle density. SAT, VAT, and VAT/SAT but not muscle density differed significantly by ethnicity. R2 values were higher for SAT than VAT across groups and improved slightly after adding WC. For SAT, R2 increased from 0.85 to 0.88 (girls) and 0.62 to 0.71 (boys) when WC was added while VAT models improved from 0.62 to 0.65 (girls) and 0.57 to 0.62 (boys). VAT values were significantly lower among Blacks than Whites with little difference for the other groups. CONCLUSION: This analysis in a multiethnic population identified BMI-z scores and WC as the major predictors of MRI-derived SAT and VAT and highlights the important ethnic differences that need to be considered in diverse populations.

Genome-wide association study of abdominal MRI-measured visceral fat: The multiethnic cohort adiposity phenotype study.

Few studies have explored the genetic underpinnings of intra-abdominal visceral fat deposition, which varies substantially by sex and race/ethnicity. Among 1,787 participants in the Multiethnic Cohort (MEC)-Adiposity Phenotype Study (MEC-APS), we conducted a genome-wide association study (GWAS) of the percent visceral adiposity tissue (VAT) area out of the overall abdominal area, averaged across L1-L5 (%VAT), measured by abdominal magnetic resonance imaging (MRI). A genome-wide significant signal was found on chromosome 2q14.3 in the sex-combined GWAS (lead variant rs79837492: Beta per effect allele = -4.76; P = 2.62 × 10-8) and in the male-only GWAS (lead variant rs2968545: (Beta = -6.50; P = 1.09 × 10-9), and one suggestive variant was found at 13q12.11 in the female-only GWAS (rs79926925: Beta = 6.95; P = 8.15 × 10-8). The negatively associated variants were most common in European Americans (T allele of rs79837492; 5%) and African Americans (C allele of rs2968545; 5%) and not observed in Japanese Americans, whereas the positively associated variant was most common in Japanese Americans (C allele of rs79926925, 5%), which was all consistent with the racial/ethnic %VAT differences. In a validation step among UK Biobank participants (N = 23,699 of mainly British and Irish ancestry) with MRI-based VAT volume, both rs79837492 (Beta = -0.026, P = 0.019) and rs2968545 (Beta = -0.028, P = 0.010) were significantly associated in men only (n = 11,524). In the MEC-APS, the association between rs79926925 and plasma sex hormone binding globulin levels reached statistical significance in females, but not in males, with adjustment for total adiposity (Beta = -0.24; P = 0.028), on the log scale. Rs79837492 and rs2968545 are located in intron 5 of CNTNAP5, and rs79926925, in an intergenic region between GJB6 and CRYL1. These novel findings differing by sex and racial/ethnic group warrant replication in additional diverse studies with direct visceral fat measurements.

Subcutaneous and visceral fat assessment by DXA and MRI in older adults and children.

OBJECTIVE: Given the importance of body fat distribution in chronic disease development, feasible methods to assess body fat are essential. This study compared dual-energy x-ray absorptiometry (DXA) in measuring visceral and subcutaneous adipose tissue (VAT and SAT) with magnetic resonance imaging (MRI). METHODS: VAT and SAT were assessed using similar DXA and MRI protocols among 1,795 elderly participants of the Adiposity Phenotype Study (APS) and 309 children/adolescents in Shape Up! Kids (SKids). Spearman correlations, Bland-Altman plots, and coefficients of determination (R2 ) assessed agreement between DXA and MRI measures. RESULTS: DXA overestimated SAT values in APS (315 vs. 229 cm2 ) and SKids (212 vs. 161 cm2 ), whereas DXA underestimated VAT measures (141 vs. 167 cm2 ) in adults only. The correlations between DXA and MRI values were stronger for SAT than VAT (APS: r = 0.92 vs. 0.88; SKids: 0.90 vs. 0.74). Bland-Altman plots confirmed better agreement for SAT than VAT despite differences by sex, ethnicity, and weight status with respective R2 values for SAT and VAT of 0.88 and 0.84 (APS) and 0.81 and 0.69 (SKids). CONCLUSION: These findings indicate that SAT by DXA reflects MRI measures in children and older adults, whereas agreement for VAT is weaker for individuals with low VAT levels.

Body Fat Distribution, Glucose Metabolism, and Diabetes Status Among Older Adults: The Multiethnic Cohort Adiposity Phenotype Study.

BACKGROUND: As the proportion of visceral (VAT) to subcutaneous adipose tissue (SAT) may contribute to type 2 diabetes (T2D) development, we examined this relation in a cross-sectional design within the Multiethnic Cohort that includes Japanese Americans known to have high VAT. The aim was to understand how ectopic fat accumulation differs by glycemic status across ethnic groups with disparate rates of obesity, T2D, and propensity to accumulate VAT. METHODS: In 2013-2016, 1,746 participants aged 69.2 (standard deviation, 2.7) years from five ethnic groups completed questionnaires, blood collections, and whole-body dual X-ray absorptiometry and abdominal magnetic resonance imaging scans. Participants with self-reported T2D and/or medication were classified as T2D, those with fasting glucose >125 and 100-125 mg/dL as undiagnosed cases (UT2D) and prediabetes (PT2D), respectively. Using linear regression, we estimated adjusted means of adiposity measures by T2D status. RESULTS: Overall, 315 (18%) participants were classified as T2D, 158 (9%) as UT2D, 518 (30%) as PT2D, and 755 (43%) as normoglycemic (NG), with significant ethnic differences (P < 0.0001). In fully adjusted models, VAT, VAT/SAT, and percent liver fat increased significantly from NG, PT2D, UT2D, to T2D (P < 0.001). Across ethnic groups, the VAT/SAT ratio was lowest for NG participants and highest for T2D cases. Positive trends were observed in all groups except African Americans, with highest VAT/SAT in Japanese Americans. CONCLUSION: These findings indicate that VAT plays an important role in T2D etiology, in particular among Japanese Americans with high levels of ectopic adipose tissue, which drives the development of T2D to a greater degree than in other ethnic groups.

Genome-wide association study of pancreatic fat: The Multiethnic Cohort Adiposity Phenotype Study.

Several studies have found associations between higher pancreatic fat content and adverse health outcomes, such as diabetes and the metabolic syndrome, but investigations into the genetic contributions to pancreatic fat are limited. This genome-wide association study, comprised of 804 participants with MRI-assessed pancreatic fat measurements, was conducted in the ethnically diverse Multiethnic Cohort-Adiposity Phenotype Study (MEC-APS). Two genetic variants reaching genome-wide significance, rs73449607 on chromosome 13q21.2 (Beta = -0.67, P = 4.50x10-8) and rs7996760 on chromosome 6q14 (Beta = -0.90, P = 4.91x10-8) were associated with percent pancreatic fat on the log scale. Rs73449607 was most common in the African American population (13%) and rs79967607 was most common in the European American population (6%). Rs73449607 was also associated with lower risk of type 2 diabetes (OR = 0.95, 95% CI = 0.89-1.00, P = 0.047) in the Population Architecture Genomics and Epidemiology (PAGE) Study and the DIAbetes Genetics Replication and Meta-analysis (DIAGRAM), which included substantial numbers of non-European ancestry participants (53,102 cases and 193,679 controls). Rs73449607 is located in an intergenic region between GSX1 and PLUTO, and rs79967607 is in intron 1 of EPM2A. PLUTO, a lncRNA, regulates transcription of an adjacent gene, PDX1, that controls beta-cell function in the mature pancreas, and EPM2A encodes the protein laforin, which plays a critical role in regulating glycogen production. If validated, these variants may suggest a genetic component for pancreatic fat and a common etiologic link between pancreatic fat and type 2 diabetes.

Biomarker-based visceral adiposity score and incident type 2 diabetes in the multiethnic cohort.

PURPOSE: Visceral adipose tissue (VAT) may be more important than subcutaneous fat in type 2 diabetes (T2D) etiology. We examined a VAT score developed in reference to MRI measurement of VAT in the Multiethnic Cohort (MEC) as a risk factor for incident T2D. METHODS: Two nested case-control studies of cancer allowed calculation of the VAT score based on anthropometric measures and 8 biomarkers among 2,556 participants without T2D. Incident cases were identified from Medicare linkages and self-reports after blood draws in 2001-2006. Cox regression with age as time metric was applied to estimate the association of the VAT score with T2D. RESULTS: During 10.1 ± 2.4 years, 355 incident T2D cases were identified. VAT scores were higher in T2D cases than among those without disease (5.06±0.43 vs. 4.95±0.41; P<0.0001) and significantly associated with T2D (HR = 2.70; 95%CI 1.60, 4.58 per unit) with similar values in men (HR = 2.99; 95%CI 1.03, 8.73) and women (HR = 2.61; 95%CI 1.39, 4.91). A significant association was observed in all five ethnic groups but only statistically significant among Japanese Americans (HR = 6.24; 95%CI 2.34, 16.68). CONCLUSION: These findings support that VAT as estimated by a biomarker-based score predicts T2D incidence beyond BMI in particular among older adults of Japanese ancestry.

Predictors of liver fat among children and adolescents from five different ethnic groups.

OBJECTIVES: As rates of obesity around the world have increased, so has the detection of high level of liver fat in children and adolescents. This may put them at risk for cardiovascular disease later in life. This analysis of a cross-sectional population-based study of children and adolescents evaluated demographic and lifestyle determinants of percent liver fat. METHODS: Healthy participants (123 girls and 99 boys aged 5-17 years) recruited by convenience sampling in three locations completed questionnaires, anthropometric measurements, and dual X-ray absorptiometry and magnetic resonance imaging (MRI) assessment. General linear models were applied to estimate the association of demographic, anthropometric, and dietary factors as well as physical activity with MRI-based percent liver fat. RESULTS: The strongest predictor of liver fat was body mass index (BMI; p < 0.0001); overweight and obesity were associated with 0.5% and 1% higher liver fat levels. The respective adjusted mean percent values were 2.9 (95% CI 2.7, 3.1) and 3.4 (95% CI 3.2, 3.6) as compared to normal weight (2.4; 95% CI 2.3, 2.6). Mean percent liver fat was highest in Whites and African Americans, intermediate in Hispanic, and lowest among Asians and Native Hawaiians/Pacific Islanders (p < 0.0001). Age (p = 0.67), sex (p = 0.28), physical activity (p = 0.74), and diet quality (p = 0.70) were not significantly related with liver fat. CONCLUSIONS: This study in multiethnic children and adolescents confirms the strong relationship of BMI with percent liver fat even in a population with low liver fat levels without detecting an association with age, sex, and dietary or physical activity patterns.

Differences in the association of diet quality with body fat distribution between men and women.

BACKGROUND/OBJECTIVE: As dietary intake and endocrine metabolism are vastly different by sex, we evaluated differences in the association of diet quality with body composition between men and women. SUBJECTS/METHODS: Close to 2000 participants from the Multiethnic Cohort completed calibrated quantitative food frequency questionnaires at cohort entry (1993-96) and clinic visit (2013-16), from which the Healthy Eating Index (HEI-2010) was computed. Adiposity measures were obtained through DXA and MRI at clinic visit. Multivariable-adjusted mean adiposity measures were estimated by tertiles of HEI-2010 scores using general linear regression. The associations of diet quality with high visceral fat (VAT) and nonalcoholic fatty liver disease (NAFLD) were examined by logistic regression. To assess sex differences, cross-product terms with the HEI-2010 were added to the models. RESULTS: Mean HEI-2010 scores were higher for women than men at cohort entry (67.4 vs. 64.0) and clinic visit (73.6 vs. 71.0). Past and current diet quality was inversely associated with adiposity measures in men and women. Although interaction terms were not significant, the magnitude of the slopes and differences in adjusted means across tertiles suggested a stronger association for women than men. When comparing individuals who maintained a high vs. poor quality diet over 20 years, women but not men showed significantly lower risks for high VAT, whereas high HEI-2010 scores predicted a lower risk of NAFLD in both sexes. CONCLUSIONS: The inverse association of diet quality with adiposity was similar in both sexes, but diet quality appeared to have a stronger influence on VAT in women than men.

Diet Quality in Midadulthood Predicts Visceral Adiposity and Liver Fatness in Older Ages: The Multiethnic Cohort Study.

OBJECTIVE: The relationship of diet quality assessed by established indices (HEI-2010, AHEI-2010, aMED, DASH) with adiposity measures was examined, especially visceral adipose tissue (VAT) and nonalcoholic fatty liver (NAFL). METHODS: Close to 2,000 participants of the Multiethnic Cohort completed validated food frequency questionnaires at cohort entry (1993-1996) and clinic visit (2013-2016) when they underwent whole-body dual-energy x-ray absorptiometry and abdominal magnetic resonance imaging scans. Linear regression was used to estimate mean values of adiposity measures by dietary index tertiles at baseline and standardized regression coefficients (ßs ) after adjusting for total adiposity and other covariates. Logistic regression of VAT and NAFL on dietary indices was also performed. RESULTS: Higher dietary quality scores at cohort entry were inversely related to all adiposity measures, with the strongest associations for percent liver fat (ßs = -0.14 to -0.08), followed by VAT (ßs = -0.11 to -0.05), BMI (ßs = -0.11 to -0.06), and total body fat (ßs = -0.09 to -0.05). Odds ratios adjusted for total adiposity ranged between 0.57 and 0.77 for NAFL and between 0.41 and 0.65 for high VAT when comparing the highest versus lowest tertiles of diet quality. CONCLUSIONS: These longitudinal findings indicate that maintaining a high-quality diet during mid-to-late adulthood may prevent adverse metabolic consequences related to VAT and NAFL.

Sex-Specific Alterations of White Matter Developmental Trajectories in Infants With Prenatal Exposure to Methamphetamine and Tobacco.

IMPORTANCE: Methamphetamine is a common illicit drug used worldwide. Methamphetamine and/or tobacco use by pregnant women remains prevalent. However, little is known about the effect of comorbid methamphetamine and tobacco use on human fetal brain development. OBJECTIVE: To investigate whether microstructural brain abnormalities reported in children with prenatal methamphetamine and/or tobacco exposure are present at birth before childhood environmental influences. DESIGN, SETTING, AND PARTICIPANTS: A prospective, longitudinal study was conducted between September 17, 2008, and February 28, 2015, at an ambulatory academic medical center. A total of 752 infant-mother dyads were screened and 139 of 195 qualified neonates were evaluated (36 methamphetamine/tobacco exposed, 32 tobacco exposed, and 71 unexposed controls). They were recruited consecutively from the community. EXPOSURES: Prenatal methamphetamine and/or tobacco exposure. MAIN OUTCOMES AND MEASURES: Quantitative neurologic examination and diffusion tensor imaging performed 1 to 3 times through age 4 months; diffusivities and fractional anisotropy (FA) assessed in 7 white matter tracts and 4 subcortical brain regions using an automated atlas-based method. RESULTS: Of the 139 infants evaluated, 72 were female (51.8%); the mean (SE) postmenstrual age at baseline was 41.5 (0.27) weeks. Methamphetamine/tobacco-exposed infants showed delayed developmental trajectories on active muscle tone (group × age, P < .001) and total neurologic scores (group × age, P = .01) that normalized by ages 3 to 4 months. Only methamphetamine/tobacco-exposed boys had lower FA (group × age, P = .02) and higher diffusivities in superior (SCR) and posterior corona radiatae (PCR) (group × age × sex, P = .002; group × age × sex, P = .01) at baseline that normalized by age 3 months. Only methamphetamine/tobacco- and tobacco-exposed girls showed persistently lower FA in anterior corona radiata (ACR) (group, P = .04; group × age × sex, P = .01). Tobacco-exposed infants showed persistently lower axial diffusion in the thalamus and internal capsule across groups (P = .02). CONCLUSIONS AND RELEVANCE: Prenatal methamphetamine/tobacco exposure may lead to delays in motor development, with less coherent fibers and less myelination in SCR and PCR only in male infants, but these abnormalities may normalize by ages 3 to 4 months after cessation of stimulant exposure. In contrast, persistently less coherent ACR fibers were observed in methamphetamine/tobacco- and tobacco-exposed girls, possibly from increased dendritic branching or spine density due to epigenetic influences. Persistently lower diffusivity in the thalamus and internal capsule of all tobacco-exposed infants suggests aberrant axonal development. Collectively, prenatal methamphetamine and/or tobacco exposure may lead to delayed motor development and white matter maturation in sex- and regional-specific manners.

Delayed early developmental trajectories of white matter tracts of functional pathways in preterm-born infants: Longitudinal diffusion tensor imaging data.

Probabilistic maps of white matter pathways related to motor, somatosensory, auditory, visual, and limbic functions, and major white matter tracts (the corpus callosum, the inferior fronto-occipital fasciculus, and the middle cerebellar peduncle) were applied to evaluate the developmental trajectories of these tracts, using longitudinal diffusion tensor imaging (DTI) obtained in term-born and preterm-born healthy infants. Nineteen term-born and 30 preterm-born infants completed MR scans at three time points: Time-point 1, 41.6±2.7 postmenstrual weeks; Time-point 2, 46.0±2.9 postmenstrual weeks; and Time-point 3, 50.8±3.7 postmenstrual weeks. The DTI-derived scalar values (fractional anisotropy, eigenvalues, and radial diffusivity) of the three time points are available in this Data article.

Probabilistic maps of the white matter tracts with known associated functions on the neonatal brain atlas: Application to evaluate longitudinal developmental trajectories in term-born and preterm-born infants.

Diffusion tensor imaging (DTI) has been widely used to investigate the development of the neonatal and infant brain, and deviations related to various diseases or medical conditions like preterm birth. In this study, we created a probabilistic map of fiber pathways with known associated functions, on a published neonatal multimodal atlas. The pathways-of-interest include the superficial white matter (SWM) fibers just beneath the specific cytoarchitectonically defined cortical areas, which were difficult to evaluate with existing DTI analysis methods. The Jülich cytoarchitectonic atlas was applied to define cortical areas related to specific brain functions, and the Dynamic Programming (DP) method was applied to delineate the white matter pathways traversing through the SWM. Probabilistic maps were created for pathways related to motor, somatosensory, auditory, visual, and limbic functions, as well as major white matter tracts, such as the corpus callosum, the inferior fronto-occipital fasciculus, and the middle cerebellar peduncle, by delineating these structures in eleven healthy term-born neonates. In order to characterize maturation-related changes in diffusivity measures of these pathways, the probabilistic maps were then applied to DTIs of 49 healthy infants who were longitudinally scanned at three time-points, approximately five weeks apart. First, we investigated the normal developmental pattern based on 19 term-born infants. Next, we analyzed 30 preterm-born infants to identify developmental patterns related to preterm birth. Last, we investigated the difference in diffusion measures between these groups to evaluate the effects of preterm birth on the development of these functional pathways. Term-born and preterm-born infants both demonstrated a time-dependent decrease in diffusivity, indicating postnatal maturation in these pathways, with laterality seen in the corticospinal tract and the optic radiation. The comparison between term- and preterm-born infants indicated higher diffusivity in the preterm-born infants than in the term-born infants in three of these pathways: the body of the corpus callosum; the left inferior longitudinal fasciculus; and the pathway connecting the left primary/secondary visual cortices and the motion-sensitive area in the occipitotemporal visual cortex (V5/MT+). Probabilistic maps provided an opportunity to investigate developmental changes of each white matter pathway. Whether alterations in white matter pathways can predict functional outcomes will be further investigated in a follow-up study.

Plasma and Cerebrospinal Fluid Biomarkers Predict Cerebral Injury in HIV-Infected Individuals on Stable Combination Antiretroviral Therapy.

OBJECTIVES: HIV-associated brain injury persists despite combination antiretroviral therapy, but contributing factors remain poorly understood. We postulated that inflammation-associated biomarkers will be associated with cerebral injury on proton magnetic resonance spectroscopy in chronically HIV-infected subjects. METHODS: Five biomarkers were measured in 197 HIV-infected subjects: soluble CD14, MCP-1, IP-10, MIP-1ß, and fractalkine. Levels of N-acetyl aspartate (NAA), Choline (Cho), Myoinositol (MI), Glutamate + Glutamine (Glx), and Creatine (Cr) were acquired in the midfrontal cortex (MFC), frontal white matter, and basal ganglia (BG). Predictive models were built through linear regression, and the best models were chosen using the Akaike Information Criterion. RESULTS: Increases in plasma or CSF MCP-1 were associated with lower NAA/Cr in the MFC and BG, whereas metabolite changes in the frontal white matter for NAA/Cr, GlxCr, and Cho/Cr were explained almost exclusively by a single factor, sCD14. Plasma and CSF levels of this factor were also significantly associated with Glx/Cr in MFC and BG. Higher CSF FKN was associated with higher NAA/Cr in BG. Best predictors for higher Cho/Cr in BG and MFC were CSF sCD14 and CSF MIP-1ß. Plasma and CSF IP-10 were only associated with Cho/Cr in MFC. Of the 3 models that simultaneously accounted for both plasma and CSF, there were more associations between CSF biomarkers and magnetic resonance spectroscopy metabolites. CONCLUSIONS: Markers of inflammation and immune activation, in particular MCP-1 and sCD14, predominantly reflecting CNS sources, contribute to the persistence of brain injury in a metabolite and region-dependent manner in chronically HIV-infected patients on stable combination antiretroviral therapy.

Structural growth trajectories and rates of change in the first 3 months of infant brain development.

IMPORTANCE: The very early postnatal period witnesses extraordinary rates of growth, but structural brain development in this period has largely not been explored longitudinally. Such assessment may be key in detecting and treating the earliest signs of neurodevelopmental disorders. OBJECTIVE: To assess structural growth trajectories and rates of change in the whole brain and regions of interest in infants during the first 3 months after birth. DESIGN, SETTING, AND PARTICIPANTS: Serial structural T1-weighted and/or T2-weighted magnetic resonance images were obtained for 211 time points from 87 healthy term-born or term-equivalent preterm-born infants, aged 2 to 90 days, between October 5, 2007, and June 12, 2013. MAIN OUTCOMES AND MEASURES: We segmented whole-brain and multiple subcortical regions of interest using a novel application of Bayesian-based methods. We modeled growth and rate of growth trajectories nonparametrically and assessed left-right asymmetries and sexual dimorphisms. RESULTS: Whole-brain volume at birth was approximately one-third of healthy elderly brain volume, and did not differ significantly between male and female infants (347 388 mm3 and 335 509 mm3, respectively, P = .12). The growth rate was approximately 1%/d, slowing to 0.4%/d by the end of the first 3 months, when the brain reached just more than half of elderly adult brain volume. Overall growth in the first 90 days was 64%. There was a significant age-by-sex effect leading to widening separation in brain sizes with age between male and female infants (with male infants growing faster than females by 200.4 mm3/d, SE = 67.2, P = .003). Longer gestation was associated with larger brain size (2215 mm3/d, SE = 284, P = 4×10-13). The expected brain size of an infant born one week earlier than average was 5% smaller than average; at 90 days it will not have caught up, being 2% smaller than average. The cerebellum grew at the highest rate, more than doubling in 90 days, and the hippocampus grew at the slowest rate, increasing by 47% in 90 days. There was left-right asymmetry in multiple regions of interest, particularly the lateral ventricles where the left was larger than the right by 462 mm3 on average (approximately 5% of lateral ventricular volume at 2 months). We calculated volume-by-age percentile plots for assessing individual development. CONCLUSIONS AND RELEVANCE: Normative trajectories for early postnatal brain structural development can be determined from magnetic resonance imaging and could be used to improve the detection of deviant maturational patterns indicative of neurodevelopmental disorders.

Effects of APOE ε4, age, and HIV on glial metabolites and cognitive deficits.

OBJECTIVE: We aimed to evaluate the combined effects of HIV and APOE ε4 allele(s) on glial metabolite levels, and on known cognitive deficits associated with either condition, across the ages. METHODS: One hundred seventy-seven participants, primarily of white and mixed race (97 seronegative subjects: aged 44.7 ± 1.3 years, 85 [87.6%] men, 28 [28.9%] APOE ε4+; 80 HIV+ subjects: aged 47.3 ± 1.1 years, 73 [91.3%] men, 23 [28.8%] APOE ε4+), were assessed cross-sectionally for metabolite concentrations using proton magnetic resonance spectroscopy in 4 brain regions and for neuropsychological performance. RESULTS: Frontal white matter myo-inositol was elevated in subjects with HIV across the age span but showed age-dependent increase in seronegative subjects, especially in APOE ε4+ carriers. In contrast, only seronegative APOE ε4+ subjects showed elevated myo-inositol in parietal cortex. All APOE ε4+ subjects had lower total creatine in basal ganglia. While all HIV subjects showed greater cognitive deficits, HIV+ APOE ε4+ subjects had the poorest executive function, fluency memory, and attention/working memory. Higher myo-inositol levels were associated with poorer fine motor function across all subjects, slower speed of information processing in APOE ε4+ subjects, and worse fluency in HIV+ APOE ε4+ subjects. CONCLUSIONS: In frontal white matter of subjects with HIV, the persistent elevation and lack of normal age-dependent increase in myo-inositol suggest that persistent glial activation attenuated the typical antagonistic pleiotropic effects of APOE ε4 on neuroinflammation. APOE ε4 negatively affects energy metabolism in brain regions rich in dopaminergic synapses. The combined effects of HIV infection and APOE ε4 may lead to greater cognitive deficits, especially in those with greater neuroinflammation. APOE ε4 allele(s) may be a useful genetic marker to identify white and mixed-race HIV subjects at risk for cognitive decline.

MRI default mode network connectivity is associated with functional outcome after cardiopulmonary arrest.

BACKGROUND: We hypothesized that the degree of preserved functional connectivity within the DMN during the first week after cardiopulmonary arrest (CPA) would be associated with functional outcome at hospital discharge. METHODS: Initially comatose CPA survivors with indeterminate prognosis at 72 h were enrolled. Seventeen CPA subjects between 4 and 7 days after CPA and 17 matched controls were studied with task-free fMRI. Independent component analysis was performed to delineate the DMN. Connectivity strength in the DMN was compared between CPA subjects and controls, as well as between CPA subjects with good outcome (discharge Cerebral Performance Category or CPC 1-2) and those with bad outcome (CPC 3-5). The relationship between connectivity strength in the posterior cingulate cortex (PCC) and precuneus (PC) within the DMN with discharge CPC was evaluated using linear regression. RESULTS: Compared to controls, CPA subjects had significantly lower connectivity strength in subregions of the DMN, the PCC and PC (p < 0.0001). Furthermore, connectivity strength in the PCC and PC was greater in CPA subjects with good outcome (n = 8) than those with bad outcome (n = 9) (p < 0.003). Among CPA subjects, the connectivity strength in the PCC and PC showed strong linear correlations with the discharge CPC (p < 0.005). CONCLUSIONS: Among initially comatose CPA survivors with indeterminate prognosis, task-free fMRI demonstrated graded disruption of DMN connectivity, especially in those with bad outcomes. If confirmed, connectivity strength in the PC/PCC may provide a clinically useful prognostic marker for functional recovery after CPA.

Progressive cerebral injury in the setting of chronic HIV infection and antiretroviral therapy.

Emerging evidence suggests that CNS injury and neurocognitive impairment persist in the setting of chronic HIV infection and combination antiretroviral therapy (CART). Yet, whether neurological injury can progress in this setting remains uncertain. Magnetic resonance spectroscopy and neurocognitive and clinical assessments were performed over 2 years in 226 HIV-infected individuals on stable CART, including 138 individuals who were neurocognitively asymptomatic (NA). Concentrations of N-acetylaspartate (NAA), creatine (Cr), choline (Cho), myoinositol, and glutamate/glutamine (Glx) were measured in the midfrontal cortex (MFC), frontal white matter (FWM), and basal ganglia (BG). Longitudinal changes in metabolite levels were determined using linear mixed effect models, as were metabolite changes in relation to global neurocognitive function. HIV-infected subjects showed significant annual decreases in brain metabolite levels in all regions examined, including NAA (2.95 %) and Cho (2.61 %) in the FWM; NAA (1.89 %), Cr (1.84 %), Cho (2.19 %), and Glx (6.05 %) in the MFC; and Glx (2.80 %) in the BG. Similar metabolite decreases were observed in the NA and subclinically impaired subgroups, including subjects with virologic suppression in plasma and CSF. Neurocognitive decline was associated with longitudinal decreases in Glx in the FWM and the BG, and in NAA in the BG. Widespread progressive changes in the brain, including neuronal injury, occur in chronically HIV-infected persons despite stable antiretroviral treatment and virologic suppression and can lead to neurocognitive declines. The basis for these findings is poorly understood and warrants further study.

Susceptibility variants for waist size in relation to abdominal, visceral, and hepatic adiposity in postmenopausal women.

Genome-wide association studies have identified common genetic variants that can contribute specifically to the risk of abdominal adiposity, as measured by waist circumference or waist-to-hip ratio. However, it is unknown whether these genetic risk factors affect relative body fat distribution in the abdominal visceral and subcutaneous compartments. The association between imaging-based abdominal fat mass and waist-size risk variants in the FTO, LEPR, LYPLAL1, MSRA, NRXN3, and TFAP2B genes was investigated. A cross-sectional sample of 60 women was selected among study participants of The Multiethnic Cohort, who were aged 60 to 65 years, of European or Japanese descent, and with a body mass index (calculated as kg/m(2)) between 18.5 and 40. Dual-energy x-ray absorptiometry and abdominal magnetic resonance imaging scans were used to measure adiposity. After adjustments for age, ethnicity, and total fat mass, the FTO variants showed an association with less abdominal subcutaneous fat and a higher visceral-to-subcutaneous abdominal fat ratio, with the variant rs9941349 showing significant associations most consistently (P=0.003 and 0.03, respectively). Similarly, the LEPR rs1137101 variant was associated with less subcutaneous fat (P=0.01) and a greater visceral-to-subcutaneous fat ratio (P=0.03) and percent liver fat (P=0.007). MSRA rs545854 variant carriers had a lower percent of leg fat. Our findings provide initial evidence that some of the genetic risk factors identified for larger waist size might also contribute to disproportionately greater intra-abdominal and liver fat distribution in postmenopausal women. If replicated, these genetic variants can be incorporated with other biomarkers to predict high-risk body fat distribution.