Genomic analysis of intracranial and subcortical brain volumes yields polygenic scores accounting for variation across ancestries.

Subcortical brain structures are involved in developmental, psychiatric and neurological disorders. Here we performed genome-wide association studies meta-analyses of intracranial and nine subcortical brain volumes (brainstem, caudate nucleus, putamen, hippocampus, globus pallidus, thalamus, nucleus accumbens, amygdala and the ventral diencephalon) in 74,898 participants of European ancestry. We identified 254 independent loci associated with these brain volumes, explaining up to 35% of phenotypic variance. We observed gene expression in specific neural cell types across differentiation time points, including genes involved in intracellular signaling and brain aging-related processes. Polygenic scores for brain volumes showed predictive ability when applied to individuals of diverse ancestries. We observed causal genetic effects of brain volumes with Parkinson's disease and attention-deficit/hyperactivity disorder. Findings implicate specific gene expression patterns in brain development and genetic variants in comorbid neuropsychiatric disorders, which could point to a brain substrate and region of action for risk genes implicated in brain diseases.

Genomic analysis of intracranial and subcortical brain volumes yields polygenic scores accounting for variation across ancestries.

Subcortical brain structures are involved in developmental, psychiatric and neurological disorders. We performed GWAS meta-analyses of intracranial and nine subcortical brain volumes (brainstem, caudate nucleus, putamen, hippocampus, globus pallidus, thalamus, nucleus accumbens, amygdala and, for the first time, the ventral diencephalon) in 74,898 participants of European ancestry. We identified 254 independent loci associated with these brain volumes, explaining up to 35% of phenotypic variance. We observed gene expression in specific neural cell types across differentiation time points, including genes involved in intracellular signalling and brain ageing-related processes. Polygenic scores for brain volumes showed predictive ability when applied to individuals of diverse ancestries. We observed causal genetic effects of brain volumes with Parkinson's disease and ADHD. Findings implicate specific gene expression patterns in brain development and genetic variants in comorbid neuropsychiatric disorders, which could point to a brain substrate and region of action for risk genes implicated in brain diseases.

Reproducible brain PET data analysis: easier said than done.

While a great deal of recent effort has focused on addressing a perceived reproducibility crisis within brain structural magnetic resonance imaging (MRI) and functional MRI research communities, this article argues that brain positron emission tomography (PET) research stands on even more fragile ground, lagging behind efforts to address MRI reproducibility. We begin by examining the current landscape of factors that contribute to reproducible neuroimaging data analysis, including scientific standards, analytic plan pre-registration, data and code sharing, containerized workflows, and standardized processing pipelines. We then focus on disparities in the current status of these factors between brain MRI and brain PET. To demonstrate the positive impact that further developing such reproducibility factors would have on brain PET research, we present a case study that illustrates the many challenges faced by one laboratory that attempted to reproduce a community-standard brain PET processing pipeline. We identified key areas in which the brain PET community could enhance reproducibility, including stricter reporting policies among PET dedicated journals, data repositories, containerized analysis tools, and standardized processing pipelines. Other solutions such as mandatory pre-registration, data sharing, code availability as a condition of grant funding, and online forums and standardized reporting templates, are also discussed. Bolstering these reproducibility factors within the brain PET research community has the potential to unlock the full potential of brain PET research, propelling it toward a higher-impact future.

Associations of Epigenetic Age Acceleration With CVD Risks Across the Lifespan: The Bogalusa Heart Study.

Although epigenetic age acceleration (EAA) might serve as a molecular signature of childhood cardiovascular disease (CVD) risk factors and further promote midlife subclinical CVD, few studies have comprehensively examined these life course associations. This study sought to test whether childhood CVD risk factors predict EAA in adulthood and whether EAA mediates the association between childhood CVD risks and midlife subclinical disease. Among 1,580 Bogalusa Heart Study participants, we estimated extrinsic EAA, intrinsic EAA, PhenoAge acceleration (PhenoAgeAccel), and GrimAge acceleration (GrimAgeAccel) during adulthood. We tested prospective associations of longitudinal childhood body mass index (BMI), blood pressure, lipids, and glucose with EAAs using linear mixed effects models. After confirming EAAs with midlife carotid intima-media thickness and carotid plaque, structural equation models examined mediating effects of EAAs on associations of childhood CVD risk factors with subclinical CVD measures. After stringent multiple testing corrections, each SD increase in childhood BMI was significantly associated with 0.6-, 0.9-, and 0.5-year increases in extrinsic EAA, PhenoAgeAccel, and GrimAgeAccel, respectively (P < 0.001 for all 3 associations). Likewise, each SD increase in childhood log-triglycerides was associated with 0.5- and 0.4-year increases in PhenoAgeAccel and GrimAgeAccel (P < 0.001 for both), respectively, whereas each SD increase in childhood high-density lipoprotein cholesterol was associated with a 0.3-year decrease in GrimAgeAccel (P = 0.002). Our findings indicate that PhenoAgeAccel mediates an estimated 27.4% of the association between childhood log-triglycerides and midlife carotid intima-media thickness (P = 0.022). Our data demonstrate that early life CVD risk factors may accelerate biological aging and promote subclinical atherosclerosis.

Effects of testosterone enanthate on aggression, risk-taking, competition, mood, and other cognitive domains during 28 days of severe energy deprivation.

RATIONALE: Behavioral effects of testosterone depend on dose, acute versus sustained formulation, duration of administration, personality, genetics, and endogenous levels of testosterone. There are also considerable differences between effects of endogenous and exogenous testosterone. OBJECTIVES: This study was the secondary behavioral arm of a registered clinical trial designed to determine if testosterone protects against loss of lean body mass and lower-body muscle function induced by a severe energy deficit typical of sustained military operations. METHODS: Behavioral effects of repeated doses of testosterone on healthy young men whose testosterone was reduced by severe energy deficit were examined. This was a double-blind, placebo-controlled, between-group study. Effects of four weekly intramuscular injections of testosterone enanthate (200 mg/week, N = 24) or matching placebo (N = 26) were evaluated. Determination of sample size was based on changes in lean body mass. Tasks assessing aggression, risk-taking, competition, social cognition, vigilance, memory, executive function, and mood were repeatedly administered. RESULTS: During a period of artificially induced, low testosterone levels, consistent behavioral effects of administration of exogenous testosterone were not observed. CONCLUSIONS: Exogeneous testosterone enanthate (200 mg/week) during severe energy restriction did not reliably alter the measures of cognition. Study limitations include the relatively small sample size compared to many studies of acute testosterone administration. The findings are specific to healthy males experiencing severe energy deficit and should not be generalized to effects of other doses, formulations, or acute administration of endogenous testosterone or studies conducted with larger samples using tests of cognitive function designed to detect specific effects of testosterone.

Harmonized Multisite MRI-Based Quantification of Human Liver Fat and Stiffness: A Pilot Study.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is a leading cause of end-stage liver disease. NAFLD diagnosis and follow-up relies on a combination of clinical data, liver imaging, and/or liver biopsy. However, intersite imaging differences impede diagnostic consistency and reduce the repeatability of the multisite clinical trials necessary to develop effective treatments. PURPOSE/HYPOTHESIS: The goal of this pilot study was to harmonize commercially available 3 T magnetic resonance imaging (MRI) measurements of liver fat and stiffness in human participants across academic sites and MRI vendors. STUDY TYPE: Cohort. SUBJECTS: Four community-dwelling adults with obesity. FIELD STRENGTH/SEQUENCE: 1.5 and 3 T, multiecho 3D imaging, PRESS, and GRE. ASSESSMENT: Harmonized proton density fat fraction (PDFF) and magnetic resonance spectroscopy (MRS) protocols were used to quantify the FF of synthetic phantoms and human participants with obesity using standard acquisition parameters at four sites that had four different 3 T MRI instruments. In addition, a harmonized magnetic resonance elastography (MRE) protocol was used to quantify liver stiffness among participants at two different sites at 1.5 and 3 T field strengths. Data were sent to a single data coordinating site for postprocessing. STATISTICAL TESTS: Linear regression in MATLAB, ICC analyses using SAS 9.4, one-sided 95% confidence intervals for the ICC. RESULTS: PDFF and MRS FF measurements were highly repeatable among sites in both humans and phantoms. MRE measurements of liver stiffness in three individuals at two sites using one 1.5 T and one 3 T instrument showed repeatability that was high although lower than that of MRS and PDFF. CONCLUSIONS: We demonstrated harmonization of PDFF, MRS, and MRE-based quantification of liver fat and stiffness through synthetic phantoms, traveling participants, and standardization of postprocessing analysis. Multisite MRI harmonization could contribute to multisite clinical trials assessing the efficacy of interventions and therapy for NAFLD. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY STAGE: 2.

Race and sex differences in the association between lifespan glycemic status and midlife cognitive function: the Bogalusa heart study.

Introduction: Glycemic markers throughout life are associated with increased risk of midlife cognitive decline, yet it is unclear whether these associations differ by race and sex. Methods: This study used cross-sectional analysis of prospectively maintained cohort. 1,295 participants in the Bogalusa Heart Study, a biracial epidemiological cohort located in a micropolitan area core setting, provided fasting plasma insulin (FPI) and glucose (FPG) biannually from 1973 to 2016. Memory, executive function (EF), attention, working memory (WM), and global cognition (GC), collected 2013-2016. Glycemic markers (i.e., FPG, FPI, and HOMA-IR) averaged within lifespan epochs (≤ 20 years, childhood/adolescence (C/A); 21-40 years, early adulthood (EA); and 40-58 years, midlife). Linear regression models were analyzed for each epoch and separate models were analyzed with sex and race, education as a covariate. Results: Sample was 59% women, 34% African American (AA). Among women, higher C/A FPG was associated with poorer memory and poorer GC. Higher EA FPG was associated with poorer WM. Among men, higher EA HOMA-IR was associated with worse attention. Higher C/A HOMA-IR and FPI were associated with better memory, as was higher EA FPI. Among AA, higher C/A FPG was associated with worse attention, EF, and GC. Higher EA HOMA-IR was associated with worse attention. Higher midlife FPI and C/A HOMA-IR were associated with worse WM and EF among White Americans (WAs). Discussion: Markers indicative of hyperglycemia at different epochs were associated with worse midlife cognition in women, AAs, and WAs; but not in men. Differences in the relationship between lifespan glycemic exposures and midlife cognition could reflect broader health disparities.

Brain Insulin Signaling is Associated with Late-Life Cognitive Decline.

Type-2 diabetes is associated with an increased risk of dementia, and the underlying mechanism might involve abnormal insulin signaling in the brain. The objective of this study was to examine the association of postmortem brain insulin signaling with late-life cognitive decline. Among participants of Religious Orders Study, a community-based clinical-pathological cohort, 150 deceased and autopsied older individuals (75 with diabetes matched to 75 without by age at death, sex, and education) had postmortem brain insulin signaling measurements collected in the prefrontal cortex using ELISA and immunohistochemistry. By using adjusted linear mixed-effects models, we examined the association of postmortem brain insulin signaling with late-life cognitive function assessed longitudinally (mean follow-up duration = 9.4 years) using a battery of neuropsychological tests. We found that a higher level of serine/threonine-protein kinase (AKT) phosphorylation (pT308AKT1/total AKT1) was associated with a faster decline in global cognition (estimate = -0.023, p = 0.030), and three domains: episodic memory (estimate = -0.024, p = 0.032), working memory (estimate = -0.018, p = 0.012), and visuospatial abilities (estimate = -0.013, p = 0.027). The level of insulin receptor substrate-1 (IRS1) phosphorylation (pS307IRS1/total IRS1) was not associated with decline in global cognition or most cognitive domains, except for perceptual speed (estimate = 0.020, p = 0.020). The density of pS616IRS1-stained cells was not associated with decline in global cognition or any of the domains. In conclusion, these findings provide novel evidence for an association between brain insulin signaling and late-life cognitive decline. AKT phosphorylation is associated with a decline in global cognition and memory in particular, whereas IRS1 phosphorylation is associated with a decline in perceptual speed.

Midlife Neuropsychological Profiles and Associated Vascular Risk: The Bogalusa Heart Study.

BACKGROUND: Individuals with Alzheimer's disease (AD) often present with coexisting vascular pathology that is expressed to different degrees and can lead to clinical heterogeneity. OBJECTIVE: To examine the utility of unsupervised statistical clustering approaches in identifying neuropsychological (NP) test performance subtypes that closely correlate with carotid intima-media thickness (cIMT) in midlife. METHODS: A hierarchical agglomerative and k-means clustering analysis based on NP scores (standardized for age, sex, and race) was conducted among 1,203 participants (age 48±5.3 years) from the Bogalusa Heart Study. Regression models assessed the association between cIMT ≥50th percentile and NP profiles, and global cognitive score (GCS) tertiles for sensitivity analysis. RESULTS: Three NP profiles were identified: Mixed-low performance [16%, n = 192], scores ≥1 SD below the mean on immediate, delayed free recall, recognition verbal memory, and information processing; Average [59%, n = 704]; and Optimal [26%, n = 307] NP performance. Participants with greater cIMT were more likely to have a Mixed-low profile [OR = 3.10, 95% CI (2.13, 4.53), p < 0.001] compared to Optimal. After adjusting for education and cardiovascular (CV) risks, results remained. The association with GCS tertiles was more attenuated [lowest (34%, n = 407) versus highest (33%, n = 403) tertile: adjusted OR = 1.66, 95% CI (1.07, 2.60), p = 0.024]. CONCLUSION: As early as midlife, individuals with higher subclinical atherosclerosis were more likely to be in the Mixed-low profile, underscoring the potential malignancy of CV risk as related to NP test performance, suggesting that classification approaches may aid in identifying those at risk for AD/vascular dementia spectrum illness.

Effect of exogenous testosterone in the context of energy deficit on risky choice: Behavioural and neural evidence from males.

Previous research has shown greater risk aversion when people make choices about lives than cash. We tested the hypothesis that compared to placebo, exogenous testosterone administration would lead to riskier choices about cash than lives, given testosterone's association with financial risk-taking and reward sensitivity. A double-blind, placebo-controlled, randomized trial was conducted to test this hypothesis (Clinical Trials Registry: NCT02734238, www.clinicaltrials.gov). We collected functional magnetic resonance imaging (fMRI) data from 50 non-obese males before and shortly after 28 days of severe exercise-and-diet-induced energy deficit, during which testosterone (200 mg testosterone enanthate per week in sesame oil) or placebo (sesame seed oil only) was administered. Because we expected circulating testosterone levels to be reduced due to severe energy deficit, testosterone administration served a restorative function to mitigate the impact of energy deficit on testosterone levels. The fMRI task involved making choices under uncertainty for lives and cash. We also manipulated whether the outcomes were presented as gains or losses. Consistent with prospect theory, we observed the reflection effect such that participants were more risk averse when outcomes were presented as gains than losses. Brain activation in the thalamus covaried with individual differences in exhibiting the reflection effect. Testosterone did not impact choice, but it increased sensitivity to negative feedback following risky choices. These results suggest that exogenous testosterone administration in the context of energy deficit can impact some aspects of risky choice, and that individual differences in the reflection effect engage a brain structure involved in processing emotion, reward and risk.

Effect of renin-angiotensin system antihypertensive medication use on cognitive function in diabetes mellitus with obesity or overweight: An ancillary study to the Action for Health in Diabetes (Look AHEAD) trial.

AIM: To determine whether antihypertensive medication (AHM) acting through the renin angiotensin system (RAS-AHM), compared with other AHM, can mitigate effects on cognitive function and risk for impairment in a population with type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: This secondary analysis of the randomized controlled Action for Health in Diabetes (Look AHEAD) study included 712 community-dwelling participants who were followed over 15 years. Logistic regression was used to relate RAS-AHM use to cognitive impairment, and linear regression was used to relate RAS-AHM use to domain-specific cognitive function after adjusting for potential confounders. RESULTS: A total of 563 individuals reported RAS-AHM use and 149 reported other-AHM use during the study. RAS-AHM users have college or higher education (53%), had higher baseline glycated haemoglobin (57 mmol/mol), and reported higher diabetes medication use (86%), while other-AHM users were more likely to be White (72%), obese (25%) and to have cardiovascular history (19%). RAS-AHM use was not associated with a reduced risk of dementia compared with other-AHM use. We did observe better executive function (Trail Making Test, part B, P < 0.04), processing speed (Digit Symbol Substitution Test, P < 0.004), verbal memory (Rey Auditory Verbal Learning Test-delayed recall, P < 0.005), and composite score (P < 0.008) among RAS-AHM users compared with other-AHM users. CONCLUSION: In this sample of adults with T2DM, free of dementia at baseline, we observed a slower decline in processing speed, executive function, verbal memory, and composite score among RAS-AHM users.

Exercise Effects on Cognition in Older African Americans: A Pilot Randomized Trial.

Introduction: Regular physical activity lowers risk for cognitive decline and neurodegenerative disorders. Older African Americans (AAs) have been underrepresented in trials that increased physical activity to improve cognitive outcomes. Methods: 56 sedentary, older, cognitively healthy AAs (avg. 69.2 ± 3.4 yrs. old) were randomized in 1:1 ratio into either a 12-week successful aging group (SAG) or a 12-week physical activity group (PAG). Participants in SAG attended weekly 60-min educational sessions in which healthy aging topics were discussed. Participants in PAG attended supervised physical activity sessions twice per week at local YMCAs (90-120 min/week) and were prescribed 2-3 days per week of home-based activity. The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) assessed cognitive function. ANCOVA models compared mean 12-week change in global cognition and subdomain scores between groups with secondary analyses for sex differences. Effect sizes for RBANS were calculated. Results: The RBANS global cognition score (SAG Est. 5.6 ± 1.8, effect size = 0.37, p = 0.003) and several subdomain scores (one-sample T tests, all p < 0.05) increased significantly within the SAG. Scores for global cognition increased more in SAG than in PAG (Change Estimate, PAG minus SAG: -4.6 ± 2.5 points, effect size = 0.31) at a trend level (p = 0.072). SAG females increased their global cognition score more than PAG females and more than males in either PAG or SAG (all p < 0.035). Discussion: A 12-week physical activity intervention (PAG) did not improve cognitive functioning among older AAs but a comparator healthy aging education program did. Inadequate physical activity dosage or duration, SAG members acting on health-related information from educational sessions, and/or social stimulation within the SAG may have contributed to these results. Future studies should combine socially engaging activities with vigorous physical activity for cognitive enhancement among cognitively healthy older African Americans. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT03474302.

Impact of COVID-19 Pandemic on Research Participation Among Older African Americans.

COVID-19 represents the newest health disparity faced by African Americans (AA). This study assessed the impact of COVID-19 on barriers and willingness to participate in research among older AAs. An online survey was sent to a nationwide sample of 65- to 85-year-old AAs between January and February 2021. Constant comparison analysis was used to extract themes. A total of 624 older AAs completed the survey. Approximately 40% of participants were willing to engage in virtual or in-person research. Of the individuals who were willing to participate in research, >50% were willing to engage in a spectrum of activities from group discussions to group exercise. Research participation themes related to logistics, technology, pandemic fears, and privacy or security. Older AAs face new research barriers that can be overcome through data use transparency and technology resources. This information can be used to encourage dementia research engagement among older AAs despite the pandemic.

Carotid Intima-Media Thickness and Midlife Cognitive Function: Impact of Race and Social Disparities in the Bogalusa Heart Study.

BACKGROUND AND OBJECTIVES: Carotid intima-media thickness (c-IMT) is a measurement of atherosclerosis, a progressive disease that develops as early as childhood and has been linked with cognitive impairment and dementia in the elderly. However, the relationship between c-IMT and midlife cognitive function and the race and social disparities in this relationship remain unclear. We examined the association between c-IMT and cognitive function in midlife among Black and White participants from a semirural community-based cohort in Bogalusa, Louisiana. METHODS: In this cross-sectional analysis of participants from the Bogalusa Heart Study, linear regression models were used to determine the association between c-IMT dichotomized above the 50th percentile (>0.87 mm), an a demographically standardized global cognitive score (GCS), and individual cognitive domain-based z scores. Stratified analyses were performed to evaluate the impact of race and the individual's education status. RESULTS: A total of 1,217 participants (age 48 ± 5.28 years) were included; 66% (804) self-identified as White, and 34% (413) self-identified as Black. Of those, 58% (708) were women, and 42% (509) were men. Having a c-IMT ≥50th percentile was inversely associated with GCS (B ± SE -0.39 ± 0.18, p = 0.03), independently of cardiovascular risk factors (CVRFs) and achieved education. The effect remained significant in Black and White participants after adjustment for CVRFs (Black participants: B ± SE -1.25 ± 0.45, p = 0.005; White participants: B ± SE -0.92 ± 0.35, p = 0.008) but not for education. The interaction between c-IMT ≥50th percentile and education was significant (p = 0.03), and stratified analysis showed an association with GCS among those with lower achieved education (B ± SE -0.81 ± 0.33, p = 0.013) independently of major CVRFs. DISCUSSION: Subclinical atherosclerosis, measured as c-IMT, was associated with worse midlife cognitive function, independently of major CVRFs. The association was buffered by education and may be stronger among Black than White participants, likely due to corresponding structural and social determinants. These findings underscore the importance of establishing preventive measures in midlife and suggest subclinical atherosclerosis as a potential target to prevent cognitive decline.

Predictors of Post-Exercise Energy Intake in Adolescents Ranging in Weight Status from Overweight to Severe Obesity.

Exercise may sensitize individuals with overweight and obesity to appetitive signals (e.g., hunger and fullness cues), overriding trait eating behaviors that contribute to overeating and obesity, such as uncontrolled eating. The objective of the current study was to measure predictors of objective ad libitum energy intake at a laboratory-based, post-exercise test-meal in adolescents ranging in weight status from overweight to severe obesity. We hypothesized that appetitive states, rather than appetitive traits, would be the strongest predictors of energy intake at a post-exercise test-meal, after controlling for body size. At Baseline, 30 adolescents (ages 10-16 years, 50% female (F), 43% non-Hispanic white (NHW), 83% with obesity (OB)) completed state and trait appetite measures and an ad libitum dinner meal following intensive exercise. Nineteen of those participants (47% F, 32% NHW, 79% OB) completed identical assessments two years later (Year 2). Energy intake (kcal) at each time point was adjusted for fat-free mass index (i.e., body size). Adjusted energy intake was reliable from Baseline to Year 2 (ICC = 0.84). Multiple pre-meal appetite ratings were associated with test-meal energy intake. In stepwise linear regression models, pre-meal prospective food consumption was the strongest and only significant predictor of test-meal energy intake at both Baseline (R2 = 0.25, p = 0.005) and Year 2 (R2 = 0.41, p = 0.003). Baseline post-exercise energy intake was associated with weight change over two years (R2 = 0.24, p = 0.04), but not with change in fat mass (p = 0.11). Appetitive traits were not associated with weight or body composition change (p > 0.22). State appetite cues were the strongest predictors of post-exercise energy intake, independent of body size. Future studies should examine whether long-term exercise programs enhance responsiveness to homeostatic appetite signals in youth with overweight and obesity, with a goal to reduce excess energy intake and risk for weight gain over time.

Practical application of in vivo MRI-based brown adipose tissue measurements in infants.

OBJECTIVE: The role of brown adipose tissue (BAT) in infant metabolism remains poorly understood, primarily because of the inherent limitation of positron emission tomography/computed tomography imaging to measure BAT, which is not suitable for infants. The aims of this method development study were to assess the feasibility, intra-rater reliability, interscan repeatability, and physiological relevance of measuring BAT in infants using magnetic resonance imaging (MRI). METHODS: A total of 10 nonsedated infants (mean age, 22.6 [1.3] days old) completed two 3-T MRI exams using chemical-shift-encoded water-fat scans 6.2 (2.8) days apart. Candidate BAT voxels in the supraclavicular region were identified based on fat signal fraction (FSF). The volumes of BAT depots were manually traced, and FSF was calculated. Whole-body fat mass was determined using dual-energy x-ray absorptiometry. RESULTS: Images were successfully obtained from 19 of 20 (95%) attempted scans. The mean BAT volume was 5.41 (SD 1.1) cm3 , and the mean FSF was 16.41% (SD 3.3%). Intra-rater analysis showed good reliability with no systemic bias (proportional bias for volume: p = 0.19; FSF: p = 0.30). Test-retest for interscan repeatability was good (intraclass correlation coefficients for volume: 0.92, p = 0.001 and intraclass correlation coefficients for FSF: 0.93, p < 0.001). FSF was inversely related to fat-free mass (r = -0.69, p = 0.03). CONCLUSIONS: This method development study supports the use of MRI to obtain reliable and quantitative measurements of BAT volume in infants.

Effects of testosterone administration on fMRI responses to executive function, aggressive behavior, and emotion processing tasks during severe exercise- and diet-induced energy deficit.

BACKGROUND: Clinical administration of testosterone is widely used due to a variety of claimed physical and cognitive benefits. Testosterone administration is associated with enhanced brain and cognitive function, as well as mood, in energy-balanced males, although such relationships are controversial. However, the effects of testosterone administration on the brains of energy-deficient males, whose testosterone concentrations are likely to be well below normal, have not been investigated. METHODS: This study collected functional magnetic resonance imaging (fMRI) data from 50 non-obese young men before (PRE) and shortly after (POST) 28 days of severe exercise-and-diet-induced energy deficit during which testosterone (200 mg testosterone enanthate per week in sesame oil, TEST) or placebo (sesame seed oil only, PLA) were administered. Scans were also collected after a post-energy-deficit weight regain period (REC). Participants completed five fMRI tasks that assessed aspects of: 1) executive function (Attention Network Task or ANT; Multi-Source Interference Task or MSIT; AXE Continuous Processing Task or AXCPT); 2) aggressive behavior (Provoked Aggression Task or AGG); and 3) latent emotion processing (Emotional Face Processing or EMO). RESULTS: Changes over time in task-related fMRI activation in a priori defined task-critical brain regions during performance of 2 out of 5 tasks were significantly different between TEST and PLA, with TEST showing greater levels of activation during ANT in the right anterior cingulate gyrus at POST and during MSIT in several brain regions at REC. Changes over time in objective task performance were not statistically significant; testosterone-treated volunteers had greater self-reported anger during AGG at POST. CONCLUSIONS: Testosterone administration can alter some aspects of brain function during severe energy deficit and increase levels of anger.

The effects of the form of sugar (solid vs. beverage) on body weight and fMRI activation: A randomized controlled pilot study.

OBJECTIVE: To test if sugar sweetened beverages (SSBs) and sugar sweetened solids (SSSs) have differential effects on body weight and reward processing in the brain. METHODS: In a single blind randomized controlled pilot trial (RCT), twenty participants with BMI between 20 and 40 kg/m2 were randomized to consume a 20 fluid ounce soda (SSB, 248 kcal) or the equivalent in solid form (SSS; similar to thick gelatin or gummy candy) daily. At baseline and day 28, fasting body weight and fed-state BOLD fMRI of the brain were assessed. Differences in fMRI signals between views of low-fat (LF (<30%)) high sugar (HS (>30%)) food, and non-food images were calculated in brain regions implicated in energy homeostasis, taste, and reward. RESULTS: All participants in the SSB (6F 4M; 8 Caucasian; 36±14 y, 28.2±5.5 kg/m2; Mean±SD) and SSS (3F 7M; 6 Caucasian; 39±12; 26.3±4.4) groups completed the study. Weight change was 0.27±0.78 kg between SSB and SSS participants. Changes in the fMRI response to LF/HS foods in reward, homeostatic and taste regions tended to not be different between the groups over the four weeks. However, activation of the right substantia nigra increased following the SSB but decreased activation following the SSS in response to LF/HS foods over 28 days (-0.32±0.12). Ratings of wanting for LF/HS foods were correlated with activation in several brain regions, including the OFC. CONCLUSIONS: Change in weight was modest between the groups in this study. Daily consumption of a SSB over 28 days led to mixed responses to LF/HS foods in areas of the brain associated with reward. Ratings of wanting are correlated with fMRI activation inside an MRI scanner.

Neuroimaging, Behavioral, and Gait Correlates of Fall Profile in Older Adults.

Prior research has suggested that measurements of brain functioning and performance on dual tasks (tasks which require simultaneous performance) are promising candidate predictors of fall risk among older adults. However, no prior study has investigated whether brain function measurements during dual task performance could improve prediction of fall risks and whether the type of subtasks used in the dual task paradigm affects the strength of the association between fall characteristics and dual task performance. In this study, 31 cognitively normal, community-dwelling older adults provided a self-reported fall profile (number of falls and fear of falling), completed a gait dual task (spell a word backward while walking on a GaitRite mat), and completed a supine dual task (rhythmic finger tapping with one hand while completing the AX continuous performance task (AX-CPT) with the other hand) during functional magnetic resonance imaging (fMRI). Gait performance, AX-CPT reaction time and accuracy, finger tapping cadence, and brain functioning in finger-tapping-related and AX-CPT-related brain regions all showed declines in the dual task condition compared to the single task condition. Dual-task gait, AX-CPT and finger tapping performance, and brain functioning were all independent predictors of fall profile. No particular measurement domain stood out as being the most strongly associated measure with fall variables. Fall characteristics are determined by multiple factors; brain functioning, motor task, and cognitive task performance in challenging dual-task conditions all contribute to the risk of falling.

Molecular correlates of MRS-based 31 phosphocreatine muscle resynthesis rate in healthy adults.

Dynamic phosphorus MRS (31 P-MRS) is a method used for in vivo studies of skeletal muscle energetics including measurements of phosphocreatine (PCr) resynthesis rate during recovery of submaximal exercise. However, the molecular events associated with the PCr resynthesis rate are still under debate. We assessed vastus lateralis PCr resynthesis rate from 31 P-MRS spectra collected from healthy adults as part of the CALERIE II study (caloric restriction), and assessed associations between PCr resynthesis and muscle mitochondrial signature transcripts and proteins (NAMPT, NQO1, PGC-1α, and SIRT1). Regression analysis indicated that higher concentration of nicotinamide phosphoribosyltransferase (NAMPT) protein, a mitochondrial capacity marker, was associated with faster PCr resynthesis. However, PCr resynthesis was not associated with greater physical fitness (VO2 peak) or messenger ribonucleic acid levels of mitochondrial function markers such as NQO1, PGC-1α, and SIRT1, suggesting that the impact of these molecular signatures on PCr resynthesis may be minimal in the context of an acute exercise bout. Together, these findings suggest that 31 P-MRS based PCr resynthesis may represent a valid non-invasive surrogate marker of mitochondrial NAMPT in human skeletal muscle.