Mitzi M. Gonzales

Insulin sensitivity as a mediator of the relationship between BMI and working memory-related brain activation.

Midlife obesity is associated with cognitive deficits and cerebral atrophy in older age. However, little is known about the early signs of these deleterious brain effects or the physiological mechanisms that underlie them. Functional magnetic resonance imaging (fMRI) allows us to detect early changes in brain response to cognitive challenges while behavioral performance is still intact. Accordingly, we examined the impact of obesity on functional activation during a 2‐Back task in 32 cognitively normal middle‐aged adults, who were classified into normal, overweight, and obese groups according to BMI. Additionally, we examined insulin sensitivity as a potential mediator of the relationship between BMI and brain activation. Insulin sensitivity is of special interest because insulin is strongly associated with both obesity and central nervous system functioning. Group differences in task‐related brain activation were examined in a priori regions of interest (ROIs) using ANOVA. The obese BMI group displayed significantly lower task‐related activation in the right parietal cortex, BA 40/7, (F(2,29) = 5.26, P = 0.011) than the normal (P = 0.016) and overweight (P = 0.047) BMI groups. Linear regression and bootstrapping methods for assessing indirect effects indicated that insulin sensitivity fully mediated the relationship between task‐related activation in the right parietal cortex and BMI ((F(3,28) = 9.03, P = 0.000), β = 0.611, P = 0.001, 95% confidence interval: −2.548 to −0.468). In conclusion, obesity in middle age was related to alterations in brain activation during a cognitive challenge and this association appeared to be mediated by insulin sensitivity.

Central artery stiffness, neuropsychological function, and cerebral perfusion in sedentary and endurance-trained middle-aged adults.

Background: Midlife vascular disease risk is a strong risk factor for late-life dementia. Central arterial stiffness, a hallmark of vascular aging, is associated with accelerated brain aging and cognitive decline. Habitual aerobic exercise is an effective lifestyle strategy to reduce central arterial stiffness and is related to lower risk of cognitive impairment. Objective: To determine the associations among cardiopulmonary fitness, neuropsychological function, central arterial stiffness, and cerebral perfusion in the sedentary and endurance-trained middle-aged adults. Methods: Twenty-six sedentary and 32 endurance-trained middle-aged adults were measured for maximal oxygen consumption, central arterial stiffness determined by aortic pulse wave velocity and carotid ultrasound, neuropsychological function, and regional cerebral blood flow assessed by MRI. Results: There were no group differences in age, sex, ethnicity, education, blood pressure, and carotid intima–media wall thickness (all P > 0.05). Neuropsychological performance and occipitoparietal perfusion were greater, and central arterial stiffness was lower in endurance-trained individuals than in sedentary individuals (all P < 0.05). Greater cardiopulmonary fitness was related to better cognitive composite scores, including memory and attention-executive function (r = 0.28–0.40, P < 0.05). Lower carotid arterial stiffness was associated with better neuropsychological outcome independent of age, sex, and education (r = −0.32 to −0.35, P < 0.05), and correlated with greater occipitoparietal blood flow (r = −0.37 to −0.51, P < 0.05). Conclusion: Lower carotid artery stiffness in endurance-trained adults is associated with better neuropsychological outcome and greater occipitoparietal perfusion.

Indirect Effects of Elevated Body Mass Index on Memory Performance Through Altered Cerebral Metabolite Concentrations

Objective Elevated body mass index (BMI) at midlife is associated with increased risk of cognitive decline in later life. The goal of the current study was to assess mechanisms of early brain vulnerability by examining if higher BMI at midlife affects current cognitive performance through alterations in cerebral neurochemistry. Methods Fifty-five participants, aged 40 to 60 years, underwent neuropsychological testing, health screen, and proton magnetic resonance spectroscopy examining N-acetylaspartate, creatine (Cr), myo-inositol (mI), choline, and glutamate concentrations in occipitoparietal gray matter. Concentrations of N-acetylaspartate, choline, mI, and glutamate were calculated as a ratio over Cr and examined in relation to BMI using multivariate regression analyses. Structural equation modeling was used to determine if BMI had an indirect effect on cognition through cerebral metabolite levels. Results Higher BMI was associated with elevations in mI/Cr (F(5,45) = 3.843, p = .006, &bgr; = 0.444, p = .002), independent of age, sex, fasting glucose levels, and systolic blood pressure. Moreover, a &khgr;2 difference test of the direct and indirect structural equation models revealed that BMI had an indirect effect on global cognitive performance (&Dgr;&khgr;2 = 19.939, df = 2, p < .001). Subsequent follow-up analyses revealed that this effect was specific to memory (&Dgr;&khgr;2 = 22.027, df = 2, p < .001). Conclusions Higher BMI was associated with elevations in mI/Cr concentrations in the occipitoparietal gray matter and indirectly related to poorer memory performance through mI/Cr levels, potentially implicating plasma hypertonicity and neuroinflammation as mechanisms underlying obesity-related brain vulnerability.

Functional MR Imaging Evidence of Altered Functional Activation in Metabolic Syndrome

BACKGROUND AND PURPOSE: MetS is a cluster of risk factors associated with significant cardiovascular morbidity and mortality and diminished cognitive function. Given that little is known about the early signs of brain vulnerability related to persistent metabolic dysfunction, we set out to determine whether cognitively healthy middle-aged individuals with MetS exhibit an altered cerebrovascular response to a cognitive challenge relative to those without MetS. MATERIALS AND METHODS: Forty neurologically healthy adults aged 40–60 years (19 with MetS and 21 healthy controls) performed a 2-back verbal working memory task during fMRI. We compared BOLD responses between the 2 groups in 8 a priori regions of interest previously shown to be associated with the 2-back in patients with cardiovascular disease. RESULTS: Age, education level, sex distribution, cognitive and emotional functioning, and task performance (accuracy and reaction time) were not different between the groups. Compared with healthy controls, individuals with MetS demonstrated a lower 2-back–related BOLD response in the right superior frontal gyrus, right superior parietal lobule, and left inferior parietal lobule. CONCLUSIONS: This study provides preliminary evidence that cognitively intact middle-aged individuals with MetS exhibit significant alterations in cerebrovascular response to a cognitive challenge. Our results also demonstrate that fMRI may identify early brain changes associated with MetS.

Functional imaging of working memory and peripheral endothelial function in middle-aged adults.

The current study examined the relationship between a prognostic indicator of vascular health, flow-mediated dilation (FMD), and working memory-related brain activation in healthy middle-aged adults. Forty-two participants underwent functional magnetic resonance imaging while completing a 2-Back working memory task. Brachial artery endothelial-dependent flow-mediated dilation (FMD) was assessed using B-mode ultrasound. The relationship between FMD and task-related brain activation in a priori regions of interest was modeled using hierarchical linear regression. Brachial FMD, was significantly related to reduced working memory-related activation in the right superior parietal lobule (beta=0.338, p=0.027), independent of age, sex, systolic blood pressure, and full scale IQ (F(5,36)=2.66, p=0.038). These data provide preliminary support for the association between a preclinical marker of endothelial dysfunction and cerebral hemodynamic alterations in healthy middle-aged adults. Considering the modifiable nature of endothelial function, additional investigations on the prognostic significance of FMD on future cognitive impairment are warranted.

Elevated Serum C-Reactive Protein Relates to Increased Cerebral Myoinositol Levels in Middle-Aged Adults

C-reactive protein (CRP), a systemic marker of inflammation, is a risk factor for late life cognitive impairment and dementia, yet the mechanisms that link elevated CRP to cognitive decline are not fully understood. In this study we examined the relationship between CRP and markers of neuronal integrity and cerebral metabolism in middle-aged adults with intact cognitive function, using proton magnetic resonance spectrocospy. We hypothesized that increased levels of circulating CRP would correlate with changes in brain metabolites indicative of early brain vulnerability. Thirty-six individuals, aged 40 to 60, underwent neuropsychological assessment, a blood draw for CRP quantification, and 1H MRS examining N-acetyl-aspartate, myo-inositol, creatine, choline, and glutamate concentrations in occipito-parietal grey matter. Independent of age, sex and education, serum CRP was significantly related to higher cerebral myo-inositol/creatine ratio (F(4,31) = 4.74, P = 0.004), a relationship which remained unchanged after adjustment for cardiovascular risk (F(5,30) = 4.356, CRP β = 0.322, P = 0.045). Because these biomarkers are detectable in midlife they may serve as useful indicators of brain vulnerability during the preclinical period when mitigating intervention is still possible.

Central Adiposity and Cortical Thickness in Midlife.

Objectives Excessive visceral fat is associated with greater metabolic fluctuation and increased risk for dementia in older adults. The aim of the current study is to directly determine the impact of central adiposity on brain structure at midlife by examining the thickness of the cerebral cortex. Methods High-resolution magnetization-prepared rapid acquisition gradient-echo images were obtained from 103 participants aged 40 to 60 years (mean [standard deviation] = 49.63 [6.47] years) on a 3-T Siemens Skyra scanner. Visceral fat was measured using dual-energy x-ray absorptiometry. Results Individuals with higher visceral fat mass and volume had significantly thicker cortex in the right posterior cingulate gyrus (&bgr; = 0.29 [p = .019] and &bgr; = 0.31 [p = .011], respectively), controlling for age, systolic blood pressure, total cholesterol level, and blood glucose level. Conclusions Visceral fat was significantly associated with thicker cortex in the posterior cingulate gyrus. Although future studies are necessary, these results indicate that central adiposity is associated with significant metabolic changes that impinge upon the central nervous system in middle age.

Dyslipidemia links obesity to early cerebral neurochemical alterations

To examine the role of hypertension, hyperglycemia, and dyslipidemia in potentially accounting for obesity‐related brain vulnerability in the form of altered cerebral neurochemistry.

Central adiposity and the functional magnetic resonance imaging response to cognitive challenge

Background:Excessive adipose tissue, particularly with a centralized distribution, propagates hormonal and metabolic disturbance. The detrimental effects of adiposity may extend beyond the periphery and target the central nervous system, increasing vulnerability to cognitive decline. The aim of the current study was to determine how central adiposity impacts the brain at midlife by examining the blood oxygen level-dependent (BOLD) response to a challenging cognitive task.Methods:Seventy-three adults, aged 40–60 years, completed a 2-back verbal working memory task during functional magnetic resonance imaging. Central adiposity was assessed with waist circumference. The association between waist circumference and task-related activation in a priori regions of interest was modeled using bootstrapping regression models corrected for multiple-comparisons.Results:Larger waist circumference was associated with diminished working-memory-related BOLD response in the right superior frontal gyrus (β=−0.008, P=0.001, 95% CI: −0.012 to −0.004) and left middle frontal gyrus (β=−0.009, P=0.002, 95% CI: −0.015 to −0.003), statistically adjusting for age, sex, systolic blood pressure and total cholesterol. Reduced task-related activation in the right superior frontal gyrus (r=−0.369, P=0.002) and left middle frontal gyrus (r=−0.266, P=0.025) were related to slower reaction time on the task, controlling for age and education.Conclusions:Larger waist circumference predicted alterations in the BOLD response that coupled with decrements in task performance. While future studies are necessary, the results suggest that similar to its role in the periphery, central adiposity may be a robust predictor of metabolic and hormonal alterations that impinge upon central nervous system functioning.

Subclinical atherosclerosis is related to lower neuronal viability in middle-aged adults: A 1H MRS study

BACKGROUND Increased carotid artery intima-media thickness (IMT) is a noninvasive marker of systemic arterial disease, associated with atherosclerosis, abnormal arterial mechanics, myocardial infarction, and stroke. In the elderly, clinically elevated IMT is related to diminished attention-executive function. In this context, previous work involving paper-and-pencil measures of cognition has demonstrated that a threshold of pathology (i.e., IMT>or=0.9 mm) is needed before IMT consistently relates to poor neuropsychological test performance. Given the critical role of arterial health in the development of cognitive dysfunction, the goal of this study was to investigate early markers of brain vulnerability by examining subclinical levels of IMT in relation to a sensitive marker of neuronal integrity, cerebral N-acetyl-aspartate/creatine (NAA/Cr) ratio, in midlife. METHODS A total of 40 participants aged 50+/-6 years, underwent neuropsychological assessment, proton magnetic resonance spectroscopy ((1)H MRS) examination of occipitoparietal grey matter and B-mode ultrasound of the common carotid artery. IMT was defined as the distance between the luminal-endothelial interface and the junction between the media and the adventitia. The relation between IMT and cerebral metabolite ratios was modeled using a single multivariate multiple regression analysis adjusted for age and current systolic blood pressure. RESULTS Increased IMT was associated with significantly lower NAA/Cr ratios (IMT beta=-0.62, p=0.001), independent of age and systolic blood pressure (F(3,36)=4.928, p=0.006). CONCLUSIONS Our study extends previous findings by demonstrating a significant relationship between IMT and NAA concentration, suggesting compromised neuronal viability even at IMT levels below thresholds for clinical end-organ damage.