Large Neutral Amino Acids Moderate the Effects of Metabolic Syndrome on Cognitive Performance in Middle-Aged Adults.

INTRODUCTION: Two large neutral amino acids (LNAA), tryptophan and tyrosine, are precursors to cerebral neurotransmitters and are involved in cognitive function. Higher levels of LNAA in young adults are associated with improved cognition, although these associations appear to reverse over time. Given that exposure to metabolic syndrome (MetS) may induce premature cognitive aging, the current project aims to fill the gap in the literature by examining the effect of LNAA on cognitive performance in midlife adults with metabolic risks. METHODS: Eighty-eight adults, ages 40-61 years, participated in this cross-sectional study. LNAA metabolites were quantified, MetS components were measured using high-performance liquid chromatography, and MetS components were assessed in the laboratory. Composite verbal memory and executive functioning scores were computed using principal component analysis. We used linear regression models to test the interaction between LNAA and MetS while covarying for sex, age, and education. RESULTS: The kynurenine/tryptophan ratio moderated the relation between MetS and verbal memory, even after adjusting for relevant covariates. Tyrosine metabolites were not significant moderators of the association between MetS and executive functioning. CONCLUSION: Our findings suggest that the detected weaker memory performance in adults with a high number of MetS components may be related to relative tryptophan depletion and possible decreases in serotonin production. Further investigation is warranted to examine the potential role of LNAA in associations between cognitive performance and metabolic risks over time.

Empirically derived psychosocial-behavioral phenotypes in Black/African American and Hispanic/Latino older adults enrolled in HABS-HD: Associations with AD biomarkers and cognitive outcomes.

INTRODUCTION: Identification of psychosocial-behavioral phenotypes to understand within-group heterogeneity in risk and resiliency to Alzheimer's disease (AD) within Black/African American and Hispanic/Latino older adults is essential for the implementation of precision health approaches. METHODS: A cluster analysis was performed on baseline measures of socioeconomic resources (annual income, social support, occupational complexity) and psychiatric distress (chronic stress, depression, anxiety) for 1220 racially/ethnically minoritized adults enrolled in the Health and Aging Brain Study-Health Disparities (HABS-HD). Analyses of covariance adjusting for sociodemographic factors examined phenotype differences in cognition and plasma AD biomarkers. RESULTS: The cluster analysis identified (1) Low Resource/High Distress (n = 256); (2) High Resource/Low Distress (n = 485); and (3) Low Resource/Low Distress (n = 479) phenotypes. The Low Resource/High Distress phenotype displayed poorer cognition and higher plasma neurofilament light chain; differences between the High Resource/Low Distress and Low Resource/Low Distress phenotypes were minimal. DISCUSSION: The identification of psychosocial-behavioral phenotypes within racially/ethnically minoritized older adults is crucial to the development of targeted AD prevention and intervention efforts.

Lower Body Mass Index at Baseline Is Related to Steeper Cognitive Decline in the Alzheimer's Disease Neuroimaging Initiative Cohort.

OBJECTIVE: Midlife obesity is a risk factor for dementia, whereas obesity in older age may be protective of cognition, a phenomenon known as the "obesity paradox." The mechanisms underlying this phenomenon and the relationship between body mass index (BMI) and cognitive function over time remain unclear. METHODS: In 1399 adults with and without mild cognitive impairment (median age 73.6 years) from the Alzheimer's Disease Neuroimaging Initiative, we modeled the effects of baseline BMI on within-person trajectories of cognitive decline using Latent Growth Curve Modeling. We also tested if the effects of BMI on cognitive decline are global or specific to memory, executive function, or language. RESULTS: Higher baseline BMI was associated with better memory ( ßBMI = 0.06, p < .05) and worse executive function ( ßBMI = -0.05, p < .05) and not associated with language. Independent of baseline diagnosis, higher baseline BMI was associated with slower rate of decline in executive function, memory, and language ( ßBMI = 0.13, 0.12, and 0.12, respectively; p < .01). Higher BMI was not associated with the intercept ( ßBMI = 0.04, p = .059) or change ( ßBMI = 0.04, p = .415) in a global cognitive factor. CONCLUSIONS: We found that higher baseline BMI was associated with slower cognitive decline in participants with and without mild cognitive impairment diagnosis. Higher BMI in this context seems to be protective of cognitive function for people at risk for dementia. Our findings also support domain-specific effects of obesity on various cognitive functions rather than a final common pathway.

Obesity and the Brain: Another Brain-Body Versus Body-Brain Conundrum.

Midlife obesity has been associated with poor cognitive functioning in older age, but the bidirectional pathways linking the brain and excessive adipose tissue require further research. In this issue of Psychosomatic Medicine, two investigations address the brain responses to food-related cues and psychological stressors relevant to obesity. Moazzami and colleagues document the relationship between abdominal obesity and brain responses to stress among patients with coronary artery disease and find that stress-related brain activity plays a potentially important role in the link between psychological distress, food cravings, and eating patterns relevant to obesity. Donofry and colleagues compare food cue-evoked functional connectivity in adults with obesity and report that brain areas involved in impaired self-regulation and reward processing may increase the risk of obesity by influencing decisions regarding diet and exercise. In this editorial, these findings are discussed in the context of brain-obesity interactions and the need for personalized multidisciplinary interventions for obesity. It is possible that functional magnetic resonance imaging and other indices of brain functioning will be useful in tailoring interventions that target weight reduction and/or cognitive functioning and monitoring treatment progress.

Association of Dementia and Vascular Risk Scores With Cortical Thickness and Cognition in Low-risk Middle-aged Adults.

BACKGROUND: Increased risk for the future development of Alzheimer disease begins as early as midlife. Algorithm-based scores, such as the Cardiovascular Risk Factors, Aging and Incidence of Dementia (CAIDE) dementia risk score, and the Framingham general cardiovascular disease (CVD) risk score, have been used to determine future risk for the development of cognitive decline and dementia. We evaluated the association between neuroimaging and cognitive measures with the 2 risk scores in middle-aged, cognitively intact adults (49±6 y). METHODS: In a cohort of 132 participants collected in 2014, magnetic resonance imaging was used to determine measures of cortical thickness in a priori regions of interest and a neuropsychological battery to assess memory and executive function. RESULTS: The CAIDE dementia risk score was significantly and inversely associated with the cortical thickness of the parahippocampal (r=-0.266; P=0.002) and superior frontal gyrus (r=-0.261; P=0.002) despite a considerable percentage of individuals (99.3%) at low risk for CVD. There was a significant negative association between CAIDE and memory (r=-0.251; P=0.003). Framingham general CVD score was not associated with brain structure or cognitive function. CONCLUSIONS: These results indicate that the CAIDE dementia risk score is associated with cortical thickness and cognitive function at midlife in a low-risk population. These data provide insight into subclinical structural and functional changes occurring during midlife associated with future risk for the development of dementia.

Apolipoprotein E genotype moderates the association between dietary polyunsaturated fat and brain function: an exploration of cerebral glutamate and cognitive performance.

Objective: To investigate the effect of Apolipoprotein E (APOE) genotype on the association between dietary polyunsaturated fat (PUFA), cognitive function, and cerebral glutamate. Methods: A participant sample of 122 middle-aged adults were grouped according to APOE genotype (ϵ4 carrier or ϵ4 non-carrier) and asked to record dietary intake for three consecutive days. All participants also underwent neuropsychological testing and a proton magnetic resonance spectroscopy (1H MRS) scan to assess glutamate in the posterior cingulate cortex. Results: Multiple regression analyses revealed a significant interaction between APOE genotype and PUFA intake on memory performance, F(1,113) = 6.749, p = .016. Greater PUFA intake was associated with better memory performance in healthy middle-aged adults who were APOE ϵ4 non-carriers, but not for ϵ4 carriers. Furthermore, there was a significant interaction between APOE genotype and PUFA intake on cerebral glutamate, in that dietary PUFA was associated with greater cerebral glutamate in APOE ϵ4 carriers, but not for ϵ4 non-carriers, F(1,114) = 5.173, p = .025. Conclusions: The findings suggest that PUFA action on the brain differs according to APOE polymorphism and points towards cerebral glutamate as a potential marker of genetic risk for Alzheimer's disease (AD). Early treatment consisting of PUFA supplementation that is tailored to APOE genotype may be an important intervention for the prevention of cognitive decline.

Nutrient intake and cerebral metabolism in healthy middle-aged adults: Implications for cognitive aging.

OBJECTIVES: Growing evidence suggests dietary factors influence cognition, but the effects of nutrient intake on cerebral metabolism in adults are currently unknown. The present study investigated the relationship between major macronutrient intake (fat, carbohydrate, and protein) and cerebral neurochemical profiles in middle-aged adults. METHODS: Thirty-six adults recorded dietary intake for 3 days prior to completing cognitive testing and a proton magnetic resonance spectroscopy (1H-MRS) scan. 1H-MRS of occipitoparietal gray matter was used to assess glutamate (Glu), N-acetyl-aspartate (NAA), choline (Cho), and myo-inositol (mI) relative to creatine (Cr) levels. RESULTS: Regression analyses revealed that high intake of polyunsaturated fatty acids (PUFAs) was associated with lower cerebral Glu/Cr (P = 0.005), and high intake of saturated fat (SFA) was associated with poorer memory function (P = 0.030) independent of age, sex, education, estimated intelligence, total caloric intake, and body mass index. DISCUSSION: In midlife, greater PUFA intake (ω-3 and ω-6) may be associated with lower cerebral glutamate, potentially indicating more efficient cellular reuptake of glutamate. SFA intake, on the other hand, was linked with poorer memory performance. These results suggest that dietary fat intake modification may be an important intervention target for the prevention of cognitive decline.

Higher visceral fat is associated with lower cerebral N-acetyl-aspartate ratios in middle-aged adults.

Excessive adipose tissue, particularly with a central distribution, consists of visceral fat, which is metabolically active and could impinge upon central nervous system functioning. The aim of the current study was to examine levels of visceral adiposity in relation to key cerebral metabolite ratios localized in the occipitoparietal grey matter. Seventy-three adults, aged between 40 and 60 years, underwent structural magnetic resonance imaging and single voxel 1H Magnetic Resonance Spectroscopy (1H MRS). Visceral fat was assessed using Dual Energy X Ray Absorptiometry (DXA). Individuals with higher visceral fat mass and volume had significantly lower ratios of N-acetyl-aspartate to total creatine (phosphocreatine + creatine, PCr + Cr) (NAA/PCr + Cr) (ß = -0.29, p = 0.03, ß = -0.28, p = 0.04). They also had significantly higher ratios of myo-inositol to total creatine (mI/PCr + Cr ) (ß = 0.36, p = 0.01, ß = 0.36, p = 0.01). Visceral fat mass and volume were not significantly related to ratios of glutamate to total creatine (Glu/PCr + Cr). While future studies are necessary, these results indicate central adiposity is associated with metabolic changes that could impinge upon the central nervous system in middle age.

Beneficial neurocognitive effects of transcranial laser in older adults.

Transcranial infrared laser stimulation (TILS) at 1064 nm, 250 mW/cm2 has been proven safe and effective for increasing neurocognitive functions in young adults in controlled studies using photobiomodulation of the right prefrontal cortex. The objective of this pilot study was to determine whether there is any effect from TILS on neurocognitive function in older adults with subjective memory complaint at risk for cognitive decline (e.g., increased carotid artery intima-media thickness or mild traumatic brain injury). We investigated the cognitive effects of TILS in older adults (ages 49-90, n = 12) using prefrontal cortex measures of attention (psychomotor vigilance task (PVT)) and memory (delayed match to sample (DMS)), carotid artery intima-media thickness (measured by ultrasound), and evaluated the potential neural mechanisms mediating the cognitive effects of TILS using exploratory brain studies of electroencephalography (EEG, n = 6) and functional magnetic resonance imaging (fMRI, n = 6). Cognitive performance, age, and carotid artery intima-media thickness were highly correlated, but all participants improved in all cognitive measures after TILS treatments. Baseline vs. chronic (five weekly sessions, 8 min each) comparisons of mean cognitive scores all showed improvements, significant for PVT reaction time (p < 0.001), PVT lapses (p < 0.001), and DMS correct responses (p < 0.05). The neural studies also showed for the first time that TILS increases resting-state EEG alpha, beta, and gamma power and promotes more efficient prefrontal blood-oxygen-level-dependent (BOLD)-fMRI response. Importantly, no adverse effects were found. These preliminary findings support the use of TILS for larger randomized clinical trials with this non-invasive approach to augment neurocognitive function in older people to combat aging-related and vascular disease-related cognitive decline.

Serum Brain-Derived Neurotrophic Factor Mediates the Relationship between Abdominal Adiposity and Executive Function in Middle Age.

OBJECTIVES: Excessive adipose tissue, especially in the abdominal area, is associated with increased risk of dementia in older adults. However, the mechanisms underlying this relationship are poorly understood. As increased adiposity is also associated with lower circulating levels of brain-derived neurotrophic factor (BDNF), a key molecule modulating brain plasticity and neuronal regeneration, we hypothesized that the changes in cognition that occur as a result of excessive abdominal adiposity would be driven by lower levels of circulating BDNF. METHODS: Fasting blood samples were obtained from 60 participants aged 40-60 years (mean±SD=52.3±5.6) and BDNF levels were assessed with an enzyme linked immunosorbent assay. Abdominal adiposity was measured using a ratio of waist circumference to hip circumference (WHR). Participants also completed a neuropsychological assessment battery to assess executive function. Statistical mediation was assessed using traditional causal steps and nonparametric bootstrapping. RESULTS: Higher WHR was significantly associated with poorer performance on the Controlled Oral Word Association (COWA) letter fluency test (ß=-0.489; p=.003) and lower levels of circulating BDNF (ß=-0.345; p=.006). Linear regression and bootstrapping methods indicated that BDNF fully mediated the relationship between WHR and performance on the COWA (ß=0.60; 95% confidence interval [-3.79, -0.26]). CONCLUSIONS: The relationship between higher WHR and verbal fluency was fully statistically mediated by circulating BDNF levels. The BDNF pathway is thus a useful probable mechanism through which executive function decline occurs in individuals with high abdominal adiposity. BDNF enhancing interventions (physical exercise and dietary restriction) could thus be used to improve executive function in these individuals.

Surgical and Nonsurgical Interventions for Obesity in Service of Preserving Cognitive Function.

OBJECTIVES: The purposes of this article are to highlight what is currently known about the mechanisms of obesity-related cognitive impairment and weight loss-related cognitive improvement, and to discuss the benefits and drawbacks of available treatments. METHODS: The article is based on a live debate, presenting the main advantages and disadvantages of exercise interventions and bariatric surgery as related to cognitive functioning. The live debate took place during a 1-day conference, Diabetes, Obesity and the Brain, sponsored by the American Psychosomatic Society in October 2013. RESULTS: Although it is well established that bariatric surgery tends to lead to greater weight loss, better glycemic control, and cognitive improvement (effect sizes ranging between 0.61 and 0.78) during the first 1 to 2 years postintervention compared with nonsurgical treatments, medical complications are possible, and follow-up data beyond 5 years are limited. In contrast, nonsurgical therapies have been extensively studied in a variety of clinical settings and have proved that they can sustain positive health outcomes up to 10 years later, but their cognitive benefits tend to be more modest (effect sizes ranging from 0.18 to 0.69) and long-term regimen compliance, especially in obese individuals, is uncertain. CONCLUSIONS: Rather than focusing on debating whether surgical or no-surgical interventions for obesity are better, additional research is needed to identify the most efficient and practical combination of approaches to ensure sustained positive health outcomes for the largest number of patients 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 (ß = 0.29 [p = .019] and ß = 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.

Polymorphisms of the peroxisome proliferator-activated receptor-γ (rs1801282) and its coactivator-1 (rs8192673) are associated with obesity indexes in subjects with type 2 diabetes mellitus.

UNLABELLED: The aim of this study was to clarify whether common single nucleotide polymorphisms (SNPs) of the Peroxisome Proliferator-Activated Receptor-γ (PPAR-γ) gene (rs1801282) and the Peroxisome Proliferator-Activated Receptor-γ Coactivator-1 (PGC-1α) gene (rs8192673) are associated with obesity indexes (BMI, waist circumference) in subjects with type 2 diabetes mellitus (T2DM) in Caucasian population. The second aim was to find an association of both polymorphisms with T2DM. METHODS: Two exonic SNPs of both genes rs1801282 of the PPAR-γ gene and rs8192673 of the PGC-1α gene) were genotyped in 881 unrelated Slovene subjects (Caucasians) with T2DM and in 348 subjects without T2DM (control subjects). RESULTS: Female homozygotes with the CC genotype of the rs8192673 had higher waist circumference in comparison with subjects with other genotypes. Homozygotes (females, males) with wild allele (Pro) of the rs1801282 (Pro12Ala polymorphism) had higher waist circumference in comparison with subjects with other genotypes. In the study, there were no differences in the distributions of the rs8192673 and the rs1801282 genotypes between patients with T2DM and controls. Linear regression analyses for both polymorphisms were performed and demonstrated an independent effect of the rs1801282 of the PPAR-γ on waist circumference in subjects with T2DM, whereas an independent effect on waist circumference was not demonstrated for the rs8192673 of the PGC-1α gene. CONCLUSIONS: In a large sample of the Caucasians the rs8192673 of the PGC-1α gene and the rs1801282 of the PPAR-γ gene were associated with waist circumference in subjects with T2DM.

Association between cardiovagal baroreflex sensitivity and baseline cerebral perfusion of the hippocampus.

PURPOSE: A failure to control perfusion pressure due to impaired baroreflex sensitivity (BRS) could potentially cause chronic brain hypoperfusion, leading to cognitive dysfunction. The primary aim of this study was to determine whether BRS was associated with regional cerebral blood flow as measured by MRI arterial spin labeling (ASL) technique. METHODS: Baroreflex sensitivity was measured using the Valsalva maneuver technique in 52 middle-aged normotensive adults (49 ± 1 years), and phase IV of the Valsalva maneuver was used for analyses. Cerebral perfusion was measured using the ASL MRI technique in 10 pre-determined brain regions of interest. RESULTS: Hippocampal perfusion was correlated with BRS (R (2) = 0.17, P = 0.01). No association was observed between BRS and cerebral perfusion in the other brain regions of interest. Partial correlational analyses revealed that BRS was an important predictor of hippocampal perfusion, explaining 11 % of the variability independent of other covariates. When participants were divided into tertiles of BRS (11.8 ± 1.9 and 3.5 ± 0.1 ms/mmHg for the highest and lowest tertiles), regional cerebral perfusion of the hippocampus was significantly lower in the lowest BRS tertile than in the highest tertile (39.1 ± 4.3 and 60.5 ± 8.4 ml/100 g/min). CONCLUSIONS: Baroreflex sensitivity in midlife is positively associated with regional cerebral perfusion of the hippocampus, and impaired BRS appears to be related to brain hypoperfusion even in apparently healthy middle-aged adults. Future longitudinal studies based on the present cross-sectional findings may help to further define the relationship between BRS to cognitive dysfunction.

Greater BOLD response to working memory in endurance-trained adults revealed by breath-hold calibration.

BACKGROUND: Cardiorespiratory fitness is associated with increased frontal and parietal activation during executive function tasks. While these findings suggest fitness-related enhancement of neuronal response, the utility of functional magnetic resonance imaging (fMRI) may be limited by potential fitness-related differences in global vascular reactivity. The aim of this study was to determine if highly fit adults display differential activation during working memory after calibration for vascular reactivity relative to their sedentary counterparts. METHODS: Thirty-two endurance-trained and 24 sedentary adults, aged 40-65 years, completed a 2-Back verbal working memory task and a breath-hold challenge during fMRI. Group differences in blood oxygen level-dependent (BOLD) response during working memory were examined across the whole brain and in a priori regions of interest (ROI) before and after breath-hold calibration using non-parametric permutation testing. Multiple regression was used to explore the association between cardiorespiratory fitness (VO2 max), age, and calibrated 2-Back-related activation within the one a priori ROI with significant group effects. RESULTS: In comparison to the endurance-trained group, the sedentary group exhibited greater BOLD signal changes in response to the breath-hold task. After, but not before calibration, the endurance-trained group displayed significantly higher 2-Back-related activation in the right middle frontal gyrus (P = 0.049). Older age predicted lower 2-Back-related activation (ß = -0.308, P = 0.031), whereas fitness predicted higher activation (ß = 0.372, P = 0.021) in this region. CONCLUSIONS: Breath-hold calibration increased detection of working memory-related BOLD response differences between sedentary and endurance-trained adults. Moreover, cardiorespiratory fitness appeared to mitigate age-related changes in BOLD during working memory in this region.

Age exacerbates the negative effect of depression on executive functioning in racial and ethnic minorities.

Age and depression may interact to produce a "double jeopardy" for cognitive impairment, and executive functioning, in cognitively unimpaired aging. Few studies have considered middle age or the ethnoracial diversity of subjects, despite evidence of more severe cognitive outcomes in historically minoritized people. In this pilot study, we investigated the impact of age on depression-related cognitive impairment and the underlying brain volumes in middle-aged non-Hispanic White adults (116), and Hispanic and Black adults (60), with a total number of 176 adults. The result shows a significant interaction between age and depression for executive functioning, specifically for middle-aged Hispanic and Black adults, but not non-Hispanic White adults. Prefrontal cortex volumes, which were reduced in the Black and Hispanic compared to the non-Hispanic White adults, partially mediated the relationship between depression level and executive functioning, across age and ethnoracial group. Collectively, these results suggest that the negative impact of depression on executive functioning and Prefrontal cortex volumes integrity may be exacerbated by age and that historically minoritized people may be particularly sensitive to this double jeopardy.

Interplay of Large Neutral Amino Acids, Metabolic Syndrome, and ApoE ε4 on Brain Integrity at Midlife.

Introduction Large neutral amino acids (LNAA) tryptophan and phenylalanine have been implicated in the pathogenesis of neurodegenerative diseases. Given limited research on the effects of LNAA on brain health across different life stages, vascular risk, and genetic backgrounds, our study aimed to explore the interaction of LNAA levels, metabolic syndrome (MetS), and the presence of the apolipoprotein E ε4 (ApoE ε4) allele brain integrity at midlife. Methods Sixty-eight adults aged 40-61 underwent a health assessment to calculate the number of MetS components, quantify LNAA, measure white matter hyperintensity (WMH) volume, and genotype ApoE ε4. Multivariate linear regression analyses were performed to test the joint effect of LNAA, MetS, and ApoE ε4 on WMH while adjusting for sex, age, and education. Results Significant 3-way interactions were observed between serum tryptophan (ß = 0.042, SE = 0.018, p < 0.05) and phenylalanine (ß = 0.044, SE = 0.013, p < 0.01) levels, number of MetS components, and ApoE ε4 alleles status on WMH volume. Neither individual LNAA levels nor MetS components alone predicted WMH volume. Conclusions The study highlights significant 3-way interactions between LNAA, MetS, and genetic risk factors in the pathology of WMH, particularly in individuals genetically predisposed to Alzheimer's disease. These interactions suggest differential impacts of LNAA on WMH volume dependent on both genetic and metabolic factors. Results emphasize the need for personalized metabolic and genetic profile assessments in neurodegenerative disease management.

Association between Large Neutral Amino Acids and Brain Integrity in Middle-Aged Adults at Metabolic Risk.

This investigation delves into the interplay between large neutral amino acids (LNAA) and metabolic syndrome (MetS) in midlife adults, examining their collective influence on brain structure and cognitive function. While LNAA, such as tryptophan and phenylalanine, are known to bolster cognition in youth, our study hypothesizes a reversal of these benefits in older adults with MetS, potentially signaling premature cognitive aging. Eighty participants between 40-61 years underwent MetS component quantification, LNAA measurement via high-performance liquid chromatography, and brain imaging to evaluate white matter hyperintensity (WMH) volume and medial temporal lobe (MTL) cortical thickness. Our linear regression analysis, adjusting for sex, age, and education, revealed that phenylalanine levels moderated the relationship between MetS and WMH volume (F(6, 69) = 3.134, p < 0.05, R2 = 0.214), suggesting that MetS's cognitive impact may be partly due to phenylalanine catabolism byproducts. However, LNAA metabolites did not significantly modulate the MetS-MTL cortical thickness relationship. The findings suggest that LNAA metabolic dysregulation, marked by elevated levels in the presence of MetS, could correlate with brain structural compromises, particularly in the form of MTL cortical thinning and increased WMH load, detectable in midlife. This nuanced understanding of LNAA's role in cognitive health amid cardiovascular risk factors is pivotal, proposing a potential biomarker for early intervention. Further research is crucial to elucidate the longitudinal influence of LNAA and MetS on brain health, thereby informing strategies to mitigate cognitive decline.

Aerobic fitness and the brain: increased N-acetyl-aspartate and choline concentrations in endurance-trained middle-aged adults.

Engagement in regular aerobic exercise is associated with cognitive benefits, but information on the mechanisms governing these changes in humans is limited. The goal of the current study was to compare neurometabolite concentrations relating to cellular metabolism, structure, and viability in endurance-trained and sedentary middle-aged adults. Twenty-eight endurance-trained and 27 sedentary adults, aged 40-65 years, underwent general health assessment, cardiorespiratory fitness measurement, neuropsychological testing, and proton magnetic resonance spectroscopy ((1)H MRS). (1)H MRS was used to examine N-acetyl-aspartate (NAA), creatine (Cr), myo-inositol (mI), choline (Cho), and glutamate (Glu) concentrations in frontal and occipitoparietal grey matter. Group differences in concentrations of NAA, Cho, mI, and Glu, calculated as ratios over Cr, were explored using ANOVA. There were no significant differences in global cognitive function, memory, and executive function performance between the groups. In comparison to sedentary adults, the endurance-trained group displayed significantly higher NAA/Cr in the frontal grey matter (F(1, 53) = 5.367, p = 0.024) and higher Cho/Cr in the occipitoparietal grey matter (F(1, 53) = 5.138, p = 0.028). Within our middle-aged sample, endurance-trained adults demonstrated higher levels of NAA/Cr in the frontal grey matter and higher Cho/Cr in the occipitoparietal grey matter. Higher levels of NAA may indicate greater neuronal integrity and higher cerebral metabolic efficiency in association with cardiorespiratory fitness, whereas increased Cho may represent increased phospholipid levels secondary to neural plasticity.

Aerobic fitness and cognitive function in midlife: an association mediated by plasma insulin.

Insulin resistance in midlife increases the risk of dementia in late-life. In contrast, habitual aerobic exercise is an established strategy to ameliorate insulin resistance which may translate into better cognitive outcome. To determine the role of plasma insulin in mediating the relation between cardiorespiratory fitness and cognitive function, fifty-eight adults completed assessments of plasma insulin levels, maximal oxygen consumption (VO2max), and neuropsychological test performance. Endurance-trained subjects demonstrated better cognitive outcome (total composite z-score: 0.21 ± 0.08 versus -0.26 ± 0.10, P = 0.001) and lower concentrations of plasma insulin (12.6 ± 0.6 versus 21.3 ± 1.5 ulU/mL, P < 0.001) than sedentary subjects. Greater VO2max was significantly associated with higher memory performance (ß = 0.37, P = 0.01) and lower plasma insulin levels (ß = -0.68, P < 0.001). The significant association between VO2max and memory performance was abolished when the indirect effect of plasma insulin was statistically removed (ß = 0.24, P = 0.19). Fitness-related cognitive enhancement may be mediated, at least in part, by plasma insulin levels.