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 has an effect on current cognitive performance through alterations in cerebral neurochemistry. Methods Fifty-five participants, aged 40–60 years, underwent neuropsychological testing, health screen, and proton magnetic resonance spectroscopy (1H MRS) examining N-acetyl-aspartate (NAA), creatine (Cr), myo-inositol (mI), choline (Cho), and glutamate (Glu) concentrations in occipitoparietal grey matter. Concentrations of NAA, Cho, mI, and Glu 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=0.006, β=0.444, p=0.002), independent of age, sex, fasting glucose levels, and systolic blood pressure. Moreover, a chi-square difference test of the direct and indirect structural equation models revealed that BMI had an indirect effect on global cognitive performance (ΔX2(df=2) =19.939, p<0.001). Subsequent follow-up analyses revealed that this effect was specific to memory (ΔX2(df=2) = 22.027, p<0.001). Conclusions Higher BMI was associated with elevations in mI/Cr concentrations in the occipitoparietal grey matter and indirectly related to poorer memory performance through mI/Cr, potentially implicating plasma hypertonicity and neuroinflammation as mechanisms underlying obesity-related brain vulnerability.

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.

BackgroundExcessive 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 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.MethodsSeventy-three adults, aged 40-60 years, completed a 2-Back verbal working memory task during functional magnetic resonance imaging (fMRI). 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.ResultsLarger 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 - -0.004) and left middle frontal gyrus (β=-0.009, p=0.002, 95% CI: -0.015 - -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.ConclusionsLarger 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.

Objective Metabolic Syndrome (MetS), the clustering of obesity, high blood pressure, and disordered glucose and lipid/lipoprotein metabolism within a single individual, is associated with poorer cognitive function. It has been hypothesized that cognitive impairment in MetS occurs primarily within the context of inflammation. MetS risk factors are also associated with thinning of the cerebral cortex. However, the mechanisms by which MetS and inflammation affect the brain are poorly understood. The present study used statistical mediation to examine the relationship between MetS risk factors, cortical thickness in a priori regions of interest (ROIs) and inflammation. ROIs were chosen from the previous literature. Research Design and Methods Forty-three adults between the ages of 40 and 60 years underwent a health screen, neuropsychological testing and structural magnetic resonance imaging. Serum levels of pro-inflammatory markers (interleukin 1, interleukin 2, interleukin 6 and C-Reactive Protein) were measured using enzyme-linked immunosorbent assays. Results A higher number of MetS risk factors were associated with thinning in the inferior frontal ROI (β=−0.35, p = 0.019) as well as higher levels of serum interleukin 2 (β=0.31, p=0.04). A higher level of serum interleukin 2 was also associated with reduced thickness in the inferior frontal gyrus (β=−0.41, p=0.013). After accounting for the effects of interleukin 2, the number of MetS risk factors was no longer associated with cortical thickness in the inferior frontal gyrus indicating successful statistical mediation. Conclusions The results indicate a potentially important role for inflammation in linking MetS to cortical thinning and cognitive vulnerability.

Older adults with cardiovascular disease (CVD) often complain about cognitive difficulties including reduced processing speed and attention. On cross-sectional examination, such reports relate more closely to mood than to cognitive performance; yet, in longitudinal studies, these complaints have foreshadowed cognitive decline over time. To test the hypothesis that self-reported cognitive difficulties reflect early changes in brain function, we examined cognitive complaints and depression in relation to blood oxygen level dependent (BOLD) response to a cognitive task in middle-aged adults at risk for CVD. Forty-nine adults (ages 40 to 60 years) completed a measure of perceived cognitive dysfunction (Cognitive Difficulties Scale), medical history questionnaire, neuropsychological assessment and functional magnetic resonance imaging (fMRI) during a working memory task. Increased report of cognitive difficulties was significantly associated with weaker task-related activation in the right superior frontal/ middle frontal gyrus (F(4,44) = 3.26; p = .020, CDS ß = -0.39; p = .009) and the right inferior frontal gyrus (F(4,44) = 3.14; p = .024, CDS ß = -0.45; p = .003), independent of age, education, and self-reported depressive symptoms. Lower activation intensity in the right superior frontal gyrus was related to trends toward poorer task performance. Thus, self-reported cognitive difficulties among cognitively normal middle-aged adults may provide important clinical information about early brain vulnerability that should be carefully monitored.

Serial recall from working memory is known to be impaired by the presence of irrelevant background speech, but several prior studies have concluded that the magnitude of the impairment is independent of the phonological relationship between to-be-remembered (TBR) and to-be-ignored (TBI) sources of information. In the present study, we examined the influence of between-stream phonological similarity in serial recall while attending to a heretofore uncontrolled variable, the phonetic feature. We found that TBI items sharing many phonetic features with TBR items produced significantly stronger working-memory impairments than TBI items with minimal phonetic feature overlap. In addition, participants were more likely to report remembering incorrect items that incorporated phonological characteristics of the TBI stream in the high-overlap condition. These findings provide evidence for subphonemic between-stream interactions and suggest that multiple parallel processes contribute to the irrelevant speech effect. We propose that a 2-component model, which combines the assumptions of process- and content-based accounts for the irrelevant speech effect, offers the best explanation for these findings.

Background and Objectives: Thyroid hormones (TH) affect cardiac function through effects on cardiac contractility and systemic vascular resistance. While TH replacement for patients with hypothyroidism might be necessary for restoration of cardiac output after an acute myocardial infarction (AMI), it could theoretically lead to excessively rapid restoration of the metabolic rate. The appropriate management of hypothyroidism in patients with AMI is unknown. We describe the practice patterns in the management of hypothyroidism in the setting of AMI as well as patients’ clinical outcomes. Material and Methods: Retrospective study of patients that were admitted to a tertiary care hospital with AMI and newly diagnosed or uncontrolled hypothyroidism (TSH ≥ 10 mIU/L) between 2011–2018. Eligible patients were identified using diagnosis codes for AMI and laboratory values, followed by medical record review. We categorized patients according to treatment status with TH and by degree of hypothyroidism. Clinical outcomes included: 30-day mortality/readmission, bleeding, stroke, arrhythmia, sudden cardiac death, and new or worsening heart failure. Summary statistics and group comparisons are presented. Results: Sixty-four patients were included, their median age was 64 years and 61% (n = 39) were women. Most of the patients (59%) had a documented history of hypothyroidism. Of these, all were restarted on levothyroxine (LT4) during the index admission when compared to patients without a history of hypothyroidism, of which 54% received LT4 treatment (p = 0.001). The median TSH in those treated with LT4 was higher (25 mIU/L) when compared to those who were not (12 mIU/L), (p = 0.007). Patients who received intravenous LT4 had higher TSH levels and other variables suggesting worse clinical presentation, but these differences were not statistically significant. No statistically significant differences were noted on clinical outcomes according to LT4 treatment status. Conclusion: A history of hypothyroidism and the degree of TSH elevation seem to guide the management of hypothyroidism in patients with AMI. The clinical effect of correcting hypothyroidism in this setting requires further evaluation.

Aims: Given that high cholesterol levels at midlife are a risk factor for future cognitive decline, the goal of the current study was to determine if cholesterol-related alterations in the cerebrovascular response to cognition could be detected at midlife. Methods: Forty adults, aged 40–60 years, performed a 2-Back working memory task during fMRI. The associations between serum total cholesterol, HDL-cholesterol, and total cholesterol/HDL-cholesterol concentrations to task-related activation intensity were modeled using multivariate multiple regression (two-tailed p < 0.02). Results: Higher levels of total cholesterol/HDL-cholesterol related to reduced working memory-related activation intensity in the left inferior parietal lobe, right superior frontal gyrus, and right middle frontal gyrus. Conclusion: These data provide preliminary support for a deleterious effect of elevated total cholesterol/HDL-cholesterol ratio on cerebrovascular support for cognition in midlife.