Novel role of DONSON in CMG helicase assembly during vertebrate DNA replication initiation.

CMG (Cdc45-MCM-GINS) helicase assembly at the replication origin is the culmination of eukaryotic DNA replication initiation. This process can be reconstructed in vitro using defined factors in Saccharomyces cerevisiae; however, in vertebrates, origin-dependent CMG formation has not yet been achieved partly due to the lack of a complete set of known initiator proteins. Since a microcephaly gene product, DONSON, was reported to remodel the CMG helicase under replication stress, we analyzed its role in DNA replication using a Xenopus cell-free system. We found that DONSON was essential for the replisome assembly. In vertebrates, DONSON physically interacted with GINS and Polε via its conserved N-terminal PGY and NPF motifs, and the DONSON-GINS interaction contributed to the replisome assembly. DONSON's chromatin association during replication initiation required the pre-replicative complex, TopBP1, and kinase activities of S-CDK and DDK. Both S-CDK and DDK required DONSON to trigger replication initiation. Moreover, human DONSON could substitute for the Xenopus protein in a cell-free system. These findings indicate that vertebrate DONSON is a novel initiator protein essential for CMG helicase assembly.

Visualizing Ribbon-to-Ribbon Heterogeneity of Chemically Unzipped Wide Graphene Nanoribbons by Silver Nanowire-Based Tip-Enhanced Raman Scattering Microscopy.

Graphene nanoribbons (GNRs), a quasi-one-dimensional form of graphene, have gained tremendous attention due to their potential for next-generation nanoelectronic devices. The chemical unzipping of carbon nanotubes is one of the attractive fabrication methods to obtain single-layered GNRs (sGNRs) with simple and large-scale production.  The authors recently found that unzipping from double-walled carbon nanotubes (DWNTs), rather than single- or multi-walled, results in high-yield production of crystalline sGNRs. However, details of the resultant GNR structure, as well as the reaction mechanism, are not fully understood due to the necessity of nanoscale spectroscopy. In this regard, silver nanowire-based tip-enhanced Raman spectroscopy (TERS) is applied for single GNR analysis and investigated ribbon-to-ribbon heterogeneity in terms of defect density and edge structure generated through the unzipping process.  The authors found that sGNRs originated from the inner walls of DWNTs showed lower defect densities than those from the outer walls. Furthermore, TERS spectra of sGNRs exhibit a large variety in graphitic Raman parameters, indicating a large variation in edge structures. This work at the single GNR level reveals, for the first time, ribbon-to-ribbon heterogeneity that can never be observed by diffraction-limited techniques and provides deeper insights into unzipped GNR structure as well as the DWNT unzipping reaction mechanism.

The Association of Multidimensional Sleep Health With HbA1c and Depressive Symptoms in African American Adults With Type 2 Diabetes.

OBJECTIVE: Sleep is important for diabetes-related health outcomes. Using a multidimensional sleep health framework, we examined the association of individual sleep health dimensions and a composite sleep health score with hemoglobin A1c (HbA1c) and depressive symptoms among African American adults with type 2 diabetes. METHODS: Participants (N = 257; mean age = 62.5 years) were recruited through local churches. Wrist-worn actigraphy and sleep questionnaire data assessed multidimensional sleep health using the RuSATED framework (regularity, satisfaction, alertness, timing, efficiency, duration). Individual sleep dimensions were dichotomized into poor or good sleep health and summed into a composite score. HbA1c was assessed using the DCA Vantage™ Analyzer or A1CNow® Self Check. Depressive symptoms were assessed using the Patient Health Questionnaire (PHQ-9). Regression models examined the association of individual sleep dimensions and composite sleep health with HbA1c and depressive symptoms. RESULTS: Higher composite sleep health scores were associated with a lower likelihood of having greater than minimal depressive symptoms (PHQ-9 ≥ 5) (odds ratio [OR] = 0.578, 95% confidence interval [CI] = 0.461-0.725). Several individual sleep dimensions, including irregularity (OR = 1.013, CI = 1.005-1.021), poor satisfaction (OR = 3.130, CI = 2.095-4.678), and lower alertness (OR = 1.866, CI = 1.230-2.833) were associated with a greater likelihood of having depressive symptoms. Neither composite sleep health scores nor individual sleep dimensions were associated with HbA1c. CONCLUSIONS: Better multidimensional sleep health is associated with lower depressive symptoms among African American adults with type 2 diabetes. Longitudinal research is needed to determine the causal association between multidimensional sleep health and depressive symptoms in this population. TRIAL REGISTRY: ClinicalTrials.gov identifier NCT04282395.

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 (KTR) 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.

Coping With Discrimination Among African Americans With Type 2 Diabetes: Factor Structure and Associations With Diabetes Control, Mental Distress, and Psychosocial Resources.

Introduction: Type 2 diabetes undermines diabetes-related health outcomes among African Americans, who have a disproportionately high incidence of the disease. Experiences of discrimination are common among African Americans and compound diabetes-related stress, exacerbating poor health outcomes. Appropriate use of coping strategies may mitigate the detrimental effect of discrimination on diabetes-related outcomes, but examining associations between coping strategies and health outcomes is needed to inform potential interventions. This study assessed the factor structure of the Coping with Discrimination Scale (CDS) among African American adults with type 2 diabetes and examined associations of CDS subscales with measures of diabetes control, mental distress, and psychosocial resources. Methods: The CDS was administered primarily through churches to African Americans with type 2 diabetes residing in Austin, Texas, and surrounding areas. Data were collected from August 2020 through April 2023. We conducted principal axis factor analysis of the CDS and determined internal consistency for each factor. We computed bivariate and partial correlations between CDS subscales and indicators of diabetes control (hemoglobin A1c, diabetes self-management), mental distress (diabetes distress, perceived stress, depressive symptoms), and psychosocial resources (resilience, social support, self-efficacy). Results: The 284 African American adults (204 women, 80 men) ranged in age from 23 to 86 years (mean [SD] = 62 [11] y). We identified 4 factors: education/advocacy, internalization, strong response, and detachment. Scores were highest for education/advocacy items and lowest for strong response items. Education/advocacy was associated with higher scores on psychosocial resources, whereas detachment was associated with lower scores. Internalization and strong response were associated with higher mental distress. Strong response was associated with higher hemoglobin A1c, and education/advocacy was associated with enhanced diabetes self-management. Conclusion: We suggest health care professionals create culturally tailored interventions that aid individuals in educating others, advocating for themselves, or recognizing situations outside one's control and detaching from responsibility, rather than internalizing experiences of discrimination or engaging in strong responses that upon reflection are detrimental to one's health.

Central arterial stiffening and intracranial atherosclerosis: the atherosclerosis risk in communities neurocognitive study (ARIC-NCS): Aortic stiffness & intracranial atherosclerosis.

OBJECTIVES: Previous studies suggest an association between central arterial stiffness (CAS) and intracranial atherosclerotic disease (ICAD) among Asian participants with stroke or hypertension; this association has not been evaluated in United States populations. We assessed the cross-sectional association of CAS with ICAD presence and burden in late-life, and differences in association by age, sex, and race. MATERIALS AND METHODS: We conducted a cross-sectional analysis of 1,285 Atherosclerosis Risk in Communities Study participants [mean age 75 (standard deviation: 5) years, 38 % male, 20  % Black] at Visit 5 (2011-2013). CAS was measured as carotid-femoral pulse wave velocity (cfPWV) using the Omron VP-1000 Plus. ICAD was assessed using high-resolution vessel wall MRI and MR angiography. We evaluated associations of a 1 standard deviation (SD) cfPWV (3.02 m/s) and high vs. non-high cfPWV (≥ 13.57 m/s vs. < 13.57 m/s) with presence of plaques (yes/no) and plaque number (0, 1-2, and >2) using multivariable logistic and ordinal logistic regression models adjusted for covariates. RESULTS: Each one SD greater cfPWV was associated with higher odds of plaque presence (odds ratio (OR)=1.32, 95 % confidence interval (CI): 1.22, 1.43), and an incrementally higher odds of number of plaques (OR 1-2 vs. 0 plaques = 1.21, 95 % CI: 1.10, 1.33; OR >2 vs. 0 plaques = 1.51, 95 % CI: 1.33,1.71). Results suggested differences by race, with greater magnitude associations among Black participants. CONCLUSIONS: CAS was positively associated with ICAD presence and burden; cfPWV may be a useful subclinical vascular measure for identification of individuals who are at high risk for cerebrovascular disease.

Change in the sub-sesamoid soft tissue thickness under different loading conditions.

[Purpose] To measure the sub-sesamoid soft tissue thickness change from non-loading to self-weight loading conditions. [Participants and Methods] The study included 17 female participants for the study. A questionnaire was used to collect the demographic data and participant anamnesis, such as the presence of foot injuries and diabetes. The measured height and weight were used to calculate the body mass index. Participants were required to stand on an evaluation device from non-loading to 100% loading conditions to measure the sub-sesamoid soft tissue thickness. [Results] Significant differences were observed between the tibial and fibular sub-sesamoid soft tissue thicknesses under non-loading and all loading conditions. Significant soft tissue thinning was observed with a change from non-loading to 25% loading condition. However, no significant differences in the rate of change were observed between the tibial and fibular sub-sesamoid soft tissue thicknesses at 100% loading. [Conclusion] The sub-fibular sesamoid soft tissue was thicker than the sub-tibial sesamoid soft tissue in all loading conditions. The sub-sesamoid soft tissue thickness change was larger during initial loading stage than during the late loading stage, which may be normal in healthy females in their 20s.

Ongoing replication forks delay the nuclear envelope breakdown upon mitotic entry.

DNA replication is a major contributor to genomic instability, and protection against DNA replication perturbation is essential for normal cell division. Certain types of replication stress agents, such as aphidicolin and hydroxyurea, have been shown to cause reversible replication fork stalling, wherein replisome complexes are stably maintained with competence to restart in the S phase of the cell cycle. If these stalled forks persist into the M phase without a replication restart, replisomes are disassembled in a p97-dependent pathway and under-replicated DNA is subjected to mitotic DNA repair synthesis. Here, using Xenopus egg extracts, we investigated the consequences that arise when stalled forks are released simultaneously with the induction of mitosis. Ara-cytidine-5'-triphosphate-induced stalled forks were able to restart with the addition of excess dCTP during early mitosis before the nuclear envelope breakdown (NEB). However, stalled forks could no longer restart efficiently after the NEB. Although replisome complexes were finally disassembled in a p97-dependent manner during mitotic progression whether or not fork stalling was relieved, the timing of the NEB was delayed with the ongoing forks, rather than the stalled forks, and the delay was dependent on Wee1/Myt1 kinase activities. Thus, ongoing DNA replication was found to be directly linked to the regulation of Wee1/Myt1 kinases to modulate cyclin-dependent kinase activities because of which DNA replication and mitosis occur in a mutually exclusive and sequential manner.

Vascular responses to simulated breath-hold diving involving multiple reflexes.

Breath-hold diving evokes a complex cardiovascular response. The degrees of hypertension induced by the diving reflex are substantial and accentuated by the underwater swimming. This condition provides a circulatory challenge to properly buffer and cushion cardiac pulsations. We determined hemodynamic changes during the diving maneuver and hypothesized that central artery compliance would be augmented during simulated breath-hold diving. A total of 20 healthy young adults were studied. Hemodynamics were measured during exercise on a cycle ergometer, apnea, face immersion in cold water (trigeminal stimulation), and simulated breath-hold diving. Arterial compliance was measured by recording the carotid artery diameter from images derived from an ultrasound machine at the cephalic portion of the common carotid artery 1-2 cm proximal to the carotid bulb, whereas arterial pressure waveforms were obtained using an arterial tonometry placed on the contralateral carotid artery and recorded on a data acquisition software. The change in diameter was divided by the change in blood pressure to calculate arterial compliance. Arterial compliance increased with simulated diving compared with rest (P = 0.007) and was elevated compared with exercise and apnea alone (P < 0.01). A significant increase in heart rate was observed with exercise, apnea, and facial immersion when compared with rest (P < 0.001). However, simulated diving brought the heart rate down to resting levels. Cardiac output increased with all conditions (P < 0.001), with an attenuated response during simulated diving compared with exercise and facial immersion (P < 0.05). Mean blood pressure was elevated during all conditions (P < 0.001), with a further elevation observed during simulated diving compared with exercise (P < 0.001), apnea (P = 0.016), and facial immersion (P < 0.001). Total peripheral resistance was decreased during exercise and facial immersion compared with rest (P < 0.001) but was increased during simulated diving compared with exercise (P < 0.001), apnea (P = 0.008), and facial immersion (P = 0.003). We concluded that central artery compliance is augmented during simulated breath-hold diving to help buffer cardiac pulsations.

Hypoxic preconditioning reduces endothelial ischemia-reperfusion injury in older adults.

Sudden blood flow restoration to an ischemic vessel paradoxically damages endothelial cells. Ischemic preconditioning, caused by repeated bouts of brief ischemia using local or remote cuff inflation before reperfusion, attenuates endothelial dysfunction following an ischemia-reperfusion injury in young adults but does not consistently protect endothelial function in older adults prone to ischemic events. Intermittent exposure to systemic hypoxemia, induced via brief bouts of breathing low levels of oxygen, attenuates endothelial dysfunction following an ischemia-reperfusion injury in young adults. The aim of this study was to determine whether systemic hypoxic preconditioning protects against ischemia-reperfusion injury in older adults. Twelve adults (five women, 57 ± 9 yr) participated in this randomized crossover trial. Endothelium-dependent vasodilation was assessed by brachial artery flow-mediated dilation using a semiautomated diagnostic ultrasound system before and after a 20-min blood flow occlusion that was preceded by either intermittent hypoxia, consisting of three 4-min hypoxic cycles at an oxygen saturation of 80% interspersed with 4-min room air cycles, or intermittent normoxia, consisting of three 4-min normoxic cycles separated by 4-min room air cycles. When preceded by intermittent normoxia, ischemia-reperfusion injury reduced flow-mediated dilation by 4.1 ± 2.6% (6.5 ± 1.7 to 2.4 ± 1.7%). In contrast, flow-mediated dilation was reduced by 2.0 ± 1.5% when ischemia-reperfusion injury was preceded by intermittent hypoxia (5.6 ± 1.7 to 3.6 ± 2.3%). In conclusion, hypoxic preconditioning significantly attenuated the reduction in brachial artery flow-mediated dilation induced by an ischemia-reperfusion injury in older adults at greater risk for ischemic events.

Relationship Between Central Artery Stiffness, Brain Arterial Dilation, and White Matter Hyperintensities in Older Adults: The ARIC Study-Brief Report.

[Figure: see text].

Total brachial artery reactivity and incident heart failure and heart failure subtypes: multi-ethnic study of atherosclerosis.

Endothelial dysfunction may be a phenotypic expression of heart failure (HF). Total brachial artery reactivity (TBAR) is a non-invasive measurement of endothelial function that has been associated with increased risk of cardiovascular outcomes. Limited information is currently available on the impact of TBAR on incident HF and its subtypes. The aim of this study was to investigate whether TBAR is associated with overall incident HF, and the two HF subtypes, HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF) in a community-based study. The sample included 5499 participants (45-84 years of age) from the Multi-Ethnic Study of Atherosclerosis who were free of cardiovascular disease at baseline. Brachial artery was imaged via ultrasound after five minutes of cuff occlusion at the right forearm. TBAR was calculated as the difference between maximum and minimum brachial artery diameters following cuff release, divided by the minimum diameter multiplied by 100%. A dichotomous TBAR variable was created based on the median value (below or above 7.9%). Participants with EF ≤ 40% were considered HFrEF and those with EF ≥ 50% were considered HFpEF. Cox proportional hazards regression models were used to calculate hazard ratios (HR) and 95% confidence intervals (CI). Over a mean follow-up period of 12.5 years, incident HF was diagnosed in 250 participants: 98 classified as HFrEF, 106 as HFpEF, and 46 with unknown or borderline EF (41-49%). Crude analysis revealed that those with TBAR below the median had a significantly greater risk of HF (HR 1.46; 95% CI 1.13-1.88, p < 0.01) and HFrEF (HR 1.61; 95% CI 1.07-2.43, p < 0.05). Following adjustment for known HF risk factors (e.g., age, sex, race, blood pressure), the strength of these relationships was attenuated. Borderline significant results were revealed in those with HFpEF (HR 1.43; 95% CI 0.97-2.12, p = 0.06). Kaplan-Meier curves suggest significantly lower risks of developing HF and HFrEF in those with TBAR above the median (log-rank p ≤ 0.05 for both). When examined as a continuous variable, with a cut point of 50% for EF, every 1-standard deviation (9.7%) increase in TBAR resulted in a 19 and 29% decrease in risk of HF (p < 0.05) and HFrEF (p = 0.05), respectively. Lower TBAR values were associated with higher rates of incident HF and HFrEF, suggesting a possible role of endothelial dysfunction in HF pathogenesis. The impact of other known HF risk factors may mediate this relationship, thus further research is warranted.

Under-appreciated and Overlooked Modes of Exercises on Key Vascular Functions.

The arterial system has two primary functions. The conduit function is to transport adequate supply of oxygen and nutrients to the tissues, and the cushioning function is to buffer and cushion the pulsatile pressure exerted by intermittent ventricular contractions. The impairments in these two functions often result from physiological changes characterized by endothelial dysfunction and arterial stiffening. Habitual physical exercise has been advocated to combat these physiological dysfunctions. However, exercise is remarkably diverse, as it can be performed in different media (water, land or snow), seasons (winter or summer), and settings (individual, pair or team). In contrast to mainstream modes of exercise including walking and running, many of the alternative or "minor" forms of exercise have been under-researched by investigators in research fields and overlooked by clinicians and practitioners in clinical settings. It remains largely unknown whether these alternative forms of exercise are associated with favorable changes in arterial stiffness and endothelium-dependent vasodilation. The current review introduces and summarizes research investigations that evaluated the impacts of these under-appreciated and overlooked exercises and their impacts on key markers of vascular functions in humans.

Female and male US Olympic athletes live 5 years longer than their general population counterparts: a study of 8124 former US Olympians.

OBJECTIVE: To quantify US female and male Olympic athletes' longevity and the years of life lost or saved due to multiple causes of death as compared with the US general population. METHODS: Former US athletes who had participated in the summer or winter Olympic Games at least once between 1912 and 2012 were included. Olympians' date of birth, death and the underlying causes of death were certified by the National Death Index. The Olympians' overall and cause-specific mortality were compared with the US general population based on the US life tables, adjusted by sex, period and age. Mortality differences between the populations were quantified using the years lost/years saved (YS) method. RESULTS: 8124 US Olympians (2301 women and 5823 men) lived 5.1 years longer (YS 95% CI 4.3 to 6.0) than the general population, based on 2309 deaths observed (225 women, 2084 men). Different causes of death contributed to longevity for Olympians as follows: 2.2 years were saved (1.9 to 2.5) from cardiovascular diseases (CVDs); cancer, 1.5 years (1.3 to 1.8); respiratory diseases (eg, influenza, pneumonia), 0.8 years (0.7 to 0.9); external causes (eg, accidents, homicides), 0.5 years (0.4 to 0.6); endocrine and metabolic diseases (eg, diabetes, hyperlipidaemia), 0.4 years (0.2 to 0.5) and digestive system diseases (eg, cirrhosis, hepatic failure), 0.3 years (0.2 to 0.4). Mortality rates due to nervous system disorders (eg, Alzheimer's and Parkinsons's diseases) and mental illness (eg, dementia, schizophrenia) were not different from the general population. CONCLUSION: US Olympians lived longer than the general population, an advantage mainly conferred by lower risks of CVD and cancer. Nervous system disorders and mental illness did not differ between US Olympians and the general population.

High hopes: lower risk of death due to mental disorders and self-harm in a century-long US Olympian cohort compared with the general population.

OBJECTIVE: To determine the risk of death due to prominent mental disorders, substance abuse, and self-harm among US Olympians compared with the general population. METHODS: All female (n=2301) and male (n=5823) US Olympians who participated in the summer or winter Games between 1912 and 2012 were followed until 2016. The National Death Index certified their vital statuses and causes of death. We performed a Standard Mortality Ratio (SMR) analysis for all causes studied and applied the years-saved (YS) method to quantify differences in the risk of death for (1) anxiety, depression and self-harm and (2) substance abuse and eating disorders. Additionally, we examined the YS across sports with greater than 100 total deaths and between medalists and non-medalists. RESULTS: US Olympians had a 32% (SMR=0.68, 95% CI 0.49 to 0.91) lower risk of death compared with the general population, resulting in a longevity advantage of 0.21 YS (95% CI 0.14 to 0.29) for deaths by depression, anxiety and self-harm and 0.12 years (95% CI 0.08 to 0.15) for substance abuse and eating disorders. There were no significant differences between medalists and non-medalists, but findings varied by sports. Most sports (eg, athletics, swimming, rowing) had significantly lower risks of deaths than the general population with the exceptions of fencing and shooting. Shooting showed a trend towards a higher risk through suicide by firearm. CONCLUSION: Olympians have a lower risk of death, favouring an increased longevity compared with the general population for mental disorders, substance abuse and suicides.

Association between circulating Galectin-3 and arterial stiffness in older adults.

Background: Galectin-3 (gal-3) is a ß-galactoside-binding lectin associated tissue fibrosis and inflammation. There is limited understanding of the relationship between gal-3 and vascular health. Our aim was to assess the association between gal-3 and arterial stiffness in older adults. Methods: We conducted a cross-sectional study of 4275 participants (mean age of 75 years) from the Atherosclerosis Risk in Communities (ARIC) Study. Central arterial stiffness was measured by carotid-femoral pulse wave velocity (cfPWV). We evaluated the association of gal-3 with cfPWV using multivariable linear regression. Results: The median (interquartile range) gal-3 concentration was 16.5 (13.8, 19.8) ng/mL and mean cfPWV was 1163±303 cm/s. Higher gal-3 concentration was associated with greater central arterial stiffness after adjustment for age, sex, race-center, heart rate, systolic blood pressure, anti-hypertensive medication use, and current smoking status (ß=36.4 cm/s change in cfPWV per log unit change in gal-3; 95% CI: 7.2, 65.5, p=0.015). The association was attenuated after adjusting for additional cardiovascular risk factors (ß=17.3, 95% CI: -14.4, 49.0). Conclusions: In community-dwelling older adults, gal-3 concentration was associated with central arterial stiffness, likely sharing common pathways with traditional cardiovascular risk factors.

Wirelessly powered dielectrophoresis of metal oxide particles using spark-gap Tesla coil.

Wirelessly powered dielectrophoresis (DEP) of metal oxide particles was performed using a spark-gap Tesla coil (TC). The main contribution of this work is the simplification of the conventional DEP setup that requires attaching wires directly to the electrodes. Wireless power from the TC generates a high output frequency and voltage, which corresponds to that used for the DEP. Therefore, a spark-gap TC was built and utilized to conduct the DEP process. Metal oxides (ZnO and Fe2 O3 ) were used as targets for the assembly. The results showed that the wirelessly powered DEP technique via a TC was successful in assembling the metal oxide particles. Positive and negative DEP phenomena were observed. Positive DEP occurred during ZnO assembly, making particles chain grow 0.92 mm toward the sparks within 60 s. Negative DEP was observed during Fe2 O3 assembly, where the repulsion of particles formed a void around the sparks with a 1.45 mm radius. The mechanism of this wireless DEP system is discussed.

Association of insulin resistance, from mid-life to late-life, with aortic stiffness in late-life: the Atherosclerosis Risk in Communities Study.

BACKGROUND: Insulin resistance may contribute to aortic stiffening that leads to end-organ damage. We examined the cross-sectional association and prospective association of insulin resistance and aortic stiffness in older adults without diabetes. METHODS: We analyzed 2571 men and women at Visit 5 (in 2011-2013), and 2350 men and women at repeat examinations from baseline at Visit 1 (in 1987-1989) to Visit 5 (in 2011-2013). Linear regression was used to estimate the difference in aortic stiffness per standard unit of HOMA-IR, TG/HDL-C, and TyG at Visit 5. Linear mixed effects were used to assess if high, as opposed to non-high, aortic stiffness (> 75th percentile) was preceded by a faster annual rate of change in log-HOMA-IR, log-TG/HDL-C, and log-TyG from Visit 1 to Visit 5. RESULTS: The mean age of participants was 75 years, 37% (n = 957) were men, and 17% (n = 433) were African American. At Visit 5, higher HOMA-IR, higher TG/HDL-C, and higher TyG were associated with higher aortic stiffness (16 cm/s per SD (95% CI 6, 27), 29 cm/s per SD (95% CI 18, 40), and 32 cm/s per SD (95% CI 22, 42), respectively). From Visit 1 to Visit 5, high aortic stiffness, compared to non-high aortic stiffness, was not preceded by a faster annual rate of change in log-HOMA-IR from baseline to 9 years (0.030 (95% CI 0.024, 0.035) vs. 0.025 (95% CI 0.021, 0.028); p = 0.15) or 9 years onward (0.011 (95% CI 0.007, 0.015) vs. 0.011 (95% CI 0.009, 0.013); p = 0.31); in log-TG/HDL-C from baseline to 9 years (0.019 (95% CI 0.015, 0.024) vs. 0.024 (95% CI 0.022, 0.026); p = 0.06) or 9 years onward (- 0.007 (95% CI - 0.010, - 0.005) vs. - 0.009 (95% CI - 0.010, - 0.007); p = 0.08); or in log-TyG from baseline to 9 years (0.002 (95% CI 0.002, 0.003) vs. 0.003 (95% CI 0.003, 0.003); p = 0.03) or 9 years onward (0 (95% CI 0, 0) vs. 0 (95% CI 0, 0); p = 0.08). CONCLUSIONS: Among older adults without diabetes, insulin resistance was associated with aortic stiffness, but the putative role of insulin resistance in aortic stiffness over the life course requires further study.

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.