Introduction Precision medicine is a growing topic of research within the medical community. However, the complex factors that influence disease progression and treatment efficacy often make the identification of small subgroups within large clinical populations challenging. Without strategies to identify subgroups that differentially respond to intervention, researchers and clinicians could overlook treatments that may benefit specific aspects within sizable clinical populations. Cerebrovascular disease results from the interaction of multiple risk factors, leading to varying pathologies including stroke and dementia. Identifying subgroups within the scope of cerebrovascular dysfunction risk will allow researchers to better identify individuals at risk for cerebrovascular disease and ultimately inform optimal treatment strategies. Latent mixture modeling (LMM) presents a novel, unbiased method to identify small homogeneous subgroups that have similar traits within the context of large heterogeneous cohorts. Using LMM, it is possible to detect the presence of latent categorical variables which correspond to unobserved subgroups. To assess the feasibility of LMM as a technique for forming subgroups that predict cerebrovascular health, we retrospectively analyzed data from 78 individuals including 12 measures of physical, metabolic, and cognitive health. Our hypothesis was that latent mixture modeling would identify subgroups formed around similar characteristics of physical, metabolic, cognitive, and psychological health. Further, we hypothesized that these subgroups would display differences in cerebrovascular reactivity (CVR). Methods Data from previous experiments conducted in our laboratory between 2018‐2020 were organized and prepared for analysis. Health measures included: body mass index, systolic blood pressure, heart rate, non‐HDL cholesterol, white blood cell count, albumin/globulin ratio, blood glucose, serum creatinine, total recall memory score, and patient‐reported perception of fear and anxiety. CVR was measured by transcranial Doppler ultrasound and calculated as the percent change (from baseline) in middle cerebral artery blood velocity (MCAv) per mmHg following a forced +9mmHg increase in end‐tidal CO2. LMM was used to identify latent classes based on the selected health measures, and then to assess whether CVR differed among the identified classes. The number of classes was picked based after examining a number of criteria including: Akaike, Bayesian, Sample Size Adjusted Bayesian Information Criteria, Entropy, and the VLMR and adjusted VLMR likelihood ratio tests. The BCH procedure was used for post‐hoc comparisons among classes. Results We identified 4 homogeneous subgroup classes within our data. CVR was found to be significantly different when comparing class 1 and class 2 (p= 0.012) and there was a trend towards significance when comparing class 2 and class 4 (p= 0.063). These data suggest that the interaction of healthspan indicators influence differences in cerebrovascular endothelial fun...
The number of persons with Alzheimer’s Disease (AD) is projected to double within the coming decades, placing great emphasis on identifying accessible risk factors. Prior to AD, there is an important transitional phase, called mild cognitive impairment (MCI), where individuals first display objective declines in cognitive functioning. Growing evidence suggests that the risk factors of AD and MCI adversely affect mitochondrial function, presenting a potential measure that may be useful in risk stratification. Metabolic flexibility represents the capacity of the mitochondria to oxidize a variety of fuel substrates (i.e., carbohydrates and fatty acids), and can be assessed using a graded exercise test. Thus, metabolic flexibility may be a useful index of mitochondrial health that can be evaluated prior to the development of clinical AD. OBJECTIVE: To determine whether cardiorespiratory fitness and metabolic flexibility are attenuated in older adults with MCI in response to a graded exercise test. HYPOTHESIS: We hypothesized that individuals with MCI would have similar baseline, but reduced peak oxygen consumption (VO2peak), fat oxidation (FatOx), and carbohydrate oxidation (CHOOx) compared to healthy controls. METHODS: 22 older adults with MCI and 21 sedentary healthy controls (HCs) matched for both age and sex underwent a modified Bruce Protocol treadmill test to assess VO2peak. FatOx and CHOOx were calculated based on ventilatory equivalents using the equations: FatOx = 1.67VO2 - 1.70VCO2 [L/min] and CHOOx = 4.585VO2 - 3.2255VCO2 [L/min], respectively. Unpaired t-tests were conducted to determine whether baseline or peak oxygen consumption, FatOx, and CHOOx were different between groups. RESULTS: The MCI and the HC groups were similar in age (73.5 + 8.81 vs. 71.2 + 6.33, p=0.33) and BMI (26.2 + 4.92 vs. 26.8 + 5.16, p=0.70). Baseline FatOx (0.09 + 0.03 vs. 0.10 + 0.05 g/min, p=0.47) and CHOOx (0.51 + 0.17 vs. 0.59 + 0.21 g/min, p=0.23) were not different between the MCI and HC groups. Peak FatOx (0.31 + 0.13 vs. 0.39 + 0.10 g/min, p=0.018*), and peak CHOOx (1.89 + 0.41 vs. 2.18 + 0.49 g/min, p=0.047*) were lower in the MCI group relative to HCs. Additionally, the MCI group had a lower absolute (1.32 + 0.33 vs. 1.61 + 0.47 L/min, p=0.027*), and relative (22.0 + 5.0 vs. 19.1 + 5.30 mL/kg/min, p=0.070) VO2peak, although the latter was not statistically significant. CONCLUSION: Peak FatOx, CHOOx, and absolute VO2peak are diminished in older adults with MCI, which may suggest impaired whole body mitochondrial capacity and metabolic flexibility. However, future studies are necessary to determine the exact physiological and behavioral components to these observed reductions. Supported by NIH Grants R01 AG058853 and K01 AG054731 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Chronic consumption of a Western diet (WD), high in added sugars and saturated fat (SFA) and low in fiber, contributes to increased cardiometabolic risk parameters, including elevated serum lipids and uric acid (UA). Additionally, long-term WD consumption is negatively associated with cognitive function and brain health. Reductions in cerebral blood flow (CBF) have been observed following acute dietary added sugar and SFA intake; however, the direct acute effects of a Western-style meal on cerebrovascular function and the underlying mechanisms are not fully understood. The purpose of this study was to determine the effects of a single Western-style meal on serum lipids and UA along with cerebrovascular function in healthy young and middle-aged adults. 11 participants [6M/5F, age: 45±14 y (range: 30-64 y); BMI: 26±3 kg/m2; BP: 118±12/74±6 mmHg] were enrolled in this randomized-controlled crossover trial. Participants were randomized to two meals that were similar in total energy (~1280 kcal) and macronutrient content. The experimental WD meal consisted of 61 g added sugars, 26 g SFA (60 g total fat), and 5 g fiber, while the control meal (CM) consisted of 16 g added sugars, 12 g SFA (60 g total fat), and 19 g fiber. Serum lipids and UA were assessed at baseline and 3 hours after consumption of each meal. Cerebrovascular reactivity (CVR) was measured at both timepoints and was assessed as the maximal % change in gray matter CBF during 3-minutes of hypercapnia. CBF was measured using pseudo-continuous arterial spin labeling (PCASL) with a single post-labeling delay and was acquired using a Siemens 3T Prisma MRI scanner. A 2x2 repeated measures ANOVA was used to quantify serum lipids and UA pre- and post-consumption of each meal. An unpaired Mann-Whitney test was used to assess post-meal changes in CVR following the WD meal and CM. Serum triglyceride (Time: p=0.0003; Meal: p=0.57; Interaction: p=0.97) and VLDL-C concentrations (Time: p=0.0005; Meal: p=0.55; Interaction: p=0.81) were higher while HDL-C (Time: p<0.0001; Meal: p=0.17; Interaction: p=0.55) and LDL-C (Time: p=0.0004; Meal: p=0.26; Interaction: p=0.94) were lower after consuming each meal with no main or interaction effect of meal type. Serum UA concentration was reduced following both meals with a greater decrease following the WD meal (Time: p<0.0001; Meal: p=0.35; Interaction: p=0.03). Post-meal % Δ CVR was increased following the WD meal compared to CM [WD (N=10): 1.88 ± 2.86% vs. CM (N=7): -0.31 ± 0.46%; p=0.03]. These results suggest serum UA concentration is reduced and CVR is increased after acute consumption of a WD meal. Future studies should explore the interaction between UA metabolism and cerebrovascular function following an acute WD meal to better understand the mechanism behind the negative association between chronic WD consumption and cognitive function. Grant Support: NIH grants P20GM103653, P20GM113125, K01AG054731 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
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