CD8+ T-cell metabolism is related to cerebrovascular reactivity in middle-aged adults.

Cerebrovascular reactivity (CVR) decreases with advancing age, contributing to increased risk of cognitive impairment; however, the mechanisms underlying the age-related decrease in CVR are incompletely understood. Age-related changes to T cells, such as impaired mitochondrial respiration, increased inflammation, likely contribute to peripheral and cerebrovascular dysfunction in animals. However, whether T-cell mitochondrial respiration is related to cerebrovascular function in humans is not known. Therefore, we hypothesized that peripheral T-cell mitochondrial respiration would be positively associated with CVR and that T-cell glycolytic metabolism would be negatively associated with CVR. Twenty middle-aged adults (58 ± 5 yr) were recruited for this study. T cells were separated from peripheral blood mononuclear cells. Cellular oxygen consumption rate (OCR) and extracellular acidification rate (ECAR, a marker of glycolytic activity) were measured using extracellular flux analysis. CVR was quantified using the breath-hold index (BHI), which reflects the change in blood velocity in the middle-cerebral artery (MCAv) during a 30-s breath-hold. In contrast to our hypothesis, we found that basal OCR in CD8+ T cells (ß = -0.59, R2 = 0.27, P = 0.019) was negatively associated with BHI. However, in accordance with our hypothesis, we found that basal ECAR (ß = -2.20, R2 = 0.29, P = 0.015) and maximum ECAR (ß = -50, R2 = 0.24, P = 0.029) were negatively associated with BHI in CD8+ T cells. There were no associations observed in CD4+ T cells. These associations appeared to be primarily mediated by an association with the pressor response to the breath-hold test. Overall, our findings suggest that CD8+ T-cell respiration and glycolytic activity may influence CVR in humans.NEW & NOTEWORTHY Peripheral T-cell metabolism is related to in vivo cerebrovascular reactivity in humans. Higher glycolytic metabolism in CD8+ T cells was associated with lower cerebrovascular reactivity to a breath-hold in middle-aged adults, which is possibly reflective of a more proinflammatory state in midlife.

Structure-Function Dissociations of Human Hippocampal Subfield Stiffness and Memory Performance.

Aging and neurodegenerative diseases lead to decline in thinking and memory ability. The subfields of the hippocampus (HCsf) play important roles in memory formation and recall. Imaging techniques sensitive to the underlying HCsf tissue microstructure can reveal unique structure-function associations and their vulnerability in aging and disease. The goal of this study was to use magnetic resonance elastography (MRE), a noninvasive MR imaging-based technique that can quantitatively image the viscoelastic mechanical properties of tissue to determine the associations of HCsf stiffness with different cognitive domains across the lifespan. Eighty-eight adult participants completed the study (age 23-81 years, male/female 36/51), in which we aimed to determine which HCsf regions most strongly correlated with different memory performance outcomes and if viscoelasticity of specific HCsf regions mediated the relationship between age and performance. Our results revealed that both interference cost on a verbal memory task and relational memory task performance were significantly related to cornu ammonis 1-2 (CA1-CA2) stiffness (p = 0.018 and p = 0.011, respectively), with CA1-CA2 stiffness significantly mediating the relationship between age and interference cost performance (p = 0.031). There were also significant associations between delayed free verbal recall performance and stiffness of both the dentate gyrus-cornu ammonis 3 (DG-CA3; p = 0.016) and subiculum (SUB; p = 0.032) regions. This further exemplifies the functional specialization of HCsf in declarative memory and the potential use of MRE measures as clinical biomarkers in assessing brain health in aging and disease.SIGNIFICANCE STATEMENT Hippocampal subfields are cytoarchitecturally unique structures involved in distinct aspects of memory processing. Magnetic resonance elastography is a technique that can noninvasively image tissue viscoelastic mechanical properties, potentially serving as sensitive biomarkers of aging and neurodegeneration related to functional outcomes. High-resolution in vivo imaging has invigorated interest in determining subfield functional specialization and their differential vulnerability in aging and disease. Applying MRE to probe subfield-specific cognitive correlates will indicate that measures of subfield stiffness can determine the integrity of structures supporting specific domains of memory performance. These findings will further validate our high-resolution MRE method and support the potential use of subfield stiffness measures as clinical biomarkers in classifying aging and disease states.

Effect of acute handgrip and aerobic exercise on wasted pressure effort and arterial wave reflections in healthy aging.

Aging increases arterial stiffness and wave reflections that augment left ventricular wasted pressure effort (WPE). A single bout of exercise may be effective at acutely reducing WPE via reductions in arterial wave reflections. In young adults (YA) acute aerobic exercise decreases, whereas handgrip increases, wave reflections. Whether acute exercise mitigates or exacerbates WPE and arterial wave reflection in healthy aging warrants further examination. The purpose of this study was to determine if there are age-related differences in WPE and wave reflection during acute handgrip and aerobic exercise. When compared with baseline, WPE increased substantially in older adults (OA) during handgrip (5,219 ± 2,396 vs. 7,019 ± 2,888 mmHg·ms, P < 0.001). When compared with baseline, there was a robust reduction in WPE in OA during moderate-intensity aerobic exercise (5,428 ± 2,084 vs. 3,290 ± 1,537 mmHg·ms, P < 0.001), despite absolute WPE remaining higher in OA compared with YA during moderate-intensity aerobic exercise (OA 3,290 ± 1,537 vs. YA 1,188 ± 962 mmHg·ms, P < 0.001). There was no change in wave reflection timing indexed to ejection duration in OA during handgrip (40 ± 6 vs. 38 ± 4%, P = 0.41) or moderate-intensity aerobic exercise (40 ± 5 vs. 42 ± 8%, P = 0.99). Conversely, there was an earlier return of wave reflection in YA during handgrip (60 ± 11 vs. 52 ± 6%, P < 0.001) and moderate-intensity aerobic exercise (59 ± 7 vs. 51 ± 9%, P < 0.001). Changes in stroke volume were not different between groups during handgrip (P = 0.08) or aerobic exercise (P = 0.47). The greater increase in WPE during handgrip and decrease in WPE during aerobic exercise suggest that aortic hemodynamic responses to acute exercise are exaggerated with healthy aging without affecting stroke volume.NEW & NOTEWORTHY We demonstrated that acute aerobic exercise attenuated, whereas handgrip augmented, left ventricular hemodynamic load from wave reflections more in healthy older (OA) compared with young adults (YA) without altering stroke volume. These findings suggest an exaggerated aortic hemodynamic response to acute exercise perturbations with aging. They also highlight the importance of considering exercise modality when examining aortic hemodynamic responses to acute exercise in older adults.

Effect of Aging on the Viscoelastic Properties of Hippocampal Subfields Assessed with High-Resolution MR Elastography.

Age-related memory impairments have been linked to differences in structural brain parameters, including the integrity of the hippocampus (HC) and its distinct hippocampal subfields (HCsf). Imaging methods sensitive to the underlying tissue microstructure are valuable in characterizing age-related HCsf structural changes that may relate to cognitive function. Magnetic resonance elastography (MRE) is a noninvasive MRI technique that can quantify tissue viscoelasticity and may provide additional information about aging effects on HCsf health. Here, we report a high-resolution MRE protocol to quantify HCsf viscoelasticity through shear stiffness, µ, and damping ratio, ξ, which reflect the integrity of tissue composition and organization. HCsf exhibit distinct mechanical properties-the subiculum had the lowest µ and both subiculum and entorhinal cortex had the lowest ξ. Both measures correlated with age: HCsf µ was lower with age (P < 0.001) whereas ξ was higher (P = 0.002). The magnitude of age-related differences in ξ varied across HCsf (P = 0.011), suggesting differential patterns of brain aging. This study demonstrates the feasibility of using MRE to assess HCsf microstructural integrity and suggests incorporation of these metrics to evaluate HC health in neurocognitive disorders.

Cardiometabolic risk factors are associated with immune cell mitochondrial respiration in humans.

Modifiable cardiometabolic risk factors induce the release of proinflammatory cytokines and reactive oxygen species from circulating peripheral blood mononuclear cells (PBMCs), resulting in increased cardiovascular disease risk and compromised immune health. These changes may be driven by metabolic reprogramming of PBMCs, resulting in reduced mitochondrial respiration; however, this has not been fully tested. We aimed to determine the independent associations between cardiometabolic risk factors including BMI, blood pressure, fasting glucose, and plasma lipids with mitochondrial respiration in PBMCs isolated from generally healthy individuals (n = 21) across the adult lifespan (12 men/9 women; age, 56 ± 21 yr; age range, 22-78 yr; body mass index, 27.9 ± 5.7 kg/m2; blood pressure, 123 ± 16/72 ± 10 mmHg; glucose, 90 ± 14 mg/dL; low-density lipoprotein cholesterol (LDL-C), 111 ± 22 mg/dL; and high-density lipoprotein cholesterol (HDL-C), 62 ± 16 mg/dL). PBMCs were isolated from whole blood by density-dependent centrifugation and used to assess mitochondrial function by respirometry. Primary outcomes included basal and maximal oxygen consumption rate (OCR), which were subsequently used to determine spare respiratory capacity and OCR metabolic potential. After we corrected for systolic blood pressure (SBP), diastolic blood pressure (DBP), and blood glucose, LDL-C was negatively associated with maximal respiration (r = -0.56, P = 0.016), spare respiratory capacity (r = -0.58, P = 0.012), and OCR metabolic potential (r = -0.71, P = 0.0011). In addition, SBP was negatively associated with OCR metabolic potential (r = -0.62, P = 0.0056) after we corrected for DBP, blood glucose, and LDL-C. These data suggest a link between blood cholesterol, SBP, and mitochondrial health that may provide insight into how cardiometabolic risk factors contribute to impaired immune cell function.NEW & NOTEWORTHY Independent of other cardiometabolic risk factors, low-density lipoprotein cholesterol, and systolic blood pressure were found to be negatively associated with several parameters of mitochondrial respiration in peripheral blood mononuclear cells of healthy adults. These data suggest that low-density lipoprotein cholesterol and systolic blood pressure may induce metabolic reprogramming of immune cells, contributing to increased cardiovascular disease risk and impaired immune health.

Amino acid and lipid associated plasma metabolomic patterns are related to healthspan indicators with ageing.

Advancing age is associated with impairments in numerous physiological systems, leading to an increased risk of chronic disease and disability, and reduced healthspan (the period of high functioning healthy life). The plasma metabolome is thought to reflect changes in the activity of physiological systems that influence healthspan. Accordingly, we utilized an LC-MS metabolomics analysis of plasma collected from healthy young and older individuals to characterize global changes in small molecule abundances with age. Using a weighted gene correlation network analysis (WGCNA), similarly expressed metabolites were grouped into modules that were related to indicators of healthspan, including clinically relevant markers of morphology (body mass index, body fat, and lean mass), cardiovascular health (systolic/diastolic blood pressure, endothelial function), renal function (glomerular filtration rate), and maximal aerobic exercise capacity in addition to conventional clinical blood markers (e.g. fasting glucose and lipids). Investigation of metabolic classes represented within each module revealed that amino acid and lipid metabolism as significantly associated with age and indicators of healthspan. Further LC-MS/MS targeted analyses of the same samples were used to identify specific metabolites related to age and indicators of healthspan, including methionine and nitric oxide pathways, fatty acids, and ceramides. Overall, these results demonstrate that plasma metabolomics profiles in general, and amino acid and lipid metabolism in particular, are associated with ageing and indicators of healthspan in healthy adults.

Practical alternatives to chronic caloric restriction for optimizing vascular function with ageing.

Calorie restriction (CR) in the absence of malnutrition exerts a multitude of physiological benefits with ageing in model organisms and in humans including improvements in vascular function. Despite the well-known benefits of chronic CR, long-term energy restriction is not likely to be a feasible healthy lifestyle strategy in humans due to poor sustained adherence, and presents additional concerns if applied to normal weight older adults. This review summarizes what is known about the effects of CR on vascular function with ageing including the underlying molecular 'energy- and nutrient-sensing' mechanisms, and discusses the limited but encouraging evidence for alternative pharmacological and lifestyle interventions that may improve vascular function with ageing by mimicking the beneficial effects of long-term CR.

The Vascular Endothelium in Chronic Kidney Disease: A Novel Target for Aerobic Exercise.

Endothelial dysfunction occurs in chronic kidney disease (CKD) and increases the risk for cardiovascular disease. The mechanisms of endothelial dysfunction seem to evolve throughout kidney disease progression, culminating in reduced L-arginine transport and impaired nitric oxide bioavailability in advanced disease. This review examines the hypothesis that aerobic exercise may reverse endothelial dysfunction by improving endothelial cell L-arginine uptake in CKD.

Voluntary wheel running augments aortic l-arginine transport and endothelial function in rats with chronic kidney disease.

Reduced nitric oxide (NO) synthesis contributes to risk for cardiovascular disease in chronic kidney disease (CKD). Vascular uptake of the NO precursor l-arginine (ARG) is attenuated in rodents with CKD, resulting in reduced substrate availability for NO synthesis and impaired vascular function. We tested the effect of 4 wk of voluntary wheel running (RUN) and/or ARG supplementation on endothelium-dependent relaxation (EDR) in rats with CKD. Twelve-week-old male Sprague-Dawley rats underwent ⅚ ablation infarction surgery to induce CKD, or SHAM surgery as a control. Beginning 4 wk following surgery, CKD animals either remained sedentary (SED) or received one of the following interventions: supplemental ARG, RUN, or combined RUN+ARG. Animals were euthanized 8 wk after surgery, and EDR was assessed. EDR was significantly impaired in SED vs. SHAM animals after 8 wk, in response to ACh (10(-9)-10(-5) M) as indicated by a reduced area under the curve (AUC; 44.56 ± 9.01 vs 100 ± 4.58, P < 0.05) and reduced maximal response (Emax; 59.9 ± 9.67 vs. 94.31 ± 1.27%, P < 0.05). AUC was not improved by ARG treatment but was significantly improved above SED animals in both RUN and RUN+ARG-treated animals. Maximal relaxation was elevated above SED in RUN+ARG animals only. l-[(3)H]arginine uptake was impaired in both SED and ARG animals and was improved in RUN and RUN+ARG animals. The results suggest that voluntary wheel running is an effective therapy to improve vascular function in CKD and may be more beneficial when combined with l-arginine.

Cardiac function and tolerance to ischemia-reperfusion injury in chronic kidney disease.

BACKGROUND: Cardiac dysfunction is an independent risk factor of ischemic heart disease and mortality in chronic kidney disease (CKD) patients, yet the relationship between impaired cardiac function and tolerance to ischemia-reperfusion (IR) injury in experimental CKD remains unclear. METHODS: Cardiac function was assessed in 5/6 ablation-infarction (AI) and sham male Sprague-Dawley rats at 20 weeks of age, 8 weeks post-surgery using an isolated working heart system. This included measures taken during manipulation of preload and afterload to produce left ventricular (LV) function curves as well as during reperfusion following a 15-min ischemic bout. In addition, LV tissue was used for biochemical tissue analysis. RESULTS: Cardiac function was impaired in AI animals during preload and afterload manipulations. Cardiac functional impairments persisted post-ischemia in the AI animals, and 36% of AI animals did not recover sufficiently to achieve aortic overflow following ischemia (versus 0% of sham animals). However, for those animals able to withstand the ischemic perturbation, no difference was observed in percent recovery of post-ischemic cardiac function between groups. Urinary NOx (nitrite + nitrate) excretion was lower in AI animals and accompanied by reduced LV endothelial nitric oxide synthase and NOx. LV antioxidants superoxide dismutase-1 and -2 were reduced in AI animals, whereas glutathione peroxidase-1/2 as well as NADPH-oxidase-4 and H(2)O(2) were increased in these animals. CONCLUSIONS: Impaired cardiac function appears to predispose AI rats to poor outcomes following short-duration ischemic insult. These findings could be, in part, mediated by increased oxidative stress via nitric oxide-dependent and -independent mechanisms.

Impaired L-arginine uptake but not arginase contributes to endothelial dysfunction in rats with chronic kidney disease.

Reduced nitric oxide bioavailability contributes to increased cardiovascular disease risk in patients with chronic kidney disease (CKD). Arginase has been implicated as a potential therapeutic target to treat vascular dysfunction by improving substrate availability for endothelial nitric oxide synthase. The purpose of this study was to determine if arginase contributes to endothelial dysfunction in the 5/6 ablation infarction (AI) rat model of CKD. Endothelium-dependent relaxation of aortic rings to acetylcholine was significantly impaired in AI animals versus sham after 8 weeks and was not improved by arginase inhibition (S-(2-Boronoethyl)-L-cysteine hydrochloride) alone or in combination with L-arginine. Additionally, scavenging of superoxide (Tempol, Tempol + L-arginine, Tempol + L-arginine + S-(2-Boronoethyl)-L-cysteine hydrochloride) was not effective, suggesting that a mechanism independent of oxidative stress contributes to endothelium-dependent relaxation in moderate to severe CKD. Aortic uptake of radiolabeled L-arginine was attenuated in AI animals and was associated with a reduced expression of the L-arginine transporter CAT-1. These data suggest that arginase does not contribute to endothelial dysfunction in CKD; however, impaired L-arginine transport may play an important role in diminishing substrate availability for nitric oxide production leading to endothelial dysfunction.

Nicotinamide riboside for peripheral artery disease: the NICE randomized clinical trial.

People with lower extremity peripheral artery disease (PAD) have increased oxidative stress, impaired mitochondrial activity, and poor walking performance. NAD+ reduces oxidative stress and is an essential cofactor for mitochondrial respiration. Oral nicotinamide riboside (NR) increases bioavailability of NAD+ in humans. Among 90 people with PAD, this randomized double-blind clinical trial assessed whether 6-months of NR, with and without resveratrol, improves 6-min walk distance, compared to placebo, at 6-month follow-up. At 6-month follow-up, compared to placebo, NR significantly improved 6-min walk (+7.0 vs. -10.6 meters, between group difference: +17.6 (90% CI: + 1.8,+∞). Among participants who took at least 75% of study pills, compared to placebo, NR improved 6-min walk by 31.0 meters and NR + resveratrol improved 6-min walk by 26.9 meters. In this work, NR meaningfully improved 6-min walk, and resveratrol did not add benefit to NR alone in PAD. A larger clinical trial to confirm these findings is needed.

Nutraceuticals in the Prevention and Therapeutic Treatment of Cardiovascular and Cerebrovascular Disease.

PURPOSE: This review overviews and highlights arterial stiffening as a key physiological process and target for the prevention and/or lowering of cardio- and cerebrovascular disease (collectively CVD) risk. METHODS: We identified nutraceutical approaches from randomized controlled trials and discussed the associated mechanisms by which these compounds lower age-related arterial stiffness. Age-related CVD are the leading cause of mortality in modernized societies. Arterial dysfunction, specifically stiffening of the large elastic arteries during midlife, is a key physiological process resulting in increased CVD risk. Current pharmaceutical approaches for lowering age-related arterial stiffness have limited efficacy, thus highlighting the need to identify novel approaches for lowering arterial stiffness and thereby CVD risk. Lifestyle interventions are a historical first-line approach to prevent and/or lower the adverse arterial stiffening effects observed with aging. Nutraceutical interventions, defined as a food or part of a food providing health benefits, are a nonpharmacological, novel lifestyle approach to lower age-associated arterial stiffness. Therefore, identifying nutraceutical approaches to lower CVD risk is clinically significant. SUMMARY: This review provides a basic, yet essential, understanding for emerging nutraceutical strategies for the prevention and therapeutic treatment of CVD.

Dietary Supplementation With NAD+-Boosting Compounds in Humans: Current Knowledge and Future Directions.

Advancing age and many disease states are associated with declines in nicotinamide adenine dinucleotide (NAD+) levels. Preclinical studies suggest that boosting NAD+ abundance with precursor compounds, such as nicotinamide riboside or nicotinamide mononucleotide, has profound effects on physiological function in models of aging and disease. Translation of these compounds for oral supplementation in humans has been increasingly studied within the last 10 years; however, the clinical evidence that raising NAD+ concentrations can improve physiological function is unclear. The goal of this review was to synthesize the published literature on the effects of chronic oral supplementation with NAD+ precursors on healthy aging and age-related chronic diseases. We identified nicotinamide riboside, nicotinamide riboside co-administered with pterostilbene, and nicotinamide mononucleotide as the most common candidates in investigations of NAD+-boosting compounds for improving physiological function in humans. Studies have been performed in generally healthy midlife and older adults, adults with cardiometabolic disease risk factors such as overweight and obesity, and numerous patient populations. Supplementation with these compounds is safe, tolerable, and can increase the abundance of NAD+ and related metabolites in multiple tissues. Dosing regimens and study durations vary greatly across interventions, and small sample sizes limit data interpretation of physiological outcomes. Limitations are identified and future research directions are suggested to further our understanding of the potential efficacy of NAD+-boosting compounds for improving physiological function and extending human health span.

Vascular determinants of hippocampal viscoelastic properties in healthy adults across the lifespan.

Arterial stiffness and cerebrovascular pulsatility are non-traditional risk factors of Alzheimer's disease. However, there is a gap in understanding the earliest mechanisms that link these vascular determinants to brain aging. Changes to mechanical tissue properties of the hippocampus (HC), a brain structure essential for memory encoding, may reflect the impact of vascular dysfunction on brain aging. We tested the hypothesis that arterial stiffness and cerebrovascular pulsatility are related to HC tissue properties in healthy adults across the lifespan. Twenty-five adults underwent measurements of brachial blood pressure (BP), large elastic artery stiffness, middle cerebral artery pulsatility index (MCAv PI), and magnetic resonance elastography (MRE), a sensitive measure of HC viscoelasticity. Individuals with higher carotid pulse pressure (PP) exhibited lower HC stiffness (ß = -0.39, r = -0.41, p = 0.05), independent of age and sex. Collectively, carotid PP and MCAv PI significantly explained a large portion of the total variance in HC stiffness (adjusted R2 = 0.41, p = 0.005) in the absence of associations with HC volumes. These cross-sectional findings suggest that the earliest reductions in HC tissue properties are associated with alterations in vascular function.

Oral nicotinamide riboside raises NAD+ and lowers biomarkers of neurodegenerative pathology in plasma extracellular vesicles enriched for neuronal origin.

Declining nicotinamide adenine dinucleotide (NAD+ ) concentration in the brain during aging contributes to metabolic and cellular dysfunction and is implicated in the pathogenesis of aging-associated neurological disorders. Experimental therapies aimed at boosting brain NAD+ levels normalize several neurodegenerative phenotypes in animal models, motivating their clinical translation. Dietary intake of NAD+ precursors, such as nicotinamide riboside (NR), is a safe and effective avenue for augmenting NAD+ levels in peripheral tissues in humans, yet evidence supporting their ability to raise NAD+ levels in the brain or engage neurodegenerative disease pathways is lacking. Here, we studied biomarkers in plasma extracellular vesicles enriched for neuronal origin (NEVs) from 22 healthy older adults who participated in a randomized, placebo-controlled crossover trial (NCT02921659) of oral NR supplementation (500 mg, 2x /day, 6 weeks). We demonstrate that oral NR supplementation increases NAD+ levels in NEVs and decreases NEV levels of Aß42, pJNK, and pERK1/2 (kinases involved in insulin resistance and neuroinflammatory pathways). In addition, changes in NAD(H) correlated with changes in canonical insulin-Akt signaling proteins and changes in pERK1/2 and pJNK. These findings support the ability of orally administered NR to augment neuronal NAD+ levels and modify biomarkers related to neurodegenerative pathology in humans. Furthermore, NEVs offer a new blood-based window into monitoring the physiologic response of NR in the brain.

Influence of mild cognitive impairment and body mass index on white matter integrity assessed by diffusion tensor imaging.

Mild cognitive impairment (MCI), a prodromal stage of Alzheimer's disease, is characterized by decreased memory and cognition, which are linked to degenerative changes in the brain. To assess whether white matter (WM) integrity is compromised in MCI, we collected diffusion-weighted images from 60 healthy older adults (OA) (69.16 ± 0.7) and 20 older adults with amnestic MCI (72.45 ± 1.9). WM integrity differences were examined using Tract-Based Spatial Statistics (TBSS). We hypothesized that those with MCI would have diminished WM integrity relative to OA. In a whole-brain comparison, those with MCI showed higher axial diffusivity in the splenium (SCC) and body of the corpus callosum (BCC), superior corona radiata (SCR), and the retrolenticular part of the internal capsule (RLIC) (p's < .05 TFCE-corrected). Additionally, significant between-group connectivity differences were observed using probabilistic tractography between the SCC, chosen from the TBSS results, and forceps major and minor (p-value's < .05). To further relate a physical health indicator to WM alterations, linear regression showed significant interactions between cognitive status and body mass index (BMI) on diffusivity outcome measures from probabilistic tractography (p-value-'s < .05). Additionally, we examined the association between relational memory, BMI, and WM integrity. WM integrity was positively associated with relational memory performance. These findings suggest that these regions may be more sensitive to early markers of neurodegenerative disease and health behaviors, suggesting that modifiable lifestyle factors may affect white matter integrity.

Hippocampal subfield viscoelasticity in amnestic mild cognitive impairment evaluated with MR elastography.

Hippocampal subfields (HCsf) are brain regions important for memory function that are vulnerable to decline with amnestic mild cognitive impairment (aMCI), which is often a preclinical stage of Alzheimer's disease. Studies in aMCI patients often assess HCsf tissue integrity using measures of volume, which has little specificity to microstructure and pathology. We use magnetic resonance elastography (MRE) to examine the viscoelastic mechanical properties of HCsf tissue, which is related to structural integrity, and sensitively detect differences in older adults with aMCI compared to an age-matched control group. Group comparisons revealed HCsf viscoelasticity is differentially affected in aMCI, with CA1-CA2 and DG-CA3 exhibiting lower stiffness and CA1-CA2 exhibiting higher damping ratio, both indicating poorer tissue integrity in aMCI. Including HCsf stiffness in a logistic regression improves classification of aMCI beyond measures of volume alone. Additionally, lower DG-CA3 stiffness predicted aMCI status regardless of DG-CA3 volume. These findings showcase the benefit of using MRE in detecting subtle pathological tissue changes in individuals with aMCI via the HCsf particularly affected in the disease.

Nicotinamide Riboside Supplementation for Treating Elevated Systolic Blood Pressure and Arterial Stiffness in Midlife and Older Adults.

Background: Aging is the primary risk factor for cardiovascular diseases, the leading cause of death worldwide. Age-related increases in systolic blood pressure (SBP) link advancing age to cardiovascular disease risk. A key mechanism mediating the increase in SBP with aging is stiffening of the large elastic arteries, which occurs due to increases in oxidative stress, inflammation, and vascular smooth muscle tone. Nicotinamide adenine dinucleotide (NAD+) is a key molecule in energy metabolism and cellular functioning which declines with advancing age and chronic disease. Dietary supplementation with NAD+ precursors, such as nicotinamide riboside, boosts NAD+ bioavailability and may improve cardiovascular health. Here, we present the protocol for a randomized, controlled trial investigating the efficacy of 3 months of oral supplementation with nicotinamide riboside for decreasing SBP and arterial stiffness in midlife and older adults with initial above-normal (120-159 mmHg) SBP (ClinicalTrials.gov Identifier: NCT03821623). The primary outcome is casual (resting) SBP and secondary outcomes include 24-h SBP and aortic stiffness. Other outcomes include assessment of safety; tolerability; adherence; diastolic BP; systemic NAD+ bioavailability; and circulating biomarkers of oxidative stress, inflammation, and sympathoadrenal activity. Methods: A randomized, double-blind, placebo-controlled, single-site parallel-group design clinical trial will be conducted in 94 (47/group) midlife and older (age ≥ 50 years) adults with initial above-normal SBP. Participants will complete baseline testing and then will be randomized to either nicotinamide riboside (500 mg, 2×/day, NIAGEN®; ChromaDex Inc.) or placebo supplementation. Outcome measures will be assessed again after 3 months of treatment. Discussion: This study is designed to establish the safety and efficacy of the NAD+ boosting compound, nicotinamide riboside, for reducing casual and 24-h SBP and aortic stiffness in midlife and older adults with above-normal SBP at baseline, a population at increased risk of cardiovascular diseases. Clinical Trial Registration: [www.ClinicalTrials.gov], identifier [NCT03821623].