Acute exercise alters brain glucose metabolism in aging and Alzheimer's disease.

There is evidence that aerobic exercise improves brain health. Benefits may be modulated by acute physiological responses to exercise, but this has not been well characterized in older or cognitively impaired adults. The randomized controlled trial 'AEROBIC' (NCT04299308) enrolled 60 older adults who were cognitively healthy (n = 30) or cognitively impaired (n = 30) to characterize the acute brain responses to moderate [45-55% heart rate reserve (HRR)] and higher (65-75% HRR) intensity acute exercise. Each participant received two fluorodeoxyglucose positron emission tomography (FDG-PET) scans, one at rest and one following acute exercise. Change in cerebral glucose metabolism from rest to exercise was the primary outcome. Blood biomarker responses were also characterized as secondary outcomes. Whole grey matter FDG-PET standardized uptake value ratio (SUVR) differed between exercise (1.045 ± 0.082) and rest (0.985 ± 0.077) across subjects [Diff = -0.060, t(58) = 13.8, P < 0.001] regardless of diagnosis. Exercise increased lactate area under the curve (AUC) [F(1,56) = 161.99, P < 0.001] more in the higher intensity group [mean difference (MD) = 97.0 ± 50.8] than the moderate intensity group (MD = 40.3 ± 27.5; t = -5.252, P < 0.001). Change in lactate AUC and FDG-PET SUVR correlated significantly (R2 = 0.179, P < 0.001). Acute exercise decreased whole grey matter cerebral glucose metabolism. This effect tracked with the systemic lactate response, suggesting that lactate may serve as a key brain fuel during exercise. Direct measurements of brain lactate metabolism in response to exercise are warranted. KEY POINTS: Acute exercise is associated with a drop in global brain glucose metabolism in both cognitively healthy older adults and those with Alzheimer's disease. Blood lactate levels increase following acute exercise. Change in brain metabolism tracks with blood lactate, suggesting it may be an important brain fuel. Acute exercise stimulates changes in brain-derived neurotrophic factor and other blood biomarkers.

Methods to characterize lactate turnover in aging and Alzheimer's disease; The LEAN study.

BACKGROUND: There is evidence that chronic exercise can benefit the brain, but the effects vary markedly between studies. One potential mechanism for exercise-related benefit is the increase in systemic lactate concentration that is well-characterized to occur during exercise. Lactate is known to cross the blood brain barrier and can be used readily as a fuel for neurons. This may be particularly important in Alzheimer's Disease, which is characterized by cerebral hypometabolism. However, little is known about how whole-body lactate metabolism differs between older adults and individuals with cognitive impairment. This information is critical when considering potential differences in responses to exercise in various cognitive diagnosis groups. METHODS: Here we describe the use of a "lactate clamp" procedure to adjust blood lactate levels to approximate those achieved during exercise, but while at rest. This trial will compare lactate oxidation between cognitively healthy older adults and cognitively impaired participants. We will further evaluate the effect of acute lactate infusion on cognitive performance. DISCUSSION: The findings of the study described here, the Lactate for Energy and Neurocognition trial (clinicaltrials.gov # NCT05207397) will add to our understanding of systemic lactate mechanics in cognitively healthy older adults and individuals with Alzheimer's Disease. These findings will be applicable to ongoing exercise trials and to future studies aimed at modulating systemic bioenergetic function in aging and Alzheimer's Disease.

Relationship of Muscle Apolipoprotein E Expression with Markers of Cellular Stress, Metabolism, and Blood Biomarkers in Cognitively Healthy and Impaired Older Adults.

BACKGROUND: Individuals with mild cognitive impairment (MCI) have reduced lipid-stimulated mitochondrial respiration in skeletal muscle. A major risk factor for Alzheimer's disease (AD), the apolipoprotein E4 (APOE4) allele, is implicated in lipid metabolism and is associated with metabolic and oxidative stress that can result from dysfunctional mitochondria. Heat shock protein 72 (Hsp72) is protective against these stressors and is elevated in the AD brain. OBJECTIVE: Our goal was to characterize skeletal muscle ApoE and Hsp72 protein expression in APOE4 carriers in relationship to cognitive status, muscle mitochondrial respiration and AD biomarkers. METHODS: We analyzed previously collected skeletal muscle tissue from 24 APOE4 carriers (60y+) who were cognitively healthy (CH, n = 9) or MCI (n = 15). We measured ApoE and Hsp72 protein levels in muscle and phosphorylated tau181 (pTau181) levels in plasma, and leveraged previously collected data on APOE genotype, mitochondrial respiration during lipid oxidation, and VO2 max. RESULTS: Muscle ApoE (p = 0.013) and plasma pTau181 levels (p < 0.001) were higher in MCI APOE4 carriers. Muscle ApoE positively correlated with plasma pTau181 in all APOE4 carriers (R2 = 0.338, p = 0.003). Hsp72 expression negatively correlated with ADP (R2 = 0.775, p = <0.001) and succinate-stimulated respiration (R2 = 0.405, p = 0.003) in skeletal muscle of MCI APOE4 carriers. Plasma pTau181 negatively tracked with VO2 max in all APOE4 carriers (R2 = 0.389, p = 0.003). Analyses were controlled for age. CONCLUSION: This work supports a relationship between cellular stress in skeletal muscle and cognitive status in APOE4 carriers.

Heat Therapy Can Improve Hepatic Mitochondrial Function and Glucose Control.

This review proposes the novel hypothesis that heat can be used as an alternative therapy to exercise to improve hepatic mitochondrial function and glucose regulation in patients with nonalcoholic fatty liver disease. Although exercise has proven benefits in treating nonalcoholic fatty liver disease, barriers to exercise in the majority of patients necessitate an alternative method of treatment.

Feasibility of a Weight Management Program Tailored for Overweight Men with Localized Prostate Cancer - A Pilot Study.

BACKGROUND: Overweight men with prostate cancer are more likely to suffer from recurrence and death following prostatectomy compared with healthy weight men. This study tested the feasibility of delivering a comprehensive program to foster weight loss before and weight maintenance after surgery in overweight men with localized prostate cancer. METHODS: Twenty overweight men scheduled for prostatectomy elected either the intervention (n = 15) or the nonintervention (n = 5). Anthropometrics, biomarkers, diet quality, nutrition literacy, quality of life, and long-term follow-up were assessed in both groups. RESULTS: The intervention led to 5.55 kg of weight loss including 3.88 kg of fat loss from baseline to surgery (mean = 8.3 weeks). The intervention significantly increased fiber, protein, fruit, nut, and vegetable intake; and decreased trans fats intake during weight loss. The intervention significantly reduced insulin, C-peptide, systolic blood pressure, leptin:adiponectin ratio, and visceral adiposity compared to the nonintervention. Post-surgically, weight loss was maintained. Changes in lipid profiles, nutrition literacy, and follow-up were not statistically significant in either group. CONCLUSION: Significant weight loss (≥5%) is feasible with a coaching intervention in overweight men preparing for prostatectomy and is associated with favorable cardiometabolic effects. This study is registered under NCT02252484 (www.clinicaltrials.gov).