First Biodistribution Study of [68Ga]Ga-NOTA-Insulin Following Intranasal Administration in Adult Vervet Monkeys.

Background: Intranasal insulin (INI) is being explored as a treatment for Alzheimer's disease (AD). Improved memory, functional ability, and cerebrospinal fluid (CSF) AD biomarker profiles have been observed following INI administration. However, the method of intranasal delivery may significantly affect outcomes. Objective: To show reliable delivery of insulin to the brain using the Aptar Cartridge Pump System (CPS) intranasal delivery system. Methods: To visualize INI biodistribution, we developed a novel PET radiotracer, Gallium 68-radiolabeled (NOTA-conjugated) insulin, [68Ga]Ga-NOTA-insulin. We used the Aptar CPS to administer [68Ga]Ga-NOTA-insulin to anesthetized healthy adult vervet monkeys and measured brain regional activity and whole-body dosimetry following PET/CT scans. Results: We observed brain penetration of [68Ga]Ga-NOTA-insulin following intranasal administration with the Aptar CPS. Radioactive uptake was seen in multiple regions, including the amygdala, putamen, hypothalamus, hippocampus, and choroid plexus. A safety profile and whole-body dosimetry were also established in a second cohort of vervets. Safety was confirmed: vitals remained stable, blood glucose levels were unchanged, and no organ was exposed to more than 2.5 mSv of radioactivity. Extrapolations from vervet organ distribution allowed for estimation of the [68Ga]Ga-NOTA-insulin absorbed dose in humans, and the maximum dose of [68Ga]Ga-NOTA-insulin that can be safely administered to humans was determined to be 185 MBq. Conclusions: The use of [68Ga]Ga-NOTA-insulin as a PET radiotracer is safe and effective for observing brain uptake in vervet monkeys. Further, the Aptar CPS successfully targets [68Ga]Ga-NOTA-insulin to the brain. The data will be essential in guiding future studies of intranasal [68Ga]Ga-NOTA-insulin administration in humans.

Oxygen uptake efficiency slope in 8- to 12-year-old boys and girls.

BACKGROUND: Oxygen uptake efficiency slope (OUES) is an objective physiological measure that can be obtained from a standard graded exercise test. However, there is conflicting evidence regarding sex differences in OUES values in children. Therefore, this study investigated potential sex differences in absolute, ratio-scaled, and allometrically scaled OUES in 8.0- to 12.0-year-old children. METHODS: Retrospective and prospective data of 18 boys and 22 girls were utilized. All participants had undergone familiarization before performing a maximal cycle ergometer test to determine OUES. These values were also ratio-scaled and allometrically scaled to mass and body surface area (BSA). Group differences were tested via independent sample t-tests (or Mann-Whitney U if not normally distributed). RESULTS: Absolute OUES values (VO2 mL∙min-1/log10VE L∙min-1) were significantly higher in boys compared to girls (1860.8±359.3 vs. 1514.3±212.6). When scaled to mass (VO2 mL∙kg-1∙min-1/log10VE L∙kg-1∙min-1), OUES was no longer significantly different between groups, but when scaled to BSA (VO2 mL∙m-2∙min-1/log10VE L∙m-2∙min-1), OUES was significantly higher in the boys than the girls (1414.4±204.2 vs. 1268.9±134.6). When allometry was applied for mass (OUES/mass0.444) boys had significantly higher value than girls (350.8±46.7 vs. 305.0±31.5). CONCLUSIONS: The present study demonstrated that boys had greater OUES values scaled to BSA and allometrically scaled to body mass. These findings provide further evidence of sex differences with OUES values in preadolescent children and implies the need for sex-specific reference values prior to using OUES for the assessment of cardiorespiratory pathology in children.

Targeting immunometabolic pathways for combination therapy in Alzheimer's disease.

The recent success of disease-modifying anti-amyloid monoclonal antibodies in slowing Alzheimer's disease (AD) symptoms has been an exciting step forward for the field. Despite successfully clearing amyloid from the brain, however, only modest symptomatic improvement has been demonstrated, and treatment-related side effects such as amyloid-related imaging abnormalities (ARIA) limit use for some. These limitations suggest that fully efficacious AD treatment may require combination therapy regimens, as are used in other complex disorders such as cancer and HIV. One reasonable strategy may be to use agents that address the biological changes that predict future amyloid accumulation, or accompany amyloid accumulation in preclinical disease states. Immunometabolic pathways, including the insulin signaling pathway, are dysregulated at the earliest stages of AD, concomitant with amyloid accumulation. It is plausible that agents that target these pathways may work synergistically with anti-amyloid therapies to halt AD progression. Insulin signaling is integrally involved in innate and adaptive immune systems, with pleiotropic effects that moderate pro- and anti-inflammatory responses. Metabolic modulators that enhance insulin sensitivity and function, such as GLP-1 receptor agonists, SGLT2 inhibitors, and insulin itself have been shown to improve immune function and reduce chronic inflammation. Additional effects of insulin and metabolic modulators demonstrated in preclinical and clinical studies of AD include increased clearance of amyloid-ß, slowed tau progression, improved vascular function and lipid metabolism, reduced synaptotoxicity, and improved cognitive and functional outcomes. A large number of compounds that treat metabolic disorders have been extensively characterized with respect to mechanism of action and safety, and thus are readily available to be repurposed for combination therapy protocols. Determining the most successful combination regimens of these agents together with disease-modifying therapies, and the appropriate timing of treatment, are promising next steps in the quest to treat and prevent AD.

Effect of maturation on parasympathetic modulation during exercise and recovery.

OBJECTIVES: This study examined the effect of maturation on parasympathetic nervous system (PNS) response from rest to light- to moderate-intensity exercise and recovery from maximal exercise in pre- (n = 10; maturity offset = -3.0 ± 1.2 years; age = 10.1 ± 1.9 years), mid- (n = 9; maturity offset = -0.1 ± 0.6 years; age = 13.7 ± 1.0 years), and postpubertal (n = 10; maturity offset = 1.9 ± 0.6 years; age = 15.6 ± 1.2 years) boys and men (n = 10; age = 24.1 ± 2.0 years). DESIGN: Participants completed seated rest, light-intensity exercise (50% HRmax), and moderate-intensity exercise (65% HRmax). Following moderate-intensity exercise, intensity was ramped to elicit maximal HR and followed by 25 min of seated recovery. Log transformed values for root mean square of successive differences (lnRMSSD), high-frequency power (lnHF) and normalized HF power (lnHFnu) assessed PNS modulation during 3 min of rest, light-intensity exercise, moderate-intensity exercise, and 3-min epochs throughout recovery. RESULTS: During light-intensity exercise, lnRMSSD and lnHF were greater in prepubertal (lnRMSSD = 3.4 ± 0.3 ms; lnHF = 5.4 ± 0.7 ms2) compared to men (lnRMSSD = 2.8 ± 0.5 ms; lnHF = 4.0 ± 0.9 ms2). During moderate-intensity exercise, lnHF differed between prepubertal and men (2.8 ± 1.0 vs. 1.4 ± 1.0 ms2). During recovery, HRV variables were greater in prepubertal compared to postpubertal and men. CONCLUSIONS: Prepubertal boys have reduced PNS withdrawal during light-intensity exercise and greater PNS reactivation following exercise.

Peripheral versus central insulin and leptin resistance: Role in metabolic disorders, cognition, and neuropsychiatric diseases.

Insulin and leptin are classically regarded as peptide hormones that play key roles in metabolism. In actuality, they serve several functions in both the periphery and central nervous system (CNS). Likewise, insulin and leptin resistance can occur both peripherally and centrally. Metabolic disorders such as diabetes and obesity share several key features including insulin and leptin resistance. While the peripheral effects of these disorders are well-known (i.e. cardiovascular disease, hypertension, stroke, dyslipidemia, etc.), the CNS complications of leptin and insulin resistance have come into sharper focus. Both preclinical and clinical findings have indicated that insulin and leptin resistance are associated with cognitive deficits and neuropsychiatric diseases such as depression. Importantly, these studies also suggest that these deficits in neuroplasticity can be reversed by restoration of insulin and leptin sensitivity. In view of these observations, this review will describe, in detail, the peripheral and central functions of insulin and leptin and explain the role of insulin and leptin resistance in various metabolic disorders, cognition, and neuropsychiatric diseases.

Intranasal insulin and orexins to treat age-related cognitive decline.

The intranasal (IN) administration of neuropeptides, such as insulin and orexins, has been suggested as a treatment strategy for age-related cognitive decline (ARCD). Because dysfunctional neuropeptide signaling is an observed characteristic of ARCD, it has been suggested that IN delivery of insulin and/or orexins may restore endogenous peptide signaling and thereby preserve cognition. IN administration is particularly alluring as it is a relatively non-invasive method that directly targets peptides to the brain. Several laboratories have examined the behavioral effects of IN insulin in young, aged, and cognitively impaired rodents and humans. These studies demonstrated improved performance on various cognitive tasks following IN insulin administration. Fewer laboratories have assessed the effects of IN orexins; however, this peptide also holds promise as an effective treatment for ARCD through the activation of the cholinergic system and/or the reduction of neuroinflammation. Here, we provide a brief overview of the advantages of IN administration and the delivery pathway, then summarize the current literature on IN insulin and orexins. Additional preclinical studies will be useful to ultimately uncover the mechanisms underlying the pro-cognitive effects of IN insulin and orexins, whereas future clinical studies will aid in the determination of the most efficacious dose and dosing paradigm. Eventually, IN insulin and/or orexin administration may be a widely used treatment strategy in the clinic for ARCD.

Ratings of Perceived Exertion and Physiological Responses in Children During Exercise.

OMNI ratings of perceived exertion (RPE) and physiological responses in children (n=7 boys, 8 girls, 11.1±1.0 years) were examined during estimation (graded exercise test [GXT] and steady-state) and production (steady-state) trials on a cycle ergometer. Peak oxygen consumption (VO2peak) was determined via a GXT with RPE estimated every 30 s. Later, two 6-min trials were completed: Participants 1) estimated RPE at ~75% of VO2peak, 2) produced a level of exertion corresponding to their RPE at ~75% of VO2peak during the GXT. Data analysis included a one-way MANOVA and a paired t-test. The target intensity during the GXT corresponded to 74.2±2.5% of VO2peak; the steady-state estimation and production trials were performed at 76.5±2.7% and 68.5±14.1% of VO2peak, respectively (p>0.05). Mean RPE at ~75% of VO2peak during the GXT and production trial was 6.7±1.5; during the steady-state estimation trial RPE was 5.8±2.0 (p>0.05). There were no differences (p>0.05) in the physiological responses. Participants estimated RPE similarly at ~75% of VO2peak during both graded and steady-state exercise, but when asked to produce a given RPE, marked variability was observed in physiological responses. These findings may have implications in optimizing exercise prescriptions for children.

Heart Rate Response and Variability Following Maximal Exercise in Overweight Children.

PURPOSE: This study examined heart rate recovery (HRR) and heart rate variability (HRV) following maximal exercise in lean (<85th percentile age- and sex-BMI percentile; n = 11 (♂=5; ♀=6); 10.1 ± 0.7 years) and overweight (≥85th age- and sex-BMI percentile; n = 11 (♂=5; ♀=6); 10.5 ± 1.2 years) children. METHOD: Participants completed a 10-min rest, followed by a graded exercise test to maximal effort. HRV, in the time and frequency domains, was assessed during rest and recovery. Also during recovery, one-minute HRR and the time constant of a monoexponential line of best fit (HRRt) were determined. RESULTS: There were no significant differences in one-minute HRR and HRRt between the lean (56 ± 7 beats∙min-1 and 160.4 ± 80.1 s, respectively) and overweight (51 ± 16 beats∙min-1 and 141.1 ± 58.1 s, respectively) groups. There also were no significant interactions between groups from rest to recovery for any HRV variables. Root mean square of successive differences (RMSSD) and high frequency power (HF) during recovery was 2.05 ± 0.49 ms and 3.30 ± 1.02 ms2 in the lean children, respectively. In the overweight children, RMSSD and HF were 1.88 ± 0.65 ms and 2.94 ± 1.27 ms2, respectively. CONCLUSION: HRR and HRV findings suggest there are no differences in autonomic function during recovery from maximal exercise in lean and obese 8- to 12-year old children.