Age-dependent Effects Research Articles

Supplemental Material for Age-Dependent Effects of Schizophrenia Genetic Risk on Cortical Thickness and Cortical Surface Area: Evaluating Evidence for Neurodevelopmental and Neurodegenerative Models of Schizophrenia

Supplemental Material for Age-Dependent Effects of Schizophrenia Genetic Risk on Cortical Thickness and Cortical Surface Area: Evaluating Evidence for Neurodevelopmental and Neurodegenerative Models of Schizophrenia

Age-dependent effects of a high-fat diet combined with dietary advanced glycation end products on cognitive function and protection with voluntary exercise.

To determine whether a high fat diet (HFD) combined with an advanced glycation end products (AGEs) diet will induce worse cognitive impairment than a HFD alone and to investigate whether voluntary exercise is capable of improving cognitive function after the combined diet, young and middle-aged male C57BL/6J mice were randomly assigned to four groups, i.e., control, HFD, combined diet, and combined diet treated with voluntary exercise. Compared to HFD, combined diet induced worse memory abilities only in middle-aged mice, as exhibited by the reduced number of crossings and reduced distance in the target zone during a probe trial. Exercise reversed combined-diet-induced cognitive impairment for both ages of mice. For young mice, the neuro-protective effects of exercise were mainly associated with inhibition of NLRP3, Dnmt3a, Dnmt3b, and H3K9me2 and elevation of OST48; it also elevated Bacilli and reduced Epsilonproteobacteria, Campylobacterales, and Helicobacter. For middle-aged mice, exercise elevated Tet2, inhibited NF-κB and NLRP3, and rebalanced circadian clock proteins and the RAGE-OST48 axis; also, exercise elevated Coriobacteriia/Coriobacteriaceae, Erysipelotrichaceae, and Allobaculum and restored intestinal permeability.

Age-dependent effects of transverse maxillary deficiency treated by microimplant-assisted rapid palatal expansion: A prospective cone-beam computed tomography study

This study investigated the results of maxillary discrepancy treated by microimplant-assisted rapid palatal expansion (MARPE) at different ages. Sixty patients (aged 11.0-34.1 years; 23 male and 37 female) were treated by MARPE. Cone-beam computed tomography scans and dental casts were taken before and after expansion. The data were compared among 4 age groups: early adolescents (aged 11-14 years), late adolescents (aged 15-19 years), young adults (aged 20-24 years), and old adults (aged 25-34.1 years). The success rates of midpalatal suture separation were 100%, 100%, 88.2%, and 85.7% for early adolescents, late adolescents, young adults, and old adults, respectively. Palatal sutures at the level of the first molar were expanded by 4.02 mm, 3.48 mm, 2.63 mm, and 2.10 mm, corresponding to 66.7%, 58.1%, 42.0%, and 37.9% of the total dental expansion. Significant differences were found in the amounts of palatal suture expansion and the ratio of skeletal dental expansion between patients aged<20 years and patients aged ≥20 years (P<0.05). Skeletal expansion constituted 69.4%, 51.3%, 39.0%, and 29.8% of the total screw expansion. Except for the comparison between young adults and old adults, there were significant differences between groups for the ratio of skeletal screw expansion (P<0.05). The midpalatal suture can be expanded by MARPE more easily in patients<20 years of age than in patients ≥20 years of age. The ratio of skeletal screw expansion decreases as age increases.

Age-Dependent Effect of Ticagrelor Monotherapy Versus Ticagrelor With Aspirin on Major Bleeding and Cardiovascular Events: A Post Hoc Analysis of the TICO Randomized Trial.

BackgroundWe aimed to evaluate the age‐dependent effect of ticagrelor monotherapy after 3‐month dual‐antiplatelet therapy (DAPT) versus ticagrelor‐based 12‐month DAPT on major bleeding and cardiovascular events in patients with acute coronary syndrome.Methods and ResultsFrom the TICO trial (Ticagrelor Monotherapy After 3 Months in the Patients Treated With New Generation Sirolimus‐eluting Stent for Acute Coronary Syndrome), which randomized 3056 patients (median age, 61 years) to the ticagrelor monotherapy after 3‐month DAPT group or ticagrelor‐based 12‐month DAPT group, this post hoc analysis evaluated the age‐dependent effect of the treatment strategies on the primary end point (a composite of major bleeding, death, myocardial infarction, stent thrombosis, stroke, or target‐vessel revascularization) using the subpopulation treatment effect pattern plot. The cutoff age for distinguishing patients with greater benefit from this strategy was also determined. The risk reduction effect of ticagrelor monotherapy after 3‐month DAPT versus ticagrelor‐based 12‐month DAPT on the primary end point gradually increased with age and was more marked from the subpopulation of age 64 years with the change point. With this cutoff value of 64 years, the occurrence of the primary end point was significantly lower in the ticagrelor monotherapy after 3‐month DAPT group than in the ticagrelor‐based 12‐month DAPT group (4.4% versus 9.0%; P=0.002) in patients aged ≥64 years (n=1278), but it was not different in those aged <64 years (n=1778) with a significant interaction (P‐interaction=0.036).ConclusionsThe age‐dependent increase in the benefit of ticagrelor monotherapy after 3‐month DAPT versus ticagrelor‐based 12‐month DAPT was observed in the patients with acute coronary syndrome. In elderly patients with acute coronary syndrome, ticagrelor monotherapy after short‐term DAPT might be more optimal than ticagrelor‐based 12‐month DAPT.

Seismic scattering and absorption of oceanic lithosphericSwaves in the Eastern North Atlantic

SUMMARYThe scattering and absorption of high-frequency seismic waves in the oceanic lithosphere is to date only poorly constrained by observations. Such estimates would not only improve our understanding of the propagation of seismic waves, but also unravel the small-scale nature of the lithosphere and its variability. Our study benefits from two exceptional situations: (1) we deployed over 10 months a mid-aperture seismological array in the central part of the Eastern North Atlantic in 5 km water depth and (2) we could observe in total 340 high-frequency (up to 30 Hz) Po and So arrivals with tens to hundreds of seconds long seismic coda from local and regional earthquakes in a wide range of backazimuths and epicentral distances up to 850 km with a travel path in the oceanic lithosphere. Moreover, the array was located about 100 km north of the Gloria fault, defining the plate boundary between the Eurasian and African plates at this location which also allows an investigation of the influence of an abrupt change in lithospheric age (20 Ma in this case) on seismic waves. The waves travel with velocities indicating upper-mantle material. We use So waves and their coda of pre-selected earthquakes to estimate frequency-dependent seismic scattering and intrinsic attenuation parameters. The estimated scattering attenuation coefficients are between 10−4 and 4 × 10−5 m−1 and are typical for the lithosphere or the upper mantle. Furthermore, the total quality factors for So waves below 5 Hz are between 20 and 500 and are well below estimates from previous modelling for observations in the Pacific Ocean. This implies that the Atlantic Ocean is more attenuative for So waves compared to the Pacific Ocean, which is inline with the expected behaviour for the lithospheric structures resulting from the slower spreading rates in the Atlantic Ocean. The results for the analysed events indicate that for frequencies above 3 Hz, intrinsic attenuation is equal to or slightly stronger than scattering attenuation and that the So-wave coda is weakly influenced by the oceanic crust. Both observations are in agreement with the proposed propagation mechanism of scattering in the oceanic mantle lithosphere. Furthermore, we observe an age dependence which shows that an increase in lithospheric age is associated with a decrease in attenuation. However, we also observe a trade-off of this age-dependent effect with either a change in lithospheric thickness or thermal variations, for example due to small-scale upwellings in the upper mantle in the southeast close to Madeira and the Canaries. Moreover, the influence of the nearby Gloria fault is visible in a reduction of the intrinsic attenuation below 3 Hz for estimates across the fault. This is the first study to estimate seismic scattering and absorption parameters of So waves for an area with several hundreds of kilometres radius centred in the Eastern North Atlantic and using them to characterize the nature of the oceanic lithosphere.

Lack of direct involvement of a diazepam long-term treatment in the occurrence of irreversible cognitive impairment: a pre-clinical approach

Several observational studies have found a link between the long-term use of benzodiazepines and dementia, which remains controversial. Our study was designed to assess (i) whether the long-term use of benzodiazepines, at two different doses, has an irreversible effect on cognition, (ii) and whether there is an age-dependent effect. One hundred and five C57Bl/6 male mice were randomly assigned to the 15 mg/kg/day, the 30 mg/kg/day diazepam-supplemented pellets, or the control group. Each group comprised mice aged 6 or 12 months at the beginning of the experiments and treated for 16 weeks. Two sessions of behavioral assessment were conducted: after 8 weeks of treatment and after treatment completion following a 1-week wash-out period. The mid-treatment test battery included the elevated plus maze test, the Y maze spontaneous alternation test, and the open field test. The post-treatment battery was upgraded with three additional tests: the novel object recognition task, the Barnes maze test, and the touchscreen-based paired-associated learning task. At mid-treatment, working memory was impaired in the 15 mg/kg diazepam group compared to the control group (p = 0.005). No age effect was evidenced. The post-treatment assessment of cognitive functions (working memory, visual recognition memory, spatial reference learning and memory, and visuospatial memory) did not significantly differ between groups. Despite a cognitive impact during treatment, the lack of cognitive impairment after long-term treatment discontinuation suggests that benzodiazepines alone do not cause irreversible deleterious effects on cognitive functions and supports the interest of discontinuation in chronically treated patients.

Will GWAS eventually allow the identification of genomic biomarkers for COVID-19 severity and mortality?

GWAS involve testing genetic variants across the genomes of many individuals to identify genotype-phenotype associations. GWAS have enabled the identification of numerous genomic biomarkers in various complex human diseases, including infectious ones. However, few of these studies are relevant for clinical practice or at the bedside. In this issue of the JCI, Nakanishi et al. characterized the clinical implications of a major genetic risk factor for COVID-19 severity and its age-dependent effect, using individual-level data in a large international multicenter consortium. This study indicates that a common COVID-19 genetic risk factor (rs10490770) associates with increased risks of morbidity and mortality, suggesting potential implications for future clinical risk management. How can the genomic biomarkers identified by GWAS be associated with the clinical outcomes of an infectious disease? In this Commentary, we evaluate the advantages and limitations of this approach.

A multicenter analysis of the prognostic value of histone H3 K27M mutation in adult high-grade spinal glioma.

High-grade spinal glioma (HGSG) is a rare but aggressive tumor that occurs in both adults and children. Histone H3 K27M mutation correlates with poor prognosis in children with diffuse midline glioma. However, the role of H3 K27M mutation in the prognosis of adults with HGSG remains unclear owing to the rarity of this mutation, conflicting reports, and the absence of multicenter studies on this topic. The authors studied a cohort of 30 adult patients with diffuse HGSG who underwent histological confirmation of diagnosis, surgical intervention, and treatment between January 2000 and July 2020 at six tertiary academic centers. The primary outcome was the effect of H3 K27M mutation status on progression-free survival (PFS) and overall survival (OS). Thirty patients (18 males and 12 females) with a median (range) age of 50.5 (19-76) years were included in the analysis. Eighteen patients had H3 K27M mutation-positive tumors, and 12 had H3 K27M mutation-negative tumors. The median (interquartile range) PFS was 3 (10) months, and the median (interquartile range) OS was 9 (23) months. The factors associated with increased survival were treatment with concurrent chemotherapy/radiation (p = 0.006 for PFS, and p ≤ 0.001 for OS) and American Spinal Injury Association grade C or better at presentation (p = 0.043 for PFS, and p < 0.001 for OS). There were no significant differences in outcomes based on tumor location, extent of resection, sex, or H3 K27M mutation status. Analysis restricted to HGSG containing necrosis and/or microvascular proliferation (WHO grade IV histological features) revealed increased OS for patients with H3 K27M mutation-positive tumors (p = 0.017). Although H3 K27M mutant-positive HGSG was associated with poor outcomes in adult patients, the outcomes of patients with H3 K27M mutant-positive HGSG were somewhat more favorable compared with those of their H3 K27M mutant-negative HGSG counterparts. Further preclinical animal studies and larger clinical studies are needed to further understand the age-dependent effects of H3 K27M mutation.

Melatonin stabilizes age-dependent alterations in erythrocyte membrane induced by ‘Artificial Light at Night’ in a chronodisrupted model of rat

Growing evidence has shown that Artificial light at night (ALAN) is one of the threatening risk factors which disrupt circadian homeodynamics of cellular processes. The chronobiological role of melatonin seems to represent an important aspect of its contribution to healthy aging. In the present study, we examined the age dependent effect of melatonin on erythrocyte membrane transporters and oxidative stress biomarkers against ALAN to understand the degree of photo-oxidative damage in chronodisrupted rat model. Young (3 months) and old (24 months) male Wistar rats were subdivided in the following four young groups (n = 4) ; (i) control (ii) melatonin (10 mg/kg) (iii) ALAN (500 lx) (iv) ALAN (500 lx) + melatonin (10 mg/kg) and four old groups (n = 4); (v) control (vi) melatonin (10 mg/kg) (vii) ALAN (500 lx) (viii) ALAN (500 lx) + melatonin (10 mg/kg) to the experimental conditions for 10 days. Our findings demonstrated that ALAN significantly enhanced erythrocyte membrane lipid hydroperoxides (LHPs), protein carbonyl (PCO) while reduced total thiol (T-SH), and sialic acid (SA) level with higher amplitude in old ALAN group is restored by exogenous supplementation of melatonin. Activity of membrane transporters, sodium potassium ATPase (NKA) and plasma membrane calcium ion ATPase (PMCA) is significantly reduced meanwhile sodium hydrogen exchanger (NHE) activity is enhanced under the influence of ALAN with higher extent in old groups is effectively ameliorated by melatonin treatment. Further melatonin reduced osmotic fragility of erythrocyte in both young and old rats. It has been concluded from results that ALAN provoked redox insult and disrupt transporters activity more prominently in erythrocyte membrane of aged groups. Exogenous supplementation of melatonin is one of the possible therapeutic approaches to reinforce circadian modulations against ALAN in aged populations.

Younger and Late Middle-Aged Adults Exhibit Different Patterns of Cognitive-Motor Interference During Locomotor Adaptation, With No Disruption of Savings.

It has been proposed that motor adaptation and subsequent savings (or faster relearning) of an adapted movement pattern are mediated by cognitive processes. Here, we evaluated the pattern of cognitive-motor interference that emerges when young and late middle-aged adults perform an executive working memory task during locomotor adaptation. We also asked if this interferes with savings of a newly learned walking pattern, as has been suggested by a study of reaching adaptation. We studied split-belt treadmill adaptation and savings in young (21 ± 2 y/o) and late middle-aged (56 ± 6 y/o) adults with or without a secondary 2-back task during adaptation. We found that young adults showed similar performance on the 2-back task during baseline and adaptation, suggesting no effect of the dual-task on cognitive performance; however, dual-tasking interfered with adaptation over the first few steps. Conversely, dual-tasking caused a decrement in cognitive performance in late middle-aged adults with no effect on adaptation. To determine if this effect was specific to adaptation, we also evaluated dual-task interference in late middle-aged adults that dual-tasked while walking in a complex environment that did not induce motor adaptation. This group exhibited less cognitive-motor interference than late middle-aged adults who dual-tasked during adaptation. Savings was unaffected by dual-tasking in both young and late middle-aged adults, which may indicate different underlying mechanisms for savings of reaching and walking. Collectively, our findings reveal an age-dependent effect of cognitive-motor interference during dual-task locomotor adaptation and no effect of dual-tasking on savings, regardless of age. Young adults maintain cognitive performance and show a mild decrement in locomotor adaptation, while late middle-aged adults adapt locomotion at the expense of cognitive performance.

Echoes of William Gowers’s concept of abiotrophy

ABSTRACT Among William Gowers’s many contributions to neurology, the concept of abiotrophy (“an essential failure of vitality”) has been relatively overlooked. In this article, we review the echoes of Gowers’s concept in neurology, ophthalmology, and aging research. We also argue that abiotrophy is broader than both heredodegeneration and neurodegeneration. Unlike the common view that it simply means premature aging, abiotrophy currently can be understood as a progressive degenerative process of a mature specialized tissue, which is nonsynchronous with normal aging and may affect organs or systems early in life, resulting from the age-dependent effects of genetic mutations or variants, even if environmental factors may also causally contribute to the process. Although the term has largely fallen out of use, there are likely to be everlasting echoes of Gowers’s concept, through which he is to be considered a source of the modern thinking about the etiology and nosology of neurological diseases.

Age and Dose-Dependent Effects of Alpha-Lipoic Acid on Human Microtubule- Associated Protein Tau-Induced Endoplasmic Reticulum Unfolded Protein Response: Implications for Alzheimer's Disease.

In human tauopathies, pathological aggregation of misfolded/unfolded proteins, particularly microtubule-associated protein tau (MAPT, tau) is considered to be an essential mechanism that triggers the induction of endoplasmic reticulum (ER) stress. Here, we assessed the molecular effects of natural antioxidant alpha-lipoic acid (ALA) in human tauR406W (hTau)-induced ER unfolded protein response (ERUPR) in fruit flies. In order to reduce hTau neurotoxicity during brain development, we used a transgenic model of tauopathy where the maximum toxicity was observed in adult flies. Then, the effects of ALA (0.001, 0.005, and 0.025% w/w of diet) in htau-induced ERUPR and behavioral dysfunctions in the ages 20 and 30 days were evaluated in Drosophila melanogaster. Data from expression (mRNA and protein) patterns of htau, analysis of eyes external morphology as well as larvae olfactory memory were confirmed by our tauopathy model. Moreover, the expression of ERUPR-related proteins involving Activating Transcription Factor 6 (ATF6), inositol regulating enzyme 1 (IRE1), and protein kinase RNA-like ER kinase (PERK) wase upregulated and locomotor function decreased in both ages of the model flies. Remarkably, the lower dose of ALA modified ERUPR and supported the reduction of behavioral deficits in youngest adults through the enhancement of GRP87/Bip, reduction of ATF6, downregulation of PERK-ATF4 pathway, and activation of the IRE1-XBP1 pathway. On the other hand, only a higher dose of ALA affected the ERUPR via moderation of PERK-ATF4 signaling in the oldest adults. As ALA also exerts higher protective effects on the locomotor function of younger adults when htauR406Wis expressed in all neurons (htau-elav) and mushroom body neurons (htau-ok), we proposed that ALA has age-dependent effects in this model. Taken together, based on our results, we conclude that aging potentially influences the ALA effective dose and mechanism of action on tau-induced ERUPR. Further molecular studies will warrant possible therapeutic applications of ALA in age-related tauopathies.

Age-dependent effects on infectivity and susceptibility to SARS-CoV-2 infection: results from nationwide contact tracing data in Greece

Background Understanding the factors that affect the transmissibility of SARS-CoV-2 remains important to keep transmission low and maximize the health benefits of vaccination. We assessed the factors associated with the transmissibility of SARS-CoV-2 based on contact tracing data. Methods From 1 October to 9 December 2020, 29,385 laboratory-confirmed SARS-CoV-2 cases (index cases, i.e. the first identified laboratory-confirmed cases or with the earliest symptom onset in a setting) and 64,608 traced contacts were identified in Greece. We assessed the prevalence of symptoms in cases, calculated secondary attack rates and assessed factors associated with infectivity and susceptibility to infection. Results There were 11,232 contacts secondarily infected (secondary attack rate: 17.4%, 95% CI:17.0–17.8). Contacts aged 0–11 and 12–17 years were less susceptible to infection than adults 65 years or older (odds ratio (OR) [95% CI]: 0.28 [0.26–0.32] and 0.44 [0.40–0.49], respectively). Index cases aged 65 years or older were more likely to infect their contacts than other adults or children/adolescents. The odds of infection [95% CI] were higher in contacts exposed within the household (1.71 [1.59–1.85] vs. other) and in cases with cough (1.17 [1.11–1.25] vs. no cough). There was an interaction between the age of the index and the age of the contact with contacts 65 years or older having a higher probability of infection when exposed to cases of similar age than to children. Conclusions Our findings highlight the role of age and age mixing in infectivity and susceptibility to SARS-CoV-2 infection. Precautions are necessary for individuals 65 or older as they have higher infectivity and susceptibility in contact with their peers.

Quantitative Cross-Sectional Analyses of Quality-of-Life Outcomes Related to Race, Sex, Age, and Clinical Stage Among Multiple Myeloma Patients at an Urban Center

Introduction. Multiple myeloma (MM) patients suffer from disease symptoms and impact on quality of life (QoL) - a patient's sense of enjoyment, well-being, and ability to carry out activities of daily living. Reports on QoL in MM have focused on clinical trials that usually involve younger patients with adequate performance status (PS), mostly Caucasians. The median age of MM onset is 69 years; advanced age is associated with multiple comorbidities and deteriorating PS. Blacks have twice the incidence of MM compared to Caucasians; they also have a higher risk of dying due to poor healthcare utilization. Here, we explored the multifactorial nature of race, sex, age, and clinical stage in patient reported QoL outcomes using quantitative cross-sectional analyses from a single center in urban setting.Methods. Participants with a diagnosis of plasma cell disorders at various stages: MGUS, smoldering myeloma (SMM), or MM (newly diagnosed, maintenance, relapsed/refractory) were sequentially enrolled for a one-time measurement of QOL outcomes. Consent and study questionnaire were conducted verbally. Participants simply responded ‘yes’ or ‘no’ to nine question prompts outlined in Table 1, followed by verbal reasoning which was transcribed by the interviewer. The questionnaire included three main domains of QoL assessment based on existing literature review and feedback with our patient population. The first is physical symptoms and function (disease-related symptoms, treatment-related adverse events, sexual health and satisfaction with care), the second is mental health (depression, spirituality), and the third is social impact (financial burden, family support). Data were analyzed using chi-square test of independence. Participants will be re-approached for a second interview to determine changes to impact across the same QoL variables over time. The questionnaires validated within the current study will be used for a longitudinal cohort study to investigate whether a greater degradation is observed in one or more QoL domains during a specific time-point of MM disease course.Results. A total of 100 patients (males n=52) were enrolled. Median age was 64 years (IQR 55 - 68); 59 were Caucasian, 34 were Black, and 7 from other racial groups. At the time of interview: 7 were newly diagnosed or receiving induction therapy, 25 were undergoing stem cell transplant (SCT), 22 were on maintenance therapy, 33 were relapsed on salvage therapy, and 13 on no therapy (MGUS/SMM). Regardless of race, age, or sex, patients on therapy felt their QOL was impacted by fatigue (67%), and myeloma symptoms (65%). Black participants reported more fatigue as an impact on their QoL compared to other racial groups, p = .009. Women reported more impact from MM on sexual intimacy, p = .04, and impact from financial burden than male participants, p = .03. Younger patients <60 years old (n=38) reported more impact from treatment-related adverse events, p = .004, disease-related symptoms, p = .02, and dissatisfaction with information received about their disease and/or treatment, p = .004, compared to patients aged >60 years. Not surprisingly, patients with active MM (n=87); newly diagnosed on therapy, those undergoing SCT, or on maintenance, and relapsed disease) reported more MM symptoms p = <.001, and suffered from more fatigue, p = <.02, with higher impact on QoL compared to those with early-stage plasma cell disorders (MGUS, SMM). However, early-stage patients felt more dissatisfaction with information received and uncertainty about what to expect, p = <.001, compared to MM patients receiving therapy. Interestingly, there were no age, sex, race, or clinical stage dependent effects observed from SCT experience, spirituality or religion, and dissatisfaction with cancer care.Conclusions. Patients <60 years were impacted more by disease-related symptoms, treatment-related adverse events, in comparison to patients >60 years. Women felt their QoL was impacted by MM's affect on sexual intimacy and resulting financial burden in comparison to men. Black participants felt greater impact from fatigue in comparison to Caucasian and other races. Active MM patients on treatment were more impacted by disease-related symptoms and fatigue compared to early-stage patients. MGUS/SMM patients not on therapy were more impacted by dissatisfaction of information received compared to patients receiving treatment at time of data collection. [Display omitted] DisclosuresBadros: Janssen: Research Funding; J&J: Research Funding; BMS: Research Funding; GlaxoSmithKline: Research Funding.

Age- and Sex-Dependent Nicotine Pretreatment Effects on the Enhancement of Methamphetamine Self-administration in Sprague-Dawley Rats

Initiation of tobacco products typically occurs in adolescence. Adolescence is a critical period in development where the maturation of brain neurocircuitry is vulnerable to nicotine. Nicotine-containing products and psychostimulants, such as methamphetamine (METH), are often coabused. Rodent studies have shown that nicotine exposure in early adolescence increases subsequent drug intake and reward. Given the exponential increase in e-cigarette use among adolescents, there is a pressing need to understand whether adolescent nicotine exposure impacts concurrent increased METH use. The objective of this study is to evaluate age, sex, and longitudinal effects of nicotine pretreatment on METH reinforcement. Male and female Sprague-Dawley rats were pretreated with a subchronic, low-dose nicotine (2×, 30 µg/kg/0.1 mL, intravenous) or saline during early adolescence (postnatal days [PN] 28-31) or adulthood (PN 86-89). Following nicotine pretreatment, on PN 32 or PN 90, animals underwent operant intravenous self-administration for METH (20 µg/kg/inf) over a 2-hour period for five consecutive days. Early adolescent nicotine exposure enhances intravenous METH self-administration in male, but not female adolescents. Male adult rats self-administer METH over the 5-day testing period, independent of nicotine exposure. In contrast, nicotine exposure increases METH self-administration in female adults during the later sessions of the 5-day testing period. Taken together, our data highlight age- and sex-dependent effects of low dose, subchronic nicotine pretreatment on subsequent intravenous METH self-administration. A majority of polysubstance users begin smoking before the age of 18. Mounting evidence highlights adolescent susceptibility to nicotine exposure on brain and behavior. With the escalation in nicotine-containing products and stimulant use among adolescents, it is important to identify the consequences from adolescent nicotine use, including polysubstance use. Our study provides evidence that adolescent nicotine exposure enhances subsequent METH use, with important sex- and age-dependent effects.

Testosterone attenuates sevoflurane-induced tau phosphorylation and cognitive impairment in neonatal male mice

BackgroundSevoflurane anaesthesia induces phosphorylation of the microtubule-associated protein tau and cognitive impairment in neonatal, but not adult, mice. The underlying mechanisms remain largely to be determined. Sex hormones can be neuroprotective, but little is known about the influence of testosterone on age-dependent anaesthesia effects. MethodsSix- and 60-day-old male mice received anaesthesia with sevoflurane 3% for 2 h daily for 3 days. Morris water maze, immunoassay, immunoblotting, co-immunoprecipitation, nanobeam technology, and electrophysiology were used to assess cognition; testosterone concentrations; tau phosphorylation; glycogen synthase kinase-3β (GSK3β) activation; binding or interaction between tau and GSK3β; and neuronal activation in mice, cells, and neurones. ResultsCompared with 60-day-old male mice, 6-day-old male mice had lower testosterone concentrations (3.03 [0.29] vs 0.44 [0.12] ng ml−1; P<0.01), higher sevoflurane-induced tau phosphorylation in brain (133 [20]% vs 100 [6]% in 6-day-old mice, P<0.01; 103 [8]% vs 100 [13]% in 60-day-old mice, P=0.77), and sevoflurane-induced cognitive impairment. Testosterone treatment increased brain testosterone concentrations (1.76 [0.10] vs 0.39 [0.05] ng ml−1; P<0.01) and attenuated the sevoflurane-induced tau phosphorylation and cognitive impairment in neonatal male mice. Testosterone inhibited the interaction between tau and GSK3β, and attenuated sevoflurane-induced inhibition of excitatory postsynaptic currents in hippocampal neurones. ConclusionsLower brain testosterone concentrations in neonatal compared with adult male mice contributed to age-dependent tau phosphorylation and cognitive impairment after sevoflurane anaesthesia. Testosterone might attenuate the sevoflurane-induced tau phosphorylation and cognitive impairment by inhibiting the interaction between tau and GSK3β.

Effects of Caffeine Ingestion on Human Standing Balance: A Systematic Review of Placebo-Controlled Trials.

Caffeine ingestion may influence balance control via numerous mechanisms. Although previously investigated using various study designs and methods, here we aimed to create the first evidence-based consensus regarding the effects of caffeine on the control of upright stance via systematic review (PROSPERO registration CRD42021226939). Embase, PubMed/MEDLINE, SPORTDiscus and Web of Science databases were searched on 27 January 2021 to identify placebo-controlled trials investigating caffeine-induced changes in human standing balance. Reference lists of eligible studies were also searched. Overall, nine studies involving a total of 290 participants were included. All studies were moderate to strong in quality according to the QualSyst tool. Balance-related outcome measures were collected across a range of different participant ages, stances and sensory conditions. The results show that younger participants’ balance was generally unaffected by caffeine ingestion. However, a significant balance impairment was observed following caffeine ingestion in all studies involving older participants (average age >65 years). Our results therefore suggest an age-dependent effect of caffeine ingestion on human standing. Further research into this effect is warranted as only one study has directly compared younger and older adults. Nonetheless, an important implication of our findings is that caffeine ingestion may increase fall risk in older adults. Furthermore, based on our findings, caffeine ingestion should be considered as a potential confounding factor when assessing human standing balance, particularly in older adults.

The distribution of [α/Fe] in the Milky Way disc

ABSTRACT Using a sample of red giant stars from the Apache Point Observatory Galactic Evolution Experiment (APOGEE) Data Release 16, we infer the conditional distribution $p([\alpha /{\rm Fe}]\, |\, [{\rm Fe}/{\rm H}])$ in the Milky Way disk for the α-elements Mg, O, Si, S, and Ca. In each bin of [Fe/H] and Galactocentric radius R, we model p([α/Fe]) as a sum of two Gaussians, representing ‘low-α’ and ‘high-α’ populations with scale heights $z_1=0.45\, {\rm kpc}$ and $z_2=0.95\, {\rm kpc}$, respectively. By accounting for age-dependent and z-dependent selection effects in APOGEE, we infer the [α/Fe] distributions that would be found for a fair sample of long-lived stars covering all z. Near the Solar circle, this distribution is bimodal at sub-solar [Fe/H], with the low-α and high-α peaks clearly separated by a minimum at intermediate [α/Fe]. In agreement with previous results, we find that the high-α population is more prominent at smaller R, lower [Fe/H], and larger |z|, and that the sequence separation is smaller for Si and Ca than for Mg, O, and S. We find significant intrinsic scatter in [α/Fe] at fixed [Fe/H] for both the low-α and high-α populations, typically ∼0.04-dex. The means, dispersions, and relative amplitudes of this two-Gaussian description, and the dependence of these parameters on R, [Fe/H], and α-element, provide a quantitative target for chemical evolution models and a test for hydrodynamic simulations of disk galaxy formation. We argue that explaining the observed bimodality will probably require one or more sharp transitions in the disk’s gas accretion, star formation, or outflow history in addition to radial mixing of stellar populations.

Perturbation of cortical activity elicits regional and age-dependent effects on unconstrained reaching behavior: a pilot study.

Contributions from premotor and supplementary motor areas to reaching behavior in aging humans are not well understood. The objective of these experiments was to examine effects of perturbations to specific cortical areas on the control of unconstrained reaches against gravity by younger and older adults. Double-pulse transcranial magnetic stimulation (TMS) was applied to scalp locations targeting primary motor cortex (M1), dorsal premotor area (PMA), supplementary motor area (SMA), or dorsolateral prefrontal cortex (DLPFC). Stimulation was intended to perturb ongoing activity inthe targeted cortical region before or after a visual cue to initiate moderately paced reaches to one of three vertical target locations. Regional effects were observed in movement amplitude both early and late in the reach. Perturbation of PMA increased reach distance before the time of peak velocity to a greater extent than all other regions. Reaches showed greater deviation from a straight-line path around the time of peak velocity and greater overall curvature with perturbation of PMA and M1 relative to SMA and DLPFC. The perturbationincreased positional variability of the reach path at the time of peak velocityand the time elapsing after peak velocity. Although perturbations had stronger effects on reaches by younger subjects, this group exhibited less reach path variability at the time of peak velocity and required less time to adjust the movement trajectory thereafter. These findings support the role of PMA in visually guided reaching and suggest an age-related change in sensorimotor processing, possibly due to a loss of cortical inhibitory control.

Peripheral Airway Impairment and Dysanapsis Define Risk of Uncontrolled Asthma in Obese Asthmatic Children

Factors that determine the relationship between obesity and poor outcomes in asthmatic children are not well understood. Dysanapsis and peripheral airway impairment (PAI) could provide an explanation in the obese asthmatic patient. To determine the effect of obesity on increased dysanapsis and PAI and establish the effect of obesity, dysanapsis, and PAI on increased risk of uncontrolled asthma. We evaluated 206 children with moderate to severe asthma, aged 4-18 years, to determine the relationship of body mass index (BMI) to increased dysanapsis and PAI, using reference values. We examined the probability of obesity, dysanapsis, and PAI increasing the risk of uncontrolled asthma by BMI categorically and BMI z scores using generalized linear model analyses. Compared with normal-weight children, overweight and obese children had increased forced vital capacity % predicted and obesity increased odds of dysanapsis by 2.32 (P=.04), while PAI showed an age-dependent effect, with increased odds of 2.09 for children younger than 12 years (P=.08) and 54.14 for those 12 years and older (P= .003). For each unit increase in BMI z score, there was an increased odds ratio of 1.57 for dysanapsis (P= .009), greater in males, OR of 3.10, P = .009, and of 1.39 for PAI for those younger than 12 years (P= .042) and of 4.60 for those 12 years and older (P= .002). Obesity's relationship to uncontrolled asthma was indirect, as not significant when adjusted for the direct effect of dysanapsis and PAI, which were highly significant predictors, with increased odds of 28.01 for dysanapsis for those younger than 12 years (P < .001) and of 3.09 for PAI (P= .005). Overweight and obesity significantly increase odds of dysanapsis and PAI, in an age and gender-specific manner, increasing the probability of uncontrolled asthma.