Resistance training and other forms of physical exercise are commonly suggested to promote brain health, yet the relationship between resistance training and brain structure in aging is poorly understood. We examined the short- and long-term influence of one year of supervised resistance training at two different loadings on brain structure in aging. In the LISA (LIve active Successful Ageing) study, well-functioning older adults at retirement age (mean age: 66 ± 2 years) were randomized to one year of heavy resistance training (HRT), moderate intensity training (MIT), or a non-exercising control group (CON). Magnetic resonance imaging (MRI) of the brain was performed at baseline, 1-, 2-, and 4-years follow ups. Trajectories of total grey matter, hippocampus, dorsolateral prefrontal cortex (dlPFC), ventrolateral prefrontal cortex (vlPFC), and white matter hyperintensities were analyzed in relation to changes in muscle strength. Individuals (n = 276) with MRI scans at all 4 timepoints were included (HRT, n = 96; MIT, n = 95; CON, n = 85). Total grey matter volume decreased with time across all groups (F3,819 = 231.549, p < 0.001, η^2 = 0.46), as did hippocampal (F3,819 = 310.07, p < 0.001, η^2 = 0.53), vlPFC (F3,818 = 74.380, p < 0.001, η^2 = 0.21), and dlPFC (F3,818 = 3.640, p = 0.013, η^2 = 0.01) volumes. White matter hyperintensity volumes increased (F3,819 = 101.876, p < 0.001, η^2 = 0.27). There were no significant group x time interactions for any of the brain structures. Additional cortical and subcortical vertex-wise analyses showed no group differences. Change in isometric leg strength was weakly associated with change in white matter hyperintensity volume across all individuals (r2 = 0.01, p = 0.048). One year of resistance training in well-functioning older adults at retirement age did not influence volume changes in selected brain regions over a 4-year period. The study was approved by the regional ethics committee and registered on clinicaltrials.gov 2014–04-24 (NCT02123641).

Background Several studies have applied resting-state functional MRI to examine whether functional brain connectivity is altered in migraine with aura patients. These studies had multiple limitations, including small sample sizes, and reported conflicting results. Here, we performed a large, cross-sectional brain imaging study to reproduce previous findings. Methods We recruited women aged 30–60 years from the nationwide Danish Twin Registry. Resting-state functional MRI of women with migraine with aura, their co-twins, and unrelated migraine-free twins was performed at a single centre. We carried out an extensive series of brain connectivity data analyses. Patients were compared to migraine-free controls and to co-twins. Results Comparisons were based on data from 160 patients, 30 co-twins, and 136 controls. Patients were similar to controls with regard to age, and several lifestyle characteristics. We replicated clear effects of age on resting-state networks. In contrast, we failed to detect any differences, and to replicate previously reported differences, in functional connectivity between migraine patients with aura and non-migraine controls or their co-twins in any of the analyses. Conclusion Given the large sample size and the unbiased population-based design of our study, we conclude that women with migraine with aura have normal resting-state brain connectivity outside of migraine attacks.

Understanding individual variability in response to physical activity is key to developing more effective and personalised interventions for healthy ageing. Here, we aimed to unpack individual differences by using longitudinal data from a randomised-controlled trial of a 12-month muscle strengthening intervention in older adults. Physical function of the lower extremities was collected from 247 participants (66.3 ± 2.5 years) at four time-points. At baseline and at year 4, participants underwent 3 T MRI brain scans. K-means longitudinal clustering was used to identify patterns of change in chair stand performance over 4 years, and voxel-based morphometry was applied to map structural grey matter volume at baseline and year 4. Results identified three groups showing trajectories of poor (33.6%), mid (40.1%), and high (26.3%) performance. Baseline physical function, sex, and depressive symptoms significantly differed between trajectory groups. High performers showed greater grey matter volume in the motor cerebellum compared to the poor performers. After accounting for baseline chair stand performance, participants were re-assigned to one of four trajectory-based groups: moderate improvers (38.9%), maintainers (38.5%), improvers (13%), and decliners (9.7%). Clusters of significant grey matter differences were observed between improvers and decliners in the right supplementary motor area. Trajectory-based group assignments were unrelated to the intervention arms of the study. In conclusion, patterns of change in chair stand performance were associated with greater grey matter volumes in cerebellar and cortical motor regions. Our findings emphasise that how you start matters, as baseline chair stand performance was associated with cerebellar volume 4 years later.

Background Research indicates detrimental effects of stress on brain health and cognitive functioning, but population-based studies using comprehensive measures of cognitive decline is lacking. The present study examined the association of midlife perceived stress with cognitive decline from young adulthood to late midlife, controlling for early life circumstances, education and trait stress (neuroticism). Methods The sample consisted of 292 members of the Copenhagen Perinatal Cohort (1959–1961) with continued participation in two subsequent follow-up studies. Cognitive ability was assessed in young adulthood (mean age 27 years) and midlife (mean age 56 years) using the full Wechsler Adult Intelligence Scale (WAIS), and perceived stress was measured at midlife using the Perceived Stress Scale. The association of midlife perceived stress with decline in Verbal, Performance and Full-Scale IQ was assessed in multiple regression models based on Full Information Maximum Likelihood estimation. Results Over a mean retest interval of 29 years, average decline in IQ score was 2.42 (SD 7.98) in Verbal IQ and 8.87 (SD 9.37) in Performance IQ. Mean decline in Full-scale IQ was 5.63 (SD 7.48), with a retest correlation of 0.83. Controlling for parental socio-economic position, education and young adult IQ, higher perceived stress at midlife was significantly associated with greater decline in Verbal (β = − 0.012), Performance (β = − 0.025), and Full-scale IQ (β = − 0.021), all p < .05. Across IQ scales, additionally controlling for neuroticism in young adulthood and change in neuroticism had only minor effects on the association of midlife perceived stress with decline. Conclusions Despite very high retest correlations, decline was observed on all WAIS IQ scales. In fully adjusted models, higher midlife perceived stress was associated with greater decline on all scales, indicating a negative association of stress with cognitive ability. The association was strongest for Performance and Full-scale IQ, perhaps reflecting the greater decline on these IQ scales compared to Verbal IQ.

Resistance training is an effective strategy to counteract the age‐related loss of muscle mass and strength in elderly, but whether the benefits of training differ between sexes is unclear. A total of 297 elderly men and women were randomized to 1 year of heavy resistance training (HRT) or control (CON). Changes in muscle function and body composition were compared between sexes and groups. Improvements in muscle strength, body fat, muscle mass and size were observed, but the absolute improvements in muscle strength (23 Nm ± 2.3 vs 11 Nm ± 2.2, P < .01) and visceral fat content (−215 g ± 50 vs −60 g ± 21, P < .01) were greater in men. Also, the relative decrease in body fat % (−6.8% ± 1.1 vs −2.7% ± 0.7, P < .05) and fat mass (−7.9% ± 1.4 vs −2.7% ± 1.0, P < .05) was more pronounced in men. Heavy resistance training improved more than CON in most muscular and body composition parameters with greater increase in muscle strength and decrease in body fat in men. Consequently, resistance training is recommendable to counteract age‐related losses of muscle mass and strength and to reduce body fat in elderly, however, with a small advantage for men in parameters that predict metabolic risk factors.

Migraine with aura is a highly prevalent disorder involving transient neurological disturbances associated with migraine headache. While the pathophysiology is incompletely understood, findings from clinical and basic science studies indicate a potential key role of the thalamus in the mechanisms underlying migraine with and without aura. Two recent, clinic-based MRI studies investigated the volumes of individual thalamic nuclei in migraine patients with and without aura using two different data analysis methods. Both studies found differences of thalamic nuclei volumes between patients and healthy controls, but the results of the studies were not consistent. Here, we investigated whether migraine with aura is associated with changes in thalamic volume by analysing MRI data obtained from a large, cross-sectional population-based study which specifically included women with migraine with aura (N = 156), unrelated migraine-free matched controls (N = 126), and migraine aura-free co-twins (N = 29) identified from the Danish Twin Registry. We used two advanced, validated analysis methods to assess the volume of the thalamus and its nuclei; the MAGeT Brain Algorithm and a recently developed FreeSurfer-based method based on a probabilistic atlas of the thalamic nuclei combining ex vivo MRI and histology. These approaches were very similar to the methods used in each of the two previous studies. Between-group comparisons were corrected for potential effects of age, educational level, BMI, smoking, alcohol, and hypertension using a linear mixed model. Further, we used linear mixed models and visual inspection of data to assess relations between migraine aura frequency and thalamic nuclei volumes in patients. In addition, we performed paired t-tests to compare volumes of twin pairs (N = 29) discordant for migraine with aura. None of our analyses showed any between-group differences in volume of the thalamus or of individual thalamic nuclei. Our results indicate that the pathophysiology of migraine with aura does not involve alteration of thalamic volume.

Background Previous studies found an association between migraine and dementia, which are two leading causes of disability. However, these studies did not differentiate between migraine types and did not investigate all prevalent dementia subtypes. The main objective of this national register-based study was to investigate whether migraine was a risk factor for dementia. Additionally, we explored potential differences in dementia risk for migraine with and without aura. Methods We obtained data on birth cohorts born between 1935 and 1956 ( n = 1,657,890) from Danish national registers. Individuals registered with migraine before age 59 ( n = 18,135) were matched (1:5) on sex and birthdate with individuals without migraine ( n = 1,378,346). Migraine was defined by International Classification of Diseases (ICD) diagnoses and dementia was defined by ICD diagnoses and anti-dementia medication. After matching, 62,578 individuals were eligible for analysis. For the statistical analyses, we used Cox regression models and adjusted for socio-demographic factors and several psychiatric and somatic morbidities. Results During a median follow-up time of 6.9 (IQR: 3.6–11.2) years, 207 individuals with migraine developed dementia. Compared with individuals without migraine, we found a 50% higher rate of dementia among individuals with migraine (HR = 1.50; 95% CI: 1.28–1.76). Individuals without aura had a 19% higher rate of dementia (HR = 1.19; 95% CI: 0.84–1.70), and individuals with aura had a two times higher rate of dementia (HR = 2.11; 95% CI: 1.48–3.00). Conclusions Our findings support the hypothesis that migraine is a midlife risk factor for dementia in later life. The higher rate of dementia in individuals with a hospital-based diagnosis of migraine with aura emphasizes the need for studies on pathological mechanisms and potential preventative measures. Furthermore, given that only hospital-based migraine diagnoses were included in this study, future research should also investigate migraine cases derived from the primary healthcare system to include less severe migraine cases.

OBJECTIVES:Previous studies indicated that stress diagnoses increase the risk of dementia. However, previous results may be biased by confounding, reverse causation and misclassification. Therefore, the main aim of this study was to investigate the association between clinically diagnosed stress in midlife and later dementia risk, while addressing limitations of previous studies. METHODS:The study population was selected from all individuals in Denmark born 1935-1956. Individuals diagnosed with stress in midlife (aged 37-58 years) were matched (1:5) with individuals without stress diagnoses based on sex and birthdate (N = 103,484). Data were retrieved from national registers. Cox regression models were adjusted for socio-demographic factors and different morbidities. RESULTS:We found a 2.20 (95% CI: 1.93-2.50) times higher rate of dementia among individuals with any stress diagnosis registered in midlife compared with no stress diagnosis. Hazard rate ratios of dementia were 1.73 (95% CI: 1.13-2.65) among individuals with acute stress reactions, 2.37 (95% CI: 2.05-2.74) among individuals with adjustment disorders, and 2.20 (95% CI: 1.73-2.80) among individuals with unspecified stress reactions. Individuals with PTSD and other stress reactions had non-significantly elevated rates of dementia. Adjustment for confounding only slightly attenuated the association, and reverse causation did not appear to bias the results substantially. CONCLUSION:Our results support the hypothesis that severe stress in midlife is an important risk factor for dementia. This finding emphasizes the importance of identifying and treating severe stress in midlife to reduce potential detrimental consequences for brain health in later life.

Background: Physical muscle function and brain hippocampus size declines with age, accelerating after the age of 60. Strength training over a few months improves physical function, but less is known about how long-term strength training affects physical function and hippocampus volume. Therefore, we aimed to investigate the effect of 1-year strength training of two different intensities upon muscle mass, function, and hippocampus volume in retirement-age individuals. Methods: In this multidisciplinary randomized controlled trial (clinicaltrials.gov: NCT02123641), participants were allocated to either a) supervised, heavy resistance training (HRT, n = 149, 3/wk), b) moderate intensity resistance training (MIT, n = 154, 3/wk) or c) non-exercise activities (CON, n = 148). 451 participants were randomized (62-70 yrs., women 61%, approximate to 80% with a chronic medical disease) and 419 were included in the intention-to-treat analysis (n = 143, 144 and 132; HRT, MIT and CON). Changes in muscle power (primary outcome), strength and size, physical function, body composition, hippocampus volume and physical/mental well-being were analyzed. Findings: Of the participants (HRT + MIT), 83% completed training at least 2/week. Leg extensor power was unchanged in all groups, but strength training had a positive effect on isometric knee extensor strength in both groups, whereas an increased muscle mass, cross-sectional area of vastus lateralis muscle, a decreased whole-body fat percentage, visceral fat content and an improved mental health (SF-36) occurred in HRT only. Further, chair-stand performance improved in all groups, whereas hippocampus volume decreased in all groups over time with no influence of strength training. Interpretation: Together, the results indicate that leg extensor power did not respond to long-term supervised strength training, but this type of training in a mixed group of healthy and chronically diseased elderly individuals can be implemented with good compliance and induces consistent changes in physiological parameters of muscle strength, muscle mass and abdominal fat.

Abstract Introduction Despite the understanding of allostatic load (AL) as a consequence of ongoing adaptation to stress, studies of the stress–AL association generally focus on a narrow conceptualization of stress and have thus far overlooked potential confounding by personality. The present study examined the cross‐sectional association of objective and subjective stress with AL, controlling for Big Five personality traits. Methods Participants comprised 5,512 members of the Copenhagen Aging and Midlife Biobank aged 49–63 years (69% men). AL was measured as a summary index of 14 biomarkers of the inflammatory, cardiovascular, and metabolic system. Objective stress was assessed as self‐reported major life events in adult life. Subjective stress was assessed as perceived stress within the past four weeks. Results Both stress measures were positively associated with AL, with a slightly stronger association for objective stress. Adjusting for personality traits did not significantly change these associations. Conclusions The results suggest measures of objective and subjective stress to have independent predictive validity in the context of personality. Further, it is discussed how different operationalizations of stress and AL may account for some of the differences in observed stress–AL associations.

AbstractIntroductionAnimal models of Alzheimer's disease show that exercise may modify β‐amyloid (Aβ) deposition. We examined the effect of a 16‐week exercise intervention on cortical Aβ in patients with mild‐to‐moderate Alzheimer's disease.MethodsThirty‐six patients with Alzheimer's disease were randomized to either one hour of aerobic exercise three times weekly for 16 weeks or usual care. Pre and post intervention, 11Carbon‐Pittsburgh compound B positron emission tomography was carried out to assess cortical Aβ, and quantified using standardized uptake value rations (SUVRs).ResultsThe intervention showed no effect on follow‐up SUVRs in a covariance analysis with group allocation, baseline intervention SUVR, age, sex, and baseline Mini–Mental State Examination as predictors. Change in SUVRs did not correlate with changes in measures of physical or aerobic fitness.DiscussionThe present findings do not support an effect of exercise on Aβ. However, the relatively short intervention period may account for a lack of efficacy. Further studies should test earlier and longer interventions.

[This corrects the article DOI: 10.1371/journal.pone.0202395.].

Objective: To examine the cross-sectional associations of Big Five personality traits with midlife allostatic load, including the role of sex, socio-demographic factors and health-related behaviours. Design: Cross-sectional analyses of 5512 members of the Copenhagen Aging and Midlife Biobank, aged 49-63 years, 69% men. Main outcome measure: Allostatic load (AL) based on 14 biomarkers representing the inflammatory, cardiovascular and metabolic system. Results: Due to significant sex × trait interactions, analyses were stratified by sex. Openness and Conscientiousness were inversely associated with AL in both sexes, and Extraversion was positively associated with AL in men. Adjusting for socio-demographic factors significantly attenuated the association of Openness in both sexes and of Extraversion in men, for whom the inverse association of Agreeableness with AL was strengthened. Further adjusting for health-related behaviours, the Conscientiousness-AL association was attenuated but remained significant, and Agreeableness remained significantly associated with AL in men. Conclusion: Results imply that higher levels of Agreeableness (in men) and Conscientiousness are associated with lower levels of AL above and beyond socio-demographic factors and health-related behaviours. The study further contributes by demonstrating the relevance of sex × trait and trait × trait interactions in the personality-health literature.

Background Progressive multiple sclerosis (MS) is characterised by diffuse changes on brain magnetic resonance imaging (MRI), which complicates the use of MRI as a diagnostic and prognostic marker. The relationship between MRI measures (conventional and non-conventional) and clinical disability in progressive MS therefore warrants further investigation. Objective To investigate the relationship between clinical disability and MRI measures in patients with progressive MS. Methods Data from 93 primary and secondary progressive MS patients who had participated in 3 phase 2 clinical trials were included in this cross-sectional study. From 3T MRI baseline scans we calculated total T2 lesion volume and analysed magnetisation transfer ratio (MTR) and the diffusion tensor imaging indices fractional anisotropy (FA) and mean diffusivity (MD) in T2 lesions, normal-appearing white matter (NAWM) and cortical grey matter. Disability was assessed by the Expanded Disability Status Scale (EDSS) and the MS functional composite. Results T2 lesion volume was associated with impairment by all clinical measures. MD and MTR in T2 lesions were significantly related to disability, and lower FA values correlated with worse hand function in NAWM. In multivariable analyses, increasing clinical disability was independently correlated with increasing T2 lesion volumes and MTR in T2 lesions. Conclusion In progressive MS, clinical disability is related to lesion volume and microstructure.

Introduction: Brain imaging studies in healthy elderly subjects suggest a positive effect of aerobic exercise on both brain structure and function, while the effects of aerobic exercise in Alzheimer's Disease (AD) has been scarcely investigated. Methods: In a single-blinded randomized MRI study, we assessed the effects of an aerobic exercise intervention on brain volume as measured by magnetic resonance imaging (MRI) and its correlation to cognitive functioning in patients with AD. The study was a sub-study of a larger randomized controlled trial (ADEX study). Forty-one patients were assigned to a control or exercise group. The exercise group performed 60-min of aerobic exercise three times per week for 16 weeks. All participants underwent whole-brain MRI at 3 Tesla and cognitive assessment at baseline and after 16 weeks. Attendance and intensity were monitored providing a total exercise load. Changes in regional brain volumes and cortical thickness were analyzed using Freesurfer software. Results: There was no effect of the type of intervention on MRI-derived brain volumes. In the entire group with and without training, Exercise load showed a positive correlation with changes in volume in the hippocampus, as well as frontal cortical thickness. Volume changes in frontal cortical thickness correlated with changes in measures of mental speed and attention and exercise load in the exercise group. Conclusion: We did not find evidence to support an effect of 16 weeks of aerobic exercise on brain volume changes in patients with AD. Longer intervention periods may be needed to affect brain structure as measured with volumetric MRI. Clinical Trial registration: ClinicalTrials.gov Identifier: NCT01681602, registered September 10th, 2012 (Retrospectively registered).

In recent years there has been an increasing focus on the relation between cerebrovascular health, physical exercise and Alzheimer's disease. The aim of the current study was to determine the effect of moderate-to-high-intensity aerobic exercise on cerebral blood flow in patients with mild to moderate Alzheimer's disease. Fifty-one patients were randomized to either usual care or moderate-to-high intensity aerobic exercise for 16 weeks. Exercise had no consistent effect on whole brain or regional cerebral blood flow. Sixteen weeks of exercise are, therefore, not sufficient to produce a consistent increase in cerebral blood flow in a relatively small sample of Alzheimer's patients.

Hearing loss in later life has been associated with risk of dementia. The impact of risk factors for dementia may change during life, and it is unknown whether hearing loss early in midlife represents a risk factor for dementia. We examined whether hearing loss diagnosed in midlife was associated with an increased risk of dementia. A cohort comprising 942,567 Danish men enrolled in the mandatory conscription board examination was followed from conscription (age 19). Cognitive ability was measured at conscription, while hearing loss was ascertained either by physicians diagnosis at conscription or by the Danish National Patient Registry from 1977 to 2016 (ICD-8:388; 389; ICD-10:H90; H91). Differences in cognitive ability in relation to hearing loss at conscription were calculated using t test, while the risk of dementia associated with hearing loss was estimated using Cox regression with adjustment for cognitive ability, education, depression, diabetes, hypertension, and cerebrovascular disease. Men with hearing loss at conscription had about 2 points (corresponding to 0.20 SD) lower mean cognitive score than those without hearing loss. During follow-up, 59,834 men had a hearing loss diagnosis, while 9114 were diagnosed with dementia. Midlife hearing loss was associated with an increased rate of dementia diagnosed before age 60 (adjusted Hazard Ratio (HR) = 1.90 [95% CI 1.59–2.76]) or at a later age (adjusted HR = 1.15 [95% CI 1.06–1.25]). Our study supports the evidence that early identification and correction of hearing loss holds promise for prevention of dementia later in life.

In recent years there has been an increasing focus on the relation between cerebrovascular health, physical exercise and Alzheimer's disease. The aim of the current study was to determine the effect of moderate-to-high-intensity aerobic exercise on cerebral blood flow in patients with mild to moderate Alzheimer's disease. Fifty-one patients were randomized to either usual care or moderate-to-high intensity aerobic exercise for 16 weeks. Exercise had no consistent effect on whole brain or regional cerebral blood flow. Sixteen weeks of exercise are, therefore, not sufficient to produce a consistent increase in cerebral blood flow in a relatively small sample of Alzheimer's patients.