Brain Aging Trajectories Research Articles

Sex differences in connectivity in the default mode network in healthy aging adults

AbstractBackgroundTwo‐thirds of individuals diagnosed with Alzheimer’s disease (AD) are women, but the reasons for women’s elevated risk are unknown, and sex differences in brain aging trajectories are poorly understood. Both symptomatic AD and aging are associated with decreased connectivity within the default mode network (DMN), which supports short‐term memory processing, while individuals with preclinical AD show increased connectivity in some DMN regions. We sought to identify sex‐based differences in DMN connectivity over the lifespan in a large cross‐sectional study of healthy adults.MethodWe examined functional MRI data from a cross‐sectional cohort of n=595 cognitively normal individuals (aged 36‐100 years; 249 females) drawn from the Human Connectome Project‐Aging (HCP‐A) dataset (Harms et al., 2018; Bookheimer et al., 2019). Preprocessing followed our previously described pipeline, with stringent motion thresholds applied. The four resting‐state scans for each individual were averaged and masked to a standard DMN parcellation (Yeo et al., 2011). We calculated within‐network connectivity of each DMN voxel using the intrinsic connectivity distribution (ICD) (Scheinost et al., 2012), a robust voxel‐based metric of functional connectivity, and used a general linear model to assess the main effect of sex on within‐network ICD with increasing age.ResultFemales showed relative hyperconnectivity in posterior DMN with age compared to males, but lower connectivity in anterior nodes (Fig 1). Specifically, z‐scores for female minus male contrasts for posterior clusters were 3.9 (posterior cingulate), 4.5 (R angular gyrus), and 4.7 (L), and for anterior clusters were ‐4.1 (R frontal pole) and ‐4.3 (L).ConclusionIn a large sample of healthy aging adults, women showed increased connectivity in posterior, and decreased connectivity in anterior, nodes of the DMN compared with their aging male counterparts. Interestingly, individuals with preclinical AD show a similar pattern of posterior hyperconnectivity, often interpreted as the compensatory response of a network under stress. These findings provide early clues to a potential role for network‐level sex differences in explaining women’s increased vulnerability to AD as they age.

Cortical remodeling across the lifespan in healthy brain reveals structural network vulnerability to neurodegeneration

AbstractBackgroundAging is the main risk factor for most of the neurodegenerative diseases. The aim of this study was to investigate typical cortical thinning changes across lifespan in the healthy brain revealing structural network vulnerability to neurodegeneration.MethodThe cohort included 128 healthy individuals aged 20‐85 years that underwent an MRI scan. Structural T1‐weighted images were used to estimate vertex‐wise cortical thickness maps, then grouped into 83 regions. For each region, cortical thickness trajectory with advancing age was estimated, including sex as covariate. Additionally, all regions were ranked based on their relative thickness at the end of the observed lifetime, assessing regional changes over time. Finally, regional mean thickness was correlated with relative change over time.ResultThe highest cortical thinning was observed in the temporal lobe (parahippocampal, entorhinal, superior and middle temporal and fusiform), in the frontal lobe (lateral orbitofrontal, superior and inferior frontal and rostral anterior cingulate), in the parietal lobe (the isthmus of cingulate, precuneus, supramarginal and inferior parietal) and in the insular cortex. Interestingly, occipital regions (cuneus, lateral occipital, lingual, pericalcarine), and motor and premotor areas (precentral, postcentral and paracentral regions) showed the least cortical thickness change relative to the whole brain. Finally, positive correlation was found between mean regional thickness and its relative change over time.ConclusionThis study highlights structural vulnerability of brain regions to aging. Furthermore, results provide information concerning trajectories of normal brain aging, identifying those areas that might be more vulnerable to the attack of neurodegeneration. Supported by: European Research Council (StG‐2016_714388_NeuroTRACK).

Characterizing brain structure among middle‐age and older Hispanics/Latinos in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) and SOL‐Investigation of Neurocognitive Aging (SOL‐INCA): Preliminary findings

AbstractBackgroundThe older Hispanic/Latino population in the U.S. is projected to grow faster than any racial/ethnic group in the country. Little is known about brain aging in this population, and we remain poorly equipped to detect and track brain changes in this population. We characterized brain aging in a sample of Hispanics/Latinos from diverse backgrounds and investigated differences by sex.MethodNunweighted=1,389 Hispanics/Latinos (ages 39‐85 years; 66% female) from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) underwent brain magnetic resonance imaging (MRI) as part of the Study of Latinos ‐ Investigation of Neurocognitive Aging MRI (SOL‐INCA MRI) ancillary study. MRI outcomes of interest included global (gray matter, total brain) and regional (lobar cortices, hippocampus) brain volumes, lateral ventricle volume, and total white matter hyperintensity (WMH) volume. All MRI measures were residualized for total cranial volume prior to calculating brain aging trajectories using linear regressions that included sex, height, and Hispanic/Latino background as terms in the model. We also tested for effect modification by sex.ResultMean age was 60.8± 10.3 years. Age was associated with decrements in total (β total =‐0.66; p<0.001) and hippocampal volumes (β hippocampus =‐0.20; p<0.001) as well as incremental enlargements in lateral ventricle and WMH volumes (β log_lateralvent =0.48; p<0.001; β log_WMH =0.54; p<0.001). Age was also inversely linked to total brain gray matter as well as all lobar cortical gray matter volumes. Age‐related decrements in total and regional brain volumes, but not lateral ventricle or WMH, were exacerbated in men relative to women (all p<0.05). Adjusting for height and background, women had larger total brain (standardized beta β total =0.27; p<0.001), frontal (β frontal =0.27; p<0.001), and parietal (β parietal =0.17; p=0.025) volumes, smaller hippocampal and lateral ventricle volumes, and larger gray matter volumes, but did not differ in WMH as compared to men.ConclusionThese findings suggest that increasing age is associated with smaller regional MRI brain measures in Hispanic/Latino individuals. Aging patterns in gray matter volumes appeared to be exacerbated among men compared to women whereas age‐related differences in lateral ventricular volume and white matter hyperintensities were consistent between sexes. Our findings help establish the trajectories of brain aging among middle‐aged and older Hispanics/Latinos.

Sex‐dependent age trajectories of subcortical brain volume: A UK Biobank study (N=39,544)

AbstractBackgroundUnderstanding the normative variation in brain structure across life may provide insights into healthy aging as well as neurological disorders such as Alzheimer’s disease (AD). Women are at greater risk of developing AD, but men tend to show faster rates of subcortical atrophy across adulthood. Sex‐dependent differences in male and female brain aging trajectories may change over the adult lifespan, and could play a role in differential risk for neurological illness. The current study maps normative trajectories (nomograms) of subcortical volume across adulthood and quantifies the interaction between age and sex in a large, healthy sample.MethodT1‐weighted brain MRI from a sample of UK Biobank participants free from psychiatric/neurological illness (; N=39,544; 44.6‐82.8 years) were segmented using FreeSurfer 7.1 to derive average left and right thalamus, putamen, pallidum, hippocampus, amygdala, caudate, nucleus accumbens and ventricle volumes. Normative quantile regression models (nomograms) were created to visualize aging trajectories for each volume. Linear mixed models were fit in binned age groups to assess age‐by‐sex interactions across middle to late adulthood.ResultNomograms showed volumetric loss across adulthood, except for ventricular volume which was larger with increasing age (). Compared to females, males showed a steeper slope of volume change with increasing age in all regions across the full age range (Cohen’s d: ‐0.14 ‐ 0.12) (). Binned‐age analysis showed males to have steeper volume loss trajectories in middle adulthood, with fewer age‐by‐sex interactions detected later in life for most structures.ConclusionIn a large sample of healthy adults, we found a structure‐specific interaction between age and sex, with males tending to show steeper age‐related volume loss trajectories compared to females until later decades of life, where trends appeared similar for men and women. This study provides normative subcortical aging trends and identifies potential sex‐dependent variations across life that may be used to understand healthy brain aging and risk for disorders such as AD.

A slower rate of sulcal widening in the brains of the nondemented oldest old

The relationships between aging and brain morphology have been reported in many previous structural brain studies. However, the trajectories of successful brain aging in the extremely old remain underexplored. In the limited research on the oldest old, covering individuals aged 85 years and older, there are very few studies that have focused on the cortical morphology, especially cortical sulcal features. In this paper, we measured sulcal width and depth as well as cortical thickness from T1-weighted scans of 290 nondemented community-dwelling participants aged between 76 and 103 years. We divided the participants into young old (between 76 and 84; mean = 80.35±2.44; male/female = 76/88) and oldest old (between 85 and 103; mean = 91.74±5.11; male/female = 60/66) groups. The results showed that most of the examined sulci significantly widened with increased age and that the rates of sulcal widening were lower in the oldest old. The spatial pattern of the cortical thinning partly corresponded with that of sulcal widening. Compared to females, males had significantly wider sulci, especially in the oldest old. This study builds a foundation for future investigations of neurocognitive disorders and neurodegenerative diseases in the oldest old, including centenarians.

Longitudinal trajectories of hippocampal volume in middle to older age community dwelling individuals

Understanding heterogeneity in brain aging trajectories is important to estimate the extent to which aging outcomes can be optimized. Although brain changes in late life are well-characterized, brain changes in middle age are not well understood. In this study, we investigated hippocampal change in a generally healthy community-living population of middle (n = 421, mean age 47.2 years) and older age (n = 411, mean age 63.0 years) individuals, over a follow-up of up to 12 years. Manually traced hippocampal volumes were analyzed using multilevel models and latent class analysis to investigate longitudinal aging trajectories and laterality and sex effects, and to identify subgroups that follow different aging trajectories. Hippocampal volumes decreased on average by 0.18%/year in middle age and 0.3%/year in older age. Men tended to experience steeper declines than women in middle age only. Three subgroups of individuals following different trajectories were identified in middle age and 2 in older age. Contrary to expectations, the subgroup containing two-thirds of older age participants maintained stable hippocampal volumes across the follow-up.

Women's brain aging: Effects of sex-hormone exposure, pregnancies, and genetic risk for Alzheimer's disease.

Sex hormones such as estrogen fluctuate across the female lifespan, with high levels during reproductive years and natural decline during the transition to menopause. Women's exposure to estrogen may influence their heightened risk of Alzheimer's disease (AD) relative to men, but little is known about how it affects normal brain aging. Recent findings from the UK Biobank demonstrate less apparent brain aging in women with a history of multiple childbirths, highlighting a potential link between sex‐hormone exposure and brain aging. We investigated endogenous and exogenous sex‐hormone exposure, genetic risk for AD, and neuroimaging‐derived biomarkers for brain aging in 16,854 middle to older‐aged women. The results showed that as opposed to parity, higher cumulative sex‐hormone exposure was associated with more evident brain aging, indicating that i) high levels of cumulative exposure to sex‐hormones may have adverse effects on the brain, and ii) beneficial effects of pregnancies on the female brain are not solely attributable to modulations in sex‐hormone exposure. In addition, for women using hormonal replacement therapy (HRT), starting treatment earlier was associated with less evident brain aging, but only in women with a genetic risk for AD. Genetic factors may thus contribute to how timing of HRT initiation influences women's brain aging trajectories.

The maternal brain: Region-specific patterns of brain aging are traceable decades after childbirth.

Pregnancy involves maternal brain adaptations, but little is known about how parity influences women's brain aging trajectories later in life. In this study, we replicated previous findings showing less apparent brain aging in women with a history of childbirths, and identified regional brain aging patterns linked to parity in 19,787 middle‐ and older‐aged women. Using novel applications of brain‐age prediction methods, we found that a higher number of previous childbirths were linked to less apparent brain aging in striatal and limbic regions. The strongest effect was found in the accumbens—a key region in the mesolimbic reward system, which plays an important role in maternal behavior. While only prospective longitudinal studies would be conclusive, our findings indicate that subcortical brain modulations during pregnancy and postpartum may be traceable decades after childbirth.

Occupational Physical Stress Is Negatively Associated With Hippocampal Volume and Memory in Older Adults.

Our jobs can provide intellectually and socially enriched environments but also be the source of major psychological and physical stressors. As the average full-time worker spends >8 h at work per weekday and remains in the workforce for about 40 years, occupational experiences must be important factors in cognitive and brain aging. Therefore, we studied whether occupational complexity and stress are associated with hippocampal volume and cognitive ability in 99 cognitively normal older adults. We estimated occupational complexity, physical stress, and psychological stress using the Work Design Questionnaire (Morgeson and Humphrey, 2006), Quantitative Workload Inventory and Interpersonal Conflict at Work Scale (Spector and Jex, 1998). We found that physical stress, comprising physical demands and work conditions, was associated with smaller hippocampal volume and poorer memory performance. These associations were independent of age, gender, brain size, socioeconomic factors (education, income, and job title), duration of the job, employment status, leisure physical activity and general stress. This suggests that physical demands at work and leisure physical activity may have largely independent and opposite effects on brain and cognitive health. Our findings highlight the importance of considering midlife occupational experiences, such as work physical stress, in understanding individual trajectories of cognitive and brain aging.

Striatal iron content is linked to reduced fronto-striatal brain function under working memory load

Non-heme iron accumulation contributes to age-related decline in brain structure and cognition via a cascade of oxidative stress and inflammation, although its effect on brain function is largely unexplored. Thus, we examine the impact of striatal iron on dynamic range of BOLD modulation to working memory load. N ​= ​166 healthy adults (age 20–94) underwent cognitive testing and an imaging session including n-back (0-, 2-, 3-, and 4-back fMRI), R2*-weighted imaging, and pcASL to measure cerebral blood flow. A statistical model was constructed to predict voxelwise BOLD modulation by age, striatal iron content and an age ​× ​iron interaction, controlling for cerebral blood flow, sex, and task response time. A significant interaction between age and striatal iron content on BOLD modulation was found selectively in the putamen, caudate, and inferior frontal gyrus. Greater iron was associated with reduced modulation to difficulty, particularly in middle-aged and younger adults with greater iron content. Further, iron-related decreases in modulation were associated with poorer executive function in an age-dependent manner. These results suggest that iron may contribute to differences in functional brain activation prior to older adulthood, highlighting the potential role of iron as an early factor contributing to trajectories of functional brain aging.

Effects of cerebrovascular micropathology upon cognitive impairment and brain aging trajectories subsequent to geriatric traumatic brain injury

Effects of cerebrovascular micropathology upon cognitive impairment and brain aging trajectories subsequent to geriatric traumatic brain injury

Trajectories of Physiological Brain Aging and Related Factors in People Aged from 20 to over-80.

In this study, we investigated a long-term trajectory of brain aging (from the 20 s to over-80) in cognitively normal (CN) individuals. We further determined whether differences in sex, education years, and apolipoprotein E ε 4 status affect age-related cortical thinning. A total of 2,944 CN individuals who underwent high-resolution (3.0-Tesla) magnetic resonance imaging were included in this study. Cortical thickness was measured using a surface-based method. Multiple linear regression analyses were performed to evaluate age-related cortical thinning and related factors. Compared to those in their 20 s/30 s, participants in their 40 s showed thinning primarily in the medial and lateral frontal and inferior parietal regions, and cortical thinning occurred across most of the cortices with increasing age. Notably, the precuneus, inferior temporal and lateral occipital regions were relatively spared until later in life. Male and lower education years were associated with greater cortical thinning with distinct regional specificity. Our findings provide an important clue to understanding the mechanism of age-related cognitive decline and new strategies for preventing the acceleration of pathological brain aging.

Accelerated and Premature Aging Characterizing Regional Cortical Volume Loss in Human Immunodeficiency Virus Infection: Contributions From Alcohol, Substance Use, and Hepatitis C Coinfection

BackgroundLife expectancy of successfully treated human immunodeficiency virus (HIV)–infected individuals is approaching normal longevity. The growing HIV population ≥50 years of age is now at risk of developing HIV-associated neurocognitive disorder, acquiring coinfection with the hepatitis C virus (HCV), and engaging in hazardous drinking or drug consumption that can adversely affect trajectories of the healthy aging of brain structures. MethodsThis cross-sectional/longitudinal study quantified regional brain volumes from 1101 magnetic resonance imaging scans collected over 14 years in 549 participants (25 to 75 years of age): 68 HIV-infected individuals without alcohol dependence, 60 HIV-infected individuals with alcohol dependence, 222 alcohol-dependent individuals, and 199 control subjects. We tested 1) whether localized brain regions in HIV-infected individuals exhibited accelerated aging, or alternatively, nonaccelerated premature aging deficits; and 2) the extent to which alcohol or substance dependence or HCV coinfection altered brain aging trajectories. ResultsThe HIV-infected cohort exhibited steeper declining volume trajectories than control subjects, consistently in the frontal cortex. Nonaccelerated volume deficits occurred in the temporal, parietal, insular, and cingulate regions of all three diagnostic groups. Alcohol and drug dependence comorbidities and HCV coinfection exacerbated HIV-related volume deficits. Accelerated age interactions in frontal and posterior parietal volumes endured in HIV-infected individuals free of alcohol or substance dependence and HCV infection comorbidities. Functionally, poorer HIV-associated neurocognitive disorder scores and Veterans Aging Cohort Study indices correlated with smaller regional brain volumes in the HIV-infected individuals without alcohol dependence and alcohol-dependent groups. ConclusionsHIV infection itself may confer a heightened risk of accelerated brain aging, potentially exacerbated by HCV coinfection and substance dependency. Confirmation would require a prospective study with a preinfection baseline.

Heterogeneity of structural and functional imaging patterns of advanced brain aging revealed via machine learning methods.

Disentangling the heterogeneity of brain aging in cognitively normal older adults is challenging, as multiple co-occurring pathologic processes result in diverse functional and structural changes. Capitalizing on machine learning methods applied to magnetic resonance imaging data from 400 participants aged 50 to 96 years in the Baltimore Longitudinal Study of Aging, we constructed normative cross-sectional brain aging trajectories of structural and functional changes. Deviations from typical trajectories identified individuals with resilient brain aging and multiple subtypes of advanced brain aging. We identified 5 distinct phenotypes of advanced brain aging. One group included individuals with relatively extensive structural and functional loss and high white matter hyperintensity burden. Another subgroup showed focal hippocampal atrophy and lower posterior-cingulate functional coherence, low white matter hyperintensity burden, and higher medial-temporal connectivity, potentially reflecting high brain tissue reserve counterbalancing brain loss that is consistent with early stages of Alzheimer's disease. Other subgroups displayed distinct patterns. These results indicate that brain changes should not be measured seeking a single signature of brain aging but rather via methods capturing heterogeneity and subtypes of brain aging. Our findings inform future studies aiming to better understand the neurobiological underpinnings of brain aging imaging patterns.

APOEε4 Genotype and Hypertension Modify 8-year Cortical Thinning: Five Occasion Evidence from the Seattle Longitudinal Study.

We investigated individual differences in longitudinal trajectories of brain aging in cognitively normal healthy adults from the Seattle Longitudinal Study covering 8 years of longitudinal change (across 5 occasions) in cortical thickness in 249 midlife and older adults (52-95 years old). We aimed to understand true brain change; examine the influence of salient risk factors that modify an individual's rate of cortical thinning; and compare cross-sectional age-related differences in cortical thickness to longitudinal within-person cortical thinning. We used Multivariate Multilevel Modeling to simultaneously model dependencies among 5 lobar composites (Frontal, Parietal, Temporal, Occipital, and Cingulate [CING]) and account for the longitudinal nature of the data. Results indicate (1) all 5 lobar composites significantly atrophied across 8 years, showing nonlinear longitudinal rate of cortical thinning decelerated over time, (2) longitudinal thinning was significantly altered by hypertension andApolipoprotein-E ε4 (APOEε4), varying by location: Frontal and CING thinned more rapidly in APOEε4 carriers. Notably, thinning of parietal and occipital cortex showed synergistic effect of combined risk factors, where individuals who were both APOEε4 carriers and hypertensive had significantly greater 8-year thinning than those with either risk factor alone or neither risk factor, (3) longitudinal thinning was 3 times greater than cross-sectional estimates of age-related differences in thickness in parietal and occipital cortices.

Premature Brain Aging in Baboons Resulting from Moderate Fetal Undernutrition.

Contrary to the known benefits from a moderate dietary reduction during adulthood on life span and health, maternal nutrient reduction during pregnancy is supposed to affect the developing brain, probably resulting in impaired brain structure and function throughout life. Decreased fetal nutrition delivery is widespread in both developing and developed countries, caused by poverty and natural disasters, but also due to maternal dieting, teenage pregnancy, pregnancy in women over 35 years of age, placental insufficiency, or multiples. Compromised development of fetal cerebral structures was already shown in our baboon model of moderate maternal nutrient reduction. The present study was designed to follow-up and evaluate the effects of moderate maternal nutrient reduction on individual brain aging in the baboon during young adulthood (4–7 years; human equivalent 14–24 years), applying a novel, non-invasive neuroimaging aging biomarker. The study reveals premature brain aging of +2.7 years (p < 0.01) in the female baboon exposed to fetal undernutrition. The effects of moderate maternal nutrient reduction on individual brain aging occurred in the absence of fetal growth restriction or marked maternal weight reduction at birth, which stresses the significance of early nutritional conditions in life-long developmental programming. This non-invasive MRI biomarker allows further longitudinal in vivo tracking of individual brain aging trajectories to assess the life-long effects of developmental and environmental influences in programming paradigms, aiding preventive and curative treatments on cerebral atrophy in experimental animal models and humans.

Normal-appearing cerebral white matter in healthy adults: mean change over 2 years and individual differences in change

Diffusion tensor imaging studies show age-related differences in cerebral white matter (WM). However, few have studied WM changes over time, and none evaluated individual differences in change across a wide age range. Here, we examined 2-year WM change in 96 healthy adults (baseline age, 19–78 years), individual differences in change, and the influence of vascular and metabolic risk thereon. Fractional anisotropy (FA), axial diffusivity, and radial diffusivity (RD) represented microstructural properties of normal-appearing WM within 13 regions. Cross-sectional analyses revealed age-related differences in all WM indices across the regions. In contrast, latent change score analyses showed longitudinal declines in axial diffusivity in association and projection fibers and increases in anterior commissural fibers. FA and RD evidenced a less consistent pattern of change. Metabolic risk mediated the effects of age on FA and RD change in corpus callosum body and dorsal cingulum. These findings underscore the importance of longitudinal studies in evaluating individual differences in change and the role of metabolic factors in shaping trajectories of brain aging.

Trajectories of brain aging in middle-aged and older adults: Regional and individual differences

The human brain changes with age. However, the rate and the trajectories of change vary among the brain regions and among individuals, and the reasons for these differences are unclear. In a sample of healthy middle-aged and older adults, we examined mean volume change and individual differences in the rate of change in 12 regional brain volumes over approximately 30months. In addition to the baseline assessment, there were two follow-ups, 15months apart. We observed significant average shrinkage of the hippocampus, entorhinal cortex, orbital–frontal cortex, and cerebellum in each of the intervals. Shrinkage of the hippocampus accelerated with time, whereas shrinkage of the caudate nucleus, prefrontal subcortical white matter, and corpus callosum emerged only at the second follow-up. Throughout both assessment intervals, the mean volumes of the lateral prefrontal and primary visual cortices, putamen, and pons did not change. Significant individual differences in shrinkage rates were observed in the lateral prefrontal cortex, the cerebellum, and all the white matter regions throughout the study, whereas additional regions (medial–temporal structures, the insula, and the basal ganglia) showed significant individual variation in change during the second follow-up. No individual variability was noted in the change of orbital frontal and visual cortices. In two white matter regions, we were able to identify factors associated with individual differences in brain shrinkage. In corpus callosum, shrinkage rate was greater in persons with hypertension, and in the pons, women and carriers of the ApoEε4 allele exhibited declines not noted in the whole sample.