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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.

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. •Iron accumulation contributes to age-related decline in brain structure and cognition.•Effects of non-heme iron accumulation on brain function are largely unexplored.•Age by striatal iron interaction on BOLD modulation found selectively in striatum.•Greater iron associated with reduced modulation in middle-aged and younger adults.•Iron-related decreases in modulation associated with age-related poorer executive function.

Aging is associated with reduced resources needed to perform difficult cognitive tasks, but the neural underpinnings are not well understood, especially as there is scant evidence linking functional brain differences to aging cognition. Therefore, the current study examined modulation of fMRI activation from easier to harder spatial distance judgments across a large lifespan sample (N=161; ages 20–94) to identify when in the lifespan modulation to difficulty begins to show deficits and if age-related modulation predicts cognition. Analyses revealed two sets of regions in which modulation increased with difficulty due to either more activation (positive modulation) or more deactivation (negative modulation) to difficulty. These two networks evidenced differential aging trajectories: a right-lateralized fronto-parietal network that decreased in modulation to difficulty between middle- and older-age, and a network of regions in ventromedial prefrontal cortex, posterior cingulate, left angular and middle frontal gyri that showed decreased modulation at the transition from younger to middle-age. Critically, older adults who maintained negative modulation to difficulty showed higher task accuracy. Further, individuals who showed greater coupling between positive and negative modulation performed better on a fluid reasoning task. Age-related preservation of coupled modulation in both cognitive control regions and regions typically associated with default network may be a salient marker of how the brain adapts to maintain cognitive function as we age. •BOLD activity is up-modulated and down-modulated in response to cognitive difficulty.•Both positive modulation and negative modulation weaken with increasing age.•Negative modulation weakens earlier in the lifespan than positive modulation.•Greater coupling of positive and negative modulation predicts higher fluid reasoning.•Greater negative modulation in older adults predicts better task accuracy.

We examined functional activation across the adult lifespan in 316 healthy adults aged 20–89years on a judgment task that, across conditions, drew upon both semantic knowledge and ability to modulate neural function in response to cognitive challenge. Activation in core regions of the canonical semantic network (e.g., left IFG) were largely age-invariant, consistent with cognitive aging studies that show verbal knowledge is preserved across the lifespan. However, we observed a steady linear increase in activation with age in regions outside the core network, possibly as compensation to maintain function. Under conditions of increased task demands, we observed a stepwise reduction across the lifespan of modulation of activation to increasing task demands in cognitive control regions (frontal, parietal, anterior cingulate), paralleling the neural equivalent of “processing resources” described by cognitive aging theories. Middle-age was characterized by decreased modulation to task-demand in subcortical regions (caudate, nucleus accumbens, thalamus), and very old individuals showed reduced modulation to task difficulty in midbrain/brainstem regions (ventral tegmental, substantia nigra). These novel findings suggest that aging of activation to demand follows a gradient along the dopaminergic/nigrostriatal system, with earliest manifestation in fronto-parietal regions, followed by deficits in subcortical nuclei in middle-age and then to midbrain/brainstem dopaminergic regions in the very old. •Lifespan sample age 20–89 finds increasing activation with age on semantic judgment.•When processing demands are increased, modulation of activation declines with age.•Modulation decline gradient: higher to lower nigrostriatal regions as age increases.•Modulation decline is stepwise with age: steep drops in middle- and very old ages.

Recent evidence indicates that the relationship between increased beta-amyloid (Aβ) deposition and functional task-activation can be characterized by a non-linear trajectory of change in functional activation (Foster et al., 2017), explaining mixed results in prior literature showing both increases and decreases in activation as a function of beta-amyloid burden in cognitively normal adults. Here we sought to replicate this nonlinear effect in the same sample using a different functional paradigm to test the generalizability of this phenomenon. Participants (N = 68 healthy adults aged 49–94) underwent fMRI (0-, 2-, 3-, 4-back working memory task; WM) and 18F-Florbetapir PET scanning. A parametric WM load contrast was used as the dependent variable in a model with age, mean cortical Aβ, and Aβ2 as predictors. Results revealed that nonlinear amyloid (Aβ2) was a significant negative predictor of modulation of activation to WM load in two large inferior clusters: bilateral subcortical nuclei and bilateral lateral cerebellum. Individuals with slightly elevated Aβ burden evidenced greater modulation as compared to individuals with little or no Aβ burden, whereas individuals with the greatest Aβ burden evidenced lesser modulation as compared to individuals with slightly elevated Aβ. Increased modulation to WM load predicted better task accuracy and executive function measured outside the scanner. The current study provides further evidence for a dose-response, nonlinear relationship between increasing Aβ burden and alteration in brain activation in cognitively healthy adults, extending the existing evidence to dynamic range of activation to task difficulty, and reconciling seemingly discrepant effects of amyloid on brain function.

One of the earliest indicators of Alzheimer's disease pathology is the presence of beta-amyloid (Αβ) protein deposition. Significant amyloid deposition is evident even in older adults who exhibit little or no overt cognitive or memory impairment. Hippocampal-based processes that help distinguish between highly similar memory representations may be the most susceptible to early disease pathology. Amyloid associations with memory have been difficult to establish, possibly because typical memory assessments do not tax hippocampal operations sufficiently. Thus, the present study utilized a spatial mnemonic discrimination task designed to tax hippocampal pattern separation/completion processes in a sample of cognitively normal middle-aged and older adults (53–98 years old) who underwent PET 18F-Florbetapir Αβ scanning. The degree of interference between studied and new information varied, allowing for an examination of mnemonic discrimination as a function of mnemonic similarity. Results indicated that greater beta-amyloid burden was associated with poorer discrimination across decreasing levels of interference, suggesting that even subtle elevation of beta-amyloid in cognitively normal adults is associated with impoverished performance on a hippocampally demanding memory task. The present study demonstrates that degree of amyloid burden negatively impacts the ability of aging adults to accurately distinguish old from increasingly distinct new information, providing novel insight into the cognitive expression of beta-amyloid neuropathology.

BOLD fMRI has provided a wealth of information about the aging brain. A common finding is that posterior regions of the brain manifest an age-related decrease in activation while the anterior regions show an age-related increase. Several neurocognitive models have been proposed to interpret these findings. However, one issue that has not been sufficiently considered to date is that the BOLD signal is based on vascular responses secondary to neural activity. Thus the above findings could be in part due to a vascular change, especially in view of the expected decline of vascular health with age. In the present study, we aim to examine age-related differences in memory-encoding fMRI response in the context of vascular aging. One hundred and thirty healthy subjects ranging from 20 to 89years old underwent a scene-viewing fMRI task and, in the same session, cerebrovascular reactivity (CVR) was measured in each subject using a CO2-inhalation task. Without accounting for the influence of vascular changes, the task-activated fMRI signal showed the typical age-related decrease in visual cortex and medial temporal lobe (MTL), but manifested an increase in the right inferior frontal gyrus (IFG). In the same individuals, an age-related CVR reduction was observed in all of these regions. We then used a previously proposed normalization approach to calculate a CVR-corrected fMRI signal, which was defined as the uncorrected signal divided by CVR. Based on the CVR-corrected fMRI signal, an age-related increase is now seen in both the left and right sides of IFG; and no brain regions showed a signal decrease with age. We additionally used a model-based approach to examine the fMRI data in the context of CVR, which again suggested an age-related change in the two frontal regions, but not in the visual and MTL regions. •Examined age-related changes in fMRI response in the context of vascular aging•An age-related reduction in cerebral vascular reactivity was observed.•Corrected fMRI signal showed age increase in both left and right frontal lobes.•No age-related decrease was observed in corrected fMRI signal.

INTRODUCTION Understanding impact of environmental properties on Alzheimer's disease (AD) is paramount. Spatial complexity of one's routinely navigated environment is an important but understudied factor. METHODS A total of 660 older adults from National Alzheimer's Coordinating Center (NACC) dataset were geolocated and environmental complexity index derived from geospatial network landmarks and points‐of‐interest. Latent models tested mediation of spatial navigation‐relevant brain volumes and diagnosis (cognitively‐healthy, mild cognitive impairment [MCI], AD) on effect of environmental complexity on spatial behavior. RESULTS Greater environmental complexity was selectively associated with larger allocentric (but not egocentric) navigation‐related brain volumes, lesser diagnosis of MCI and AD, and better spatial behavioral performance, through indirect hierarchical mediation. DISCUSSION Findings support hypothesis that spatially complex environments positively impact navigation neural circuitry and spatial behavior function. Given the vulnerability of these very circuits to AD pathology, residing in spatially complex environments may be one factor to help stave off the brain atrophy that accompanies spatial navigation deficits across the AD spectrum.

Aging affects various structural and metabolic properties of the brain. However, associations among various aspects of brain aging are unclear. Moreover, those properties and associations among them may be modified by age-associated increase in vascular risk. In this study, we measured volume of brain regions that vary in their vulnerability to aging and estimated local iron content via T2* relaxometry. In 113 healthy adults (19–83years old), we examined prefrontal cortex (PFC), primary visual cortex (VC), hippocampus (HC), entorhinal cortex (EC), caudate nucleus (Cd), and putamen (Pt). In some regions (PFC, VC, Cd, and Pt) age-related differences in iron and volume followed similar patterns. However, in the medial–temporal structures, volume and iron content exhibited different age trajectories. Whereas age-related volume reduction was mild in HC and absent in EC, iron content evidenced significant age-related declines. In hypertensive participants significantly greater iron content was noted in all examined regions. Thus, iron content as measured by T2* may be a sensitive index of regional brain aging and may reveal declines that are more prominent than gross anatomical shrinkage. ►Aging differentially affects regional brain volume and iron concentration, but the relative magnitude of those effects have not been compared in vivo. ►In a sample of healthy adults, we observed similar patterns of age-related differences in volume and T2* (index of iron) neocortex and neostriatum content. ►In contrast, in the medial–temporal structures, iron accumulation showed stronger association with age than volume did. ►Hypertensive participants exhibited higher iron concentration than normotensives of the same age. ►Iron content as measured by T2* may be a sensitive index of regional brain aging.

Little is known about the neural correlates of within-person variability in cognitive performance. We investigated associations between regional brain volumes and trial-to-trial, block-to-block, and day-to-day variability in choice–reaction time, and episodic and working memory accuracy. Healthy younger (n=25) and older (n=18) adults underwent 101 daily assessments of cognitive performance, and their regional brain volumes were measured manually on magnetic resonance images. Results showed that smaller prefrontal white matter volumes were associated with higher block-to-block variability in choice–reaction time performance, with a stronger association observed among older adults. Smaller volumes of the dorsolateral prefrontal cortex covaried with higher block-to-block variability in episodic memory (number–word pair) performance. This association was stronger for younger adults. The observed associations between variability and brain volume were not due to individual differences in mean performance. Trial-to-trial and day-to-day variability in cognitive performance were unrelated to regional brain volume. We thus report novel findings demonstrating that block-by-block variability in cognitive performance is associated with integrity of the prefrontal regions and that between-person differences in different measures of variability of cognitive performance reflect different age-related constellations of behavioral and neural antecedents. ► Prefrontal white volume is related to block-to-block variability in reaction time. ► Prefrontal cortex volume is related to block-to-block variability in memory. ► These associations vary systematically between adult age groups.