White Matter Integrity Supports BOLD Signal Variability and Cognitive Performance in the Aging Human Brain

Decline in cognitive performance in old age is linked to both suboptimal neural processing in grey matter (GM) and reduced integrity of white matter (WM), but the whole-brain structure-function-cognition associations remain poorly understood. Here we apply a novel measure of GM processing–moment-to-moment variability in the blood oxygenation level-dependent signal (SD_BOLD)—to study the associations between GM function during resting state, performance on four main cognitive domains (i.e., fluid intelligence, perceptual speed, episodic memory, vocabulary), and WM microstructural integrity in 91 healthy older adults (aged 60-80 years). We modeled the relations between whole-GM SD_BOLD with cognitive performance using multivariate partial least squares analysis. We found that greater SD_BOLD was associated with better fluid abilities and memory. Most of regions showing behaviorally relevant SD_BOLD (e.g., precuneus and insula) were localized to inter- or intra-network “hubs” that connect and integrate segregated functional domains in the brain. Our results suggest that optimal dynamic range of neural processing in hub regions may support cognitive operations that specifically rely on the most flexible neural processing and complex cross-talk between different brain networks. Finally, we demonstrated that older adults with greater WM integrity in all major WM tracts had also greater SD_BOLD and better performance on tests of memory and fluid abilities. We conclude that SD_BOLD is a promising functional neural correlate of individual differences in cognition in healthy older adults and is supported by overall WM integrity.     

Physical Activity and Cardiorespiratory Fitness Are Beneficial for White Matter in Low-Fit Older Adults

Physical activity (PA) and cardiorespiratory fitness (CRF) are associated with better cognitive function in late life, but the neural correlates for these relationships are unclear. To study these correlates, we examined the association of both PA and CRF with measures of white matter (WM) integrity in 88 healthy low-fit adults (age 60–78). Using accelerometry, we objectively measured sedentary behavior, light PA, and moderate to vigorous PA (MV-PA) over a week. We showed that greater MV-PA was related to lower volume of WM lesions. The association between PA and WM microstructural integrity (measured with diffusion tensor imaging) was region-specific: light PA was related to temporal WM, while sedentary behavior was associated with lower integrity in the parahippocampal WM. Our findings highlight that engaging in PA of various intensity in parallel with avoiding sedentariness are important in maintaining WM health in older age, supporting public health recommendations that emphasize the importance of active lifestyle.     

The Relevance of Short-Range Fibers to Cognitive Efficiency and Brain Activation in Aging and Dementia

The integrity of structural connectivity in a functional brain network supports the efficiency of neural processing within relevant brain regions. This study aimed to quantitatively investigate the short- and long-range fibers, and their differential roles in the lower cognitive efficiency in aging and dementia. Three groups of healthy young, healthy older adults and patients with Alzheimer''s disease (AD) participated in this combined functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI) study on prospective memory (PM). Short- and long-range fiber tracts within the PM task engaged brain networks were generated. The correlation between the fMRI signal change, PM performance and the DTI characters were calculated. FMRI results showed that the PM-specific frontal activations in three groups were distributed hierarchically along the rostrocaudal axis in the frontal lobe. In an overall PM condition generally activated brain network among the three groups, tractography was used to generate the short-range fibers, and they were found impaired in both healthy older adults and AD patients. However, the long-range fiber tracts were only impaired in AD. Additionally, the mean diffusivity (MD) of short-range but not long-range fibers was positively correlated with fMRI signal change and negatively correlated with the efficiency of PM performance. This study suggests that the disintegrity of short-range fibers may contribute more to the lower cognitive efficiency and higher compensatory brain activation in healthy older adults and more in AD patients.     

White Matter Hyperintensities among Older Adults Are Associated with Futile Increase in Frontal Activation and Functional Connectivity during Spatial Search

The mechanisms by which aging and other processes can affect the structure and function of brain networks are important to understanding normal age-related cognitive decline. Advancing age is known to be associated with various disease processes, including clinically asymptomatic vascular and inflammation processes that contribute to white matter structural alteration and potential injury. The effects of these processes on the function of distributed cognitive networks, however, are poorly understood. We hypothesized that the extent of magnetic resonance imaging white matter hyperintensities would be associated with visual attentional control in healthy aging, measured using a functional magnetic resonance imaging search task. We assessed cognitively healthy older adults with search tasks indexing processing speed and attentional control. Expanding upon previous research, older adults demonstrate activation across a frontal-parietal attentional control network. Further, greater white matter hyperintensity volume was associated with increased activation of a frontal network node independent of chronological age. Also consistent with previous research, greater white matter hyperintensity volume was associated with anatomically specific reductions in functional magnetic resonance imaging functional connectivity during search among attentional control regions. White matter hyperintensities may lead to subtle attentional network dysfunction, potentially through impaired frontal-parietal and frontal interhemispheric connectivity, suggesting that clinically silent white matter biomarkers of vascular and inflammatory injury can contribute to differences in search performance and brain function in aging, and likely contribute to advanced age-related impairments in cognitive control.     

Interleukin-6, Age,and Corpus Callosum Integrity

The contribution of inflammation to deleterious aging outcomes is increasingly recognized; however, little is known about the complex relationship between interleukin-6 (IL-6) and brain structure, or how this association might change with increasing age. We examined the association between IL-6, white matter integrity, and cognition in 151 community dwelling older adults, and tested whether age moderated these associations. Blood levels of IL-6 and vascular risk (e.g., homocysteine), as well as health history information, were collected. Processing speed assessments were administered to assess cognitive functioning, and we employed tract-based spatial statistics to examine whole brain white matter and regions of interest. Given the association between inflammation, vascular risk, and corpus callosum (CC) integrity, fractional anisotropy (FA) of the genu, body, and splenium represented our primary dependent variables. Whole brain analysis revealed an inverse association between IL-6 and CC fractional anisotropy. Subsequent ROI linear regression and ridge regression analyses indicated that the magnitude of this effect increased with age; thus, older individuals with higher IL-6 levels displayed lower white matter integrity. Finally, higher IL-6 levels were related to worse processing speed; this association was moderated by age, and was not fully accounted for by CC volume. This study highlights that at older ages, the association between higher IL-6 levels and lower white matter integrity is more pronounced; furthermore, it underscores the important, albeit burgeoning role of inflammatory processes in cognitive aging trajectories.     

Physical Activity in Non-Frail and Frail Older Adults

Introduction

Physical activity (PA) is important for healthy ageing. Better insight into objectively measured PA levels in older adults is needed, since most previous studies employed self-report measures for PA assessment, which are associated with overestimation of PA.

Aim

This study aimed to provide insight in objectively measured indoor and outdoor PA of older adults, and in PA differences by frailty levels.

Methods

Data were collected among non-frail (N = 74) and frail (N = 10) subjects, aged 65 to 89 years. PA, measured for seven days with accelerometers and GPS-devices, was categorized into three levels of intensity (sedentary, light, and moderate-to-vigorous PA).

Results

Older adults spent most time in sedentary and light PA. Subjects spent 84.7%, 15.1% and 0.2% per day in sedentary, light and moderate-to-vigorous PA respectively. On average, older adults spent 9.8 (SD 23.7) minutes per week in moderate-to-vigorous activity, and 747.0 (SD 389.6) minutes per week in light activity. None of the subjects met the WHO recommendations of 150 weekly minutes of moderate-to-vigorous PA. Age-, sex- and health status-adjusted results revealed no differences in PA between non-frail and frail older adults. Subjects spent significantly more sedentary time at home, than not at home. Non-frail subjects spent significantly more time not at home during moderate-to-vigorous activities, than at home.

Conclusions

Objective assessment of PA in older adults revealed that most PA was of light intensity, and time spent in moderate-to-vigorous PA was very low. None of the older adults met the World Health Organization recommendations for PA. These levels of MVPA are much lower than generally reported based on self-reported PA. Future studies should employ objective methods, and age specific thresholds for healthy PA levels in older adults are needed. These results emphasize the need for effective strategies for healthy PA levels for the growing proportion of older adults.     

Age-related neural dedifferentiation in the motor system

Recent neuroimaging studies using multi-voxel pattern analysis (MVPA) show that distributed patterns of brain activation elicited by different visual stimuli are less distinctive in older adults than in young adults. However, less is known about the effects of aging on the neural representation of movement. The present study used MVPA to compare the distinctiveness of motor representations in young and older adults. We also investigated the contributions of brain structure to age differences in the distinctiveness of motor representations. We found that neural distinctiveness was reduced in older adults throughout the motor control network. Although aging was also associated with decreased gray matter volume in these regions, age differences in motor distinctiveness remained significant after controlling for gray matter volume. Our results suggest that age-related neural dedifferentiation is not restricted to sensory perception and is instead a more general feature of the aging brain.     

Age Differences in Neural Activity during Slot Machine Gambling: An fMRI Study

This study aimed to assess the potential association between age-related prefrontal brain changes and slot machine gambling, an activity that has become increasingly popular among older adults. Functional magnetic resonance imaging was used to assess healthy older and younger adults whilst playing a slot machine. Results revealed that the older group over-recruited several bilateral and contralateral brain structures relative to the younger group. Specifically, older adults exhibited increased neural activation in the superior prefrontal cortex and left orbitofrontal cortex, indicating greater reliance on these structures. These results suggest a compensatory mechanism, by which older adults recruit a greater number of neural networks from both hemispheres to complete the same gambling task as their younger peers. The broader implications of these findings are discussed in relation to theories of neurocognitive and degenerative change that occurs in late adulthood.     

Asociación entre la longitud de los telómeros y deterioro cognitivo en adultos mayores

IntroductionCognitive impairment is a transition stage between normal aging and dementia, the prevalence of last one increases with age; the damage of the functions and physical integrity, places the older adult in a greater susceptibility to get sick. Telomere length is a hallmark of aging to characterize this phenotype, as well as a biomarker that reflects the underlying state of the cell. In this work, the relative length of telomeres in older adults with cognitive impairment was correlated.Material and methodsObservational-analytical study, in samples of adult patients older than 65 years with and without cognitive impairment, in whom the relative length of telomeres was measured.ResultsNinety samples of older adults were included in the study and in the association analysis according to multivariate logistic models, cognitive impairment showed almost five times more risk for telomere shortening in relation to the presence of the diagnosis of cognitive impairment (Odds ratio 4.88, p = 0.027).ConclusionsWhen correlating the relative length of telomeres in older adults diagnosed with cognitive impairment, this association was confirmed for shorter.     

Aging Brain from a Network Science Perspective: Something to Be Positive About?

To better understand age differences in brain function and behavior, the current study applied network science to model functional interactions between brain regions. We observed a shift in network topology whereby for older adults subcortical and cerebellar structures overlapping with the Salience network had more connectivity to the rest of the brain, coupled with fragmentation of large-scale cortical networks such as the Default and Fronto-Parietal networks. Additionally, greater integration of the dorsal medial thalamus and red nucleus in the Salience network was associated with greater satisfaction with life for older adults, which is consistent with theoretical predictions of age-related increases in emotion regulation that are thought to help maintain well-being and life satisfaction in late adulthood. In regard to cognitive abilities, greater ventral medial prefrontal cortex coherence with its topological neighbors in the Default Network was associated with faster processing speed. Results suggest that large-scale organizing properties of the brain differ with normal aging, and this perspective may offer novel insight into understanding age-related differences in cognitive function and well-being.     

fMRI-EEG study of healthy human brain responses to functional loads

The functional magnetic resonance imaging (fMRI) and EEG responses to identical functional (visual and motor) loads have been compared in ten healthy subjects with the use of individual structural MRIs of the brain. It has been established that an increase in the coherence of the EEG α waves corresponds mostly to the zone of the fMRI response (as a +BOLD reaction). Reactive rearrangements, according to the data of fMRI and, particularly, EEG studies, are characterized by pronounced interindividual variation, which increases along with the functional test complexity. The fMRI responses have shown a greater locality and closer dependence on the modality of presented stimuli than EEG rearrangements, which underline the systemic character of brain response to functional loads. The ?BOLD response accompanying the local +BOLD effect is more generalized, without distinct topographic referencing to the functional load modality; it conforms most of all to the decrease in the EEG’s coherence.     

Disruption of large-scale brain systems in advanced aging

Cognitive decline is commonly observed in advanced aging even in the absence of disease. Here we explore the possibility that normal aging is accompanied by disruptive alterations in the coordination of large-scale brain systems that support high-level cognition. In 93 adults aged 18 to 93, we demonstrate that aging is characterized by marked reductions in normally present functional correlations within two higher-order brain systems. Anterior to posterior components within the default network were most severely disrupted with age. Furthermore, correlation reductions were severe in older adults free from Alzheimer's disease (AD) pathology as determined by amyloid imaging, suggesting that functional disruptions were not the result of AD. Instead, reduced correlations were associated with disruptions in white matter integrity and poor cognitive performance across a range of domains. These results suggest that cognitive decline in normal aging arises from functional disruption in the coordination of large-scale brain systems that support cognition.     

Greater BOLD Variability in Older Compared with Younger Adults during Audiovisual Speech Perception

Older adults exhibit decreased performance and increased trial-to-trial variability on a range of cognitive tasks, including speech perception. We used blood oxygen level dependent functional magnetic resonance imaging (BOLD fMRI) to search for neural correlates of these behavioral phenomena. We compared brain responses to simple speech stimuli (audiovisual syllables) in 24 healthy older adults (53 to 70 years old) and 14 younger adults (23 to 39 years old) using two independent analysis strategies: region-of-interest (ROI) and voxel-wise whole-brain analysis. While mean response amplitudes were moderately greater in younger adults, older adults had much greater within-subject variability. The greatly increased variability in older adults was observed for both individual voxels in the whole-brain analysis and for ROIs in the left superior temporal sulcus, the left auditory cortex, and the left visual cortex. Increased variability in older adults could not be attributed to differences in head movements between the groups. Increased neural variability may be related to the performance declines and increased behavioral variability that occur with aging.     

Evaluation of Metabolic Risk in Prepubertal Girls Versus Boys in Relation to Fitness and Physical Activity

BackgroundLow levels of cardiorespiratory fitness (CRF) and physical activity (PA) are associated with a risk of the development of metabolic syndrome. Contradictory findings are reported in the literature regarding the influence of sex and CRF and PA on metabolic changes.ObjectiveThe aim of this study was to analyze the effects of CRF and PA on lipid and carbohydrate metabolism biomarkers in boys and girls.MethodsA total of 82 prepubertal boys and 55 girls (7–12 years of age) were classified according to sex, low or high CRF, and performance or nonperformance of PA. Anthropometric and blood pressure (BP) measurements, plasma lipid profile values, glucose and insulin levels, and homeostasis model assessment for insulin resistance were analyzed.ResultsThe percentage of boys with high CRF and performance of PA was higher than that of girls (P < 0.05). When children of the same sex were compared, higher values for body mass index and waist circumference z-scores were found for boys with low CRF compared with boys with high CRF (P < 0.001) without differences between girls, and in all groups classified by PA. Systolic and diastolic BPs were higher in boys than in girls, in both CRF and PA groups (P < 0.05). In the low CRF and no PA groups, girls had higher plasma glucose, total cholesterol, and low-density lipoprotein cholesterol levels than boys, with higher high-density lipoprotein cholesterol and apolipoprotein A levels (P < 0.05).ConclusionsSex in relation to CRF and PA could affect the plasma lipid profile. These changes in girls are associated with low CRF and low levels of PA. Considering these results, we suggest the need to improve CRF and promote PA, especially in girls, to reduce metabolic risk.     

The Cognitive Control of Memory: Age Differences in the Neural Correlates of Successful Remembering and Intentional Forgetting

Successful memory encoding depends on the ability to intentionally encode relevant information (via differential encoding) and intentionally forget that which is irrelevant (via inhibition). Both cognitive processes have been shown to decline in aging and are theorized to underlie age-related deficits in the cognitive control of memory. The current study uses the Directed Forgetting paradigm in conjunction with fMRI to investigate age-related differences in both cognitive processes, with the specific aim of elucidating neural evidence supporting these theorized deficits. Results indicate relatively preserved differential encoding, with age differences consistent with previous models of age-related compensation (i.e., increased frontal and bilateral recruitment). Older adults did display noticeable differences in the recruitment of brain regions related to intentional forgetting, specifically exhibiting reduced activity in the right superior prefrontal cortex, a region shown to be critical to inhibitory processing. However, older adults exhibited increased reliance on processing in right inferior parietal lobe associated with successful forgetting. Activity in this region was negatively correlated with activity in the medial temporal lobe, suggesting a shift in the locus of inhibition compared to the frontally mediated inhibition observed in younger adults. Finally, while previous studies found intentional and incidental forgetting to be dissociable in younger adults, this differentiation appears to be reduced in older adults. The current results are the first to provide neural evidence for an age-related reduction in processes that support intentional forgetting.     

Physical Activity and Bone Health in Schoolchildren: The Mediating Role of Fitness and Body Fat

Background

The relationship between physical activity (PA) and bone health is well known, although the role of percent body fat (%BF) and fitness as confounders or mediators in this relationship remains uncertain.

Objective

To examine whether the association between PA and bone mineral content (BMC) is mediated by %BF and cardiorespiratory fitness (CRF).

Methods

In this cross sectional study, BMC, total %BF (by DXA), vigorous PA (VPA), CRF, age and height were measured in 132 schoolchildren (62 boys, aged 8–11 years). ANCOVA was used to test differences in BMC by %BF, CRF and VPA, controlling for different sets of confounders. Simple mediation analyses and serial multiple mediation analyses were fitted to examine whether the relationship between PA and BMC is mediated by %BF and fitness.

Results

Children with high %BF had higher total body BMC than their peers after controlling for all sets of confounders. Children with good CRF or VPA had significantly less total body BMC after controlling for age and sex but in children with good CRF this inverse relation disappeared after adjusting by %BF. %BF and CRF both act as a full mediator in the association between VPA and BMC, after inclusion of the potential confounders in the models.

Conclusion

Fitness and %BF seem to have a mediator role on the relationship between physical activity and bone mass.     

Disruptions in Brain Networks of Older Fallers Are Associated with Subsequent Cognitive Decline: A 12-Month Prospective Exploratory Study

Cognitive impairment and impaired mobility are major public health concerns. There is growing recognition that impaired mobility is an early biomarker of cognitive impairment and dementia. The neural basis for this association is currently unclear. We propose disrupted functional connectivity as a potential mechanism. In this 12-month prospective exploratory study, we compared functional connectivity of four brain networks– the default mode network (DMN), fronto-executive network (FEN), fronto-parietal network (FPN), and the primary motor sensory network (SMN) – between community-dwelling older adults with ≥ two falls in the last 12 months and their non-falling counterparts (≤ one fall in the last 12 months). Functional connectivity was examined both at rest and during a simple motor tapping task. Compared with non-fallers, fallers showed more connectivity between the DMN and FPN during right finger tapping (p = 0.04), and significantly less functional connectivity between the SMN and FPN during rest (p≤0.05). Less connectivity between the SMN and FPN during rest was significantly associated with greater decline in both cognitive function and mobility over the12-month period (r = −0.32 and 0.33 respectively; p≤0.04). Thus, a recent history of multiple falls among older adults without a diagnosis of dementia may indicate sub-clinical changes in brain function and increased risk for subsequent decline.     

Changes in memory processing with age

Over the years, a large body of literature has shown that humans display losses in memory with age, but that not all types of memory are affected equally. Similarly, recent evidence from functional neuroimaging experiments has revealed that, depending on the task, older adults can display greater or lesser activity in task-relevant brain areas compared with younger adults. Recent behavioral and neurophysiological experiments are furthering our understanding of the effects of aging on cognition. It appears that some brain changes seen with age may be compensatory.     

Under-recruitment and nonselective recruitment: dissociable neural mechanisms associated with aging

Frontal contributions to cognitive decline in aging were explored using functional MRI. Frontal regions active in younger adults during self-initiated (intentional) memory encoding were under-recruited in older adults. Older adults showed less activity in anterior-ventral regions associated with controlled use of semantic information. Under-recruitment was reversed by requiring semantic elaboration suggesting it stemmed from difficulty in spontaneous recruitment of available frontal resources. In addition, older adults recruited multiple frontal regions in a nonselective manner for both verbal and nonverbal materials. Lack of selectivity was not reversed during semantically directed encoding even when under-recruitment was diminished. These findings suggest two separate forms of age-associated change in frontal cortex: under-recruitment and nonselective recruitment. The former is reversible and potentially amenable to cognitive training; the latter may reflect a less malleable change associated with cognitive decline in advanced aging.     

Rapid and Quantitative Assay of Amyloid-Seeding Activity in Human Brains Affected with Prion Diseases

The infectious agents of the transmissible spongiform encephalopathies are composed of amyloidogenic prion protein, PrP^Sc. Real-time quaking-induced conversion can amplify very small amounts of PrP^Sc seeds in tissues/body fluids of patients or animals. Using this in vitro PrP-amyloid amplification assay, we quantitated the seeding activity of affected human brains. End-point assay using serially diluted brain homogenates of sporadic Creutzfeldt–Jakob disease patients demonstrated that 50% seeding dose (SD₅₀) is reached approximately 10¹⁰/g brain (values varies 10^8.79–10.63/g). A genetic case (GSS-P102L) yielded a similar level of seeding activity in an autopsy brain sample. The range of PrP^Sc concentrations in the samples, determined by dot-blot assay, was 0.6–5.4 μg/g brain; therefore, we estimated that 1 SD₅₀ unit was equivalent to 0.06–0.27 fg of PrP^Sc. The SD₅₀ values of the affected brains dropped more than three orders of magnitude after autoclaving at 121°C. This new method for quantitation of human prion activity provides a new way to reduce the risk of iatrogenic prion transmission.