Perceptual and conceptual processing of visual objects across the adult lifespan

Abstract: Making sense of the external world is vital for multiple domains of cognition, and so it is crucial that object recognition is maintained across the lifespan. We investigated age differences in perceptual and conceptual processing of visual objects in a population-derived sample of 85 healthy adults (24–87 years old) by relating measures of object processing to cognition across the lifespan. Magnetoencephalography (MEG) was recorded during a picture naming task to provide a direct measure of neural activity, that is not confounded by age-related vascular changes. Multiple linear regression was used to estimate neural responsivity for each individual, namely the capacity to represent visual or semantic information relating to the pictures. We find that the capacity to represent semantic information is linked to higher naming accuracy, a measure of task-specific performance. In mature adults, the capacity to represent semantic information also correlated with higher levels of fluid intelligence, reflecting domain-general performance. In contrast, the latency of visual processing did not relate to measures of cognition. These results indicate that neural responsivity measures relate to naming accuracy and fluid intelligence. We propose that maintaining neural responsivity in older age confers benefits in task-related and domain-general cognitive processes, supporting the brain maintenance view of healthy cognitive ageing

Distinct components of cardiovascular health are linked with age-related differences in cognitive abilities

Cardiovascular ageing contributes to cognitive impairment. However, the unique and synergistic contributions of multiple cardiovascular factors to cognitive function remain unclear because they are often condensed into a single composite score or examined in isolation. We hypothesized that vascular risk factors, electrocardiographic features and blood pressure indices reveal multiple latent vascular factors, with independent contributions to cognition. In a population-based deep-phenotyping study (n = 708, age 18–88), path analysis revealed three latent vascular factors dissociating the autonomic nervous system response from two components of blood pressure. These three factors made unique and additive contributions to the variability in crystallized and fluid intelligence. The discrepancy in fluid relative to crystallized intelligence, indicative of cognitive decline, was associated with a latent vascular factor predominantly expressing pulse pressure. This suggests that higher pulse pressure is associated with cognitive decline from expected performance. The effect was stronger in older adults. Controlling pulse pressure may help to preserve cognition, particularly in older adults. Our findings highlight the need to better understand the multifactorial nature of vascular aging

Poorer White Matter Microstructure Predicts Slower and More Variable Reaction Time Performance: Evidence for a Neural Noise Hypothesis in a Large Lifespan Cohort

Most prior research has focused on characterizing averages in cognition, brain characteristics, or behavior, and attempting to predict differences in these averages among individuals. However, this overwhelming focus on mean levels may leave us with an incomplete picture of what drives individual differences in behavioral phenotypes by ignoring the variability of behavior around an individual's mean. In particular, enhanced white matter (WM) structural microstructure has been hypothesized to support consistent behavioral performance by decreasing Gaussian noise in signal transfer. Conversely, lower indices of WM microstructure are associated with greater within-subject variance in the ability to deploy performance-related resources, especially in clinical populations. We tested a mechanistic account of the “neural noise” hypothesis in a large adult lifespan cohort (Cambridge Centre for Ageing and Neuroscience) with over 2500 adults (ages 18-102; 1508 female; 1173 male; 2681 behavioral sessions; 708 MRI scans) using WM fractional anisotropy to predict mean levels and variability in reaction time performance on a simple behavioral task using a dynamic structural equation model. By modeling robust and reliable individual differences in within-person variability, we found support for a neural noise hypothesis (Kail, 1997), with lower fractional anisotropy predicted individual differences in separable components of behavioral performance estimated using dynamic structural equation model, including slower mean responses and increased variability. These effects remained when including age, suggesting consistent effects of WM microstructure across the adult lifespan unique from concurrent effects of aging. Crucially, we show that variability can be reliably separated from mean performance using advanced modeling tools, enabling tests of distinct hypotheses for each component of performance

Ageing increases reliance on sensorimotor prediction through structural and functional differences in frontostriatal circuits

This is the author accepted manuscript. It is currently under an indefinite embargo pending publication by Nature Publishing Group.The control of voluntary movement changes markedly with age. A critical component of motor control is the integration of sensory information with predictions of the consequences of action, arising from internal models of movement. This leads to sensorimotor attenuation – a reduction in the perceived intensity of sensations from self-generated compared to external actions. Here we show that sensorimotor attenuation occurs in 98% of adults in a population-based cohort (n=325; 18-88 years; the Cambridge Centre for Ageing and Neuroscience). Importantly, attenuation increases with age, in proportion to reduced sensory sensitivity. This effect is associated with differences in the structure and functional connectivity of the pre-supplementary motor area (pre-SMA), assessed with magnetic resonance imaging. The results suggest that ageing alters the balance between the sensorium and predictive models, mediated by the pre-SMA and its connectivity in frontostriatal circuits. This shift may contribute to the motor and cognitive changes observed with age.Cam-CAN research was supported by the Biotechnology and Biological Sciences Research Council (BB/H008217/1). JBR and NW were supported by the James S. McDonnell Foundation 21st Century Science Initiative, Scholar Award in Understanding Human Cognition. JBR was also supported by Wellcome Trust [103838] and the Medical Research Council [MC-A060-5PQ30]. DMW was supported by the Wellcome Trust [097803], Human Frontier Science Program and the Royal Society Noreen Murray Professorship in Neurobiology. RNH was supported by the Medical Research Council [MC-A060-5PR10]. RAK was supported by a Sir Henry Wellcome Trust Postdoctoral Fellowship [107392]. LG was funded by a Rubicon grant from the Netherlands Organisation for Scientific Research (NWO)

Preserved cognitive functions with age are determined by domain-dependent shifts in network responsivity

Healthy ageing has disparate effects on different cognitive domains. The neural basis of these differences, however, is largely unknown. We investigated this question by using Independent Components Analysis to obtain functional brain components from 98 healthy participants aged 23–87 years from the population-based Cam-CAN cohort. Participants performed two cognitive tasks that show age-related decrease (fluid intelligence and object naming) and a syntactic comprehension task that shows age-related preservation. We report that activation of task-positive neural components predicts inter-individual differences in performance in each task across the adult lifespan. Furthermore, only the two tasks that show performance declines with age show age-related decreases in task-positive activation of neural components and decreasing default mode (DM) suppression. Our results suggest that distributed, multi-component brain responsivity supports cognition across the adult lifespan, and the maintenance of this, along with maintained DM deactivation, characterizes successful ageing and may explain differential ageing trajectories across cognitive domains.The Cambridge Centre for Ageing and Neuroscience (Cam-CAN) research was supported by the Biotechnology and Biological Sciences Research Council (grant number BB/H008217/1). K.A.T. is supported by Wellcome Trust (RG73750-RRZA/040) and British Academy Postdoctoral Fellowship (PF160048)

Multiple determinants of lifespan memory differences

Memory problems are among the most common complaints as people grow older. Using structural equation modeling of commensurate scores of anterograde memory from a large (N = 315), population-derived sample (www.cam-can.org), we provide evidence for three memory factors that are supported by distinct brain regions and show differential sensitivity to age. Associative memory and item memory are dramatically affected by age, even after adjusting for education level and fluid intelligence, whereas visual priming is not. Associative memory and item memory are differentially affected by emotional valence, and the age-related decline in associative memory is faster for negative than for positive or neutral stimuli. Gray-matter volume in the hippocampus, parahippocampus and fusiform cortex, and a white-matter index for the fornix, uncinate fasciculus and inferior longitudinal fasciculus, show differential contributions to the three memory factors. Together, these data demonstrate the extent to which differential ageing of the brain leads to differential patterns of memory loss

Noradrenergic-dependent functions are associated with age-related locus coeruleus signal intensity differences

Abstract: The locus coeruleus (LC), the origin of noradrenergic modulation of cognitive and behavioral function, may play an important role healthy ageing and in neurodegenerative conditions. We investigated the functional significance of age-related differences in mean normalized LC signal intensity values (LC-CR) in magnetization-transfer (MT) images from the Cambridge Centre for Ageing and Neuroscience (Cam-CAN) cohort - an open-access, population-based dataset. Using structural equation modelling, we tested the pre-registered hypothesis that putatively noradrenergic (NA)-dependent functions would be more strongly associated with LC-CR in older versus younger adults. A unidimensional model (within which LC-CR related to a single factor representing all cognitive and behavioral measures) was a better fit with the data than the a priori two-factor model (within which LC-CR related to separate NA-dependent and NA-independent factors). Our findings support the concept that age-related reduction of LC structural integrity is associated with impaired cognitive and behavioral function

HSP70-binding protein HSPBP1 regulates chaperone expression at a posttranslational level and is essential for spermatogenesis

Molecular chaperones play key roles during growth, development, and stress survival. The ability to induce chaperone expression enables cells to cope with the accumulation of nonnative proteins under stress and complete developmental processes with an increased requirement for chaperone assistance. Here we generate and analyze transgenic mice that lack the cochaperone HSPBP1, a nucleotide-exchange factor of HSP70 proteins and inhibitor of chaperone-assisted protein degradation. Male HSPBP1(−/−) mice are sterile because of impaired meiosis and massive apoptosis of spermatocytes. HSPBP1 deficiency in testes strongly reduces the expression of the inducible, antiapoptotic HSP70 family members HSPA1L and HSPA2, the latter of which is essential for synaptonemal complex disassembly during meiosis. We demonstrate that HSPBP1 affects chaperone expression at a posttranslational level by inhibiting the ubiquitylation and proteasomal degradation of inducible HSP70 proteins. We further provide evidence that the cochaperone BAG2 contributes to HSP70 stabilization in tissues other than testes. Our findings reveal that chaperone expression is determined not only by regulated transcription, but also by controlled degradation, with degradation-inhibiting cochaperones exerting essential prosurvival functions

An assessment of affective, cognitive and neural mechanisms underpinning social gambling behaviour in older adulthood

In recent decades, poker machine gambling has become a popular form of entertainment and recreation for retirees. Given the well-documented changes in cognitive and socioemotional functioning in late adulthood, it is surprising that these psychological mechanisms have received little attention within the gambling realm. This thesis, therefore, aimed to address this gap in the knowledge and documents a comprehensive series of studies which examined how subjective, psychophysiological, behavioural and neural changes experienced in late adulthood impact upon gambling outcomes. Study 1 investigated subjective affect and arousal in young (N = 34) and old (N = 32) participants as well as electrodermal arousal to varying gambling outcomes. Results affirmed a ‘positivity bias in old age’ for self-reported affect to gambling in general. However, there was no evidence to suggest that this positivity effect is reflected in electrodermal levels. Study 2 therefore employed a physiological index more sensitive to affective valence than electrodermal response – facial electromyography. It was found that compared to their younger peers (N = 32), the older adults (N = 30) exhibited subtle differences in the patterns of response to discrete win and loss events. Further, the older group demonstrated a bias for forgetting losses.Study 3 directly tested age-related differences in gambling within the behavioural domain. Results showed that the older adults (N = 30) persisted gambling longer than the younger adults (N = 30) in a lose-only setting, and that neuropsychological and physiological functioning is related to gambling behaviours. Lastly, Study 4 used functional magnetic resonance imaging to investigate potential age-related differences to gambling at the neural level. It was found that in comparison to the younger group (N = 8), the older group (N = 10) showed over-recruitment of bilateral and contralateral brain structures and in particular, demonstrated increased activation of the prefrontal cortices when engaged in gambling. Taken together, these studies indicate that the gambling profile of older adults consists of affective, cognitive, autonomic and neural differences to that of their younger peers. The broader implications of these findings are discussed in relation to the neurocognitive developmental changes in late adulthood, and their impact upon the popular social pastime of poker machine gambling