Resting-state anticorrelations between medial and lateral prefrontal cortex: Association with working memory, aging, and individual differences

We examined how variation in working memory (WM) capacity due to aging or individual differences among young adults is associated with intrinsic or resting-state anticorrelations, particularly between (1) the medial prefrontal cortex (MPFC), a component of the default-mode network (DMN) that typically decreases in activation during external, attention-demanding tasks, and (2) the dorsolateral prefrontal cortex (DLPFC), a component of the fronto-parietal control network that supports executive functions and WM and typically increases in activation during attention-demanding tasks. We compared the magnitudes of MPFC-DLPFC anticorrelations between healthy younger and older participants (Experiment 1) and related the magnitudes of these anticorrelations to individual differences on two behavioral measures of WM capacity in two independent groups of young adults (Experiments 1 and 2). Relative to younger adults, older adults exhibited reductions in WM capacity and in MPFC-DLPFC anticorrelations. Within younger adults, greater MPFC-DLPFC anticorrelation at rest correlated with greater WM capacity. These findings show that variation in MPFC-DLPFC anticorrelations, whether related to aging or to individual differences, may reflect an intrinsic functional brain architecture supportive of WM capacity.National Institutes of Health (U.S.) (National Institute on Aging Grant R21 AG030770)National Institutes of Health (U.S.) (Grant T32 GM007484)Barbara J. Weedon Fund Fellowshi

Cognition, Persuasion and Decision Making in Older Consumers

Older adults constitute a rapidly growing demographic segment, but relatively little is known about them within consumer contexts: how they process information, respond to persuasive messages, and make decisions. We discuss extant findings from consumer behavior and related disciplines (e.g., cognitive psychology, neuroscience, social psychology, gerontology) as they pertain to the effects of aging on consumer memory, persuasion and decisionPeer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47045/1/11002_2005_Article_5903.pd

Shared and selective neural correlates of inhibition, facilitation, and shifting processes during executive control

A network of prefrontal and parietal regions has been implicated in executive control processes. However, the extent to which individual regions within this network are engaged in component control processes, such as inhibition of task-irrelevant stimulus attributes or shifting (switching) between attentional foci, remains controversial. Participants (N = 17) underwent functional magnetic resonance imaging while performing a global–local task in which the global and local levels could facilitate or interfere with one another. Stimuli were presented in blocks in which participants either constantly shifted between the global and local levels, or consistently responded to one level only. Activations related to inhibition and shifting processes were observed in a large network of bilateral prefrontal, parietal, and basal ganglia regions. Region of interest analyses were used to classify each region within this network as being common to inhibition and shifting, or preferential to one component process. Several regions were classified as being preferential to inhibition, including regions within the dorsolateral and ventrolateral prefrontal cortex, the parietal lobes, and the temporal–parietal junction. A limited set of regions in the parietal lobes and left dorsolateral prefrontal cortex were classified as preferential to shifting. There was a very large set of regions displaying activation common to both inhibition and shifting processes, including regions within the dorsolateral prefrontal cortex, anterior cingulate, and basal ganglia. Several of these common regions were also involved during facilitation, suggesting that they are responsive to the number of task-salient channels of information, rather than purely to demands on control processes.National Institute of Mental Health (U.S.) (MH061426)National Institute on Aging (AG021847

Genetic variants and functional pathways associated with resilience to Alzheimer\u27s disease.

Approximately 30% of older adults exhibit the neuropathological features of Alzheimer\u27s disease without signs of cognitive impairment. Yet, little is known about the genetic factors that allow these potentially resilient individuals to remain cognitively unimpaired in the face of substantial neuropathology. We performed a large, genome-wide association study (GWAS) of two previously validated metrics of cognitive resilience quantified using a latent variable modelling approach and representing better-than-predicted cognitive performance for a given level of neuropathology. Data were harmonized across 5108 participants from a clinical trial of Alzheimer\u27s disease and three longitudinal cohort studies of cognitive ageing. All analyses were run across all participants and repeated restricting the sample to individuals with unimpaired cognition to identify variants at the earliest stages of disease. As expected, all resilience metrics were genetically correlated with cognitive performance and education attainment traits (P-values \u3c 2.5 × 10-20), and we observed novel correlations with neuropsychiatric conditions (P-values \u3c 7.9 × 10-4). Notably, neither resilience metric was genetically correlated with clinical Alzheimer\u27s disease (P-values \u3e 0.42) nor associated with APOE (P-values \u3e 0.13). In single variant analyses, we observed a genome-wide significant locus among participants with unimpaired cognition on chromosome 18 upstream of ATP8B1 (index single nucleotide polymorphism rs2571244, minor allele frequency = 0.08, P = 2.3 × 10-8). The top variant at this locus (rs2571244) was significantly associated with methylation in prefrontal cortex tissue at multiple CpG sites, including one just upstream of ATPB81 (cg19596477; P = 2 × 10-13). Overall, this comprehensive genetic analysis of resilience implicates a putative role of vascular risk, metabolism, and mental health in protection from the cognitive consequences of neuropathology, while also providing evidence for a novel resilience gene along the bile acid metabolism pathway. Furthermore, the genetic architecture of resilience appears to be distinct from that of clinical Alzheimer\u27s disease, suggesting that a shift in focus to molecular contributors to resilience may identify novel pathways for therapeutic targets

Sex differences in the genetic architecture of cognitive resilience to Alzheimer\u27s disease.

Approximately 30% of elderly adults are cognitively unimpaired at time of death despite the presence of Alzheimer\u27s disease neuropathology at autopsy. Studying individuals who are resilient to the cognitive consequences of Alzheimer\u27s disease neuropathology may uncover novel therapeutic targets to treat Alzheimer\u27s disease. It is well established that there are sex differences in response to Alzheimer\u27s disease pathology, and growing evidence suggests that genetic factors may contribute to these differences. Taken together, we sought to elucidate sex-specific genetic drivers of resilience. We extended our recent large scale genomic analysis of resilience in which we harmonized cognitive data across four cohorts of cognitive ageing, in vivo amyloid PET across two cohorts, and autopsy measures of amyloid neuritic plaque burden across two cohorts. These data were leveraged to build robust, continuous resilience phenotypes. With these phenotypes, we performed sex-stratified [n (males) = 2093, n (females) = 2931] and sex-interaction [n (both sexes) = 5024] genome-wide association studies (GWAS), gene and pathway-based tests, and genetic correlation analyses to clarify the variants, genes and molecular pathways that relate to resilience in a sex-specific manner. Estimated among cognitively normal individuals of both sexes, resilience was 20-25% heritable, and when estimated in either sex among cognitively normal individuals, resilience was 15-44% heritable. In our GWAS, we identified a female-specific locus on chromosome 10 [rs827389, β (females) = 0.08, P (females) = 5.76 × 10-09, β (males) = -0.01, P(males) = 0.70, β (interaction) = 0.09, P (interaction) = 1.01 × 10-04] in which the minor allele was associated with higher resilience scores among females. This locus is located within chromatin loops that interact with promoters of genes involved in RNA processing, including GATA3. Finally, our genetic correlation analyses revealed shared genetic architecture between resilience phenotypes and other complex traits, including a female-specific association with frontotemporal dementia and male-specific associations with heart rate variability traits. We also observed opposing associations between sexes for multiple sclerosis, such that more resilient females had a lower genetic susceptibility to multiple sclerosis, and more resilient males had a higher genetic susceptibility to multiple sclerosis. Overall, we identified sex differences in the genetic architecture of resilience, identified a female-specific resilience locus and highlighted numerous sex-specific molecular pathways that may underly resilience to Alzheimer\u27s disease pathology. This study illustrates the need to conduct sex-aware genomic analyses to identify novel targets that are unidentified in sex-agnostic models. Our findings support the theory that the most successful treatment for an individual with Alzheimer\u27s disease may be personalized based on their biological sex and genetic context

Insights into the ageing mind: a view from cognitive neuroscience,”

REVIEWS Behavioural research on ageing has mapped contrasting patterns of decline and stability in cognition across the adult lifespan. Both cross-sectional and longitudinal studies find robust declines in abilities such as encoding new memories of episodes or facts, working memory (the simultaneous short-term maintenance and manipulation of information involving EXECUTIVE PROCESSES) and processing speed (the speed with which information can be processed). By contrast, short-term memory (a component process of working memory), autobiographical memory, semantic knowledge and emotional processing remain relatively stable. This variable vulnerability of human abilities across the adult lifespan indicates that ageing has distinctive effects on the neural systems that subserve various abilities. Understanding age-associated changes in cognition is challenging for several reasons. First, it is often difficult to separate the effects of normal ageing from those of pathological processes that compromise cognition. Most older adults experience some form of age-related neural pathology, because ageing is associated strongly with risk for Alzheimer's disease, Parkinson's disease, diabetes, hypertension and arteriosclerosis. However, research involving highly select and healthy older adults indicates that even in the best case, normal ageing is associated with changes in the neural basis of cognition. Second, because age cannot be experimentally manipulated, conclusions regarding the effects of ageing are necessarily correlational. Third, studies of ageing are often based on cross-sectional comparisons between age groups, to avoid the time and expense of longitudinal research. Few studies have followed individuals from young adulthood into old age, although an increasing number of studies have examined longitudinal changes above the age of 60. Fourth, many brain and mental changes occur in parallel during ageing, and correlational approaches make it challenging to relate particular changes in the brain with particular mental changes. In an effort to infer causal relationships with ageing, researchers attempt to show that age is related to some, but not other, neurocognitive functions. Even with these challenges, advances in brain imaging methods have allowed unprecedented insights into the neural correlates of healthy ageing. This review summarizes recent work in the cognitive neuroscience of ageing, with an emphasis on human neuropsychological and neuroimaging research, that demonstrates the varied nature of age-related neural and psychological changes. We discuss several of the most pressing issues in the cognitive neuroscience of ageing in an attempt to sketch a research agenda for the future. INSIGHTS INTO THE AGEING MIND: A VIEW FROM COGNITIVE NEUROSCIENCE Trey Hedden and John D. E. Gabrieli As we grow older, we may grow wiser, but we can also experience memory loss and cognitive slowing that can interfere with our daily routines. The cognitive neuroscience of human ageing, which relies largely on neuroimaging techniques, relates these cognitive changes to their neural substrates, including structural and functional changes in the prefrontal cortex, medial temporal lobe regions and white matter tracts. Much remains unknown about how normal ageing affects the neural basis of cognition, but recent research on individual differences in the trajectory of ageing effects is helping to distinguish normal from pathological origins of agerelated cognitive changes. EXECUTIVE PROCESSES General purpose cognitive mechanisms for goal-oriented organization and manipulation of information stored in working memory, and for switching among several tasks and sources of information. NATURE REVIEWS | NEUROSCIENC

Insights into the ageing mind: a view from cognitive neuroscience,”

REVIEWS Behavioural research on ageing has mapped contrasting patterns of decline and stability in cognition across the adult lifespan. Both cross-sectional and longitudinal studies find robust declines in abilities such as encoding new memories of episodes or facts, working memory (the simultaneous short-term maintenance and manipulation of information involving EXECUTIVE PROCESSES) and processing speed (the speed with which information can be processed). By contrast, short-term memory (a component process of working memory), autobiographical memory, semantic knowledge and emotional processing remain relatively stable. This variable vulnerability of human abilities across the adult lifespan indicates that ageing has distinctive effects on the neural systems that subserve various abilities. Understanding age-associated changes in cognition is challenging for several reasons. First, it is often difficult to separate the effects of normal ageing from those of pathological processes that compromise cognition. Most older adults experience some form of age-related neural pathology, because ageing is associated strongly with risk for Alzheimer's disease, Parkinson's disease, diabetes, hypertension and arteriosclerosis. However, research involving highly select and healthy older adults indicates that even in the best case, normal ageing is associated with changes in the neural basis of cognition. Second, because age cannot be experimentally manipulated, conclusions regarding the effects of ageing are necessarily correlational. Third, studies of ageing are often based on cross-sectional comparisons between age groups, to avoid the time and expense of longitudinal research. Few studies have followed individuals from young adulthood into old age, although an increasing number of studies have examined longitudinal changes above the age of 60. Fourth, many brain and mental changes occur in parallel during ageing, and correlational approaches make it challenging to relate particular changes in the brain with particular mental changes. In an effort to infer causal relationships with ageing, researchers attempt to show that age is related to some, but not other, neurocognitive functions. Even with these challenges, advances in brain imaging methods have allowed unprecedented insights into the neural correlates of healthy ageing. This review summarizes recent work in the cognitive neuroscience of ageing, with an emphasis on human neuropsychological and neuroimaging research, that demonstrates the varied nature of age-related neural and psychological changes. We discuss several of the most pressing issues in the cognitive neuroscience of ageing in an attempt to sketch a research agenda for the future. INSIGHTS INTO THE AGEING MIND: A VIEW FROM COGNITIVE NEUROSCIENCE Trey Hedden and John D. E. Gabrieli As we grow older, we may grow wiser, but we can also experience memory loss and cognitive slowing that can interfere with our daily routines. The cognitive neuroscience of human ageing, which relies largely on neuroimaging techniques, relates these cognitive changes to their neural substrates, including structural and functional changes in the prefrontal cortex, medial temporal lobe regions and white matter tracts. Much remains unknown about how normal ageing affects the neural basis of cognition, but recent research on individual differences in the trajectory of ageing effects is helping to distinguish normal from pathological origins of agerelated cognitive changes. EXECUTIVE PROCESSES General purpose cognitive mechanisms for goal-oriented organization and manipulation of information stored in working memory, and for switching among several tasks and sources of information. NATURE REVIEWS | NEUROSCIENC

Insights into the ageing mind: a view from cognitive neuroscience,”

REVIEWS Behavioural research on ageing has mapped contrasting patterns of decline and stability in cognition across the adult lifespan. Both cross-sectional and longitudinal studies find robust declines in abilities such as encoding new memories of episodes or facts, working memory (the simultaneous short-term maintenance and manipulation of information involving EXECUTIVE PROCESSES) and processing speed (the speed with which information can be processed). By contrast, short-term memory (a component process of working memory), autobiographical memory, semantic knowledge and emotional processing remain relatively stable. This variable vulnerability of human abilities across the adult lifespan indicates that ageing has distinctive effects on the neural systems that subserve various abilities. Understanding age-associated changes in cognition is challenging for several reasons. First, it is often difficult to separate the effects of normal ageing from those of pathological processes that compromise cognition. Most older adults experience some form of age-related neural pathology, because ageing is associated strongly with risk for Alzheimer's disease, Parkinson's disease, diabetes, hypertension and arteriosclerosis. However, research involving highly select and healthy older adults indicates that even in the best case, normal ageing is associated with changes in the neural basis of cognition. Second, because age cannot be experimentally manipulated, conclusions regarding the effects of ageing are necessarily correlational. Third, studies of ageing are often based on cross-sectional comparisons between age groups, to avoid the time and expense of longitudinal research. Few studies have followed individuals from young adulthood into old age, although an increasing number of studies have examined longitudinal changes above the age of 60. Fourth, many brain and mental changes occur in parallel during ageing, and correlational approaches make it challenging to relate particular changes in the brain with particular mental changes. In an effort to infer causal relationships with ageing, researchers attempt to show that age is related to some, but not other, neurocognitive functions. Even with these challenges, advances in brain imaging methods have allowed unprecedented insights into the neural correlates of healthy ageing. This review summarizes recent work in the cognitive neuroscience of ageing, with an emphasis on human neuropsychological and neuroimaging research, that demonstrates the varied nature of age-related neural and psychological changes. We discuss several of the most pressing issues in the cognitive neuroscience of ageing in an attempt to sketch a research agenda for the future. INSIGHTS INTO THE AGEING MIND: A VIEW FROM COGNITIVE NEUROSCIENCE Trey Hedden and John D. E. Gabrieli As we grow older, we may grow wiser, but we can also experience memory loss and cognitive slowing that can interfere with our daily routines. The cognitive neuroscience of human ageing, which relies largely on neuroimaging techniques, relates these cognitive changes to their neural substrates, including structural and functional changes in the prefrontal cortex, medial temporal lobe regions and white matter tracts. Much remains unknown about how normal ageing affects the neural basis of cognition, but recent research on individual differences in the trajectory of ageing effects is helping to distinguish normal from pathological origins of agerelated cognitive changes. EXECUTIVE PROCESSES General purpose cognitive mechanisms for goal-oriented organization and manipulation of information stored in working memory, and for switching among several tasks and sources of information. NATURE REVIEWS | NEUROSCIENC