Objectives: To identify novel associations between modifiable physical and health variables, Alzheimer’s disease (AD) biomarkers, and cognitive function in a cohort of older adults with Mild Cognitive Impairment (MCI). Methods: Metrics of cardiometabolic risk, stress, inflammation, neurotrophic/growth factors, AD, and cognition were assessed in 154 MCI participants (Mean age = 74.1 years) from the Alzheimer’s Disease Neuroimaging Initiative. Partial Least Squares analysis was employed to examine associations among these physiological variables and cognition. Results: Latent variable 1 revealed a unique combination of AD biomarkers, neurotrophic/growth factors, education, and stress that were significantly associated with specific domains of cognitive function, including episodic memory, executive function, processing speed, and language, representing 45.2% of the cross-block covariance in the data. Age, body mass index, and metrics tapping basic attention or premorbid IQ were not significant. Conclusions: Our data-driven analysis highlights the significant relationships between metrics associated with AD pathology, neuroprotection, and neuroplasticity, primarily with tasks tapping episodic memory, executive function, processing speed, and verbal fluency rather than more basic tasks that do not require mental manipulation (basic attention and vocabulary). These data also indicate that biological metrics are more strongly associated with episodic memory, executive function, and processing speed than chronological age in older adults with MCI.

Executive function (EF) is essential for humans to effectively engage in cognitively demanding tasks. In adults, EF is subserved by frontoparietal regions in the multiple demand (MD) network, which respond to various cognitively demanding tasks. However, children initially show poor EF and prolonged development. Do children recruit the same network as adults? Is it functionally and connectionally distinct from adjacent language cortex, as in adults? And is this activation or connectivity dependent on age or ability? We examine task-dependent (spatial working memory and passive language tasks) and resting state functional data in 44 adults (18-38 years, 68% female) and 37 children (4-12 years, 35% female). Subject-specific functional regions of interest (ss-fROIs) show bilateral MD network activation in children. In both children and adults, these MD ss-fROIs are not recruited for linguistic processing and are connectionally distinct from language ss-fROIs. While MD activation was lower in children than in adults (even in motion- and performance-matched groups), both showed increasing MD activation with better performance, especially in right hemisphere ss-fROIs. We observe this relationship even when controlling for age, cross-sectionally and in a small longitudinal sample of children. These data suggest that the MD network is selective to cognitive demand in children, is distinct from adjacent language cortex, and increases in selectivity as performance improves. These findings show that neural structures subserving domain-general EF emerge early and are sensitive to ability even in children. This research advances understanding of how high-level human cognition emerges and could inform interventions targeting cognitive control.Significance statement:This study provides evidence that young children already show differentiated brain network organization between regions that process cognitive demand and language. These data support the hypothesis that children recruit a similar network as adults to process cognitive demand, and despite immature characteristics, children’s selectivity looks more adult-like as their executive function ability increases. Mapping early stages of network organization furthers our understanding of the functional architecture underlying domain-general executive function. Determining typical variability underlying cognitive processing across developmental periods helps establish a threshold for executive dysfunction. Early markers of dysfunction are necessary for effective early identification, prevention, and intervention efforts for individuals struggling with deficits in processing cognitive demand.

Is language distinct from other cognition? Does the neural machinery for language emerge from general-purpose neural mechanisms early in development, becoming tuned for language only after years of experience and maturation? In adults, language is supported by a frontotemporal network that is functionally and connectionally dissociated from adjacent domain-general cortex supporting other, more general cognitive functions. We scanned young children (2-9 years of age) on an auditory language localizer, spatial working memory localizer (engaging the domain-general multiple demand (MD) network), and a resting state scan. Subject-specific functional regions of interest (fROIs) defined with the language task showed consistent selectivity to auditory sentences in key left hemisphere regions, and were not engaged for spatial working memory, showing similar domain-specificity as reported in adults; and despite known prolonged development of frontal cortices, the left inferior frontal cortex (“Broca’s area”) showed some of the most robust specificity for linguistic content. Thus, despite immature language skills, young children already have left-lateralized brain regions dedicated to linguistic content. Children also showed higher within-network (language-language) connectivity than between-network connectivity (language-to-MD fROIs defined with the working memory task), in both hemispheres, but with higher within-network connectivity on the left. Language-selectivity increased with age (replicated in a subset of children scanned longitudinally) while specificity of language connectivity did not change with age (again replicated longitudinally), suggesting that connectivity is more static than, and may perhaps earmark, functional specificity. By age 2, the language network is specialized for linguistic processing (domain-specific) function, is distinct from adjacent cortex, and is not engaged in other higher-order cognitive processing.

Executive function (EF) is essential for human cognition, allowing individuals to effectively engage in cognitively demanding tasks. In adults, EF is subserved by a set of frontoparietal brain regions (termed the multiple demand (MD) network) which show robust responses to a wide variety of cognitively demanding tasks (i.e., domain-general) and reflect cognitive effort exerted on the task. But while essential, children initially show poor EF skills with prolonged development of these skills. Do children recruit the same network as adults? Is it functionally and connectionally distinct from adjacent language cortex as it is in adults? And is this activation or connectivity dependent on age or on the individual's EF task performance? We scanned 44 adults and 37 children ages 4-12 years for two separate tasks (MD spatial working memory task and passive language task) and a resting-state fMRI scan. Because motion is a concern in child samples, we asked a subset of adult subjects to participate in additional "wiggly" scans of the MD task and to move slightly during those scans. We defined subject-specific functional regions of interest (ss-fROIs) and found bilateral activation of the MD network in children. In both children and adults, these ss-fROIs are not recruited for linguistic processing and are also connectionally distinct from language ss-fROIs. MD activation in children was lower than that observed in adults, but it was unrelated to motion as evidenced by motion-matched comparisons between children and adult groups and by repeated measures comparisons within the adult group. Right-lateralized ss-fROIs showed increasing load-based MD responses that were robustly associated with performance, demonstrated both cross-sectionally and in a subset of children scanned longitudinally about one year apart. These data suggest that even in young children the MD network is selective to cognitive demand, is distinct from adjacent cortex, and increases in its selectivity as a child improves their EF skills, independently of age. Overall, these findings show that neural structures subserving domain-general EF emerge early and are sensitive to ability in both children and adults. This research advances our understanding of how high-level human cognition emerges and can inform interventions targeting cognitive control.

A limited number of studies examine cognitive aging in Black or African American older adults. The purpose of this study was to explore the relationship between health-related fitness metrics, education, and cognition at baseline and over a 4-year follow-up in a sample of 321 Black or African American older adults in the Health and Retirement Study (HRS). Physical fitness was assessed with measures of gait speed, peak expiratory flow, grip strength, and body mass index. Global cognition was assessed with an adapted version of the Telephone Interview for Cognitive Status (TICS). Analyses of relative importance and hierarchical multiple regression were used to examine baseline cross-sectional relationships. Multiple logistic regression was used to examine prospective relationships with longitudinal cognitive status. Education was the strongest predictor of global cognition at baseline and follow-up. More years of education significantly increased the odds of maintaining cognitive status at 4-year follow-up. After accounting for education, gait speed was independently associated with baseline cognitive performance and accounted for additional variance. Grip strength, peak expiratory flow, and body mass index were not significantly associated with cognition. The results indicated that modifiable variables, including years of educational attainment and gait speed, were more strongly associated with global cognition than other modifiable variables including body mass index, grip strength, and peak expiratory flow. The lack of observed associations between other fitness variables and cognition may be attributable to the brief assessment methods implemented, which was necessitated by the large-scale, epidemiological approach of the HRS.