Effects of estrogen on spatial navigation and memory.

RATIONALE: Animal studies suggest that the so-called "female" hormone estrogen enhances spatial navigation and memory. This contradicts the observation that males generally out-perform females in spatial navigation and tasks involving spatial memory. A closer look at the vast number of studies actually reveals that performance differences are not so clear. OBJECTIVES: To help clarify the unclear performance differences between men and women and the role of estrogen, we attempted to isolate organizational from activational effects of estrogen on spatial navigation and memory. METHODS: In a double-blind, placebo-controlled study, we tested the effects of orally administered estradiol valerate (E2V) in healthy, young women in their low-hormone menstrual cycle phase, compared to healthy, young men. Participants performed several first-person, environmentally rich, 3-D computer games inspired by spatial navigation and memory paradigms in animal research. RESULTS: We found navigation behavior suggesting that sex effects dominated any E2 effects with men performing better with allocentric strategies and women with egocentric strategies. Increased E2 levels did not lead to general improvements in spatial ability in either sex but to behavioral changes reflecting navigation flexibility. CONCLUSION: Estrogen-driven differences in spatial cognition might be better characterized on a spectrum of navigation flexibility rather than by categorical performance measures or skills.

Cardiorespiratory fitness is associated with fMRI signal in right cerebellum lobule VIIa Crus I and II during spatial navigation in older adult women.

Spatial navigation is a cognitive skill critical for accomplishing daily goal-directed behavior in a complex environment; however, older adults exhibit marked decline in navigation performance with age. Neuroprotective interventions that enhance the functional integrity of navigation-linked brain regions, such as those in the medial temporal lobe memory system, may preserve spatial navigation performance in older adults. Importantly, a well-established body of literature suggests that cardiorespiratory fitness has measurable effects on neurobiological integrity in the medial temporal lobes, as well as in other brain areas implicated in spatial navigation, such as the precuneus and cerebellum. However, whether cardiorespiratory fitness modulates brain activity in these regions during navigation in older adults remains unknown. Thus, the primary objective of the current study was to examine cardiorespiratory fitness as a modulator of fMRI activity in navigation-linked brain regions in cognitively healthy older adults. To accomplish this objective, cognitively intact participants (N = 22, aged 60-80 years) underwent cardiorespiratory fitness testing to estimate maximal oxygen uptake ( V · O2max) and underwent whole-brain high-resolution fMRI while performing a virtual reality navigation task. Our older adult sample demonstrated significant fMRI signal in the right and left retrosplenial cortex, right precuneus, right and left inferior parietal cortex, right and left cerebellum lobule VIIa Crus I and II, right fusiform gyrus, right parahippocampal cortex, right lingual gyrus, and right hippocampus during encoding of a virtual environment. Most importantly, in women but not men (N = 16), cardiorespiratory fitness was positively associated with fMRI activity in the right cerebellum lobule VIIa Crus I and II, but not other navigation-linked brain areas. These findings suggest that the influence of cardiorespiratory fitness on brain function extends beyond the hippocampus, as observed in other work, to the cerebellum lobule VIIa Crus I and II, a component of the cerebellum that has recently been linked to cognition and more specifically, spatial processing.

Five-factor model personality traits and 24-h urinary cortisol in the Baltimore Longitudinal Study of Aging.

Stress is implicated in models of personality and health as a mechanism that explains why traits like conscientiousness and neuroticism are associated with long-term health outcomes. Evidence for an association between personality and cortisol, a biological marker of stress, however, has been inconsistent. This study examined the association between Five-Factor Model personality traits and 24-h urinary cortisol (operationalised as a ratio of urinary free cortisol to creatinine) measured up to 12 times over intervals as long as 30 years in the Baltimore Longitudinal Study of Aging (Mage  = 61.21, SD = 15.46; 49% female). There was a modest association between conscientiousness and lower mean-level cortisol that was attenuated only slightly in the fully-adjusted model. Neuroticism and the other traits were unrelated to cortisol levels, and none of the traits was related to cortisol change over time. The null association for neuroticism suggests that its relation with long-term health may be primarily through pathways other than cortisol. The modest association between conscientiousness and 24-h urinary cortisol replicates a previous finding with a longer-term measure of cortisol measured from hair, which calls for more research on the robustness and replicability of this finding. Cortisol may be one pathway through which conscientiousness is associated with health outcomes.

Intact circadian rhythm despite cortisol hypersecretion in Alzheimer's disease: A meta-analysis.

Hypersecretion of the glucocorticoid steroid hormone cortisol by individuals with Alzheimer's disease (AD) has been suspected for several decades, during which time dozens of examinations of this phenomenon have been conducted and published. The goals of this investigation were to summarize this sizeable body of literature, test whether participant and methodological characteristics modify the magnitude of the AD-associated basal cortisol hypersecretion, and examine whether cortisol circadian rhythmicity is maintained among individuals with AD. To this end, the present meta-analysis and systematic review examined over 300 comparisons of indices of basal HPA-axis functioning between individuals with AD and cognitively normal older adults. AD was associated with basal cortisol elevations (g = 0.45) but the magnitude of the effect was not systematically impacted by any of the participant characteristics considered or the time-of-day of the cortisol sampling. Further, there was no evidence of group differences among direct indices of circadian rhythmicity such as the cortisol awakening response or the diurnal cortisol slope. These results suggest that basal hypersecretion of cortisol, but not circadian dysrhythmia, is characteristic of individuals with AD. Mechanistically, the observed hypersecretion is consistent with the theorized AD-driven deterioration of the hippocampus and subsequent reduction in hypothalamic-pituitary-adrenal axis inhibition. Further investigation is warranted to elucidate the role and timing of cortisol elevations in the progression of AD.

Prediabetes and working memory in older adults.

Insulin sensitivity, pancreatic ß-cell function, fasting glucose, and 2-h post-load glucose were related to cognition in cognitively healthy nondiabetic older adults. Thirty-five adults (⩾65 years) underwent a 2-h oral glucose tolerance test and cognitive testing. Seventeen had normal glucose tolerance and 18 had intermediate hyperglycaemia or prediabetes (World Health Organization criteria). Fasting glucose and 2-h post-load glucose and oral glucose tolerance test-derived measures of ß-cell function (oral disposition index) and insulin sensitivity were analysed as predictors of four cognitive domains: verbal episodic memory, verbal fluency, executive function, and working memory. The prediabetes group had significantly worse working memory performance than the normal glucose tolerance group. Controlling for age and education, decreased oral disposition index, and increased 2-h post-load glucose were significantly related to worse working memory performance. Prediabetes may worsen working memory in healthy older adults. Reduced pancreatic ß-cell function should be investigated as a contributor to age-related cognitive decline.

Longitudinal Change in Cortisol Levels Across the Adult Life Span.

BACKGROUND: Cortisol is a key stress hormone implicated in the pathogenesis of many age-related diseases. Longitudinal information on cortisol exposure has been restricted to animal models and a small number of human studies. The purpose of the present study was to quantify longitudinal change in cortisol across the adult life span. METHODS: We conducted a prospective longitudinal study of 24-hour urinary free cortisol excretion from ages 20 to 90 years and older. Participants were 1,814 men and women from the Baltimore Longitudinal Study of Aging who provided a total of 5,527 urine specimens for analysis. The average duration of longitudinal follow-up was 6.6 years. The primary outcome measure was 24-hour urinary free cortisol to creatinine ratio (UFC/Cr) as determined by liquid chromatography/mass spectrometry. RESULTS: UFC/Cr follows a U-shaped pattern across the life span with decreases in UFC/Cr in the 20s and 30s, relative stability in the 40s and 50s, and increases thereafter. This pattern of change was robust with respect to adjustment for several potential confounding factors. CONCLUSIONS: Age-related changes in cortisol exposure raise important questions about the potential protective or exacerbating role of cortisol exposure in predicting medical, physiological, and behavioral outcomes.

Age-related differences in brain activations during spatial memory formation in a well-learned virtual Morris water maze (vMWM) task.

The current study applied a rodent-based virtual Morris water maze (vMWM) protocol to an investigation of differences in search performance and brain activations between young and older male human adults. All participants completed in-lab practice and testing before performing the task in the fMRI scanner. Behavioral performance during fMRI scanning - measured in terms of corrected cumulative proximity (CCProx) to the goal - showed that a subgroup of older good performers attained comparable levels of search accuracy to the young while another subgroup of older poor performers exhibited consistently lower levels of search accuracy than both older good performers and the young. With regard to brain activations, young adults exhibited greater activations in the cerebellum and cuneus than all older adults, as well as older poor performers. Older good performers exhibited higher activation than older poor performers in the orbitofrontal cortex (BA 10/11), as well as in the cuneus and cerebellum. Brain-behavior correlations further showed that activations in regions involved in visuomotor control (cerebellum, lingual gyrus) and egocentric spatial processing (premotor cortex, precuneus) correlated positively with search accuracy (i.e., closer proximity to goal) in all participants. Notably, activations in the anterior hippocampus correlated positively with search accuracy (CCProx inversed) in the young but not in the old. Taken together, these findings implicated the orbitofrontal cortex and the cerebellum as playing crucial roles in executive and visuospatial processing in older adults, supporting the proposal of an age-related compensatory shift in spatial memory functions away from the hippocampus toward the prefrontal cortex.

Distributed cognition in aviation operations: a gate-to-gate study with implications for distributed crewing.

The network analysis method, Event Analysis of Systemic Teamwork (EAST), was used to examine routine aviation operations from multiple perspectives from six key areas (i.e. Dispatch, ATC, ATM, Maintenance, Loading, and the Cockpit). Data was collected over a five-day observational field trial at an international air cargo operator. Researchers recorded the activities of agents operating within the six key areas over three outbound and two inbound flights. Three networks (i.e. social, information and task) were created for four key phases of flight: (i) pre-flight checks and engines start (ii) taxi, take-off and assent, (iii) descent, landing and taxi, and (iv) park and shut down. The networks represent a 'work audit' of short-haul cargo operations, which enabled a detailed understanding of the interactions and connections within the current system. Implications for the future of distributed crewing concepts are discussed. Practitioner Summary: An analysis of the aviation system was undertaken using the amalgamated data from three outbound and two inbound flights. These analyses show the social, information and task interactions for cargo operations. This has been used to specify requirements for future distributed crewing options.

Cortisol relates to regional limbic system structure in older but not younger adults.

We investigated if the relationship between age and regional limbic system brain structure would be moderated by diurnal cortisol output and diurnal cortisol slope. Participants aged 23-83 years collected seven salivary cortisol samples each day for 10 consecutive days and underwent magnetic resonance imaging. Age, sex, cortisol, and an age x cortisol interaction were tested as predictors of hippocampal and amygdalar volume and caudal and rostral anterior cingulate cortex (ACC) thickness. We found significant interactions between age and cortisol on left and right amygdalar volumes and right caudal ACC thickness. Older adults with higher cortisol output had smaller left and right amygdalar volumes than older adults with lower cortisol output and younger adults with higher cortisol output. Older and younger adults with lower cortisol output had similar amygdalar volumes. Older adults with a steeper decline in diurnal cortisol had a thicker right caudal ACC than younger adults with a similarly shaped cortisol slope. Hippocampal volume was not related to either cortisol slope or output, nor was pallidum volume which was assessed as an extra-limbic control region. Results suggest that subtle differences in cortisol output are related to differences in limbic system structure in older but not younger adults.

Are there Sex Differences in Confidence and Metacognitive Monitoring Accuracy for Everyday, Academic, and Psychometrically Measured Spatial Ability?

The current study evaluated sex differences in (1) self-perceptions of everyday and academic spatial ability, and (2) metacognitive monitoring accuracy for measures of spatial visualization and spatial orientation. Undergraduate students completed the Paper Folding Test, Spatial Relations Test, and the Revised Purdue Spatial Visualization Test while making confidence judgments (CJs) for each trial. They also made global estimates of performance and rated their ability to perform several everyday and academic spatial scenarios. Across multiple spatial measures, female students displayed lower confidence in their item-level monitoring and global assessments of performance than did male students, even when no actual differences in spatial performance occurred. Women were also less confident in their self-assessments of their visualspatial ability for scientific domains than were men. However, the absolute and relative accuracy of CJs did not differ as a function of sex suggesting that women can monitor their spatial performance as well as men.

Extrahippocampal Contributions to Age-Related Changes in Spatial Navigation Ability.

Age-related decline in spatial navigation is well-known and the extant literature emphasizes the important contributions of a hippocampus-dependent spatial navigation system in mediating this decline. However, navigation is a multifaceted cognitive domain and some aspects of age-related navigational decline may be mediated by extrahippocampal brain regions and/or systems. The current review presents an overview of some key cognitive domains that contribute to the age-related changes in spatial navigation ability, and elucidates such domains in the context of an increased engagement of navigationally relevant extrahippocampal brain regions with advancing age. Specifically, this review focuses on age-related declines in three main areas: (i) allocentric strategy use and switching between egocentric and allocentric strategies, (ii) associative learning of landmarks/locations and heading directions, and (iii) executive functioning and attention. Thus far, there is accumulating neuroimaging evidence supporting the functional relevance of the striatum for egocentric/response strategy use in older adults, and of the prefrontal cortex for mediating executive functions that contribute to successful navigational performance. Notably, the functional role of the prefrontal cortex was particularly emphasized via the proposed relevance of the fronto-locus coeruleus noradrenergic system for strategy switching and of the fronto-hippocampal circuit for landmark-direction associative learning. In view of these putative prefrontal contributions to navigation-related functions, we recommend future spatial navigation studies to adopt a systems-oriented approach that investigates age-related alterations in the interaction between the prefrontal cortex, the hippocampus, and extrahippocampal regions, as well as an individual differences approach that clarifies the differential engagement of prefrontal executive processes among older adults.

The effect of Alzheimer's disease on spatial navigation strategies.

Hippocampal and basal forebrain (BF) atrophy is associated with allocentric navigation impairment in Alzheimer's disease (AD) and may lead to recruitment of compensatory navigation strategies. We examined navigation strategy preference, its association with allocentric navigation, and the role of hippocampal and BF volumes in this association in early clinical stages of AD. Sixty nine participants-amnestic mild cognitive impairment (aMCI) due to AD (n = 28), AD dementia (n = 21), and cognitively normal (CN) older adults (n = 20)-underwent virtual Y-maze strategy assessment, real-space navigation testing, cognitive assessment, and hippocampal and BF volumetry. Preference for egocentric over allocentric strategy increased with AD severity (aMCI: 67% vs. 33%; dementia: 94% vs. 6%), which contrasted with preference in the CN group (39% vs. 61%). Those with aMCI who preferred egocentric strategy had worse allocentric navigation. Among those with aMCI, hippocampal and BF atrophy explained up to 25% of the association between strategy preference and allocentric navigation. The preference for egocentric strategy in AD may reflect recruitment of compensatory extrahippocampal navigation strategies as adaptation to hippocampal and BF neurodegeneration.

Age-related similarities and differences in monitoring spatial cognition.

Spatial cognitive performance is impaired in later adulthood but it is unclear whether the metacognitive processes involved in monitoring spatial cognitive performance are also compromised. Inaccurate monitoring could affect whether people choose to engage in tasks that require spatial thinking and also the strategies they use in spatial domains such as navigation. The current experiment examined potential age differences in monitoring spatial cognitive performance in a variety of spatial domains including visual-spatial working memory, spatial orientation, spatial visualization, navigation, and place learning. Younger and older adults completed a 2D mental rotation test, 3D mental rotation test, paper folding test, spatial memory span test, two virtual navigation tasks, and a cognitive mapping test. Participants also made metacognitive judgments of performance (confidence judgments, judgments of learning, or navigation time estimates) on each trial for all spatial tasks. Preference for allocentric or egocentric navigation strategies was also measured. Overall, performance was poorer and confidence in performance was lower for older adults than younger adults. In most spatial domains, the absolute and relative accuracy of metacognitive judgments was equivalent for both age groups. However, age differences in monitoring accuracy (specifically relative accuracy) emerged in spatial tasks involving navigation. Confidence in navigating for a target location also mediated age differences in allocentric navigation strategy use. These findings suggest that with the possible exception of navigation monitoring, spatial cognition may be spared from age-related decline even though spatial cognition itself is impaired in older age.

Computerized cognitive training during physical inactivity improves executive functioning in older adults.

The hippocampus is closely tied to spatial navigation, a central component in cognitive functioning, and critically involved in age-associated cognitive decline and dementia. This study evaluated a novel, cognitive computerized spatial navigation training (CSNT) program targeting the hippocampus, with expectation of mitigating possible cognitive decline with bed rest (BR). During a 14-day BR study with 16 healthy, older men (mean age = 60 ± 3, range = 55-65 years), half received CSNT for 12 days in 50-min sessions and half were controls (watching documentaries). This design uniquely controlled diet, sleep, and other personal and environmental activities. Although there were no cognitive declines in controls post-BR, CSNT participants demonstrated significant increases in executive/attention ability and processing speed, and continued spatial navigation testing showed improvement to 400 days post-BR. This intervention may prove useful to mitigate cognitive declines known to occur in long periods of immobilization and could have broader implications in protecting against age-related cognitive decline.

The application of a rodent-based Morris water maze (MWM) protocol to an investigation of age-related differences in human spatial learning.

The current study applied a rodent-based Morris water maze (MWM) protocol to an investigation of search performance differences between young and older adult humans. To investigate whether similar age-related decline in search performance could be seen in humans based on the rodent-based protocol, we implemented a virtual MWM (vMWM) that has characteristics similar to those of the MWM used in previous studies of spatial learning in mice. Through the use of a proximity to platform measure, robust differences were found between healthy young and older adults in search performance. After dividing older adults into good and poor performers based on a median split of their corrected cumulative proximity values, the age effects in place learning were found to be largely related to search performance differences between the young and poor-performing older adults. When compared with the young, poor-performing older adults exhibited significantly higher proximity values in 83% of 24 place trials and overall in the probe trials that assessed spatial learning in the absence of the hidden platform. In contrast, good-performing older adults exhibited patterns of search performance that were comparable with that of the younger adults in most place and probe trials. Taken together, our findings suggest that the low search accuracy in poor-performing older adults stemmed from potential differences in strategy selection, differences in assumptions or expectations of task demands, as well as possible underlying functional and/or structural changes in the brain regions involved in vMWM search performance. (PsycINFO Database Record

The Aging Navigational System.

The discovery of neuronal systems dedicated to computing spatial information, composed of functionally distinct cell types such as place and grid cells, combined with an extensive body of human-based behavioral and neuroimaging research has provided us with a detailed understanding of the brain's navigation circuit. In this review, we discuss emerging evidence from rodents, non-human primates, and humans that demonstrates how cognitive aging affects the navigational computations supported by these systems. Critically, we show 1) that navigational deficits cannot solely be explained by general deficits in learning and memory, 2) that there is no uniform decline across different navigational computations, and 3) that navigational deficits might be sensitive markers for impending pathological decline. Following an introduction to the mechanisms underlying spatial navigation and how they relate to general processes of learning and memory, the review discusses how aging affects the perception and integration of spatial information, the creation and storage of memory traces for spatial information, and the use of spatial information during navigational behavior. The closing section highlights the clinical potential of behavioral and neural markers of spatial navigation, with a particular emphasis on neurodegenerative disorders.

Vestibular Loss in Older Adults Is Associated with Impaired Spatial Navigation: Data from the Triangle Completion Task.

BACKGROUND: Vestibular inputs have been shown to play a critical role in spatial navigation. In this study, we sought to evaluate whether vestibular loss due to aging contributes to impaired spatial navigation as measured by the triangle completion task (TCT). MATERIALS AND METHODS: We recruited three types of participants: young controls <55 years of age, older controls ≥55 years of age, and older patients from a Neurotology Clinic with evidence of vestibular physiologic impairment but who did not have any known vestibular disorder. We performed the cervical vestibular-evoked myogenic potential to evaluate saccular function and video head impulse testing to quantify horizontal semicircular canal vestibulo-ocular reflex gain. To assess spatial navigation ability, we administered the TCT, in which participants were conveyed along two segments of a pre-drawn triangular path and instructed to complete the final segment independently. We measured the angle (degrees) and distance (centimeters) of deviation from the correct trajectory. We evaluated the influence of vestibular inputs on TCT performance. RESULTS: Forty-eight adults participated in the study (mean age: 62.0 years; 52.1% females), including 9 young controls, 15 older controls, and 24 clinic patients. Clinic patients had the greatest distance of deviation (67.7 cm), followed by older controls (45.4 cm), then young controls (27.8 cm; p < 0.01). Similarly, clinic patients had greater rotational angles (22.1°) compared to older (13.3°) and younger controls (12.4°; p < 0.01). Following multivariate linear regression adjusting for demographic variables, loss of otolith function was associated with an 18.2 cm increase in distance of deviation (95% CI: 15.2-47.4) and a 9.2° increase in rotational angle (95% CI: 3.0-15.5). Abnormal semicircular canal function was associated with a 26.0 cm increase in distance of deviation (95% CI: 0.2-51.8) and a 10.8° increase in rotational angle (95% CI: 3.0-15.5). Participants with both otolith and canal abnormalities had a larger distance error (ß = 25.3, 95% CI: 6.2-44.4) and angle of deviation (ß = 18.1, 95% CI: 10.1-26.2) than with either condition alone. CONCLUSION: Vestibular loss in older adults was associated with poorer performance on a dynamic spatial navigation task relative to old and young controls.

Long-term cortisol measures predict Alzheimer disease risk.

OBJECTIVE: To examine whether long-term measures of cortisol predict Alzheimer disease (AD) risk. METHOD: We used a prospective longitudinal design to examine whether cortisol dysregulation was related to AD risk. Participants were from the Baltimore Longitudinal Study of Aging (BLSA) and submitted multiple 24-hour urine samples over an average interval of 10.56 years. Urinary free cortisol (UFC) and creatinine (Cr) were measured, and a UFC/Cr ratio was calculated to standardize UFC. To measure cortisol regulation, we used within-person UFC/Cr level (i.e., within-person mean), change in UFC/Cr over time (i.e., within-person slope), and UFC/Cr variability (i.e., within-person coefficient of variation). Cox regression was used to assess whether UFC/Cr measures predicted AD risk. RESULTS: UFC/Cr level and UFC/Cr variability, but not UFC/Cr slope, were significant predictors of AD risk an average of 2.9 years before AD onset. Elevated UFC/Cr level and elevated UFC/Cr variability were related to a 1.31- and 1.38-times increase in AD risk, respectively. In a sensitivity analysis, increased UFC/Cr level and increased UFC/Cr variability predicted increased AD risk an average of 6 years before AD onset. CONCLUSIONS: Cortisol dysregulation as manifested by high UFC/Cr level and high UFC/Cr variability may modulate the downstream clinical expression of AD pathology or be a preclinical marker of AD.