Frailty and Cognitive Function in Older Adults: A Systematic Review and Meta-Analysis of Cross-Sectional Studies.

The relationship between cognitive function and frailty among older adults is a growing area of research due to the implications of cognitive and physical decline for functional independence in late life. Multiple studies demonstrate a meaningful relationship between these two factors, which together may constitute increased risk of negative health outcomes for older adults. The current analysis was conducted to 1) systematically review current evidence for differences in cognitive performance based on frailty status among older adults and provide quantitative evidence for the magnitude of this effect, and 2) assess the influence of demographic and methodological variables on this effect. The preregistered protocol (CRD42018087138) included a search of EBSCOhost, Pubmed, and Embase online databases and reference lists to identify cross-sectional studies comparing frail and non-frail or robust older adults (60+) on cognitive performance. In total, 42 effects were retrieved from 38 studies, expressed as Hedges' g, and pooled based on a random-effects model. Results indicated an overall significant, negative effect of frailty status on cognitive function among tests of global cognitive function (g = 0.734: 95% CI = 0.601-0.867) and individual cognitive domains (g = 0.439: 95% CI = 0.342-0.535). Age, frailty assessment used, and cognitive status of the sample did not significantly moderate the overall effect. Post-hoc moderator analysis revealed that difference in mean age of frail and robust groups significantly moderated the overall effect (R2 = 0.38, ß = .0974, 95% CI = 0.0537-0.141). Implications for future research are discussed.

Pre-Morbid IQ Moderates the Relationship between Cognitive Performance and Performance-Based Functional Status in Older Adults.

Objectives: The current study sought to evaluate the relationship between cognitive performance and Instrumental Activities of Daily Living (IADL) performance in a population of community dwelling older adults, and assess to what extent this relationship is moderated by cognitive reserve (Premorbid-IQ)Methods: 123 community-dwelling older adults completed a general cognitive assessment, a word-reading based premorbid-IQ estimate (PMIQE) measure, and the performance-based Direct Assessment of Functional Status, Revised (DAFS-R). Moderated regression analysis was used to assess the influence of PMIQE on the relationship between cognitive performance and IADLs.Results: There was a significant main effect of cognitive performance on IADLs, and no main effect of PMIQE on functional IADLs. There was a significant moderating effect of PMIQE on the relationship between cognitive performance and IADLs performance, such that at higher levels of PMIQE, cognitive performance scores became slightly less predictive of weaknesses in IADLs.Conclusions: Results suggest that for individuals with high reserve, assessment of cognitive performance alone may not be robust a predictor of IADLs functioning.Clinical implications: In estimating functional abilities as a consequence of cognitive performance, consideration should be given to premorbid-IQ/cognitive reserve.

A Multi-method Investigation of the Personality Correlates of Functional Ability in Older Adults.

OBJECTIVES: This study evaluated the role of personality in predicting functional ability (FA) in older adults using self-report, collateral report, and performance-based measures of FA. METHODS: Participants included older adults (N = 131) who completed a personality measure (NEO-FFI), a self-report of FA (OARS ADL), and participated in a performance-based assessment of FA (DAFS-R). In addition, each participant had a collateral complete a collateral report of FA (OARS ADL). Bivariate correlations were computed to assess how Five Factor Model traits were related to self-report, collateral, and performance-based measures of FA. RESULTS: Neuroticism was negatively related to self-reported FA (r = - .27) and collateral-reported FA (r = - .18) and Conscientiousness was positively related to self-reported FA (r = .25). None of the traits were significantly related to the performance-based measure of FA. CONCLUSIONS: These results suggest that personality traits can impact self-reported FA in older adults and underscore the importance of assessing FA in older adults using multiple methods, particularly performance-based measures. CLINICAL IMPLICATIONS: Clinicians should consider how personality may impact FA in older adults and multiple methods of FA performance should be examined to better tailor recommendations.

TrkB signalling pathway mediates the protective effects of exercise in the diabetic rat retina.

Diabetic retinopathy is a leading cause of vision loss. Treatment options for early retinopathy are sparse. Exercise protects dying photoreceptors in models of retinal degeneration, thereby preserving vision. We tested the protective effects of exercise on retinal and cognitive deficits in a type 1 diabetes model and determined whether the TrkB pathway mediates this effect. Hyperglycaemia was induced in Long Evans rats via streptozotocin injection (STZ; 100 mg/kg). Following confirmed hyperglycaemia, both control and diabetic rats underwent treadmill exercise for 30 min, 5 days/week at 0 m/min (inactive groups) or 15 m/min (active groups) for 8 weeks. A TrkB receptor antagonist (ANA-12), or vehicle, was injected 2.5 h before exercise training. We measured spatial frequency and contrast sensitivity using optokinetic tracking biweekly post-STZ; retinal function using electroretinography at 4 and 8 weeks; and cognitive function and exploratory behaviour using Y-maze at 8 weeks. Retinal neurotrophin-4 was measured using ELISA. Compared with non-diabetic controls, diabetic rats showed significantly reduced spatial frequency and contrast sensitivity, delayed electroretinogram oscillatory potential and flicker implicit times and reduced cognitive function and exploratory behaviour. Exercise interventions significantly delayed the appearance of all deficits, except for exploratory behaviour. Treatment with ANA-12 significantly reduced this protection, suggesting a TrkB-mediated mechanism. Despite this, no changes in retinal neurotrohin-4 were observed with diabetes or exercise. Exercise protected against early visual and cognitive dysfunction in diabetic rats, suggesting that exercise interventions started after hyperglycaemia diagnosis may be a beneficial treatment. The translational potential is high, given that exercise treatment is non-invasive, patient controlled and inexpensive.

Exercise and Cyclic Light Preconditioning Protect Against Light-Induced Retinal Degeneration and Evoke Similar Gene Expression Patterns.

To compare patterns of gene expression following preconditioning cyclic light rearing versus preconditioning aerobic exercise. BALB/C mice were preconditioned either by rearing in 800 lx 12:12 h cyclic light for 8 days or by running on treadmills for 9 days, exposed to toxic levels of light to cause light-induced retinal degeneration (LIRD), then sacrificed and retinal tissue harvested. Subsets of mice were maintained for an additional 2 weeks and for assessment of retinal function by electroretinogram (ERG). Both preconditioning protocols partially but significantly preserved retinal function and morphology and induced similar leukemia inhibitory factor (LIF) gene expression pattern. The data demonstrate that exercise preconditioning and cyclic light preconditioning protect photoreceptors against LIRD and evoke a similar pattern of retinal LIF gene expression. It may be that similar stress response pathways mediate the protection provided by the two preconditioning modalities.

Aerobic exercise protects retinal function and structure from light-induced retinal degeneration.

Aerobic exercise is a common intervention for rehabilitation of motor, and more recently, cognitive function (Intlekofer and Cotman, 2013; Wood et al., 2012). While the underlying mechanisms are complex, BDNF may mediate much of the beneficial effects of exercise to these neurons (Ploughman et al., 2007; Griffin et al., 2011; Real et al., 2013). We studied the effects of aerobic exercise on retinal neurons undergoing degeneration. We exercised wild-type BALB/c mice on a treadmill (10 m/min for 1 h) for 5 d/week or placed control mice on static treadmills. After 2 weeks of exercise, mice were exposed to either toxic bright light (10,000 lux) for 4 h to induce photoreceptor degeneration or maintenance dim light (25 lux). Bright light caused 75% loss of both retinal function and photoreceptor numbers. However, exercised mice exposed to bright light had 2 times greater retinal function and photoreceptor nuclei than inactive mice exposed to bright light. In addition, exercise increased retinal BDNF protein levels by 20% compared with inactive mice. Systemic injections of a BDNF tropomyosin-receptor-kinase (TrkB) receptor antagonist reduced retinal function and photoreceptor nuclei counts in exercised mice to inactive levels, effectively blocking the protective effects seen with aerobic exercise. The data suggest that aerobic exercise is neuroprotective for retinal degeneration and that this effect is mediated by BDNF signaling.

Perivascular space burden interacts with APOE-ε4 status on cognition in older adults.

Enlarged perivascular spaces (ePVS) may adversely affect cognition. Little is known about how basal ganglia ePVS interact with apolipoprotein (APOE)-ε4 status. Vanderbilt Memory and Aging Project participants (n = 326, 73 ± 7, 59% male) underwent 3 T brain MRI at baseline to assess ePVS and longitudinal neuropsychological assessments. The interaction between ePVS volume and APOE-ε4 carrier status was related to baseline outcomes using ordinary least squares regressions and longitudinal cognition using linear mixed-effects regressions. ePVS volume interacted with APOE-ε4 status on cross-sectional naming performance (ß = -0.002, p = 0.002), and executive function excluding outliers (ß = 0.001, p = 0.009). There were no significant longitudinal interactions (p-values>0.10) except for Coding excluding outliers (ß = 0.002, p = 0.05). While cross-sectional models stratified by APOE-ε4 status indicated greater ePVS related to worse cognition mostly in APOE-ε4 carriers, longitudinal models stratified by APOE-ε4 status showed greater ePVS volume related to worse cognition among APOE-ε4 non-carriers only. Results indicated that greater ePVS volume interacts with APOE-ε4 status on cognition cross-sectionally. Longitudinally, the association of greater ePVS volume and worse cognition appears stronger in APOE-ε4 non-carriers, possibly due to the deleterious effects of APOE-ε4 on cognition across the lifespan.

Strategic filtering of high-energy visible light expands neural correlates of functional vision particularly in older participants.

In this study we assessed the neural correlates of functional vision while varying patterns of light filtration. Four filter conditions used relatively flat filtering across the visible spectrum while one filter was a step filter that selectively absorbed violet light (wavelengths below about 415 nm). Neural effects were quantified by measuring the BOLD response ((T2*-based fMRI) while subjects performed a challenging visual task (judging gap direction in Landolt Cs that randomly varied in size). In general (based on p < 0.01 directional criterion not corrected for aggregated error), as filtering increased (less interference by bright light), brain activity associated with the task also increased. This effect, even using the most conservative statistics, was most evident when using the violet filter (especially for the older subjects) despite only reducing the very highest energy portion of the visible spectrum. This finding suggests that filtering can increase neural activity associated with functional vision; such effects might be achievable through filtering just the highest visible energy (violet).

Mean arterial pressure, fitness, and executive function in middle age and older adults.

Previous literature suggests that higher fitness is related to better executive function in older adulthood, but the mechanisms underlying this association are poorly understood. While many studies have focused on these associations in older adulthood, recent evidence suggests the importance of cardiorespiratory fitness (CRF) and long-term blood pressure control on cognitive functioning. The purpose of the current study was to examine whether mean arterial pressure (MAP) mediated the association between CRF and executive function in middle age and older adults. Participants were adults (age 40+) without any self-reported psychiatric and neurological disorders or cognitive impairment from the Nathan Kline Institute Rockland Sample (N = 224, M age = 56). CRF was defined by V̇O2max estimated via a bike test, neuropsychological testing was used to examine executive functioning, and MAP was calculated from systolic and diastolic blood pressure recordings. Mediation models were analyzed controlling for age, sex, and education. Results indicated that higher CRF was associated with better inhibition (B = -0.0048, t = -2.16, p = 0.03) and there was a significant indirect effect of greater CRF on better inhibition through lower MAP (B = -0.0011; CI [-0.0026, -0.0002]). There were additional significant indirect effects of greater CRF and better fluency (B = 0.0028; CI [.0009, 0.0053]) and planning (B = 0.0037; CI [.0014, 0.0074]) through lower MAP. This suggests that MAP may be an underlaying physiological mechanism by which CRF influences executive function in mid- and older adulthood.

Physical activity moderates the association between executive function and functional connectivity in older adults.

Recent evidence suggests that physical activity may influence the functional connectivity of the aging brain. The purpose of this study was to examine the influence of physical activity on the association between executive function and functional connectivity of key brain networks and graph theory metrics in community-dwelling older adults. Participants were 47 older adults (M = 73 years; SD = 5.92) who participated in neuropsychological testing, physical activity measurements, and magnetic resonance imaging (MRI). Seed-to-voxel moderation analyses and graph theory analyses were conducted. Physical activity was significantly positively associated with default mode network functional connectivity (DMN FC; Posterior Cingulate Gyrus, p-FDR = 0.005; Frontal Pole (L), p-FDR = 0.005; Posterior Cingulate Gyrus, p-FDR = 0.006; Superior Frontal Gyrus (L), p-FDR = 0.016) and dorsal attention network functional connectivity (DAN FC; Inferior Frontal Gyrus Pars Opercularis (R), p-FDR = 0.044). The interaction between physical activity and executive function on the DMN FC and DAN FC was analyzed. The interaction between executive function and physical activity was significantly associated with DMN FC. When this significant interaction was probed, the association between physical activity and DMN FC differed between levels of high and low executive function such that the association was only significant at levels of high executive function. These results suggest that greater physical activity in later life is associated with greater DMN and DAN FC and provides evidence for the importance of physical activity in cognitively healthy older adults.

Exercise interventions do not impact brain volume change in older adults: a systematic review and meta-analysis.

Exercise interventions have been shown to positively impact cognitive function in older adults, but the mechanisms underlying the neuroprotective effects of exercise on the brain are not well understood. Here, we aimed to synthesize and quantitatively analyze the current literature on exercise interventions and brain volume change in older adults and to examine the impact of key demographic and intervention features as well as study quality. This study was pre-registered with PROSPERO (CRD42018091866). EBSCOhost, Cochrane Library, Embase, and reference lists were searched to identify randomized-controlled trials (RCTs) of exercise interventions for healthy older adults and older adults (60+) with mild cognitive impairment (MCI). A total of 69 effects from 14 studies were pooled and expressed as Hedge's g using a random-effects model. Results indicated that there was no significant difference in brain volume outcomes for older adults that completed an exercise intervention compared to older adults in control groups (g = 0.012, p = 0.728, 95% CI = -0.055, .078). These results were confirmed using multilevel analysis to account for nesting of effects within studies (g = 0.009, p = 0.826, 95% CI = -0.072, 0.090) and using conservative post-hoc models to address possible non-independence of multiple outcome domains and sample nonindependence. No significant heterogeneity was detected, limiting moderator analyses. The implications for future research are discussed.

The Relations Between Physical Activity Level, Executive Function, and White Matter Microstructure in Older Adults.

The population of older adults is increasing, indicating a need to examine factors that may prevent or mitigate age-related cognitive decline. The current study examined whether microstructural white matter characteristics mediated the relation between physical activity and executive function in older adults without any self-reported psychiatric and neurological disorders or cognitive impairment (N = 43, mean age = 73 y). Physical activity was measured by average intensity and number of steps via accelerometry. Diffusion tensor imaging was used to examine microstructural white matter characteristics, and neuropsychological testing was used to examine executive functioning. Parallel mediation models were analyzed using microstructural white matter regions of interest as mediators of the association between physical activity and executive function. Results indicated that average steps was significantly related to executive function (ß = 0.0003, t = 2.829, P = .007), while moderate to vigorous physical activity was not (ß = 0.0007, t = 1.772, P = .08). White matter metrics did not mediate any associations. This suggests that microstructural white matter characteristics alone may not be the mechanism by which physical activity impacts executive function in aging.

Evidence for exercise-related plasticity in functional and structural neural network connectivity.

The number of studies investigating exercise and cardiorespiratory fitness (CRF)-related changes in the functional and structural organization of brain networks continues to rise. Functional and structural connectivity are critical biomarkers for brain health and many exercise-related benefits on the brain are better represented by network dynamics. Here, we reviewed the neuroimaging literature to better understand how exercise or CRF may facilitate and maintain the efficiency and integrity of functional and structural aspects of brain networks in both younger and older adults. Converging evidence suggests that increased exercise performance and CRF modulate functional connectivity of the brain in a way that corresponds to behavioral changes such as cognitive and motor performance improvements. Similarly, greater physical activity levels and CRF are associated with better cognitive and motor function, which may be brought about by enhanced structural network integrity. This review will provide a comprehensive understanding of trends in exercise-network studies as well as future directions based on the gaps in knowledge that are currently present in the literature.

Education Differentially Buffers Cognitive Performance in Black and White Older Adults.

OBJECTIVES: Given that black American older adults are more likely to have lower educational attainment and perform worse on cognitive tests than white Americans, we examined whether increased education would confer greater cognitive advantage to black Americans on measures of global and specific domains of cognitive function. METHODS: The sample included 522 community-dwelling older adults from a larger study. An analysis of covariance was conducted with race and education as between-participant factors and global cognition as the dependent variable. A multivariate analysis of covariance was conducted with five cognitive domains (immediate memory, visuospatial/constructional ability, language, attention, and delayed memory) as the dependent variables. RESULTS: Significant main effects indicated that black Americans, F(1,516) = 29.18, p < .001, and individuals with less education, F(1,516) = 44.93, p < .001, evidenced lower cognitive functioning, controlling for age and overall health status, and the interaction term reached statistical significance, F(1,516) = 7.95, p = .005. The impact of education on global cognitive function for black participants was more than twice as large (Cohen's d = 1.30) than for white participants (Cohen's d = .52). There was a significant race × education interaction for the cognitive domain of attention (p < .001) and a composite measure of non-memory domains (i.e., language, visuospatial/constructional, and attention; p < .001). DISCUSSION: Our findings suggest that educational attainment is particularly important for black Americans with respect to global cognitive function, attention, and non-memory domains.

Body mass index and its relation to neuropsychological functioning and brain volume in healthy older adults.

Obesity is a growing concern worldwide because of its adverse health effects, including its negative impact on cognitive functioning. This concern is especially relevant for older adults, who are already likely to experience some cognitive decline and loss of brain volume due to aging, (Gea et al., 2002). However, there is some evidence that higher body mass index (BMI) may actually be protective in later life (Hughes et al., 2009; Luchsinger et al., 2007; Nilsson and Nilsson, 2009; Sturman et al., 2008). Therefore, the purpose of the current study was to assess the relationship between BMI and neuropsychological functioning in older adults, and concurrently the relationship between BMI and brain volume. Older adults (N = 88) reported height and weight to determine BMI (M = 26.5) based on Centers for Disease Control and Prevention (CDC) guidelines. Cognitive function was assessed with the Repeatable Battery for Assessment of Neuropsychological Status (RBANS). Brain volume measurements were evaluated via structural MRI. Results indicated no association between BMI and neuropsychological functioning. There was a significant association between BMI and total grey matter volume while controlling for age and years of education (ß = 0.208, p = .026, ΔR2 = 0.043), indicating that as BMI increased, brain volume in these areas modestly increased. However, these results did not survive multiple comparison corrections and were further attenuated to near significance when sex was explicitly added as an additional covariate. Nevertheless, while replication is clearly needed, these results suggest that moderately greater BMI in later life may modestly attenuate concomitant grey matter volume decline.

Lutein and Zeaxanthin Are Positively Associated with Visual-Spatial Functioning in Older Adults: An fMRI Study.

Lutein (L) and zeaxanthin (Z) are two xanthophyll carotenoids that have antioxidant and anti-inflammatory properties. Previous work has demonstrated their importance for eye health and preventing diseases such as age-related macular degeneration. An emerging literature base has also demonstrated the importance of L and Z in cognition, neural structure, and neural efficiency. The present study aimed to better understand the mechanisms by which L and Z relate to cognition, in particular, visual-spatial processing and decision-making in older adults. We hypothesized that markers of higher levels of L and Z would be associated with better neural efficiency during a visual-spatial processing task. L and Z were assessed via standard measurement of blood serum and retinal concentrations. Visual-spatial processing and decision-making were assessed via a judgment of line orientation task (JLO) completed during a functional magnetic resonance imaging (fMRI) scan. The results demonstrated that individuals with higher concentrations of L and Z showed a decreased blood-oxygen-level dependent (BOLD) signal during task performance (i.e., "neural efficiency") in key areas associated with visual-spatial perception, processing, decision-making, and motor coordination, including the lateral occipital cortex, occipital pole, superior and middle temporal gyri, superior parietal lobule, superior and middle frontal gyri, and pre- and post-central gyri. To our knowledge, this is the first investigation of the relationship of L and Z to visual-spatial processing at a neural level using in vivo methodology. Our findings suggest that L and Z may impact brain health and cognition in older adults by enhancing neurobiological efficiency in a variety of regions that support visual perception and decision-making.

Neuroprotective Effects of Voluntary Exercise in an Inherited Retinal Degeneration Mouse Model.

PURPOSE: Our previous investigations showed that involuntary treadmill exercise is neuroprotective in a light-induced retinal degeneration mouse model, and it may act through activation of tropomyosin-related kinase B (TrkB) receptors. This study investigated whether voluntary running wheel exercise can be neuroprotective in an inheritable model of the retinal degenerative disease retinitis pigmentosa (RP), rd10 mice. METHODS: Breeding pairs of rd10 and C57BL/6J mice were given free-spinning (active) or locked (inactive) running wheels. Pups were weaned into separate cages with their parents' respective wheel types, and visual function was tested with ERG and a virtual optokinetic system at 4, 5, and 6 weeks of age. Offspring were killed at 6 weeks of age and retinal cross-sections were prepared for photoreceptor nuclei counting. Additionally, separate cohorts of active and inactive rd10 pups were injected daily for 14 days after eye opening with a selective TrkB receptor antagonist (ANA-12) or vehicle solution and assessed as described above. RESULTS: Mice in the rd10 active group exhibited significant preservation of visual acuity, cone nuclei, and total photoreceptor nuclei number. Injection with ANA-12 precluded the preservation of visual acuity and photoreceptor nuclei number in rd10 mice. CONCLUSIONS: Voluntary running partially protected against the retinal degeneration and vision loss that otherwise occurs in the rd10 mouse model of RP. This protection was prevented by injection of ANA-12, suggesting that TrkB activation mediates exercise's preservation of the retina. Exercise may serve as an effective, clinically translational intervention against retinal degeneration.