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Homocysteine (Hcy) is a vascular risk factor associated with cognitive impairment and cerebrovascular disease but has also been implicated in Alzheimer's disease (AD). Using multivariate Scaled Subprofile Model (SSM) analysis, we sought to identify a network pattern in structural neuroimaging reflecting the regionally distributed association of plasma Hcy with subcortical gray matter (SGM) volumes and its relation to other health risk factors and cognition in 160 healthy older adults, ages 50-89. We identified an SSM Hcy-SGM pattern that was characterized by bilateral hippocampal and nucleus accumbens volume reductions with relative volume increases in bilateral caudate, pallidum, and putamen. Greater Hcy-SGM pattern expression was associated with greater white matter hyperintensity (WMH) volume, older age, and male sex, but not with other vascular and AD-related risk factors. Mediation analyses revealed that age predicted WMH volume, which predicted Hcy-SGM pattern expression, which, in turn, predicted cognitive processing speed performance. These findings suggest that the multivariate SSM Hcy-SGM pattern may be indicative of cognitive aging, reflecting a potential link between vascular health and cognitive dysfunction in healthy older adults.

Objective: To evaluate the construct validity of the NIH Toolbox Cognitive Battery (NIH TB-CB) in the healthy oldest-old (85+ years old). Method: Our sample from the McKnight Brain Aging Registry consists of 179 individuals, 85 to 99 years of age, screened for memory, neurological, and psychiatric disorders. Using previous research methods on a sample of 85 + y/o adults, we conducted confirmatory factor analyses on models of NIH TB-CB and same domain standard neuropsychological measures. We hypothesized the five-factor model (Reading, Vocabulary, Memory, Working Memory, and Executive/Speed) would have the best fit, consistent with younger populations. We assessed confirmatory and discriminant validity. We also evaluated demographic and computer use predictors of NIH TB-CB composite scores. Results: Findings suggest the six-factor model (Vocabulary, Reading, Memory, Working Memory, Executive, and Speed) had a better fit than alternative models. NIH TB-CB tests had good convergent and discriminant validity, though tests in the executive functioning domain had high inter-correlations with other cognitive domains. Computer use was strongly associated with higher NIH TB-CB overall and fluid cognition composite scores. Conclusion: The NIH TB-CB is a valid assessment for the oldest-old samples, with relatively weak validity in the domain of executive functioning. Computer use’s impact on composite scores could be due to the executive demands of learning to use a tablet. Strong relationships of executive function with other cognitive domains could be due to cognitive dedifferentiation. Overall, the NIH TB-CB could be useful for testing cognition in the oldest-old and the impact of aging on cognition in older populations.

Canine cognitive dysfunction (CCD) is a form of dementia that shares many similarities with Alzheimer’s disease. Given that physical activity is believed to reduce risk of Alzheimer’s disease in humans, we explored the association between physical activity and cognitive health in a cohort of companion dogs, aged 6–18 years. We hypothesized that higher levels of physical activity would be associated with lower (i.e., better) scores on a cognitive dysfunction rating instrument and lower prevalence of dementia, and that this association would be robust when controlling for age, comorbidities, and other potential confounders. Our sample included 11,574 companion dogs enrolled through the Dog Aging Project, of whom 287 had scores over the clinical threshold for CCD. In this observational, cross-sectional study, we used owner-reported questionnaire data to quantify dog cognitive health (via a validated scale), physical activity levels, health conditions, training history, and dietary supplements. We fit regression models with measures of cognitive health as the outcome, and physical activity—with several important covariates—as predictors. We found a significant negative relationship between physical activity and current severity of cognitive dysfunction symptoms (estimate = − 0.10, 95% CI: − 0.11 to − 0.08, p

Declines in processing speed performance occur in aging and are a critical marker of functional independence in older adults. Numerous studies suggest that Useful Field of View (UFOV) training may ameliorate cognitive decline in older adults. Despite its efficacy, little is known about the neural correlates of this task. The current study is the first to investigate the coherence of functional connectivity during UFOV task completion. A total of 336 participants completed the UFOV task while undergoing task-based functional magnetic resonance imaging (fMRI). Ten spherical regions of interest (ROIs), selected a priori, were created based on regions with the greatest peak BOLD activation patterns in the UFOV fMRI task and regions that have been shown to significantly relate to UFOV fMRI task performance. We used a weighted ROI-to-ROI connectivity analysis to model task-specific functional connectivity strength between these a priori selected ROIs. We found that our UFOV fMRI network was functionally connected during task performance and was significantly associated to UFOV fMRI task performance. Within-network connectivity of the UFOV fMRI network showed comparable or better predictive power in accounting for UFOV accuracy compared to 7 resting state networks, delineated by Yeo and colleagues. Finally, we demonstrate that the within-network connectivity of UFOV fMRI task accounted for scores on a measure of “near transfer”, the Double Decision task, better than the aforementioned resting state networks. Our data elucidate functional connectivity patterns of the UFOV fMRI task. This may assist in future targeted interventions that aim to improve synchronicity within the UFOV fMRI network. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11357-022-00632-1.

INTRODUCTION: Physical activity (PA) is recognized as one of the key lifestyle behaviors that reduces risk of developing dementia late in life. However, PA also leads to increased respiration, and in areas with high levels of air pollution, PA may increase exposure to pollutants linked with higher risk of developing dementia. Here, we investigate whether air pollution attenuates the association between PA and dementia risk. METHODS: This prospective cohort study included 35,562 adults 60 and older from the UK Biobank. Average acceleration magnitude (ACC(ave)) from wrist-worn accelerometers was used to assess PA levels. Air pollution levels (NO, NO(2), PM(10), PM(2.5), PM(2.5–10), and PM(2.5 absorbance)) were estimated with land use regression methods. Incident all-cause dementia was derived from inpatient hospital records and death registry data. RESULTS: In adjusted models, ACC(ave) was associated with reduced risk of developing dementia (HR [CI]=0.71 [0.60,0.83]), while air pollution variables were not associated with dementia risk. There were significant interactions between ACC(ave) and PM(2.5) (HR(interaction) [CI]=1.33 [1.13,1.57]) and PM(2.5 absorbance) (HR(interaction) [CI]=1.24 [1.07,1.45]) on incident dementia. At the lowest tertiles of pollution, ACC(ave) was associated with reduced risk of incident dementia (HR(PM 2.5) [CI]=0.66 [0.49,0.91], HR(PM 2.5 absorbance) [CI]=0.60 [0.44,0.81]). At the highest tertiles of these pollutants, there was no significant association of ACC(ave) with incident dementia (HR(PM 2.5) [CI]=0.88 [0.68,1.14], HR(PM 2.5 absorbance) [CI]=0.79 [0.60,1.04]). CONCLUSIONS: PA is associated with reduced risk of developing all-cause dementia. However, exposure to even moderate levels of air pollution attenuates the benefits of PA on risk of dementia.

Executive function is a cognitive domain that typically declines in non-pathological aging. Two cognitive control networks that are vulnerable to aging—the cingulo-opercular (CON) and fronto-parietal control (FPCN) networks—play a role in various aspects of executive functioning. However, it is unclear how communication within these networks at rest relates to executive function subcomponents in older adults. This study examines the associations between CON and FPCN connectivity and executive function performance in 274 older adults across working memory, inhibition, and set-shifting tasks. Average CON connectivity was associated with better working memory, inhibition, and set-shifting performance, while average FPCN connectivity was associated solely with working memory. CON region of interest analyses revealed significant connections with classical hub regions (i.e., anterior cingulate and anterior insula) for each task, language regions for verbal working memory, right hemisphere dominance for inhibitory control, and widespread network connections for set-shifting. FPCN region of interest analyses revealed largely right hemisphere fronto-parietal connections important for working memory and a few temporal lobe connections for set-shifting. These findings characterize differential brain-behavior relationships between cognitive control networks and executive function in aging. Future research should target these networks for intervention to potentially attenuate executive function decline in older adults.

Speed-of-processing abilities decline with age yet are important in performing instrumental activities of daily living. The useful field of view, or Double Decision task, assesses speed-of-processing and divided attention. Performance on this task is related to attention, executive functioning, and visual processing abilities in older adults, and poorer performance predicts more motor vehicle accidents in the elderly. Cognitive training in this task reduces risk of dementia. Structural and functional neural correlates of this task suggest that higher-order resting state networks may be associated with performance on the Double Decision task, although this has never been explored. This study aimed to assess the association of within-network connectivity of the default mode network, dorsal attention network, frontoparietal control network, and cingulo-opercular network with Double Decision task performance, and subcomponents of this task in a sample of 267 healthy older adults. Multiple linear regressions showed that connectivity of the cingulo-opercular network is associated with visual speed-of-processing and divided attention subcomponents of the Double Decision task. Cingulo-opercular network and frontoparietal control network connectivity is associated with Double Decision task performance. Stronger connectivity is related to better performance in all cases. These findings confirm the unique role of the cingulo-opercular network in visual attention and sustained divided attention. Frontoparietal control network connectivity, in addition to cingulo-opercular network connectivity, is related to Double Decision task performance, a task implicated in reduced dementia risk. Future research should explore the role these higher-order networks play in reduced dementia risk after cognitive intervention using the Double Decision task.

Sedentary behavior (SB) is associated with cardiometabolic disease and mortality, but its association with dementia is currently unclear. This study investigates whether SB is associated with incident dementia regardless of engagement in physical activity (PA). A total of 146,651 participants from the UK Biobank who were 60 years or older and did not have a diagnosis of dementia (mean [SD] age: 64.59 [2.84] years) were included. Self-reported leisure-time SBs were divided into two domains: time spent watching television (TV) or time spent using a computer. A total of 3,507 individuals were diagnosed with all-cause dementia over a mean follow-up of 11.87 (±1.17) years. In models adjusted for a wide range of covariates, including time spent in PA, time spent watching TV was associated with increased risk of incident dementia (HR [95% CI] = 1.24 [1.15 to 1.32]) and time spent using a computer was associated with decreased risk of incident dementia (HR [95% CI] = 0.85 [0.81 to 0.90]). In joint associations with PA, TV time and computer time remained significantly associated with dementia risk at all PA levels. Reducing time spent in cognitively passive SB (i.e., TV time) and increasing time spent in cognitively active SB (i.e., computer time) may be effective behavioral modification targets for reducing risk of dementia regardless of engagement in PA.

Episodic memory is widely recognized as a critically important aspect of cognition that is often impacted by cognitive and brain aging. Prior work has shown that episodic memory is related to the presence of teeth-like folds on the dentate gyrus, called dentation. We hypothesized that episodic memory performance relates to overall hippocampal structure (i.e., dentation and volume) in an oldest-old cohort. We used data from the McKnight Brain Aging Registry, which consisted of cognitively healthy 85+-year-old adults. We conducted a canonical correlation analysis on 111 participants between a set of episodic memory tests and a set of characterizations of hippocampal structure. The analysis yielded a strong canonical correlation between episodic memory and hippocampal structure (r = 0.491, p = HighlightsWe characterized hippocampal dentation in a healthy oldest-old sample.Hippocampal structure is related to episodic memory in healthy oldest-old adults.Memory functioning is related to both hippocampal volume and dentation.

Cognitive training has shown promise for improving cognition in older adults. Age-related neuroanatomical changes may affect cognitive training outcomes. White matter hyperintensities are one common brain change in aging reflecting decreased white matter integrity. The current study assessed (1) proximal cognitive training performance following a 3-month randomized control trial and (2) the contribution of baseline whole-brain white matter hyperintensity load, or total lesion volume (TLV), on pre-post proximal training change. Sixty-two healthy older adults were randomized to either adaptive cognitive training or educational training control interventions. Repeated-measures analysis of covariance revealed two-way group × time interactions such that those assigned cognitive training demonstrated greater improvement on proximal composite (total training composite) and sub-composite (processing speed training composite, working memory training composite) measures compared to education training counterparts. Multiple linear regression showed higher baseline TLV associated with lower pre-post change on processing speed training sub-composite (β = -0.19, p = 0.04), but not other composite measures. These findings demonstrate the utility of cognitive training for improving post-intervention proximal performance in older adults. Additionally, pre-post proximal processing speed training change appears to be particularly sensitive to white matter hyperintensity load versus working memory training change. These data suggest that TLV may serve as an important factor for consideration when planning processing speed-based cognitive training interventions for remediation of cognitive decline in older adults.

Background and ObjectivesIn high-pollution areas, physical activity may have a paradoxical effect on brain health by increasing particulate deposition in the lungs. We examined whether physical activity modifies associations of air pollution (AP) with brain volumes in an epidemiologic framework.MethodsThe UK Biobank enrolled >500,000 adult participants from 2006 to 2010. Wrist accelerometers, multimodal MRI with T1 images and T2 fluid-attenuated inversion recovery data, and land use regression were used to estimate vigorous physical activity (VigPA), structural brain volumes, and AP, respectively, in subsets of the full sample. We evaluated associations among AP interquartile ranges, VigPA, and brain structure volumes and assessed interactions between AP and VigPA.ResultsEight thousand six hundred participants were included, with an average age of 55.55 (SD 7.46) years. After correction for multiple testing, in overall models, VigPA was positively associated with gray matter volume (GMV) and negatively associated with white matter hyperintensity volume (WMHV), while NO2, PM2.5absorbance, and PM2.5 were negatively associated with GMV. NO2 and PM2.5absorbance interacted with VigPA on WMHV (false discovery rate–corrected interaction p = 0.037). Associations between these air pollutants and WMHVs were stronger among participants with high VigPA. Similarly, VigPA was negatively associated with WMHV for those in areas of low NO2 and PM2.5absorbance but was null among those living in areas of high NO2 and PM2.5absorbance.DiscussionPhysical activity is associated with beneficial brain outcomes, while AP is associated with detrimental brain outcomes. VigPA may exacerbate associations of AP with white matter hyperintensity lesions, and AP may attenuate the beneficial associations of physical activity with these lesions.

Declines in processing speed performance occur in aging and are a critical marker of functional independence in older adults. Studies suggest that Useful Field of View (UFOV) training may ameliorate cognitive decline. Despite its efficacy, little is known about the neural correlates of this task. Within the current study, 233 healthy older adults completed a UFOV-based task while undergoing functional magnetic resonance imaging (fMRI). During the “stimulus” portion of this task, participants must identify a target in the center of the screen and the location of a target in the periphery, among distractors. During the “probe” portion, participants must decide if the object in the center and the location of the target in the periphery were identical to the “stimulus” screen. Widespread bilateral whole-brain activation was observed when activation patterns of the “probe” contrast were subtracted from the “stimulus” contrast. Conversely, the subtraction of “stimulus” from “probe” was associated with discrete activation patterns consisting of 13 clusters. Additionally, when evaluating the variance associated with task accuracy, specific subregions were identified that may be critical for task performance. Our data elucidate the functional neural correlates of a UFOV-based task, a task used in both cognitive training paradigms and assessment of function.

BACKGROUND: Air pollution may cause inflammatory and oxidative stress damage to the brain, leading to neurodegenerative disease. The association between air pollution and dementia, and modification by apolipoprotein E genotype 4 (APOE-ε4) has yet to be fully investigated. OBJECTIVES: To examine associations of air pollution with three types of incident dementias (Alzheimer’s disease (AD), frontotemporal dementia (FTD), and vascular dementia (VAD)), and their potential modification by APOE-ε4 genotype. METHODS: The UK Biobank enrolled >500,000 participants (2006–2010) with ongoing follow-up. We used annual averages of air pollution (PM(2.5), PM(10), PM(2.5–10), PM(2.5absorbance), NO(2), NO(X)) for 2010 scaled to interquartile ranges (IQR). We included individuals aged ≥ 60 years, with no dementia diagnosis prior to January 1, 2010. Time to incident dementia and follow-up time were reported from baseline (01/01/2010) to last censor event (death, last hospitalization, or loss to follow-up). Cox proportional hazard ratios (HR) and 95% confidence intervals (95% CI) were calculated to estimate the association of air pollutants and incident dementia, and modification of these associations by APOE-ε4. RESULTS: Our sample included 187,194 individuals (including N= 680 AD, N=377 VAD, N= 63 FTD) with a mean follow-up of 7.04 years. We observed consistent associations of PM(2.5) with greater risk of all-cause dementia (HR=1.17, 95% CI: 1.10, 1.24) and AD (HR=1.17, 95% CI: 1.06, 1.29). NO(2) was also associated with greater risk of any incident dementia (HR=1.18, 95% CI: 1.10, 1.25), AD (HR=1.15, 95% CI: 1.04, 1.28) and VAD (HR=1.18, 95% CI: 1.03, 1.35). APOE-ε4 did not modify the association between any air pollutants and dementia. DISCUSSION: PM(2.5) and NO(2) levels were associated with several types of dementia, and these associations were not modified by APOE-ε4. Findings from the UK Biobank support and extend to other epidemiological evidence for the potential association of air pollutants with detrimental brain health during aging.

While total white matter hyperintensity (WMH) volume on magnetic resonance imaging (MRI) has been associated with hippocampal atrophy, less is known about how the regional distribution of WMH volume may differentially affect the hippocampus in healthy aging. Additionally, apolipoprotein E (APOE) e4 carriers may be at an increased risk for greater WMH volumes and hippocampal atrophy in aging. The present study sought to investigate whether regional WMH volume mediates the relationship between age and hippocampal volume and if this association is moderated by APOE e4 status in a group of 190 cognitively healthy adults (APOE e4 status [carrier/non-carrier] = 59/131), ages 50-89. Analyses revealed that temporal lobe WMH volume significantly mediated the relationship between age and average bilateral hippocampal volume, and this effect was moderated by APOE e4 status (-0.020 (SE = 0.009), 95% CI, [-0.039, -0.003]). APOE e4 carriers, but not non-carriers, showed negative indirect effects of age on hippocampal volume through temporal lobe WMH volume (APOE e4 carriers: -0.016 (SE = 0.007), 95% CI, [-0.030, -0.003]; APOE e4 non-carriers: .005 (SE = 0.006), 95% CI, [-0.006, 0.017]). These findings remained significant after additionally adjusting for sex, years of education, hypertension status and duration, cholesterol status, diabetes status, Body Mass Index, history of smoking, and the Wechsler Adult Intelligence Scale-IV Full Scale IQ. There were no significant moderated mediation effects for frontal, parietal, and occipital lobe WMH volumes, with or without covariates. Our findings indicate that in cognitively healthy older adults, elevated WMH volume regionally localized to the temporal lobes in APOE e4 carriers is associated with reduced hippocampal volume, suggesting greater vulnerability to brain aging and the risk for Alzheimer's disease.

Objective Training in a divided attention/speed-of-processing task called Useful Field of View (UFOV) reduced dementia risk in older adults. Higher connectivity in resting-state networks involved in attention/inter-network modulation (cingulo-opercular network(CON); frontoparietal control network(FPCN)) relates to better UFOV performance. Cognitive status relates to CON connectivity and UFOV performance. Therefore, it may be an important third variable to consider. This study assessed the mediation of cognitive status on the relationship between CON/FPCN connectivity and UFOV performance. Methods 266 healthy older adults (age M = 71.4, SD = 5.18; 92% Caucasian) were recruited through a clinical trial at the University of Florida and the University of Arizona. Cognitive status was defined by the NIH Toolbox Fluid Composite score, assessing processing speed, attention/inhibition, executive functioning, and working/episodic memory. UFOV via the Double Decision assessment was administered. Participants underwent resting-state functional magnetic resonance imaging. Average within-network connectivity of CON and FPCN were extracted with the CONN Toolboxv18b via SPM12. Mediation of cognitive status on the relationship between CON/FPCN connectivity and UFOV performance was assessed controlling for sex, age, education, and site. Results Cognitive status fully mediated the indirect effect of CON on UFOV [b = −0.1776; 95%CI (−0.3194, −0.0684)] Figure 1, and FPCN on UFOV [b = −0.1461; 95%CI (−0.2934, −0.0342)] Figure 2. Conclusions Cognitive status accounted in part for the association between CON/FPCN connectivity and UFOV performance. Older adults with higher cognitive status had stronger functional connectivity and better UFOV performance. Future research should explore the influence of cognitive status on functional connectivity after UFOV training, and investigate which cognitive domains are most influential.

Age-related differences in dorsolateral prefrontal cortex (DLPFC) structure and function have each been linked to working memory. However, few studies have integrated multimodal imaging to simultaneously investigate relationships among structure, function, and cognition. We aimed to clarify how specifically DLPFC structure and function contribute to working memory in healthy older adults. In total, 138 participants aged 65–88 underwent 3 T neuroimaging and were divided into higher and lower groups based on a median split of in-scanner n-back task performance. Three a priori spherical DLPFC regions of interest (ROIs) were used to quantify blood-oxygen-level-dependent (BOLD) signal and FreeSurfer-derived surface area, cortical thickness, and white matter volume. Binary logistic regressions adjusting for age, sex, education, and scanner type revealed that greater left and right DLPFC BOLD signal predicted the probability of higher performing group membership (P values.05). Importantly, this suggests BOLD signal and surface area may independently contribute to working memory performance in healthy older adults.

Physical activity and cognitive functioning are strongly intertwined. However, the causal relationships underlying this association are still unclear. Physical activity can enhance brain functions, but healthy cognition may also promote engagement in physical activity. Here, we assessed the bidirectional relationships between physical activity and general cognitive functioning using Latent Heritable Confounder Mendelian Randomization (LHC-MR). Association data were drawn from two large-scale genome-wide association studies (UK Biobank and COGENT) on accelerometer-measured moderate, vigorous, and average physical activity (N = 91,084) and cognitive functioning (N = 257,841). After Bonferroni correction, we observed significant LHC-MR associations suggesting that increased fraction of both moderate (b = 0.32, CI95% = [0.17,0.47], P = 2.89e − 05) and vigorous physical activity (b = 0.22, CI95% = [0.06,0.37], P = 0.007) lead to increased cognitive functioning. In contrast, we found no evidence of a causal effect of average physical activity on cognitive functioning, and no evidence of a reverse causal effect (cognitive functioning on any physical activity measures). These findings provide new evidence supporting a beneficial role of moderate and vigorous physical activity (MVPA) on cognitive functioning.

In an influential study of young adults in 2000, Miyake and colleagues identified three independent components of executive function—set shifting, inhibition of prepotent responses, and updating and monitoring of working memory—which, although separable in a confirmatory factor analysis, were moderately correlated. Since that time, only a few studies have tried to replicate this factor structure in older adults, with inconsistent findings. The goals of the present study were to use the same executive function tests in young adults (ages 18-32) and two groups of older adults (ages 60-73 and 74-98), and compare the factor structure across groups. A full three-factor model of shifting, inhibition and updating was confirmed in young adults, but unlike Miyake’s finding, the factors were uncorrelated or weakly correlated. In both older groups, a two-factor solution was indicated, with tests of updating and inhibition associated with one factor and tests of shifting representing the other factor. In the young-older group, the two factors were moderately correlated (.30) and in the old-older group, they were strongly correlated (.53). A nested factors model of the data in the old-older group indicated that a common factor loaded on all but one of the tests and accounted for all of the variance in updating and inhibition. Only shifting retained factor-specific variance. We concluded that in young adulthood, shifting, updating, and inhibition may operate relatively independently. As people age, however, and processing becomes less efficient, they may rely increasingly on general executive control processes, reallocating their limited resources to optimize performance.

Previous work has confirmed the benefits of aerobic exercise for brain aging, however mechanisms underlying these effects remain unclear. Two measures of exercise, time spent in moderate-to-vigorous physical activity (MVPA) and cardiorespiratory fitness (CRF), may reflect different pathways linking activity to brain health. Using data from the UK Biobank, the largest sample combining neuroimaging and objectively measured MVPA available to date (n = 7148, nmale = 3062, nfemale = 4086; age = 62.14 ± 7.40 years), we found that, when adjusted for covariates including MVPA, CRF was positively associated with overall gray matter volume (FDR p = 1.28E-05). In contrast, when adjusted for covariates including CRF, MVPA was positively associated with left and right hippocampal (FDR pleft = 0.01; FDR pright = 0.02) volumes, but not overall gray matter volume. Both CRF and MVPA were inversely associated with white matter hyperintensity lesion loads (FDR pCRF = 0.002; pMVPA = 0.02). Our results suggest separable effects of engagement in exercise behaviors (MVPA) and the physiological effects of exercise (CRF) on structural brain volumes, which may have implications for differential pathways linking exercise and brain benefits.

Subjective memory complaints (SMCs) may be an important early indicator of cognitive aging and preclinical Alzheimer's disease risk. This study investigated whether age-related differences in right or left hippocampal volume underlie SMCs, if these relationships differ by hypertension status, and how they are related to objective memory performance in a group of 190 healthy older adults, 50-89 years of age. Analyses revealed a significant mediation of the relationship between age and mild SMCs by right hippocampal volume that was moderated by hypertension status. This moderated mediation effect was not observed with left hippocampal volume. Additionally, a moderated serial mediation model showed that age predicted right hippocampal volume, which predicted SMCs, and in turn predicted objective memory performance on several measures of verbal selective reminding in individuals with hypertension, but not in non-hypertensives. Together, these findings suggest that even mild SMCs, in the context of hypertension, provide an early indicator of cognitive aging, reflecting a potential link among vascular risk, SMCs, and the preclinical risk for Alzheimer's disease.

BackgroundAccelerometers are included in a wide range of devices that monitor and track physical activity for health-related applications. However, the clinical utility of the information embedded in their rich time-series data has been greatly understudied and has yet to be fully realized. Here, we examine the potential for fractal complexity of actigraphy data to serve as a clinical biomarker for mortality risk.MethodsWe use detrended fluctuation analysis (DFA) to analyze actigraphy data from the National Health and Nutrition Examination Survey (NHANES; n = 11,694). The DFA method measures fractal complexity (signal self-affinity across time-scales) as correlations between the amplitude of signal fluctuations in time-series data across a range of time-scales. The slope, α, relating the fluctuation amplitudes to the time-scales over which they were measured describes the complexity of the signal.ResultsFractal complexity of physical activity (α) decreased significantly with age (p = 1.29E−6) and was lower in women compared with men (p = 1.79E−4). Higher levels of moderate-to-vigorous physical activity in older adults and in women were associated with greater fractal complexity. In adults aged 50–79 years, lower fractal complexity of activity (α) was associated with greater mortality (hazard ratio = 0.64; 95% confidence interval = 0.49–0.82) after adjusting for age, exercise engagement, chronic diseases, and other covariates associated with mortality.ConclusionsWearable accelerometers can provide a noninvasive biomarker of physiological aging and mortality risk after adjusting for other factors strongly associated with mortality. Thus, this fractal analysis of accelerometer signals provides a novel clinical application for wearable accelerometers, advancing efforts for remote monitoring of physiological health by clinicians.

BACKGROUND: Brain imaging measurements can provide evidence of possible preclinical Alzheimer’s disease (AD). Their ability to predict individual imminent clinical conversion remains unclear. OBJECTIVE: To investigate the ability of pre-specified volumetric magnetic resonance imaging (MRI) and fluorodeoxyglucose positron emission tomography (FDG-PET) measurements to predict which cognitively unimpaired older participants would subsequently progress to amnestic mild cognitive impairmfluorodeoxyglucoseent (aMCI) within 2 years. METHODS: From an apolipoprotein E4 (APOE4) enriched prospective cohort study, 18 participants subsequently progressed to the clinical diagnosis of aMCI or probable AD dementia within 1.8 ± 0.8 years (progressors); 20 participants matched for sex, age, education, and APOE allele dose remained cognitively unimpaired for at least 4 years (non-progressors). A complementary control group not matched for APOE allele dose included 35 non-progressors. Groups were compared on baseline FDG-PET and MRI measures known to be preferentially affected in the preclinical and clinical stages of AD and by voxel-wise differences in regional gray matter volume and glucose metabolism. Receiver Operating Characteristic, binary logistic regression, and leave-one-out procedures were used to predict clinical outcome for the a priori measures. RESULTS: Compared to non-progressors and regardless of APOE-matching, progressors had significantly reduced baseline MRI and PET measurements in brain regions preferentially affected by AD and reduced hippocampal volume was the strongest predictor of an individual’s imminent progression to clinically significant memory decline (79% sensitivity/78% specificity among APOE-matched cohorts). CONCLUSION: Regional MRI and FDG-PET measurements may be useful in predicting imminent progression to clinically significant memory decline.

Objective The NIH Toolbox (NIHTB) Cognitive assessment battery has not been validated in the oldest-old population (85 years and older). Factor analysis of the NIHTB cognitive measures with “gold-standard” measures of the same cognition domains has revealed convergent and discriminant validity of these measures in a young adult population. Here we investigate if there is convergent and discriminant validity among the NIHTB and validated measures in the oldest old. Methods An exploratory factor analysis using the principal-axis factor extraction with Varimax rotation was conducted to determine the factor structure of the NIH Toolbox Cognitive Battery and other validated measures of cognition in the healthy oldest-old population. The sample, collected as part of the McKnight Brain Aging Registry, included 170 independent, healthy, community-dwelling adults aged 85+. Results Results indicated four factors with eigenvalues exceeding one with 58.6% variance explained. These four factors were interpreted as Memory, Working Memory, Speed/Attention, and Language. NIHTB Dimensional Change Card Sort test was removed due to low correlations with other measures. Conclusion Most tests from the NIH Toolbox converged with other tests of the same domain and were discriminable from tests of different domains, especially for memory, working memory, and language. The first factor, Speed/Attention, included attention and processing speed measures, but also canonical executive functioning measures such as Trails B. This overlap indicates that executive functioning tasks that rely on motor speed task demands (like the NIHTB DCCS) may mask preserved aspects of executive function in the oldest old. Further work is needed to confirm this interpretation.

Hypertension is a major health concern in the developed world, and its prevalence increases with advancing age. The impact of hypertension on the function of the renal and cardiovascular systems is well studied; however, its influence on the brain regions important for cognition has garnered less attention. We utilized the Cyp1a1‐Ren2 xenobiotic‐inducible transgenic rat model to mimic both the age of onset and rate of induction of hypertension observed in humans. Male, 15‐month‐old transgenic rats were fed 0.15% indole‐3‐carbinol (I3C) chow to slowly induce renin‐dependent hypertension over a 6‐week period. Systolic blood pressure significantly increased, eventually reaching 200 mmHg by the end of the study period. In contrast, transgenic rats fed a control diet without I3C did not show significant changes in blood pressure (145 mmHg at the end of study). Hypertension was associated with cardiac, aortic, and renal hypertrophy as well as increased collagen deposition in the left ventricle and kidney of the I3C‐treated rats. Additionally, rats with hypertension showed reduced savings from prior spatial memory training when tested on the hippocampus‐dependent Morris swim task. Motor and sensory functions were found to be unaffected by induction of hypertension. Taken together, these data indicate a profound effect of hypertension not only on the cardiovascular‐renal axis but also on brain systems critically important for learning and memory. Future use of this model and approach may empower a more accurate investigation of the influence of aging on the systems responsible for cardiovascular, renal, and neurological health.

See related article, p 2952 The use of telemedicine for the assessment and follow-up of patients who have suffered a stroke or other neurological conditions has increased dramatically over the past decade. There are several compelling reasons for this, including the need for initial screening and rapid clinical decision making and triage. Telemedicine may also reduce costs associated with routine follow-up visits, increase the number of cases that can be followed by the limited number of neurologists with stroke specialty available in some localities, and improve access to health care for disabled patients, particularly those living far from specialized stroke services.1 In this context, telephone assessment measures of cognitive functions have gained in popularity, providing clinicians with a way of conducting an initial evaluation of patients remotely or before coming to the hospital or outpatient office for more detailed assessments. The Telephone Interview for Cognitive Status (TICS)2 has been used for patients with reported changes in cognitive function to determine whether dementia or less severe mild cognitive impairment (MCI) is present, with accuracy that may depend on the severity of impairment.3 This type of assessment has been particularly useful for research studies in which the goal is to exclude individuals with early stage dementia and possible neurodegenerative disease or to help identify potential study participants with cognitive dysfunction to be confirmed in follow-up face-to-face detailed cognitive assessments. The Telephone Montreal Cognitive Assessment (T-MoCA), which was developed as an alternative to the TICS, provides a means of assessing mental status based on the parts of the MoCA that can be administered over the phone.4 The MoCA and its telephone-based versions may have particular clinical value for the assessment of patients with nonamnestic MCI, who can have greater impairments related to attention and executive functioning.5 Despite the …

Human lifespans are exceptionally long compared with those of other primates. A key element in exploring the evolution of human longevity is understanding how modern humans grow older. Our current understanding of common age-related changes in human health and function stems mostly from studies in industrialized societies, where older adulthood is often associated with an increased incidence of chronic diseases. However, individuals who engage in different lifestyles across industrialized and non-industrialized contexts may display variance in age-related changes in health and function. Here, we explore aspects of physical function in a non-industrialized context using three objective measures of physical function. We assessed physical activity levels, walking endurance and muscle strength in two East African populations: Hadza hunter–gatherers in Tanzania and Pokot pastoralists in Kenya. Both Hadza and Pokot participants displayed significant age-related differences in most, but not all, functional measures. Our results suggest that some age-related differences in physical function seen in industrialized contexts could be consistently experienced by most humans, while other age-related differences may vary across populations. Studies of ageing should expand to include a broad range of populations so we can create a more comprehensive understanding of how senescence varies across different lifestyle contexts. This article is part of the theme issue ‘Evolution of the primate ageing process’.

ObjectiveTo study longitudinal relationships between type 2 diabetes mellitus (T2DM), cortical thickness, and cognitive function in older people with normal cognition, mild cognitive impairment, and Alzheimer disease (AD).MethodsThe sample was derived from the Alzheimer's Disease Neuroimaging Initiative cohort who underwent brain MRI and cognitive tests annually for 5 years. Presence of T2DM was based on fasting blood glucose ≥7.0mml/L or the use of glucose-lowering agents. We used latent growth curve modeling to explore longitudinal relationships between T2DM, cortical thickness, and cognitive function, adjusting for relevant covariates and testing for interactions.ResultsThere were 124 people with T2DM (mean age 75.5 years, SD 6.2) and 693 without T2DM (mean age 75.1 years, SD 6.9) with at least 1 MRI available. AD and lower cortical thickness at study entry was associated with a lower chance of having a MRI available at each follow-up phase (all p < 0.001). T2DM was associated with lower baseline cortical thickness (p = 0.01). We found no direct effect of T2DM on decline in cortical thickness or cognitive function, but there was an indirect pathway linking T2DM and cognitive decline via baseline cortical thickness (β = −0.17, p = 0.022). There was an interaction between T2DM and education whereby the negative effect of T2DM on baseline cortical thickness was reduced in those with greater education (β = 0.34, p = 0.037). These associations changed minimally when adjusted for baseline cognitive diagnosis.ConclusionsIn an older cohort with low cerebrovascular disease burden, T2DM contributes to cognitive decline via neurodegeneration. Prior brain and cognitive reserve may protect against this effect.

This study evaluated whether the relation between subjective memory complaints and cognitive performance is influenced by the presence of hypertension in the elderly. One hundred and five healthy older adults, 70-89 years of age, with and without hypertension treatment or diagnosis, completed a scale of subjective memory complaints. Participants were divided into those with mild memory concerns and those with minimal or no complaints. All participants completed a battery of neuropsychological tests including measures of verbal and non-verbal memory. After controlling for differences in age, gender, education, and overall intellectual ability, there were significant main effects for memory concerns and significant interactions for memory complaints and hypertension on several measures of memory performance. There were no main effects for hypertension on memory performance. Simple effects analyses of the interactions showed that the hypertensive complainers demonstrated poorer performance on measures of long-term memory and greater reliance on short-term recall than the hypertensive non-complainers. There were no differences in memory performance for the non-hypertensive groups. Among healthy elderly community-dwelling adults, those with mild subjective memory complaints in the context of hypertension demonstrated greater objective cognitive difficulties than those without hypertension as well as a greater reliance on a less efficient learning strategy. These findings suggest that memory concerns in the presence of hypertension may be important when evaluating treatment efficacy in these individuals and for identifying differences in cognitive aging.

Background/ObjectivesPhysical activity (PA) protects against a wide range of diseases. Engagement in habitual PA has been shown to be heritable, motivating the search for specific genetic variants that may ultimately inform efforts to promote PA and target the best type of PA for each individual.Subjects/MethodsWe used data from the UK Biobank to perform the largest genome-wide association study of PA to date, using three measures based on self-report (n=277,656) and two measures based on wrist-worn accelerometry data (n=67,808). We examined genetic correlations of PA with other traits and diseases, as well as tissue-specific gene expression patterns. With data from the Atherosclerosis Risk in Communities (ARIC; n=8,556) study, we performed a meta-analysis of our top hits for moderate-to-vigorous PA (MVPA).ResultsWe identified 26 genome-wide loci across the five PA measures examined. Upon meta-analysis of the top hits for MVPA with results from the ARIC study, 8 of 10 remained significant at p−8. Interestingly, among these, the rs429358 variant in theAPOEgene was the most strongly associated with MVPA. Variants inCADM2, a gene recently implicated in risk-taking behavior and other personality and cognitive traits, were found to be associated with regular engagement in strenuous sports or other exercises. We also identified thirteen loci consistently associated (pConclusionsThese results provide new insight into the genetic basis of habitual PA, and the genetic links connecting PA with other traits and diseases.