Learning ratio performance on a brief visual learning and memory test moderates cognitive training gains in Double Decision task in healthy older adults.

Cognitive training using a visual speed-of-processing task, called the Useful Field of View (UFOV) task, reduced dementia risk and reduced decline in activities of daily living at a 10-year follow-up in older adults. However, there was variability in the achievement of cognitive gains after cognitive training across studies, suggesting moderating factors. Learning trials of visual and verbal learning tasks recruit similar cognitive abilities and have overlapping neural correlates with speed-of-processing/working memory tasks and therefore could serve as potential moderators of cognitive training gains. This study explored the association between the Hopkins Verbal Learning Test-Revised (HVLT-R) and Brief Visuospatial Memory Test-Revised (BVMT-R) learning with a commercial UFOV task called Double Decision. Through a secondary analysis of a clinical trial, we assessed the moderation of HVLT-R and BVMT-R learning on Double Decision improvement after a 3-month speed-of-processing/attention and working memory cognitive training intervention in a sample of 75 cognitively healthy older adults. Multiple linear regressions showed that better baseline Double Decision performance was significantly associated with better BVMT-R learning (ß = - .303). This association was not significant for HVLT-R learning (ß = - .142). Moderation analysis showed that those with poorer BVMT-R learning improved the most on the Double Decision task after cognitive training. This suggests that healthy older adults who perform below expectations on cognitive tasks related to the training task may show the greatest training gains. Future cognitive training research studying visual speed-of-processing interventions should account for differing levels of visuospatial learning at baseline, as this could impact the magnitude of training outcomes and efficacy of the intervention.

Regional covariance of white matter hyperintensity volume patterns associated with hippocampal volume in healthy aging.

Hippocampal volume is particularly sensitive to the accumulation of total brain white matter hyperintensity volume (WMH) in aging, but how the regional distribution of WMH volume differentially impacts the hippocampus has been less studied. In a cohort of 194 healthy older adults ages 50-89, we used a multivariate statistical method, the Scaled Subprofile Model (SSM), to (1) identify patterns of regional WMH differences related to left and right hippocampal volumes, (2) examine associations between the multimodal neuroimaging covariance patterns and demographic characteristics, and (3) investigate the relation of the patterns to subjective and objective memory in healthy aging. We established network covariance patterns of regional WMH volume differences associated with greater left and right hippocampal volumes, which were characterized by reductions in left temporal and right parietal WMH volumes and relative increases in bilateral occipital WMH volumes. Additionally, we observed lower expression of these hippocampal-related regional WMH patterns were significantly associated with increasing age and greater subjective memory complaints, but not objective memory performance in this healthy older adult cohort. Our findings indicate that, in cognitively healthy older adults, left and right hippocampal volume reductions were associated with differences in the regional distribution of WMH volumes, which were exacerbated by advancing age and related to greater subjective memory complaints. Multivariate network analyses, like SSM, may help elucidate important early effects of regional WMH volume on brain and cognitive aging in healthy older adults.

Impact of age and apolipoprotein E ε4 status on regional white matter hyperintensity volume and cognition in healthy aging.

OBJECTIVE: White matter hyperintensity (WMH) volume is a neuroimaging marker of lesion load related to small vessel disease that has been associated with cognitive aging and Alzheimer's disease (AD) risk. METHOD: The present study sought to examine whether regional WMH volume mediates the relationship between APOE ε4 status, a strong genetic risk factor for AD, and cognition and if this association is moderated by age group differences within a sample of 187 healthy older adults (APOE ε4 status [carrier/non-carrier] = 56/131). RESULTS: After we controlled for sex, education, and vascular risk factors, ANCOVA analyses revealed significant age group by APOE ε4 status interactions for right parietal and left temporal WMH volumes. Within the young-old group (50-69 years), ε4 carriers had greater right parietal and left temporal WMH volumes than non-carriers. However, in the old-old group (70-89 years), right parietal and left temporal WMH volumes were comparable across APOE ε4 groups. Further, within ε4 non-carriers, old-old adults had greater right parietal and left temporal WMH volumes than young-old adults, but there were no significant differences across age groups in ε4 carriers. Follow-up moderated mediation analyses revealed that, in the young-old, but not the old-old group, there were significant indirect effects of ε4 status on memory and executive functions through left temporal WMH volume. CONCLUSIONS: These findings suggest that, among healthy young-old adults, increased left temporal WMH volume, in the context of the ε4 allele, may represent an early marker of cognitive aging with the potential to lead to greater risk for AD.

The impact of a tDCS and cognitive training intervention on task-based functional connectivity.

Declines in several cognitive domains, most notably processing speed, occur in non-pathological aging. Given the exponential growth of the older adult population, declines in cognition serve as a significant public health issue that must be addressed. Promising studies have shown that cognitive training in older adults, particularly using the useful field of view (UFOV) paradigm, can improve cognition with moderate to large effect sizes. Additionally, meta-analyses have found that transcranial direct current stimulation (tDCS), a non-invasive form of brain stimulation, can improve cognition in attention/processing speed and working memory. However, only a handful of studies have looked at concomitant tDCS and cognitive training, usually with short interventions and small sample sizes. The current study assessed the effect of a tDCS (active versus sham) and a 3-month cognitive training intervention on task-based functional connectivity during completion of the UFOV task in a large older adult sample (N = 153). We found significant increased functional connectivity between the left and right pars triangularis (the ROIs closest to the electrodes) following active, but not sham tDCS. Additionally, we see trending behavioral improvements associated with these functional connectivity changes in the active tDCS group, but not sham. Collectively, these findings suggest that tDCS and cognitive training can be an effective modulator of task-based functional connectivity above and beyond a cognitive training intervention alone.

Associations between physical exercise type, fluid intelligence, executive function, and processing speed in the oldest-old (85 +).

BACKGROUND: While much is known about the effects of physical exercise in adult humans, literature on the oldest-old (≥ 85 years old) is sparse. The present study explored the relationship between self-reported engagement in physical exercise and cognition in the oldest-old. METHODS: The sample included 184 cognitively healthy participants (98 females, MoCA mean score = 24.81) aged 85 to 99 years old (mean = 88.49 years). Participants completed the Community Healthy Activities Model Program for Seniors (CHAMPS) questionnaire and a cognitive battery including NIH-TB, Coding, Symbol Search, Letter Fluency, and Stroop task. Three groups of participants - sedentary (n = 58; MoCA mean score = 24; 36 females; mean age = 89.03), cardio (n = 60; MoCA mean score = 25.08; 29 females; mean age = 88.62), and cardio + strength training (n = 66; MoCA mean score = 25.28; 33 females; mean age = 87.91) - were derived from responses on CHAMPS. RESULTS: Analyses controlled for years of education, NIH-TB Crystallized Composite, and metabolic equivalent of tasks. The cardio + strength training group had the highest cognitive performances overall and scored significantly better on Coding (p < 0.001) and Symbol Search (p < 0.05) compared to the sedentary group. The cardio + strength training group scored significantly better on Symbol Search, Letter Fluency, and Stroop Color-Word compared to the cardio group (p < 0.05). CONCLUSIONS: Our findings suggest self-reported exercise in the oldest-old is linked to better performance on cognitive measures of processing speed and executive functioning, and that there may be a synergistic effect of combining aerobic and resistance training on cognition.

Connecting memory and functional brain networks in older adults: a resting-state fMRI study.

Limited research exists on the association between resting-state functional network connectivity in the brain and learning and memory processes in advanced age. This study examined within-network connectivity of cingulo-opercular (CON), frontoparietal control (FPCN), and default mode (DMN) networks, and verbal and visuospatial learning and memory in older adults. Across domains, we hypothesized that greater CON and FPCN connectivity would associate with better learning, and greater DMN connectivity would associate with better memory. A total of 330 healthy older adults (age range = 65-89) underwent resting-state fMRI and completed the Hopkins Verbal Learning Test-Revised (HVLT-R) and Brief Visuospatial Memory Test-Revised (BVMT-R) in a randomized clinical trial. Total and delayed recall scores were assessed from baseline data, and a learning ratio calculation was applied to participants' scores. Average CON, FPCN, and DMN connectivity values were obtained with CONN Toolbox. Hierarchical regressions controlled for sex, race, ethnicity, years of education, and scanner site, as this was a multi-site study. Greater within-network CON connectivity was associated with better verbal learning (HVLT-R Total Recall, Learning Ratio), visuospatial learning (BVMT-R Total Recall), and visuospatial memory (BVMT-R Delayed Recall). Greater FPCN connectivity was associated with better visuospatial learning (BVMT-R Learning Ratio) but did not survive multiple comparison correction. DMN connectivity was not associated with these measures of learning and memory. CON may make small but unique contributions to learning and memory across domains, making it a valuable target in future longitudinal studies and interventions to attenuate memory decline. Further research is necessary to understand the role of FPCN in learning and memory.

Sedentary Behavior and Incident Dementia Among Older Adults.

Importance: Sedentary behavior is associated with cardiometabolic disease and mortality, but its association with dementia is unclear. Objective: To investigate whether accelerometer-assessed sedentary behavior is associated with incident dementia. Design, Setting, and Participants: A retrospective study of prospectively collected data from the UK Biobank including 49 841 adults aged 60 years or older without a diagnosis of dementia at the time of wearing the wrist accelerometer and living in England, Scotland, or Wales. Follow-up began at the time of wearing the accelerometer (February 2013 to December 2015) and continued until September 2021 in England, July 2021 in Scotland, and February 2018 in Wales. Exposures: Mean daily sedentary behavior time (included in the primary analysis) and mean daily sedentary bout length, maximum daily sedentary bout length, and mean number of daily sedentary bouts (included in the secondary analyses) were derived from a machine learning-based analysis of 1 week of wrist-worn accelerometer data. Main Outcome and Measures: Incident all-cause dementia diagnosis from inpatient hospital records and death registry data. Cox proportional hazard models with linear and cubic spline terms were used to assess associations. Results: A total of 49 841 older adults (mean age, 67.19 [SD, 4.29] years; 54.7% were female) were followed up for a mean of 6.72 years (SD, 0.95 years). During this time, 414 individuals were diagnosed with incident all-cause dementia. In the fully adjusted models, there was a significant nonlinear association between time spent in sedentary behavior and incident dementia. Relative to a median of 9.27 hours/d for sedentary behavior, the hazard ratios (HRs) for dementia were 1.08 (95% CI, 1.04-1.12, P < .001) for 10 hours/d, 1.63 (95% CI, 1.35-1.97, P < .001) for 12 hours/d, and 3.21 (95% CI, 2.05-5.04, P < .001) for 15 hours/d. The adjusted incidence rate of dementia per 1000 person-years was 7.49 (95% CI, 7.48-7.49) for 9.27 hours/d of sedentary behavior, 8.06 (95% CI, 7.76-8.36) for 10 hours/d, 12.00 (95% CI, 10.00-14.36) for 12 hours/d, and 22.74 (95% CI, 14.92-34.11) for 15 hours/d. Mean daily sedentary bout length (HR, 1.53 [95% CI, 1.03-2.27], P = .04 and 0.65 [95% CI, 0.04-1.57] more dementia cases per 1000 person-years for a 1-hour increase from the mean of 0.48 hours) and maximum daily sedentary bout length (HR, 1.15 [95% CI, 1.02-1.31], P = .02 and 0.19 [95% CI, 0.02-0.38] more dementia cases per 1000 person-years for a 1-hour increase from the mean of 1.95 hours) were significantly associated with higher risk of incident dementia. The number of sedentary bouts per day was not associated with higher risk of incident dementia (HR, 1.00 [95% CI, 0.99-1.01], P = .89). In the sensitivity analyses, after adjustment for time spent in sedentary behavior, the mean daily sedentary bout length and the maximum daily sedentary bout length were no longer significantly associated with incident dementia. Conclusions and Relevance: Among older adults, more time spent in sedentary behaviors was significantly associated with higher incidence of all-cause dementia. Future research is needed to determine whether the association between sedentary behavior and risk of dementia is causal.

Task-based functional connectivity of the Useful Field of View (UFOV) fMRI task.

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.

Association of homocysteine-related subcortical brain atrophy with white matter lesion volume and cognition in healthy aging.

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.

The longitudinal impact of the COVID-19 pandemic on health behaviors, psychosocial factors, and cognitive functioning in older adults.

Background: Older adults are at a greater risk for contracting and experiencing severe illness from COVID-19 and may be further affected by pandemic-related precautions (e.g., social distancing and isolation in quarantine). However, the longitudinal impact of the COVID-19 pandemic on older adults is unclear. The current study examines changes in health behaviors, psychosocial factors, and cognitive functioning in a large sample of older adults using a pre-pandemic baseline and longitudinal follow-up throughout 9 months of the COVID-19 pandemic. Methods: One hundred and eighty-nine older adults (ages 65-89) were recruited from a multisite clinical trial to complete additional virtual assessments during the COVID-19 pandemic. Mixed effects models evaluated changes in health behaviors, psychosocial factors, and cognitive functioning during the pandemic compared to a pre-pandemic baseline and over the course of the pandemic (i.e., comparing the first and last COVID-19 timepoints). Results: Compared to their pre-pandemic baseline, during the pandemic, older adults reported worsened sleep quality, perceived physical health and functioning, mental health, slight increases in depression and apathy symptoms, reduced social engagement/perceived social support, but demonstrated better performance on objective cognitive tasks of attention and working memory. Throughout the course of the pandemic, these older adults reported continued worsening of perceived physical health and function, fewer depression symptoms, and they demonstrated improved cognitive performance. It is important to note that changes on self-report mood measures and cognitive performance were relatively small regarding clinical significance. Education largely served as a protective factor, such that greater years of education was generally associated with better outcomes across domains. Conclusions: The present study provides insights into the longitudinal impact of the COVID-19 pandemic on health behaviors, psychosocial factors, and cognitive functioning in a population disproportionately affected by the virus. Replicating this study design in a demographically representative older adult sample is warranted to further inform intervention strategies targeting older adults negatively impacted by the COVID-19 pandemic.

Leisure-time sedentary behaviors are differentially associated with all-cause dementia regardless of engagement in physical activity.

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.

Association of Physical Activity with Incidence of Dementia Is Attenuated by Air Pollution.

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 yrs and older from the UK Biobank. Average acceleration magnitude (ACCave) from wrist-worn accelerometers was used to assess PA levels. Air pollution levels (NO, NO2, PM10, PM2.5, PM2.5-10, and PM2.5 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, ACCave was associated with reduced risk of developing dementia (HR = 0.71, 95% confidence interval [CI] = 0.60-0.83), whereas air pollution variables were not associated with dementia risk. There were significant interactions between ACCave and PM2.5 (HRinteraction = 1.33, 95% CI = 1.13-1.57) and PM2.5 absorbance (HRinteraction = 1.24, 95% CI = 1.07-1.45) on incident dementia. At the lowest tertiles of pollution, ACCave was associated with reduced risk of incident dementia (HRPM 2.5 = 0.66, 95% CI = 0.49-0.91; HRPM 2.5 absorbance = 0.60, 95% CI = 0.44-0.81). At the highest tertiles of these pollutants, there was no significant association of ACCave with incident dementia (HRPM 2.5 = 0.88, 95% CI = 0.68-1.14; HRPM 2.5 absorbance = 0.79, 95% CI = 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.

Higher white matter hyperintensity load adversely affects pre-post proximal cognitive training performance in healthy older adults.

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 (ß = -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.

Proximal improvement and higher-order resting state network change after multidomain cognitive training intervention in healthy older adults.

Prior randomized control trials have shown that cognitive training interventions resulted in improved proximal task performance, improved functioning of activities of daily living, and reduced dementia risk in healthy older adults. Neural correlates implicated in cognitive training include hub brain regions of higher-order resting state networks including the default mode network, dorsal attention network, frontoparietal control network, and cingulo-opercular network. However, little is known about resting state network change after cognitive training, or the relation between functional brain changes and improvement in proximal task performance. We assessed the 1) change in proximal task performance, 2) change in higher-order resting state network connectivity via functional magnetic resonance imaging, and 3) association between these variables after a multidomain attention/speed-of-processing and working memory randomized control trial in a sample of 58 healthy older adults. Participants in the cognitive training group improved significantly on seven out of eight training tasks immediately after the training intervention with the largest magnitude of improvement in a divided attention/speed-of-processing task, the Double Decision task. Only the frontoparietal control network had significantly strengthened connectivity in the cognitive training group at the post-intervention timepoint. Lastly, higher frontoparietal control network connectivity was associated with improved Double Decision task performance after training in the cognitive training group. These findings show that the frontoparietal control network may strengthen after multidomain cognitive training interventions, and this network may underlie improvements in divided attention/speed-of-processing proximal improvement.

The association between head motion during functional magnetic resonance imaging and executive functioning in older adults.

Minimizing head motion during functional magnetic resonance imaging (fMRI) is important for maintaining the integrity of neuroimaging data. While there are a variety of techniques to control for head motion, oftentimes, individuals with excessive in-scanner motion are removed from analyses. Movement in the scanner tends to increase with age; however, the cognitive profile of these "high-movers" in older adults has yet to be explored. This study aimed to assess the association between in-scanner head motion (i.e., number of "invalid scans" flagged as motion outliers) and cognitive functioning (e.g., executive functioning, processing speed, and verbal memory performance) in a sample of 282 healthy older adults. Spearman's Rank-Order correlations showed that a higher number of invalid scans was significantly associated with poorer performance on tasks of inhibition and cognitive flexibility and with older age. Since performance in these domains tend to decline as a part of the non-pathological aging process, these findings raise concerns regarding the potential systematic exclusion due to motion of older adults with lower executive functioning in neuroimaging samples. Future research should continue to explore prospective motion correction techniques to better ensure the collection of quality neuroimaging data without excluding informative participants from the sample.

Functional Neural Correlates of a Useful Field of View (UFOV)-Based fMRI Task in Older Adults.

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.

Higher-order resting state network association with the useful field of view task 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.

Cingulo-opercular and frontoparietal control network connectivity and executive functioning in older adults.

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.

Frontal White Matter Hyperintensities and Executive Functioning Performance in Older Adults.

Frontal lobe structures decline faster than most other brain regions in older adults. Age-related change in the frontal lobe is associated with poorer executive function (e.g., working memory, switching/set-shifting, and inhibitory control). The effects and presence of frontal lobe white matter hyperintensities (WMH) on executive function in normal aging is relatively unknown. The current study assessed relationships between region-specific frontal WMH load and cognitive performance in healthy older adults using three executive function tasks from the NIH Toolbox (NIHTB) Cognition Battery. A cohort of 279 healthy older adults ages 65-88 completed NIHTB and 3T T1-weighted and FLAIR MRI. Lesion Segmentation Toolbox quantified WMH volume and generated lesion probability maps. Individual lesion maps were registered to the Desikan-Killiany atlas in FreeSurfer 6.0 to define regions of interest (ROI). Independent linear regressions assessed relationships between executive function performance and region-specific WMH in frontal lobe ROIs. All models included age, sex, education, estimated total intracranial volume, multi-site scanner differences, and cardiovascular disease risk using Framingham criteria as covariates. Poorer set-shifting performance was associated with greater WMH load in three frontal ROIs including bilateral superior frontal (left ß = -0.18, FDR-p = 0.02; right ß = -0.20, FDR-p = 0.01) and right medial orbitofrontal (ß = -0.17, FDR-p = 0.02). Poorer inhibitory performance associated with higher WMH load in one frontal ROI, the right superior frontal (right ß = -0.21, FDR-p = 0.01). There were no significant associations between working memory and WMH in frontal ROIs. Our study demonstrates that location and pattern of frontal WMH may be important to assess when examining age-related differences in cognitive functions involving switching/set-shifting and inhibition. On the other hand, working memory performance was not related to presence of frontal WMH in this sample. These data suggest that WMH may contribute selectively to age-related declines in executive function. Findings emerged beyond predictors known to be associated with WMH presence, including age and cardiovascular disease risk. The spread of WMH within the frontal lobes may play a key role in the neuropsychological profile of cognitive aging. Further research should explore whether early intervention on modifiable vascular factors or cognitive interventions targeted for executive abilities may help mitigate the effect of frontal WMH on executive function.

Influence of regional white matter hyperintensity volume and apolipoprotein E ε4 status on hippocampal volume in healthy older adults.

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) ε4 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 ε4 status in a group of 190 cognitively healthy adults (APOE ε4 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 ε4 status (-0.020 (SE = 0.009), 95% CI, [-0.039, -0.003]). APOE ε4 carriers, but not non-carriers, showed negative indirect effects of age on hippocampal volume through temporal lobe WMH volume (APOE ε4 carriers: -0.016 (SE = 0.007), 95% CI, [-0.030, -0.003]; APOE ε4 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 ε4 carriers is associated with reduced hippocampal volume, suggesting greater vulnerability to brain aging and the risk for Alzheimer's disease.