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.

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.

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.

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.

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.

Validity of the NIH toolbox cognitive battery in a healthy oldest-old 85+ sample.

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.

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.

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.

Source recognition discriminability impairment in Huntington's versus Alzheimer's disease: Evidence from the CVLT-3.

Research suggests that individuals with Huntington's disease (HD) perform better than individuals with Alzheimer's disease (AD) on the California Verbal Learning Test (CVLT) Yes/No Recognition trial. However, those with HD have been shown to have deficits comparable to those with AD on the Source Recognition Discriminability (RD) index (which assesses the ability to distinguish between List A targets and List B distractors), suggesting that HD may involve selective impairment in aspects of yes/no recognition that rely on source memory. However, whether individuals with HD and AD show comparable deficits on Source RD across stages of dementia severity has not been adequately investigated. We examined performance on the CVLT-3 List A vs. List B RD index in individuals with HD or AD and mild or moderate dementia. Among individuals with mild dementia, scores were higher in the HD versus AD group, whereas among individuals with moderate dementia, scores were comparable between the HD and AD groups; this corresponded to differential performance across dementia stages among individuals with HD, but not AD. The present findings suggest that, relative to AD, HD may be associated with disproportionate decline in aspects of yes/no recognition that rely on source memory.

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.

Age-related differences in memory for "who," "when," and "where" are detectable in middle-aged adults.

Our study examined age-related differences across the adult lifespan using a recently developed test assessing memory for "who, when, and where" in addition to associations among these elements. Young (ages 18-25), middle-aged (ages 40-55), and older adults (ages 60+) were asked to remember a sequence of pictures of different faces paired with different places and place the pairs in the correct sequence. Young adults remembered significantly mores face-place pairs in the correct sequence than middle-aged (p < .05) and older adults (p < .05), but there were no significant differences between middle-aged and older adults. Furthermore, young adults remembered significantly more face-place pairs irrespective of sequence than older adults (p < .05). However, there were no other significant differences among the groups.Using a rapidly administered test that integrates aspects of everyday episodic memory, we found evidence for age-related differences in test performance beginning in middle age.

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.

Medication Management Performance in Parkinson's Disease: Examination of Process Errors.

OBJECTIVE: Individuals with Parkinson's disease (PD) are at risk for increased medication mismanagement, which can lead to worse clinical outcomes. However, the nature of the errors (i.e., undertaking or overtaking medications) contributing to mismanagement and their relationship to cognition in PD is unknown. Therefore, this study sought to examine errors committed on the Medication Management Ability Assessment (MMAA) between PD participants with normal cognition (PD-NC) or mild cognitive impairment (PD-MCI) relative to healthy adults (HA). METHOD: HA (n = 74), PD-NC (n = 102), and PD-MCI (n = 45) participants were administered the MMAA to assess undertaking, overtaking, and overall errors as well as overall performance (total score). Additionally, participants were administered a comprehensive neuropsychological battery from which cognitive composites of Attention, Learning, Memory, Language, Visuospatial, and Executive Functioning were derived. RESULTS: Separate negative binomial regression analyses indicated the PD-MCI group performed significantly worse overall on the MMAA (total score) and committed more undertaking and overall errors relative to HA and PD-NC. In the PD-MCI group, poorer MMAA performance was associated with worse delayed memory performance, whereas cognitive performance was not related to MMAA in HA or PC-NC. CONCLUSION: Compared to PD and healthy adults with normal cognition, PD-MCI patients exhibited greater difficulty with medication management, particularly with undertaking medications. Poorer medication management in PD-MCI was associated with worse delayed recall. Thus, PD-MCI patients experiencing memory problems may require additional assistance with their medications. Findings have clinical relevance suggesting that objective measures of medication errors may assist clinicians in identifying PD patients needing adherence strategies.

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.

Independent Contributions of Dorsolateral Prefrontal Structure and Function to Working Memory in Healthy Older Adults.

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). Binary logistic regressions also adjusting for total intracranial volume revealed left DLPFC surface area that significantly predicted the probability of being in the higher performing group (P = 0.017). The left DLPFC BOLD signal and surface area were not significantly associated and did not significantly interact to predict group membership (P values>.05). Importantly, this suggests BOLD signal and surface area may independently contribute to working memory performance in healthy older adults.