Functional Network Alterations Associated with Cognition in Pre-Clinical Alzheimer's Disease.

Objective: Accumulation of cerebral amyloid-ß (Aß) is a risk factor for cognitive decline and defining feature of Alzheimer's disease (AD). Aß is implicated in brain network disruption, but the extent to which these changes correspond with observable cognitive deficits in pre-clinical AD has not been tested. This study utilized individual-specific functional parcellations to sensitively evaluate the relationship between network connectivity and cognition in adults with and without Aß deposition. Participants and Methods: Cognitively unimpaired adults ages 45-85 completed amyloid positron emission tomography, resting-state-functional magnetic resonance imaging (fMRI), and neuropsychological tests of episodic memory and executive function (EF). Participants in the upper tertile of mean standard uptake value ratio were considered Aß+ (n = 50) while others were Aß- (n = 99). Individualized functional network parcellations were generated from resting-state fMRI data. We examined the effects of group, network, and group-by-network interactions on memory and EF. Results: We observed several interactions such that within the Aß+ group, preserved network integrity (i.e., greater connectivity within specific networks) was associated with better cognition, whereas network desegregation (i.e., greater connectivity between relative to within networks) was associated with worse cognition. This dissociation was most apparent for cognitive networks (frontoparietal, dorsal and ventral attention, limbic, and default mode), with connectivity relating to EF in the Aß+ group specifically. Conclusions: Using an innovative approach to constructing individual-specified resting-state functional connectomes, we were able to detect differences in brain-cognition associations in pre-clinical AD. Our findings provide novel insight into specific functional network alterations occurring in the presence of Aß that relate to cognitive function in asymptomatic individuals. Impact statement Elevated cerebral amyloid-ß is a biomarker of pre-clinical Alzheimer's disease (AD). Associations between amyloidosis, functional network disruption, and cognitive impairment are evident in the later stages of AD, but these effects have not been substantiated in pre-clinical AD. Using individual-specific parcellations that maximally localize functional networks, we identify network alterations that relate to cognition in pre-clinical AD that have not been previously reported. We demonstrate that these effects localize to networks implicated in cognition. Our findings suggest that there may be subtle, amyloid-related alterations in the functional connectome that are detectable in pre-clinical AD, with potential implications for cognition in asymptomatic individuals.

Demographic differences in performance validity test failure.

OBJECTIVE: The present study investigated demographic differences in performance validity test (PVT) failure in a Veteran sample. METHOD: Data were extracted from clinical neuropsychological evaluations. Only veterans who identified as men, as either European American/White (EA) or African American/Black (AA) were included (n = 1261). We investigated whether performance on two frequently used PVTs, the Test of Memory Malingering (TOMM), and the Medical Symptom Validity Test (MSVT), differed by age, education, and race using separate logistic regressions. RESULTS: Veterans with younger age, less education, and Veterans Affairs (VA) service-connected disability were significantly more likely to fail both PVTs. Race was not a significant predictor of MSVT failure, but AA patients were significantly more likely than EA patients to fail the TOMM. For all significant demographic predictors in the models, effects were small. In a subsample of patients who were given both PVTs (n = 461), the effects of race on performance remained. CONCLUSIONS: Performance on the TOMM and MSVT differed by age and level of education. Performance on the TOMM differed between EA and AA patients, whereas performance on the MSVT did not. These results suggest that demographic factors may play a small but measurable role in performance on specific PVTs.

Fiber Ball White Matter Modeling Reveals Microstructural Alterations in Healthy Brain Aging.

Age-related white matter degeneration is characterized by myelin breakdown and neuronal fiber loss that preferentially occur in regions that myelinate later in development. Conventional diffusion MRI (dMRI) has demonstrated age-related increases in diffusivity but provide limited information regarding the tissue-specific changes driving these effects. A recently developed dMRI biophysical modeling technique, Fiber Ball White Matter (FBWM) modeling, offers enhanced biological interpretability by estimating microstructural properties specific to the intra-axonal and extra-axonal spaces. We used FBWM to illustrate the biological mechanisms underlying changes throughout white matter in healthy aging using data from 63 cognitively unimpaired adults ages 45-85 with no radiological evidence of neurodegeneration or incipient Alzheimer's disease. Conventional dMRI and FBWM metrics were computed for two late-myelinating (genu of the corpus callosum and association tracts) and two early-myelinating regions (splenium of the corpus callosum and projection tracts). We examined the associations between age and these metrics in each region and tested whether age was differentially associated with these metrics in late- vs. early-myelinating regions. We found that conventional metrics replicated patterns of age-related increases in diffusivity in late-myelinating regions. FBWM additionally revealed specific intra- and extra-axonal changes suggestive of myelin breakdown and preferential loss of smaller-diameter axons, yielding in vivo corroboration of findings from histopathological studies of aged brains. These results demonstrate that advanced biophysical modeling approaches, such as FBWM, offer novel information about the microstructure-specific alterations contributing to white matter changes in healthy aging. These tools hold promise as sensitive indicators of early pathological changes related to neurodegenerative disease.

Protocol for a randomized controlled trial of mindfulness-based stress reduction to improve attentional control in older adults (HealthyAgers trial).

BACKGROUND: Mindfulness meditation is a form of mind-body intervention that has increasing scientific support for its ability to reduce age-related declines in cognitive functioning, improve affective health, and strengthen the neural circuitry supporting improved cognitive and affective health. However, the majority of existent studies have been pilot investigations with small sample sizes, limited follow-up data, and a lack of attention to expectancy effects. Here, we present the study design of a Phase I/II, efficacy trial-HealthyAgers trial-that examines the benefits of a manualized mindfulness-based stress reduction program in improving attentional control and reducing mind-wandering in older adults. METHODS: One hundred fifty older adults (ages 65-85 years) will be randomized into one of two groups: an eight-week mindfulness program or an eight-week, placebo-controlled, lifestyle education program. Behavioral and neuroimaging assessments are conducted before and after the training. Participants are then invited to booster sessions once every three months for a period of 12 months with post-intervention follow-up assessments conducted at 6-months and 12-months. The primary outcomes for the study are behavioral measures of attentional control and mind-wandering. Additional, secondary outcomes include network strength in an a priori defined neuromarker of attentional control, fluid and everyday cognition, emotion regulation strategy use, and markers of inflammation. DISCUSSION: This study will establish the efficacy of a group-based, low-cost mind-body intervention for the inter-related facets of attentional control and mind-wandering in older adults. Strengths of this study include a well-designed, placebo-controlled comparison group, use of web/mobile application to track study adherence, and longitudinal follow-up. TRIAL REGISTRATION: Clinicaltrials.gov (# NCT03626532 ). Registered August 4, 2018.

Greater Diffusion Restriction in White Matter in Preclinical Alzheimer Disease.

OBJECTIVE: The Alzheimer's continuum is biologically defined by beta-amyloid deposition, which at the earliest stages is superimposed upon white matter degeneration in aging. However, the extent to which these co-occurring changes is characterized is relatively underexplored. The goal of this study was to use diffusional kurtosis imaging (DKI) and biophysical modeling to detect and describe amyloid-related white matter changes in preclinical Alzheimer disease. METHODS: Cognitively unimpaired participants ages 45 to 85 years completed brain magnetic resonance imaging, amyloid positron emission tomography (florbetapir), neuropsychological testing, and other clinical measures at baseline in a cohort study. We tested whether beta-amyloid-negative (AB-) and -positive (AB+) participants differed on DKI-based conventional (ie, fractional anisotropy [FA], mean diffusivity [MD], mean kurtosis) and modeling (ie, axonal water fraction [AWF], extra-axonal radial diffusivity [De,⊥ ]) metrics, and whether these metrics were associated with other biomarkers. RESULTS: We found significantly greater diffusion restriction (higher FA/AWF, lower MD/De,⊥ ) in white matter in AB+ than AB- (partial η2 =0.08-0.19), more notably in the extra-axonal space within primarily late myelinating tracts. Diffusion metrics predicted amyloid status incrementally over age (area under the curve = 0.84) with modest yet selective associations, where AWF (a marker of axonal density) correlated with speed/executive functions and neurodegeneration, whereas De,⊥ (a marker of gliosis/myelin repair) correlated with amyloid deposition and white matter hyperintensity volume. INTERPRETATION: These results support prior evidence of a nonmonotonic change in diffusion behavior, where an early increase in diffusion restriction is hypothesized to reflect inflammation and myelin repair prior to an ensuing decrease in diffusion restriction, indicating glial and neuronal degeneration. ANN NEUROL 2022;91:864-877.

Employing Connectome-Based Models to Predict Working Memory in Multiple Sclerosis.

Introduction: Individuals with multiple sclerosis (MS) are vulnerable to deficits in working memory (WM), but the search for neural correlates of WM within circumscribed areas has been inconclusive. Given the widespread neural alterations observed in MS, predictive modeling approaches that capitalize on whole-brain connectivity may better capture individual differences in WM. Materials and Methods: We applied connectome-based predictive modeling to functional magnetic resonance imaging data from WM tasks in two independent samples with relapsing-remitting MS. In the internal sample (ninternal = 36), cross-validation was used to train a model to predict accuracy on the Paced Visual Serial Addition Test from functional connectivity. We hypothesized that this MS-specific model would successfully predict performance on the N-back task in the validation cohort (nvalidation = 36). In addition, we assessed the generalizability of existing WM networks derived in healthy young adults to these samples, and we explored anatomical differences between the healthy and MS networks. Results: We successfully derived an MS-specific predictive model of WM in the internal sample (full: rs = 0.47, permuted p = 0.011), but the predictions were not significant in the validation cohort (rs = -0.047; p = 0.78, mean squared error [MSE] = 0.006, R2 = -2.21%). In contrast, the healthy networks successfully predicted WM in both MS samples (internal: rs = 0.33 p = 0.049, MSE = 0.009, R2 = 13.4%; validation cohort: rs = 0.46, p = 0.005, MSE = 0.005, R2 = 16.9%), demonstrating their translational potential. Discussion: Functional networks identified in a large sample of healthy individuals predicted significant variance in WM in MS. Networks derived in small samples of people with MS may have limited generalizability, potentially due to disease-related heterogeneity. The robustness of models derived in large clinical samples warrants further investigation. ClinicalTrials.gov ID: NCT03244696.

Impact of mindfulness training on in-the-moment attentional control and emotion dysregulation in older adults: secondary analysis of a pilot, placebo-controlled randomized controlled trial.

Mindfulness-based interventions show increasing promise for improving attention and emotion regulation- processes that critically support healthy aging. Given their complex, multi-faceted nature, identifying specific aspects of attention and emotion regulation that are modifiable with training in older adults, particularly compared with active control groups, is an ongoing challenge. We performed pre-registered, secondary analyses of a pilot randomized controlled trial comparing the effects of a four-week mindfulness-based attention training (MBAT) group and a lifestyle education (LifeEd) active control group on attention and emotion dysregulation in older adults. Differential training outcomes were assessed for: (a) in-the-moment effects of mind-wandering on sustained attention, measured by performance decrements preceding self-reported mind-wandering, and (b) self-reported emotion dysregulation. Baseline working memory (WM) performance was tested as a moderator of training effects. There were no significant between-group differences for change in in-the-moment effects of mind-wandering on attention or emotion dysregulation. However, baseline WM moderated training effects, such that older adults with higher WM showed greater reductions in emotion dysregulation following mindfulness training. This has potential implications for identifying aging cohorts that may benefit most from this type of training.

Comparison of conventional and actuarial neuropsychological criteria for mild cognitive impairment in a clinical setting.

INTRODUCTION: Evidence-based practice in neuropsychology involves the use of validated tests, cutoff scores, and interpretive algorithms to identify clinically significant cognitive deficits. Recently, actuarial neuropsychological criteria (ANP) for identifying mild cognitive impairment were developed, demonstrating improved criterion validity and temporal stability compared to conventional criteria (CNP). However, benefits of the ANP criteria have not been investigated in non-research, clinical settings with varied etiologies, severities, and comorbidities. This study compared the utility of CNP and ANP criteria using data from a memory disorders clinic. METHOD: Data from 500 non-demented older adults evaluated in a Veterans Affairs Medical Center memory disorders clinic were retrospectively analyzed. We applied CNP and ANP criteria to the Repeatable Battery for the Assessment of Neuropsychological Status, compared outcomes to consensus clinical diagnoses, and conducted cluster analyses of scores from each group. RESULTS: The majority (72%) of patients met both the CNP and ANP criteria and both approaches were susceptible to confounding factors such as invalid test data and mood disturbance. However, the CNP approach mislabeled impairment in more patients with non-cognitive disorders and intact cognition. Comparatively, the ANP approach misdiagnosed patients with depression at a third of the rate and those with no diagnosis at nearly half the rate of CNP. Cluster analyses revealed groups with: 1) minimal impairment, 2) amnestic impairment, and 3) multi-domain impairment. The ANP approach yielded subgroups with more distinct neuropsychological profiles. CONCLUSIONS: We replicated previous findings that the CNP approach is over-inclusive, particularly for those determined to have no cognitive disorder by a consensus team. The ANP approach yielded fewer false positives and better diagnostic specificity than the CNP. Despite clear benefits of the ANP vs. CNP, there was substantial overlap in their performance in this heterogeneous sample. These findings highlight the critical role of clinical interpretation when wielding these empirically-derived tools.

Working memory training for adult glioma patients: a proof-of-concept study.

BACKGROUND: CogMed Working Memory Training (CWMT) is a computer-based program shown to improve working memory (WM) among those with cognitive impairments. No study to date has investigated its feasibility, acceptability, and satisfaction in adult patients with glioma, despite the well-documented incidence of WM impairment in this population. METHODS: Twenty patients with glioma and objective and/or perceived WM deficits enrolled in the study: 52% high-grade, 60% female, Mage = 47 (range = 21-72 years). Adverse events were monitored to determine safety. Feasibility and acceptability were assessed based on established metrics. Satisfaction was explored by exit-interviews. Neurocognitive tests and psychological symptoms were analyzed at baseline and post-CWMT to estimate effect sizes. RESULTS: Of 20 enrolled patients, 16 completed the intervention (80% retention rate). Reasons for withdrawal included time burden (n = 2); tumor-related fatigue (n = 1) or loss to follow-up (n = 1). No adverse events were determined to be study-related. Adherence was 69% with reasons for nonadherence similar to those for study withdrawal. The perceived degree of benefit was only moderate. Baseline to post-CWMT assessments showed medium to large effects on neurocognitive tasks. Psychological symptoms remained stable throughout the study period. CONCLUSIONS: CWMT was found to be safe and acceptable in adult patients with glioma. Enrollment, retention rates, and treatment adherence were all adequate and comparable to studies recruiting similar populations. Only moderate perceived benefit was reported despite demonstrated improvements in objectively-assessed WM. This may indicate that the time commitment and intervention intensity (5 weeks of 50-min training sessions on 5 days/week) outweighed the perceived benefits of the program. (Trial Registration Number: NCT03323450 registered on 10/27/2017).

Mindfulness and Attention: Current State-of-Affairs and Future Considerations.

This review examines longitudinal studies of changes in components of attention following mindfulness training. A total of 57 retreat studies, non-randomized trials, and randomized controlled trials were identified. Employing the classical taxonomy proposed by Posner and Petersen (1990), outcome measures were broadly categorized based on whether they involved maintenance of an aroused state (alerting), selective prioritization of attention to target items (orienting), or assessed conflict monitoring (executive attention). Although many non-randomized and retreat studies provide promising evidence of gains in both alerting and conflict monitoring following mindfulness training, evidence from randomized controlled trials, especially those involving active control comparison groups, is more mixed. This review calls attention to the urgent need in our field of contemplative sciences to adopt the methodological rigor necessary for establishing mindfulness meditation as an effective cognitive rehabilitation tool. Although studies including wait-listed control comparisons were fruitful in providing initial feasibility data and pre-post effect sizes, there is a pressing need to employ standards that have been heavily advocated for in the broader cognitive and physical training literatures. Critically, inclusion of active comparison groups and explicit attention to the reduction of demand characteristics are needed to disentangle the effects of placebo from treatment. Further, detailed protocols for mindfulness and control groups and examination of theoretically guided outcome variables with established metrics for reliability and validity are key ingredients in the systematic study of mindfulness meditation. Adoption of such methodological rigor will allow for causal claims supporting mindfulness training as an efficacious treatment modality for cognitive rehabilitation and enhancement.

Connectome-based models predict attentional control in aging adults.

There are well-characterized age-related differences in behavioral and neural responses to tasks of attentional control. However, there is also increasing recognition of individual variability in the process of neurocognitive aging. Using connectome-based predictive modeling, a method for predicting individual-level behaviors from whole-brain functional connectivity, a sustained attention connectome-based prediction model (saCPM) has been derived in young adults. The saCPM consists of two large-scale functional networks: a high-attention network whose strength predicts better attention and a low-attention network whose strength predicts worse attention. Here we examined the generalizability of the saCPM for predicting inhibitory control in an aging sample. Forty-two healthy young adults (n = 21, ages 18-30) and older adults (n = 21, ages 60-80) performed a modified Stroop task, on which older adults exhibited poorer performance, indexed by higher reaction time cost between incongruent and congruent trials. The saCPM generalized to predict reaction time cost across age groups, but did not account for age-related differences in performance. Exploratory analyses were conducted to characterize the effects of age on functional connectivity and behavior. We identified subnetworks of the saCPM that exhibited age-related differences in strength. The strength of two low-attention subnetworks, consisting of frontoparietal, medial frontal, default mode, and motor nodes that were more strongly connected in older adults, mediated the effect of age group on performance. These results support the saCPM's ability to capture attention-related patterns reflected in each individual's functional connectivity signature across both task context and age. However, older and younger adults exhibit functional connectivity differences within components of the saCPM networks, and it is these connections that better account for age-related deficits in attentional control.

Aging and Attentional Control: Examining the Roles of Mind-Wandering Propensity and Dispositional Mindfulness.

OBJECTIVES: Aging is associated with declines in performance on certain laboratory tasks of attentional control. However, older adults tend to report greater mindful, present-moment attention and less mind-wandering (MW) than young adults. For older adults, high levels of these traits may be protective for attentional performance. This study examined age-related differences in global (i.e., full-task) and local (i.e., pre-MW) attentional control and explored the variance explained by MW and mindfulness. METHODS: Cross-sectional comparisons were conducted on data from a previously reported sample of 75 older adults (ages, 60-75 years) and a new sample of 50 young adults (ages, 18-30 years). All participants completed a Go/No-Go task and a Continuous Performance Task with quasi-random MW probes. RESULTS: There were few age-related differences in attentional control. Although MW was not associated with decrements in global performance, local performance measures revealed deleterious effects of MW, which were present across age groups. Older adults reported higher trait mindfulness and less MW than young adults, and these variables helped explain the lack of observed age-related differences in attentional control. CONCLUSIONS: Individual differences in dispositional mindfulness and MW propensity explain important variance in attentional performance across age. Increasing present-moment focus and reducing lapses in attention represent important targets for cognitive rehabilitation interventions. (JINS, 2018, 24, 876-888).

Mindfulness Training for Healthy Aging: Impact on Attention, Well-Being, and Inflammation.

The growing interest in mindfulness interventions for use in aging samples has been met with promising evidence of cognitive, emotional, and physiological benefits. The purpose of this review is to provide an overview of the impact of mindfulness training on three areas of functioning in older adults: behavioral and neural correlates of attentional performance, psychological well-being, and systemic inflammation. We have previously proposed that mindfulness training is uniquely suited as a rehabilitative tool for conferring both cognitive and emotional benefits for older adults. Specifically, mindfulness training's promotion of focused attention may mitigate the decline of attentional control abilities across late development and allow older adults to capitalize on their preserved emotion regulation abilities. Existing evidence points to some improvements in facets of attentional control in older adults, although some studies have shown no benefits in performance. Further, there is evidence of enhancements in both psychological and physical aspects of well-being, and accompanying improvements in systemic inflammation, following mindfulness training. The scientific investigation of mindfulness training is still relatively nascent, with only a limited number of studies, particularly randomized controlled trials utilizing active comparison conditions. It will be important for future research to incorporate placebo-controlled comparison groups to clearly establish the causal role of mindfulness practices in promoting holistic health in older adults.

Dispositional mindfulness and the wandering mind: Implications for attentional control in older adults.

Age-related cognitive decline brings decreases in functional status. Dispositional mindfulness, the tendency towards present-moment attention, is hypothesized to correspond with enhanced attention, whereas mind-wandering may be detrimental to cognition. The relationships among mindfulness, task-related and task-unrelated thought, and attentional control performance on Go/No-Go and Continuous Performance tasks were examined in older adults. Dispositional mindfulness was negatively associated with task-unrelated thought and was positively associated with reactive control, but not proactive control or Go/No-Go performance. Although mind-wandering was not directly associated with performance, task-unrelated thought mediated the mindfulness-proactive control relation. Fewer task-unrelated thoughts were associated with lower proactive control. Interestingly, this effect was moderated by working memory such that it was present for those with low-average, but not high, working memory. This study highlights the importance of dispositional mindfulness and mind-wandering propensity in accounting for individual differences in attentional control in older adults, providing important targets for future cognitive remediation interventions.

Executive functions and theory of mind as predictors of social adjustment in childhood traumatic brain injury.

This study examined whether executive function and theory of mind mediate the effects of pediatric traumatic brain injury (TBI) on social adjustment, relative to children with orthopedic injury (OI). Participants included 19 children with severe TBI, 41 children with complicated mild/moderate TBI, and 57 children with OI. They completed measures of executive function, as well as cognitive, affective, and conative theory of mind. Parents provided ratings of children's social adjustment. Children with severe TBI performed more poorly than children with OI on executive function and theory of mind tasks and were rated by parents as having more behavioral symptoms and worse communication and social skills. Executive function and theory of mind were positively correlated with social skills and communication skills, and negatively correlated with behavioral symptoms. In multiple mediator models, theory of mind and executive function were not significant direct predictors of any measure of social adjustment, but mediated the association between injury and adjustment for children with severe TBI. Theory of mind was a significant independent mediator when predicting social skills, but executive function was not. TBI in children, particularly severe injury, is associated with poor social adjustment. The impact of TBI on children's social adjustment is likely mediated by its effects on executive function and theory of mind.