Influence of affective states on informant impression of neuropsychiatric symptoms in people living with MCI.

Objectives: Alzheimer's disease (AD) and mild cognitive impairment (MCI) are often accompanied by neuropsychiatric symptoms (NPS; e.g. depression/apathy/irritability) causing challenges for people living with dementia/caregivers and predicting worse disease progression. Accurately assessing NPS is critical to research on AD/MCI. However, there are limitations to both self-reports and clinician evaluations; the field often relies on informants to assess NPS. Informants' perception of NPS are influenced by disease and caregiver factors that may lead to biased assessments. We aimed to assess the relationship between participants self-reported affective states (valence/arousal) and informant-reported NPS.Methods: Data from a double-blinded intervention design (primarily testing neurostimulation's effect on NPS) were used to examine the relationship between participant-reported affective states and informant-reported NPS over 1 month. Forty participants (24 females) with MCI and NPS (mean age = 71.7, SD = 7) were enrolled along with informants (primarily spouses/partners) who regularly interact with participants. NPS assessment occurred weekly and at pre- and post-intervention, and participant-reported affective states were assessed at 14 timepoints.Results: Generalized Estimating Equations showed that participant levels of arousal, but not valence, were significantly related to corresponding informant-reported NPS at weekly (arousal: B= -0.59, SE = 0.27, Wald's χ2 = 4.61, p=.032; valence: B = 0.17, SE = 0.19, Wald's χ2 = 0.80, p=.37) and pre-/post- (arousal: B= -4.00, SE = 1.58, Wald's χ2 = 6.42, p=.011; valence: B= -3.34, SE = 1.80, Wald's χ2 = 3.43, p=.06) assessments.Conclusion: The findings indicate that informant-reported NPS may be more strongly influenced by arousal, and informants may be less attuned to valence in people living with MCI.

Learning Clique Subgraphs in Structural Brain Network Classification with Application to Crystallized Cognition.

Structural brain networks constructed from diffusion MRI are important biomarkers for understanding human brain structure and its relation to cognitive functioning. There is increasing interest in learning differences in structural brain networks between groups of subjects in neuroimaging studies, leading to a variable selection problem in network classification. Traditional methods often use independent edgewise tests or unstructured generalized linear model (GLM) with regularization on vectorized networks to select edges distinguishing the groups, which ignore the network structure and make the results hard to interpret. In this paper, we develop a symmetric bilinear logistic regression (SBLR) with elastic-net penalty to identify a set of small clique subgraphs in network classification. Clique subgraphs, consisting of all the interconnections among a subset of brain regions, have appealing neurological interpretations as they may correspond to some anatomical circuits in the brain related to the outcome. We apply this method to study differences in the structural connectome between adolescents with high and low crystallized cognitive ability, using the crystallized cognition composite score, picture vocabulary and oral reading recognition tests from NIH Toolbox. A few clique subgraphs containing several small sets of brain regions are identified between different levels of functioning, indicating their importance in crystallized cognition.

Increased segregation of structural brain networks underpins enhanced broad cognitive abilities of cognitive training.

A major challenge in the cognitive training field is inducing broad, far-transfer training effects. Thus far, little is known about the neural mechanisms underlying broad training effects. Here, we tested a set of competitive hypotheses regarding the role of brain integration versus segregation underlying the broad training effect. We retrospectively analyzed data from a randomized controlled trial comparing neurocognitive effects of vision-based speed of processing training (VSOP) and an active control consisting of mental leisure activities (MLA) in older adults with MCI. We classified a subset of participants in the VSOP as learners, who showed improvement in executive function and episodic memory. The other participants in the VSOP (i.e., VSOP non-learners) and a subset of participants in the MLA (i.e., MLA non-learners) served as controls. Structural brain networks were constructed from diffusion tensor imaging. Clustering coefficients (CCs) and characteristic path lengths were computed as measures of segregation and integration, respectively. Learners showed significantly greater global CCs after intervention than controls. Nodal CCs were selectively enhanced in cingulate cortex, parietal regions, striatum, and thalamus. Among VSOP learners, those with more severe baseline neurodegeneration had greater improvement in segregation after training. Our findings suggest broad training effects are related to enhanced segregation in selective brain networks, providing insight into cognitive training related neuroplasticity.

Attitudes Toward Computers Moderate the Effect of Computerized Cognitive Trainings in Oldest-Old Senior Living Center Residents.

BACKGROUND AND OBJECTIVES: Computerized cognitive interventions (CCIs) have been increasingly implemented among older adults with mild cognitive impairment (MCI). However, older individuals' attitudes toward technology may limit CCI engagement. This exploratory-developmental study examined whether a "multi-functional interactive computer system" (MICS), which provides pleasurable activities via computer, would improve attitudes toward computers and in turn increase the efficacy of a subsequent CCI. RESEARCH DESIGN AND METHODS: A phase one double-blind trial randomized 49 seniors with MCI to a MICS + CCI condition or a CCI-only condition. Attitudes toward technology use was assessed using The Attitudes Toward Computers Questionnaire (ATCQ), and cognition was assessed using episodic memory and executive function composite scores at baseline, the ends of MICS and CCI phases, and 3-month follow-up. RESULTS: The MICS + CCI group did not show significantly greater improvement in cognition than the CCI only group. Secondary analyses indicated that improvement in executive function from baseline occurred in both groups. Participants who did show improved attitudes toward computers, whether through MICS or simply computer exposure itself, showed improvement in executive function. DISCUSSION AND IMPLICATION: Participants in the MICS + CCI group used MICS less than expected. A more structured and supervised approach may be needed to facilitate MICS exposure. Improved attitudes toward computers regardless of MICS exposure may benefit candidates for CCI.

Dysregulation of inflammation, neurobiology, and cognitive function in PTSD: an integrative review.

Compelling evidence from animal and human research suggest a strong link between inflammation and posttraumatic stress disorder (PTSD). Furthermore, recent findings support compromised neurocognitive function as a key feature of PTSD, particularly with deficits in attention and processing speed, executive function, and memory. These cognitive domains are supported by brain structures and neural pathways that are disrupted in PTSD and which are implicated in fear learning and extinction processes. The disruption of these supporting structures potentially results from their interaction with inflammation. Thus, the converging evidence supports a model of inflammatory dysregulation and cognitive dysfunction as combined mechanisms underpinning PTSD symptomatology. In this review, we summarize evidence of dysregulated inflammation in PTSD and further explore how the neurobiological underpinnings of PTSD, in the context of fear learning and extinction acquisition and recall, may interact with inflammation. We then present evidence for cognitive dysfunction in PTSD, highlighting findings from human work. Potential therapeutic approaches utilizing novel pharmacological and behavioral interventions that target inflammation and cognition also are discussed.

Geriatric assessment with management intervention in older adults with cancer: a randomized pilot study.

BACKGROUND: Older adults receiving cancer therapy have heightened risk for treatment-related toxicity. Geriatric assessment (GA) can identify impairments, which may contribute to vulnerability and adverse outcomes. GA management interventions can address these impairments and have the potential to improve outcomes when implemented. METHODS: We conducted a randomized pilot study comparing GA with management interventions versus usual care in patients with stage III/IV solid tumor malignancies (N = 71). In all patients, a trained coordinator conducted and scored a baseline GA with pre-determined cutoffs for impairment. For patients randomized to the intervention arm, an algorithm was used to identify GA management recommendations based upon identified impairments. Recommendations were relayed to the primary oncologist for implementation. GA was repeated at 3 months. The primary outcome was grade 3-5 chemotherapy toxicity. Secondary outcomes included feasibility, hospitalizations, dose reductions, dose delays, and early treatment discontinuation. RESULTS: The mean participant age was 76 (70-89). The total number of GA management recommendations relayed was 409, of which 35.4% were implemented by the primary oncologist. Incidence of grade 3-5 chemotherapy toxicity did not differ between the two groups. Prevalence of hospitalization, dose reductions, dose delays, and early treatment discontinuation also did not differ between the two groups. CONCLUSIONS: An algorithm can be used to guide GA management recommendations in older adults with cancer. However, reliance upon the primary oncologist for execution resulted in a low prevalence of implementation. Future work should aim to understand barriers to implementation and explore alternate models of implementing geriatric-focused care for older adults with cancer.

The Moderating Effect of Personality Type on the Relationship between Leisure Activity and Executive Control in Older Adults.

We examined the moderating effect of personality on the association between leisure activities and executive control in healthy community-dwelling older adults. We found two distinct personality typologies: individuals with a Resilient personality were characterized by emotional stability and self-confidence; whereas, those who resembled an Overcontrolled personality tended to be introverted, but also low on neuroticism. Resilient individuals were more likely than Overcontrolled individuals to demonstrate higher executive function and attention as a result of participation in mental activities. These results suggest that personality might be important to include in studies that test the efficacy of activity interventions for improving cognition.

Brain imaging studies of emotional well-being: a scoping review.

This scoping review provides an overview of previous empirical studies that used brain imaging techniques to investigate the neural correlates of emotional well-being (EWB). We compiled evidence on this topic into one accessible and usable document as a foundation for future research into the relationship between EWB and the brain. PRISMA 2020 guidelines were followed. We located relevant articles by searching five electronic databases with 95 studies meeting our inclusion criteria. We explored EWB measures, brain imaging modalities, research designs, populations studied, and approaches that are currently in use to characterize and understand EWB across the literature. Of the key concepts related to EWB, the vast majority of studies investigated positive affect and life satisfaction, followed by sense of meaning, goal pursuit, and quality of life. The majority of studies used functional MRI, followed by EEG and event-related potential-based EEG to study the neural basis of EWB (predominantly experienced affect, affective perception, reward, and emotion regulation). It is notable that positive affect and life satisfaction have been studied significantly more often than the other three aspects of EWB (i.e., sense of meaning, goal pursuit, and quality of life). Our findings suggest that future studies should investigate EWB in more diverse samples, especially in children, individuals with clinical disorders, and individuals from various geographic locations. Future directions and theoretical implications are discussed, including the need for more longitudinal studies with ecologically valid measures that incorporate multi-level approaches allowing researchers to better investigate and evaluate the relationships among behavioral, environmental, and neural factors. Systematic review registration: https://osf.io/t9cf6/.

Unifying framework for cognitive training interventions in brain aging.

Cognitive training is a promising tool for slowing or preventing cognitive decline in older adults at-risk for dementia. Its success, however, has been limited by a lack of evidence showing that it reliably causes broad training effects: improvements in cognition across a range of domains that lead to real-world benefits. Here, we propose a framework for enhancing the effect of cognitive training interventions in brain aging. The focus is on (A) developing cognitive training task paradigms that are informed by population-level cognitive characteristics and pathophysiology, and (B) personalizing how these sets are presented to participants during training via feedback loops that aim to optimize "mismatch" between participant capacity and training demands using both adaptation and random variability. In this way, cognitive training can better alter whole-brain topology in a manner that supports broad training effects in the context of brain aging.

Blood biomarkers as surrogate endpoints of treatment responses to aerobic exercise and cognitive training (ACT) in amnestic mild cognitive impairment: the blood biomarkers study protocol of a randomized controlled trial (the ACT Trial).

BACKGROUND: Alzheimer's disease (AD) is an epidemic with tremendous public health impacts because there are currently no disease-modifying therapeutics. Randomized controlled trials (RCTs) for prevention of AD dementia often use clinical endpoints that take years to manifest (e.g., cognition) or surrogate endpoints that are costly or invasive (e.g., magnetic resonance imaging [MRI]). Blood biomarkers represent a clinically applicable alternative surrogate endpoint for RCTs that would be both cost-effective and minimally invasive, but little is known about their value as surrogate endpoints for treatment responses in the prevention of AD dementia. METHODS: The objective of this study is to investigate blood neuropathological, neurodegenerative, and neurotrophic biomarkers as surrogate endpoints for treatment responses to three interventions in older adults with amnestic mild cognitive impairment (aMCI, a prodromal stage of AD): aerobic exercise, cognitive training, and combined aerobic exercise and cognitive training (ACT). We chose these three sets of biomarkers for their unique mechanistic associations with AD pathology, neurodegeneration and neurogenesis. This study is built on the ACT Trial (1R01AG055469), a single-blinded, multi-site, 2 × 2 factorial phase II RCT that examines the synergistic effects of a 6-month ACT intervention on cognition and MRI biomarkers (AD-signature cortical thickness and hippocampal volume) (n = 128). In this ACT Trial blood biomarkers study, we will enroll 120 ACT Trial participants with aMCI and measure blood biomarkers at baseline and at 3, 6, 12, and 18 months. The goals are to (1) determine the effect of interventions on blood biomarkers over 6 months, (2) evaluate blood biomarkers as surrogate endpoints for predicting cognitive responses to interventions over 18 months, and (3, exploratory) examine blood biomarkers as surrogate endpoints for predicting brain MRI biomarker responses to interventions over 18 months. DISCUSSION: This study aims to identify new blood biomarkers that can track cognitive decline or AD-related brain atrophy among patients with aMCI subjected to a regimen of aerobic exercise and cognitive training. Findings from this study will drive the further use of blood biomarkers in developing effective prevention and treatment strategies for AD dementia. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03313895. Registered on 18 October 2017.

Amyloid and FDG PET of Successful Cognitive Aging: Global and Cingulate-Specific Differences.

BACKGROUND: Some individuals, called Supernormals (SN), maintain excellent memory in old age. While brain structural and functional integrity in SN seem to be aging-resistant, their amyloidosis and neural injury status has not been well studied. OBJECTIVE: The goal of this study was to compare cortical amyloid deposition and glucose metabolism between SN and older adults with normal cognition (NC), amnestic mild cognitive impairment (MCI), and Alzheimer's disease (AD). METHODS: Subjects from the ADNI database were included if they received T1-weighted MRI, amyloid PET, FDG-PET, and cognitive testing within a 6-month period, yielding 27 AD, 69 MCI, 172 NC, and 122 SN. PET standardized uptake value ratios (SUVrs) were calculated for the whole cortex and 68 regions of interest, with whole cerebellum serving as reference. RESULTS: SN had lower whole cortex amyloid than MCI, and higher glucose metabolism than all others. Regional analysis revealed that amyloid burden and glucose metabolism in the right isthmus cingulate cortex differed in SN compared to others, while SN glucose metabolism also differed from others in several frontal and temporal regions. CONCLUSION: Preserved cortical glucose metabolism, and lower levels of amyloidosis and glucose hypometabolism in the right isthmus cingulate cortex, contributes to the Supernormal phenomenon. These findings may be informative for development of early screening biomarkers and therapeutic targets for modification of cognitive trajectories.

Efficacy and mechanisms of combined aerobic exercise and cognitive training in mild cognitive impairment: study protocol of the ACT trial.

BACKGROUND: Developing non-pharmacological interventions with strong potential to prevent or delay the onset of Alzheimer's disease (AD) in high-risk populations is critical. Aerobic exercise and cognitive training are two promising interventions. Aerobic exercise increases aerobic fitness, which in turn improves brain structure and function, while cognitive training improves selective brain function intensively. Hence, combined aerobic exercise and cognitive training may have a synergistic effect on cognition by complementary strengthening of different neural functions. Few studies have tested the effects of such a combined intervention, and the findings have been discrepant, largely due to varying doses and formats of the interventions. METHODS/DESIGN: The purpose of this single-blinded, 2 × 2 factorial phase II randomized controlled trial is to test the efficacy and synergistic effects of a 6-month combined cycling and speed of processing training intervention on cognition and relevant mechanisms (aerobic fitness, cortical thickness, and functional connectivity in the default mode network) in older adults with amnestic mild cognitive impairment. This trial will randomize 128 participants equally to four arms: cycling and speed of processing, cycling only, speed of processing only, or attention control for 6 months, and then follow them for another 12 months. Cognition and aerobic fitness will be assessed at baseline and at 3, 6, 12, and 18 months; cortical thickness and functional connectivity at baseline and at 6, 12, and 18 months; Alzheimer's disease (AD) conversion at 6, 12, and 18 months. The specific aims are to (1) determine the efficacy and synergistic effects of the combined intervention on cognition over 6 months, (2) examine the underlying mechanisms of the combined intervention, and (3) calculate the long-term effect sizes of the combined intervention on cognition and AD conversion. The analysis will use intention-to-treat and linear mixed-effects modeling. DISCUSSION: This trial will be among the first to test the synergistic effects on cognition and mechanisms (relevant to Alzheimer's-associated neurodegeneration) of a uniquely conceptualized and rigorously designed aerobic exercise and cognitive training intervention in older adults with mild cognitive impairment. It will advance Alzheimer's prevention research by providing precise effect-size estimates of the combined intervention. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03313895 . Registered on 18 October 2017.

Feasibility study of an attention training application for older adults.

BACKGROUND: Technology-based attention training has demonstrated promise in its potential to improve cognitive functioning in older people. Developing mobile applications, with older users specifically in mind, may support future dissemination of these interventions and integration into daily life. AIMS AND OBJECTIVES: The purpose of this pilot study was to test the feasibility of an Attention Training Application (ATA) for community-dwelling older adults using mobile technology. DESIGN: A descriptive, mixed-methods design was used to capture older adults' feedback on the usability and acceptability of the ATA. METHODS: A convenience sample of older adults (n = 9) from two independent living facilities participated in a 2-hour training and practice session with the ATA. Participants were given personally tailored instructions for using the mobile device and the ATA specifically. Following a practice session, participants provided ratings on multiple components of the ATA and completed an audio-recorded, semi-structured interview to provide detailed descriptions of their experience and perceptions. An iterative process of content analysis was used to characterise the open-ended responses. RESULTS: Participants rated the ATA favourably overall on several 0-10 scales including likeability [8.5 (1.6)], interest [8.8 (2.3)] and satisfaction [8.2 (1.9)]. The qualitative analyses revealed several issues relevant to the feasibility of the ATA among older people including the importance of the technological background of the user, limiting negative feedback, challenges with the touch screen interface, personal preferences for challenge, extending the practice period and the difficulty of the dual-task condition. CONCLUSIONS: The use of the ATA is feasible in the older adult population. Future development should specifically consider personal characteristics as well as preferences to maximise usability and acceptability among older people. IMPLICATIONS FOR PRACTICE: Older adults enjoyed the ATA. This opens doors to user-friendly technological interventions that may be effective in assisting older adults maintain and possibly even improve their cognitive function.