Risk-Taking Behavior Differs Between Older Adults with and without Mild Cognitive Impairment.

Background: Adequately evaluating risk and making decisions is vital but understudied for older adults living independently but with compromised cognition, as seen in those with mild cognitive impairment (MCI), specifically those with amnestic MCI (aMCI) which is associated with higher risk of conversion to Alzheimer's disease. Objective: We propose to comprehensively evaluate risk-taking behaviors across domains important for everyday activities between an aMCI group and their cognitively healthy counterparts (HC). Methods: A case-control study design. Data on risk-taking behaviors via the Domain-Specific Risk-Taking Scale (DOSPERT), and candidate confounding mental health factors (i.e., neurodegeneration, depression, and fatigue) were collected. Analyses on group difference and interaction between group and confounding factors on risk-taking behaviors were conducted. Results: The aMCI group showed a higher likelihood of risk-taking than HC (t = 4.38, df = 73, p < 0.001). Moderation analysis showed fatigue (F = 5.91, p = 0.018) and presence of depression (F = 4.52, p = 0.037), but not neurodegeneration, as significant moderators for group and DOSPERT total score, controlling for sex. In post-hoc analyses, there was a significant relationship between both fatigue (B = -7.83, SE = 3.65, t = -2.14, p = 0.036), and presence of depression (B = -20.80, SE = 9.97, t = -2.09, p = 0.041), with DOSPERT total score for HC but not for aMCI. There were no significant relationships between neurodegeneration, fatigue, or depression with any specific risk-taking domains after correction for multiple comparisons. Conclusions: Our results show differences in risk-taking behavior between older adults with and without intact cognition, and overall decision-making is affected by fatigue and depression in HC but not aMCI, together suggesting the importance of cognition in the ability to adjust risk-taking behaviors.

Positive affect disrupts neurodegeneration effects on cognitive training plasticity in older adults.

Cognitive training for older adults varies in efficacy, but it is unclear why some older adults benefit more than others. Positive affective experience (PAE), referring to high positive valence and/or stable arousal states across everyday scenarios, and associated functional networks can protect plasticity mechanisms against Alzheimer's disease neurodegeneration, which may contribute to training outcome variability. The objective of this study is to investigate whether PAE explains variability in cognitive training outcomes by disrupting the adverse effect of neurodegeneration on plasticity. The study's design is a secondary analysis of a randomized control trial of cognitive training with concurrent real or sham brain stimulation (39 older adults with mild cognitive impairment; mean age, 71). Moderation analyses, with change in episodic memory or executive function as the outcome, PAE or baseline resting-state connectivity as the moderator and baseline neurodegeneration as the predictor are the methods used in the study. The result of the study is that PAE stability and baseline default mode network (DMN) connectivity disrupted the effect of neurodegeneration on plasticity in executive function but not episodic memory. The study concludes that PAE stability and degree of DMN integrity both explained cognitive training outcome variability, by reducing the adverse effect of neurodegeneration on cognitive plasticity. We highlight the need to account for PAE, brain aging factors and their interactions with plasticity in cognitive training.

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.

Effect of online tDCS to left somatomotor cortex on neuropsychiatric symptoms among older adults at risk for dementia.

BACKGROUND: Neuropsychiatric symptoms (NPS) in mild cognitive impairment (MCI) cause distress to patients and caregivers, and accelerate progression to dementia. Transcranial direct current stimulation (tDCS) is a promising non-invasive treatment for NPS. OBJECTIVE/HYPOTHESIS: This pilot study assessed behavioral and neural effects of a 4-week anodal tDCS intervention targeting left sensorimotor cortex (LSMC: left precentral/postcentral gyri) during visual attention (compared to online sham tDCS), in 40 older adults (24 females, mean age = 71) with MCI. METHODS: A phase 0 double-blinded randomized control trial was conducted. NPS (patient-reported mood symptoms plus a caregiver-reported questionnaire) and fMRI were measured at baseline and immediately post-intervention. RESULTS: Generalized Estimating Equations found no significant group by time interactions for either NPS measure. However, there was evidence of decreased patient-reported NPS (Wald's χ2 = 3.80, p = .051), decreased LSMC activation during visual attention (Wald's χ2 = 2.93, p = .087), and increased LSMC-amygdala resting-state functional connectivity (rsFC; Wald's χ2 = 3.13, p = .077) in intervention group from pre-to post-intervention. Decrease in LSMC activation (Wald's χ2 = 9.20, p = .002) and increase in LSMC-amygdala rsFC (Wald's χ2 = 4.72, p = .030) related to decreased patient-reported NPS. Increased positive valence across sessions was significantly associated with intervention-related NPS improvement (Wald's χ2 = 22.92, p < .001). There were no findings for caregiver-reported NPS. Effects were stronger for left postcentral compared to left precentral gyrus. CONCLUSION: We found tentative evidence that tDCS applied to LSMC during visual attention in older adults with MCI improved NPS via changes in LSMC activation and LSMC-amygdala rsFC, suggesting improved emotion regulation. Patient-reported NPS was more sensitive to these changes than caregiver-reports, and effects were strongest for left postcentral gyrus. Follow-up studies should perform precise mechanistic investigation and efficacy testing.

CCA identifies a neurophysiological marker of adaptation capacity that is reliably linked to internal locus of control of cognition in amnestic MCI.

Locus of control (LOC) describes whether an individual thinks that they themselves (internal LOC) or external factors (external LOC) have more influence on their lives. LOC varies by domain, and a person's LOC for their intellectual capacities (LOC-Cognition) may be a marker of resilience in older adults at risk for dementia, with internal LOC-Cognition relating to better outcomes and improved treatment adherence. Vagal control, a key component of parasympathetic autonomic nervous system (ANS) regulation, may reflect a neurophysiological biomarker of internal LOC-Cognition. We used canonical correlation analysis (CCA) to identify a shared neurophysiological marker of ANS regulation from electrocardiogram (during auditory working memory) and functional connectivity (FC) data. A canonical variable from root mean square of successive differences (RMSSD) time series and between-network FC was significantly related to internal LOC-Cognition (ß = 0.266, SE = 0.971, CI = [0.190, 4.073], p = 0.031) in 65 participants (mean age = 74.7, 32 female) with amnestic mild cognitive impairment (aMCI). Follow-up data from 55 of these individuals (mean age = 73.6, 22 females) was used to show reliability of this relationship (ß = 0.271, SE = 0.971, CI = [0.033, 2.630], p = 0.047), and a second sample (40 participants with aMCI/healthy cognition, mean age = 72.7, 24 females) showed that the canonical vector biomarker generalized to visual working memory (ß = 0.36, SE = 0.136, CI = [0.023, 0.574], p = 0.037), but not inhibition task RMSSD data (ß = 0.08, SE = 1.486, CI = [- 0.354, 0.657], p = 0.685). This canonical vector may represent a biomarker of autonomic regulation that explains how some older adults maintain internal LOC-Cognition as dementia progresses. Future work should further test the causality of this relationship and the modifiability of this biomarker.

Brain Small-Worldness Properties and Perceived Fatigue in Mild Cognitive Impairment.

BACKGROUND: Perceived fatigue is among the most common complaints in older adults and is substantially influenced by diminished resources or impaired structure of widespread cortical and subcortical regions. Alzheimer's disease and its preclinical stage-mild cognitive impairment (MCI)-are considered a brain network disease. It is unknown, however, whether those with MCI will therefore perceive worse fatigue, and whether an impaired global brain network will worsen their experience of fatigue. METHODS: In this pilot case-control study of age-, sex-, and education-matched MCI and their cognitively healthy counterparts (HCs), perceived fatigue was measured using Multidimensional Fatigue Inventory, and diffusion tensor imaging tractography data were analyzed using graph theory methods to explore small-worldness properties: segregation and integration. RESULTS: Perceived fatigue was more severe in MCI than HCs. Despite a trend for greater network alterations in MCI, there were no significant group differences in integration or segregation. Greater perceived fatigue was related to higher segregation across groups; more perceived fatigue was related to higher segregation and lower integration in MCI but not HCs. CONCLUSION: Findings of this study support the notion that altered whole-brain small-worldness properties in brain aging or neurodegeneration may underpin perceived fatigue.

Cortical thickness and resting-state cardiac function across the lifespan: A cross-sectional pooled mega-analysis.

Understanding the association between autonomic nervous system [ANS] function and brain morphology across the lifespan provides important insights into neurovisceral mechanisms underlying health and disease. Resting-state ANS activity, indexed by measures of heart rate [HR] and its variability [HRV] has been associated with brain morphology, particularly cortical thickness [CT]. While findings have been mixed regarding the anatomical distribution and direction of the associations, these inconsistencies may be due to sex and age differences in HR/HRV and CT. Previous studies have been limited by small sample sizes, which impede the assessment of sex differences and aging effects on the association between ANS function and CT. To overcome these limitations, 20 groups worldwide contributed data collected under similar protocols of CT assessment and HR/HRV recording to be pooled in a mega-analysis (N = 1,218 (50.5% female), mean age 36.7 years (range: 12-87)). Findings suggest a decline in HRV as well as CT with increasing age. CT, particularly in the orbitofrontal cortex, explained additional variance in HRV, beyond the effects of aging. This pattern of results may suggest that the decline in HRV with increasing age is related to a decline in orbitofrontal CT. These effects were independent of sex and specific to HRV; with no significant association between CT and HR. Greater CT across the adult lifespan may be vital for the maintenance of healthy cardiac regulation via the ANS-or greater cardiac vagal activity as indirectly reflected in HRV may slow brain atrophy. Findings reveal an important association between CT and cardiac parasympathetic activity with implications for healthy aging and longevity that should be studied further in longitudinal research.

Autonomic flexibility reflects learning and associated neuroplasticity in old age.

Effective learning in old age, particularly in those at risk for dementia, is essential for prolonging independent living. Individual variability in learning, however, is remarkable; that is, months of cognitive training to improve learning may be beneficial for some individuals but not others. So far, little is known about which neurophysiological mechanisms account for the observed variability in learning induced by cognitive training in older adults. By combining Lövdén et al.'s (2010, A theoretical framework for the study of adult cognitive plasticity. Psychological Bulletin, 136, 659-676) framework proposing the role of adaptation capacity in neuroplasticity and a neurovisceral integration model of the relationship between autonomic nervous system (ANS) and brain with a novel shapelet analytical approach that allows for accurate and interpretable analysis of time series data, we discovered an acute, ECG-derived ANS segment in response to cognitive training tasks at baseline that predicted learning outcomes from a 6-week cognitive training intervention. The relationship between the ANS segment and learning was robust in both cross-participant and cross-task analyses among a group of older adults with amnestic mild cognitive impairment. Furthermore, the revealed ANS shapelet significantly predicted training-induced neuroplasticity in the dorsal anterior cingulate cortex and select frontal regions during task fMRI. Across outcome measures, individuals were less likely to prospectively benefit from the cognitive training if their ECG data were more similar to this particular ANS segment at baseline. Our findings are among the first empirical evidence to confirm that adaptation capacity, indexed by ANS flexibility, predicts individual differences in learning and associated neuroplasticity beyond individual characteristics (e.g., age, education, neurodegeneration, total training).

Processing speed and attention training modifies autonomic flexibility: A mechanistic intervention study.

Adaptation capacity is critical for maintaining cognition, yet it is understudied in groups at risk for dementia. Autonomic nervous system (ANS) is critical for neurovisceral integration and is a key contributor to adaptation capacity. To determine the central nervous system's top-down regulation of ANS, we conducted a mechanistic randomized controlled trial study, using a 6-week processing speed and attention (PS/A)-targeted intervention. Eighty-four older adults with amnestic mild cognitive impairment (aMCI) were randomized to a 6-week PS/A-targeted intervention or an active control without PS/A. Utilizing repeated measures (i.e., PS/A test different from the intervention, resting and cognitive task-based ECG, and resting fMRI) at baseline, immediately post-intervention (post-test), and 6-month follow-up, we aimed to test whether PS/A causally influences vagal control of ANS via their shared central neural pathways in aMCI. We indexed vagal control of ANS using high-frequency heart rate variability (HF-HRV) extracted from ECG data. Functional brain connectivity patterns were extracted from fMRI using advanced statistical tools. Compared to the control group, the intervention group showed significant improvement in PS/A, HF-HRV, salience network (SN), central executive network (CEN), and frontal parietal network (FPN) connectivity at post-test; the effect on SN, CEN, and FPN remained at 6-month follow-up. Changes in PS/A and SN connectivity significantly predicted change in HF-HRV from baseline to post-test and/or 6-month-follow-up. Age, neurodegeneration, nor sex did not affect these relationships. This work provides novel support for top-down regulation of PS/A and associated SN on vagal control of ANS. Intervening PS/A may be a viable approach for promoting adaptation capacity in groups at risk for dementia.

A generic brain connectome map linked to different types of everyday decision-making in old age.

Making reasonable decisions related to financial and health scenarios is a crucial capacity that can be difficult for older adults to maintain as they age, yet few studies examine neurocognitive factors that are generalizable to different types of everyday decision-making capacity. Here we propose an innovative approach, based on individual risk-taking preference, to identify neural profiles that may help predict older adults' everyday decision-making capacity. Using performance and cognitive arousal information from two gambling tasks, we identified three decision-making preference groups: ambiguity problem-solvers (A), risk-seekers (R), and a control group without strong risk-taking preferences (C). Comparisons of the number of connections within white matter tracts between A vs. C and R vs. C groups resulted in features consistent with the theory of dual neural functional systems involved in decision-making. Unique tracts from the A vs. C contrast were primarily centered in dorsal frontal regions/reflective system; unique tracts from the R vs. C contrast were centered in the ventral frontal regions/impulsive system; and shared tracts from both contrasts were centered in the basal ganglia, coordinating the switch between the two types of decision-making preference. Number of connections from the tracts differentiating A vs. C significantly predicted financial and health/safety decision-making capacity, and the association remained significant after controlling for multiple socioeconomic and cognitive factors. The connectome identified may provide insight into a generic white matter mechanism related to everyday decision-making capacity in older age.

Stress adaptation in older adults with and without cognitive impairment: an fMRI pattern-based similarity analysis.

BACKGROUND: The capacity to adapt to environmental stressors is essential for older adults' health and well-being. It is unclear how cognitive impairment may disrupt the capacity. Here we examined the relationship between self-perceptions of stress and the neurobiological response to a laboratory model of stress adaptation in amnestic mild cognitive impairment (aMCI), a group at high risk for dementia. RESULTS: aMCI group and cognitively healthy controls did not differ in neurobiological acute stress recovery (indexed by similarity in neural patterns at baseline and after recovery from cognitive challenges). However, compared to controls, aMCI group had significantly lower scores on PSS-PW. Notably, higher PSS-PW was associated with greater acute neural recovery in controls, but not aMCI. METHODS: We assessed self-perceptions of stress adaptation with the Perceived Stress Scale subscales, measuring perceived helplessness (i.e., negatively worded items, PSS-NW) and self-efficacy (i.e., positively worded items, PSS-PW) in response to stress. At a subsequent laboratory fMRI visit, we indexed neurobiological stress adaptation by assessing and comparing functional network connectivity at baseline and immediately following, and after recovery from, cognitive challenges. CONCLUSIONS: Studying stress adaptation in aMCI may shed light on pathways that contribute to the onset and progress of cognitive deterioration in aging.

A Systematic Review for Functional Neuroimaging Studies of Cognitive Reserve Across the Cognitive Aging Spectrum.

OBJECTIVE: Cognitive reserve has been proposed to explain the discrepancy between clinical symptoms and the effects of aging or Alzheimer's pathology. Functional magnetic resonance imaging (fMRI) may help elucidate how neural reserve and compensation delay cognitive decline and identify brain regions associated with cognitive reserve. This systematic review evaluated neural correlates of cognitive reserve via fMRI (resting-state and task-related) studies across the cognitive aging spectrum (i.e., normal cognition, mild cognitive impairment, and Alzheimer's disease). METHOD: This review examined published articles up to March 2017. There were 13 cross-sectional observational studies that met the inclusion criteria, including relevance to cognitive reserve, subjects 60 years or older with normal cognition, mild cognitive impairment, and/or Alzheimer's disease, at least one quantitative measure of cognitive reserve, and fMRI as the imaging modality. Quality assessment of included studies was conducted using the Newcastle-Ottawa Scale adapted for cross-sectional studies. RESULTS: Across the cognitive aging spectrum, medial temporal regions and an anterior or posterior cingulate cortex-seeded default mode network were associated with neural reserve. Frontal regions and the dorsal attentional network were related to neural compensation. Compared to neural reserve, neural compensation was more common in mild cognitive impairment and Alzheimer's disease. CONCLUSIONS: Neural reserve and compensation both support cognitive reserve, with compensation more common in later stages of the cognitive aging spectrum. Longitudinal and intervention studies are needed to investigate changes between neural reserve and compensation during the transition between clinical stages, and to explore the causal relationship between cognitive reserve and potential neural substrates.

Cortical thickness is associated with altered autonomic function in cognitively impaired and non-impaired older adults.

KEY POINTS: The parasympathetic nervous system (PNS) is critical for adaptation to environment demands. Alzheimer's disease (AD), via frontal compensatory processes, may affect PNS regulation, thereby compromising older adults' capacity for adaptation, and increasing morbidity and mortality risk. Here we found that AD-associated neurodegeneration accompanied an overactive anterior cingulate cortex, which in turn resulted in a high level of PNS activity at rest, as well as strong PNS activity withdrawal in response to the mental effort. This discovery provides the first line of evidence to suggest that AD-associated neurodegeneration links to altered PNS regulation during mental effort in older adults, and that the compensatory processes accompanying frontal hyperactivation appear to be responsible for these alterations. ABSTRACT: The parasympathetic nervous system (PNS) is critical for adaptation to environment demands. PNS can reflect an individual's regulatory capacity of frontal brain regions and has been linked to cognitive capacity. Yet, the relationship of PNS function to cognitive decline and abnormal frontal function that characterize preclinical progression toward Alzheimer's disease (AD) is unclear. Here, we aimed to elucidate the relationship between PNS function and AD-associated neurodegeneration by testing two competing hypotheses involving frontal regions' activity (neurodegeneration vs. compensation). In 38 older human adults with amnestic mild cognitive impairment (aMCI) or normative cognition, we measured AD-associated neurodegeneration (AD signature cortical thickness; ADSCT), resting-state functional magnetic resonance imaging of frontal regions' spontaneous activation, and an electrocardiography measure of PNS (high frequency heart rate variability; HF-HRV). HF-HRV was assessed at rest and during a cognitive task protocol designed to capture HF-HRV reactivity. Higher HF-HRV at rest was significantly related to both more severe AD-associated neurodegeneration (lower ADSCT scores) and worse cognitive ability. Cognitive impairments were also related to greater suppression of HF-HRV reactivity. High activities of the anterior cingulate cortex significantly mediated relationships between ADSCT and both HF-HRV at rest and HF-HRV reactivity. Notably, these relationships were not affected by the clinical phenotype. We show that AD-associated neurodegeneration is associated with altered PNS regulation and that compensatory processes linked to frontal overactivation might be responsible for those alterations. This finding provides the first line of evidence in a new framework for understanding how early-stage AD-associated neurodegeneration affects autonomic regulation.

Amygdala functional connectivity is associated with locus of control in the context of cognitive aging.

Locus of control (LOC) measures the extent to which individuals perceive control over their lives. Those with a more "internal" LOC feel self-sufficient and able to determine important aspects of their own future, while those with a more "external" LOC feel that their lives are governed by events beyond their control. Reduced internal LOC and increased external LOC have been found in cognitive disorders, but the neural substrates of these control perceptions are yet unknown. In the present study, we explored the relationship between amygdala functional connectivity and LOC in 18 amnestic mild cognitive impairment (MCI) and age-, sex-, and education-matched, 22 cognitively healthy controls (HC). Participants completed cognitive challenge tasks (Stroop Word Color task and Dual 1-back) for 20min, and underwent resting-state functional magnetic resonance imaging immediately before and after the tasks. We found significantly lower internal LOC and higher external LOC in the MCI group than the HC group. Compared to HC, MCI group showed significantly stronger positive associations between internal LOC and baseline right amygdala connections (including right middle frontal gyrus and anterior cingulate cortex), and stronger negative associations between internal LOC and change of these right amygdala connections. Across all participants, external LOC explained the relationships between associations of another set of right amygdala connections (including middle cingulate cortex and right superior frontal gyrus), both at baseline and for change, and performance in the cognitive challenge tasks. Our findings indicate that the right amygdala networks might be critical in understanding the neural mechanisms underlying LOC's role in cognitive aging.