Contrasting two models of utilitarian reasoning.

One influential framework for examining human moral cognition has been a dual process model, in which utilitarian judgment (e.g., infliction of harm for the greater good) is associated with cognitive control processes, while non-utilitarian judgment (e.g., avoiding such harms) is associated with emotional, automatic processes. Another framework of moral cognition, the two-dimensional model of utilitarian psychology, posits that utilitarian choices may reflect either instrumental harm, i.e., inflicting harm on an individual for the greater good; or impartial beneficence, i.e., impartially and altruistically acting for the benefit of the overall welfare. We evaluated preregistered hypotheses (https://osf.io/m425d) derived from these models of moral cognition in a sample of 275 neurologically healthy older adults. Our results suggest that both the dual process and two-dimensional models provided insights regarding utilitarian reasoning, including three cardinal domains of conflict between utilitarianism and common-sense morality: agent-centered permissions, special obligations, and personal rights. One prediction of the dual process-based model was supported by our findings, with higher emotionality associated with decreased endorsement of utilitarian judgments (b = - 0.12, p < .001). We also found partial support for the two-dimensional model, as utilitarian judgments about dilemmas involving agent-centered permissions and personal rights were dissociated; however, both sets of judgments were associated with utilitarian judgments involving special obligations (p < .001 and p = .008, respectively). We propose that our findings, with support for some elements of the dual process and two-dimensional models, can be integrated into a revised two-dimensional model of utilitarian judgment as including impartial beneficence and acceptance of attributable harms.

Roles of physical activity and diet in cognitive aging: is more better?

Objective: To determine the synergistic effects of nutrition, specifically adherence to the Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet, and physical activity on cognition and brain outcomes in a cross-sectional healthy aging cohort. Methods: A total of 132 adults (age range 52-91; Clinical Dementia Rating = 0) from the UCSF Brain Aging Project completed a 15-item MIND diet food frequency questionnaire and an 11-item self-report measure of weekly physical activity (Physical Activity Scale [PASE]). Cognitive outcomes included executive functioning, episodic memory, and language. Neuroimaging outcomes consisted of total grey matter volume and total white matter volume, adjusted for total intracranial volumes. All regression interaction models adjusted for age, sex, education, and a composite vascular burden score. Results: There was a significant interaction between PASE and MIND on executive functioning and total grey matter volume. Low levels of both related to disproportionately poorer cognitive and brain structural outcomes. Increasing levels of either, but not both, PASE or MIND related to better executive functioning and gray matter outcomes. For memory, language, and total white matter volume, the interaction between PASE and MIND showed the same directionality but did not reach statistical significance. Conclusions: Higher levels of physical activity associated with better executive functioning and gray matter volume, particularly when diet was poor. Similarly, higher levels of MIND diet adherence were associated with better brain and cognitive outcomes when physical activity was low. However, highest levels of physical activity and MIND diet together did not necessarily lead to disproportionately better cognitive and brain volume outcomes.

Sex Differences in the Relationship between Perceived Stress and Cognitive Trajectories.

OBJECTIVE: Chronic stress adversely affects cognition, in part due to stress-induced inflammation. Rodent models suggest females are more resilient against stress-related cognitive dysfunction than males; however, few studies have examined this in humans. We examined sex differences in the relationship between perceived stress, cognitive functioning, and peripheral inflammation over time among cognitively normal older adults. DESIGN: Longitudinal observational study. SETTING: University research center. PARTICIPANTS: 274 community-dwelling older adults (baseline age: M=70.7, SD=7.2; 58% women; Clinical Dementia Rating=0) who completed at least two study visits. MEASUREMENTS: Neurocognitive functioning and perceived stress (Perceived Stress Scale [PSS]) were assessed at each visit. Plasma was analyzed for interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α) in a subset of 147 participants. Linear mixed effects models examined the interaction between average PSS (i.e., averaged within persons across visits), sex, and time on cognitive domains and on inflammatory markers. RESULTS: The interaction between stress, sex, and time predicted executive functioning (ß = 0.26, SE = 0.10, p = 0.01) such that higher average PSS related to steeper declines in men, but not in women. Among the 147 participants with inflammatory data, higher average PSS was associated with steeper increases in IL-6 over time in men, but not in women. CONCLUSION: Consistent with animal models, results showed older men were more vulnerable to negative effects of stress on cognitive aging, with domain-specific declines in executive function. Findings also suggest systemic immunological mechanisms may underlie increased risk for cognitive decline in men with higher levels of stress. Future work is needed to examine the potential efficacy of person-specific stress interventions.

Physical activity measurement in older adults: Wearables versus self-report.

Physical activity (PA) is associated with preserved age-related body and brain health. However, PA quantification can vary. Commercial-grade wearable monitors are objective, low burden tools to capture PA but are less well validated in older adults. Self-report PA questionnaires are widely accepted and more frequently used but carry inherent limitations. We aimed to compare these commonly used PA measures against one another and examine their convergent validity with a host of relevant outcomes. We also examined the factors that drive differences in PA self-reporting styles in older adults. 179 older adults completed 30-day Fitbit Flex2™ monitoring and reported PA levels via two widely used PA questionnaires: PASE and CHAMPS-METs (metabolic expenditure calories burned). Participants also completed measures of cardiometabolic (hypertension diagnosis, resting heart rate, A1C levels), cognitive (memory, processing speed, executive functioning), and brain MRI (medial temporal lobe volume) outcomes. The discrepancy between objective Fitbit monitoring and self-reported PA was evaluated using a sample-based z difference score. There were only modest relationships across all PA metrics. Fitbit step count demonstrated a stronger association with the PASE, whereas Fitbit calories burned was more strongly associated with CHAMPS-MET. Fitbit outcomes had more consistent convergence with relevant outcomes of interest (e.g., cardiometabolic and brain health indices) when compared to subjective measures; however, considerable heterogeneity within these associations was observed. A higher degree of overreporting was associated with worse memory and executive performances, as well as hypertension diagnoses. We build on prior findings that wearable, digital health indicators of PA demonstrate greater construct validity than self-report in older adults. We further show important clinical features (e.g., poorer cognitive status) of older adults that could contribute to a higher level of overreporting on self-report measures. Characterization of what PA measures truly operationalize will help elucidate relationships between most relevant facets of PA and outcomes of interest.

Wisdom and fluid intelligence are dissociable in healthy older adults.

OBJECTIVES: The relationship between wisdom and fluid intelligence (Gf) is poorly understood, particularly in older adults. We empirically tested the magnitude of the correlation between wisdom and Gf to help determine the extent of overlap between these two constructs. DESIGN: Cross-sectional study with preregistered hypotheses and well-powered analytic plan (https://osf.io/h3pjx). SETTING: Memory and Aging Center at the University of California San Francisco, located in the USA. PARTICIPANTS: 141 healthy older adults (mean age = 76 years; 56% female). MEASUREMENTS: Wisdom was quantified using a well-validated self-report-based scale (San Diego Wisdom Scale or SD-WISE). Gf was assessed via composite measures of processing speed (Gf-PS) and executive functioning (Gf-EF). The relationships of SD-WISE scores to Gf-PS and Gf-EF were tested in bivariate correlational analyses and multiple regression models adjusted for demographics (age, sex, and education). Exploratory analyses evaluated the relationships between SD-WISE and age, episodic memory performance, and dorsolateral and ventromedial prefrontal cortical volumes on magnetic resonance imaging. RESULTS: Wisdom showed a small, positive association with Gf-EF (r = 0.181 [95% CI 0.016, 0.336], p = .031), which was reduced to nonsignificance upon controlling for demographics, and no association with Gf-PS (r = 0.019 [95% CI -0.179, 0.216], p = .854). Wisdom demonstrated a small, negative correlation with age (r = -0.197 [95% CI -0.351, -0.033], p = .019), but was not significantly related to episodic memory or prefrontal volumes. CONCLUSIONS: Our findings indicate that most of the variance in wisdom (>95%) is unaccounted for by Gf. The independence of wisdom from cognitive functions that reliably show age-associated declines suggests that it may hold unique potential to bolster decision-making, interpersonal functioning, and other everyday activities in older adults.

The Rapid Naming Test: Development and initial validation in typically aging adults.

ObjectiveProgressive word-finding difficulty is a primary cognitive complaint among healthy older adults and a symptom of pathological aging. Classic measures of visual confrontation naming, however, show ceiling effects among healthy older adults. To address the need for a naming test that is sensitive to subtle, age-related word-finding decline, we developed the Rapid Naming Test (RNT), a computerized, one-minute, speeded visual naming test.MethodFunctionally intact older (n = 145) and younger (n = 69) adults completed the RNT. Subsets of older adults also completed neuropsychological tests, a self-report scale of functional decline, amyloid-ß PET imaging, and repeat RNT administration to determine test-retest reliability.ResultsRNT scores were normally distributed and exhibited good test-retest reliability. Younger adults performed better than older adults. Within older adults, lower scores were associated with older age. Higher scores correlated with measures of language, processing speed, and episodic learning and memory. Scores were not correlated with visuospatial or working memory tests. Worse performance was related to subjective language decline, even after controlling for a classic naming test and speed. The RNT was also negatively associated with amyloid-ß burden.ConclusionsThe RNT appears to be a reliable test that is sensitive to subtle, age-related word-finding decline. Convergent and divergent validity are supported by its specific associations with measures relying on visual naming processes. Ecological validity is supported by its relationship with subjective real-world language difficulties. Lastly, worse performance was related to amyloid-ß deposition, an Alzheimer's disease biomarker. This study represents a key step toward validating a novel, sensitive naming test in typically aging adults.

Lower White Matter Volume and Worse Executive Functioning Reflected in Higher Levels of Plasma GFAP among Older Adults with and Without Cognitive Impairment.

OBJECTIVE: There are minimal data directly comparing plasma neurofilament light (NfL) and glial fibrillary acidic protein (GFAP) in aging and neurodegenerative disease research. We evaluated associations of plasma NfL and plasma GFAP with brain volume and cognition in two independent cohorts of older adults diagnosed as clinically normal (CN), mild cognitive impairment (MCI), or Alzheimer's dementia. METHODS: We studied 121 total participants (Cohort 1: n = 50, age 71.6 ± 6.9 years, 78% CN, 22% MCI; Cohort 2: n = 71, age 72.2 ± 9.2 years, 45% CN, 25% MCI, 30% dementia). Gray and white matter volumes were obtained for total brain and broad subregions of interest (ROIs). Neuropsychological testing evaluated memory, executive functioning, language, and visuospatial abilities. Plasma samples were analyzed in duplicate for NfL and GFAP using single molecule array assays (Quanterix Simoa). Linear regression models with structural MRI and cognitive outcomes included plasma NfL and GFAP simultaneously along with relevant covariates. RESULTS: Higher plasma GFAP was associated with lower white matter volume in both cohorts for temporal (Cohort 1: ß = -0.33, p = .002; Cohort 2: ß = -0.36, p = .03) and parietal ROIs (Cohort 1: ß = -0.31, p = .01; Cohort 2: ß = -0.35, p = .04). No consistent findings emerged for gray matter volumes. Higher plasma GFAP was associated with lower executive function scores (Cohort 1: ß = -0.38, p = .01; Cohort 2: ß = -0.36, p = .007). Plasma NfL was not associated with gray or white matter volumes, or cognition after adjusting for plasma GFAP. CONCLUSIONS: Plasma GFAP may be more sensitive to white matter and cognitive changes than plasma NfL. Biomarkers reflecting astroglial pathophysiology may capture complex dynamics of aging and neurodegenerative disease.

Reduced utilitarian willingness to violate personal rights during the COVID-19 pandemic.

The COVID-19 pandemic poses many real-world moral dilemmas, which can pit the needs and rights of the many against the needs and rights of the few. We investigated moral judgments in the context of the contemporary global crisis among older adults, who are at greatest personal risk from the pandemic. We hypothesized that during this pandemic, individuals would give fewer utilitarian responses to hypothetical dilemmas, accompanied by higher levels of confidence and emotion elicitation. Our pre-registered analysis (https://osf.io/g2wtp) involved two waves of data collection, before (2014) and during (2020) the COVID-19 pandemic, regarding three categories of moral dilemmas (personal rights, agent-centered permissions, and special obligations). While utilitarian responses considered across all categories of dilemma did not differ, participants during the 2020 wave gave fewer utilitarian responses to dilemmas involving personal rights; that is, they were less willing to violate the personal rights of others to produce the best overall outcomes.

Interbatch Reliability of Blood-Based Cytokine and Chemokine Measurements in Community-Dwelling Older Adults: A Cross-Sectional Study.

Blood-based inflammatory markers hold considerable promise for diagnosis and prognostication of age-related neurodegenerative disease, though a paucity of research has empirically tested how reliably they can be measured across different experimental runs ("batches"). We quantified the interbatch reliability of 13 cytokines and chemokines in a cross-sectional study of 92 community-dwelling older adults (mean age = 74; 48% female). Plasma aliquots from the same blood draw were parallelly processed in 2 separate batches using the same analytic platform and procedures (high-performance electrochemiluminescence by Meso Scale Discovery). Interbatch correlations (Pearson's r) ranged from small and nonsignificant (r = .13 for macrophage inflammatory protein-1 alpha [MIP-1α]) to very large (r > .90 for interferon gamma [IFNγ], interleukin-10 [IL-10], interferon gamma-induced protein 10 [IP-10], MIP-1ß, thymus and activation-regulated chemokine [TARC]) with most markers falling somewhere in between (.67 ≤ r ≤ .90 for IL-6, tumor necrosis factor alpha [TNF-α], Eotaxin, Eotaxin-3, monocyte chemoattractant protein-1 [MCP-1], MCP-4, macrophage-derived chemokine [MDC]). All markers, except for IL-6 and MCP-4, showed significant differences in absolute values between batches, with discrepancies ranging in effect size (Cohen's d) from small to moderate (0.2 ≤ |d| ≤ 0.5 for IL-10, IP-10, MDC) to large or very large (0.68 ≤ |d| ≤ 1.5 for IFNγ, TNF-α, Eotaxin, Eotaxin-3, MCP-1, MIP-1α, MIP-1ß, TARC). Relatively consistent associations with external variables of interest (age, sex, systolic blood pressure, body mass index, cognition) were observed across batches. Taken together, our results suggest heterogeneity in measurement reliability of blood-based cytokines and chemokines, with some analytes outperforming others. Future work is needed to evaluate the generalizability of these findings while identifying potential sources of batch effect measurement error.

Tripartite Relationship Among Synaptic, Amyloid, and Tau Proteins: An In Vivo and Postmortem Study.

OBJECTIVE: To test the hypothesis that fundamental relationships along the amyloid, tau, and neurodegeneration (A/T/N) cascade depend on synaptic integrity in older adults in-vivo and postmortem. METHODS: Two independent observational, cross-sectional cohorts: 1) in-vivo community-dwelling, clinically normal adults from the UCSF Memory and Aging Center completed lumbar puncture and MRI (exclusion criteria, CDR>0), and 2) postmortem decedents from the Rush Memory and Aging Project (exclusion criteria, inability to sign informed consent). In-vivo measures included cerebrospinal fluid (CSF) synaptic proteins (synaptotagmin-1, SNAP-25, neurogranin, and GAP-43), Aß42/40, ptau181, and MRI gray matter volume (GMV). Postmortem measures captured brain tissue levels of presynaptic proteins (complexin-I, complexin-II, VAMP, and SNARE complex), and neuritic plaque and neurofibrillary tangle (NFT) counts. Regression models tested statistical moderation of synaptic protein levels along the A/T/N cascade (synaptic proteins*amyloid on tau, and synaptic proteins*tau on GMV). RESULTS: 68 in-vivo older adults (age=71y, 43%F) and 633 decedents (age=90y, 68%F, 34% clinically normal) were included. Each in-vivo CSF synaptic protein moderated the relationship between Aß42/40 and ptau181 (-0.23<𝛽s<-0.12, ps<0.05) and the relationship between ptau and GMV (-0.49<𝛽s<-0.32, ps<0.05). Individuals with more abnormal CSF synaptic protein demonstrated expected relationships between Aß-ptau and ptau-brain volume, effects that were absent or reversed in those with more normal CSF synaptic protein. Postmortem analyses recapitulated CSF models. More normal brain tissue levels of complexin-I, VAMP, and SNARE moderated the adverse relationship between neuritic plaque and NFT counts (-0.10<𝛽s<-0.08, ps<0.05). CONCLUSIONS: Pathogenic relationships of Aß and tau may depend on synaptic state. Synaptic markers may help identify risk and/or resilience to AD proteinopathy.

Specific cortical and subcortical grey matter regions are associated with insomnia severity.

BACKGROUND: There is an increasing awareness that sleep disturbances are a risk factor for dementia. Prior case-control studies suggested that brain grey matter (GM) changes involving cortical (i.e, prefrontal areas) and subcortical structures (i.e, putamen, thalamus) could be associated with insomnia status. However, it remains unclear whether there is a gradient association between these regions and the severity of insomnia in older adults who could be at risk for dementia. Since depressive symptoms and sleep apnea can both feature insomnia-related factors, can impact brain health and are frequently present in older populations, it is important to include them when studying insomnia. Therefore, our goal was to investigate GM changes associated with insomnia severity in a cohort of healthy older adults, taking into account the potential effect of depression and sleep apnea as well. We hypothesized that insomnia severity is correlated with 1) cortical regions responsible for regulation of sleep and emotion, such as the orbitofrontal cortex and, 2) subcortical regions, such as the putamen. METHODS: 120 healthy subjects (age 74.8±5.7 years old, 55.7% female) were recruited from the Hillblom Healthy Aging Network at the Memory and Aging Center, UCSF. All participants were determined to be cognitively healthy following a neurological evaluation, neuropsychological assessment and informant interview. Participants had a 3T brain MRI and completed the Insomnia Severity Index (ISI), Geriatric Depression Scale (GDS) and Berlin Sleep Questionnaire (BA) to assess sleep apnea. Cortical thickness (CTh) and subcortical volumes were obtained by the CAT12 toolbox within SPM12. We studied the correlation of CTh and subcortical volumes with ISI using multiple regressions adjusted by age, sex, handedness and MRI scan type. Additional models adjusting by GDS and BA were also performed. RESULTS: ISI and GDS were predominantly mild (4.9±4.2 and 2.5±2.9, respectively) and BA was mostly low risk (80%). Higher ISI correlated with lower CTh of the right orbitofrontal, right superior and caudal middle frontal areas, right temporo-parietal junction and left anterior cingulate cortex (p<0.001, uncorrected FWE). When adjusting by GDS, right ventral orbitofrontal and temporo-parietal junction remained significant, and left insula became significant (p<0.001, uncorrected FWE). Conversely, BA showed no effect. The results were no longer significant following FWE multiple comparisons. Regarding subcortical areas, higher putamen volumes were associated with higher ISI (p<0.01). CONCLUSIONS: Our findings highlight a relationship between insomnia severity and brain health, even with relatively mild insomnia, and independent of depression and likelihood of sleep apnea. The results extend the previous literature showing the association of specific GM areas (i.e, orbitofrontal, insular and temporo-parietal junction) not just with the presence of insomnia, but across the spectrum of severity itself. Moreover, our results suggest subcortical structures (i.e., putamen) are involved as well. Longitudinal studies are needed to clarify how these insomnia-related brain changes in healthy subjects align with an increased risk of dementia.

Association of remote mild traumatic brain injury with cortical amyloid burden in clinically normal older adults.

We investigated whether clinically normal older adults with remote, mild traumatic brain injury (mTBI) show evidence of higher cortical Aß burden. Our study included 134 clinically normal older adults (age 74.1 ± 6.8 years, 59.7% female, 85.8% white) who underwent Aß positron emission tomography (Aß-PET) and who completed the Ohio State University Traumatic Brain Injury Identification questionnaire. We limited participants to those reporting injuries classified as mTBI. A subset (N = 30) underwent a second Aß-PET scan (mean 2.7 years later). We examined the effect of remote mTBI on Aß-PET burden, interactions between remote mTBI and age, sex, and APOE status, longitudinal Aß accumulation, and the interaction between remote mTBI and Aß burden on memory and executive functioning. Of 134 participants, 48 (36%) reported remote mTBI (0, N = 86; 1, N = 31, 2+, N = 17; mean 37 ± 23 years since last mTBI). Effect size estimates were small to negligible for the association of remote mTBI with Aß burden (p = .94, η2 < 0.01), and for all interaction analyses. Longitudinally, we found a non-statistically significant association of those with remote mTBI (N = 11) having a faster rate of Aß accumulation (B = 0.01, p = .08) than those without (N = 19). There was no significant interaction between remote mTBI and Aß burden on cognition. In clinically normal older adults, history of mTBI is not associated with greater cortical Aß burden and does not interact with Aß burden to impact cognition. Longitudinal analyses suggest remote mTBI may be associated with more rapid cortical Aß accumulation. This finding warrants further study in larger and more diverse samples with well-characterized lifelong head trauma exposure.

Development and validation of the Uniform Data Set (v3.0) executive function composite score (UDS3-EF).

INTRODUCTION: Cognitive composite scores offer a means of precisely measuring executive functioning (EF). METHODS: We developed the Uniform Data Set v3.0 EF composite score (UDS3-EF) in 3507 controls from the National Alzheimer's Coordinating Center dataset using item-response theory and applied nonlinear and linear demographic adjustments. The UDS3-EF was validated with other neuropsychological tests and brain magnetic resonance imaging from independent research cohorts using linear models. RESULTS: Final model fit was good-to-excellent: comparative fit index = 0.99; root mean squared error of approximation = 0.057. UDS3-EF scores differed across validation cohorts (controls > mild cognitive impairment > Alzheimer's disease-dementia ≈ behavioral variant frontotemporal dementia; P < 0.001). The UDS3-EF correlated most strongly with other EF tests (ßs = 0.50 to 0.85, Ps < 0.001) and more with frontal, parietal, and temporal lobe gray matter volumes (ßs = 0.18 to 0.33, Ps ≤ 0.004) than occipital gray matter (ß = 0.12, P = 0.04). The total sample needed to detect a 40% reduction in UDS3-EF change (n = 286) was ≈40% of the next best measure (F-words; n = 714). CONCLUSIONS: The UDS3-EF is well suited to quantify EF in research and clinical trials and offers psychometric and practical advantages over its component tests.

Worth the Wait: Delayed Recall after 1 Week Predicts Cognitive and Medial Temporal Lobe Trajectories in Older Adults.

METHOD: Clinically normal older adults (52-92 years old) were followed longitudinally for up to 8 years after completing a memory paradigm at baseline [Story Recall Test (SRT)] that assessed delayed recall at 30 min and 1 week. Subsets of the cohort underwent neuroimaging (N = 134, mean age = 75) and neuropsychological testing (N = 178-207, mean ages = 74-76) at annual study visits occurring approximately 15-18 months apart. Mixed-effects regression models evaluated if baseline SRT performance predicted longitudinal changes in gray matter volumes and cognitive composite scores, controlling for demographics. RESULTS: Worse SRT 1-week recall was associated with more precipitous rates of longitudinal decline in medial temporal lobe volumes (p = .037), episodic memory (p = .003), and executive functioning (p = .011), but not occipital lobe or total gray matter volumes (demonstrating neuroanatomical specificity; p > .58). By contrast, SRT 30-min recall was only associated with longitudinal decline in executive functioning (p = .044). CONCLUSIONS: Memory paradigms that capture longer-term recall may be particularly sensitive to age-related medial temporal lobe changes and neurodegenerative disease trajectories. (JINS, 2020, xx, xx-xx).

Sex-related differences in the relationship between ß-amyloid and cognitive trajectories in older adults.

Objective: We aimed to test the hypothesis that elevated neocortical ß-amyloid (Aß), a hallmark feature of Alzheimer's disease (AD), predicts sex-specific cognitive trajectories in clinically normal older adults, with women showing greater risk of decline than men. Method: Florbetapir Aß positron emission tomography (PET) was acquired in 149 clinically normal older adults (52% female, Mage = 74). Participants underwent cognitive testing at baseline and during annual follow-up visits over a timespan of up to 5.14 years. Mixed-effects regression models evaluated whether relations between baseline neocortical Standardized Uptake Value Ratio (SUVR) and composite scores of episodic memory, executive functioning, and processing speed were moderated by sex (male/female) and apolipoprotein E (APOE) status (ε4 carrier/noncarrier). Results: Higher baseline SUVR was associated with longitudinal decline in episodic memory in women (b = -1.32, p < .001) but not men (b = -0.30, p = .28). Female APOE ε4 carriers with elevated SUVR showed particularly precipitous declines in episodic memory (b = -4.33, p < .001) whereas other cognitive domains were spared. SUVR did not predict changes in executive functioning or processing speed, regardless of sex (ps >.63), though there was a main effect of SUVR on processing speed (b = 2.50, p = .003). Conclusions: Clinically normal women with elevated Aß are more vulnerable to episodic memory decline than men. Understanding sex-related differences in AD, particularly in preclinical stages, is crucial for guiding precision medicine approaches to early detection and intervention. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Plasma Glial Fibrillary Acidic Protein Levels Differ Along the Spectra of Amyloid Burden and Clinical Disease Stage.

BACKGROUND: Measuring plasma glial fibrillary acidic protein (GFAP) alongside cortical amyloid-ß (Aß) may shed light on astrocytic changes in aging and Alzheimer's disease (AD). OBJECTIVE: To examine associations between plasma GFAP and cortical Aß deposition in older adults across the typical aging-to-AD dementia spectrum. METHODS: We studied two independent samples from UCSF (Cohort 1, N = 50; Cohort 2, N = 37) covering the spectra of clinical severity (CDR Sum of Boxes; CDR-SB) and Aß-PET burden. Aß-PET was completed with either florbetapir or Pittsburgh Compound B and standardized uptake value ratios were converted to the Centiloid (CL) scale for analyses. All participants with CDR-SB > 0 were Aß-PET positive, while clinically normal participants (CDR-SB = 0) were a mix of Aß-PET positive and negative. Regression analyses evaluated main effect and interaction associations between plasma GFAP, Aß-PET, and clinical severity. RESULTS: In both cohorts, plasma GFAP increased linearly with Aß-PET CLs in clinically normal older adults. In Cohort 2, which included participants with more severe clinical dysfunction and Aß-PET burden, the association between Aß and GFAP became curvilinear (inverted U-shape; quadratic model R2 change = 0.165, p = 0.009), and Aß-PET interacted with CDR-SB (R2 change = 0.164, p = 0.007): older adults with intermediate functional impairment (CDR-SB = 0.5-4.0) showed a weak (negative) association between Aß-PET CLs and plasma GFAP, while older adults with dementia (CDR-SB > 4.0) showed a strong, negative association of higher Aß-PET CLs with lower plasma GFAP. CONCLUSION: The relationship between astrocytic integrity and cortical Aß may be highly dynamic, with linear, positive associations early in disease that diverge in more severe disease stages.

REM sleep is associated with white matter integrity in cognitively healthy, older adults.

There is increasing awareness that self-reported sleep abnormalities are negatively associated with brain structure and function in older adults. Less is known, however, about how objectively measured sleep associates with brain structure. We objectively measured at-home sleep to investigate how sleep architecture and sleep quality related to white matter microstructure in older adults. 43 cognitively normal, older adults underwent diffusion tensor imaging (DTI) and a sleep assessment within a six-month period. Participants completed the PSQI, a subjective measure of sleep quality, and used an at-home sleep recorder (Zeo, Inc.) to measure total sleep time (TST), sleep efficiency (SE), and percent time in light sleep (LS), deep sleep (DS), and REM sleep (RS). Multiple regressions predicted fractional anisotropy (FA) and mean diffusivity (MD) of the corpus callosum as a function of total PSQI score, TST, SE, and percent of time spent in each sleep stage, controlling for age and sex. Greater percent time spent in RS was significantly associated with higher FA (ß = 0.41, p = 0.007) and lower MD (ß = -0.30, p = 0.03). Total PSQI score, TST, SE, and time spent in LS or DS were not significantly associated with FA or MD (p>0.13). Percent time spent in REM sleep, but not quantity of light and deep sleep or subjective/objective measures of sleep quality, positively predicted white matter microstructure integrity. Our results highlight an important link between REM sleep and brain health that has the potential to improve sleep interventions in the elderly.

Aging and Positive Mood: Longitudinal Neurobiological and Cognitive Correlates.

OBJECTIVE: Despite the losses commonly associated with aging, older adults seem to possess particularly preserved emotional regulation. To further understand this phenomenon, the authors examined longitudinal trajectories between age, depressive symptoms, brain structure, and cognition. METHODS: Seven hundred and sixteen functionally intact older adults (age M = 67.9, 56.8% female), followed longitudinally (visit range: 1-13, M = 2.5), completed cognitive testing and the Geriatric Depression Scale (GDS). A subset (N = 327) underwent 3T brain MRI. Mixed-effects linear regression models were conducted controlling for sex, education, and total intracranial volume. RESULTS: There was a significant interaction between age and time on GDS, such that GDS improved with increasing age over time, but attenuated around age 71 (age*time b = 0.10, p <0.001). Fractional anisotropy (FA) and mean diffusivity interacted with age to predict longitudinal changes in GDS (FA: b = -0.02, p = 0.01; MD: b = 0.03, p = 0.007), such that age-related benefits on GDS were attenuated in those with declining FA. Executive function (EF) and processing speed also interacted with age to predict longitudinal changes in GDS (EF: b = -0.04, p = 0.03; speed: b = 0.04, p = 0.04). Again, the positive effect of age on GDS attenuated in those with worsening EF and speed. There were no associations with memory, semantic fluency, or gray matter (p values >0.05). CONCLUSION: EF, processing speed, and white matter integrity moderated the longitudinal relationship between age and mood. Previous studies demonstrate the link between positivity and better cognitive control, leading to improved mood in older adults. Our results are not only consistent, but establish a potential neurobiological correlate. Future research further exploring biological mechanisms driving psychological processes may have important therapeutic implications.

An IL-18-centered inflammatory network as a biomarker for cerebral white matter injury.

Chronic systemic sterile inflammation is implicated in the pathogenesis of cerebrovascular disease and white matter injury. Non-invasive blood markers for risk stratification and dissection of inflammatory molecular substrates in vivo are lacking. We sought to identify whether an interconnected network of inflammatory biomarkers centered on IL-18 and all previously associated with white matter lesions could detect overt and antecedent white matter changes in two populations at risk for cerebral small vessel disease. In a cohort of 167 older adults (mean age: 76, SD 7.1, 83 females) that completed a cognitive battery, physical examination, and blood draw in parallel with MR imaging including DTI, we measured cerebral white matter hyperintensities (WMH) and free water (FW). Concurrently, serum levels of a biologic network of inflammation molecules including MPO, GDF-15, RAGE, ST2, IL-18, and MCP-1 were measured. The ability of a log-transformed population mean-adjusted inflammatory composite score (ICS) to associate with MR variables was demonstrated in an age and total intracranial volume adjusted model. In this cohort, ICS was significantly associated with WMH (ß = 0.222, p = 0.013), FW (ß = 0.3, p = 0.01), and with the number of vascular risk factor diagnoses (r = 0.36, p<0.001). In a second cohort of 131 subjects presenting for the evaluation of acute neurologic deficits concerning for stroke, we used serum levels of 11 inflammatory biomarkers in an unbiased principal component analysis which identified a single factor significantly associated with WMH. This single factor was strongly correlated with the six component ICS identified in the first cohort and was associated with WMH in a generalized linear regression model adjusted for age and gender (p = 0.027) but not acute stroke. A network of inflammatory molecules driven by IL-18 is associated with overt and antecedent white matter injury resulting from cerebrovascular disease and may be a promising peripheral biomarker for vascular white matter injury.