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.

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 Role of Spirituality in Conceptualizations of Health Maintenance and Healthy Aging Among Latin American Immigrants.

OBJECTIVES: We aimed to investigate ways in which spirituality was conceptualized in relationship to maintaining brain health and healthy aging in a cohort of older adults who immigrated to the United States from diverse regions of Latin America, in order to ultimately develop culturally-tailored brain health promotion approaches. DESIGN: We conducted a qualitative study using semi-structured interviews. SETTING: Participants were recruited from community centers and by a memory care center at a large academic medical center. PARTICIPANTS: We interviewed 30 Spanish-speaking immigrants over age 60. Questions addressed perspectives about the brain, aging, and dementia. Interviews were coded for themes. MEASUREMENTS: Thematic analysis was used to analyze participants' responses. RESULTS: We identified 5 themes: (1) expressing gratitude to God for mental and physical health, (2) putting the onus of life and death in God's hands, (3) using church as a place to socialize and build community as an approach to leading a healthy lifestyle, (4) using prayer as nourishment for the soul and the brain, and (5) gaining inner-peace and calm, and thus maintaining a healthy life, due to a connection with God. CONCLUSION: The incorporation of customized spiritual interventions may be a mechanism by which to increase the effectiveness of brain health promotion efforts.

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).

Medication Dosing Schedules, Medication Knowledge, and Dosing Errors of Adults Taking Complex Drug Regimens.

This study examined how patients take complex medication regimens at home. Participants were primary care patients, 21 years or older, and prescribed three or more medications. Interviews assessed medication dosing schedules, medication knowledge, and dosing errors. Participants (N=441) were middle aged (mean 56.9); the majority were Hispanic/Latino (73.4%), had limited English proficiency (59.0%), and had limited health literacy (89.0%). One in five participants dosed medication five or more times per day, although no participants in the sample had a label instructing them to take medication more than times times daily. On average, participants correctly identified the purpose of 65% of their medications. Half of participants made one or more dosing errors. Less than high school education and a regimen size of six or more medications were independently associated with less medication knowledge, whereas language discordant label instructions were associated with dosing errors. Screening for regimen dosing complication and interventions to simplify dosing schedules are needed.

Associations Between Cognitive Impairment Severity and Barriers to Healthcare Engagement Among Older Adults.

Objectives: To assess whether older adults with a cognitive impairment were more likely to report challenges interacting with medical providers, or to avoid needed medical care. Methods: Data for this exploratory, cross-sectional analysis were from older adults (N = 493) ages 60-82 participating in the "LitCog" cohort study. Multivariable generalized linear models compared cognitive impairment (none, mild, moderate, severe) with validated measures of healthcare engagement. Results: A moderate cognitive impairment was associated with delays in medical care due to embarrassment (RR 5.34.95% CI 1.30-22.0) and discomfort asking the doctor questions (RR 4.07, 95% CI 1.00-16.5). Conclusions: Intermediate cognitive deficits, such as with mild cognitive impairment (MCI) or mild dementias, may impact meaningful engagement with healthcare systems, potentially affecting timely detection and appropriate management of cognitive concerns and other chronic medical conditions. More research is needed to understand mechanisms underlying this relationship.

Long-term impact of the COVID-19 pandemic on self-management of chronic conditions among high-risk adults in the USA: protocol for the C3 observational cohort study.

INTRODUCTION: COVID-19 is an unprecedented public health threat in modern times, especially for older adults or those with chronic illness. Beyond the threat of infection, the pandemic may also have longer-term impacts on mental and physical health. The COVID-19 & Chronic Conditions ('C3') study offers a unique opportunity to assess psychosocial and health/healthcare trajectories over 5 years among a diverse cohort of adults with comorbidities well-characterised from before the pandemic, at its onset, through multiple surges, vaccine rollouts and through the gradual easing of restrictions as society slowly returns to 'normal'. METHODS AND ANALYSIS: The C3 study is an extension of an ongoing longitudinal cohort study of 'high-risk' adults (aged 23-88 at baseline) with one or more chronic medical conditions during the COVID-19 pandemic. Five active studies with uniform data collection prior to COVID-19 were leveraged to establish the C3 cohort; 673 adults in Chicago were interviewed during the first week of the outbreak. The C3 cohort has since expanded to include 1044 participants across eight survey waves (T1-T8). Four additional survey waves (T9-T12) will be conducted via telephone interviews spaced 1 year apart and supplemented by electronic health record and pharmacy fill data, for a total of 5 years of data post pandemic onset. Measurement will include COVID-19-related attitudes/behaviours, mental health, social behaviour, lifestyle/health behaviours, healthcare use, chronic disease self-management and health outcomes. Mental health trajectories and associations with health behaviours/outcomes will be examined in a series of latent group and mixed effects modelling, while also examining mediating and moderating factors. ETHICS AND DISSEMINATION: This study was approved by Northwestern University's Feinberg School of Medicine Institutional Review Board (STU00215360). Results will be published in international peer-reviewed journals and summaries will be provided to the funders of the study.

Prevalence of anxiety and depressive symptoms and impact on self-management among adults with chronic conditions in Chicago, Illinois, USA, during the COVID-19 pandemic: a cross-sectional survey.

OBJECTIVES: To examine the prevalence of mental health symptoms during the first surge of COVID-19 in the USA, and their associations with COVID-19-related emotional distress, health self-management and healthcare utilisation. DESIGN: Cross-sectional analysis of wave 3 (1-22 May 2020) survey data from the ongoing Chicago COVID-19 Comorbidities (C3) study. SETTING: Seven academic and community health centres in Chicago, Illinois. PARTICIPANTS: 565 adults aged 23-88 with one or more chronic conditions completing at least one prior C3 study wave. PRIMARY AND SECONDARY OUTCOME MEASURES: Clinically relevant anxiety and depressive symptoms as measured using Patient-Reported Outcomes Measurement Information System short forms. Self-reported emotional and health-related responses to COVID-19 were measured through a combination of single-item questions and validated measures. RESULTS: Rates of anxiety and depressive symptoms were 14% (81/563) and 15% (84/563), respectively. Anxiety and depressive symptoms were then each separately associated with greater worry about contracting COVID-19 (relative risk (RR) 2.32, 95% CI 1.52 to 3.53; RR 1.67, 95% CI 1.10 to 2.54), greater stress (RR 4.93, 95% CI 3.20 to 7.59; RR 3.01, 95% CI 1.96 to 4.61) and loneliness (RR 3.82, 95% CI 2.21 to 6.60; RR 5.37, 95% CI 3.21 to 8.98), greater avoidance of the doctor (RR 1.62, 95% CI 1.06 to 2.49; RR 1.54, 95% CI 1.00 to 2.36) and difficulty managing health (least square means (LS Means) 6.09, 95% CI 5.25 to 6.92 vs 4.23, 95% CI 3.70 to 4.75; LS Means 5.85, 95% CI 5.04 to 6.65 vs 4.22, 95% CI 3.70 to 4.75) and medications (LS Means 3.71, 95% CI 2.98 to 4.43 vs 2.47, 95% CI 2.02 to 2.92) due to the pandemic. CONCLUSIONS: Identifying and addressing mental health concerns may be an important factor to consider in COVID-19 prevention and management among high-risk medical populations.

Mild Motor Signs Matter in Typical Brain Aging: The Value of the UPDRS Score Within a Functionally Intact Cohort of Older Adults.

Objectives: To characterize the clinical correlates of subclinical Parkinsonian signs, including longitudinal cognitive and neural (via functional connectivity) outcomes, among functionally normal older adults. Methods: Participants included 737 functionally intact community-dwelling older adults who performed prospective comprehensive evaluations at ~15-months intervals for an average of 4.8 years (standard deviation 3.2 years). As part of these evaluations, participants completed the Unified Parkinson's Disease Rating Scale (UPDRS) longitudinally and measures of processing speed, executive functioning and verbal episodic memory. T1-weighted structural scans and task-free functional MRI scans were acquired on 330 participants. We conducted linear mixed-effects models to determine the relationship between changes in UPDRS with cognitive and neural changes, using age, sex, and education as covariates. Results: Cognitive outcomes were processing speed, executive functioning, and episodic memory. Greater within-person increases in UPDRS were associated with more cognitive slowing over time. Although higher average UPDRS scores were significantly associated with overall poorer executive functions, there was no association between UPDRS and executive functioning longitudinally. UPDRS scores did not significantly relate to longitudinal memory performances. Regarding neural correlates, greater increases in UPDRS scores were associated with reduced intra-subcortical network connectivity over time. There were no relationships with intra-frontoparietal or inter-subcortical-frontoparietal connectivity. Conclusions: Our findings add to the aging literature by indicating that mild motor changes are negatively associated with cognition and network connectivity in functionally intact adults.

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.

Get Moving! Increases in Physical Activity Are Associated With Increasing Functional Connectivity Trajectories in Typically Aging Adults.

Background: Physical activity closely relates to cognition and brain structure as we age. However, the neural mechanisms underlying this relationship in humans remain less clear. Functional connectivity (FC), measured by task-free functional MRI (tf-fMRI) is a dynamic marker of network activity and may be a sensitive indicator of the brain's response to exercise over time. We aimed to test the longitudinal relationship between physical activity and FC trajectories in functionally normal older adults. Methods: Two hundred and twelve functionally normal, longitudinally-followed older adults completed the Physical Activity Scale for the Elderly (PASE) and tf-fMRI scans at each visit [mean = 1.5 visits (range:1-3)]. We studied FC of the default mode network (DMN), frontal-parietal (FP), subcortical networks (SubCort), and frontal-subcortical inter-network connectivity (FS), given that previous studies implicate these regions in age-related changes. Linear mixed-effects models examined the relationship between within-person changes in PASE and FC (in SD units), covarying for age, sex, education and systemic cardiovascular risk factors (heart rate, BMI and systolic blood pressure). We additionally examined models covarying for DTI fractional anisotropy (FA) and mean diffusivity (MD) of tracts underlying networks of interest, as a marker of cerebrovascular disease. Furthermore, we examined the longitudinal relationship between PASE and neuropsychological trajectories. Results: In our first model, within-subject increases in physical activity tracked with increasing SubCort (ß = 0.33, p = 0.007) and FS inter-network (ß = 0.27, p = 0.03) synchrony, while between-subject parameters did not reach significance (ß = -0.042 to -0.07, ps > 0.37). No significant longitudinal associations were observed between PASE and DMN (ß = -0.02 p = 0.89) or FP networks (ß = 0.15, p = 0.23). Adjusting for markers of cerebrovascular health (FA/MD) did not change estimated effects (SubCort: ß = 0.31, p = 0.01, FS inter-network: ß = 0.28, p = 0.03). Associations between changes in physical activity and neuropsychological trajectories were small (ß = -0.14 to 0.002) and did not reach statistical significance (p-values >0.42). Conclusions: Our findings suggest that changes in exercise over time are specifically associated with frontal-subcortical processes in older adults. This relationship appears to be independent of cardio- or cerebrovascular disease, possibly driven by a more direct neural response to exercise.

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.