Comparative assessment of Alzheimer's disease-related biomarkers in plasma and neuron-derived extracellular vesicles: a nested case-control study.

Introduction: Alzheimer's disease (AD) is currently defined according to biomarkers reflecting the core underlying neuropathological processes: Aß deposition, Tau, and neurodegeneration (ATN). The soluble phase of plasma and plasma neuron-derived extracellular vesicles (NDEVs) are increasingly being investigated as sources of biomarkers. The aim of this study was to examine the comparative biomarker potential of these two biofluids, as well as the association between respective biomarkers. Methods: We retrospectively identified three distinct diagnostic groups of 44 individuals who provided samples at baseline and at a mean of 3.1 years later; 14 were cognitively unimpaired at baseline and remained so (NRM-NRM), 13 had amnestic MCI that progressed to AD dementia (MCI-DEM) and 17 had AD dementia at both timepoints (DEM-DEM). Plasma NDEVs were isolated by immunoaffinity capture targeting the neuronal markers L1CAM, GAP43, and NLGN3. In both plasma and NDEVs, we assessed ATN biomarkers (Aß42, Aß40, total Tau, P181-Tau) alongside several other exploratory markers. Results: The Aß42/Aß40 ratio in plasma and NDEVs was lower in MCI-DEM than NRM-NRM at baseline and its levels in NDEVs decreased over time in all three groups. Similarly, plasma and NDEV-associated Aß42 was lower in MCI-DEM compared to NRM-NRM at baseline and its levels in plasma decreased over time in DEM-DEM. For NDEV-associated proBDNF, compared to NRM-NRM, its levels were lower in MCI-DEM and DEM-DEM at baseline, and they decreased over time in the latter group. No group differences were found for other exploratory markers. NDEV-associated Aß42/Aß40 ratio and proBDNF achieved the highest areas under the curve (AUCs) for discriminating between diagnostic groups, while proBDNF was positively associated with Mini-Mental State Examination (MMSE) score. No associations were found between the two biofluids for any assessed marker. Discussion: The soluble phase of plasma and plasma NDEVs demonstrate distinct biomarker profiles both at a single time point and longitudinally. The lack of association between plasma and NDEV measures indicates that the two types of biofluids demonstrate distinct biomarker signatures that may be attributable to being derived through different biological processes. NDEV-associated proBDNF may be a useful biomarker for AD diagnosis and monitoring.

The associations between unmet needs with protective factors, risk factors and outcomes among care partners of community-dwelling persons living with dementia.

OBJECTIVES: Describe the prevalence and types of unmet needs among community-dwelling dementia care partners (CPs) and determine associations between unmet needs with protective factors, risk factors and outcomes. METHOD: A cross-sectional analysis of 638 racially and cognitively diverse community-dwelling persons living with dementia (PLWD) and their CPs participating in a comprehensive in-home assessment of dementia-related needs. Unmet CP needs (19 items, 6 domains) were rated by a clinician using the Johns Hopkins Dementia Care Needs Assessment (JHDCNA). Multivariate linear regression models were used to examine associations between total percent unmet CP needs with demographic, protective and risk factors. RESULTS: Nearly all CPs had at least one unmet need (99.53%), with a mean of 5.7 (±2.6). The most common domains with ≥1 unmet need were memory disorder education, care skills and knowledge of resources (98%), legal issues/concerns (73.8%), CP mental health (44.6%) and access to informal support (42.7%). Adjusted multivariate models suggest the strongest consistent predictive factors relate to informal emotional support, CP physical health, use or difficulty getting formal services/supports (both for CPs and PLWD), and CP time spent with PLWD. Greater levels of unmet needs were associated with worse PLWD outcomes and CP outcomes, after adjusting for demographics. CONCLUSIONS: CPs have high rates of diverse, but modifiable unmet needs. Data suggest optimal approaches to dementia care should take a family-centered home-based approach that includes routine CP needs assessment, offer targeted interventions that include both traditional medical supports as well as strategies to increase and leverage informal social networks, and ones that can bridge and coordinate medical with non-medical supports. These findings can be used to inform new approaches to support CPs, improve PLWD and CP outcomes, and target groups most at risk for inequities.

Financial incentives promote engagement in employment services for unemployed adults in treatment for opioid use disorder.

BACKGROUND: Promoting employment among unemployed adults with substance use disorder is a difficult challenge for which existing interventions have had limited effects. This study examined whether financial incentives could increase engagement in employment services for unemployed adults in treatment for opioid use disorder. METHODS: The study was conducted from 2014 to 2019 in Baltimore, MD. After a 3-month abstinence initiation and training period, participants (N = 91) were randomly assigned to a Control group or an Incentive group and were invited to work with an employment specialist to seek employment in a community job for 12 months. Participants assigned to the Control group (n = 47) did not receive incentives for working with the employment specialist. Participants assigned to the Incentive group (n = 44) could earn financial incentives for working with the employment specialist, but had to provide opiate- and cocaine-negative urine samples to maximize pay. RESULTS: Incentive participants attended the employment services and worked with the employment specialist on significantly more days than Control participants (41.8 % versus 1.1 % of days; OR = 40.42, 95 % CI = 32.46-48.38, p < .001), and for significantly more hours than Control participants (3.58 versus 1.25 h, on average; OR=2.34, 95 % CI=1.83-2.85, p < .001). Incentive participants were more likely to be retained than Control participants when analyses were based solely on attendance (HR=0.12, 95 % CI=0.06-0.25, p < .001) and attendance and employment combined (HR=0.15, 95 % CI=0.07-0.31, p < .001). CONCLUSIONS: Financial incentives were effective in promoting engagement in employment services for individuals who often do not utilize employment services.

Fatigue Symptoms During the First Year Following ARDS.

BACKGROUND: Fatigue is commonly reported by ARDS survivors, but empirical data are scarce. RESEARCH QUESTION: This study evaluated fatigue prevalence and associated variables in a prospective study of ARDS survivors. STUDY DESIGN AND METHODS: This analysis is part of the ARDSNet Long-Term Outcomes Study (ALTOS) conducted at 38 US hospitals. Using age- and sex-adjusted, time-averaged random effects regression models, we evaluated associations between the validated Functional Assessment of Chronic Illness Therapy-Fatigue Scale with patient and critical illness variables, and with physical, cognitive, and mental health status at 6 and 12 months following ARDS. RESULTS: Among ARDS survivors, 501 of 711 (70%) and 436 of 659 (66%) reported clinically significant symptoms of fatigue at 6 and 12 months, respectively, with 41% and 28% reporting clinically important improvement and worsening (n = 638). At 6 months, the prevalence of fatigue (70%) was greater than that of impaired physical functioning (50%), anxiety (42%), and depression (36%); 46% reported both impaired physical function and fatigue, and 27% reported co-existing anxiety, depression, and fatigue. Fatigue was less severe in men and in those employed prior to ARDS. Critical illness variables (eg, illness severity, length of stay) had little association with fatigue symptoms. Worse physical, cognitive, and mental health symptoms were associated with greater fatigue at both the 6- and 12-month follow-up. INTERPRETATION: During the first year following ARDS, more than two-thirds of survivors reported clinically significant fatigue symptoms. Due to frequent co-occurrence, clinicians should evaluate and manage survivors' physical, cognitive, and mental health status when fatigue is endorsed.

Association between allostatic load and health behaviours: a latent class approach.

BACKGROUND: Allostatic load (AL) has been characterised in many ways throughout the literature; however, its relationship to health behaviours has only been studied in limited populations. We aimed to uncover qualitative patterns of biological indicators in AL and determine if those patterns were associated with certain health behaviours. METHODS: We conducted latent class analysis using biological indicators from a multiethnic population. We fit latent class regression of class on health behaviours (smoking, poor diet, physical activity and alcohol use) to measure the association between each latent class of AL and each health behaviour. RESULTS: Four classes, 'Metabolic+Cholesterol, 'Blood Pressure', 'Metabolic+Blood Pressure' and 'Low', were found in the sample. Latent class regression showed that physical activity and alcohol use were significantly associated with the 'Metabolic+Blood Pressure' class. CONCLUSION: Less physical activity was required to improve AL than was previously found. Low to moderate alcohol use was beneficial for lower AL. Implications of the amount of physical activity necessary to lower AL is discussed.

Exploration of Factor Structure and Measurement Invariance by Gender for a Modified Shortened Adapted Social Capital Assessment Tool in India.

Social capital is defined as the nature of the social relationship between individuals or groups and the embedded resources available through their social network. It is considered as a critical determinant of health and well-being. Thus, it is essential to assess the performance of any tool when meaningfully comparing social capital between specific groups. Using measurement invariance (MI) analysis, this paper explored the factor structure of the social capital of men and women measured by a modified Shortened Adapted Social Capital Assessment Tool (SASCAT-I) in rural Uttar Pradesh (UP), India. The study sample comprised 5,287 men (18-101 years) and 7,186 women (15-45 years) from 6,218 randomly selected households who responded to SASCAT-I during a community-level cross-sectional survey. Social capital factor structure was examined by both exploratory and confirmatory factor analysis (CFA), and MI across genders was investigated using multigroup CFA. While disregarding gender, four unique factors (Organizational Participation, Social Support, Trust, and Social Cohesion) represented the structure of social capital. The MI analysis presented a partial metric-invariance indicating factor loadings for Organizational Participation and Social Support were the same across genders. The gender-stratified analysis demonstrated that a four-factor solution was best fitted for both men and women. Men and women of rural UP interpreted social capital differently as the perception of Trust and Social Cohesion varied across genders. For any future applications of SASCAT-I, we recommend gender-stratified factor analysis to quantify social capital's measure, acknowledging its multidimensionality.

MIND at Home-Streamlined: Study protocol for a randomized trial of home-based care coordination for persons with dementia and their caregivers.

BACKGROUND: Dementia is associated with high health care costs, premature long-term care (LTC) placement, medical complications, reduced quality of life, and caregiver burden. Most health care providers and systems are not yet organized or equipped to provide comprehensive long-term care management for dementia, although a range of effective symptoms and supportive care approaches exist. The Maximizing Independence at Home-Streamlined (MIND-S) is a promising model of home-based dementia care coordination designed to efficiently improve person-centered outcomes, while reducing care costs. This report describes the rationale and design of an NIA-funded randomized controlled trial to test the impact of MIND-S on time to LTC placement, person with dementia outcomes (unmet needs, behavior, quality of life), family caregiver outcomes (unmet needs, burden), and cost offset at 18 (primary end point) and 24 months, compared to an augmented usual care group. METHODS: This is a 24-month, parallel group, randomized trial evaluating MIND-S in a cohort of 304 community-living persons with dementia and their family caregivers in Maryland. MIND-S dyads receive 18 months of care coordination by an interdisciplinary team comprised of trained non-clinical community workers (e.g. Memory Care Coordinators), a registered nurse, and a geriatric psychiatrist. Intervention components include in-home dementia-related needs assessments; individualized care planning; implementation of standardized evidence-based care strategy protocols; and ongoing monitoring and reassessment. Outcomes are assessed by blinded evaluators at baseline, 4.5, 9, 13.5, 18, and 24 months. DISCUSSION: Trial results will provide rigorous data to inform innovations in effective system-level approaches to dementia care.

Dementia severity and the longitudinal costs of informal care in the Cache County population.

BACKGROUND: Dementia costs are critical for influencing healthcare policy, but limited longitudinal information exists. We examined longitudinal informal care costs of dementia in a population-based sample. METHODS: Data from the Cache County Study included dementia onset, duration, and severity assessed by the Mini-Mental State Examination (MMSE), Clinical Dementia Rating Scale (CDR), and Neuropsychiatric Inventory (NPI). Informal costs of daily care (COC) was estimated based on median Utah wages. Mixed models estimated the relationship between severity and longitudinal COC in separate models for MMSE and CDR. RESULTS: Two hundred and eighty-seven subjects (53% female, mean (standard deviation) age was 82.3 (5.9) years) participated. Overall COC increased by 18% per year. COC was 6% lower per MMSE-point increase and compared with very mild dementia, COC increased over twofold for mild, fivefold for moderate, and sixfold for severe dementia on the CDR. CONCLUSIONS: Greater dementia severity predicted higher costs. Disease management strategies addressing dementia progression may curb costs.

A randomized controlled trial of a community-based dementia care coordination intervention: effects of MIND at Home on caregiver outcomes.

OBJECTIVE: To assess whether MIND at Home, a community-based, multicomponent, care coordination intervention, reduces unmet caregiving needs and burden in informal caregivers of persons with memory disorders. METHODS: An 18-month randomized controlled trial of 289 community-living care recipient (CR)-caregiver (informal caregivers, i.e., unpaid individuals who regularly assisted the CR) dyads from 28 postal code areas of Baltimore, Maryland was conducted. All dyads and the CR's primary care physician received the written needs assessment results and intervention recommendations. Intervention dyads then received an 18-month care coordination intervention delivered by nonclinical community workers to address unmet care needs through individualized care planning, referral and linkage to dementia services, provision of caregiver dementia education and skill-building strategies, and care progress monitoring by an interdisciplinary team. Primary outcome was total percent of unmet caregiver needs at 18 months. Secondary outcomes included objective and subjective caregiver burden measures, quality of life (QOL), and depression. RESULTS: Total percent of unmet caregiver needs declined in both groups from baseline to 18 months, with no statistically significant between-group difference. No significant group differences occurred in most caregiver burden measures, depression, or QOL. There was a potentially clinically relevant reduction in self-reported number of hours caregivers spent with the CR for MIND participants compared with control subjects. CONCLUSION: No statistically significant impacts on caregiver outcomes were found after multiple comparison adjustments. However, MIND at Home appeared to have had a modest and clinically meaningful impact on informal caregiver time spent with CRs.

Difference by sex but not by race/ethnicity in the visceral adipose tissue-depressive symptoms association: the Multi-Ethnic Study of Atherosclerosis.

BACKGROUND: Prior studies have investigated the association of clinical depression and depressive symptoms with body weight (i.e. body mass index (BMI) and waist circumference), but few have examined the association between depressive symptoms and intra-abdominal fat. Of these a limited number assessed the relationship in a multi-racial/ethnic population. METHODS: Using data on 1017 men and women (45-84 years) from the Multi-Ethnic Study of Atherosclerosis (MESA) Body Composition, Inflammation and Cardiovascular Disease Study, we examined the cross-sectional association between elevated depressive symptoms (EDS) and CT-measured visceral fat mass at L2-L5 with multivariable linear regression models. EDS were defined as a Center for Epidemiological Studies Depression score ≥16 and/or anti-depressant use. Covariates included socio-demographics, inflammatory markers, health behaviors, comorbidities, and body mass index (BMI). Race/ethnicity (Whites [referent group], Chinese, Blacks and Hispanics) and sex were also assessed as potential modifiers. RESULTS: The association between depressive symptoms and visceral fat differed significantly by sex (p=0.007), but not by race/ethnicity. Among men, compared to participants without EDS, those with EDS had greater visceral adiposity adjusted for BMI and age (difference=122.5 cm2, 95% CI=34.3, 210.7, p=0.007). Estimates were attenuated but remained significant after further adjustment by socio-demographics, inflammatory markers, health behaviors and co-morbidities (difference=94.7 cm2, 95% CI=10.5, 178.9, p=0.028). Among women, EDS was not significantly related to visceral adiposity in the fully adjusted model. CONCLUSIONS: Sex, but not race/ethnicity, was found to modify the relationship between EDS and visceral fat mass. Among men, a significant positive association was found between depressive symptoms and visceral adiposity. No significant relationship was found among women.

The use of multiple versus single assessment time points to improve screening accuracy in identifying children at risk for later serious antisocial behavior.

Guided by Kraemer et al.'s (Psychological Methods, 3:257-271, 1999) framework for measuring the potency of risk factors, we sought to improve on the classification accuracy reported in Petras et al. (Journal of the American Academy of Child and Adolescent Psychiatry 43:88-96, 2004a) and Petras et al. (Journal of the American Academy of Child and Adolescent Psychiatry 44:790-797, 2005) by using multiple as opposed to single point in time assessments of early aggressive and disruptive behavior in the classification of youth who would likely benefit from targeted preventive interventions. Different from Petras et al. (2004a, 2005), the outcome used in this study included serious antisocial behavior in young adulthood as well as in adolescence. Among males, the use of multiple time points did not yield greater classification accuracy than the highest single time points, that is, third and fifth grades. For females, although fifth grade represented the best single time point in terms of classification accuracy, no significant association was found between earlier time points and the later outcome, rendering a test of the multiple time points hypothesis moot. The findings presented in this study have strong implications for the design of targeted intervention for violence prevention, indicating that the screening quality based on aggression ratings during the elementary years is rather modest, particularly for females.