Sex-differences in the association of social health and marital status with blood-based immune and neurodegeneration markers in a cohort of community-dwelling older adults.

BACKGROUND: The immune system has been proposed to play a role in the link between social health and all-cause dementia risk. We explored cross-sectional and longitudinal associations between social health, immune system balance and plasma neurodegeneration markers in community-dwelling older adults, and explored whether the balance between innate and adaptive immunity mediates associations between social health and both cognition and total brain volume. METHODS: Social health markers (social support, marital status, loneliness) were measured in the Rotterdam Study between 2002-2008. Immune system cell counts and balance were assessed repeatedly from 2002 to 2016 using white blood-cell-based indices and individual counts (granulocyte-to-lymphocyte ratio (GLR), platelet-to-lymphocyte ratio (PLR), and systemic immune-inflammation index (SII)). Plasma neurodegeneration biomarkers (amyloid-ß40, amyloid-ß42, total tau and neurofilament light chain) were measured once from blood samples collected between 2002-2008. Global cognitive function and total brain volume (MRI) were measured at the follow-up visit between 2009-2014. We used linear mixed models to study longitudinal associations and performed causal mediation analyses. RESULTS: In 8374 adults (mean age 65.7, 57 % female), never married participants (n = 394) had higher GLR, PLR and SII compared to married peers at baseline and during follow-up, indicating imbalance towards innate immunity. Being never married was associated with higher plasma amyloid-ß40, and being widowed or divorced with higher plasma total tau levels at baseline. Widowed or divorced males, but not females, had higher GLR, PLR and SII at baseline. Higher social support was associated with lower PLR in females, but higher PLR in males. Loneliness was not associated with any of the immune system balance ratios. Never married males had higher levels of all plasma neurodegeneration markers at baseline. Immune system balance did not mediate associations between social health and cognition or total brain volume, but does interact with marital status. CONCLUSION: This study indicates that marital status is associated with blood-based immune system markers toward innate immunity and higher levels of plasma neurodegeneration markers. This is particularly evident for never married or previously married male older adults compared to married or female peers.

Quantifying Physical Resilience after Knee or Hip Surgery in Older Australian Women Based on Long-Term Physical Functioning Trajectories.

INTRODUCTION: To improve outcomes after knee or hip surgery, better insight is needed in long-term recovery patterns in the context of ageing-related decline. We examined long-term trajectories of physical functioning (PF) in older women with and without hip and knee surgery and described profiles of cases with higher and lower resilience after surgery. METHODS: This observational study used data from 10,434 women (73-79 years) who completed survey 2 of the Australian Longitudinal Study on Women's Health. Data were used from surveys 2 (1999) to 6 (2011). Covariable-adjusted linear mixed models were run to examine the surgery-by-time (-12 to +12 years) interaction in association with PF (SF-36 subscale). The differences between observed and expected PF were calculated, with positive/negative values reflecting higher/lower resilience, respectively. RESULTS: Women with hip surgery (n = 982) had lower PF than those without surgery (n = 8,117) (p < 0.001). Among hip surgery patients, the decline was more rapid pre-surgery than post-surgery (Δslope = -0.7, p < 0.001). Women with knee surgery (n = 1,144) had lower PF than those without surgery (n = 7,971), but with a slower rate of decline (p = 0.01). Among knee surgery patients, the rate of decline was similar pre- and post-surgery (Δslope = -0.3, p = 0.25). Both in hip and knee patients, women with higher resilience had fewer comorbidities and symptoms and were more often physically active and independent in daily activities than those with lower resilience (all p < 0.05). CONCLUSION: Compared with women without surgery, PF was lower and declined more rapidly around the time of hip surgery, but not for knee surgery. Women with better long-term recovery after surgery had fewer health problems and were more independent around the time of surgery.

The association of the STarT Back Screening Tool and type of leg pain with low back pain disability trajectories: a prospective cohort study.

BACKGROUND: Multiple factors influence the recovery process of low back pain (LBP). The identification and increased knowledge of prognostic factors might contribute to a better understanding of the course of LBP. The purpose of this study is to investigate the association of the STarT Back Screening Tool (SBST) risk score and the type of leg pain (non-radiating LBP, referred non-radicular, and radicular radiating leg pain) with the disability trajectory (at baseline, the slope, and recovery at one year) in adults with low back pain. METHODS: This is a prospective cohort study in 347 patients with low back pain who sought physiotherapy care at three primary care practices in the Netherlands. Linear mixed models were estimated to describe the association of the SBST risk score and the type of leg pain with disability at baseline, the slope in the disability trajectory, and at twelve months follow-up. RESULTS: A medium/high risk score on the SBST is associated with higher baseline disability scores on the Oswestry Disability Index (ODI), faster initial recovery, and still a higher disability ODI score at 12 months follow-up. Non-radicular referred and radicular radiating leg pain were associated with worse baseline disability ODI scores in LBP. This association was not present for the initial recovery or at the 12 months follow-up. CONCLUSION: The SBST is associated with the LBP recovery trajectory. The SBST might be a useful tool to predict the disability trajectory in a heterogeneous group of people with low back pain in primary care and might, therefore, be recommended in future clinical practice guidelines. The type of leg pain was not associated with the recovery trajectory of LBP. Future research might focus on evaluating different types of leg pain. TRIAL REGISTRATION: Clinicaltrials.gov: 109,643.

Assessing dynamical resilience indicators in older adults: a prospective feasibility cohort study.

PURPOSE: Measuring dynamical resilience indicators based on time series data may improve the prediction of health deterioration in older adults after hospital discharge. We examined the feasibility of an intensive prospective cohort study examining dynamical resilience indicators based on time series data of symptoms and physical activity in acutely ill older adults who visited the Emergency Department (ED). METHODS: This is a prospective cohort study with time series data from symptom questionnaires and activity trackers. Thirty older adults (aged 75.9 ± 5.5 years, 37% female) who were discharged from the ED of a tertiary hospital in the Netherlands were included in the study. We monitored self-reported symptoms using a daily online questionnaire, and physical activity using an activity tracker for 30 days. Descriptive data on participant eligibility and adherence to and acceptability of the assessments were collected. RESULTS: Of 134 older patients visiting the ED, 109/134 (81%) were eligible for inclusion and 30/109 (28%) were included. Twenty-eight (93%) of the included participants completed follow-up. Regarding the adherence rate, 78% of participants filled in the questionnaire and 80% wore the activity tracker. Three (10%) participants completed fewer than three questionnaires. Most participants rated the measurements as acceptable and seven (23%) participants experienced an adverse outcome in the 30 days after discharge. CONCLUSION: Such an intensive prospective cohort study examining dynamical resilience indicators in older adults was feasible. The quality of the collected data was sufficient, some adjustments to the measurement protocol are recommended. This study is an important first step to study resilience in older adults.

The need for systems thinking to advance Alzheimer's disease research.

Despite extensive research efforts to mechanistically understand late-onset Alzheimer's disease (LOAD) and other complex mental health disorders, curative treatments remain elusive. We emphasize the multiscale multicausality inherent to LOAD, highlighting the interplay between interconnected pathophysiological processes and risk factors. Systems thinking methods, such as causal loop diagrams and systems dynamic models, offer powerful means to capture and study this complexity. Recent studies developed and validated a causal loop diagram and system dynamics model using multiple longitudinal data sets, enabling the simulation of personalized interventions on various modifiable risk factors in LOAD. The results indicate that targeting factors like sleep disturbance and depressive symptoms could be promising and yield synergistic benefits. Furthermore, personalized interventions showed significant potential, with top-ranked intervention strategies differing significantly across individuals. We argue that systems thinking approaches can open new prospects for multifactorial precision medicine. In future research, systems thinking may also guide structured, model-driven data collection on the multiple interactions in LOAD's complex multicausality, facilitating theory development and possibly resulting in effective prevention and treatment options.

No association between markers of systemic inflammation and endothelial dysfunction with Alzheimer's disease progression: a longitudinal study.

INTRODUCTION: Systemic inflammation and endothelial dysfunction are potentially modifiable factors implicated in Alzheimer's disease (AD), which offer potential therapeutic targets to slow disease progression. METHODS: We investigated the relationship between baseline circulating levels of inflammatory (TNF-α, IL-1ß) and endothelial cell markers (VCAM-1, ICAM-1, E-selectin) and 18-month cognitive decline (ADAS-cog12) in 266 mild-to-moderate AD patients from the NILVAD study. We employed individual growth models to examine associations, potential mediation, and interaction effects while adjusting for confounders. RESULTS: The average increase in ADAS-cog12 scores over all patients was 8.1 points in 18 months. No significant association was found between the markers and the rate of cognitive decline. Mediation analysis revealed no mediating role for endothelial cell markers, and interaction effects were not observed. DISCUSSION: Our results do not support the role of systemic inflammation or endothelial dysfunction in progression in persons with AD.

The association of physical activity and sedentary behaviour with low back pain disability trajectories: A prospective cohort study.

BACKGROUND: Multiple factors influence the recovery process of low back pain (LBP). The identification and increased knowledge of risk factors might contribute to a better understanding of the course of LBP. OBJECTIVES: To investigate the association of habitual physical activity (PA) and sedentary behaviour (SB), measured at baseline, with disability trajectories in adults with LBP. METHODS: A prospective cohort study where habitual PA levels were measured using the Short QUestionnaire to ASsess Health enhancing physical activity (SQUASH), SB was calculated as average sedentary hours per day, and LBP disability using the Oswestry Disability Index (ODI). Participants completed the questionnaires at one and a half, three, six, and twelve months. Linear mixed models were estimated to describe the association of habitual PA levels SB measured at baseline with disability trajectories. Other predictors were gender, education level, age, pain, number of previous episodes of LBP, and duration of LBP. RESULTS: Habitual SB measured at baseline in adults (n = 347) with LBP were not associated with disability trajectories. For PA, participants with one metabolic equivalent of task (MET) hour per day above average recovered 0.04 [95% CI 0.004 to 0.076] points on the ODI per month faster than participants with an average amount of MET hours per day. CONCLUSIONS: Habitual SB was not associated with LBP disability trajectories over a one-year follow-up. High levels of habitual PA at baseline were associated with improved recovery in LBP disability trajectory, but the finding is not clinically relevant.

Social health and subsequent cognitive functioning in people aged 50 years and older: examining the mediating roles of depressive symptoms and inflammatory biomarkers in two European longitudinal studies.

BACKGROUND: Social health markers, including marital status, contact frequency, network size, and social support, have been shown to be associated with cognition. However, the mechanisms underlying these associations remain poorly understood. We investigated whether depressive symptoms and inflammation mediated associations between social health and subsequent cognition. METHODS: In the English Longitudinal Study of Ageing (ELSA), a nationally representative longitudinal study in England, UK, we sampled 7136 individuals aged 50 years or older living in private households without dementia at baseline or at the intermediate mediator assessment timepoint, who had recorded information on at least one social health marker and potential mediator. We used four-way decomposition to examine to what extent depressive symptoms, C-reactive protein, and fibrinogen mediated associations between social health and subsequent standardised cognition (verbal fluency and delayed and immediate recall), including cognitive change, with slopes derived from multilevel models (12-year slope). We examined whether findings were replicated in the Swedish National Study on Aging and Care in Kungsholmen (SNAC-K), a population-based longitudinal study in Sweden, in a sample of 2604 individuals aged 60 years or older living at home or in institutions in Kungsholmen (central Stockholm) without dementia at baseline or at the intermediate mediator assessment timepoint (6-year slope). Social health exposures were assessed at baseline, potential mediators were assessed at an intermediate timepoint (wave 2 in ELSA and 6-year follow-up in SNAC-K); cognitive outcomes were assessed at a single timepoint (wave 3 in ELSA and 12-year follow-up in SNAC-K), and cognitive change (between waves 3 and 9 in ELSA and between 6-year and 12-year follow-ups in SNAC-K). FINDINGS: The study sample included 7136 participants from ELSA, of whom 3962 (55·5%) were women and 6934 (97·2%) were White; the mean baseline age was 63·8 years (SD 9·4). Replication analyses included 2604 participants from SNAC-K, of whom 1604 (61·6%) were women (SNAC-K did not collect ethnicity data); the mean baseline age was 72·3 years (SD 10·1). In ELSA, we found indirect effects via depressive symptoms of network size, positive support, and less negative support on subsequent verbal fluency, and of positive support on subsequent immediate recall (pure indirect effect [PIE] 0·002 [95% CI 0·001-0·003]). Depressive symptoms also partially mediated associations between less negative support and slower decline in immediate recall (PIE 0·001 [0·000-0·002]) and in delayed recall (PIE 0·001 [0·000-0·002]), and between positive support and slower decline in immediate recall (PIE 0·001 [0·000-0·001]). We did not observe mediation by inflammatory biomarkers. Findings of mediation by depressive symptoms in the association between positive support and verbal fluency and between positive support and change in immediate recall were replicated in SNAC-K. INTERPRETATION: The findings of this study provide new insights into mechanisms linking social health with cognition, suggesting that associations between interactional aspects of social health, especially social support, and cognition are partly underpinned by depressive symptoms. FUNDING: EU Joint Programme-Neurodegenerative Disease Research (JPND) and Alzheimer's Society. TRANSLATION: For the Swedish translation of the abstract see Supplementary Materials section.

External validation of six COVID-19 prognostic models for predicting mortality risk in older populations in a hospital, primary care, and nursing home setting.

OBJECTIVES: To systematically evaluate the performance of COVID-19 prognostic models and scores for mortality risk in older populations across three health-care settings: hospitals, primary care, and nursing homes. STUDY DESIGN AND SETTING: This retrospective external validation study included 14,092 older individuals of ≥70 years of age with a clinical or polymerase chain reaction-confirmed COVID-19 diagnosis from March 2020 to December 2020. The six validation cohorts include three hospital-based (CliniCo, COVID-OLD, COVID-PREDICT), two primary care-based (Julius General Practitioners Network/Academisch network huisartsgeneeskunde/Network of Academic general Practitioners, PHARMO), and one nursing home cohort (YSIS) in the Netherlands. Based on a living systematic review of COVID-19 prediction models using Prediction model Risk Of Bias ASsessment Tool for quality and risk of bias assessment and considering predictor availability in validation cohorts, we selected six prognostic models predicting mortality risk in adults with COVID-19 infection (GAL-COVID-19 mortality, 4C Mortality Score, National Early Warning Score 2-extended model, Xie model, Wang clinical model, and CURB65 score). All six prognostic models were validated in the hospital cohorts and the GAL-COVID-19 mortality model was validated in all three healthcare settings. The primary outcome was in-hospital mortality for hospitals and 28-day mortality for primary care and nursing home settings. Model performance was evaluated in each validation cohort separately in terms of discrimination, calibration, and decision curves. An intercept update was performed in models indicating miscalibration followed by predictive performance re-evaluation. MAIN OUTCOME MEASURE: In-hospital mortality for hospitals and 28-day mortality for primary care and nursing home setting. RESULTS: All six prognostic models performed poorly and showed miscalibration in the older population cohorts. In the hospital settings, model performance ranged from calibration-in-the-large -1.45 to 7.46, calibration slopes 0.24-0.81, and C-statistic 0.55-0.71 with 4C Mortality Score performing as the most discriminative and well-calibrated model. Performance across health-care settings was similar for the GAL-COVID-19 model, with a calibration-in-the-large in the range of -2.35 to -0.15 indicating overestimation, calibration slopes of 0.24-0.81 indicating signs of overfitting, and C-statistic of 0.55-0.71. CONCLUSION: Our results show that most prognostic models for predicting mortality risk performed poorly in the older population with COVID-19, in each health-care setting: hospital, primary care, and nursing home settings. Insights into factors influencing predictive model performance in the older population are needed for pandemic preparedness and reliable prognostication of health-related outcomes in this demographic.