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.

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.

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.

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.

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.

Availability of Cognitive Resources in Early Life Predicts Transitions Between Cognitive States in Middle and Older Adults From Europe.

Background and Objectives: The existing literature highlights the importance of reading books in middle-to-older adulthood for cognitive functioning; very few studies, however, have examined the importance of childhood cognitive resources for cognitive outcomes later in life. Research Design and Methods: Using data from 11 countries included in the Survey of Health, Ageing, and Retirement in Europe (SHARE) data set (N = 32,783), multistate survival models (MSMs) were fit to examine the importance of access to reading material in childhood on transitions through cognitive status categories (no cognitive impairment and impaired cognitive functioning) and death. Additionally, using the transition probabilities estimated by the MSMs, we estimated the remaining years of life without cognitive impairment and total longevity. All models were fit individually in each country, as well as within the pooled SHARE sample. Results: Adjusting for age, sex, education, and childhood socioeconomic status, the overall pooled estimate indicated that access to more books at age 10 was associated with a decreased risk of developing cognitive impairment (adjusted hazard ratio = 0.79, confidence interval: 0.76-0.82). Access to childhood books was not associated with risk of transitioning from normal cognitive functioning to death, or from cognitive impairment to death. Total longevity was similar between participants reporting high (+1 standard deviation [SD]) and low (-1 SD) number of books in the childhood home; however, individuals with more access to childhood books lived a greater proportion of this time without cognitive impairment. Discussion and Implications: Findings suggest that access to cognitive resources in childhood is protective for cognitive aging processes in older adulthood.

Exploring the potential impact of multi-factor precision interventions in Alzheimer's disease with system dynamics.

Numerous clinical trials based on a single-cause paradigm have not resulted in efficacious treatments for Alzheimer's disease (AD). Recently, prevention trials that simultaneously intervened on multiple risk factors have shown mixed results, suggesting that careful design is necessary. Moreover, intensive pilot precision medicine (PM) trial results have been promising but may not generalize to a broader population. These observations suggest that a model-based approach to multi-factor precision medicine (PM) is warranted. We systematically developed a system dynamics model (SDM) of AD for PM using data from two longitudinal studies (N=3660). This method involved a model selection procedure in identifying interaction terms between the SDM components and estimating individualized parameters. We used the SDM to explore simulated single- and double-factor interventions on 14 modifiable risk factors. We quantified the potential impact of double-factor interventions over single-factor interventions as 1.5 [95% CI: 1.5-2.6] and of SDM-based PM over a one-size-fits-all approach as 3.5 [3.1, 3.8] ADAS-cog-13 points in 12 years. Although the model remains to be validated, we tentatively conclude that multi-factor PM could come to play an important role in AD prevention.

Trajectories of Physical Function and Behavioral, Psychological, and Social Well-Being in a Cohort of Swedish Older Adults.

Background and Objectives: Successful aging has been described as a multifactorial and dynamic process. The aims of the study were to detect aging trajectories of physical function and behavioral, psychological, and social well-being; and to explore the correlations between functional versus well-being trajectories by age group. Research Design and Methods: Data were gathered from the Swedish National Study on Aging and Care in Kungsholmen (N = 1,375). Subjects' physical function was assessed through walking speed and chair-stand tests, behavioral well-being through participation in mental and physical activities, psychological well-being through life satisfaction and positive affect, and social well-being through social connections and support. All exposures were standardized (z-scores). Linear mixed models were used to estimate trajectories of physical function and well-being over a 12-year follow-up. Results: The steepest declines were seen for physical function (relative change [RC] in z-scores across ages; RC = 3.01), followed by behavioral well-being (RC = 2.15), psychological well-being (RC = 2.01), and social well-being (RC = 0.76). Correlations between physical function and the different well-being domains were weak, especially for slopes. Stronger intercept correlations were observed among the oldest-compared to the youngest-old, especially with behavioral (r = 0.39 vs r = 0.24) and psychological (r = 0.33 vs r = 0.22) well-being. Discussion and Implications: Physical function declines the fastest throughout aging. The different well-being domains decline at a slower rate, which may be a possible sign of compensation against age-related functional decline, especially among the youngest-old, for whom discordances between physical function and the different well-being domains were more common.

Determinants of quality of life in family caregivers in MCI: a comparison with mild dementia.

OBJECTIVES: The aim of the current study was to investigate the health-related quality of life (HRQol) of the family caregiver in MCI, explore possible determinants and study possible differences with mild dementia. METHODS: This secondary data analysis included 145 persons with MCI and 154 persons with dementia and their family caregivers from two Dutch cohort studies. HRQoL was measured with the VAS of the EuroQol-5D-3L version. Regressions analyses were conducted to examine potential demographic and clinical determinants of the caregiver's HRQoL. RESULTS: The mean EQ5D-VAS in family caregivers of persons with MCI was 81.1 (SD 15.7), and did not significantly differ from family caregivers in mild dementia (81.9 (SD 13.0)). In MCI, patient measurements were not significantly associated with caregiver mean EQ5D-VAS. Concerning caregiver characteristics, being a spouse and a lower educational level were associated with a lower mean EQ5D-VAS (in a multiple linear regression model: unstandardized B -8.075, p = 0.013 and unstandardized B -6.162, p = 0.037 resp.). In mild dementia, the NPI item irritability showed an association with caregiver EQ5D-VAS in bivariate linear regression analyses. CONCLUSION: Results indicate that especially family caregiver characteristics seem to influence family caregiver HRQoL in MCI. Future research should include other potential determinants such as burden, coping strategies and relationship quality.

DementiaNet facilitates a sustainable transition toward integrated primary dementia care: A long-term evaluation.

INTRODUCTION: Care integration is a promising strategy to achieve sustainable health-care systems. With DementiaNet, a 2-year program, we facilitated collaboration between primary health-care professionals. We studied changes in primary dementia care integration during and after DementiaNet participation. METHODS: A longitudinal follow-up study was performed. Networks started between 2015 and 2020; follow-up ended in 2021. Quantitative and quantitative data were collected annually to assess quality of care, network collaboration, and number of crisis admissions. Growth modeling was used to identify changes over time. RESULTS: Thirty-five primary care networks participated. Network collaboration and quality of care of newly formed networks increased significantly in the first 2 years (respectively, 0.35/year, P < .001; 0.29/year, P < .001) and thereafter stabilized. CONCLUSION: Primary care networks improved their collaboration and quality of care during DementiaNet participation, which persisted after the program ended. This indicates that DementiaNet facilitated a sustainable transition toward integrated primary dementia care.

Capturing postural blood pressure dynamics with near-infrared spectroscopy-measured cerebral oxygenation.

Orthostatic hypotension (OH) is highly prevalent in older adults and associated with dizziness, falls, lower physical and cognitive function, cardiovascular disease, and mortality. OH is currently diagnosed in a clinical setting with single-time point cuff measurements. Continuous blood pressure (BP) devices can measure OH dynamics but cannot be used for daily life monitoring. Near-infrared spectroscopy (NIRS) has potential diagnostic value in measuring cerebral oxygenation continuously over a longer time period, but this needs further validation. This study aimed to compare NIRS-measured (cerebral) oxygenation with continuous BP and transcranial Doppler-measured cerebral blood velocity (CBv) during postural changes. This cross-sectional study included 41 participants between 20 and 88 years old. BP, CBv, and cerebral (long channels) and superficial (short channels) oxygenated hemoglobin (O2Hb) were measured continuously during various postural changes. Pearson correlations between BP, CBv, and O2Hb were calculated over curves and specific characteristics (maximum drop amplitude and recovery). BP and O2Hb only showed good curve-based correlations (0.58-0.75) in the initial 30 s after standing up. Early (30-40 s) and 1-min BP recovery associated significantly with O2Hb, but no consistent associations were found for maximum drop amplitude and late (60-175 s) recovery values. Associations between CBv and O2Hb were poor, but stronger for long-channel than short-channel measurements. BP associated well with NIRS-measured O2Hb in the first 30 s after postural change. Stronger associations for CBv with long-channel O2Hb suggest that long-channel NIRS specifically reflects cerebral blood flow during postural transitions, necessary to better understand the consequences of OH such as intolerance symptoms.

Simulating the multicausality of Alzheimer's disease with system dynamics.

INTRODUCTION: In Alzheimer's disease (AD), cognitive decline is driven by various interlinking causal factors. Systems thinking could help elucidate this multicausality and identify opportune intervention targets. METHODS: We developed a system dynamics model (SDM) of sporadic AD with 33 factors and 148 causal links calibrated with empirical data from two studies. We tested the SDM's validity by ranking intervention outcomes on 15 modifiable risk factors to two sets of 44 and 9 validation statements based on meta-analyses of observational data and randomized controlled trials, respectively. RESULTS: The SDM answered 77% and 78% of the validation statements correctly. Sleep quality and depressive symptoms yielded the largest effects on cognitive decline with which they were connected through strong reinforcing feedback loops, including via phosphorylated tau burden. DISCUSSION: SDMs can be constructed and validated to simulate interventions and gain insight into the relative contribution of mechanistic pathways.

Improved Postoperative Outcomes after Prehabilitation for Colorectal Cancer Surgery in Older Patients: An Emulated Target Trial.

BACKGROUND: The aim of this study was to assess the effect of a multimodal prehabilitation program on perioperative outcomes in colorectal cancer patients with a higher postoperative complication risk, using an emulated target trial (ETT) design. PATIENTS AND METHODS: An ETT design including overlap weighting based on propensity score was performed. The study consisted of all patients with newly diagnosed colorectal cancer (2016-2021), in a large nonacademic training hospital, who were candidate to elective colorectal cancer surgery and had a higher risk for postoperative complications defined by: age ≥ 65 years and or American Society of Anesthesiologists score III/IV. Intention-to-treat (ITT) and per-protocol analyses were performed to evaluate the effect of prehabilitation compared with usual care on perioperative complications and length of stay (LOS). RESULTS: Two hundred fifty-one patients were included: 128 in the usual care group and 123 patients in the prehabilitation group. In the ITT analysis, the number needed to treat to reduce one or more complications in one person was 4.2 (95% CI 2.6-10). Compared with patients in the usual care group, patients undergoing prehabilitation had a 55% lower comprehensive complication score (95% CI -71 to -32%). There was a 33% reduction (95% CI -44 to -18%) in LOS from 7 to 5 days. CONCLUSIONS: This study showed a clinically relevant reduction of complications and LOS after multimodal prehabilitation in patients undergoing colorectal cancer surgery with a higher postoperative complication risk. The study methodology used may serve as an example for further larger multicenter comparative effectiveness research on prehabilitation.

What Do We Know about Social and Non-Social Factors Influencing the Pathway from Cognitive Health to Dementia? A Systematic Review of Reviews.

The heterogeneous and multi-factorial nature of dementia requires the consideration of all health aspects when predicting the risk of its development and planning strategies for its prevention. This systematic review of reviews provides a comprehensive synthesis of those factors associated with cognition in the context of dementia, identifying the role of social aspects and evidencing knowledge gaps in this area of research. Systematic reviews and meta-analyses from 2009-2021 were searched for within Medline, PsycINFO, CINAHL Complete, Cochrane, and Epistemonikos. Reviewers independently screened, reviewed, and assessed the records, following the PRISMA-2020 guidelines. From 314 included studies, 624 cognitive-related factors were identified, most of them risk factors (61.2%), mainly belonging to the group of 'somatic comorbidities' (cardiovascular disease and diabetes) and 'genetic predispositions'. The protective factors (20%) were mainly related to lifestyle, pointing to the Mediterranean diet, regular physical activity, and cognitively stimulating activities. Social factors constituted 9.6% of all identified factors. Research on biological and medical factors dominates the reviewed literature. Greater social support and frequent contact may confer some protection against cognitive decline and dementia by delaying its onset or reducing the overall risk; however, overall, our findings are inconsistent. Further research is needed in the fields of lifestyle, psychology, social health, and the protective factors against cognitive decline and dementia.

Sedentary behaviour and brain health in middle-aged and older adults: A systematic review.

Sedentary behaviour may increase the risk of dementia. Studying physiological effects of sedentary behaviour on cerebral health may provide new insights into the nature of this association. Accordingly, we reviewed if and how acute and habitual sedentary behaviour relate to brain health factors in middle-aged and older adults (≥45 years). Four databases were searched. Twenty-nine studies were included, with mainly cross-sectional designs. Nine studies examined neurotrophic factors and six studied functional brain measures, with the majority of these studies finding no associations with sedentary behaviour. The results from studies on sedentary behaviour and cerebrovascular measures were inconclusive. There was a tentative association between habitual sedentary behaviour and structural white matter health. An explanatory pathway for this effect might relate to the immediate vascular effects of sitting, such as elevation of blood pressure. Nevertheless, due to the foremost cross-sectional nature of the available evidence, reverse causality could also be a possible explanation. More prospective studies are needed to understand the potential of sedentary behaviour as a target for brain health.