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.

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.

Cerebral blood flow in sleep: A systematic review and meta-analysis.

Sleep plays an essential role in physiology, allowing the brain and body to restore itself. Despite its critical role, our understanding of the underlying processes in the sleeping human brain is still limited. Sleep comprises several distinct stages with varying depths and temporal compositions. Cerebral blood flow (CBF), which delivers essential nutrients and oxygen to the brain, varies across brain regions throughout these sleep stages, reflecting changes in neuronal function and regulation. This systematic review and meta-analysis assesses global and regional CBF across sleep stages. We included, appraised, and summarized all 38 published sleep studies on CBF in healthy humans that were not or only slightly (<24 h) sleep deprived. Our main findings are that CBF varies with sleep stage and depth, being generally lowest in NREM sleep and highest in REM sleep. These changes appear to stem from sleep stage-specific regional brain activities that serve particular functions, such as alterations in consciousness and emotional processing.

Mapping complex public health problems with causal loop diagrams.

This paper presents causal loop diagrams (CLDs) as tools for studying complex public health problems like health inequality. These problems often involve feedback loops-a characteristic of complex systems not fully integrated into mainstream epidemiology. CLDs are conceptual models that visualize connections between system variables. They are commonly developed through literature reviews or participatory methods with stakeholder groups. These diagrams often uncover feedback loops among variables across scales (e.g. biological, psychological and social), facilitating cross-disciplinary insights. We illustrate their use through a case example involving the feedback loop between sleep problems and depressive symptoms. We outline a typical step-by-step process for developing CLDs in epidemiology. These steps are defining a specific problem, identifying the key system variables involved, mapping these variables and analysing the CLD to find new insights and possible intervention targets. Throughout this process, we suggest triangulating between diverse sources of evidence, including domain knowledge, scientific literature and empirical data. CLDs can also be evaluated to guide policy changes and future research by revealing knowledge gaps. Finally, CLDs may be iteratively refined as new evidence emerges. We advocate for more widespread use of complex systems tools, like CLDs, in epidemiology to better understand and address complex public health problems.

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.

A multiscale hybrid model for exploring the effect of Resolvin D1 on macrophage polarization during acute inflammation.

Dysregulated inflammation underlies various diseases. Specialized pro-resolving mediators (SPMs) like Resolvin D1 (RvD1) have been shown to resolve inflammation and halt disease progression. Macrophages, key immune cells that drive inflammation, respond to the presence of RvD1 by polarizing to an anti-inflammatory type (M2). However, RvD1's mechanisms, roles, and utility are not fully understood. This paper introduces a gene-regulatory network (GRN) model that contains pathways for RvD1 and other SPMs and proinflammatory molecules like lipopolysaccharides. We couple this GRN model to a partial differential equation-agent-based hybrid model using a multiscale framework to simulate an acute inflammatory response with and without the presence of RvD1. We calibrate and validate the model using experimental data from two animal models. The model reproduces the dynamics of key immune components and the effects of RvD1 during acute inflammation. Our results suggest RvD1 can drive macrophage polarization through the G protein-coupled receptor 32 (GRP32) pathway. The presence of RvD1 leads to an earlier and increased M2 polarization, reduced neutrophil recruitment, and faster apoptotic neutrophil clearance. These results support a body of literature that suggests that RvD1 is a promising candidate for promoting the resolution of acute inflammation. We conclude that once calibrated and validated on human data, the model can identify critical sources of uncertainty, which could be further elucidated in biological experiments and assessed for clinical use.

Applying systems thinking to unravel the mechanisms underlying orthostatic hypotension related fall risk.

Orthostatic hypotension (OH) is an established and common cardiovascular risk factor for falls. An in-depth understanding of the various interacting pathophysiological pathways contributing to OH-related falls is essential to guide improvements in diagnostic and treatment opportunities. We applied systems thinking to multidisciplinary map out causal mechanisms and risk factors. For this, we used group model building (GMB) to develop a causal loop diagram (CLD). The GMB was based on the input of experts from multiple domains related to OH and falls and all proposed mechanisms were supported by scientific literature. Our CLD is a conceptual representation of factors involved in OH-related falls, and their interrelatedness. Network analysis and feedback loops were applied to analyze and interpret the CLD, and quantitatively summarize the function and relative importance of the variables. Our CLD contains 50 variables distributed over three intrinsic domains (cerebral, cardiovascular, and musculoskeletal), and an extrinsic domain (e.g., medications). Between the variables, 181 connections and 65 feedback loops were identified. Decreased cerebral blood flow, low blood pressure, impaired baroreflex activity, and physical inactivity were identified as key factors involved in OH-related falls, based on their high centralities. Our CLD reflects the multifactorial pathophysiology of OH-related falls. It enables us to identify key elements, suggesting their potential for new diagnostic and treatment approaches in fall prevention. The interactive online CLD renders it suitable for both research and educational purposes and this CLD is the first step in the development of a computational model for simulating the effects of risk factors on falls.

Refining the causal loop diagram: A tutorial for maximizing the contribution of domain expertise in computational system dynamics modeling.

Complexity science and systems thinking are increasingly recognized as relevant paradigms for studying systems where biology, psychology, and socioenvironmental factors interact. The application of systems thinking, however, often stops at developing a conceptual model that visualizes the mapping of causal links within a system, e.g., a causal loop diagram (CLD). While this is an important contribution in itself, it is imperative to subsequently formulate a computable version of a CLD in order to interpret the dynamics of the modeled system and simulate "what if" scenarios. We propose to realize this by deriving knowledge from experts' mental models in biopsychosocial domains. This article first describes the steps required for capturing expert knowledge in a CLD such that it may result in a computational system dynamics model (SDM). For this purpose, we introduce several annotations to the CLD that facilitate this intended conversion. This annotated CLD (aCLD) includes sources of evidence, intermediary variables, functional forms of causal links, and the distinction between uncertain and known-to-be-absent causal links. We propose an algorithm for developing an aCLD that includes these annotations. We then describe how to formulate an SDM based on the aCLD. The described steps for this conversion help identify, quantify, and potentially reduce sources of uncertainty and obtain confidence in the results of the SDM's simulations. We utilize a running example that illustrates each step of this conversion process. The systematic approach described in this article facilitates and advances the application of computational science methods to biopsychosocial systems. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

A Global Sharing Mechanism of Resources: Modeling a Crucial Step in the Fight against Pandemics.

To face crises like the COVID-19 pandemic, resources such as personal protection equipment (PPE) are needed to reduce the infection rate and protect those in close contact with patients. The increasing demand for those products can, together with pandemic-related disruptions in the global supply chain, induce major local resource scarcities. During the first phase of the COVID-19 pandemic, we witnessed a reflex of 'our people first' in many regions. In this paper, however, we show that a cooperative sharing mechanism can substantially improve the ability to face epidemics. We present a stylized model in which communities share their resources such that each can receive them whenever a local epidemic flares up. Our main finding is that cooperative sharing can prevent local resource exhaustion and reduce the total number of infected cases. Crucially, beneficial effects of sharing are found for a large range of possible community sizes and cooperation combinations, not only for small communities being helped by large communities. Furthermore, we show that the success of sharing resources heavily depends on having a sufficiently long delay between the onsets of epidemics in different communities. These results thus urge for the pairing of a global sharing mechanism with measures to slow down the spread of infections from one community to the other. Our work uses a stylized model to convey an important and clear message to a broad public, advocating that cooperative sharing strategies in international resource crises are the most beneficial strategy for all. It stresses essential underlying principles of and contributes to designing a resilient global supply chain mechanism able to deal with future pandemics by design, rather than being subjected to the coincidental and unequal distribution of opportunities per community that we see at present.

Population Attributable Fractions for Modifiable Risk Factors of Incident Dementia in Cognitively Normal and Mild Cognitively Impaired Older Adults: Data from Two Cohort Studies.

BACKGROUND: Recent global meta-analyses show that 40% of dementia cases can be attributed to twelve modifiable risk factors. OBJECTIVE: To investigate how health promotion strategies may differ in specific populations, this study estimated population attributable fractions (PAFs) of these risk factors for dementia in cognitively normal (CN) individuals and individuals with mild cognitive impairment (MCI) in United States and Greek cohorts. METHODS: We re-analyzed data from the National Alzheimer's Coordinating Centre (NACC, n = 16,147, mean age 75.2±6.9 years, 59.0% female) and the Hellenic Longitudinal Investigation of Aging and Diet (HELIAD, n = 1,141, mean age 72.9±5.0 years, 58.0% female). PAFs for the total samples and CN and MCI subgroups were calculated based on hazard ratios for the risk of dementia and risk factor prevalence in NACC (9 risk factors) and HELIAD (10 risk factors). RESULTS: In NACC, 2,630 participants developed MCI (25.1%) and 3,333 developed dementia (20.7%) during a mean follow-up of 4.9±3.5 years. Weighted overall PAFs were 19.4% in the total sample, 15.9% in the CN subgroup, and 3.3% in the MCI subgroup. In HELIAD, 131 participants developed MCI (11.2%) and 68 developed dementia (5.9%) during an average follow-up of 3.1±0.86 years. Weighted overall PAFs were 65.5% in the total sample, 65.8% in the CN subgroup and 64.6% in the MCI subgroup. CONCLUSION: Translation of global meta-analysis data on modifiable risk factors should be carefully carried out per population. The PAFs of risk factors differ substantially across populations, directing health policy making to tailored risk factor modification plans.

Mapping the multicausality of Alzheimer's disease through group model building.

Alzheimer's disease (AD) is a complex, multicausal disorder involving several spatiotemporal scales and scientific domains. While many studies focus on specific parts of this system, the complexity of AD is rarely studied as a whole. In this work, we apply systems thinking to map out known causal mechanisms and risk factors ranging from intracellular to psychosocial scales in sporadic AD. We report on the first systemic causal loop diagram (CLD) for AD, which is the result of an interdisciplinary group model building (GMB) process. The GMB was based on the input of experts from multiple domains and all proposed mechanisms were supported by scientific literature. The CLD elucidates interaction and feedback mechanisms that contribute to cognitive decline from midlife onward as described by the experts. As an immediate outcome, we observed several non-trivial reinforcing feedback loops involving factors at multiple spatial scales, which are rarely considered within the same theoretical framework. We also observed high centrality for modifiable risk factors such as social relationships and physical activity, which suggests they may be promising leverage points for interventions. This illustrates how a CLD from an interdisciplinary GMB process may lead to novel insights into complex disorders. Furthermore, the CLD is the first step in the development of a computational model for simulating the effects of risk factors on AD.