Evaluating Disease-Modifying Agents: A Simulation Framework for Alzheimer’s Disease

Guo, Shien; Getsios, Denis; Revankar, Nikhil; Xu, Peng; Thompson, G.; Bobula, Joel; Lacey, Loretto; Gaudig, Maren

doi:10.1007/s40273-014-0203-5

Cited by 20 publications

(33 citation statements)

References 29 publications

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“…In this ailment, there is an impairment of the cerebral cortex with complex processes; involving the production of senile plaques, neurofibrillary tangles, synapse loss and neuroinflammation; leading to the progressive cognitive decline and memory loss [ 2 , 3 ]. At the present time, about 50 millions of people worldwide suffer from the disease, which creates a heavy burden on the health care systems of many countries [ 4 , 5 , 6 ]. Therefore, discovery of novel drugs for AD is an urgent task.…”

Section: Introductionmentioning

confidence: 99%

Synthesis, In Silico and In Vitro Evaluation of Some Flavone Derivatives for Acetylcholinesterase and BACE-1 Inhibitory Activity

Tran

et al. 2020

Molecules

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Acetylcholinesterase (AChE) and β-secretase (BACE-1) have become attractive therapeutic targets for Alzheimer’s disease (AD). Flavones are flavonoid derivatives with various bioactive effects, including AChE and BACE-1 inhibition. In the present work, a series of 14 flavone derivatives was synthesized in relatively high yields (35–85%). Six of the synthetic flavones (B4, B5, B6, B8, D6 and D7) had completely new structures. The AChE and BACE-1 inhibitory activities were tested, giving pIC50 3.47–4.59 (AChE) and 4.15–5.80 (BACE-1). Three compounds (B3, D5 and D6) exhibited the highest biological effects on both AChE and BACE-1. A molecular docking investigation was conducted to explain the experimental results. These molecules could be employed for further studies to discover new structures with dual action on both AChE and BACE-1 that could serve as novel therapies for AD.

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Section: Introductionmentioning

confidence: 99%

Synthesis, In Silico and In Vitro Evaluation of Some Flavone Derivatives for Acetylcholinesterase and BACE-1 Inhibitory Activity

Tran

et al. 2020

Molecules

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“…2014 Weibull shape: 1.85 Weibull scale: 4.60 + 0.11 BsAge – 0.0009 BsAge 2 + 0.33 Female + 0.023 BsMMSE Institutionalization Guo et al. 2014 In institutional care by MMSE (%) Mild (25–30) 0.0 Mild-moderate (20–24) 0.0 Moderate (15–19) 3.2 Moderate-severe (10–14) 17.1 Severe (0–9) 39.3 Disease severity MMSE thresholds [18] CDR-SB thresholds [19] ADAS-Cog13 thresholds [20] CN 29–30 0–0.5 0–4 SMC 28–29 0.5–1 4–7 EMCI 26–28 1–2.5 7–12 LMCI 25–26 2.5–4.5 12–15 Mild AD 23–25 4.5–7 15–21 Mild-moderate AD 20–23 7–9.5 21–28 Moderate AD 15–20 9.5–13 28–43 Moderate-severe AD 10–15 13–16 43–56 Severe AD 0–10 16–18 56–85 Utilities Patients [17] 0.99-0.041 DS Caregiver …”

Section: Methodsmentioning

confidence: 99%

“…In the alternative approach, results derived from the Dependence in AD in England study are used to assign a probability of institutionalization to each patient based on disease severity level [17] . The user should take into account the differences in the structure of long-term care systems when picking between different approaches.…”

Section: Methodsmentioning

confidence: 99%

Alzheimer's disease Archimedes condition‐event simulator: Development and validation

Kansal

Tafazzoli

Ishak³

et al. 2018

A&D Transl Res & Clin Interv

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IntroductionSeveral advances have been made in Alzheimer's Disease (AD) modeling, however, there remains a need for a simulator that represents the full scope of disease progression and can be used to study new disease-modifying treatments for early-stage and even prodromal AD.MethodsWe developed AD Archimedes condition-event simulator, a patient-level simulator with a focus on simulating the effects of early interventions through changes in biomarkers of AD. The simulator incorporates interconnected predictive equations derived from longitudinal data sets.ResultsThe results of external validations on AD Archimedes condition-event simulator showed that it provides reasonable estimates once compared to literature results on transition to dementia AD, institutionalization, and mortality. A case study comparing a disease-modifying treatment and a symptomatic treatment also showcases the benefits of early treatment.DiscussionThe AD Archimedes condition-event simulator is designed to perform economic evaluation on various interventions through close tracking of disease progression and the related clinical outcomes.

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“…Instead, it is likely that mortality will need to be modelled based on patient characteristics and their expected disease progression. Available models have clearly shown that differences in assumptions can have a significant effect on results [43][44][45] and the nuances of modelling mortality alongside AD progression.…”

Section: Uncertain Mortality Effects Of Treatment May Have Large Effementioning

confidence: 99%

Current issues and future research priorities for health economic modelling across the full continuum of Alzheimer's disease

Gustavsson

Green

Jones

et al. 2017

Alzheimer's & Dementia

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Available data and models for the health-economic evaluation of treatment in Alzheimer's disease (AD) have limitations causing uncertainty to decision makers. Forthcoming treatment strategies in preclinical or early AD warrant an update on the challenges associated with their economic evaluation. The perspectives of the co-authors were complemented with a targeted review of literature discussing methodological issues and data gaps in AD health-economic modelling. The methods and data available to translate treatment efficacy in early disease into long-term outcomes of relevance to policy makers and payers are limited. Current long-term large-scale data accurately representing the continuous, multifaceted, and heterogeneous disease process are missing. The potential effect of disease-modifying treatment on key long-term outcomes such as institutionalization and death is uncertain but may have great effect on cost-effectiveness. Future research should give priority to collaborative efforts to access better data on the natural progression of AD and its association with key long-term outcomes.

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Evaluating Disease-Modifying Agents: A Simulation Framework for Alzheimer’s Disease

Cited by 20 publications

References 29 publications

Synthesis, In Silico and In Vitro Evaluation of Some Flavone Derivatives for Acetylcholinesterase and BACE-1 Inhibitory Activity

Synthesis, In Silico and In Vitro Evaluation of Some Flavone Derivatives for Acetylcholinesterase and BACE-1 Inhibitory Activity

Alzheimer's disease Archimedes condition‐event simulator: Development and validation

Current issues and future research priorities for health economic modelling across the full continuum of Alzheimer's disease

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