An Improved Model for Disease Progression in Patients From the Alzheimer's Disease Neuroimaging Initiative

Johnson & Johnson Pharmaceutical Research & Development, Raritan, NJ, USA.
The Journal of Clinical Pharmacology (Impact Factor: 2.48). 06/2011; 52(5):629-44. DOI: 10.1177/0091270011405497
Source: PubMed


The objective of this analysis was to develop a semi-mechanistic nonlinear disease progression model using an expanded set of covariates that captures the longitudinal change of Alzheimer's Disease Assessment Scale (ADAS-cog) scores from the Alzheimer's Disease Neuroimaging Initiative study that consisted of 191 Alzheimer disease patients who were followed for 2 years. The model describes the rate of progression and baseline disease severity as a function of influential covariates. The covariates that were tested fell into 4 categories: (1) imaging volumetric measures, (2) serum biomarkers, (3) demographic and genetic factors, and (4) baseline cognitive tests. Covariates found to affect baseline disease status were years since disease onset, hippocampal volume, and ventricular volume. Disease progression rate in the model was influenced by age, total cholesterol, APOE ε4 genotype, Trail Making Test (part B) score, and current levels of impairment as measured by ADAS-cog. Rate of progression was slower for mild and severe Alzheimer patients compared with moderate Alzheimer patients who exhibited faster rates of deterioration. In conclusion, this model describes disease progression in Alzheimer patients using novel covariates that are important for understanding the worsening of ADAS-cog scores over time and may be useful in the future for optimizing study designs through clinical trial simulations.

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    • "Doody et al. [8] performed mixed effects regression modeling to predict longitudinal performance on standard clinical measures of AD. A sigmoidal model of the longitudinal changes in AD assessment cognitive sub-scale (ADAScog) was developed by Samtani et al. [9]. Yet, the main contributors in their predictive model were demographic factors and clinical assessment. "

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    • "In this analysis, we focused on mean placebo response, but it is also possible to evaluate such covariates with patient level data. Ito et al. [16], Rogers et al. [17], Samtani et al. [18], and Faltaos et al. [19] reported several other key covariates that affect the disease progression (such as age, gender, ApoE4 status). Future research will evaluate covariates which influence disease progression using all available data in CAMD database. "
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    ABSTRACT: Background: The placebo response and the underlying disease progression is difficult to differentiate in longitudinal Alzheimer's disease (AD) studies, yet it is crucial to understand for designing clinical trials and interpreting results. Objectives: The placebo response in ADAS-cog11 from various studies was evaluated against model predictions derived from historical placebo data to demonstrate potential interpretation of study results using a prior understanding of expected disease progression. Methods: The placebo response component from a previously published disease progression model was used to estimate the longitudinal placebo response, and the disease progression in the placebo group in various case studies were evaluated. In addition, placebo data from the Coalition Against Major Diseases (CAMD) database in mild to moderate AD patients is described. Results: The case studies demonstrated potential different results in disease progression in a placebo group, and the impact on understanding the magnitude of drug effect. Baseline cognitive function is an important covariate of disease progression, therefore, it is important to evaluate the baseline severity and predict disease progression accordingly when comparing trial results. Furthermore, study duration, sample size, and study design may affect the placebo response, all of which have the potential to confound understanding of study results. Conclusion: The recent failures in Phase III AD studies are not likely due to insufficient cognitive decline in the control groups. A meta-analytic approach using all available data provides a robust understanding of placebo effect, disease progression, and potential interpretation of treatment effects, and offers a useful tool to aid in both trial design and interpretation.
    Journal of Alzheimer's disease: JAD 06/2013; 37(1). DOI:10.3233/JAD-130575 · 4.15 Impact Factor
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    • "This relationship did not hold for females where there was no difference on any of the NPS variables for those with a total cholesterol above 200 (n = 88) and those females with lower cholesterol (n = 39). A recent study found that total cholesterol was the significant biomarker in a model predicting progression [47] "
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    ABSTRACT: Numerous serum and plasma based biomarkers of systemic inflammation have been linked to both neuropsychiatric disorders and Alzheimer's disease (AD). The present study investigated the relationship of clinical biomarkers of cardiovascular risk (cholesterol, triglycerides, and homocysteine) and a panel of markers of systemic inflammation (CRP, TNF-α, IL1-ra, IL-7, IL-10, IL-15, IL-18) and microvascular pathology (ICAM-1, VCAM-1) to neuropsychiatric symptoms in a sample with mild AD. Biomarker data was analyzed on a sample of 194 diagnosed with mild to moderate probable AD. The sample was composed of 127 females and 67 males. The presence of neuropsychiatric symptoms was gathered from interview with caretakers/family members using the Neuropsychiatric Inventory. For the total sample, IL-15, VCAM (vascular adhesion molecule), and triglycerides were significantly and negatively related to number of neuropsychiatric symptoms, and total cholesterol and homocysteine were positively related and as a group accounted for 16.1% of the variance. When stratified by gender, different patterns of significant biomarkers were found with relationships more robust for males for both total symptoms and symptom clusters. A combination of biomarkers of systemic inflammation, microvascular pathology, and clinical biomarkers of cardiovascular risk can account for a significant portion of the variance in the occurrence of neuropsychiatric symptoms in AD supporting a vascular and inflammatory component of psychiatric disorders found in AD. Gender differences suggest distinct impact of specific risks with total cholesterol, a measure of cardiovascular risk, being the strongest marker for males and IL-15, a marker of inflammation, being the strongest for females.
    Journal of Alzheimer's disease: JAD 02/2013; 35(2). DOI:10.3233/JAD-122359 · 4.15 Impact Factor
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