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2.  Modeling the course of Alzheimer's disease to improve clinical trials: symposium report 
In a symposium held at the Clinical Trials in Alzheimer's Disease conference in Monte Carlo, Monaco (29 to 31 October 2012) three different, not mutually exclusive approaches to improve and facilitate clinical trials with anti-dementia drugs were presented and discussed. All three approaches are summarized in this manuscript. Core suggestions are: stratification of trial participants at the outset of studies, using cognitive and disease-course characteristics available at baseline; creating new composite cognitive scores for optimizing responsiveness to decline in early and very early Alzheimer's disease; and replacing some of the conventional long-term placebo-controlled trials in advanced stages of drug development, using the placebo group simulation approach. Future efforts should focus on incorporating, where appropriate, the suggestions provided at the symposium into clinical trials now being planned.
doi:10.1186/alzrt183
PMCID: PMC3706927  PMID: 23767782
3.  Factors that influence survival in a probable Alzheimer disease cohort 
Introduction
This longitudinal study examined multiple factors that influence survival in a cohort of Alzheimer patients followed over two decades.
Methods
Time to death after symptom onset was determined in 641 probable AD patients who were evaluated annually until death or loss to follow-up, and information was entered into a longitudinal database. Date of death was available for everyone including those eventually lost. Baseline variables included age, sex, race, disease severity, a calculated index of rate of initial cognitive decline from symptom onset to cohort entry (pre-progression rate or PPR), years of education, and medical comorbidities (diabetes, hypertension, hyperlipidemia, coronary disease, cerebrovascular disease). Multivariable Cox proportional hazard regression analysis was used to analyze the baseline and/or time dependent association in Mini-mental Status Exam (MMSE) severity, Physical Self Maintenance Scale (PSMS), Persistency Index (PI) of exposure to antipsychotic and antidementia drugs, and psychotic symptoms (hallucinations, delusions) with mortality.
Results
Baseline covariates significantly associated with increased survival were younger age (p = .0016), female sex (p = .0001), and a slower PPR (p < .0001). Overall disease severity at baseline, medical comorbidities, and education did not influence time to death. Time-dependent changes in antipsychotic drug use, development of psychotic symptoms, antidementia drug use, and observed MMSE change were not predictive. In the final model the only time-dependent covariate that significantly decreased survival was worsening of functional ability on the PSMS (hazard ratio = 1.10; CI: 1.07-1.11).
Conclusions
In this large AD cohort survival is influenced by age, sex, and the development of functional disability during follow-up. The most important predictor of mortality was a faster rate of cognitive decline at the initial patient visit (PPR). The currently available antidementia drugs do not prolong survival in Alzheimer patients.
doi:10.1186/alzrt119
PMCID: PMC3506931  PMID: 22594761
5.  Progress in understanding variability in cognitive responses to cholinesterase inhibitor treatment 
Limitations on the duration of clinical trials, and the constraints of participant selection for such studies, have left many unanswered questions regarding the optimal duration of drug treatment for Alzheimer's disease patients, as well as the subgroups of patients that benefit most. Carefully designed observational studies in naturalistic settings can provide important supplementary information to aid clinical decision-making and patient counseling. A paper by Wattmo and colleagues published recently in Alzheimer's Research & Therapy has provided important new information on differential responses to cholinesterase inhibitor (ChEI) treatment in specific subgroups of patients over a 3-year follow-up period. All of the participants in their study were started on one of three ChEIs after their initial assessment, and periodic assessments of cognitive change and the dosage of ChEIs as well as concomitant medications were subsequently recorded. In addition to providing strong evidence of nondifferential effects on cognition of the three ChEIs as used in this practice, the study identified clinically significant differences in the responses of specific subgroups of patients to the initiation of ChEI treatment. Of particular interest to clinicians is the finding that older patients and those with worse cognitive functioning at baseline had a better treatment response. The notion that treatment may be futile in the oldest or the most impaired patients was thus not supported by Wattmo and colleagues' cohort. Additional well-designed naturalistic studies of this type are needed to advance our knowledge of the long-term outcomes obtained with different therapeutic agents, and of the covariates that significantly modify responses to Alzheimer's disease treatments.
doi:10.1186/alzrt92
PMCID: PMC3218807  PMID: 21999183
6.  Should EOAD patients be included in clinical trials? 
Alzheimer disease (AD) is a devastating neurodegenerative disease affecting 1 in 68 in the population. An arbitrary cutoff 65 years as the age of onset to distinguish between early- and late-onset AD has been proposed and has been used in the literature for decades. As the majority of patients develop AD after 65 years of age, most clinical trials address this population. While the early-onset cases represent only 1% to 6% of AD cases, this population is the active working subset and thus contributes to a higher public health burden per individual, and early-onset cases are the most devastating at the level of the individual and their families. In this review, we compare and contrast the clinical, neuropsychological, imaging, genetic, biomarker, and pathological features of these two arbitrary groups. Finally, we discuss the ethical dilemma of non-abandonment and justice as it pertains to exclusion of the early-onset AD patients from clinical trials.
doi:10.1186/alzrt63
PMCID: PMC3109413  PMID: 21345175
7.  Predicting progression of Alzheimer's disease 
Introduction
Clinicians need to predict prognosis of Alzheimer's disease (AD), and researchers need models of progression to develop biomarkers and clinical trials designs. We tested a calculated initial progression rate to see whether it predicted performance on cognition, function and behavior over time, and to see whether it predicted survival.
Methods
We used standardized approaches to assess baseline characteristics and to estimate disease duration, and calculated the initial (pre-progression) rate in 597 AD patients followed for up to 15 years. We designated slow, intermediate and rapidly progressing groups. Using mixed effects regression analysis, we examined the predictive value of a pre-progression group for longitudinal performance on standardized measures. We used Cox survival analysis to compare survival time by progression group.
Results
Patients in the slow and intermediate groups maintained better performance on the cognitive (ADAScog and VSAT), global (CDR-SB) and complex activities of daily living measures (IADL) (P values < 0.001 slow versus fast; P values < 0.003 to 0.03 intermediate versus fast). Interaction terms indicated that slopes of ADAScog and PSMS change for the slow group were smaller than for the fast group, and that rates of change on the ADAScog were also slower for the intermediate group, but that CDR-SB rates increased in this group relative to the fast group. Slow progressors survived longer than fast progressors (P = 0.024).
Conclusions
A simple, calculated progression rate at the initial visit gives reliable information regarding performance over time on cognition, global performance and activities of daily living. The slowest progression group also survives longer. This baseline measure should be considered in the design of long duration Alzheimer's disease clinical trials.
doi:10.1186/alzrt25
PMCID: PMC2874261  PMID: 20178566
8.  Persistent treatment with cholinesterase inhibitors and/or memantine slows clinical progression of Alzheimer disease 
Introduction
There are no empiric data to support guidelines for duration of therapy with antidementia drugs. This study examined whether persistent use of antidementia drugs slows clinical progression of Alzheimer disease (AD) assessed by repeated measures on serial tests of cognition and function.
Methods
Six hundred forty-one probable AD patients were followed prospectively at an academic center over 20 years. Cumulative drug exposure was expressed as a persistency index (PI) reflecting total years of drug use divided by total years of disease symptoms. Baseline and annual testing consisted of Mini-Mental State Examination (MMSE), Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), Baylor Profound Mental Status Examination (BPMSE), Clinical Dementia Rating-Sum of Boxes (CDR-SB), Physical Self-Maintenance Scale (PSMS), and Instrumental Activities of Daily Living (IADL). Annual change in slope of neuropsychological and functional tests as predicted by follow-up time, PI, and the interaction of these two variables was evaluated.
Results
PI was associated with significantly slower rates of decline (with, without adjustment for covariates) on MMSE (P < 0.0001), PSMS (P < 0.05), IADL (P < 0.0001), and CDR-SB (P < 0.001). There was an insignificant trend (P = 0.053) for the PI to be associated with slower rate of decline on BPMSE. The association of PI with ADAS-Cog followed a quadratic trend (P < 0.01). Analysis including both linear and quadratic terms suggests that PI slowed ADAS-Cog decline temporarily. The magnitude of the favorable effect of a rate change in PI was: MMSE 1 point per year, PSMS 0.4 points per year, IADL 1.4 points per year, and CDR-SB 0.6 points per year. The change in mean test scores is additive over the follow-up period (3 ± 1.94 years).
Conclusions
Persistent drug treatment had a positive impact on AD progression assessed by multiple cognitive, functional, and global outcome measures. The magnitude of the treatment effect was clinically significant. Positive treatment effects were even found in those with advanced disease.
doi:10.1186/alzrt7
PMCID: PMC2874259  PMID: 19845950

Results 1-8 (8)