Estimating sample sizes for predementia Alzheimer's trials based on the Alzheimer's Disease Neuroimaging Initiative
ABSTRACT This study modeled predementia Alzheimer's disease clinical trials. Longitudinal data from cognitively normal (CN) and mild cognitive impairment (MCI) participants in the Alzheimer's Disease Neuroimaging Initiative were used to calculate sample size requirements for trials using outcome measures, including the Clinical Dementia Rating scale sum of boxes, Mini-Mental State Examination, Alzheimer's Disease Assessment Scale-cognitive subscale with and without delayed recall, and the Rey Auditory Verbal Learning Task. We examined the impact on sample sizes of enrichment for genetic and biomarker criteria, including cerebrospinal fluid protein and neuroimaging analyses. We observed little cognitive decline in the CN population at 36 months, regardless of the enrichment strategy. Nonetheless, in CN subjects, using Rey Auditory Verbal Learning Task total as an outcome at 36 months required the fewest subjects across enrichment strategies, with apolipoprotein E genotype ε4 carrier status requiring the fewest (n = 499 per arm to demonstrate a 25% reduction in disease progression). In MCI, enrichment reduced the required sample sizes for trials, relative to estimates based on all subjects. For MCI, the Clinical Dementia Rating scale sum of boxes consistently required the smallest sample sizes. We conclude that predementia clinical trial conduct in Alzheimer's disease is enhanced by the use of biomarker inclusion criteria.
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ABSTRACT: Brain atrophy measured using structural MRI has been widely used as an imaging biomarker for disease diagnosis and tracking of pathological progression in neurodegenerative diseases. In this work, we present a generalised and extended formulation of the Boundary Shift Integral (gBSI) using probabilistic segmentations in order to estimate anatomical changes between 2 time points. This method adaptively estimates a non-binary XOR region-of-interest from probabilistic brain segmentations of the baseline and repeat scans, in order to better localise and capture the brain atrophy. We evaluate the proposed method by comparing the sample size requirements for a hypothetical clinical trial of Alzheimer’s disease to that needed for the current implementation of BSI as well as a fuzzy implementation of BSI. The gBSI method results in a modest, but reduced sample size, providing increased sensitivity to disease changes through the use of the probabilistic XOR region.Neurobiology of Aging 08/2014; 36. DOI:10.1016/j.neurobiolaging.2014.04.035 · 4.85 Impact Factor
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ABSTRACT: Introduction: Longitudinal assessment of cognitive decline in amnestic mild cognitive impairment (aMCI) and Alzheimer?s disease (AD) often involves the use of both informant-based and objective cognitive assessments. As efforts have focused on identifying individuals in pre-clinical stages, instruments that are sensitive to subtle cognitive changes are needed. The Alzheimer?s Questionnaire (AQ) has demonstrated high sensitivity and specificity in identifying aMCI and AD; however its ability to measure longitudinal change has not been assessed. The aims of this study are to assess the sensitivity to change of the AQ and to determine whether the AQ predicts change in global cognition and function in cognitively normal (CN), aMCI, and AD subjects. Methods: Data from 202 individuals participating in a brain and body donation program were utilized for this study (101 CN, 62 aMCI, 39?AD). AD and aMCI individuals were matched on age, education, and gender to CN individuals. Sensitivity to change of the AQ was assessed in addition to the AQ?s ability to predict change in global cognition and function. The Mini Mental State Exam (MMSE) and Functional Activities Questionnaire (FAQ) were used as gold standard comparisons of cognition and function. Sample size calculations for a 25% treatment effect were also carried out for all three groups. Results: The AQ demonstrated small sensitivity to change in the aMCI and CN groups (d=0.33, d=0.23, respectively) and moderate sensitivity to change in the AD group (d=0.43). The AQ was associated with increases in the Clinical Dementia Rating Global Score (OR=1.20 (1.09, 1.32), P <0.001). Sample size calculations found that the AQ would require substantially fewer subjects than the MMSE given a 25% treatment effect. Conclusions: Although the AQ demonstrated small sensitivity to change in aMCI and CN individuals in terms of effect size, the AQ may be superior to objective cognitive tests in terms of required sample size for a clinical trial. As clinicians and researchers continue to identify and treat individuals in earlier stages of AD, there is a need for instruments that are sensitive to cognitive changes in these earlier stages.Alzheimer's Research and Therapy 01/2015; 7(1). DOI:10.1186/s13195-014-0092-z · 3.50 Impact Factor
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ABSTRACT: Background Non-pharmacological interventions may improve cognition and quality of life, reduce disruptive behaviors, slow progression from Mild Cognitive Impairment (MCI) to dementia, and delay institutionalization. It is important to look at their trial designs as well as outcomes to understand the state of the evidence supporting non-pharmacological interventions in Alzheimer’s disease (AD). An analysis of trial design strengths and limitations may help researchers clarify treatment effect and design future studies of non-pharmacological interventions for MCI related to AD. Methods A systematic review of the methodology of Randomized Controlled Trials (RCTs) targeting physical activity, cognitive interventions, and socialization among subjects with MCI in AD reported until March 2014 was undertaken. The primary outcome was CONSORT 2010 reporting quality. Secondary outcomes were qualitative assessments of specific methodology problems. Results 23 RCT studies met criteria for this review. Eight focused on physical activity, fourteen on cognitive interventions, and one on the effects of socialization. Most studies found a benefit with the intervention compared to control. CONSORT reporting quality of physical activity interventions was higher than that of cognitive interventions. Reporting quality of recent studies was higher than older studies, particularly with respect to sample size, control characteristics, and methodology of intervention training and delivery. However, the heterogeneity of subjects identified as having MCI and variability in interventions and outcomes continued to limit generalizability. Conclusions The role for non-pharmacological interventions targeting MCI is promising. Future studies of RCTs for non-pharmacological interventions targeting MCI related to AD may benefit by addressing design limitations.The Journal of Nutrition Health and Aging 02/2014; 19(2). DOI:10.1007/s12603-014-0565-6 · 2.66 Impact Factor