The Alzheimer research community is actively pursuing novel biomarker and other biologic measures to characterize disease progression or to use as outcome measures in clinical trials. One product of these efforts has been a large literature reporting power calculations and estimates of sample size for planning future clinical trials and cohort studies with longitudinal rate of change outcome measures. Sample size estimates reported in this literature vary greatly depending on a variety of factors, including the statistical methods and model assumptions used in their calculation. We review this literature and suggest standards for reporting power calculation results. Regardless of the statistical methods used, studies consistently find that volumetric neuroimaging measures of regions of interest, such as hippocampal volume, outperform global cognitive scales traditionally used in clinical treatment trials in terms of the number of subjects required to detect a fixed percentage slowing of the rate of change observed in demented and cognitively impaired populations. However, statistical methods, model assumptions, and parameter estimates used in power calculations are often not reported in sufficient detail to be of maximum utility. We review the factors that influence sample size estimates, and discuss outstanding issues relevant to planning longitudinal studies of Alzheimer's disease.
"Both these factors likely resulted in somewhat lower atrophy rates. Nevertheless, the resulting sample size estimates for hippocampal atrophy were in the same order of magnitude , i.e., several hundred per arm, as those found in ADNI . As an aside, the absolute values of these estimates are only indicative. "
[Show abstract][Hide abstract] ABSTRACT: Scales of global cognition and behavior, often used as endpoints for intervention trials in Alzheimer's disease (AD) and mild cognitive impairment (MCI), are insufficiently responsive (i.e., relatively insensitive to change). Large patient samples are needed to detect beneficial drug effects. Therefore, magnetic resonance imaging (MRI) measures of cerebral atrophy have been proposed as surrogate endpoints.
To examine how neuropsychological assessment compares to MRI in this respect.
We measured hippocampal atrophy, cortical thickness, and performance on neuropsychological tests in memory clinic patients at baseline and after two years. Neurologists rated the patients as cognitively normal (n = 28; Clinical Dementia Rating, CDR = 0) or as impaired (n = 34; CDR > 0). We administered five tests of memory, executive functioning, and verbal fluency. A composite neuropsychological score was calculated by taking the mean of the demographically corrected standard scores. MRI was done on a 3 Tesla scanner. Volumetric measurements of the hippocampus and surrounding cortex were made automatically using FreeSurfer software.
The composite neuropsychological score deteriorated 0.6 SD in the impaired group, and was virtually unchanged in the normal group. Annual hippocampal atrophy rates were 3.4% and 0.6% in the impaired and normal cognition groups, respectively. Estimates of required sample sizes to detect a 50% reduction in rate of change were larger using rate of hippocampal atrophy (n = 131) or cortical thickness (n = 488) as outcome compared to change scores on neuropsychological assessment (n = 62).
Neuropsychological assessment is more responsive than MRI measures of brain atrophy for detecting disease progression in memory clinic patients with MCI or AD.
[Show abstract][Hide abstract] 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.
Neurobiology of aging 04/2012; 34(1). DOI:10.1016/j.neurobiolaging.2012.03.006 · 5.01 Impact Factor
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