Twelve-month metabolic declines in probable Alzheimer's disease and amnestic mild cognitive impairment assessed using an empirically pre-defined statistical region-of-interest: findings from the Alzheimer's Disease Neuroimaging Initiative

Abstract

Alzheimer's disease (AD) is characterized by specific and progressive reductions in fluorodeoxyglucose positron emission tomography (FDG PET) measurements of the cerebral metabolic rate for glucose (CMRgl), some of which may precede the onset of symptoms. In this report, we describe twelve-month CMRgl declines in 69 probable AD patients, 154 amnestic mild cognitive impairment (MCI) patients, and 79 cognitively normal controls (NCs) from the AD Neuroimaging Initiative (ADNI) using statistical parametric mapping (SPM). We introduce the use of an empirically pre-defined statistical region-of-interest (sROI) to characterize CMRgl declines with optimal power and freedom from multiple comparisons, and we estimate the number of patients needed to characterize AD-slowing treatment effects in multi-center randomized clinical trials (RCTs). The AD and MCI groups each had significant twelve-month CMRgl declines bilaterally in posterior cingulate, medial and lateral parietal, medial and lateral temporal, frontal and occipital cortex, which were significantly greater than those in the NC group and correlated with measures of clinical decline. Using sROIs defined based on training sets of baseline and follow-up images to assess CMRgl declines in independent test sets from each patient group, we estimate the need for 66 AD patients or 217 MCI patients per treatment group to detect a 25% AD-slowing treatment effect in a twelve-month, multi-center RCT with 80% power and two-tailed alpha=0.05, roughly one-tenth the number of the patients needed to study MCI patients using clinical endpoints. Our findings support the use of FDG PET, brain-mapping algorithms and empirically pre-defined sROIs in RCTs of AD-slowing treatments.

Figure 1

Statistical brain maps of significant twelve-month CMRgl declines in A) probable AD patients and B) MCI patients (p<0.005, uncorrected for multiple comparisons). The brain maps were generated using baseline and follow-up images acquired in all of the subjects in each patient group (except for those studied on the HRRT and HiRez scanners) and smoothing to a spatial resolution of 12mm FWHM). Findings are projected onto the lateral and medial surfaces of the left and right cerebral hemispheres and are also shown on horizontal sections at the specified distances above or below a horizontal section between the anterior and posterior commissures; the right side of each section corresponds to the right hemisphere.

Figure 2

Statistical brain maps of the spared sROI (in the blue color scale) and twelve-month CMRgl decline sROI (in the red-to-yellow color scale) in A) probable AD patients and B) MCI patient groups. The brain maps were generated using baseline and follow-up images acquired in the each patient group's training set (except for those studied on the HRRT and HiRez scanners) using images with a spatial resolution of 8 mm FWHM. The spared and decline sROIs in each group were subsequently used to estimate the number of patients needed to test AD-slowing treatments in the independent test set, shown in Tables 3 and 4.

Figure 3

Magnitude and standard deviation of twelve-month CMRgl-to-spared sROI decline in the probable AD, MCI, and NC groups using A) the probable AD sROI and B) the MCI sROI. The ROIs were empirically predefined using the relevant patient group's data set and the magnitude of twelve-month decline-to-spared CMRgl decline in these sROIs were characterized in the independent test dataset from the same patient group. In each comparison, the twelve-month decline-to-spared CMRgl declines were significantly different in the three subject groups (AD>MCI>NC).