TY - JOUR T1 - <strong>Strength of the Cerebral Metabolic Posterior Default Mod Network in Amnestic Mild Cognitive Impairment in Heterozygotes and Homozygotes for the Largest Identified Genetic Risk Factor for Late Onset Alzheimer's Disease</strong> JF - Journal of Nuclear Medicine JO - J Nucl Med SP - 1660 LP - 1660 VL - 59 IS - supplement 1 AU - Mrinaalika Sivakumar AU - April Alcantara AU - Daniel Silverman Y1 - 2018/05/01 UR - http://jnm.snmjournals.org/content/59/supplement_1/1660.abstract N2 - 1660Objectives: The default connectivity of the human brain - as defined by component analyses of FDG-PET brain scans to identify regions having magnitudes of high activity within subject correlations during relative cognitive rest - has attracted recent interest for its potential clinical value as a biomarker of neurological deterioration in the course of neurodegenerative conditions such as Alzheimer’s disease (AD). A separate line of recent investigation has demonstrated that people bearing the largest genetic risk factor for late onset AD, the apoliprotein E epsilon 4 allele (ApoE4), possess metabolic alterations in posterior cortical regions that can precede diagnosis of Alzheimer’s disease by many years or even decades. In the present analysis, we compared groups of subjects who were homozygote versus heterozygote carriers of ApoE4 (ApoE4-positive) with respect to the strength of the metabolic connectivity of the posterior components of their resting metabolic networks. Methods A total of 200 FDG-PET scans, acquired from ApoE4-positive amnestic Mild Cognitive Impairement (MCI) subjects (n=100) who participated in the Alzheimer's Disease Neuroimaging Initiative (ADNI) were drawn from their baseline and 2-year longitudinal follow-up visits. Five standardized volumes of interest (sVOI's) were applied to each scan to sample activity in each subject's pons, left and right posterior cingulate cortex (PCC), and left and right parietotemporal cortex (PTC) in the vicinity of Brodmann areas 39 and 40. After normalizing all subjects' PCC and PTC derived sVOI's to their own pontine metabolism, activities derived from left and right PCC and PTCs were averaged to yield measurements that were then utilized in analyses of regional cerebral metabolism. Each subject was also characterized by clinical and laboratory data including age (av. 72.4), education (av. 16.4 yrs), cognitive status (av. MMSE = 27.2), and whether their genotypes were heterozygous (ApoE 3-4) or homozygous (ApoE 4-4) for ApoE4 carriage. Results The 100 subjects were drawn from the homozygote (n=46) and heterozygote (n=54) subpopulations. ApoE 4-4 and ApoE3-4 groups did not differ significantly in years of education (16.22 ±2.8, 16.62 ±2.4 mean ±SD, respectively), baseline MMSE scores (26.9 ±2.4, 27.41 ±2.5), baseline PCC metabolism (3.46 ±0.345, 3.47 ±.192) or baseline PTC metabolism (3.11 ±0.348, 3.13 ±0.228). The homozygote group was younger (70.0 ±6.1, 74.7 ±5.4). Between the baseline and two-year follow up scan, 36 (78%) of ApoE 4-4 subjects and 43 (80%) of ApoE3-4 subjects demonstrated unilateral decline in either the PCC or PTC cortical regions, and in the majority of those brains (54% and 56%, respectively), metabolic decline occurred in both PCC and PTC. Connectivity analyses of these posterior regions at baseline revealed a very high level of inter-correlation (r= 0.82), and this was observed to be similar for both genotype subgroups (r= 0.75, r =0.73), as was the mean relative ratios of activity between the two regions (PCC 15.8% greater than PTC metabolism). These relationships also persisted in stratified analyses adjusting for subjects’ ages and MMSE scores. Conclusions While gene dosage studies have repeatedly demonstrated that homozygosity for ApoE4 confers increased risk relative to heterozygosity for developing AD, regions comprising the posterior metabolic network previously shown to exhibit decline highly sensitive to the earliest stages of AD behaved qualitatively and quantitatively nearly identically in both subgroups of subjects with amnestic MCI. This was true for all respects tested, including the strength of their connectivity assessed by intercorrelated magnitudes of activity and the likelihood of undergoing separate or coordinated metabolic decline over the subsequent two years. ER -