Nonlinear and Non-Monotonic Relationship between Default Mode Network Connectivity and Hippocampal Volumes across the ADNI Cohort Cross-Sectionally and Longitudinally (P06.025)

OBJECTIVE: Investigate connectivity in Alzheimer9s Disease Neuroimaging Initiative (ADNI). BACKGROUND: The human brain forms a complex network to exchange information that is dependent on multiple scales spanning the genetic/molecular to the systems/behavioral level. Alzheimer9s disease (AD) disrupts this highly interdependent, multi-scale organization. This AD-related disruption has been investigated at the systems level using task-free fMRI (TF-fMRI), demonstrating increased connectivity in frontal networks (i.e. aDMN) and decreased connectivity in parietal networks (i.e. pDMN). However, these findings are not universally reproducible in TF-fMRI studies that use group-wise comparisons to detect changes in connectivity (i.e. control vs. MCI vs. AD). Therefore, we used TF-fMRI data from ADNI to investigate the relationship between connectivity and a continuous measure of the structural integrity of the brain9s complex network (hippocampal volumes) across all diagnostic categories. DESIGN/METHODS: All ADNI subjects with adequate quality TF-fMRI and structural MRI were included in the analysis. Standard preprocessing of data was performed. Coherence based regional homogeneity values were extracted from the aDMN and pDMN. Given the inverse relationship of the aDMN and pDMN these were converted to aDMN/pDMN ratios and modeled against normalized hippocampal volumes using natural splines and localized regression. RESULTS: The natural spline fit of baseline data excluding extreme atrophy was significant (F=2.79, p = 0.0294), non-monotonic and nonlinear. Longitudinal data followed the trajectory predicted by the fit of baseline cross-sectional data. Localized regression of the entire cohort followed the same trajectory. CONCLUSIONS: This nonlinear relationship between DMN connectivity and hippocampal volume has significant implications for the design of studies to investigate the impact of AD on the systems level organization of the brain. Traditional comparison between diagnostic categories will have highly variable results depending on the composition of the cohorts selected, which may explain conflicting reports in the literature pertaining to the magnitude and direction of connectivity changes in the aDMN and pDMN. Disclosure: Dr. Jones has nothing to disclose. Dr. Murphy has nothing to disclose. Dr. Gunter has nothing to disclose. Dr. Vemuri has nothing to disclose. Dr. Wiste has nothing to disclose. Dr. Gregg has nothing to disclose. Dr. Boeve has received research support from Cephalon, Inc.; Allon Therapeutics; and GE Healthcare. Dr. Knopman has received personal compensation for activities with Eli Lilly & Company. Dr. Knopman has received personal compensation in an editorial capacity for Neurology. Dr. Knopman has received research support from TauRx. Dr. Bernstein has nothing to disclose. Dr. Petersen has received personal compensation for activities with Pfizer, Inc., Janssen Alzheimer9s Immunotherapy, Elan Pharmaceuticals, GE Healthcare, and Novartis. Dr Weiner is engaged in consulting activities for Astra Zeneca, Araclon, Medivation/Pfizer, Ipsen, TauRx Therapeutics LTD, Bayer Healthcare, Biogen Idec, Exonhit Therapeutics, Servier, Synarc, Pfizer, Janssen, Harvard University and KLJ Associates. Dr. We....Dr. Weiner owns stock options in Synarc and Elan.Dr. Weiner has received research support from Merck & Co., Inc. and Avid Radiopharmaceuticals. Dr. Jack has received personal compensation for activities with Janssen, Eisai Inc., General Electric, Johnson & Johnson, and Eli Lilly & Company. Dr. Jack has received research support from Pfizer Inc, Allon, and Baxter. Dr. Jack has received research support from Allon and Baxter.