Graph Theoretical Analysis of Resting-State Functional Connectivity MRI in Alzheimer's Disease Detects Network Dysfunction before Clinical Symptoms (P06.022)

OBJECTIVE: To determine if resting-state functional-connectivity MRI (rs-fcMRI) is sensitive to functional brain changes in Alzheimer9s disease (AD) before the onset of clinical symptoms. BACKGROUND: Previous research has demonstrated that AD exhibits dramatic effects on rs-fcMRI during the symptomatic course of clinical disease. However, AD pathology accumulates and exhibits a pathological influence many years prior to onset of symptoms. The impact of this pathology on rs-fcMRI and large scale neural function is unclear. DESIGN/METHODS: We collected rs-fcMRI and cerebrospinal fluid (CSF) on 205 CDR 0 patients, 90 CDR 0.5 patients, and 31 CDR 1 patients. CDR 0 patients were further classified as 132 showing no signs of AD pathology, 46 showed signs of CSF amyloid pathology, and 13 showed signs of CSF amyloid pathology and neurodegeneration (tau). We calculated three graph theoretical measures, path length, clustering coefficient and modularity, which were compared based on both clinical and pathological status. We also assessed the classifying potential of these measures using linear discriminant analysis (LDA). RESULTS: We observed declines in clustering coefficient and modularity, but not path length, as a function of increasing AD (indexed by CDR). LDA was able to classify patients with symptomatic AD (CDR>0) compared to those without symptomatic AD (CDR=0). The CDR 0 group with AD pathology had graph theory metrics that were between CDR 0 with no pathology and mild symptomatic AD phenotype (CDR=0.5). While the accuracy of the LDA was weaker than symptomatic vs non-symptomatic AD, this classifier still performed significantly better than chance. CONCLUSIONS: This work extends previous work using graph theory in AD by showing that changes in graph measures is stepwise with respect to disease severity. These data suggest that the presence of AD pathology is sufficient to cause rs-fcMRI dysfunction similar to that seen in symptomatic AD. Supported by: Medical Scientist Training Program Grant to WUSTL (MRB) (5T32GM007200-37), Knight Alzheimer9s Disease Research Center (ADRC) Pilot Grant (3255 ADRC 26) (BMA), National Institute of Mental Health (NIMH) (K23MH081786) (BMA), National Institute of Nursing Research (NINR) (R01NR012907 and R01NR012657) (BMA), Dana Foundation (DF10052) (BMA), Alene and Meyer Kopolov Fund for Geriatric Psychiatry and Neurology (BMA),National Institute of Aging (NIA) (P01AG026276, P01AG026276, P01AG03991 and P50 AG05681) (JCM). Disclosure: Dr. Brier has nothing to disclose. Dr. Thomas has nothing to disclose. Dr. Rubins has nothing to disclose. Dr. Morris has received personal compensation for activities with Esteve Company, Eisai Inc., Janssen, GlaxoSmithKline, Inc., Novartis, Otsuka, and Pfizer Inc. Dr. Morris has received personal compensation in an editorial capacity for Medlink. Dr. Morris has received research support from Janssen, Eli Lilly & Company, and Pfizer, Inc. Dr. Ances has received personal compensation from Lily Pharmaceutical for serving on a scientific advisory board that was evaluating an Pfizer antidementia drug.