Longitudinal degradation of the default/salience network axis in symptomatic individuals with elevated amyloid burden.

Resting-state functional connectivity MRI (rs-fcMRI) is a non-invasive imaging technique that has come into increasing use to understand disrupted neural network function in neuropsychiatric disease. However, despite extensive study over the past 15 years, the development of rs-fcMRI as a biomarker has been impeded by a lack of reliable longitudinal rs-fcMRI measures. Here we focus on longitudinal change along the Alzheimer's disease (AD) trajectory and demonstrate the utility of Template Based Rotation (TBR) in detecting differential longitudinal rs-fcMRI change between higher and lower amyloid burden individuals with mildly impaired cognition. Specifically, we examine a small (N = 24), but densely sampled (~5 observations over ~3 years), cohort of symptomatic individuals with serial rs-fcMRI imaging and PiB-PET imaging for β-amyloid pathology. We observed longitudinal decline of the Default Mode and Salience network axis (DMN/SAL) among impaired individuals with high amyloid burden. No other networks showed differential change in high vs. low amyloid individuals over time. The standardized effect size of AD related DMN/SAL change is comparable to the standardized effect size of amyloid-related change on the mini-mental state exam (MMSE) and hippocampal volume (HV). Last, we show that the AD-related change in DMN/SAL connectivity is almost completely independent of change on MMSE or HV, suggesting that rs-fcMRI is sensitive to an aspect of AD progression that is not captured by these other measures. Together these analyses demonstrate that longitudinal rs-fcMRI using TBR can capture disease-relevant network disruption in a clinical population.