Biomarkers in Randomized Clinical Trials: Magnetic Resonance Imaging

Background: It is essential that randomized clinical trials (RCTs) incorporate biomarkers of disease progression that would be sensitive to the effects of disease-modifying treatments. Magnetic resonance imaging (MRI) can be safely repeated over time, and is routinely performed in clinical centers, making it an ideal modality to be incorporated into RCTs. Summary: This chapter discusses potential structural MRI biomarkers that have been proposed for a number of different neurodegenerative disorders, including Alzheimer's disease (AD), dementia with Lewy bodies (DLB), frontotemporal dementia (FTD), progressive supranuclear palsy syndrome (PSPS), and Parkinson's disease (PD). All of these disorders represent targets for ongoing and future RCTs. Rates of hippocampal atrophy and ventricular expansion provide excellent biomarkers of disease progression in AD, and may also provide biomarkers in prodromal and preclinical phases of the disease, as well as in DLB. Rates of ventricular expansion also perform well in FTD, although regional frontal and temporal measurements could also be useful. Rates of midbrain atrophy provide the most feasible MRI biomarker in PSPS. In contrast, PD is not associated with specific patterns of cerebral atrophy and further work is needed in order to define useful MRI biomarkers. Sample size calculations using these MRI biomarkers are presented and discussed. Key Messages: Rates of cerebral atrophy provide valuable potential biomarkers of disease progression in neurodegenerative disorders, and have already begun to be utilized as outcome measures in RCTs. Measurements from other structural and functional MRI modalities require more longitudinal validation, but may prove to be useful in the future.