State-of-the-art imaging of neuromodulatory subcortical systems in aging and Alzheimer's disease: Challenges and opportunities

Primary prevention trials have shifted their focus to the earliest stages of Alzheimer's disease (AD). Autopsy data indicates that the neuromodulatory subcortical systems' (NSS) nuclei are specifically vulnerable to initial tau pathology, indicating that these nuclei hold great promise for early detection of AD in the context of the aging brain. The increasing availability of new imaging methods, ultra-high field scanners, new radioligands, and routine deep brain stimulation implants has led to a growing number of NSS neuroimaging studies on aging and neurodegeneration. Here, we review findings of current state-of-the-art imaging studies assessing the structure, function, and molecular changes of these nuclei during aging and AD. Furthermore, we identify the challenges associated with these imaging methods, important pathophysiologic gaps to fill for the AD NSS neuroimaging field, and provide future directions to improve our assessment, understanding, and clinical use of in vivo imaging of the NSS.