Associations Between Hyperactive Neuropsychiatric Symptoms and Brain Morphology in Mild Cognitive Impairment and Alzheimer's Disease

Background: Hyperactive neuropsychiatric symptoms (NPS) (i.e., agitation, disinhibition, and irritability) are among the most challenging symptoms to manage in Alzheimer's disease (AD). However, their underlying brain correlates have been poorly studied. Objective: We aimed to investigate the associations between the total score of hyperactive NPS and brain structures in participants with AD, mild cognitive impairment (MCI), and cognitively normal older adults (CN). Methods: Neuropsychiatric and 3T MRI data from 216 AD, 564 MCI, and 660 CN participants were extracted from the Alzheimer's Disease Neuroimaging Initiative database. To define NPS and brain structures' associations, we fitted a general linear model (GLM) in two ways: 1) an overall GLM including all three groups (AD, MCI, CN) and 2) three pair-wise GLMs (AD versus MCI, MCI versus CN, AD versus CN). The cortical changes as a function of NPS total score were investigated using multiple regression analyses. Results: Results from the overall GLM include associations between 1) agitation and the right parietal supramarginal surface area in the MCI-CN contrast, 2) disinhibition and the cortical thickness of the right frontal pars opercularis and temporal inferior in the AD-MCI contrast, and 3) irritability and the right frontal pars opercularis, frontal superior, and temporal superior volumes in the MCI-CN contrast. Conclusions: Our study shows that each hyperactive NPS is associated with distinct brain regions in AD, MCI, and CN (groups with different levels of cognitive performance). This suggests that each NPS is associated with a unique signature of brain morphology, including variations in volume, thickness, or area.