Mild-Behavioral Impairment (MBI) is a neurobehavioral syndrome characterized by later-life onset of NPS as an at-risk state for dementia. While decreased white matter integrity in regions associated with NPS is identified in AD, evidence in pre-dementia risk groups is sparse.

To determine white matter neural correlates of neuropsychiatric symptoms (NPS) in an at-risk group for incident cognitive decline and dementia.

ADNI subjects with diffusion tensor imaging (DTI) data and neuropsychiatric inventory questionnaire scores were included (n=161). Exploratory DTI analysis examined the relation of NPS classified into MBI domains, and changes in large white matter tracts in those with normal cognition (NC; n=70), and Mild Cognitive Impairment (MCI; n=91). Multiple linear regression, adjusted for age, gender and education was conducted.

Patterns of white matter integrity associated with each MBI domain varied for each pre-dementia population. MBI domain specific analysis identified: 1) Impaired Drive/Motivation(apathy)- reduced fractional anisotropy (FA) in posterior limb of the internal capsule(PLIC) in MCI; 2) Emotional Dysregulation(mood/anxiety symptoms) - reduced FA in PLIC and cingulum in NC, and axial and radial diffusivity (AD;RD) in the uncinate fasciculus in MCI; 3) Impulse Dyscontrol(agitation)- altered FA, AD, RD and mean diffusivity (MD) in inferior fronto-occipital fasciculus, posterior thalamic radiation, cingulum and superior longitudinal fasciculus(SLF) in NC, and white matter changes were observed in SLF, PLIC and fornix in MCI; 4) Social Inappropriateness(impaired social cognition) - reduced FA within SLF in MCI; 5) Abnormal Thought/Perception(Psychosis) – altered FA, AD, and MD in the corpus callosum, cingulum and external capsule in MCI. All aforementioned results were significant (p<0.05).

Distinct patterns of white matter changes associated with MBI domains were observed. A common tract affected in NC and MCI was the SLF. These findings will improve our understanding of the role of NPS in neurodegenerative disease while potentially uncovering novel imaging biomarkers for early detection/ treatment.