Structural white matter connectivity differences independent of gray matter loss in mild cognitive impairment with neuropsychiatric symptoms: Early indicators of Alzheimer's disease using network-based statistics.

Background: Depression and circadian rhythm disruptions are non-cognitive neuropsychiatric symptoms (NPS) that can appear at any stage of the Alzheimer's disease (AD) continuum. Evidence suggests that NPS are linked to AD pathophysiology and hippocampal dysfunction.

Objective: To examine structural white matter (WM) connectivity and its association with gray matter (GM) atrophy and to identify specific AD-related neural networks linked to NPS in individuals with mild cognitive impairment (MCI).

Methods: Ninety-six older adults participants were divided into three groups based on the Global Depression Scale, Neuropsychiatric Inventory, Clinical Dementia Rating, and Mini-Mental Status Examination. Twelve individuals with MCI and NPS (MCI+) and 49 without NPS (MCI-) were classified, along with 35 age and gender-matched healthy individuals. Voxel-based morphometry and tract-based spatial statistics were employed to identify structural and microstructural alterations. Network-based statistics analyzed structural WM connectivity differences between MCI groups and healthy controls.

Results: Significant structural WM connectivity and GM loss were exclusively observed in MCI+ individuals compared to controls. The hippocampus, amygdala, and sensory cortex showed GM atrophy (p < 0.05), while the thalamus, pallidum, putamen, caudate, hippocampus, and sensory and frontal cortices exhibited structural WM connectivity loss (p < 0.01). These data indicate early limbic system involvement even without GM atrophy.

Conclusions: Structural WM connectivity loss within the Papez circuit may precede and potentially predict GM atrophy in the temporal lobe of individuals with MCI+. These findings highlight the importance of investigating structural WM alterations in the prodromal phase of AD, which may inform diagnostic and therapeutic strategies in early AD.