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.