Biomarkers

Neuropsychiatric symptoms (NPS) constitute a major challenge for patients with Alzheimer's disease (AD). We explored NPS clusters in AD and longitudinally evaluated their association with function and structural neuroimaging markers.

Participants with AD (N = 111) were included from the Ontario Neurodegenerative Disease Research Initiative. NPS were assessed using the Neuropsychiatric Inventory Questionnaire (NPI-Q). NPS clusters were identified through exploratory factor analysis at baseline. We evaluated 34 bilateral cortical regions of interest (ROIs) and 9 bilateral subcortical ROIs using volumetric information from MRI data evaluated annually over 3 years. We examined longitudinal associations between NPS clusters with basic (ADLs) and instrumental (iADLs) activities of daily living, as well as with subcortical and cortical volumes, using mixed linear regression models controlling for age, sex, MoCA, education level, and visit number.

Factor analysis identified four symptom clusters explaining 62% of the variance. These were labeled "behavioral" (disinhibition, irritability, motor disturbance, and agitation), "psychotic" (hallucinations, delusions, and euphoria), "neurovegetative" (apathy and appetite), and "affective" (depression, anxiety, nighttime behavior) clusters. The "behavior" cluster was longitudinally associated with left middle temporal (β = -382.6, p = .006), right lingual (β = -456.0, p = .01), right nucleus accumbens (β = -5656.6, p = .004), and right thalamic (β = -700.7, p = .008) volumes. The "neurovegetative" cluster was longitudinally associated with left fusiform (β = -195.4, p = .03), left middle temporal (β = -282.3, p = .001), and right nucleus accumbens (β = -3176.7, p = .01). The "affective" cluster was associated with left rostral anterior cingulate (β = -1423.4, p = .0003), right entorhinal (β = -804.3, p = .03), right medial orbitofrontal (β = -830.6, p = .001), right pars opercularis (β = -911.6, p = .001), and left putamen (β = -729.5, p = .004) volumes. Longitudinally, all clusters predicted iADL outcomes and clusters 1, 3, and 4 predicted ADL outcomes. Greater NPS burden, male sex, visit number, older age, and lower MoCA predicted worse function.

NPS clusters in AD separate into behavioral, psychotic, neurovegetative, and affective dimensions. These clusters demonstrate unique associations with function and neuroimaging markers.