Neuropsychiatric Symptom Clusters and Their Association With Brain Structure in Alzheimer Disease.

Objective

Neuropsychiatric symptoms (NPS) constitute a major challenge in Alzheimer disease (AD). We applied a component-based symptom paradigm by deriving Neuropsychiatric Inventory Questionnaire (NPI-Q) clusters and evaluating their longitudinal associations with regional brain volumes and functional outcomes (instrumental activities of daily living, activities of daily living [ADLs]).

Methods

Participants with AD (N=111) were from the Ontario Neurodegenerative Disease Research Initiative. NPS were assessed using the NPI-Q. Symptom clusters were identified via principal components analysis at baseline. Magnetic resonance imaging-derived volumes for 34 cortical and 9 subcortical regions were obtained annually over 3 years. Longitudinal associations between NPS clusters and functional outcomes were examined using linear mixed-effects models adjusting for age, sex, Montreal Cognitive Assessment (MoCA), education, visit number, and cholinesterase inhibitor use.

Results

Four clusters explained 62% of variance: hyperactivity (disinhibition, irritability, motor disturbance, agitation), psychosis (hallucinations, delusions, euphoria), neurovegetative (apathy, appetite), and affective (depression, anxiety, nighttime behavior). The hyperactivity cluster was associated with the left middle temporal (β=-0.24, P=.025) and right nucleus accumbens (β=-0.28, P=.007). The neurovegetative cluster was associated with the left middle temporal (β=-0.50, P<.001) and right nucleus accumbens (β=-0.55, P<.001). The affective cluster showed the strongest associations with the left rostral anterior cingulate (β=-0.42, P=.002) and right medial orbitofrontal cortex (β=-0.47, P=.001). All clusters predicted iADL outcomes; clusters 1, 3, and 4 also predicted ADL outcomes. Greater NPS burden, male sex, age, lower MoCA, and later visits predicted worse function.

Conclusion

NPS in AD separate into hyperactivity, psychosis, neurovegetative, and affective clusters, supporting a cluster-based paradigm linking co-occurring behavioral symptoms with brain structure and functional decline.