Association of Variation in Behavioral Symptoms with Initial Cognitive Phenotype in Adults with Dementia Confirmed by Neuropathology

Abstract

Importance: Behavioral and psychological symptoms of dementia (BPSDs) in association with amnestic and nonamnestic cognitive phenotypes have not been evaluated across diagnoses of Alzheimer disease pathology (ADP), Lewy body-related pathology (LRP), and mixed pathology (ADP-LRP). Objectives: To determine the clinical phenotypes at the initial visit that are associated with the nature and severity of BPSDs in patients with ADP, LRP, and ADP-LRP. Design, Setting, and Participants: This retrospective longitudinal cohort study included 2422 participants with neuropathologically confirmed ADP, LRP, or mixed ADP-LRP in the National Alzheimer Coordinating Center database from June 20, 2005, to September 4, 2019. Participants had a mean (SD) interval of 5.5 (2.8) years from initial visit to autopsy. Main Outcomes and Measures: Clinician-determined diagnosis of change across 10 BPSDs (agitation, apathy, depression, delusions, disinhibition, auditory hallucinations, visual hallucinations, irritability, personality change, and rapid eye movement [REM] sleep behavior) and the highest severity score for behavioral change on the Neuropsychiatric Inventory Questionnaire (NPI-Q). Results: A total of 2422 participants (1187 with ADP, 904 with ADP-LRP, and 331 with LRP) were included in the analysis (1446 men [59.7%]; mean [SD] age, 74.4 [10.1] years). Compared with initial amnestic symptoms, executive symptoms were associated with a higher risk for 7 of the 10 BPSDs (hazard ratio [HR] range, 1.28-2.45), and visuospatial symptoms were associated with a higher risk for 2 of the 10 BPSDs (HR range, 1.91-2.51), but neither were associated with a low risk for any BPSD. Language symptoms were associated with a low risk of onset for 3 of 10 BPSDs (HR range, 0.43-0.79) and a high risk for 1 BPSD (personality change) (HR, 1.42 [95% CI, 1.10-1.83]). Participants with LRP had a lower risk for agitation (HR, 0.74 [95% CI, 0.60-0.92]), disinhibition (HR, 0.78 [95% CI, 0.62-0.99]), and irritability (HR, 0.81 [95% CI, 0.68-0.96]) and a higher risk for apathy (HR, 1.19 [95% CI, 1.02-1.38]), depression (HR, 1.32 [95% CI, 1.12-1.55]), auditory (HR, 2.00 [95% CI, 1.37-2.93]) and visual (HR, 2.78 [95% CI, 2.21-3.49]) hallucinations, and REM sleep behavior changes (HR, 4.77 [95% CI, 3.61-6.31]) compared with the ADP group. The ADP-LRP group had a higher risk for delusions (HR, 1.27 [95% CI, 1.08-1.48]), auditory (HR, 1.62 [95% CI, 1.21-2.15]) and visual (HR, 1.57 [95% CI, 1.30-1.89]) hallucinations, and REM sleep behavior changes (HR, 2.10 [95% CI, 1.63-2.70]) than the ADP group and a lower risk for visual hallucinations (HR, 0.56 [95% CI, 0.45-0.71]) and REM sleep behavior changes (HR, 0.44 [95% CI, 0.34-0.57) than the LRP group. Overall, women showed a lower risk of agitation (HR, 0.86 [95% CI, 0.75-0.98]), apathy (HR, 0.79 [95% CI, 0.71-0.87]), visual hallucinations (HR, 0.76 [95% CI, 0.64-0.90]), irritability (HR, 0.77 [95% CI, 0.69-0.86]), and REM sleep behavior change (HR, 0.45 [95% CI, 0.35-0.58]) and a higher risk of depression (HR, 1.26 [95% CI, 1.13-1.41]). Older age was associated with a lower risk of most BPSDs (HR range, 0.98-0.99) except delusions (HR, 1.00 [95% CI, 1.00-1.01]) and auditory hallucinations (HR, 0.99 [95% CI, 0.97-1.00]) and a low NPI-Q composite score (β =-0.07 [95% CI,-0.08 to-0.05]; P