Cognitive trajectory of psychosis subtypes in alzheimer's disease. preliminary results from non linear mixed effect (nlme) models in alzheimer's disease neuroimaging initiative (adni2)

Objectives: The psychosis phenotype in Alzheim- er’s disease (AD) may be comprised of two subtypes: paranoid (persecutory delusions) and misidentifica- tion (misidentification phenomena +- visual and au- ditory hallucinations), and each subtype may have distinct neuropathological underpinnings. There is robust evidence that psychosis is associated with a faster speed of cognitive decline using linear and non-linear models of disease progression, but wheth- er the trajectory is subtype dependent has not been explored. This study aimed to investigate the impact of psychosis subtypes on the rate of disease progres- sion evaluated by the Alzheimer’s Disease Assess- ment Scale (Adas-cog), in a longitudinal dataset ADNI2. Materials and Methods: Data on ADNI2 partici- pants who were categorised as late mild cognitive impairment (LMCI) or AD over a 4 years observa- tion period were included in the analysis (n=528). There were 96 psychotic subjects, among these 38 with pure paranoid subtype, 29 pure misidentifica- tion subtype and 29 with both. Potential confounding covariates, including Mini Mental State Examina- tion, Functional Activity Questionnaire, Clinical De- mentia Rating, Neuropsychiatric Inventory, age, education, gender, apoE4 status and concomitant medications were also explored. Data were fitted with logistic models based on Richard’s function (Samtani 2012). Estimation was performed using the SAEM algorithm implemented in the Monolix soft- ware (version 4.3.3). Model selection was made us- ing visual predictive checks and likelihood ratio test. The effect of psychosis and paranoid and misidenti- fication subtypes were explored on the rate of dis- ease progression. Results: The presence of psychotic symptoms sig- nificantly increased the rate of disease progression, indexed by an increase from 1,3 to 3.0% in ADAS- cog scores per year (P-value=0.00061): Hallucina- tions increased the rate of progression from 1.5 to 3.8% (P-value=0.0012) and delusions from 1.4 to 3.2% (P-value=0.0017). The presence of both psy- chotic subtypes increased the rate of progression from 1.3 to 3.9% (P-value=0.0016) misidentifica- tion subtype alone from 1.3 to 2.8% (P-value=0.021), whereas paranoid subtype was not significantly as- sociated with change in the rate of progression. Discussion: We found that the presence of psycho- sis determinates faster cognitive decline, confirming previous findings. The presence of both subtypes, and of the misidentification subtype alone, is associ- ated with faster disease progression, after control- ling for potential confounding factors. Instead paranoid subtype was found not to have impact on disease progression. Conclusions: We presented a disease progression model in AD and LMCI incorporating the impact of psychosis subtype on the worsening of ADAS-cog scores over the time.