Prediction of Psychosis Onset in Alzheimer Disease: The Role of Cognitive Impairment, Depressive Symptoms, and Further Evidence for Psychosis Subtypes

Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
American Journal of Geriatric Psychiatry (Impact Factor: 4.24). 05/2006; 14(4):352-60. DOI: 10.1097/01.JGP.0000192500.25940.1b
Source: PubMed


Psychotic symptoms in Alzheimer disease (AD+P) identify a heritable phenotype associated with more rapid cognitive decline. The authors have proposed that AD+P is itself a composite of a misidentification and a paranoid subtype with increased cognitive impairment restricted to the misidentification type. Most prior studies of the clinical correlates of AD+P have been limited, however, by the inclusion of prevalent cases.
Subjects with possible or probable AD or mild cognitive impairment (MCI) without psychosis at study entry were assessed at the time of initial presentation and then annually. Psychotic symptoms were assessed using the CERAD Behavioral Rating Scale. Survival analyses used Cox proportional hazard models with time-dependent covariates to examine the predictors of psychosis onset.
A total of 288 subjects completed at least one follow-up examination. Mean duration of follow-up was 22.1 months. The incidence of psychosis was 0.19 per person-year. Cognitive impairment was associated with onset of psychosis, largely as a result of its association with onset of the misidentification, but not the paranoid, subtype. Including psychotropic medication use in the model revealed an association of antidepressant use with the onset of psychosis. This latter association appeared to arise from an underlying association between depression and the risk of psychosis onset rather than from antidepressant treatment.
These findings are consistent with the hypothesis that the misidentification and the paranoid subtypes each define a more biologically homogeneous group than AD+P as a whole. Further exploration of the relationship between depressive symptoms and psychosis in patients with AD is warranted.

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    • "The examination of possible predictors of the development of psychotic symptoms in patients with Alzheimer’s disease is clinically relevant. Several studies have suggested that greater cognitive impairment predicts an increased risk of the onset of psychosis in patients with Alzheimer’s disease.5.6 Several neuroimaging studies have implicated the frontal lobe, parietal lobe, striatal regions, and insula in the manifestation of delusions in patients with the disease.7–11 In a previous study12 examining structural brain abnormalities, significant findings indicated an association between low volumes of regional gray matter in several areas and delusions in patients with Alzheimer’s disease. "
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    ABSTRACT: Structural brain abnormalities associated with delusions in Alzheimer's disease are poorly understood. In addition, whether the neural substrate underlying the delusions develops before the onset of the delusions is unclear. In this study, we used a voxel-based morphometry approach to examine the existence of regional structural abnormalities at baseline in patients with Alzheimer's disease who did and who did not develop delusions. Using the Neuropsychiatric Inventory, we identified patients with Alzheimer's disease who exhibited delusions during a 2-year period. All the patients had undergone a magnetic resonance imaging examination at the start of the study period (baseline). We conducted a voxel-based morphometry analysis using statistical parametric mapping (SPM5) software and compared the results of patients with Alzheimer's disease who did and did not develop delusions. Compared with the patients who did not develop delusions (n = 35), the patients who did develop delusions (n = 18) had significantly smaller gray matter volumes on both sides of the parahippocampal gyrus, the right posterior cingulate gyrus, the right orbitofrontal cortex, both sides of the inferior frontal cortex, the right anterior cingulate, and the left insula. Structural brain abnormalities involving both the frontal and medial temporal lobes may be crucial to the expression of delusions in patients with Alzheimer's disease.
    Full-text · Article · Jan 2013 · Neuropsychiatric Disease and Treatment
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    • "One of the most consistent correlates of AD+P in prior studies is greater burden of cognitive impairment, whether measured as degree of cognitive impairment at time of psychosis or as more rapid cognitive decline [1, 10, 25]. Our current findings are congruent with the former of these prior observations; however, we did not measure the rate of cognitive decline in this study because of the limited number of subjects who have had follow-up assessments entered to date. "
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    ABSTRACT: Approximately 50% of late-onset Alzheimer's disease (AD) patients develop psychosis (AD+P), a heritable phenotype associated with more rapid cognitive decline. Prior studies conflict regarding whether apolipoprotein E (APOE) ϵ4 alleles are associated with AD+P, possibly due to small sample sizes, inconsistent diagnostic criteria, and different methodologies to assess psychosis. We used the National Alzheimer's Coordinating Center Uniform Data Set to evaluate the largest uniformly characterized sample of AD+P subjects studied to date for the association of APOE ϵ4 genotype, along with other demographic and clinical variables. Greater cognitive impairment and depressive symptoms were associated with AD+P, while the Caucasian race was protective. Neither APOE ϵ4 carrier status nor allele number was associated with psychosis. The AD+P phenotype is not associated with the APOE ϵ4 genotype. AD+P may represent a useful phenotype for the discovery of non-APOE ϵ4 genetic variation contributing to the risk of AD.
    Full-text · Article · Mar 2011 · International Journal of Alzheimer's Disease
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    • "Psychotic symptoms were also correlated with the severity of other behavioural symptoms in our subjects. This is congruent with prior reports demonstrating the associations of psychosis with agitation (Lopez et al., 2003), aggression (reviewed in Sweet et al., 2003), and depressive symptoms (Lyketsos et al., 2001; Bassiony et al., 2002; Wilkosz et al., 2006). Perhaps reflecting, in part, these correlations, psychotic symptoms in late onset Alzheimer's disease subjects are associated with increased caregiver distress (Kaufer et al., 1998). "
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    ABSTRACT: Determining the genetic architecture of late onset Alzheimer's disease remains an important research objective. One approach to the identification of novel genetic variants contributing to the disease is the classification of biologically meaningful subgroups within the larger late-onset Alzheimer's disease phenotype. The occurrence of psychotic symptoms in patients with late-onset Alzheimer's disease may identify one such group. We attempted to establish methods for the reliable assessment of psychotic symptoms in a large, geographically dispersed collection of families, multiply affected with late onset Alzheimer's disease, who were participants in the larger National Institute on Aging Late Onset Alzheimer's Disease Family Study; and to characterize the correlates and familial aggregation of psychosis within this cohort. We found that reliable assessments of psychotic symptoms during in-person or phone interviews were readily implemented. The presence of psychosis in late onset Alzheimer's disease was significantly associated with degree of cognitive impairment, and significantly, albeit modestly, correlated with the severity of other behavioural symptoms. Psychosis significantly aggregated within late onset Alzheimer's disease families suggesting that it may identify a genetically determined subgroup. Future studies should examine the linkage and association of psychosis with genetic variation within these families.
    Full-text · Article · Feb 2010 · Brain
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