Phenomenology and clinical correlates of delusions in Alzheimer disease.

OBJECTIVES: The objectives of this study were to determine whether anosognosia, depression, and elevated mood are associated with delusions in Alzheimer disease (AD), and to examine the validity of standardized diagnostic criteria for psychosis of dementia. METHOD: The authors assessed a consecutive series of 771 patients with AD attending a dementia clinic with a comprehensive neuropsychologic and psychiatric evaluation that included specific measures of delusions, hallucinations, anosognosia, depression, and elevated mood. RESULTS: Delusions were found in one-third of the patients and hallucinations in 7%. Most patients with hallucinations also had delusions. A principal component analysis of the Psychosis Dementia Scale, which rates the presence and severity of delusions, produced the factors of paranoid misidentification and expansive delusions. Paranoid, but not expansive, delusions increased across the stages of the illness. Anosognosia and depression were significantly and independently associated with the presence of delusions, whereas elevated mood was significantly associated with expansive, but not paranoid, delusions. A multiple logistic regression analysis demonstrated that delusions in AD were significantly associated with depression, anosognosia, overt aggression, and agitation. CONCLUSIONS: Anosognosia, depression, global cognitive deficits, and elevated mood are the main psychiatric correlates of paranoid misidentification and expansive delusions in AD, whereas overt aggression and agitation are the most frequent behavioral concomitants of psychosis in AD.     

Behavioral and psychological symptoms of dementia in an Indian population: comparison between Alzheimer's disease and vascular dementia

BACKGROUND: Differential patterns of brain lesions in patients with Alzheimer's disease (AD) or vascular dementia (VaD) can result in differing clinical courses and presentations. METHOD: Thirty patients with AD were compared with 29 patients with VaD for differences in behavioral symptoms using the Behavioral Pathology in Alzheimer's Disease (BEHAV-AD) rating scale. RESULTS: Patients with AD had significantly more delusions, hallucinations, anxieties and phobias and caregiver distress than patients with VaD. CONCLUSIONS: Behavioral symptoms in both AD and VaD exhibit specific longitudinal patterns. An understanding of the pattern can aid the treating physician in giving appropriate advice to caregivers regarding the course of the illness and also help them in planning appropriate interventions.     

Behavioral differences between white matter lacunar dementia and Alzheimer's disease: a comparison on the neuropsychiatric inventory

BACKGROUND AND PURPOSE: Behavioral abnormalities account for much of the morbidity of vascular dementia (VaD) and Alzheimer's disease (AD). The goals of the study were to compare the behavioral changes in patients with VaD associated with ischemic white matter subcortical changes and lacunar infarctions (VaD-WSI) to those in patients with AD. METHODS: Thirty outpatients with VaD and multiple lacunar infarctions in the periventricular white matter and 30 AD patients, matched for age and severity of dementia, were enrolled in this prospective study. The behavioral abnormalities of these patients were assessed by interviewing their caregivers with the Neuropsychiatric Inventory. RESULTS: A similar spectrum of noncognitive behavioral changes was found in AD and WSI patients. In VaD-WSI, the severity of delusions, hallucinations, aggression, irritability, aberrant motor behavior, nighttime behavior and appetite changes was correlated with cognitive decline, whereas depression, apathy, anxiety and euphoria were unrelated to the severity of dementia. In AD, none of the behavioral changes correlated with the severity of dementia. CONCLUSION: Behavioral changes are frequent in VaD-WSI and are present regardless of the severity of the cognitive decline. It is therefore important to assess behavioral as well as cognitive changes at early stages of the illness, to ensure appropriate treatment.     

Incidence of and risk factors for hallucinations and delusions in patients with probable AD

OBJECTIVE: To examine the incidence of and risk factors for hallucinations and delusions associated with patients clinically diagnosed with probable AD. BACKGROUND: Estimates of the incidence of psychosis in AD range widely from 10% to 75%. The risk factors for psychosis of AD are not known, although multiple studies indicate that AD patients with psychosis demonstrate greater cognitive and functional impairment. METHODS: The authors conducted psychiatric evaluations of 329 patients with probable AD from the University of California at San Diego Alzheimer's Disease Research Center to determine the incidence of hallucinations and delusions. They examined data from annual clinical and neuropsychological evaluations to determine whether there were specific risk factors for the development of hallucinations and delusions. RESULTS: Using Cox survival analyses, the cumulative incidence of hallucinations and delusions was 20.1% at 1 year, 36.1% at 2, 49.5% at 3, and 51.3% at 4 years. Parkinsonian gait, bradyphrenia, exaggerated general cognitive decline, and exaggerated semantic memory decline were significant predictors. Age, education, and gender were not significant predictors. CONCLUSIONS: The authors found a relatively high incidence of hallucinations and delusions in patients diagnosed with probable AD and suggest that specific neurologic signs, cognitive abilities, and accelerated decline may be predictive markers for their occurrence.     

Psychotic symptoms in Alzheimer disease: evidence for subtypes.

OBJECTIVE: Psychotic symptoms in Alzheimer disease (AD) identify a phenotype with distinct neurobiology and genetic architecture. The authors investigated whether AD with psychosis is homogeneous or is a composite of subtypes. METHODS: Authors performed factor and cluster analyses of the psychotic-symptom items of the CERAD Behavioral Rating Scale in 188 probable and possible AD subjects who have displayed at least one psychotic symptom. RESULTS: Exploratory factor analysis resulted in a one-factor solution that comprised misidentification delusions, auditory and visual hallucinations, and the misidentification of people. Persecutory delusions were also frequently present and were independent of the misidentification/hallucination factor. Cluster analysis yielded similar results. CONCLUSION: Misidentification/hallucinations and persecutory delusions may identify two subtypes of psychosis in AD. Longitudinal study is needed to determine whether these proposed subtypes remain stable and independent over time or merge into a single group over the course of illness.     

Neuroimaging of delusions in Alzheimer's disease

MEDLINE, Embase and PsycINFO were searched using the keywords "imaging", "neuroimaging", "CT", "MRI", "PET", "SPECT", "Alzheimer's", "dementia", "delusions" and "psychosis" to find studies specifically assessing or reporting on neuroimaging of delusions in Alzheimer's Dementia (AD), separate from hallucinations or psychosis in general in AD. Twenty-five studies were found meeting criteria and are included in this review which reports on structural, regional perfusion, metabolic and receptor binding imaging modalities assessing delusions as a whole, as well as persecutory and misidentification delusional subtypes. The majority of studies implicate right-sided pathology, primarily frontal lobe. Left-frontal predominance and release, secondary to right-sided pathology, may create a hyperinferential state resulting in the formation of delusions. This perturbation and imbalance of normal networks is associated with delusional phenomenology. Temporal lobe structures are also important in misidentification syndromes, which have a different natural history than paranoid delusions. Consistent with the neuropathological and genetic literature, neuroimaging has shown that paranoid versus misidentification delusions are associated with different phenomenology and different neural substrates. Delusional subtype is an important factor in understanding the neurobiological underpinnings of delusions in dementia. We also discuss methodological issues related to neuroimaging of delusions in AD.     

The efficacy and safety of risperidone in the treatment of psychosis of Alzheimer's disease and mixed dementia: a meta-analysis of 4 placebo-controlled clinical trials

BACKGROUND: Dementia typically includes behavioral and psychological symptoms of dementia (BPSD) as well as cognitive decline. Psychosis of Alzheimer's disease (AD) is a specific component of AD, characterized by delusions, misidentifications, and hallucinations. METHODS: This study is a meta-analysis of patients with psychosis of AD from four large placebo-controlled clinical trials of risperidone in dementia. Three trials included patients diagnosed with heterogeneous symptoms of BPSD (those with psychosis of AD were included in this analysis), while one trial included only those diagnosed with psychosis of AD. Efficacy was measured using the Behavioral Pathology in Alzheimer's Disease (BEHAVE-AD) Psychosis subscale and Clinical Global Impression (CGI). RESULTS: Primary analyses in the psychosis of AD population demonstrated that risperidone significantly improved scores on the BEHAVE-AD Psychosis subscale and CGI scale compared with placebo. Secondary analyses demonstrated that patients with more severe symptoms showed a more pronounced response to treatment with risperidone compared with placebo than those patients with less severe symptoms. Extrapyramidal symptoms and somnolence were more frequent with risperidone than placebo (p=0.04). Cerebrovascular adverse events and all-cause mortality were observed more frequently, although not statistically significantly, with risperidone versus placebo. CONCLUSIONS: This meta-analysis of psychosis of AD showed improvement in psychotic symptoms and general clinical improvement in patients with psychosis of AD treated with risperidone compared with placebo. The benefits of treatment were most significant in patients with severe symptoms. The safety profile of risperidone in this psychosis of AD population was similar to the more general BPSD population.     

The effects of olanzapine in reducing the emergence of psychosis among nursing home patients with Alzheimer's disease

BACKGROUND: Elderly patients with Alzheimer's disease (AD) commonly exhibit psychotic symptoms, prompting clinicians to administer antipsychotics. This article compares the effects of olanzapine and placebo in the emergence of hallucinations or delusions in AD patients with symptoms of agitation/aggression but little or no psychotic symptomatology at baseline. METHOD: A multicenter, double-blind, placebo-controlled study was conducted in nursing home patients with AD according to DSM-IV criteria and symptoms of agitation/aggression and/or psychosis. Patients (N = 206) were randomly assigned to receive either placebo or fixed-dose olanzapine (5, 10, or 15 mg/day) for up to 6 weeks. This article analyzes data from a subgroup of patients (N = 165) with no or minimal delusions and/or hallucinations at baseline as measured by the Neuropsychiatric Inventory-Nursing Home Version (NPI/NH). Three subsets of patients were identified on the basis of their symptoms at baseline: those with no clinically significant hallucinations, those with no clinically significant delusions, and those with no clinically significant delusions or hallucinations. RESULTS: Of the patients without hallucinations or delusions at baseline (N = 75), the placebo-treated patients showed significantly greater development of these symptoms compared with olanzapine-treated patients overall (NPI/NH hallucinations + delusions mean change score, +2.73 vs. +0.27, p = .006). Similarly, of the patients without baseline hallucinations (N = 153), the placebo-treated patients showed greater hallucinations score increases than did olanzapine-treated patients overall (+1.25 vs. +0.33, p = .026), whereas patients without baseline delusions (N = 87) showed no significant treatment effects. Olanzapine had a favorable safety profile in each patient subset. CONCLUSION: These results suggest that, overall, olanzapine effectively attenuated emergence of psychosis in a short-term trial of patients with Alzheimer's disease.     

The psychotic phenomenon in probable Alzheimer's disease: a positron emission tomography study

Positron emission tomography was used to examine the mechanisms of the psychotic phenomenon in Alzheimer's disease (AD). Data from 2 patients with delusions and 2 with hallucinations were compared with those of 5 AD patients without psychosis. The patients with paranoid delusions had diminished relative regional cerebral blood flow (rel-CBF) in the left dorsolateral prefrontal and left medial temporal cortices. The patients with visual hallucinations showed diminished rel-CBF in the right parietal, left medial temporal, and left dorsolateral prefrontal cortices. These findings support the hypothesis that a frontal-temporal abnormality is associated with paranoid delusions in AD. By contrast, visual hallucinations are associated with parietal as well as frontal and temporal lobe dysfunction. In these patients, a left prefrontal-temporal cortex dysfunction appears to be a common denominator for the development of the psychotic phenomenon in AD.     

Long-term follow-up and phenomenologic differences distinguish among late-onset schizophrenia, late-life depression, and progressive dementia.

OBJECTIVE: The diagnosis of patients with late-life onset of hallucinations and delusions but an absence of mood or cognitive disorder remains controversial. The authors used long-term follow-up and phenomenology to assess whether outcome varied by diagnosis. METHODS: Twenty-eight individuals with late-life psychosis but no mood or cognitive disorder were compared with 48 individuals with late-life major depression and 47 individuals with psychotic symptoms and late-life dementia. All subjects were followed for a minimum of 1 year. Data from the last time examined were used to determine likelihood of death at 84 months by Kaplan-Meier analysis in all groups and the likelihood of developing dementia in the depression and late-life onset psychosis groups at 120 months. RESULTS: Patients with dementia-plus-psychosis were more likely to die at 84 months than those with major depression or late-onset hallucinations and delusions. Subjects with depression or late-onset hallucinations and delusions did not differ in likelihood of developing dementia at 120 months. CONCLUSIONS: These results support the hypothesis that a condition characterized by psychiatric symptoms and no mood symptoms can begin in later life and that this disorder is not a precursor to dementia.     

Subtypes of depression among patients with Alzheimer's disease and other dementias

ObjectivesWe compared the prevalence of subtypes of depression in patients with Alzheimer's disease (AD), vascular dementia (VaD), and unspecified dementia (UD).MethodsUsing the Integrated Healthcare Information Services database, we conducted an analysis of subtypes of depression (major depressive disorder, depressive disorder not otherwise specified, dysthymic disorder; depressive psychosis, and adjustment disorder depressive) among patients with AD, VaD, and UD. Six thousand four hundred and forty patients aged 60 years or older with dementia (2947 with AD, 725 with VaD, and 2768 with UD) were identified from January 1 to December 31, 2001. Both subtypes of depression and dementia subgroups were diagnosed using criteria from the International Classification of Diseases, 9th version.ResultsThe overall prevalence of depressive disorders was 27.41%. The prevalence of depressive disorders was significantly higher in VaD (44.14%) and UD (32.48%) patients compared with AD (18.53%, P < .0001) patients. The AD patients had the lowest prevalence of all subtypes of depression. The VaD patients, compared with both AD and UD (P < .005), had a significantly higher prevalence of: 1) depressive disorder not otherwise specified, 2) major depressive disorder, and 3) dysthymic disorder. Adjustment disorder with depressive symptoms was more common in the UD subgroup, whereas the rate of depressive psychosis was similar in all dementia subgroupsConclusionsThis study supports the view that depressive disorders are more prevalent in VaD compared with UD and AD, and provides indicators to the clinician for further evaluation of depression in dementia subgroups     

Neuropathological substrates of psychiatric symptoms in prospectively studied patients with autopsy-confirmed dementia with lewy bodies

OBJECTIVE: This investigation was undertaken to clarify the neuropathological substrates of key psychiatric symptoms in dementia with Lewy bodies. METHOD: The authors studied 112 autopsy-confirmed cases of dementia with Lewy bodies in patients who had had annual standardized clinical evaluations until their death. The relationships of persistent psychiatric symptoms (visual hallucinations, delusions, depression) to plaques (Consortium to Establish a Registry for Alzheimer's Disease protocol), tangles (Braak staging), and Lewy bodies (consensus Lewy body staging) were evaluated. In addition, symptom frequency and persistent symptoms were compared in the patients with Lewy body dementia and 90 patients with autopsy-confirmed Alzheimer's disease studied prospectively during life. RESULTS: The main neuropathological correlate of persistent visual hallucinations was the presence of less severe tangle pathology, but there was no significant association between tangle pathology and persistent delusions. Lewy body staging was associated with the presence of persistent visual hallucinations and persistent delusions. All baseline psychiatric features were significantly more frequent in dementia with Lewy bodies than in Alzheimer's disease, as were persistent visual hallucinations, but patients who had dementia with Lewy bodies and severe tangle pathology had a clinical symptom profile more similar to that of Alzheimer's disease patients and were less likely to have neocortical Lewy bodies. CONCLUSIONS: The modest proportion of patients with Lewy body dementia and more severe tangle pathology resembled Alzheimer's disease patients clinically. Unlike Alzheimer's disease, dementia with Lewy bodies showed a significant inverse association between tangle burden and psychosis.     

Duration of untreated psychosis and time to treatment response for delusions and hallucinations

OBJECTIVE: Duration of untreated psychosis is associated with time to treatment response among patients with schizophrenia. However, individual psychotic symptoms have not been investigated in this context. The authors examined the relationship between duration of untreated psychosis and time to response for hallucinations and delusions. METHOD: Data were available for 118 patients with first-episode schizophrenia in a longitudinal treatment study. Patients received open-label treatment with conventional antipsychotics and were followed for up to 5 years. Duration of untreated psychosis was correlated with time to response for delusions and hallucinations, and predictors of time to response were examined. RESULTS: Time to response for delusions was significantly longer than that for hallucinations. Duration of untreated psychosis was significantly correlated with time to response for delusions but not for hallucinations. In regression analyses, duration of untreated psychosis was the only predictor for time to response for delusions; it was not a predictor for hallucinations. CONCLUSIONS: The results suggest that duration of untreated psychosis may be specifically associated with time to response for delusions. This association may have clinical implications.     

The relationship between delusions and depression in Alzheimer's disease

OBJECTIVES: The aim of this investigation was to study the relationship between delusions and depression in Alzheimer's disease (AD). DESIGN: This was a cross-sectional, case control study. SETTING: Neuropsychiatry Service, the Johns Hopkins School of Medicine, USA. PARTICIPANTS: 303 community-residing patients with probable AD according to NINCDS/ADRDA criteria were included in the study. Seventy-five patients with delusions only were compared to a control group of 228 patients who had neither delusions nor hallucinations. Patients with only hallucinations or both delusions and hallucinations were excluded. MEASURES: Patients were assessed clinically for the presence of delusions using the DSM-IV glossary definitions. They were also rated on standardized measures of depression, cognitive impairment, staging of dementia, general medical health, and functional impairment. RESULTS: There was an association between delusions and depression among patients with AD. Before adjustment for other variables, the presence of depression conferred a 1.8-fold (95% confidence intervals (CI) = 1.0-3.1; p = 0.04) higher risk of delusions. After adjustment for multiple other variables, this risk increased further to 6.8-fold (95% CI = 2.1-21.6; p = 0.001). CONCLUSIONS; Delusions in AD are strongly associated with depression after statistical adjustment for all confounding variables, which might distort this association. This finding has implications for our understanding of the etio-pathogenesis and management of delusions and depression in AD.     

Prevalence and clinical correlates of psychotic symptoms in Alzheimer's disease

Psychotic symptoms occur commonly in Alzheimer's disease (AD), predict a more rapid rate of cognitive decline and increase the risk of aggressive behaviour. Seventy patients with probable AD, recruited from an old age psychiatry service, were assessed to determine the prevalence and clinical correlates of delusions and hallucinations. Psychiatric symptoms were measured using the Behavioural Pathology in Alzheimer's Disease Rating Scale (BEHAVE-AD), Hamilton Rating Scale for Depression (HRSD) and the Depressive Signs Scale (DSS). Thirty-four per cent of the sample experienced delusions and 11% hallucinations in the previous month. Men were more likely than women to have experienced psychotic symptoms. Psychotic and non-psychotic groups did not differ in age, age at illness onset, dementia severity, HRSD or DSS scores. This study confirms the high prevalence of psychotic symptoms in AD patients encountered in clinical practice, and suggests that psychosis and depression represent independent behavioural disturbances in AD. © 1998 John Wiley & Sons, Ltd.     

Stage-specific gender differences in cognitive and neuropsychiatric manifestations of vascular dementia

Studies on gender differences in the clinical manifestations of vascular dementia (VaD) are still lacking. In the present study, gender comparisons of cognitive and neuropsychiatric profiles were conducted separately for mild and moderate-to-severe VaD in a total of 467 patients with VaD. There were no significant gender differences in cognitive manifestations, except that females performed better on immediate verbal recall than males in mild stage. Women were more likely to exhibit delusions (15.5% vs 7.4%), hallucinations (9.5% vs 3.4%), and depression (43.1% vs 27.3%) in mild stage. The predominance of male patients was observed in apathy at moderate-to-severe stage (50.5% vs 34.8%). To conclude, gender differences existed in neuropsychiatric symptoms of VaD and were especially pronounced in mild stage. Delusions, hallucinations, and depression were more prevalent in females in mild VaD, with the male predominance only in apathy in the later stage.     

Behavioural pathology in Alzheimer's disease with special reference to apolipoprotein E genotype

The aim of this study was to define the co-occurrence of behavioural symptoms and Alzheimer's disease (AD) in relation to apolipoprotein E (APOE) genotype. Probable AD patients from the Alzheimer's Day Clinic (n = 139) were assessed with the 'Behavioural Pathology in Alzheimer's Disease' rating scale, and their APOE genotype was determined. This study demonstrated no relationship between presence of the APOE epsilon4 allele and any of the behavioural symptoms assessed, including delusions, hallucinations, depression, activity disturbances, aggressiveness and anxiety. Activity disturbances, delusions, hallucinations and aggressiveness paralleled the severity of AD, increasing in frequency with the severity of the dementia. The prevalence of delusions, hallucinations, aggressiveness and depression were found to be associated with lower levels of education.     

An instrumental study of the relationship between extrapyramidal signs and psychosis in Alzheimer's disease

Neurobehavioral disturbances often coexist with extrapyramidal signs (EPS) in patients with Alzheimer's disease (AD). In the present study, we examined the relationships between delusions and hallucinations and EPS by using standard observer ratings and sensitive electromyographic (EMG) measures in 52 patients with probable AD. On the basis of observer ratings, 36.5% of the patients exhibited psychotic features and 63.5% exhibited parkinsonism. Severity of clinically rated parkinsonism and the EMG measure of bradykinesia were significantly correlated with severity of neurobehavioral disturbances in this sample. The association between parkinsonism and delusions and hallucinations suggests a subcortical mechanism in the etiopathology of psychosis in AD.     

Role of serotonin transporter polymorphisms in the behavioural and psychological symptoms in probable Alzheimer disease patients

BACKGROUND/AIMS: Alzheimer disease (AD) patients commonly suffer from behavioural and psychological symptoms of dementia (BPSD). A genetic component to BPSD development in AD has been demonstrated. This is an investigation of whether the linked polymorphic region and variable number tandem repeat variants of the serotonin transporter (SERT) are associated with BPSD. METHODS: The longitudinal measures of BPSD of our large cohort of 367 AD patients were assessed by the Neuropsychiatric Inventory. Measures with good evidence of serotonergic involvement (delusions, hallucinations, depression, anxiety, agitation/aggression and irritability) were related to genotype and allele frequencies of the linked polymorphic region and variable number tandem repeat variants. RESULTS: Analysis revealed significant relationships between the linked polymorphic region variant long allele with irritability and the variable number tandem repeat 10-repeat allele with psychosis, but no associations were found with depression, anxiety or agitation/aggression. CONCLUSION: Our data and review of previous studies suggest SERT could play a minor role in development of psychosis and aggressive/irritable tendencies; however, further investigations are required in large, well-characterized cohorts.