Abstract
In Alzheimer’s disease (AD) patients with delusions, clinical outcomes and mortality result from a combination of psychological, biological, functional, and environmental factors. We determined the effect of delusions on mortality risk, clinical outcomes linked to comprehensive geriatric assessment (CGA), cognitive, depressive, and neuropsychiatric symptoms (NPS) in 380 consecutive AD patients with Mini-Mental State Examination, Clinical Dementia Rating scale, 15-item Geriatric Depression Scale, and Neuropsychiatric Inventory (NPI), assessing one-year mortality risk using the Multidimensional Prognostic Index (MPI). We included 121 AD patients with delusions (AD-D) and 259 AD patients without delusions (AD-noD). AD-D patients were significantly older, with higher age at onset and cognitive impairment, a more severe stage of dementia, and more depressive symptoms than AD-noD patients. Disease duration was slightly higher in AD-D patients than in those without delusions, although this difference was not statistically significant. At CGA, AD-D patients showed a higher grade of disability in basic and instrumental activities of daily living, and an increased risk of malnutrition and bedsores. The two groups of patients significantly differed in MPI score (AD-D: 0.65 versus AD-noD: 0.51, p < 0.0001) and MPI grade. AD-D patients showed also a significant higher score in NPI of the following NPS than AD-noD patients: hallucinations, agitation/aggression, depression mood, apathy, irritability/lability, aberrant motor activity, sleep disturbances, and eating disorders. Therefore, AD-D patients showed higher dementia severity, and higher impairment in cognitive and depressive symptoms, and several neuropsychiatric domains than AD-noD patients, and this appeared to be associated with higher multidimensional impairment and increased risk of mortality.
Keywords
INTRODUCTION
Delusion is a belief that is clearly false and that indicates an abnormality in the affected person’s content of thought, typically occurring in the context of neurological or mental illness. Three main criteria define a belief to be considered delusional, i.e., certainty (held with absolute conviction), incorrigibility (not changeable by compelling counterargument or proof to the contrary), and impossibility or falsity of content [1, 2].
Delusion content may include a variety of themes (e.g., persecutory, referential, somatic, religious, and grandiose) [3] and is a common, disabling, and persistent symptom in the course of dementia [4–7]. The mechanisms underlying delusions in Alzheimer’s disease (AD) patients have not been fully clarified [8, 9]. Delusions in AD patients may be related to female gender [10–14], whereas other studies reported that males were more likely to have delusions than females [15], or no significant difference [16]. The relationships between delusions and age [10, 16], educational level [17], and severity of dementia [18] have also been controversial in previous reports [12, 19–22]. Some studies reported that there was a significant correlation between delusions and scores on generalized cognitive tests such as the Mini-Mental State Examination (MMSE) [17, 24] whereas other studies reported that there was no significant correlation[13, 16].
In AD patients with delusions, clinical outcomes and mortality result from a combination of psychological, biological, functional, and environmental factors. Therefore, outcome measures linked to multidimensional impairment may be extremely important in making clinical decisions, especially for drug treatment. Recently, a Multidimensional Prognostic Index (MPI) for one-year all-cause mortality and derived from a standardized Comprehensive Geriatric Assessment (CGA) was developed and validated in two independent cohorts of older hospitalized patients for acute diseases (Table 1) [25] or relapse of chronic diseases [26–38], and it was used to track global response to treatment in patients with specific chronic morbidity [31, 39]. The aim of the present study was to determine the prevalence and the effects of delusions in patients with AD on mortality risk, clinical outcomes linked to CGA, and cognitive, depressive, and neuropsychiatric symptoms (NPS).
METHODS
Subjects
This study was conducted on the basis of the guidelines for Good Clinical Practice, the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) and was approved by the local ethics committee. Written informed consent for research was obtained from each patient or from.
Patients consecutively evaluated from September 2007 to March 2015 at the Alzheimer’s Evaluation Unit of the Geriatrics Unit of the IRCCS “Casa Sollievo della Sofferenza”, Italy, were screened for eligibility. Inclusion criteria were: 1) age ≥65 years; 2) ability to provide an informed consent or availability of a relatives or a legal guardian in the case of severe demented patients; 3) diagnosis of AD according to the criteria of the National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer’s Disease and Related Disorders Association Work Group (NINCDS-ADRDA) [40]; 4) a complete CGA. Exclusion criteria were: 1) diagnosis of vascular dementia (VaD); 2) presence of serious comorbidity, tumors and other diseases that could be causally related to cognitive impairment (ascertained blood infections, vitamin B12 deficiency, anemia, disorders of the thyroid, kidneys, or liver); 3) history of alcohol or drug abuse, head trauma, and other causes that can cause memoryimpairment.
Cognitive evaluation and diagnosis of dementia
In all patients, cognitive status was screened with the MMSE [23], and the Clinical Dementia Rating scale (CDR) [41]. In particular, the CDR was a scale designed to grade subjects from normal function through various stages of dementia. It is composed of several domains assessing cognition and function and rated according to the degree of cognitive loss as follows: 0 (no dementia), 0.5 (uncertain or deferred diagnosis), 1 (mild dementia), 2 (moderate dementia), and 3 (severe dementia) [42].
Dementia was diagnosed following the Diagnostic and Statistical Manual of Mental Disorders - Fifth Edition (DMS-5) [3]. Diagnoses of possible/probable AD were made according to the NINCDS-ADRDA criteria [40]. Diagnoses of possible/probable VaD were made according to the criteria of the National Institute of Neurological Disorders and Stroke - Association Internationale pour la Recherche et l’Enseignement en Neurosciences Work Group (NINDS-AIREN) [42]. In unclear cases, differential diagnosis between AD and VaD was based also on the Hachinski Ischemic Score: scores ≤4 were considered as probable AD, scores ≥7 were diagnosed as VaD [44]. Diagnosis of AD and VaD was always supported by neuroimaging evidence (CT scan and/or NMR). In particular, the presence of multiple cortical/subcortical infarcts or an infarct in a strategic area such as the thalamus or temporal lobe and/or lesions of the white matter indicated probable VaD; the absence of the above-mentioned cerebrovascular lesions indicated AD. The age at onset (AAO) of AD symptoms was estimated by semistructured interviews with the patients’ caregivers [45] and disease duration and delusion symptom duration were also calculated for AD patients.
Neuropsychiatric and depressive assessment
Depressive symptoms were evaluated using the 15-item Geriatric Depression Scale (GDS-15) [46]. The Neuropsychiatric Inventory (NPI) is based on a structured interview with a caregiver and/or patient’s relative [47]. The following 12 neuropsychiatric domains were evaluated: delusions, hallucinations, agitation/aggression, depression mood, anxiety, euphoria, apathy, disinhibition, irritability/lability, aberrant motor activity, sleep disturbances, and eating disorders. For each domain, a screening question is asked to determine if the behavioral change is present or absent. If the answer is positive the domain is explored at greater depth with the sub-questions. If the sub-questions confirm the screening question, frequency is rated from 1 to 4 and severity is scored from 1 to 3. The product (severity × frequency) is calculated for each behavioral change present during the previous month or since the last evaluation. Patients with NPS were identified on the basis of the following parameters: presence of any delusions or hallucinations on the NPI (i.e., a score of ≥1 on either subscale), and/or dysphoria score >6, anxiety score >6, disinhibition score >4, irritability/lability score >2, and/or score on the apathy, agitation/aggression, euphoria, aberrant motor behavior, sleep disturbance, and eating disorder subscale >1 [47]. Symptoms reported on the subscale delusions were classified in delusions of theft, delusion of infidelity, delusion of abandonment, and delusion of persecution.
The comprehensive geriatric assessment (CGA)
A CGA was carried out using assessment instruments widely employed in geriatric practice. Functional status was evaluated by activities of daily living (ADL) index [48], and by instrumental activities of daily living (IADL) scale [49]. Cognitive status was screened by the Short Portable Mental Status Questionnaire (SPMSQ) [50]. Comorbidity was examined using the Cumulative Illness Rating Scale Comorbidity Index (CIRS-CI) [51]. Nutritional status was explored with the Mini Nutritional Assessment (MNA) [52]. The Exton-Smith Scale (ESS) was used to evaluate the risk of developing pressure sores [53]. Medication use was defined according to the Anatomical Therapeutics Chemical Classification code system, and the number of drugs used by patients was recorded. Social aspects included household composition, home service, and institutionalization.
The Multidimensional Prognostic Index (MPI)
To predict mortality and evaluate frailty we used the MPI [25], an algorithm developed by the inclusion of information from the domains of the CGA. For each domain a tripartite hierarchy was used, i.e., 0 = no problems, 0.5 = minor problems, and 1 = major problems. The sum of the calculated scores from the eight domains was divided by 8 to obtain a final MPI risk score between 0 = no risk and 1 = higher risk of mortality. Also, the MPI was expressed as three grades of risk: MPI-1 low risk (MPI value ≤0.33), MPI-2 moderate risk (MPI value between 0.34 and 0.66) and MPI-3 severe risk (MPI value >0.66). To calculate the MPI is available an informatics, easy to use free tool (http://www.operapadrepio.it/contenuti/ricerca/Calculate_MPI.zip, Apple Store).
Statistical analyses
For dichotomous variables, hypotheses regarding differences between the groups were tested using the Fisher’s exact test. This analysis was made using the 2-Way Contingency Table Analysis available at the Interactive Statistical Calculation Pages (The R Project for Statistical Computing; available at URL http://www.r-project.org/). For continuous variables, normal distribution was verified by the Shapiro-Wilk normality test and the one-sample Kolgomorov-Smirnov test. For normally-distributed variables, hypotheses regarding differences among the groups were compared by means of the Welch two sample t-test or by means of the analysis of variance (ANOVA) under general linear model. For non-normally-distributed variables, hypotheses regarding differences among the groups were compared by means of the Wilcoxon rank sum test with continuity correction or by means of the Kruskal-Wallis rank sum test. All the statistical analyses were made with the R Ver. 2.8.1 statistical software package (The R Project for Statistical Computing; available at URL http://www.r-project.org/). Tests in which the p value was smaller than the type I error rate α= 0.05 were declared significant.
RESULTS
Clinical and functional characteristics of AD patients with and without delusions
During the enrolment period, 395 elderly patients were screened for the inclusion in the study. Of these, 5 patients were excluded because they were younger than 65 years, 6 patients had an incomplete examination, and 4 patients had severe comorbidity associated with cognitive impairment. Thus, the final population included 380 patients, 143 men (37.6%) and 247 women (62.4%) with a mean age of 80.06 years ± 5.68 and a range from 65 to 96 years. Therefore, 121 patients had a diagnosis of AD with delusions (AD-D) and 259 patients of AD without delusions (AD-noD).
Demographic and clinical characteristics of AD-D patients and AD-noD patients are summarized in Table 2. The two groups of patients did not differ in following parameters: gender distribution (p = 0.636), educational level (p = 0.055), CIRS-CI (p = 0.364), number of medications (p = 0.370), and social support network distribution (p = 0.338). AD-D patients were significantly older (81.62 versus 79.32 years, p < 0.0001), with higher AAO (79.22 versus 77.21 years, p < 0.0001), higher grade of cognitive impairment (MMSE: 13.74 versus 15.93, p < 0.0001), a more severe stage of dementia (CDR: 2.21 versus 1.79, p < 0.0001), and more depressive symptoms (GDS-15:7.11 versus 5.75, p = 0.004) than AD-noD patients. Disease duration was slightly higher in AD-D patients than in those without delusions (2.26 versus 2.40), although this difference was not statistically significant (p = 0.076), and delusion symptom onset began 1.1 years after AAO of the disease in AD-D patients (mean delusion symptom duration: 1.3 years). Moreover, AD-D patients showed a higher disability at the ADL (2.57 versus 3.53, p < 0.0001) and IADL (0.54 versus 2.68, p < 0.0001), a higher risk of malnutrition (MNA: 18.14 versus 21.51, p < 0.0001) and bedsores (ESS: 15.56 versus 16.00, p < 0.0001). The two groups of patients significantly differed in MPI score (AD-D: 0.65 versus AD-noD: 0.51, p < 0.0001) and in MPI grade (AD-D: MPI-1 = 9.9% , MPI-2 = 41.3% and MPI-3 = 48.8% versus AD-noD: MPI-1 = 25.5% , MPI-2 = 50.6% and MPI-3 = 23.9% , p < 0.0001).
Neuropsychiatric symptoms in AD patients with and without delusions
NPS in AD-D and AD-noD patients are summarized in Table 3. AD-D patients showed a significantly higher score about product (severity × frequency) of the following neuropsychiatric domains than AD-noD patients: hallucinations (4.45 versus 0.68, p < 0.0001), agitation/aggression (6.97 versus 3.28, p < 0.0001), depression mood (5.07 versus 3.92, p = 0.007), apathy (8.93 versus 7.11, p < 0.0001), irritability/lability (7.40 versus 2.99, p < 0.0001), aberrant motor activity (3.04 versus 0.61, p < 0.0001), sleep disturbances (6.35 versus 3.82, p < 0.0001), and eating disorders (3.92 versus 1.97, p < 0.0001). In according to the subscale delusions, AD-D patients showed the presence of following delusion types (Table 4): delusions of theft (50.4%), delusions of infidelity (8.3%), delusions of abandonment (25.6%), and delusions of persecution (15.7%). Figure 1 shows a visual analogic picture of the delusion types in AD-D by dementia severity. Even if the overall distribution of delusion types did not differ among the three groups of patients, subjects with moderate cognitive impairment demonstrated higher frequency in all delusion types even if not significant. Figure 2 shows a visual analogic picture of the delusion types in AD-D by MPI grade. Patients with MPI-3 demonstrated a significant higher frequency in delusions of theft (p = 0.001) and delusions of infidelity (p = 0.032). Patients with MPI-2 demonstrated a significant higher frequency in delusions of abandonment (p = 0.032).
DISCUSSION
In the present study, using a relatively large sample of AD patients, we investigated the presence/absence of delusions. AD-D patients were older and showed higher AAO, higher cognitive impairment a more severe stage of dementia, and more depressive symptoms than AD-noD patients. Moreover, the presence of delusions in AD-D appeared to influence also the development of several other NPS, including hallucinations, agitation/aggression, depression mood, apathy, irritability/lability, aberrant motor activity, sleep disturbances, and eating disorders. The presence of delusions could also significantly influence the multidimensional assessment of these AD patients, as showed by the significantly worsening in several domains of the CGA and the increased mortality risk evaluated with the MPI.
NPS in dementia are often more distressing, impairing, and costly than cognitive symptoms, representing a major health burden for older adults [54]. In the present study, the point prevalence of delusions in AD was of 31.8% . In other similar case series, estimates of the prevalence of delusions in AD vary widely, from a point prevalence of 15% to 76% [55–59]. These estimates may vary with different methods and samples among the studies, with the highest rates being found when structured assessment instruments are used [60]. Among delusion types, in the present case series, we found a 50% of AD patients with delusions of theft and a quarter of the sample with delusions of abandonment confirming previous studies on delusional beliefs in AD [56, 61] showing a higher prevalence of delusions of theft (20–75% of persecutory delusions) [59].
In our study, the role of gender did not impact the development of delusions in AD. Gender and other demographic variables showed contrasting findings as possible risk factors or predictors of delusions in AD, as pointed out in two reviews on this topic by Fischer [62] and Cipriani and colleagues [60]. According to Devanand and colleagues [63] and Bassiony and Lyketsos [12], we found that delusions in AD were associated with older age. Furthermore, in the present study, AD-D patients showed a significantly higher score in depressive symptoms and NPS including hallucinations, agitation/aggression, depression mood, apathy, irritability/lability, aberrant motor activity, sleep disturbances, and eating disorders. Delusions have been associated with agitation or aggression in patients with dementia [65, 66]. Lam and colleagues showed that delusional ideation in AD patients was significantly associated with hallucinations, aggressiveness, and affective disturbances [67]. The association between delusions and hallucinations was confirmed also in a cross-sectional case–control study where 9% of patients experienced both delusion and hallucinations, 22% had delusions only, and 3% had hallucinations only [68]. Furthermore, according to Paulsen and colleagues [69], the cumulative incidence rates for hallucinations and delusions in patients with a clinical diagnosis of probable AD was 20.1% , 36.1% , 49.5% , and 51.3% , at 1-, 2-, 3-, and 4-year post-baseline evaluations, indicating that the severity of cognitive impairment and the rate of cognitive decline were predictive of delusions, similar to the present study in which AD-D patients showed higher AAO, dementia severity, and a higher level of cognitive impairment than AD-noD patients. In a review by Ropacki and Jeste [22], the severity of cognitive impairment showed a significantly positive association with the presence of NPS in AD patients in twenty studies, and no association in ten studies. In the present study, disease duration was slightly higher in AD-D patients than in those without delusions, although this difference was not statistically significant, and delusion symptom onset began 1.1 years after AAO of the disease in AD-D patients. These findings may suggest that the AD-D group may be a potential sub-type of patients and that this NPS did not appear only due to advanced stages of the disease in our sample. Specifically, Ropacki and Jeste [22] have suggested that AD patients with delusions should be regarded as a more aggressive sub-type of the disease. However, Bassiony and Lyketsos [12] have suggested that this may not be the case given that delusions may commonly co-exist with other NPS and are unlikely to occur in isolation. On the other hand, NPS can manifest also nearly in the course of neurodegenerative diseases and Mild Behavioral Impairment (MBI) has been proposed as a diagnostic construct aimed to identify patients with an increased risk of developing dementia, but who may or may not have cognitive symptoms [70]. Very recently, the NPS Professional Interest Area of the International Society to Advance Alzheimer Research and Treatment (ISTAART) proposed research diagnostic criteria for MBI, as an extension of the pre-existing MBI construct to include, but not mandate cognitive impairment, including mild cognitive impairment in the MBI framework [71].
In the present study, the presence of delusions could significantly influence the multidimensional assessment of these AD patients, as showed by the significant worsening in several domains of the CGA and in the increased mortality risk assessed with the MPI. In particular, AD-D patients showed at CGA performed with all MPI domains a higher grade of disability in ADL and IADL, and an increased risk of malnutrition (MNA score) and bedsores (EES score) than patients with AD-noD, confirming also higher cognitive impairment assessed with the SPMSQ. These findings confirmed previous studies suggesting an impact of delusional thoughts on functional status in AD [72–74], with also some notable exceptions [75, 76]. A systematic review on this topic also suggested there may be an association between delusions in AD and impaired real-world functioning [77]. MPI is a valuable prognostic tool wide validated in older hospitalized patients with dementia and other acute and chronic diseases [26–29] that permits a clear risk mortality stratification, representing one of the better options in this field as recently showed in two extensive systematic reviews [78, 79]. In the present study, AD-D patients showed a higher risk of mortality assessed with the MPI, and AD patients with MPI-3, therefore at increased mortality risk, demonstrated a significant higher frequency in delusions of theft and delusions of infidelity, confirming previous reports suggesting that NPS commonly may lead to earlier nursing home placement, excess morbidity, and mortality [80]. Furthermore, Tsai and colleagues proposed delusions as a suicide risk factor in dementia, with 7 out of 117 demented patients presenting delusions that attempted suicide [81].
Mechanisms underlying delusion in patients with AD remain unclear. The etiology of NPS in neurodegenerative disorders is complex including a variety of interactions between genetic and personality factors, medication exposure, neurochemical changes, and comorbid conditions, particularly cognitive impairment [82]. For delusions associated with dementia and AD, possible underlying mechanisms included three models: 1) delusions can evolve from brain damage, caused by dementia; 2) delusions can evolve from the person’s response to the environment, which is restricted by the impairments caused by dementia; and 3) delusions might reflect a separate disorder unrelated to dementia [83]. Some neuroimaging studies have suggested an association between psychotic symptoms in AD and frontal lobe dysfunction [58, 84]. Several postmortem studies emphasized the important role of senile plaque and neurofibrillary tangle density in AD plus delusions, suggesting that frontal senile plaques and neurofibrillary tangles are associated with delusions [85, 86]. Neurofibrillary tangle burden is higher in the left orbitofrontal cortex of AD patients who had higher agitation scores [87]. An association between delusions and atrophy primarily in the right frontoparietal regions was identified [88]. Some limitations of the present study must be acknowledged. In fact, nonetheless the large sample of AD patients investigated, the main limitation was the cross-sectional nature of our findings and without a direction of causality, the associations among delusions and different sociodemographic, clinical, cognitive, and NPS could not have a predictive impact. Furthermore, the study population comprising only Caucasian patients recruited in a single center,so it could be possible that our results may not be applicable in other populations. Larger prospective multicenter studies are therefore needed to confirm the present findings. In the present study, AD-D patients were significantly older and showed a higher impairment in cognitive, depressive, and NPS than AD-noD patients. In particular, AD-D patients showed a significantly higher score in several neuropsychiatric domains, including hallucinations, agitation/aggression, depression mood, apathy, irritability/lability, aberrant motor activity, sleep disturbances, and eating disorders. Moreover, among CGA-based clinical outcomes, AD-D patients showed a higher disability, an increased risk of malnutrition and bedsores, and a higher multidimensional impairment with an increased risk of mortality assessed with theMPI.
