Impact of Dementia-Related Behavioral Symptoms on Healthcare Resource Use and Caregiver Burden: Real-World Data from Europe and the United States

INTRODUCTION

Dementia means the inability to function independently in everyday activities after significant cognitive decline, the most common etiology of which is Alzheimer’s disease (AD). Around 50 million people have dementia worldwide and it is currently the fifth leading cause of death [1]. The global prevalence of dementia is projected to reach 82 million in 2030 and 152 million in 2050 [1]. Dementia mainly affects older people; however, it is not considered a normal part of aging. It is one of the most disabling conditions worldwide and the disease burden increases with the aging global population. Dementia has significant social and economic implications: In 2015, the total global societal cost was estimated at US$ 818 billion, equivalent to 1.1%of global gross domestic product [1]. There is currently no available treatment to cure or slow the progressive course of dementia, although several treatments are being investigated in clinical trials.

The main symptom of dementia is the progressive impairment in cognitive function, affecting an individual’s memory, thinking, orientation, comprehension, learning, language, and judgement. Cognitive impairment (CI) is commonly accompanied by neurobehavioral symptoms, which can include depression or dysphoria (a profound sense of unease or dissatisfaction), anxiety, apathy, psychosis, irritability, aggression, impulsivity, and sleep disorders [2–4]. Neurobehavioral symptoms affect nearly all patients living with dementia at some point in their disease course [3, 5, 6] and increase as the disease progresses [6].

Three European studies (the Maastricht Study of Behavior in Dementia, the Réseaux Alzheimer Français, and the European AD Consortium [EADC]) provided details of the most common neurobehavioral symptoms in dementia. Apathy was the most common abnormality (observed in 48–64%of patients across the studies), followed by depression (37–57%) and anxiety (34–46%). Agitation and irritability were also common symptoms [2, 5, 7, 8].

Neurobehavioral symptoms are a major challenge and drive a large proportion of the social burden of dementia, for both patients and their caregivers; and thus they are important targets for intervention [4, 9, 10]. These symptoms have become the focus of research in recent years [2, 4] and are now recognized to be as clinically significant as cognitive decline [9].

Some of this research has focused on groups of symptoms. A consensus review paper from the EADC suggested there was some evidence for groups of correlated symptoms which could be studied together [2]; however, most studies do not use symptom groups but study individual symptoms or total symptom scores. van der Linde et al. (2013) carried out a literature review including 62 studies in order to identify clusters or factors of behavioral and psychological symptoms in dementia [4]. The studies investigating symptom groups showed relatively consistent results, i.e., generally the included studies used the following symptom groups: affective symptoms (including depression and anxiety), psychosis (including delusions and hallucinations), hyperactivity (including irritability and aggression), and euphoria. The authors suggested symptom groups may differ in their associations, treatment, and underlying biology. Of interest, no clear differences were seen between studies of populations with different levels of cognitive function, i.e., mild CI to moderate/severe dementia [4]. In agreement with this, Zuidema et al. (2007) found that groups of neuropsychiatric symptoms were relatively stable across dementia stages in Dutch nursing home residents [11]. Furthermore, two studies investigating co-occurrence of symptoms using factor analysis found that the factor structure was largely consistent across non-dementia groups (patients with mild CI subtypes and with mild to moderate CI) and was similar, although with weaker associations, to that seen in a population with dementia [12, 13]. Yet, other studies are in disagreement with these findings, suggesting that greater CI or dementia severity is associated with higher rates of neurobehavioral symptoms [6, 14, 15].

Studying symptom groups allows similar symptoms to be studied together, which might strengthen results and may point to differences in their etiology and treatment [4]. However, little research has investigated the effect of these specific symptom groups on health-related outcomes, particularly healthcare resource use (HCRU) and patient quality of life (QoL).

In light of the previous research, the primary aim of the current study was to investigate the impact of neurobehavioral symptoms (namely agitation/aggression and related symptoms [AARS]) in dementia on health-related outcomes of HCRU, patient QoL, and caregiver burden.

MATERIALS AND METHODS

RESULTS

DISCUSSION

We analyzed real-world data for patients with dementia, obtained via their treating physicians and their caregivers. Associations between groups of neurobehavioral symptoms and HCRU, patient QoL, and caregiver burden were examined by multiple regression analyses.

Each symptom group of interest (AARS with psychosis, AARS without psychosis, and other behavioral symptoms [non-AARS]) had a positive association with the HCRU variables of interest (hospitalizations, consultations, and use of medications), i.e., HCRU was greater with the presence of these symptoms. Overall, AARS with psychosis generally had the strongest detrimental effect on the HCRU outcomes: hospitalizations in the last 12 months (for any condition and relating to CI), consultations in the last 12 months, and current antipsychotic treatment, compared with patients with AARS without psychosis and patients with no behavioral symptoms (the control group).

In addition, each symptom group had a negative association with proxy measures of patient QoL (the EQ-5D-3L and EQ-VAS), i.e., patient QoL was decreased. The magnitude of effect was comparable in patients with AARS with and without psychosis for the EQ-5D-3L measure but larger in patients with AARS with psychosis compared with those with AARS without psychosis for the EQ-VAS. Furthermore, each symptom group had a positive association with each ADL outcome, indicating that patients with these symptoms required greater help with everyday activities. The magnitude of effect was clearly largest in patients with AARS with psychosis versus the other symptom groups, i.e., they required the greatest help with ADLs.

In general, symptom groups were also associated with greater caregiver burden as seen through measures of caregiver QoL (EQ-5D-3L and EQ-VAS), effects on work and activity impairment (WPAI), and the impact of patient dementia on their life (ZBI). As with the other measures, the magnitude of the effect was generally larger in caregivers of patients with AARS with psychosis versus caregivers of patients with AARS without psychosis.

Regression analysis covariates that were found to be most often significantly related to the outcomes were dementia severity (moderate and severe versus mild) and patients’ living situation (whether they were in nursing home versus in the community). Of interest, several covariates differed between locations in Europe compared with in the US; for example, a larger number of hospitalizations for CI, total consultations, and the use of any treatment were seen in the US versus Europe. Whereas a decrease in patient and caregiver QoL was significantly related to the Europe region versus the US. This warrants further investigation but could potentially be owing to the different healthcare and funding environments between Europe and the US; for example, there are more government owned and run universal healthcare systems in Europe compared with American hybrid (predominantly private sector) systems and generally higher healthcare spending.

Overall, all three symptom groups had detrimental effects on HCRU, patient QoL, and caregiver burden, which highlights the overall burden of CI/dementia. To add to this, the higher the neurobehavioral symptom burden, particularly aggressive, agitated symptoms with additional psychosis, the more detrimental effect it seemed to have on health-related outcomes. The finding that patients’ dementia severity and living situation were the factors most related to the outcomes is not surprising. It makes sense that increasing disease severity increases burden, owing to patients’ increasing needs as their disease progresses, and several studies support this finding [6, 14, 15]. Still, this relationship is not clear cut as there are a number of other studies which have found that neurobehavioral symptoms are relatively stable across CI and dementia stages [4, 11–13]. A community versus a nursing home living situation was particularly detrimental to caregiver burden. This could also be expected as community living would put increased pressure on caregivers, owing to the lack of formal or additional care associated with living at home.

Our results are also in agreement with previous research showing that AARS and psychosis are consistent problems for caregivers across the whole range of dementias [4]. For example, aggression and agitation are some of the most frequently cited symptoms associated with caregiver depression, burden, and burnout [6, 10, 23, 24]. Plus, neurobehavioral symptoms are often cited as one of the main reasons for referring patients to nursing homes, and in particular symptoms such as physical aggression, psychosis, anxiety, hallucinations, and depression [25].

Detrimental effects of dementia on patient QoL, HCRU, and costs have also been previously reported. For example, Handels et al. (2018) reported costs related to formal and informal care use, and patient-reported and proxy QoL in patients with dementia in 8 European countries, noticing differences due to organization and management of care between countries [26]. We believe the current study is the first of its kind, adding evidence of the specific burden of neurobehavioral symptoms to previously described factors contributing to lower patient QoL, greater HCRU, and caregiver burden.

According to a consensus statement by Finkel et al. (1996), ‘The behavioral and neuropsychological signs and symptoms of dementia are integral elements of the disease process and, therefore, are a legitimate concern of healthcare providers. These symptoms present severe problems to all those who interact with the patients as well as to the patients themselves, and to society and its health services’ [9]. In a consensus paper from the EADC, Robert et al. (2005) suggested that further understanding of these symptoms was needed as it may offer better treatment opportunities [2]. The current results are in agreement with previous findings that have suggested the presence of groups of symptoms in dementia that can be studied together, which might strengthen results, expose differences in their etiology, and lead to new options for treatment [4]. However, at this stage in the research there is a large amount of individual variability, and distinct symptom groups have yet to be established.

The current study offers a number of applications and implications for ongoing research. For example, there are implications for intervention development, and identifying patients and caregivers at risk of problems, e.g., depression and burnout. The research suggests that particular support should be given to caregivers of patients expressing aggression, agitation, and other neurobehavioral symptoms [24].

Furthermore, while there are currently no effective treatments to slow the progression of CI in dementia, there are a range of interventions that may help to manage neurobehavioral symptoms. Although treating AARS in dementia is seen as a major challenge, practical strategies can be applied for common behavioral symptoms, including using both non-pharmacologic measures (such as ergotherapy, physical therapy, music therapy, and work with family members) and medications (e.g., risperidone, haloperidol, or aripiprazole for agitation and aggressiveness) [27, 28].

Future research should focus on building a consensus on how to study AARS symptoms, e.g., whether they should be treated as single symptoms or in clusters, taking into account correlations with other similar symptoms. van der Linde et al. (2013) highlighted the issue of heterogeneity of symptoms in their literature review and suggested that authors should carefully address their research questions and hypotheses to decide if symptoms should be studied in groups or individually [4]. Finkel et al. (1996) offered their views on the importance of developing more applicable methods for assessing neurobehavioral signs and symptoms, including longitudinal evaluations; and of further work on their underlying pathogenic mechanisms and the clinical, social, and societal impact [9]. Finally, aging populations and demographic changes suggest that countries around the world are facing huge challenges in the current and future long-term management and funding of people with dementia [26].

This study has several limitations that should be considered. For example, the sample collected was pseudo-random rather than a truly random sample, since the physicians were required to collect data for the next 10 consecutively consulting patients. The retrospective nature of the data collection meant that the methodology relied on accurate reporting by physicians and caregivers. In light of this, missing data were to be expected and may have influenced results, and there may have been recall bias. Missing data can cause various problems, such as reducing statistical power and precision, causing bias, and reducing the representativeness of the sample, which may affect the conclusions that can be drawn from the data. In light of this, the missing values for each variable of interest are presented in Supplementary Table 4 and should be considered when interpreting the results.

Owing to the potential unreliability of self-reported patient responses, particularly from those with more severe levels of CI, the patient QoL measures were completed by the caregiver on the patients’ behalf and the ADLs were reported by the physician on the patient record form. However, this approach could have led to inaccuracies, as demonstrated in some other studies which have shown a degree of discordance between patient- and caregiver-reported QoL; particularly with caregivers reporting lower levels of patient QoL compared with patient self-evaluations [29–31]. Also, it is uncertain how frequently physicians would have directly observed ADLs.

Furthermore, this was a point-in-time rather than a longitudinal survey, which meant data may have been used to assess the association between factors but not causality. Another potential limitation was that only 53.7%of patients were female, whereas a predominance of female dementia patients has generally been reported [32, 33]. There was also low number of patients with severe CI; the patient population was heavily weighted towards those with mild to moderate disease. Likewise, there were other features of the sample that merit further discussion. For example, there was low current use of antipsychotic medication (in 7.2%of patients), which could be associated with the small number of psychiatrists in the physician population (16.4%versus 41.8%for both PCPs and geriatricians/neurologists). In addition, a much higher proportion of patients were living at home compared with in a nursing home (90.2%versus 9.8%), which could be linked to the generally mild to moderate versus severe dementia population. There was also a smaller number of responses from caregivers compared with patients: 1,357 and 5,861 respondents, respectively. This could be because participation in the survey was voluntary or perhaps owing to an element of bias, where caregivers of more severe patients were more likely to have responded.

In line with previous findings, the majority (> 80%) of dementia patients in this study experienced neurobehavioral symptoms. However, although most of the patients without behavioral symptoms (a total of 1,086 patients) had mild dementia (74.1%), compared with 21.8%with moderate and 4.1%with severe dementia, previous research has suggested that several neurobehavioral symptoms, including depression, irritability, and night-time disturbances, could be present at prodromal or early stages in various dementias [6, 11]. This did not seem to be evident in our study population and may suggest an element of bias as very severe patients may not have consulted as often.

This study also has a number of strengths. For example, it included a large sample size from multiple study sites and countries. The setting was reflective of real-world practice, which is important for future decision-making regarding forthcoming clinical studies, new treatment options, and research and development. The study also used a wide variety of instruments to measure HCRU, proxy patient QoL, and caregiver burden. Some of the included instruments have been specially designed, for example, to reflect the stresses of caregivers of dementia patients (e.g., the ZBI).

In conclusion, this study suggests that certain combinations of behaviors, involving AARS and psychosis, may impact health-related outcomes such as HCRU, patient QoL, and caregiver burden in dementia. Our results have implications for intervention development for dementia patients who report clusters of symptoms and their caregivers, and for identifying patients or caregivers at risk of problems.