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Abstract
Objectives To investigate the relationship among patients’ apathy, cognitive impairment, depression, anxiety, and caregiver burden in amyotrophic lateral sclerosis (ALS).
Design A cross-sectional study design was used.
Setting The study was conducted at a tertiary hospital in Wuhan, Hubei, China.
Participants A total of 109 patients with ALS and their caregivers were included.
Outcome measures Patients with ALS were screened using the Edinburgh Cognitive and Behavioural Screen, Beck Depression Inventory-II, Generalised Anxiety Disorder-7 and Apathy Scale to assess their cognition, depression, anxiety and apathy, respectively. The primary caregivers completed the Zarit Burden Interview. The association between apathy, cognitive impairment, depression, anxiety and caregiver burden was analysed using logistic regression. Mediation models were employed to investigate the mediating effect of patients’ apathy on the relationship between depression/anxiety and caregiver burden.
Results Patients in the high caregiver burden group exhibited significantly higher levels of depression, anxiety and apathy compared with those in the low caregiver burden group (p<0.05). There was a positive association observed between caregiver burden and disease course (rs=0.198, p<0.05), depression (rs=0.189, p<0.05), anxiety (rs=0.257, p<0.05) and apathy (rs=0.388, p<0.05). There was a negative association between caregiver burden and the Revised ALS Functional Rating Scale (rs=−0.275, p<0.05). Apathy was an independent risk factor for higher caregiver burden (OR 1.121, 95% CI 1.041 to 1.206, p<0.05). Apathy fully mediated the relationship between depression and caregiver burden (β=0.35, 95% CI 0.16 to 0.54, p<0.05) while partially mediating the relationship between anxiety and caregiver burden (β=0.34, 95% CI 0.16 to 0.52, p<0.05).
Conclusions Apathy, depression and anxiety exerted a detrimental impact on caregiver burden in individuals with ALS. Apathy played a mediating role in the relationship between depression and caregiver burden and between anxiety and caregiver burden. These findings underscore the importance of identifying apathy and developing interventions for its management within the context of ALS.
- Motor neuron disease
- Depression and mood disorders
- Caregiver Burden
- Cognition
- behaviour
Data availability statement
Data are available upon reasonable request. The raw data of this article will be available by contacting the corresponding author.
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
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STRENGTHS AND LIMITATIONS OF THIS STUDY
The cross-sectional study assessed cognitive function, depression, anxiety, apathy and caregiver burden at the same time.
The Edinburgh Cognitive and Behavioural Amyotrophic Lateral Sclerosis (ALS) Screen, a recommended ALS-specific cognitive and behavioural scale was used in the study.
A mediation model was used to explore the mediating effect of patients’ apathy between depression, anxiety and caregiver burden.
The study was conducted in a specific hospital in Hubei Province, China, which limits the generalisability of the findings to other populations.
The study lacks detailed information about the caregivers’ medical history, education and work.
Introduction
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterised by progressive degeneration of upper and lower motor neurons.1 Patients with ALS usually experience a complete loss of motor function within 3–5 years, necessitating the use of gastrostomy and non-invasive ventilation in advanced stages.2 3 Over the past decade, it has been widely recognised that cognitive impairments are present in up to 50% of ALS patients, with 5%–15% meeting diagnostic criteria for frontotemporal dementia (FTD).4 The predisposition to behavioural and psychological symptoms, coupled with declining motor abilities, imposes a substantial physical and mental burden on caregivers, thereby rendering caregiving an arduous task that significantly undermines their well-being.5–7 A comprehensive understanding of factors associated with high caregiver burden is imperative for developing interventions to support caregivers and improve patients’ quality of life.
In previous studies, depression, anxiety and cognitive and behavioural impairments have been shown to increase caregiver burden. However, high-quality evidence has only been found for overall behavioural impairments.8–10 In ALS patients, behavioural symptoms include behavioural disinhibition, apathy, loss of sympathy, stereotyped behaviour and altered eating behaviour. Among these symptoms, apathy has the highest prevalence.10 Apathy is conceptualised as a multidimensional syndrome, including cognitive, behavioural, emotional and social dimensions.11 In ALS-frontotemporal spectrum disorder, the most prominent aspect of apathy is its behavioural dimension characterised by reduced motivation for goal-directed behaviour.12–14 Consequently, this lack of motivation may lead to non-adherence to recommended treatments among patients and hinder emotional responses to their caregivers,15 16 thereby significantly increasing caregiver burden. The revised diagnostic criteria for ALS with behavioural impairment emphasise apathy as a core feature, highlighting its importance in clinical research and customised interventions.4
Previous studies evaluating the impact of apathy on caregiver burden have overlooked the potential confounding effects and interactions among patients’ cognitive impairments, emotional disorders and apathy.8 17 Notably, previous research has reported significant differences in depression and anxiety levels between patients with and without apathy.18 In ALS patients, cognitive impairments can manifest as executive difficulties and non-executive cognitive dysfunction (such as language deficits, memory impairment and certain psychiatric changes).4 Traditional assessment tools like the Mini-Mental State Examination and the Montreal Cognitive Assessment lack sensitivity in identifying cognitive impairments specific to ALS patients due to their susceptibility to physical dysfunction.19 20 To address this limitation, the Edinburgh Cognitive and Behavioural ALS Screen (ECAS), a concise scale designed specifically for evaluating cognitive and behavioural impairments in ALS patients, has been extensively validated for reliability and validity across various regions.4 21–25 However, despite its utility in other areas of research related to ALS, no prior studies have used the ECAS to investigate caregiver burden or apathy.26 Furthermore, existing literature predominantly focuses on Caucasian populations, while there is a dearth of research involving Chinese populations; thus highlighting potential disparities that may arise from cultural differences between Eastern and Western societies.
This cross-sectional study aimed to investigate the relationship between patients’ apathy, cognitive impairment, depression, anxiety and caregiver burden in patients with ALS. A comprehensive understanding of the factors influencing caregiver burden can provide valuable professional guidance to caregivers and facilitate the development of interventions in clinical practice.
Methods
Study participants
This is a single-centre cross-sectional study conducted between May 2019 and December 2021 at the Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology. Patients diagnosed with probable or definite ALS based on the revised El Escorial Criteria27 were recruited. Simultaneously, the primary caregiver of each ALS patient was included. The primary caregiver referred to someone who provided continuous healthcare outside the hospital, usually the patient’s spouse or children.28 29 No paid caregivers or healthcare professionals were involved in this research. Patients with ALS combined with frontotemporal lobe dementia (ALS-FTD) were excluded. Patients with comorbid neurological disorders, such as cerebrovascular disease, Alzheimer’s disease, Parkinson’s disease and schizophrenia, were also excluded from the study. Those experiencing severe breathing difficulties and dysarthria (defined as forced vital capacity (%) ≤70% or any bulbar subitem in the revised ALS Functional Rating Scale (ALSFRS-R) ≤2 points) were excluded. Furthermore, ALS patients with comorbid systemic diseases that may potentially cause cognitive impairment, including diabetes mellitus, alcoholic cirrhosis of the liver, chronic obstructive pulmonary disease and renal failure, were also excluded. The study initially recruited 131 patients with ALS and 131 matched caregivers, ultimately only 109 ALS patients and their caregivers were included in the final study, while 22 patients with ALS were excluded for specific reasons (online supplemental figure 1). The sample size was determined based on the Events Per Variable (EPV) criterion: at least 10 EPV in the logistic regression analysis.30
Supplemental material
Data acquisition
Two well-trained neurologists performed the physical examinations, motor function assessments and neuropsychological evaluations.
Motor function evaluation and disease staging
The ALSFRS-R was employed for the evaluation of the motor function of patients with ALS.31 The ALSFRS-R consists of 12 items encompassing four subdomains of motor function; each item is rated on a scale from 0 (no function) to 4 (normal function), resulting in a total score ranging from 0 to 48. Higher scores indicate better motor function. The disease progression rate was calculated using the formula: (48-ALSFRS-R)/disease duration (months). Additionally, based on King’s staging system, patients were categorised into stages ranging from stage 1 (symptom onset) to stage 4 (gastrostomy and non-invasive ventilation).32
Cognitive function assessment
The ECAS is a specialised screening tool designed for the identification of cognitive impairments in patients with ALS.33 The ECAS evaluates three ALS-specific cognitive domains (language, verbal fluency and executive function) and two ALS-non-specific cognitive domains (memory and visuospatial function). Additionally, the ECAS includes a concise caregiver-administered questionnaire to evaluate behavioural and psychological abnormalities in patients. For this study, the Chinese version of the ECAS was used, with a total cut-off value of 81.92.23
Depression, anxiety and apathy evaluation
Depression was assessed using the Beck Depression Inventory-II (BDI-II), a 21-item depression self-rating scale with each item ranging from 0 (no symptoms) to 3 (severe symptoms).34 The BDI-II was a revised version of the original BDI as per the Diagnostic and Statistical Manual of Mental Disorder-IV. It has gained widespread recognition as one of the most widely used instruments for measuring depressive symptoms globally. A clinical cut-off value of 10 is recommended for interpreting BDI-II scores, with higher scores indicating the severity of depression.35 36
Anxiety symptoms were measured using the Generalised Anxiety Disorder-7 (GAD-7) questionnaire.37 The GAD-7 comprises seven items; each item is rated on a scale ranging from 0 (not at all) to 3 (nearly every day). Higher scores indicate more severe anxiety symptoms. The GAD-7 questionnaire has been validated in diverse populations and serves as a user-friendly tool for clinicians. A cut-off score of 10 on the GAD-7 is considered indicative of elevated anxiety symptoms.38 39
The Apathy Scale (AS), consisting of 14 items ranging from 0 to 42, was employed to assess apathy levels, with higher scores indicating more severe symptoms. The AS was adapted from the original Apathy Evaluation Scale (AES) developed by Robert Marin.40 Compared with the AES, the AS is briefer and easier to administer, while maintaining a wide range of scores to identify potential apathy. Previous studies have confirmed the reliability and validity of the AS scale in patients with neurodegenerative diseases.41 42 Clinically significant apathy is defined as a score above 14 based on prior research findings.42
Caregiver burden
The burden on primary caregivers was assessed using the Zarit Burden Interview (ZBI) during the patient’s hospitalisation. If the accompanying person during hospitalisation was not the patient’s primary caregiver, the assessment was completed 1 week after discharge via telephone. A fully revised version of the ZBI, comprising 22 items rated on a scale from 0 to 4 with a total score ranging from 0 to 88 was employed in this study.43 Higher ZBI scores indicate increased caregiver burden. The ZBI is the most widely used tool for assessing caregiver burden; previous studies have demonstrated excellent reliability and validity of the ZBI.44 Based on a predefined cut-off value for the ZBI, participants were categorised into two subgroups: low burden (ZBI ≤24) and high burden (ZBI >24) groups.45
Statistical analysis
The normality of data was assessed by the Shapiro-Wilk test. Normally distributed continuous variables were presented as mean (SD), and non-normally distributed continuous variables were reported as median (25% quartile, 75% quartile). Categorical variables were described as frequencies and percentages. Comparisons between the two groups were performed using the Student’s t-test, Mann-Whitney U test or χ2 test, according to the data types. The correlation between clinical features and caregiver burden was analysed using Spearman’s analysis. Binary logistic regression was performed to assess factors influencing caregiver burden. A mediation model was used to investigate the potential interactions among cognitive impairment, depression, anxiety and caregiver burden. The data included in the final analyses were complete and free of any missing values. Statistically significant was defined as p<0.05. All statistical analyses were carried out using SPSS software (V.27.0).
Patient and public involvement
All participants provided written informed consent. The involvement of patients or the public in our research’s design, conducting, reporting or dissemination plans was not sought.
Results
No demographic differences between the high and low caregiver burden groups
In this study, 109 patients with ALS were included, with an average age of 55 years and a median disease course of 11 months. Based on the milestones of disease progression, 72.48% of the patients were classified as King’s stage 1–2, indicating a relatively early course of the disease. The low-burden group consisted of 60 patients, while the high-burden group consisted of 49 patients. Height and weight followed a normal distribution, whereas age, disease duration, ALSFRS-R total score and subitem scores were non-normally distributed. There were no significant differences in age, sex, height, weight, disease course, education level, ALSFRS-R score, disease progression rate or King’s stage between the high and low caregiver burden groups (p>0.05) (table 1).
Demographic and clinical characteristics
Psychological differences between high and low caregiver burden groups
Depression, anxiety and cognitive function were evaluated using the aforementioned scales. In this study, 44.95% of caregivers experienced high levels of caregiver burden, while 36.70% of ALS patients met the threshold for clinical apathy (table 2). No significant difference in cognition between the groups with high and low caregiver burden, as indicated by both the total ECAS score and subdomain scores. However, the high caregiver burden group exhibited a higher prevalence of depression and anxiety symptoms compared with the low caregiver burden group (p<0.05). The high caregiver burden group demonstrated a significantly higher AS score than their counterparts (p<0.05), indicating a greater level of apathy within this subgroup (table 2).
Cognitive and psychological characteristics
Clinical and psychological factors correlating with caregiver burden
A correlation analysis was performed to explore the factors influencing caregiver burden. Caregiver burden showed positive association with disease course (rs=0.198, p<0.05), depression (rs=0.189, p<0.05), anxiety (rs=0.257, p<0.05) and apathy (rs=0.388, p<0.05). Caregiver burden exhibited a negative association with ALSFRS-R scores (rs=−0.275, p<0.05). After applying the Bonferroni correction, significant correlations between caregiver burden and ALSFRS-R, anxiety and apathy remained evident (p<0.05/7). No correlation was found between patients’ age or cognitive function and caregiver burden (table 3). Furthermore, binary logistic regression was employed to investigate the impact of cognitive function, depression, anxiety and apathy on caregiver burden perception by caregivers themselves. In the regression model, each one-point increase in the AS score of ALS patients was associated with an 11.7% increase in the likelihood that caregivers perceived the burden to be high (OR 1.121, 95% CI 1.041 to 1.206, p<0.05). In contrast, patients’ depression, anxiety and cognitive function did not affect caregiver burden in the regression model (online supplemental table 1 and figure 1).
Supplemental material
The relationship between clinical features and caregiver burden
Patients’ apathy is a risk factor for caregiver burden. ALSFRS-R, Revised Amyotrophic Lateral Sclerosis Functional Rating Scale; AS, Apathy Scale; BDI-II, Beck Depression Inventory-II; ECAS, Edinburgh Cognitive and Behavioural Screen; GAD-7, Generalised Anxiety Disorder-7.
Apathy mediates the association between emotional disorders and caregiver burden
The inconsistent results between the correlation analysis and regression model drove us to investigate the interaction among depression, anxiety, cognitive function, apathy and caregiver burden. Apathy, depression and caregiver burden were validated by pairwise correlations (p<0.05) using simple linear regression (online supplemental table 2). When apathy was used as an intermediary variable, the association between depression and caregiver burden was no longer statistically significant (indirect effects; figure 2A). Apathy, anxiety and caregiver burden were also pairwise correlated (p<0.05) through simple linear regression (online supplemental table 3). When apathy served as an intermediary variable, the association between anxiety and caregiver burden remained statistically significant (p<0.05) (indirect effect; figure 2B), although the regression coefficient decreased. Apathy, cognition and caregiver burden were not pairwise correlated (online supplemental table 4).
Supplemental material
Supplemental material
Supplemental material
(A) The mediation effect of apathy between depression and caregiver burden. (B) The mediation effect of apathy between anxiety and caregiver burden. *, p<0.05; **p<0.001. β, standardised regression coefficient.
Discussion
The current study demonstrates that apathy in ALS patients constitutes a risk factor for heightened caregiver burden. Moreover, the mediating role of apathy in the associations between depression, anxiety and caregiver burden underscores its profound impact on the latter. These findings emphasise the imperative of recognising apathy in ALS patients.
Caregiver burden refers to the stressors experienced by caregivers due to providing physical and psychological care to patients, encompassing not only social and economic costs but also mental and emotional costs.46 The rapid deterioration in ALS results in a heightened caregiver burden compared with other diseases.47 High caregiver burden hurts both the prognosis of patients with ALS and the physical and mental health of their caregivers. Previous studies have primarily focused on the influence of patient depression and anxiety on caregiver burden.48 49 Apathy, the most common behavioural disorder in ALS patients,12–14 may contribute to non-adherence with treatment recommendations,15 16 leading to disease deterioration and increased caregiver burden. Even after excluding the motor and cognitive confounders among patients with ALS, apathy still exerts effects on functional independence in daily living, thereby potentially increasing the physiological burden for caregivers.50 Additionally, patients with apathy are less emotionally responsive towards their caregivers, resulting in an elevated psychological burden.
Consistent with recent studies, our findings demonstrate a positive correlation between higher levels of depression, anxiety and apathy and increased caregiver burden.51 52 Notably, in our mediation model, the association between patients’ depression and caregiver burden was fully mediated by patients’ apathy. However, the relationship between patients’ anxiety and caregiver burden was only partially mediated by patients’ apathy. On the one hand, this phenomenon may be related to the neuronal circuits underlying apathy, depression and anxiety. Both apathy and depression are associated with the dysfunction in subcortical, frontal–parietal circuitries involved in autoactivation and reward processing.53–56 Anxiety, on the other hand, primarily stems from dysfunction in the basolateral amygdala and anterodorsal bed nucleus of the stria terminalis.57 58 Conversely, there is a significant overlap between the manifestations of depression and apathy.59 60 In contrast, clinical manifestations of anxiety and apathy differ markedly as ALS patients with anxiety often exhibit heightened concerns regarding their physical condition and a greater need for disease care, thereby imposing an additional burden on caregivers.
To investigate the relationship between cognitive function and caregiver burden, we employed the ECAS to evaluate the cognitive function of patients in this study. Our findings revealed no significant difference in cognition between the high and low caregiver burden groups, and regression analysis indicated that patients’ cognitive function did not influence caregiver burden, which is consistent with a previous study.26 Prior research on various neurodegenerative disorders has emphasised that the behavioural and psychological symptoms of dementia, rather than cognition per se, substantially contribute to increased caregiver burden.61 62 In a comparative study where the degree of cognitive dysfunction was similar, caring for patients with Lewy body dementia was reported to be more distressing compared with caring for Alzheimer’s disease patients due to more severe behavioural and psychological symptoms observed at early stages of Lewy body dementia.63 Family members rarely complain about challenging issues solely caused by cognitive impairments (eg, memory and visuospatial impairments) during home care. Overall, our results reinforce that cognition does not significantly impact caregiver burden.
The current study has several limitations. First, discrepancies commonly arise between patients’ and caregivers’ assessments of symptoms, particularly for apathy, possibly due to caregiver burden or lack of patient insight.64 65 The Dimensional Apathy Scale (DAS) is the gold standard for evaluating apathy in neurodegenerative diseases. It is available in two versions: a self-report and a caregiver-report version.66 Using the DAS in future studies will enhance the understanding of patients’ apathy and caregiver burden. Additionally, more appropriate anxiety assessment scales exist for ALS patients, for example, the State and Trait Anxiety Inventory Form Y.67 Second, most caregivers in this study were the patients’ spouses, which partially mitigates confounding by caregiver’s age. However, it is essential to consider other factors such as occupation, income and education, which may also influence the assessment of caregiver burden. Future studies should aim to gather more comprehensive information about caregivers. Lastly, although our sample size was larger than that of previous studies, it is worth noting that our participants were recruited solely from a single research centre in central China. Conducting multicentre studies would be beneficial in minimising bias arising from variations in economic levels and cultural backgrounds.
Conclusions
In conclusion, apathy is a crucial risk factor contributing to increased caregiver burden in patients with ALS. Apathy exerts both direct and indirect effects on caregiver burden through its association with emotional disorders. Behavioural disturbances, particularly apathy, are prevalent among individuals with ALS-frontotemporal spectrum disorders. Early identification of apathy and provision of enhanced social support to caregivers hold significant benefits for the management of ALS patients and the well-being of their caregivers.
Data availability statement
Data are available upon reasonable request. The raw data of this article will be available by contacting the corresponding author.
Ethics statements
Patient consent for publication
Ethics approval
This study involves human participants. The study protocol was approved by the Ethics Committee of the Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology (ID: TJ-IRB20201219). Participants gave informed consent to participate in the study before taking part.
Acknowledgments
We express our sincere gratitude to all the participants who actively contributed to this study.
References
Footnotes
Contributors MZ contributed to the study design and acted as guarantor. ZG, WD, JT and ZL contributed to data acquisition. ZG and WD contributed to data interpretation and statistical analysis. ZG and WD drafted the manuscript. MZ revised the manuscript. ZG and WD contributed equally to this work.
Funding This study was supported by the National Natural Science Foundation of China (Grant No. 8227052605) and the Bethune Charitable Foundation.
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, conduct, reporting or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.