Clinical determinants of apathy and its impact on health-related quality of life in early Parkinson disease : Medicine

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Research Article: Observational Study

Clinical determinants of apathy and its impact on health-related quality of life in early Parkinson disease

Choi, Seong-Min MD, PhDa,b,c; Cho, Soo Hyun MD, PhDa,b; Choe, Youngshik PhDd; Kim, Byeong C. MD, PhDa,b,c,*

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Medicine 102(2):p e32674, January 13, 2023. | DOI: 10.1097/MD.0000000000032674
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Abstract

1. Introduction

Apathy is a syndrome of primary motivational loss not attributable to cognitive impairment, emotional stress, or diminished level of consciousness.[1] It is a common neuropsychiatric symptom that can occur in patients with various neurodegenerative disorders. The prevalence of apathy is more common in neurodegenerative diseases, such as progressive supranuclear palsy, frontotemporal dementia, and Huntington disease, which prominently involve the prefrontal cortex and caudate nuclei.[2] Apathy is associated with caregiver burden, decreased response to treatment, and poor long-term prognosis in various neurological diseases.[3] Therefore, recognition of apathy associated with neurological disease may be important for patient care.

Apathy is a common non-motor symptom of Parkinson disease (PD), but its prevalence and clinical correlates in PD vary across studies. It is found in patients with de novo PD, with a higher prevalence in patients with advanced PD.[2] It can precede the onset of motor symptoms of PD and be considered as a premotor symptom suggestive of PD development.[4] Apathy caused by PD is associated with motor dysfunction and various non-motor symptoms, particularly depression and cognitive dysfunction.[5] It can affect the health-related quality of life (HRQoL) of patients with PD and their caregivers,[2,6] however, some studies have shown that apathy was not an independent predictor of poor HRQoL in patients with PD.[7] Therefore, the aim of this study was to describe the prevalence of apathy in patients with early PD and to investigate the clinical determinants of apathy and its impact on HRQoL.

2. Subjects and Methods

We consecutively enrolled patients with PD from the outpatient clinic of our hospital. Inclusion criteria were as follows: a diagnosis of PD according to the United Kingdom Parkinson’s Disease Society Brain Bank clinical diagnostic criteria,[8] modified Hoehn–Yahr (mHY) stages 1 to 3, and a disease duration ≤5 years. Exclusion criteria were as follows: neurodegenerative disorders other than PD, dementia, and any clinically significant lesion on brain magnetic resonance imaging. This study was approved by the Institutional Review Board of our hospital and conducted in accordance with the ethical standards laid down by the Declaration of Helsinki.

Demographic information, such as age, sex, disease duration, and formal education duration, were obtained. Severity of motor symptoms and activities of daily living (ADL) were assessed according to the mHY stage[9] and parts III and II of the Unified Parkinson’s Disease Rating Scale (UPDRS-III and UPDRS-II, respectively).[10] The Non-Motor Symptoms Scale (NMSS) was used to evaluate non-motor symptoms of PD,[11] the Mini-Mental Status Examination (MMSE) to evaluate global cognitive functioning,[12] Beck Depression Inventory (BDI) to evaluate depression,[13] the Beck Anxiety Inventory (BAI) to evaluate anxiety,[14] the Apathy Evaluation Scale (AES) to evaluate apathy,[15] and the Parkinson’s Disease Questionnaire-8 (PDQ-8) to evaluate HRQoL.[16,17] Apathy was assessed using the self-report version of the AES (AES-S), and a cutoff score of 38/39 was used to distinguish apathetic from non-apathetic PD.[15,18]

To compare clinical characteristics of patients with apathetic and non-apathetic PD, the independent-sample t test was performed for continuous variables, and chi-square test was performed for categorical variables. The analysis of covariance was performed to compare non-motor variables between the 2 groups after controlling for the mHY stage and UPDRS-III and UPDRS-II scores, which were significantly different in the t test. The P values were then Bonferroni-corrected for multiple comparisons. The univariate linear regression analysis was performed to explore potential factors affecting the PDQ-8 score. The multivariate linear regression analysis was performed to identify independent factors associated with AES and explore independent clinical variables to predict the PDQ-8 score. Data were analyzed using Statistical Package for the Social Sciences version 27.0 for Windows (IBM Corp.; Armonk, NY), and a P value <.05 was considered to be statistically significant.

3. Results

We enrolled 324 patients, including 134 men and 190 women, with a mean age of 67.4 ± 9.5 years. The mean disease duration was 17.9 ± 16.8 months, and mean duration of formal education was 8.8 ± 4.7 years. Apathy was found in 110 (33.9%) patients with PD. There were no significant differences in age, sex, disease duration, or formal education duration between patients with apathetic and non-apathetic PD. Compared with patients with non-apathetic PD, those with apathetic PD had significantly higher mHY stage and UPDRS-II score. There was no significant difference in the UPDRS-III score between the 2 groups. Among non-motor variables, compared with patients with non-apathetic PD, those with apathetic PD had significantly higher NMSS total, BDI, BAI, AES, and PDQ-8 scores, which were statistically significant after controlling for the mHY stage and UPDRS-III and UPDRS-II scores. There was no significant difference in the MMSE score between the 2 groups (Table 1).

Table 1 - Clinical characteristics of patients with early apathetic and non-apathetic Parkinson disease.
No apathy (n = 214) Apathy (n = 110) P value ANCOVA P value Corrected P value
Age (yr) 67.0 ± 9.4 68.2 ± 9.6 .284
Sex (male:female) 91: 123 43: 67 .634
Disease duration (mo) 16.9 ± 16.5 19.8 ± 17.4 .140
Formal education (yr) 9.1 ± 4.6 8.3 ± 4.9 .140
mHY stage 1.8 ± 0.6 2.0 ± 0.7 .003
UPDRS-III score 21.1 ± 10.0 23.2 ± 10.4 .082
UPDRS-II score 5.4 ± 4.5 9.9 ± 7.8 <.001
NMSS total score 38.2 ± 26.4 67.4 ± 38.5 <.001 <.001 <.001
MMSE score 26.3 ± 3.2 25.8 ± 3.5 .152 .744 1.000
BDI score 8.4 ± 7.4 18.05 ± 12.0 <.001 <.001 <.001
BAI score 7.5 ± 6.3 14.9 ± 10.8 <.001 <.001 <.001
AES score 30.4 ± 6.0 46.4 ± 6.1 <.001 <.001 <.001
PDQ-8 score 3.9 ± 3.8 8.9 ± 6.5 <.001 <.001 <.001
Data are presented as mean ± standard deviation. Covariates of ANCOVA were the mHY stage and UPDRS-III and UPDRS-II scores. The corrected P values were Bonferroni corrected for multiple comparisons. Bold font indicates statistical significance.
AES = Apathy Evaluation Scale, ANCOVA = analysis of covariance, BAI = Beck Anxiety Inventory, BDI = Beck Depression Inventory, mHY = modified Hoehn and Yahr scale, MMSE = Mini-Mental State Examination, NMSS = Non-Motor Symptoms Scale, PDQ-8 = Parkinson’s Disease Questionnaire-8, UPDRS = Unified Parkinson’s Disease Rating Scale.

In the multivariate regression analysis, NMSS domain 3 score and BDI score were significantly correlated with the AES score. However, age, sex, disease duration, formal education duration, and UPDRS-III; UPDRS-II; NMSS total; MMSE; and BAI scores were not correlated with the AES score (Table 2).

Table 2 - Factors associated with the Apathy Evaluation Scale score.
β P value
Age (yr) −0.052 .974
Sex (male:female) −0.001 .985
Disease duration (mo) 0.060 .992
Formal education (yr) −0.015 .947
UPDRS-III score 0.064 .980
UPDRS-II score 0.097 .680
NMSS total score 0.032 .444
NMSS domain 3 score 0.432 <.001
MMSE score 0.005 .948
BDI score 0.317 <.001
BAI score 0.056 .534
Bold font indicates statistical significance.
BAI = Beck Anxiety Inventory, BDI = Beck Depression Inventory, MMSE = Mini-Mental State Examination, NMSS = Non-Motor Symptoms Scale, UPDRS = Unified Parkinson’s Disease Rating Scale.

The univariate linear regression analysis was performed to explore potential factors affecting the PDQ-8 score. There were statistically significant associations between the PDQ-8 score and age, disease duration, formal education duration, and UPDRS-III; UPDRS-II; NMSS total; MMSE; BDI; BAI; and AES scores. Sex was not associated with the PDQ-8 score (Table 3).

Table 3 - Univariate regression analysis to explore potential factors affecting the PDQ-8 score in patients with early Parkinson disease.
B (SE) P value
Age (yr) 0.078 (0.032) .015
Sex 0.390 (0.620) .529
Disease duration (mo) 0.073 (0.018) .005
Formal education (yr) −0.184 (0.066) <.001
UPDRS-III score 0.163 (0.028) <.001
UPDRS-II score 0.616 (0.035) <.001
NMSS total score 0.124 (0.006) <.001
MMSE score −0.234 (0.092) .011
BDI score 0.338 (0.024) <.001
BAI score 0.380 (0.027) <.001
AES score 0.319 (0.026) <.001
Bold font indicates statistical significance.
AES = Apathy Evaluation Scale, BAI = Beck Anxiety Inventory, BDI = Beck Depression Inventory, MMSE = Mini-Mental State Examination, NMSS = Non-Motor Symptoms Scale, PDQ-8 = Parkinson’s Disease Questionnaire-8, UPDRS = Unified Parkinson’s Disease Rating Scale.

In the final multivariate linear regression analysis to explore the independent predictors of the PDQ-8 score, we included all variables associated with the AES or PDQ-8 score in the aforementioned analysis. AES score as well as UPDRS-III; UPDRS-II; NMSS total; NMSS domain 3; and BAI scores were significant independent predictors of the PDQ-8 score (Table 4).

Table 4 - Multivariate regression analysis to explore predictors of the PDQ-8 score in patients with early Parkinson disease.
β P value
Age (yr) −0.060 .817
Disease duration (mo) −0.005 .877
Formal education (yr) 0.019 .942
UPDRS-III score 0.114 .001
UPDRS-II score 0.190 <.001
NMSS total score 0.355 <.001
NMSS domain 3 score 0.206 <.001
MMSE score 0.040 .941
BDI score 0.054 .408
BAI score 0.162 <.001
AES score 0.083 <.044
Bold font indicates statistical significance.
AES = Apathy Evaluation Scale, BAI = Beck Anxiety Inventory, BDI = Beck Depression Inventory, MMSE = Mini-Mental State Examination, NMSS = Non-Motor Symptoms Scale, PDQ-8 = Parkinson’s Disease Questionnaire-8, UPDRS = Unified Parkinson’s Disease Rating Scale.

4. Discussion

In this study on apathy and its impact on HRQoL in patients with early PD, we observed that the clinical determinants of apathy were NMSS domain 3 score and BDI score; apathy was an independent predictor of HRQoL; other significant predictors of HRQoL were motor dysfunction, the ADL status, global non-motor symptoms, and anxiety.

Apathy is a common non-motor symptom that can occur in all stages of PD.[2] The prevalence of apathy in PD is variable, ranging from 15 to 70%, depending on the stage of PD and diagnostic methods used.[2,18,19] In a previous study, apathy was found in 20 to 36% of patients with new-onset PD, 40% of those with PD without dementia, and 60% of those of PD with dementia.[2] In our PD cohort, the prevalence of apathy was 33.9%, similar to that of new-onset PD in the previous study, probably because we enrolled patients with early PD with a short disease duration of 17.9 months.[2,18]

In a previous study, apathy in PD was associated with older age, higher motor scores, more severe disability, depression, and cognitive dysfunction.[5,19] In the present study, NMSS domain 3 score and BDI score were independent factors affecting the AES score, consistent with previous reports. The relationship between apathy and higher mHY stage suggests that nigrostriatal pathway dysfunction might play a role in the development of apathy.[20] However, UPDRS motor and ADL scores were not related to the AES score in our study, indicating that apathy in PD should not be considered an entirely dopamine-dependent symptom.[5,20] We also found that the BDI score was significantly associated with the AES score. The association between depression and apathy in patients with PD has been reported in many studies.[5,7,20] However, apathy and depression share several clinical characteristics and are, therefore, difficult to differentiate clinically.[2] Scales to evaluate apathy that are devoid of depression-related items are required. Contrary to previous studies, our study showed that the MMSE score was not significantly associated with the AES scores, probably because patients with dementia were excluded while those with relatively low education were included in our study.

HRQoL in PD is affected by various demographic and clinical factors.[21,22] Activity limitation, which is significantly related to motor impairment, is the strongest predictor of HRQoL in PD.[23] Similarly, the UPDRS motor and ADL scores were independent predictors of HRQoL in this study. Including patients with early PD who do not have significant activity limitations might have provided an advantage in investigating non-motor symptoms affecting HRQoL. Non-motor symptoms affecting HRQoL in patients with PD include cognitive impairment, neuropsychiatric symptoms, autonomic disorders, and sleep disturbance.[22,24,25] Among neuropsychiatric symptoms, depression is the most frequently identified determinant of HRQoL in patients with PD.[21,24] However, depression was not an independent determinant of HRQoL in our PD cohort. Cognitive dysfunction is also a potential factor determining HRQoL in patients with PD,[23,26] however, the MMSE score was not an independent factor determining HRQoL in our study. These discrepancies occurred probably because we enrolled patients with early PD patients in our study with a relatively low prevalence of depression and cognitive dysfunction. In contrast, apathy and anxiety were significant factors affecting HRQoL in our PD cohort. Some studies have reported apathy as a predictor of HRQoL in patients with PD, whereas other have not.[7,24,25,27,28] This discrepancy of the results regarding relationship between apathy and HRQoL in patients with PD might be related to the differences in the patients group, the disease severity, and the apathy scale used. This should be considered when investigating apathy affecting HRQoL in patients with PD.

This study has several limitations. First, no control group was included. Therefore, the prevalence of apathy could not be compared between patients with PD and controls. Second, we did not differentiate apathy from depression. It remains unclear whether apathy is a symptom of depression or an independent syndrome.[20] Therefore, depression and apathy rating scales without items related to overlapping symptoms are necessary, when considering depression and apathy as distinct syndromes.

5. Conclusions

In the present study, depression was a clinical determinant of apathy, and apathy and anxiety were independent non-motor symptoms that determined poor HRQoL in patients with early PD. Therefore, identifying and managing these non-motor symptoms in patients with early PD could help improve patients’ HRQoL.

Author contributions

Conceptualization: Seong-Min Choi.

Data curation: Seong-Min Choi, Byeong C. Kim.

Formal analysis: Seong-Min Choi, Soo Hyun Cho, Youngshik Choe.

Funding acquisition: Seong-Min Choi, Soo Hyun Cho.

Investigation: Soo Hyun Cho, Byeong C. Kim.

Methodology: Seong-Min Choi, Soo Hyun Cho.

Project administration: Seong-Min Choi, Byeong C. Kim.

Resources: Seong-Min Choi, Soo Hyun Cho.

Software: Seong-Min Choi, Youngshik Choe.

Supervision: Seong-Min Choi, Byeong C. Kim.

Validation: Seong-Min Choi.

Visualization: Soo Hyun Cho, Youngshik Choe.

Writing – original draft: Seong-Min Choi, Soo Hyun Cho.

Writing – review & editing: Seong-Min Choi, Byeong C. Kim.

Abbreviations:

ADL =
activities of daily living
AES =
Apathy Evaluation Scale
BAI =
Beck Anxiety Inventory
BDI =
Beck Depression Inventory
HRQoL =
health-related quality of life
mHY =
modified Hoehn–Yahr
MMSE =
Mini-Mental Status Examination
NMSS =
Non-Motor Symptoms Scale
PD =
Parkinson disease
PDQ-8 =
Parkinson’s Disease Questionnaire-8
UPDRS =
Unified Parkinson’s Disease Rating Scale

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Keywords:

anxiety; apathy; Parkinson disease (PD); quality of life (QoL)

Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.