Neurol Sci (2014) 35:729–734 DOI 10.1007/s10072-013-1591-6
ORIGINAL ARTICLE
Apathy and associated factors in Mexican patients with Parkinson’s disease Mayela Rodrı´guez-Violante • Paulina Gonza´lez-Latapi • Amin Cervantes-Arriaga • Daniel Martı´nez-Ramı´rez • Salvador Vela´zquez-Osuna • Azyadeh Camacho-Ordon˜ez
Received: 20 September 2013 / Accepted: 22 November 2013 / Published online: 5 December 2013 Ó Springer-Verlag Italia 2013
Abstract Apathy is one of the most common behavioral disturbances in Parkinson’s disease (PD) with a reported prevalence of 17–51 %. Apathy has been associated with depression, cognitive deficits, and poor quality of life. The objective of this study was to determine the prevalence of apathy in Mexican subjects with PD and its correlation with clinical and demographic characteristics. A crosssectional, descriptive, and analytic study was carried out. Consecutive subjects with PD attending the National Institute of Neurology and Neurosurgery in Mexico City were included. Demographic and other relevant clinical data were collected. The Apathy Scale was applied to all subjects. A cut-off score of C14 was used. A total of 241 non-demented patients (52.7 % male) were included. Apathy was found in 43 % of subjects. Lower body mass index, older age of PD onset, cognitive decline and disease severity were all related to apathy. The use of dopamine agonists or rasagiline was more common in patients with low apathy scores. Our results show that the prevalence of apathy in Mexican subjects with PD is similar to other reports.
M. Rodrı´guez-Violante (&) P. Gonza´lez-Latapi A. Cervantes-Arriaga D. Martı´nez-Ramı´rez A. Camacho-Ordon˜ez Clinical Laboratory of Neurodegenerative Diseases, National Institute of Neurology and Neurosurgery, Insurgentes Sur #3877 Col. La Fama, 14269 Mexico City, Mexico e-mail: [email protected] M. Rodrı´guez-Violante D. Martı´nez-Ramı´rez S. Vela´zquez-Osuna Movement Disorders Clinic, National Institute of Neurology and Neurosurgery, Mexico City, Mexico
Keywords Apathy Apathy Scale Body mass index Dopamine agonist Parkinson’s disease
Introduction Parkinson’s disease (PD) is one of the most common neurodegenerative disorders. Traditionally, the hallmark features of PD have included motor symptoms, particularly tremor, rigidity, postural instability and bradykinesia. Recently, neuropsychiatric symptoms have been described as highly prevalent and disabling symptoms of PD. Apathy has been identified as a major neuropsychiatric feature in PD [1], with prevalence between 17 and 51 % [2]. Clinical characteristics of apathy include lack of initiative and effort to perform everyday activities, lack of intellectual interest regarding personal or social issues and indifference or flattening of affect [3]. Diagnostic criteria include symptoms comprised into three groups: cognitive symptoms, behavioral symptoms and emotional symptoms [4]. Cognitive deficits and a decrease in quality of life have been associated with apathy [5]. Recently, a study carried out in Chilean population reported that higher scores for apathy in the Apathy Scale (AS) correlated with the most advanced Hoehn and Yahr stages. A greater age, longer period of illness and greater compromise of motor ability were also determinants of apathy in this study [6]. The Apathy Scale is the only scale to meet criteria to be ‘‘recommended’’ by the Movement Disorder Society Task Force to assess apathy in PD patients [2]. The aim of the present study was to determine the prevalence of apathy in Mexican patients with Parkinson’s disease as well as its correlation with demographic and clinical characteristics.
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730 Table 1 Clinical and demographic characteristics of subjects with and without apathy
Neurol Sci (2014) 35:729–734
PD-apathy (n = 104)
PD-no apathy (n = 137)
Female
48.0 (50)
46.7 (64)
Male
51.9 (54)
53.2 (73)
p
Gender, % (n)
Age, mean (SD)
0.897
64.9 (13.5)
60.2 (12.5)
0.007
Years of schooling, mean (SD)
7.6 (5.0)
9.0 (4.7)
0.028
Body mass index, mean (SD)
25.4 (3.9)
27.6 (4.3)
\0.001
57.8 (14.2)
54.0 (13.3)
Age of PD onset, mean (SD)
0.034
Classification of onset by age, % (n) Early-onset PD
12.5 (13)
16.7 (23)
0.496
Late-onset PD
87.5 (91)
83.2 (114)
0.496
54.8 (57)
56.9 (78)
0.794
Asymmetry, % (n) Right PD subtype, % (n) Tremor dominant
60.5 (63)
64.2 (88)
0.781
Rigid akinetic PIGD
31.7 (33) 7.6 (8)
29.9 (41) 5.8 (8)
0.781 0.781
Hoehn and Yahr, mean (SD) MDS-UPDRS Movement disorder society-Unified Parkinson’s Disease Rating Scale, MoCA Montreal Cognitive Assessment, PD Parkinson’s disease, PIGD postural instability and gait disorder, SD standard deviation
MDS-UPDRS score, mean (SD)
2.2 (0.7) 48.5 (23.3)
UPDRS part I, mean (SD)
11.1 (7.2)
8.5 (6.0)
UPDRS part II, mean (SD)
15.2 (9.3)
12.2 (7.4)
UPDRS part III, mean (SD)
38.4 (16.4)
28.9 (16.1)
UPDRS part IV, mean (SD) MoCA score, mean (SD)
Subjects and methods Consecutive subjects fulfilling the criteria for Parkinson’s disease according to the United Kingdom Parkinson’s Disease Society—Brain Bank were included [7]. All patients were seen at the Movement Disorders outpatient clinic of the National Institute of Neurology and Neurosurgery between August 2012 and July 2013. Demographic and other relevant clinical data were collected. A neurologist with expertise in movement disorders performed the neurological evaluation. Levodopa daily dose, levodopa equivalent daily dose (LEDD) and dopamine agonist (DA) LEDD were calculated [8]. Disease severity was measured in terms of Hoehn and Yahr (HY) stage [9]. All subjects were evaluated with the Spanish version of the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) [10]. Patients were clinically classified as tremor dominant, rigidity dominant and postural-gait instability dominant [11, 12]. Cognitive status was assessed using the Montreal Cognitive Assessment (MoCA) [13]; if educational years were \12, a point was added to total score in MoCA. The Spanish version of the AS developed by Starkstein was applied to all patients. The AS is a 14-item questionnaire that screens for and evaluates the severity of apathetic symptoms in PD subjects. The scores on
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2.4 (0.8) 63.9 (26.1)
0.005 \0.001 0.003 0.008 \0.001
2.5 (4.8)
1.4 (3.5)
0.035
21.1 (5.8)
23.1 (4.4)
0.004
the AS range from 0 to 42 points, with higher scores indicating greater severity of symptoms. Each item provides four possible answers (not at all, slightly, some or a lot). The scale has been found to have high internal consistency and good inter-rater reliability. A cut-off score C14 on the AS has a sensitivity of 66 % and specificity of 100 % for the detection of apathy [14]. The Institutional Review Board and local ethics committee approved the study. All subjects provided written informed consent before participating. Statistical analysis Independent t tests were used for comparison of continuous variables. Differences in proportions of categorical variables were analyzed by Chi-square test. A binary logistic regression analysis was performed to determine the impact of each factor for the presence of apathy. Agreement between the AS and MDS-UPDRS item 1.5 (apathy) was assessed by the kappa coefficient (B0 = poor, 0.01–0.20 = slight, 0.21–0.40 = fair, 0.41–0.60 = moderate, 0.61–0.80 = substantial, and 0.81–1 = almost perfect). A p value \0.05 was considered as statistically significant. All data were analyzed using SPSS version 17.0 (SPSS Inc., Chicago, IL).
Neurol Sci (2014) 35:729–734 Table 2 Comparison of treatment between patients with and without apathy
DBS deep brain stimulation surgery, LEDD levodopa equivalent daily dose, PD Parkinson’s disease, SSRI selective serotonin reuptake inhibitor, SD standard deviation
731
PD-apathy (n = 104)
PD-no apathy (n = 137)
p
Levodopa, % (n)
82.6 (86)
69.3 (95)
0.023
Levodopa, mean dose ± SD
471 ± 348.4
422.6 ± 393.7
0.327
Dopamine agonist, % (n)
48.0 (50)
63.5 (87)
0.019
Pramipexole, % (n)
44.2 (46)
54.0 (74)
0.143
Pramipexole, mean dose ± SD
2.1 ± 1.0
2.1 ± 1.1
0.892
Rotigotine, % (n)
3.8 (4)
8.0 (11)
0.103
Rotigotine, mean dose ± SD
6.0 ± 2.4
8.8 ± 3.8
0.095
Rasagiline, % (n)
3.8 (4)
12.4 (17)
Entacapone, % (n)
5.7 (6)
6.5 (9)
Amantadine, % (n)
11.5 (12)
8.7 (12)
0.021 [0.999 0.518
Biperiden, % (n)
13.4 (14)
10.9 (15)
0.531
Antidepressants, % (n)
24.0 (25)
13.1 (18)
0.028
Tricyclic antidepressants, % (n)
4.8 (5)
3.6 (5)
0.655
15.3 (16)
7.2 (10)
0.045
Other, % (n) DBS surgery, % (n)
3.8 (4) 1.9 (2)
12.1 (3) 2.9 (4)
0.448 0.520
LEDD mean dose ± SD
604.4 ± 345.6
594.5 ± 414.8
0.851
SSRI, % (n)
Results A total of 241 (52.7 % male and 47.3 % female) consecutive patients were included. The mean age of the sample was 62.3 ± 13.1 years. Mean age at disease onset was 55.6 ± 13.8 years. Mean disease duration was 6.6 ± 5.6 years. According to the HY stage, 94.4 % of the sample had mild to moderate disease (HY 1–3). Regarding antiparkinsonian treatment, 75.8 % received levodopa, with a mean daily dosage of 588.4 ± 317.49 mg; 63.7 % were taking a dopamine agonist (DA-LEDD 193.18 ± 97.2 mg). Mean LEDD of the sample was of 598.9 ± 384.8. Only six patients had undergone deep brain stimulation surgery, with the electrode placed bilaterally on the subthalamic nucleus. Mean AS score was 21.3 ± 6.2. Overall, 43.2 % of the patients had apathy. Table 1 shows demographic and clinical characteristics for subjects with and without apathy. Subjects with apathy were older, less educated, had a higher age at disease onset and a lower mean body mass index (BMI). The presence of apathy was associated with a higher HY. In addition, subjects with apathy had a higher mean MDS-UPDRS score for all four parts. Moreover, a greater number of subjects with apathy also reported depressive mood according to the MDS-UPDRS item 1.3 (75.9 vs. 52.5 %, p \ 0.001). With regard to the MDSUPDRS item 1.5, 40.6 % of all subjects referred apathy. The kappa coefficient measurement of agreement between AS score and apathy status assessed by MDS-UPDRS item 1.5 was fair (k = 0.249, p \ 0.001). The prevalence of cognitive decline, defined as a MoCA score of \26, was 73.2 % for PD subjects with apathy and
62.1 % for the group without apathy (p = 0.10). Apathy was associated with a lower mean MoCA score. With regard to treatment, levodopa and antidepressant use were significantly different between subjects with and without apathy. Dopamine agonist and rasagiline use were significantly higher in PD subjects without apathy. Table 2 compares treatment between subjects with and without apathy. With regard to antidepressant use, patients treated with a selective serotonin reuptake inhibitor (SSRI) had a higher prevalence of apathy (p = 0.045). After assessing for multicollinearity of the variables using variance inflation factors, a multivariate regression model with apathy status as the dependent variable was performed. The independent variables included were age, disease duration, years of schooling, BMI, MDS-UPDRS part I, MDS-UPDRS part II, MDS-UPDRS part III, MDSUPDRS part IV and MoCA score. The use of antidepressant, levodopa, dopamine agonist and rasagiline was also included in the model. For this model, BMI (B = -0.128, p = 0.002), MDS-UPDRS part III score (B = 0.031, p = 0.01) and use of rasagiline (B = -1.4, p = 0.042) were the only factors to remain significantly associated with apathy. Years of schooling presented a tendency towards statistical significance (p = 0.054).
Discussion Apathy is frequently reported as a non-motor symptom in PD subjects. In this study, apathy was present in 43 % of our sample. To our knowledge, this is the largest study in
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732
Latin America to report the prevalence of apathy among PD subjects. With regard to clinical and demographic factors, MDSUPDRS part III score and a lower BMI were all related with apathy in our study. An inverse association between apathy and BMI has also been reported in nursing home residents without PD. Furthermore, during 3 months of follow-up, subjects with apathy lost more weight than subjects without apathy [15]. The present study is the first to report this association in subjects with PD. Due to the cross-sectional design, it is not possible to assess if the loss of weight is a direct consequence of the apathy. Pedersen et al. [16] described a relationship between motor symptom severity and apathy in PD subjects suggesting that apathy may be a sign of disease progression and severity in PD. In our study, PD subjects with apathy had a higher MDS-UPDRS total mean score. In the multivariate analysis, a significant relationship between a higher AS score and more severe motor symptoms (MDSUPDRS part III) was seen. Several studies found that levodopa treatment may improve apathy [17–19]. On the other hand, a recent study using specific instruments to rate apathy was unable to find differences in LEDD between patients with or without apathy [20]. In our sample, levodopa was used more frequently among PD subjects with apathy; this may be due to a more severe motor disease as measured by the motor part of the MDS-UPDRS. Nevertheless, there was no significant difference in mean dosage between subjects with and without apathy. Moreover, the use of levodopa was not an independent predictor on the regression model. Whether levodopa treatment may improve apathy remains unclear. Previous non-controlled studies have shown an improvement in apathy related to Parkinson’s disease after reintroduction of a dopaminergic agonist [21]. The post hoc analysis of the RECOVER study reported a significant improvement in the Non-motor Symptom Scale (NMSS) ‘‘Mood/apathy’’ domain. This improvement was specific to the cognitive components of apathy [22]. A class effect of dopamine agonists was found in our study using a bivariate analysis, with a greater number of subjects without apathy receiving these drugs as part of their treatment. Nevertheless, the use of dopamine agonists was not statistically associated with apathy in the multivariate analysis. On this matter, is should be mentioned that younger patients are less prone to be apathetic, but at the same time are more frequently treated with a dopamine agonist. In the present study, a greater number of subjects without apathy were receiving rasagiline. In a previous report, individuals taking monoamine oxidase (MAO) inhibitors were less likely to be apathetic [23]. The effect of selective MAO-B inhibitors on apathy may be explained
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Neurol Sci (2014) 35:729–734
by an enhancement in dopaminergic activity. MAO inhibitors proved to be independently associated with a lower frequency of apathy in the multivariate analysis. Whether rasagiline may be useful for treating or preventing apathy in PD patients warrants more study. An association between apathy and lower cognitive functioning has been reported in most studies of apathy in PD [24, 25]. Regarding cognitive status, the MoCA score in our subjects with apathy was significantly lower than in subjects without apathy but was not independently associated with the regression model. Previous studies have reported a relationship between older and less educated patients with the presence of apathy [26]. In our study, patients with fewer years of education showed a tendency (p = 0.054) towards a higher prevalence of apathy. A larger sample may be needed to better assess this association. The association between apathy and depression in PD has been variable. Existing evidence suggests that these entities are correlated in PD, although recent studies have noted that they may be separable in individual subjects [27–29]. In our sample, a greater proportion of subjects with apathy were taking antidepressants, when compared to those without apathy. Furthermore, SSRIs were the most commonly prescribed antidepressants. The use of SSRIs has been associated with a greater frequency of apathy in subjects with PD [30, 31]; this effect has not been observed for other antidepressants. Although a difference was found in the bivariate analysis, the use of antidepressants failed to show a statistically significant effect on the prevalence of apathy after the regression analysis. Limitations of this study include the lack of a formal assessment for depression. Nevertheless, the evaluation of MDS-UPDRS item 1.3 is a useful marker for depressive mood among PD subjects [32, 33]. Another drawback of our study was the fact that a complete neuropsychological examination was not performed; in particular, thorough cognitive assessment would have been important since some patients scored less than 27 in the MoCA test. In addition, this study was conducted in a tertiary care center, which may hinder the generalization of our findings to primary and secondary care scenarios. Recently, it has been reported that the right onset of motor symptoms may be related to worst apathy levels [34], but we did not assess that association. To our knowledge, this is one of the largest studies to date to analyze the clinical and demographic factors associated with apathy in PD subjects. It is also the first report of apathy in Mexican population. The prevalence of apathy in Mexican PD subjects is similar to what has been reported in other studies. Our results suggest that apathy is related to disease severity in terms of motor impairment.
Neurol Sci (2014) 35:729–734
Modifiable risk factors such as the subject’s BMI seem to also play a role in the presence of apathy among Mexican PD subjects. Conflict of interest The authors have no conflict of interest to report.
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ORIGINAL ARTICLE
Apathy and associated factors in Mexican patients with Parkinson’s disease Mayela Rodrı´guez-Violante • Paulina Gonza´lez-Latapi • Amin Cervantes-Arriaga • Daniel Martı´nez-Ramı´rez • Salvador Vela´zquez-Osuna • Azyadeh Camacho-Ordon˜ez
Received: 20 September 2013 / Accepted: 22 November 2013 / Published online: 5 December 2013 Ó Springer-Verlag Italia 2013
Abstract Apathy is one of the most common behavioral disturbances in Parkinson’s disease (PD) with a reported prevalence of 17–51 %. Apathy has been associated with depression, cognitive deficits, and poor quality of life. The objective of this study was to determine the prevalence of apathy in Mexican subjects with PD and its correlation with clinical and demographic characteristics. A crosssectional, descriptive, and analytic study was carried out. Consecutive subjects with PD attending the National Institute of Neurology and Neurosurgery in Mexico City were included. Demographic and other relevant clinical data were collected. The Apathy Scale was applied to all subjects. A cut-off score of C14 was used. A total of 241 non-demented patients (52.7 % male) were included. Apathy was found in 43 % of subjects. Lower body mass index, older age of PD onset, cognitive decline and disease severity were all related to apathy. The use of dopamine agonists or rasagiline was more common in patients with low apathy scores. Our results show that the prevalence of apathy in Mexican subjects with PD is similar to other reports.
M. Rodrı´guez-Violante (&) P. Gonza´lez-Latapi A. Cervantes-Arriaga D. Martı´nez-Ramı´rez A. Camacho-Ordon˜ez Clinical Laboratory of Neurodegenerative Diseases, National Institute of Neurology and Neurosurgery, Insurgentes Sur #3877 Col. La Fama, 14269 Mexico City, Mexico e-mail: [email protected] M. Rodrı´guez-Violante D. Martı´nez-Ramı´rez S. Vela´zquez-Osuna Movement Disorders Clinic, National Institute of Neurology and Neurosurgery, Mexico City, Mexico
Keywords Apathy Apathy Scale Body mass index Dopamine agonist Parkinson’s disease
Introduction Parkinson’s disease (PD) is one of the most common neurodegenerative disorders. Traditionally, the hallmark features of PD have included motor symptoms, particularly tremor, rigidity, postural instability and bradykinesia. Recently, neuropsychiatric symptoms have been described as highly prevalent and disabling symptoms of PD. Apathy has been identified as a major neuropsychiatric feature in PD [1], with prevalence between 17 and 51 % [2]. Clinical characteristics of apathy include lack of initiative and effort to perform everyday activities, lack of intellectual interest regarding personal or social issues and indifference or flattening of affect [3]. Diagnostic criteria include symptoms comprised into three groups: cognitive symptoms, behavioral symptoms and emotional symptoms [4]. Cognitive deficits and a decrease in quality of life have been associated with apathy [5]. Recently, a study carried out in Chilean population reported that higher scores for apathy in the Apathy Scale (AS) correlated with the most advanced Hoehn and Yahr stages. A greater age, longer period of illness and greater compromise of motor ability were also determinants of apathy in this study [6]. The Apathy Scale is the only scale to meet criteria to be ‘‘recommended’’ by the Movement Disorder Society Task Force to assess apathy in PD patients [2]. The aim of the present study was to determine the prevalence of apathy in Mexican patients with Parkinson’s disease as well as its correlation with demographic and clinical characteristics.
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730 Table 1 Clinical and demographic characteristics of subjects with and without apathy
Neurol Sci (2014) 35:729–734
PD-apathy (n = 104)
PD-no apathy (n = 137)
Female
48.0 (50)
46.7 (64)
Male
51.9 (54)
53.2 (73)
p
Gender, % (n)
Age, mean (SD)
0.897
64.9 (13.5)
60.2 (12.5)
0.007
Years of schooling, mean (SD)
7.6 (5.0)
9.0 (4.7)
0.028
Body mass index, mean (SD)
25.4 (3.9)
27.6 (4.3)
\0.001
57.8 (14.2)
54.0 (13.3)
Age of PD onset, mean (SD)
0.034
Classification of onset by age, % (n) Early-onset PD
12.5 (13)
16.7 (23)
0.496
Late-onset PD
87.5 (91)
83.2 (114)
0.496
54.8 (57)
56.9 (78)
0.794
Asymmetry, % (n) Right PD subtype, % (n) Tremor dominant
60.5 (63)
64.2 (88)
0.781
Rigid akinetic PIGD
31.7 (33) 7.6 (8)
29.9 (41) 5.8 (8)
0.781 0.781
Hoehn and Yahr, mean (SD) MDS-UPDRS Movement disorder society-Unified Parkinson’s Disease Rating Scale, MoCA Montreal Cognitive Assessment, PD Parkinson’s disease, PIGD postural instability and gait disorder, SD standard deviation
MDS-UPDRS score, mean (SD)
2.2 (0.7) 48.5 (23.3)
UPDRS part I, mean (SD)
11.1 (7.2)
8.5 (6.0)
UPDRS part II, mean (SD)
15.2 (9.3)
12.2 (7.4)
UPDRS part III, mean (SD)
38.4 (16.4)
28.9 (16.1)
UPDRS part IV, mean (SD) MoCA score, mean (SD)
Subjects and methods Consecutive subjects fulfilling the criteria for Parkinson’s disease according to the United Kingdom Parkinson’s Disease Society—Brain Bank were included [7]. All patients were seen at the Movement Disorders outpatient clinic of the National Institute of Neurology and Neurosurgery between August 2012 and July 2013. Demographic and other relevant clinical data were collected. A neurologist with expertise in movement disorders performed the neurological evaluation. Levodopa daily dose, levodopa equivalent daily dose (LEDD) and dopamine agonist (DA) LEDD were calculated [8]. Disease severity was measured in terms of Hoehn and Yahr (HY) stage [9]. All subjects were evaluated with the Spanish version of the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) [10]. Patients were clinically classified as tremor dominant, rigidity dominant and postural-gait instability dominant [11, 12]. Cognitive status was assessed using the Montreal Cognitive Assessment (MoCA) [13]; if educational years were \12, a point was added to total score in MoCA. The Spanish version of the AS developed by Starkstein was applied to all patients. The AS is a 14-item questionnaire that screens for and evaluates the severity of apathetic symptoms in PD subjects. The scores on
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2.4 (0.8) 63.9 (26.1)
0.005 \0.001 0.003 0.008 \0.001
2.5 (4.8)
1.4 (3.5)
0.035
21.1 (5.8)
23.1 (4.4)
0.004
the AS range from 0 to 42 points, with higher scores indicating greater severity of symptoms. Each item provides four possible answers (not at all, slightly, some or a lot). The scale has been found to have high internal consistency and good inter-rater reliability. A cut-off score C14 on the AS has a sensitivity of 66 % and specificity of 100 % for the detection of apathy [14]. The Institutional Review Board and local ethics committee approved the study. All subjects provided written informed consent before participating. Statistical analysis Independent t tests were used for comparison of continuous variables. Differences in proportions of categorical variables were analyzed by Chi-square test. A binary logistic regression analysis was performed to determine the impact of each factor for the presence of apathy. Agreement between the AS and MDS-UPDRS item 1.5 (apathy) was assessed by the kappa coefficient (B0 = poor, 0.01–0.20 = slight, 0.21–0.40 = fair, 0.41–0.60 = moderate, 0.61–0.80 = substantial, and 0.81–1 = almost perfect). A p value \0.05 was considered as statistically significant. All data were analyzed using SPSS version 17.0 (SPSS Inc., Chicago, IL).
Neurol Sci (2014) 35:729–734 Table 2 Comparison of treatment between patients with and without apathy
DBS deep brain stimulation surgery, LEDD levodopa equivalent daily dose, PD Parkinson’s disease, SSRI selective serotonin reuptake inhibitor, SD standard deviation
731
PD-apathy (n = 104)
PD-no apathy (n = 137)
p
Levodopa, % (n)
82.6 (86)
69.3 (95)
0.023
Levodopa, mean dose ± SD
471 ± 348.4
422.6 ± 393.7
0.327
Dopamine agonist, % (n)
48.0 (50)
63.5 (87)
0.019
Pramipexole, % (n)
44.2 (46)
54.0 (74)
0.143
Pramipexole, mean dose ± SD
2.1 ± 1.0
2.1 ± 1.1
0.892
Rotigotine, % (n)
3.8 (4)
8.0 (11)
0.103
Rotigotine, mean dose ± SD
6.0 ± 2.4
8.8 ± 3.8
0.095
Rasagiline, % (n)
3.8 (4)
12.4 (17)
Entacapone, % (n)
5.7 (6)
6.5 (9)
Amantadine, % (n)
11.5 (12)
8.7 (12)
0.021 [0.999 0.518
Biperiden, % (n)
13.4 (14)
10.9 (15)
0.531
Antidepressants, % (n)
24.0 (25)
13.1 (18)
0.028
Tricyclic antidepressants, % (n)
4.8 (5)
3.6 (5)
0.655
15.3 (16)
7.2 (10)
0.045
Other, % (n) DBS surgery, % (n)
3.8 (4) 1.9 (2)
12.1 (3) 2.9 (4)
0.448 0.520
LEDD mean dose ± SD
604.4 ± 345.6
594.5 ± 414.8
0.851
SSRI, % (n)
Results A total of 241 (52.7 % male and 47.3 % female) consecutive patients were included. The mean age of the sample was 62.3 ± 13.1 years. Mean age at disease onset was 55.6 ± 13.8 years. Mean disease duration was 6.6 ± 5.6 years. According to the HY stage, 94.4 % of the sample had mild to moderate disease (HY 1–3). Regarding antiparkinsonian treatment, 75.8 % received levodopa, with a mean daily dosage of 588.4 ± 317.49 mg; 63.7 % were taking a dopamine agonist (DA-LEDD 193.18 ± 97.2 mg). Mean LEDD of the sample was of 598.9 ± 384.8. Only six patients had undergone deep brain stimulation surgery, with the electrode placed bilaterally on the subthalamic nucleus. Mean AS score was 21.3 ± 6.2. Overall, 43.2 % of the patients had apathy. Table 1 shows demographic and clinical characteristics for subjects with and without apathy. Subjects with apathy were older, less educated, had a higher age at disease onset and a lower mean body mass index (BMI). The presence of apathy was associated with a higher HY. In addition, subjects with apathy had a higher mean MDS-UPDRS score for all four parts. Moreover, a greater number of subjects with apathy also reported depressive mood according to the MDS-UPDRS item 1.3 (75.9 vs. 52.5 %, p \ 0.001). With regard to the MDSUPDRS item 1.5, 40.6 % of all subjects referred apathy. The kappa coefficient measurement of agreement between AS score and apathy status assessed by MDS-UPDRS item 1.5 was fair (k = 0.249, p \ 0.001). The prevalence of cognitive decline, defined as a MoCA score of \26, was 73.2 % for PD subjects with apathy and
62.1 % for the group without apathy (p = 0.10). Apathy was associated with a lower mean MoCA score. With regard to treatment, levodopa and antidepressant use were significantly different between subjects with and without apathy. Dopamine agonist and rasagiline use were significantly higher in PD subjects without apathy. Table 2 compares treatment between subjects with and without apathy. With regard to antidepressant use, patients treated with a selective serotonin reuptake inhibitor (SSRI) had a higher prevalence of apathy (p = 0.045). After assessing for multicollinearity of the variables using variance inflation factors, a multivariate regression model with apathy status as the dependent variable was performed. The independent variables included were age, disease duration, years of schooling, BMI, MDS-UPDRS part I, MDS-UPDRS part II, MDS-UPDRS part III, MDSUPDRS part IV and MoCA score. The use of antidepressant, levodopa, dopamine agonist and rasagiline was also included in the model. For this model, BMI (B = -0.128, p = 0.002), MDS-UPDRS part III score (B = 0.031, p = 0.01) and use of rasagiline (B = -1.4, p = 0.042) were the only factors to remain significantly associated with apathy. Years of schooling presented a tendency towards statistical significance (p = 0.054).
Discussion Apathy is frequently reported as a non-motor symptom in PD subjects. In this study, apathy was present in 43 % of our sample. To our knowledge, this is the largest study in
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732
Latin America to report the prevalence of apathy among PD subjects. With regard to clinical and demographic factors, MDSUPDRS part III score and a lower BMI were all related with apathy in our study. An inverse association between apathy and BMI has also been reported in nursing home residents without PD. Furthermore, during 3 months of follow-up, subjects with apathy lost more weight than subjects without apathy [15]. The present study is the first to report this association in subjects with PD. Due to the cross-sectional design, it is not possible to assess if the loss of weight is a direct consequence of the apathy. Pedersen et al. [16] described a relationship between motor symptom severity and apathy in PD subjects suggesting that apathy may be a sign of disease progression and severity in PD. In our study, PD subjects with apathy had a higher MDS-UPDRS total mean score. In the multivariate analysis, a significant relationship between a higher AS score and more severe motor symptoms (MDSUPDRS part III) was seen. Several studies found that levodopa treatment may improve apathy [17–19]. On the other hand, a recent study using specific instruments to rate apathy was unable to find differences in LEDD between patients with or without apathy [20]. In our sample, levodopa was used more frequently among PD subjects with apathy; this may be due to a more severe motor disease as measured by the motor part of the MDS-UPDRS. Nevertheless, there was no significant difference in mean dosage between subjects with and without apathy. Moreover, the use of levodopa was not an independent predictor on the regression model. Whether levodopa treatment may improve apathy remains unclear. Previous non-controlled studies have shown an improvement in apathy related to Parkinson’s disease after reintroduction of a dopaminergic agonist [21]. The post hoc analysis of the RECOVER study reported a significant improvement in the Non-motor Symptom Scale (NMSS) ‘‘Mood/apathy’’ domain. This improvement was specific to the cognitive components of apathy [22]. A class effect of dopamine agonists was found in our study using a bivariate analysis, with a greater number of subjects without apathy receiving these drugs as part of their treatment. Nevertheless, the use of dopamine agonists was not statistically associated with apathy in the multivariate analysis. On this matter, is should be mentioned that younger patients are less prone to be apathetic, but at the same time are more frequently treated with a dopamine agonist. In the present study, a greater number of subjects without apathy were receiving rasagiline. In a previous report, individuals taking monoamine oxidase (MAO) inhibitors were less likely to be apathetic [23]. The effect of selective MAO-B inhibitors on apathy may be explained
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by an enhancement in dopaminergic activity. MAO inhibitors proved to be independently associated with a lower frequency of apathy in the multivariate analysis. Whether rasagiline may be useful for treating or preventing apathy in PD patients warrants more study. An association between apathy and lower cognitive functioning has been reported in most studies of apathy in PD [24, 25]. Regarding cognitive status, the MoCA score in our subjects with apathy was significantly lower than in subjects without apathy but was not independently associated with the regression model. Previous studies have reported a relationship between older and less educated patients with the presence of apathy [26]. In our study, patients with fewer years of education showed a tendency (p = 0.054) towards a higher prevalence of apathy. A larger sample may be needed to better assess this association. The association between apathy and depression in PD has been variable. Existing evidence suggests that these entities are correlated in PD, although recent studies have noted that they may be separable in individual subjects [27–29]. In our sample, a greater proportion of subjects with apathy were taking antidepressants, when compared to those without apathy. Furthermore, SSRIs were the most commonly prescribed antidepressants. The use of SSRIs has been associated with a greater frequency of apathy in subjects with PD [30, 31]; this effect has not been observed for other antidepressants. Although a difference was found in the bivariate analysis, the use of antidepressants failed to show a statistically significant effect on the prevalence of apathy after the regression analysis. Limitations of this study include the lack of a formal assessment for depression. Nevertheless, the evaluation of MDS-UPDRS item 1.3 is a useful marker for depressive mood among PD subjects [32, 33]. Another drawback of our study was the fact that a complete neuropsychological examination was not performed; in particular, thorough cognitive assessment would have been important since some patients scored less than 27 in the MoCA test. In addition, this study was conducted in a tertiary care center, which may hinder the generalization of our findings to primary and secondary care scenarios. Recently, it has been reported that the right onset of motor symptoms may be related to worst apathy levels [34], but we did not assess that association. To our knowledge, this is one of the largest studies to date to analyze the clinical and demographic factors associated with apathy in PD subjects. It is also the first report of apathy in Mexican population. The prevalence of apathy in Mexican PD subjects is similar to what has been reported in other studies. Our results suggest that apathy is related to disease severity in terms of motor impairment.
Neurol Sci (2014) 35:729–734
Modifiable risk factors such as the subject’s BMI seem to also play a role in the presence of apathy among Mexican PD subjects. Conflict of interest The authors have no conflict of interest to report.
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