Differentiating Between Apathy and Depression in Patients With Parkinson Disease Dementia

Abstract

In Parkinson disease (PD), apathy and depression often overlap, making it difficult to differentiate between them. This study sought to analyze apathy and depression in patients with PD dementia (PDD). Forty patients were diagnosed with PDD using the Movement Disorder Society criteria. A statistically significant correlation was identified between worsening dementia and an improvement in depression (r = .3695; r ² = .1365, 95% confidence interval [CI]: 0.0985 to 05.894, P = .0044) and between worsening dementia and worsening apathy (r = −.2578, r ² = .0664, 95% CI: −0.5025 to .0251, P = .036). Depression had a greater correlation with advanced motor symptoms (r = .4988, r ² = .2438, 95% CI: 0.2218-0.7013, P = .0005]. In conclusion, depression was associated with less advanced PDD and more intense motor features, while apathy was associated with more advanced cognitive impairment.

Introduction

Parkinson disease (PD) was for a long time characterized by its motor symptoms and signs. ^1,2 However, over the years, the nonmotor manifestations became better characterized and can now be identified in most, if not all, patients. ^2,3 The nonmotor manifestations of PD involve autonomic, neurologic, and neuropsychiatric dysfunctions. The most common neuropsychiatric phenomena include dementia, apathy, and depression, ^{4 -7} which are sometimes confused as they are very closely related. ⁸

Parkinson disease dementia (PDD) is characterized by cognitive impairment that is sufficient to compromise the ability to perform activities of daily living and planning and organizational, executive, visuospatial, and language abilities. ⁹ It has a prevalence of 30% to 40% in patients with PD and a cumulative prevalence of 48% to 75% after 15 years of follow-up. ¹⁰

Depression is considered the neuropsychiatric condition most frequently found in PD ^5,6 and has a prevalence of 40% to 76% in PD and 13% in PDD. ^10,11 It is one of the main factors determining a worsening of patients’ quality of life and affects primarily cognitive functions as well as, to a lesser extent, executive functions. ^9,11,12 Depressive symptoms occur in any stage of the disease and can even be observed before motor symptoms. ¹³

Apathy is another condition frequently found in PD ^9,14 and has a prevalence of 16% to 60% in PD and 50% in PDD. ^8,10,15,16 It interferes with patients’ activities of daily living, reduces the response to dopaminergic treatment, and worsens the patient’s quality of life, causing considerable distress for the carer. Although apathy can precede motor symptoms and tends to improve after the dopaminergic treatment is started, it returns as the PD progresses and is more frequent when PDD is present. ⁸ Patients with PD with apathy have been found to be more likely to have greater motor deficiency, major executive dysfunction, and a greater risk of developing dementia than patients with PD without the condition. ¹²

Although there is some overlap of signs and symptoms between apathy and depression, clinical evidence helps to differentiate between the 2 conditions. ^6,17 The main piece of clinical evidence is that in apathy the patient’s mood is primarily “neutral,” while in depression it is clearly negative and causes emotional suffering. ¹⁴ Another important factor is that apathy can be present without depression and vice versa. ^14,18 In addition, there are signs and symptoms associated exclusively with apathy, while others are associated exclusively with depression. The former includes reduced initiative, reduced participation in outside activities, loss of interest in social events or daily activities, reduced interest in starting new activities, reduced interest in the world around the individual, emotional indifference, reduced emotional reactions, fewer displays of affection than usual, and a lack of concern about other people’s feelings and interests. Exclusively depressive symptoms include sadness, feelings of guilt, negative thoughts and feelings, helplessness, despair, pessimism, self-criticism, anxiety, and suicidal thoughts. ¹² It is against this background that this study sought to identify the characteristics of depression and apathy in individuals with PDD.

Material and Methods

Forty-nine patients who had been seen at the neurology service at Campos Gerais Regional University Hospital and INOVARE Serviços de Saúde Ltda. and agreed to take part in the study were selected in accordance with the MRC London Neurodegenerative Diseases Brain Bank diagnostic criteria. All the participants signed a voluntary informed consent form. The exclusion criteria, which were intended to exclude patients whose signs and symptoms made it impossible to perform a cognitive assessment or apply the proposed tests, were as follows: (1) advanced stage PD, (2) severe psychotic symptoms, and (3) another dementia not associated with PD. The study was approved by the State University of Ponta Grossa Research Ethics Committee (reference no. FA 631.285 FA).

All the patients were assessed during the ON phase of levodopa therapy, preferably 2 hours after the medication had been administered. Clinical assessment was carried out by a team trained in movement disorders. Patients were classified according to motor changes on the Hoehn and Yahr scale and the Unified Parkinson’s Disease Rating Scale III (UPDRS-III). ^19,20 Parkinson disease dementia was diagnosed using the International Parkinson and Movement Disorder Society criteria for PDD. ²¹ Cognition was assessed with Scales for Outcomes in Parkinson’s Disease–Cognition (SCOPA-Cog); a score of less than 22 out of a possible maximum of 43 was considered to indicate cognitive deficit. ²² Depression was measured with the Montgomery-Åsberg Depression Rating Scale (MADRS). A score of 0 to 7 corresponded to the absence of symptoms, 8 to 19 corresponded to mild depression, 20 to 34 corresponded to moderate depression, and 35 to 60 corresponded to severe depression. ²³ Apathy was measured with the Apathy Evaluation Scale (AES) and was considered to be present when the patient’s score was greater than 14 (on a scale from 0 to 72). ^17,18

The groups were tested for normality with the Shapiro-Wilk test, which revealed that all the groups had a normal distribution. Statistical differences between the means of the groups were determined using 1-tailed Student t test. Correlations were measured using the Pearson correlation coefficients. Fisher exact test was used to analyze the differences between the expected and observed values. The results are given as mean (standard deviation) or as a value followed by a 95% confidence interval (r, 95% CI). Differences were considered significant when P < .05. The statistical analysis was performed with version 99 of Statistica for Windows.

Results

The ratio of males to females for the 49 patients was 1.88:1. Forty (81.63%) had PDD, and of these, 39 (97.5%) satisfied the diagnostic criteria for apathy and 27 (67.5%) satisfied the criteria for depression. The 27 (67.5%) patients with depression also presented with apathy, that is, depression was detected only in patients with apathy. Apathy without depression was present in 12 (30%) patients, and 1 (2.05%) individual had no neuropsychiatric manifestations (Table 1).

Table 1.

Prevalence of Apathy and Depression in PD Patients With and Without PDD.^a

Variables	Total No. of Patients (N = 49)		Patients With PDD (N = 40)
	Apathy	No Apathy	Apathy	No Apathy
No depression	15 (30.61%)	1 (2.04%)	12 (30%)	1 (2.5%)
Mild depression	18 (36.63%)	0	14 (35%)	0
Moderate depression	13 (26.53%)	0	11 (27.5%)	0
Severe depression	2 (4.08%)	0	2 (5%)	0
Total	48 (97.85%)	1 (2.04%)	39 (97.5%)	1 (2.5%)

Abbreviations: PD, Parkinson disease; PDD, Parkinson disease dementia.

^aDepression evaluated on the MADRS scale: 0 to 7 no symptoms, 8 to 19 mild depression, 20 to 34 moderate depression, and 35 to 60 severe depression. Apathy was evaluated on the AES scale using a cutoff value of 14.

In comparison of patients with and without PDD, there were no statistically significant differences in terms of age, age of onset of symptoms, disease duration, duration of levodopa therapy, or motor symptoms on the Hoehn and Yahr scale or the UPDRS-III. There was, however, a statistically significant difference in cognitive function on the SCOPA-Cog scale and years of schooling between the 2 groups (Table 2).

Table 2.

Epidemiologic Data and UPDRS-III, SCOPA-COG, MADRS, and AES Scores of Patients With PD.^a,b

Variables	PD	PDD SCOPA-COG < 22	No PDD SCOPA-COG ≥ 22	P (With and Without PDD)
n	49 (100%)	40 (81.63%)	9 (18.37%)	1
Gender				1
Male	32 (65.31%)	26 (65.0%)	6 (66.67%)
Female	17 (34.69%)	14 (35.0%)	3 (33.33%)
Age	69.55 (11.37)	70.075 (10.80)	66.89 (14.21)	.454
Age at onset of symptoms	60.23 (12.45)	60.51 (12.34)	58.875 (13.76)	.932
Disease duration	8.16 (8.36)	8.45 (8.88)	6.89 (5.71)	.932
Duration of levodopa therapy	5.52 (5.12)	5.26 (4.99)	6.67 (5.81)	.461
UPDRS-III	20.92 (11.34)	22.05 (11.27)	15.89 (10.86)	.142
Hoehn and Yahr	2.29 (1.22)	2.25 (1.25)	2.50 (1.09)	.584
Years of schooling	6.90 (5.58)	5.925 (4.96)	19.44 (6.38)	.008c
SCOPA-Cog	13.65 (7.60)	11.25 (6.05)	24.33 (3.28)	<.0001c
MADRS	13.08 (9.88)	13.48 (9.48)	11.33 (11.97)	.562
AES	21.35 (3.63)	21.43 (3.85)	21.0 (2.55)	.754

Abbreviations: AES, Apathy Evaluation Scale; MADRS, Montgomery-Åsberg Depression Rating Scale; PD, Parkinson disease; UPDRS-III, Unified Parkinson’s Disease Rating Scale-III; SCOPA-Cog, Scales for Outcomes in Parkinson’s Disease–Cognition.

^aAge, years of schooling, disease duration, and duration of levodopa therapy are given in years.

^b P, statistical significance.

^cStatistically significant value.

No statistically significant differences were observed between the patients with and without PDD in terms of depression on the MADRS scale and apathy on the AES scale (Table 2). Of all the patients, only 1, who had PDD, did not present with apathy. Most of the patients with PD either did not have depression or had mild depression (Table 1).

There was no correlation between MADRS and AES scores in patients with PDD (r = −.2478, r2 = .0664, 95% CI: −0.5025 to 0.0251, P = .3683). However, there was a statistically significant correlation in these patients between a worsening of dementia and an improvement in depression, which could be observed in the direct correlation between SCOPA-Cog scores and depression on the MADRS scale (r = .3695, r2 = .1365, 95% CI: 0.0985-0.5894, P = .0044). In contrast, worsening apathy in these patients was directly correlated with progression of dementia, as seen in the inverse correlation between AES and SCOPA-Cog scores (r = −.2578, r ² = .0664, 95% CI: −0.5025 to −0.0251, P = .036; Table 3).

Table 3.

Correlation between Depression and Apathy in PDD.

Correlations	Depression	Apathy
Correlations present	There was an improvement in depression scores on the MADRS scale with increasing cognitive impairment on the SCOPA-Cog scale (r = .3695). Depression scores on the MADRS scale were greater in patients with more severe motor impairment (HY, r = .4988) and (UPDRS III r = .4483).	Apathy on the AES scale worsened as cognitive impairment increased (SCOPA-COG r = −.2578). Although there was a correlation between motor changes and cognitive impairment (r = −.4089), apathy was not correlated with worsening motor symptoms (UPDRS-III r = −.4390).
Correlations not present	Disease duration Duration of levodopa therapy	Disease duration Duration of levodopa therapy

Abbreviations: AES, Apathy Evaluation Scale; HY, Hoehn and Yahr; MADRS, Montgomery-Åsberg Depression Rating Scale; r, Pearson correlation coefficient; SCOPA-Cog, Scales for Outcomes in Parkinson’s Disease–Cognition; UPDRS-III, Unified Parkinson’s Disease Rating Scale.

A greater rate of motor decline corresponded to more severe signs and symptoms of dementia, as observed in both the inverse correlations between SCOPA-Cog and UPDRS scores (r = −.4089, r ² = .1672, 95% CI: −0.6390 to −0.1116, P = .0043] and between SCOPA-Cog scores and the results on the Hoehn and Yahr scale (r = −.3355; r ² =.1126, 95% CI: −0.058 to −0.0268, P = .0171). Apathy on the AES scale had an inverse correlation with motor symptoms on the UPDRS scale (r = −.4390; r ² = .1927; 95% CI: −0.6411 to −0.1801, P = .0007). Depression on the MADRS scale had a direct correlation both with motor scores on the UPDRS-III scale (r = .4988, r ² = .2438, 95% CI: 0.2218-0.7013, P = .0005) and with scores on the Hoehn and Yahr scale (r = .4483, r ² = .2010, 95% CI: 0.1590-0.6667, P = .0037) in patients with PDD (Table 3).

There was an association between greater cognitive deficits and duration of levodopa use, which could be observed in the inverse correlation between SCOPA-Cog scores and duration of levodopa use in years (r = −.2759, r ² = .0761, 95% CI: −0.5409 to 0.0388, P = .042) in patients with PDD. There was no correlation between disease duration or duration of levodopa therapy and AES or MADRS scores or between disease duration and SCOPA-Cog scores in these patients (Table 3).

Discussion

We studied apathy and depression in patients with PDD and their correlation with other characteristics of PD, such as motor symptoms and treatment. An association was found between more severe dementia (ie, SCOPA-Cog <22) and more advanced motor impairment on the UPDRS-III and Hoehn and Yahr scales. These findings were expected as more severe motor symptoms. ¹⁰ An association was also found between severity of dementia and longer use of levodopa, which can be explained by the fact that PD is diagnosed, and levodopa treatment started, before the onset of PDD. ¹⁰ Although there is extensive overlap between the symptoms of both conditions, the present study found several differences as well as similarities between apathy and depression in terms of their correlations with the clinical and epidemiologic characteristics of patients with PDD.

Apathy (ie, AES ≥14) was more frequent than depression (MADRS ≥8). Apathy and depression had a prevalence of 97.5% and 67.5% in patients with PDD, respectively, higher values than those reported by Emre et al (23%-50% and 13% in PDD, respectively). ¹⁰ Another important finding was the presence of apathy without depression in 30% of the patients, confirming that the former can be present without the latter, as reported in studies that found even higher prevalence, from 28% to 42%. ^8,18 Although a prevalence of 6% to 28% was expected, ⁵ depression was not found without apathy, a finding that may be explained by the small sample size and the large number of patients with advanced PD in the study. This significant prevalence of apathy in PDD should be borne in mind when choosing suitable treatment to avoid treating a depressive disorder that is not present and so reduce the chance of triggering or worsening apathy because of inappropriate use of serotonin receptor inhibitors. ^8,10,12

Apathy was found to be associated with more advanced dementia, while depression was associated with dementia in its less advanced stages, in agreement with other studies in the literature. ^4,8 Three main frontostriatal changes, which occur one after the other, are proposed to explain this phenomenon. Firstly, dopaminergic changes in PD affect the motor circuit directly associated with the dorsal striatum (the putamen nucleus and dorsal caudate nucleus) and then the ventral striatum (ventral caudate nucleus and nucleus accumbens), so that in early PD, there is severe dopamine depletion in the dorsal striatum and relatively little depletion in the ventral striatum. ²⁴ In this phase, specific nuclei in the thalamus and the prefrontal cortex that are important for normal motor function are also affected. Secondly, the circuit that connects the dorsolateral frontal cortex to the dorsal caudate nucleus is affected by PD. Thirdly, the disease affects structures in the limbic system that connect the orbitofrontal cortex and the ventral caudate nucleus and the anterior cingulate cortex and nucleus accumbens. Hence, in the early stages of PD, frontal lobe dysfunction is believed to reflect cortical deafferentation in relation to dopamine depletion in the corpus striatum. In the advanced stages of the disease, the deficiency in the cerebral cortex is a result of actual cortical dopamine depletion. ^12,25

Parkinson disease dementia is associated with dopamine loss in dopaminergic pathways to the prefrontal cortex, and, to a lesser extent, in the ventral tegmental area. Finally, the appearance of Lewy bodies, which normally occurs in the advanced stages of PD, contributes to the development of severe PDD. ^6,25 There has been shown to be an association between hypofunction in the pathways involving the dorsal caudate nucleus and the orbitofrontal cortex (including connections with the amygdala), the same circuits that have been associated with the onset of PD when PDD is less prevalent. This may explain the finding that depression is more correlated with less severe cognitive changes. ^10,26 As the disease progresses, hypofunction of the circuit involving the anterior cingulate cortex and nucleus accumbens (including connections with the amygdala) occurs in patients with apathy, followed by changes in the pathways involving the ventral caudate nucleus and orbitofrontal cortex. ^{26 -28} In the advanced stages of PD, patients have dopamine depletion in the corpus striatum (putamen, globus pallidus, and caudate nucleus) as well as the frontal cortex, increasing the prevalence and severity of apathy as dementia and Lewy bodies progresses, ^12,27 in agreement with the findings of the present study. Apathy, rather than depression, therefore has the strongest association with more severe cognitive dysfunction in PD. ^5,12,27

However, the opposite was observed for the associations between depression and motor symptoms and between apathy and motor symptoms on the UPDRS-III and Hoehn and Yahr scales. There was a statistically significant correlation between motor symptoms and depression, but not apathy, on the latter scale. Depression was directly correlated with scores on the motor scales (the more advanced the motor symptoms, the more severe the depression), although an inverse correlation was expected, that is, more frequent and severe depression in less advanced stages of PD, as hypofunction of the pathways that depend on the dorsal caudate nucleus occurs in the initial stages of the disease. ^5,25 The results for the correlation between apathy and motor symptoms were also surprising. Apathy would be expected to have a weaker association, or no association, with less advanced motor symptoms, ^5,27 as in the initial stages of PD, there is compensatory hyperactivity in the dopaminergic pathway to the prefrontal cortex and dopamine depletion in the dorsal caudate nucleus. ²⁸ A possible explanation for the strong correlations between both depression and motor symptoms and apathy and motor symptoms, contradicting what was expected, may lie in the fact that the patients included in the study were being treated with levodopa, which improves ventral striatal activity, ²⁴ and were in the ON period (approximately 2 hours after they had last taken their medication) when their motor skills were assessed. These patients’ motor disturbances were therefore controlled or less intense, leading to lower scores on the UPDRS-III and Hoehn and Yahr scales.

This effect caused by levodopa treatment was not, however, observed in the assessment of neuropsychiatric dysfunctions. The explanation for this paradox is that levodopa does not cause significant changes in the activity of dopaminergic projections to the frontal cortex, as they are mediated largely by D1 dopamine receptors, but stimulates mainly D2 receptors, which predominate in the corpus striatum. Levodopa therapy is therefore not expected to lead to fluctuations in nonmotor disturbances in PD. ^25,26

Our findings indicate (1) that apathy in PDD is common and more prevalent than depression and (2) that apathy has a greater association with more advanced dementia and can be present with or without depression, whereas depression occurs in less advanced stages of PDD. The results highlight the importance of differentiating between apathy and depression so that therapy can be planned appropriately for patients with PD, particularly those in the more advanced stages of the disease.