Correlations of apathy and depression with postural instability in Parkinson disease

Journal of the Neurological Sciences 338 (2014) 162–165

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Correlations of apathy and depression with postural instability in Parkinson disease Anhar Hassan a,b,⁎, Srikant Vallabhajosula c, Laura B. Zahodne d, Dawn Bowers a,e, Michael S. Okun a, Hubert H. Fernandez f, Chris J. Hass a a

Department of Neurology, Center for Movement Disorders and Neurorestoration, University of Florida, Gainesville, FL, USA Department of Neurology, Mayo Clinic, Rochester, MN, USA Department of Physical Therapy Education, Elon University, Elon, NC, USA d Department of Neurology and Taub Institute for Research on Alzheimer's Disease and The Aging Brain, Columbia University College of Physicians and Surgeons, New York, NY, USA e Clinical & Health Psychology, University of Florida, Gainesville, FL, USA f Center for Neurological Restoration, Cleveland Clinic, Cleveland, OH, USA b c

a r t i c l e

i n f o

Article history: Received 10 June 2013 Received in revised form 22 December 2013 Accepted 24 December 2013 Available online 2 January 2014 Keywords: Parkinsonism Mood Affect Gait Rating scales Posturography

a b s t r a c t Background: Postural instability (PI) in Parkinson's disease (PD) is associated with depression and apathy based on UPDRS scores. We sought to examine the link using more objective PI measures. Methods: Demographic, clinical, depression and apathy data were recorded for PD patients prospectively recruited from an outpatient university movement disorders clinic. PI was objectively evaluated using the standing center of pressure sway area. Results: Thirty-seven PD patients participated in the study. Bivariate analysis revealed that PI was significantly correlated to both apathy (p = 0.018) and depression (p = 0.014). Hierarchical regression revealed that apathy significantly predicted PI but depression did not significantly add to the prediction. Also, depression did not significantly predict PI and the addition of apathy did not increase this prediction. Conclusion: Apathy and depression are both associated with objective measures of PI, and apathy appears a stronger predictor of PI than depression. Concomitant improvement in PI may be important to consider when measuring apathy or depression interventions in PD. © 2014 Elsevier B.V. All rights reserved.

1. Introduction

2. Methods

Parkinson's disease (PD) is characterized by both non-motor and motor features which impact quality of life [1–3]. The non-motor symptoms of apathy and depression have been associated with the cardinal motor finding of postural instability (PI) [4]. Apathy is defined as a deficit of motivation, goal-directed behavior, and emotion [5]. It is a distinct entity to depression, reliably distinguished by validated scales [6,7]. Prior studies have utilized the simple UPDRS motor subscale axial items to assess the presence of PI in apathetic and depressed PD patients [7–9]. Objective laboratory measures of PI have not been employed despite their validated use in PD populations [10,11]. This study sought to confirm and to better characterize the relationship between PI, depression and apathy in PD through the use of objective laboratory measures of PI.

2.1. Patients

⁎ Corresponding author at: Mayo Clinic 200 First St SW, Rochester, MN 55905, USA. Tel.: +1 507 238 1038; fax: +1 507 538 6012. E-mail address: [email protected] (A. Hassan). 0022-510X/$ – see front matter © 2014 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jns.2013.12.040

PD patients with and without apathy were recruited from our Movement Disorders Center to participate in two separate prospective intervention studies aimed at improving apathy (n = 17) or postural control (n = 20). All subjects provided written informed consent, and the studies were approved by the Institution Review Board. This is a post-hoc analysis, and the data presented here are from the baseline evaluations of these studies. Inclusion criteria for both studies were: patients with PD confirmed by a movement disorder neurologist and aged 30 or older. Exclusion criteria were: atypical parkinsonism or other neurodegenerative diseases; brain insult including stroke, mass lesions or major head trauma; prior deep brain stimulation or other brain surgeries; dementia based on the Mini-Mental State Examination (MMSE) score ≤26 and the Dementia Rating Scale (DRS) score ≤130; or unstable medical illnesses. Demographic variables obtained included: gender, age, PD duration, and UPDRS motor subscale scores. Apathy was measured using the Starkstein Apathy Scale (AS), a modification of the Marin Apathy Scale [7]. This is a validated measure for apathy in the PD population. In general, an AS score of N 14 represents significant apathy symptoms.

A. Hassan et al. / Journal of the Neurological Sciences 338 (2014) 162–165

Depressive symptoms were evaluated using the Beck Depression Inventory I or -II (BDI) [12] one of the most commonly used screening scales for depression in PD. In general, patients with a BDI score of ≥14 represent significant depressive symptoms. The BDI contains four items that relate to apathy, and this was not corrected for. 2.2. Postural instability assessment Ground reaction forces were recorded (360 Hz) from two force platforms (type 4060-10, Bertec Corp., Columbus, OH) embedded level with the floor. During three quiet stance trials, participants stood still for 20 s with their feet in a self-selected, comfortable stance width with one foot on each platform. Patients were tested in a levodopa on-state. Ground reaction forces and moments from the two force platforms were used to calculate the location of the net center of pressure (COP). The net COP displacement is reflective of the output of the central nervous system as it attempts to manage the body position to keep the center of mass within the base of support. COP sway area (cm2) was then calculated as the product of the maximum displacement in the mediolateral and anteroposterior directions.

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significant apathy. The subjects with apathy had significantly greater mean UPDRS total scores (31.7 vs. 23.7, p = 0.012), similar UPDRS posture scores (0.7 vs. 0.9, p = 0.513) and greater mean BDI scores (15.1 vs. 7.6, p = 0.009) compared to the non-apathetic subjects. The subjects with significant depression had significantly greater mean UPDRS total scores (34.0 vs. 25.9, p = 0.022), lower mean UPDRS posture scores (0.2 vs. 1.0, p = 0.002), and greater mean AS scores (19.3 vs. 13.2, p = 0.010) compared to the subjects without significant depressive symptoms (Table 2). The mean sway area was 4.2 (±2.7) cm2. The mean sway area significantly correlated with AS score (rho = .393, p = 0.018) and BDI score (rho = .401, p = 0.014). The AS explained 12% of the variance (represented by R2 in Table 3) in sway area [F(1,35) = 4.641; p = 0.038]. When BDI was added to the model, only an additional 2% of variance was explained [F(2,35) = 2.644; p = 0.086]. The BDI explained 10% of the variance in sway area [F(1,35) = 3.63; p = 0.065]. When AS was added to the model, only an additional 4% of variance was explained (Table 3).

4. Discussion 2.3. Statistical analysis Standard descriptive statistics were used (mean, standard deviation) to describe our cohort. The primary response variable in this analysis was the mean sway area. Using Spearman's correlation we evaluated the measures of apathy and depression (AS and BDI-II) to the mean sway area. Using two-sided t-test, we compared the demographic characteristics and AS, BDI, and PI scores between those with and without apathy and depression. Using chi square, categorical variables were compared between those with and without apathy and depression. We then explored the association of PI (using the mean sway area) with measures of depression and apathy using hierarchical regression models. These models were used to determine how well apathy and depression could predict PI among PD. The collinearity statistics indicated a high tolerance value of 0.662 between depression and apathy predictors suggesting that both these scores were not covariates and could be used in the regression model. No other predictors were used in the model. The alpha-value was set at 0.05.

This study showed that objective measurements of PI significantly correlated with either apathy or depression in our PD cohort. This confirms previous observations which utilized only UPDRS motor subscores as an indirect measure of PI [4,6,8]. Importantly, objective PI measures were more reliable than UPDRS subscores in our study. The apathy and non-apathy groups had similar UPDRS subscores, while the depressed group appeared to have better stability than nondepressed subjects using UPDRS subscores. Notably, the frequencies of apathy and depression in patients in this cohort were representative of those found in other populations of PD patients [6,9]. Apathy and depression may occur individually or coexist in PD patients, similar to our cohort [13]. Apathetic or depressed PD patients appeared more parkinsonian, by approximately 8 or 9 points on the UPDRS scale, in our study. In depressed patients, this observation has been previously explained by the overlap of physical embodiment of mood disturbance with parkinsonian signs. Apathetic patients are not considered to have more severe parkinsonism, apart from correlations found in one study, and may relate to coexistent depression [8,14].

3. Results Thirty-seven PD subjects (24 male; 65%) participated with a mean age of 67 ± 9 years and a mean disease duration of 95 ± 51 months (Table 1). They were median Hoehn and Yahr (H&Y) stage 2 (interquartile range 1). The mean apathy score was 15 ± 7 (range 5–29) (n = 36) and the mean depression score was BDI 12 ± 9 (range 0– 34). Eleven of 37 (30%) PD patients had a BDI score N 14, representing significant depression in our cohort, whereas a higher proportion, 23 of the 37 (62%) PD patients, had an AS score of N, representing

Table 2 Mean (SD) and statistical comparisons between the two groups differentiated by AS scores and BDI scores. Group 1

Variables

Patients (n = 37)

Age (years) Disease duration (months) UPDRS Total Posture Gait Balance H&Y scorea BDI

Age (years), mean (±SD; range) Gender (male) Hoehn and Yahr (H&Y) stagea, median (±interquartile range) Disease duration (months), mean (±SD, range) UPDRS-III scoreb, mean (±SD; range) UPDRS posture subscoreb, mean (±SD; range) UPDRS gait subscore, mean (±SD; range) UPDRS balance subscore, mean (±SD; range) Apathy scale, mean (±SD; range) BDI score, mean (±SD; range)

67 (±9; 45–82) 24 (65%) 2 (±1) 95 (±51; 7–192) 28 (±10; 13–52) 1 (±1; 0–3) 1 (±1; 0–3) 1 (±1; 0–2) 15 (±7; 5–29) 12 (±9; 0–34)

Age (years) Disease duration (months) UPDRS Total Posture Gait Balance H&Y scorea AS score

Table 1 Demographic and clinical data for PD patients.

a b

Data for 32 subjects. Data for 36 subjects.

n

Group 2

n

t-Statistic

AS N 14 68.6 (8.3) 97.1 (45.5)

20 20

AS ≤ 14 63.2 (9.0) 96.3 (57.7)

16 16

1.86 0.04

31.7 (8.8) 0.7 (0.8) 0.8 (0.6) 0.7 (0.7) 2.4 (0.5) 15.1 (9.7)

20 20 20 20 19 20

23.7 (8.9) 0.9 (0.6) 0.6 (0.8) 0.6 (0.8) 2.4 (0.6) 7.6 (6.4)

15 15 16 16 12 16

2.65 −0.66 1.00 0.10 −0.11 2.77

BDI ≥ 14 68.8 (8.1) 95.5 (37.7)

10 10

BDI b 14 65.7 (9.4) 94.5 (55.9)

27 27

0.92 0.05

34.0 (8.6) 0.2 (0.4) 0.9 (0.9) 0.9 (0.9) 2.6 (0.6) 19.3 (5.5)

10 10 10 10 10 10

25.9 (8.9) 1.0 (0.7) 0.6 (0.6) 0.5 (0.7) 2.3 (0.5) 13.2 (6.1)

26 26 27 27 22 26

2.47 −3.44 1.18 1.38 1.14 2.75

a H&Y reported as median (interquartile range). ⁎ significant correlation (p ≤ 0.05).

p 0.071 0.966 0.012⁎ 0.513 0.326 0.924 0.914 0.009⁎

0.362 0.960 0.019⁎ 0.002⁎ 0.247 0.178 0.262 0.010⁎

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A. Hassan et al. / Journal of the Neurological Sciences 338 (2014) 162–165

Table 3 Summary of hierarchical regression analysis for variables predicting postural instability. Category

Model

Predictor

B

SE B

β

R2

F

p-Value

Association of postural instability with apathy

1 2

0.07 0.08 0.06 0.05 0.06 0.08

0.35 0.25 0.17 0.31 0.17 0.25

4.64 2.64

0.038⁎ 0.086

1 2

0.14 0.10 0.05 0.09 0.05 0.10

0.120 0.138

Association of postural instability with depression

AS AS BDI BDI BDI AS

0.096 0.138

3.63 2.64

0.065¥ 0.086

Note: B — unstandardized coefficient; SE — standard error; β — standardized coefficient; AS — apathy score; BDI — Beck Depression Inventory; ⁎ significant correlation (p ≤ 0.05); and ¥ correlation showing trend towards significance (0.05 b p ≤ 0.07).

Cognitive impairment has been previously correlated with postural instability, apathy, and depression, and thus may be a confounding factor [7,9,15]. We excluded demented patients to remove this variable from the data (all MMSE N26), however this does not exclude mild cognitive impairment which may have impacted our findings. The association of PI, apathy and depression raises the possibility of a shared underpinning pathophysiology. Imaging and pathologic studies of these entities in PD, as well as non-PD neurodegenerative disorders, have revealed complex findings with much overlap. Apathy and depression are well-characterized anatomically, and share prefrontal cortex and cingulate deficits [16–18]. The neuroanatomical basis for postural instability is less clear. However, apathy, depression and PI all localize to basal ganglia circuitry, share dopaminergic dysfunction, and are generally considered levodopa-resistant entities [16–21]. Other shared neurotransmitters include cholinergic and catecholaminergic dysfunction [22–24]. In addition, subthalamic nucleus deep brain stimulation frequently impacts these entities producing variable results: apathy may be newly provoked, depression worsens or improves, and PI frequently improves, provoking considerable interest into the mechanism of this [21,25]. Interestingly, serotonergic or noradrenergic medications used to treat depression in PD patients have been associated with postural instability and falls or apathy [26]. These findings suggest a more complex interplay of other modulating neurotransmitters, where increasing noradrenaline or serotonin availability in a dopamine or acetylcholine depleted environment may worsen PI and apathy, but improve depression. This will require further evaluation. Overall, the strengths of this study were the strict exclusion criteria, the use of standardized scales, and the employment of objective measures for quantitating PI. The proportion of PD subjects with apathy (62%) is representative of PD populations, reported to range from 7% up to 70% [27]. Limitations include the selected subject sample, composed of PD patients likely to derive benefit from apathy or postural instability interventional treatment. The lack of control data is a potential weakness. As the study size was small, verification of these findings in a larger study population is indicated. Also, patients were all tested in a levodopa on-state, which may have worsened postural instability in some. In addition, antidepressant or other antiparkinsonian medication uses were not evaluated which may have impacted our findings. Future research will be required to better define the pathophysiology and treatments for apathy, depression and PI. Addressing these issues in PD patients is critical as they can result in a negative impact on quality of life in PD. Objectively exploring PI and its relationship to other non-motor symptoms, such as anosmia, dysautonomia and REM sleep behavior disorder may help with the subgrouping of non-motor symptoms into more specific neural networks. Treatments potentially effective for apathy (e.g. cholinesterase inhibitors, noradrenergic medications) and depression could also help improve PI. 5. Conclusions Apathy and depression are significantly correlated with objective measures of PI in PD patients, and these are more robust measures than UPDRS motor subscores. Apathy appears as a stronger predictor

of PI than depression. Concomitant improvement in PI may be important to account for when measuring interventions addressing apathy or depression in PD. Conflict of interest The authors declare that they have no conflicts of interest to disclose for this work. For the full financial disclosure of the previous 12 months, Dr. Hassan, Dr Vallabhajosula, Dr. Zahodne, Dr. Bowers and Dr. Hass declare that they have no conflicts of interest to disclose. Dr. Okun has received support from the National Parkinson Foundation, the National Institute of Health, the Michael J. Fox Foundation, and the Parkinson Alliance; performed CME for PeerView, Prime, CSF, and Vanderbilt. Dr. Fernandez has received research support from Abbott, Acadia, Biotie Therapeutics, EMD-Serono, the Huntington Study Group, Ipsen, Merz Pharmaceuticals, the Michael J. Fox Foundation, the Movement Disorders Society, the National Parkinson Foundation, the NINDS of the NIH, Novartis, the Parkinson Study Group, and Teva; honoraria from the University of South Florida Continuing Medical Education (CME), the Cleveland Clinic CME, Medical Communications Media, Health Professions Conferencing, Ipsen, Merz Pharmaceuticals, and the US World Meds; and royalty payments from Demos Publishing, Manson Publishing, and Springer Publishing; he is also a consultant for Merz Pharmaceuticals, Ipsen Pharmaceuticals, and United Biosource Corporation and received a stipend from the Movement Disorders Society for serving as the medical editor of the Movement Disorders Society website. References [1] Chaudhuri KR, Yates L, Martinez-Martin P. The non-motor symptom complex of Parkinson's disease: a comprehensive assessment is essential. Curr Neurol Neurosci Rep Jul 2005;5(4):275–83. [2] Chapuis S, Ouchchane L, Metz O, Gerbaud L, Durif F. Impact of the motor complications of Parkinson's disease on the quality of life. Mov Disord 2005;20:224–30. [3] Martinez-Martin P, Rodriguez-Blazquez C, Kurtis MM, Chaudhuri KR, on Behalf of the NMSS Validation Group. The impact of non-motor symptoms on healthrelated quality of life of patients with Parkinson's disease. Mov Disord 2011;26:399–406. [4] Reijnders JS, Ehrt U, Lousberg R, Aarsland D, Leentjens AF. The association between motor subtypes and psychopathology in Parkinson's disease. Parkinsonism Relat Disord Jun 2009;15(5):379–82. [5] Starkstein S, Leentjens AF. The nosological position of apathy in clinical practice. J Neurol Neurosurg Psychiatry 2008;79:1088–92. [6] Pedersen KF, Alves G, Aarsland D, Larsen JP. Occurrence and risk factors for apathy in Parkinson disease: a 4-year prospective longitudinal study. J Neurol Neurosurg Psychiatry 2009;80:1279–82. [7] Starkstein SE, Mayberg HS, Preziosi TJ, Andrezejewski P, Leiguarda R, Robinson RG. Reliability, validity, and clinical correlates of apathy in Parkinson's disease. J Neuropsychiatry Clin Neurosci 1992;4(2):134–9. [8] Cubo E, Benito-León J, Coronell C, Armesto D, on behalf of the ANIMO Study Group. Clinical correlates of apathy in patients recently diagnosed with Parkinson's disease: the ANIMO study. Neuroepidemiology 2012;38:48–55. http://dx.doi.org/10.1159/ 000334314. [9] Ziropadja L, Stefanova E, Petrovic M, Stojkovic T, Kostic VS. Apathy and depression in Parkinson's disease: the Belgrade PD study report. Parkinsonism Relat Disord 2012;18:339–42. [10] Bloem BR, Beckley DJ, van Hilten BJ, Roos RAC. Clinimetrics of postural instability in Parkinson's disease. J Neurol 1998;245:669–73. [11] Biaszczyk JW, Orawiec R, Duda-Kiodowska D, Opala G. Assessment of postural instability in patients with Parkinson's disease. Exp Brain Res Oct 2007;183(1):107–14.

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