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Journal of the Neurological Sciences 377 (2017) 207–211

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Decreased baroreflex sensitivity in Parkinson's disease is associated with orthostatic hypotension Andrej Blaho a,c, Stanislav Šutovský a,⁎, Peter Valkovič b, Pavel Šiarnik a, Marek Sýkora a,d, Peter Turčáni a a

1st Department of Neurology, Medical Faculty, Comenius University and University Hospital, Bratislava, Slovakia 2nd Department of Neurology, Medical Faculty, Comenius University and University Hospital, Bratislava, Slovakia Department of Neurology, Hospital of Trenčín, Slovakia d Department of Neurology, St. John's Hospital, Medical Faculty, Sigmund Freud University, Vienna, Austria b c

a r t i c l e

i n f o

Article history: Received 16 October 2016 Received in revised form 11 March 2017 Accepted 27 March 2017 Available online 28 March 2017 Keywords: Parkinson's disease Autonomic dysfunction Baroreflex sensitivity Orthostatic hypotension

a b s t r a c t Background: Autonomic dysfunction is a substantial part of extrapyramidal diseases, including Parkinson's disease (PD). Baroreflex is an important determinant of short-term blood pressure regulation and cardiovascular variability. Impaired baroreflex sensitivity (BRS) in PD has been a subject of investigation in several studies, however the relationship between BRS and orthostatic hypotension (OH) is still poorly understood. Objective: To compare the BRS of Parkinson's disease patients with those of an age-matched control population, and to determine BRS association with blood pressure, orthostatic hypotension and antiparkinson treatment. Patients and methods: The study included 52 patients with Parkinson's disease and 52 controls. We assessed autonomic dysfunction with a Finometer device using the method of spontaneous fluctuations of blood pressure (BP) and the R-R interval in time domain, expressed as baroreflex sensitivity. Supine and standing blood pressure were measured under standard conditions. Results: BRS values were significantly lower in the PD group as compared to the control group: 4.0 ± 2.0 vs. 6.4 ± 3.8 ms/mmHg (p = 0.001). We determined a significant correlation between decreased BRS values and increased systolic BP (p = 0.003) as well as between decreased BRS values and orthostatic hypotension (OH), in the PD group (p = 0.048). Moreover, patients with PD and OH had significantly lower BRS as compared with patients with PD without OH (3.2 ± 2 versus 4.5 ± 2, p = 0.045). We also determined that BRS values were significantly lower in the PD population treated with LDOPA + COMTI as compared to the LDOPA + COMTI untreated patients (3.0 ± 1.5 vs. 4.8 ± 2.0, p b 0.001). Conclusion: BRS was significantly lower in the PD group, supine hypertension and orthostatic hypotension was strongly associated with low BRS. We determined for the first time that orthostatic hypotension strongly correlates with decreased baroreflex sensitivity in PD patients. Moreover, orthostatic hypotension was associated with low BRS not only qualitatively but also quantitatively. We also revealed a strong association between LDOPA + COMTI therapy and decreased BRS in the literature for the first time. © 2017 Elsevier B.V. All rights reserved.

1. Introduction Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor dysfunction (typically tremor, rigidity, bradykinesia, later postural instability) and non-motor symptoms. Lewy bodies characteristic for PD are also present in autonomic centres and nerves such as the dorsal motor nucleus of the vagus nerve and glossopharyngeal nerve, in Abbreviations: PD, Parkinson's disease; BP, blood pressure; BRS, baroreflex sensitivity; RBD, REM sleep behaviour disorder; BMI, body mass index; LED, levodopa equivalent dose; SBP, systolic blood pressure; DBP, diastolic blood pressure; ΔSBP, difference between supine SBP and standing SBP; OH, orthostatic hypotension; H&Y staging, Hoehn & Yahr staging; HRV, heart rate variability; AH, arterial hypertension. ⁎ Corresponding author. E-mail address: [email protected] (S. Šutovský).

http://dx.doi.org/10.1016/j.jns.2017.03.044 0022-510X/© 2017 Elsevier B.V. All rights reserved.

the gastrointestinal submucosal plexus and postganglionic sympathetic nervous system, already in the premotor stage, prior to the involvement of substantia nigra [1]. This damage can lead to autonomic dysfunction. Dysautonomia is one of the significant non-motor symptoms, and thus can already be present in the early stages of PD and precede classic motor symptoms [2]. The prevalence of dysautonomia in PD varies from 14 to 80%, depending on the population and methodology [3]. OH typically occurs in cases of older patients with a longer duration of the disease and is often associated with other symptoms of dysautonomia, cognitive decline, and visual hallucinations [4]. Some authors attribute the worsening of OH to dopaminergic treatment, but it occurs mainly due to the Parkinson's disease itself [5]. The severity of OH correlates with the degree of cardiac sympathetic noradrenergic denervation rather than dopaminergic deficit in the putamen. Moreover,

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patients with PD and OH have a decreasing number of catecholaminergic neurons in the nucleus tractus solitarius with subsequent baroreflex dysfunction [6,7]. BR is an important determinant of the short-term regulation of blood pressure and cardiovascular variability [8]. A lesion in any part of the BR regulation circuit can cause a decline in BRS [3]. Alterations in the baroreceptor-heart rate reflex (baroreflex sensitivity) contribute to sympathetic–parasympathetic imbalance, playing a major role in the development and progression of many cardiovascular disorders [9]. Autonomic dysfunction is a common accompaniment of Parkinson's disease, so there is a presumption of baroreflex affection. BRS in PD was first examined by Appenzeller and Goss. They concluded that BRS was pathological in some PD patients [11]. Szili Torok (2001) and Meelvan den Abeelen (2012) also reported impaired baroreflex sensitivity in PD patients [12,13]. Only a few studies dealt with the relationship between baroreflex and OH in PD. Oka et al. (2007) reported no association between the fall in SBP on HUT and baroreflex sensitivity [4] in the comprehensive study. On the other hand, Jain et al. emphasises that the failure of the baroreflex is one of the three determinants underlying the cardiovascular autonomic abnormalities attending PD along with cardiac and extracardiac sympathetic denervation [14]. According to this study, patients with PD + OH have severely decreased functions of both sympathetic and parasympathetic components of the arterial baroreflex [14]. Another important aspect is the influence of antiparkinsonian treatment, namely levodopa on the autonomic functions, especially on BRS and OH. There are only a few studies dealing with this aspect in the literature. The study of Mesec et al. (1993) reported no influence of the levodopa treatment on BRS and OH [15]. On the other hand, Oka et al. (2001) reported a decrease of BRS during the late IV phase of Valsalva manoeuvre after Levodopa treatment whereby this decrease was unrelated to the disease duration [16]. We did not find any study in the literature dealing with the relationship between LDOPA + COMTI treatment and BRS. Aim of the study The first goal of this study is to compare the BRS values of Parkinson's disease patients with an age-matched control population. The second goal is to determine the BRS association with other monitored variables, including blood pressure and orthostatic hypotension, cardiovascular risk factors (arterial hypertension, ischemic heart disease, diabetes mellitus, BMI), H&Y score, duration of the disease, and non-motor symptoms (loss of smell, REM sleep behaviour disorder RBD, obstipation, depression, anxiety). The third goal is to determine the impact of antiparkinson treatment administered in parallel (recalculated to totally equivalent doses of Ldopa – LED) to BRS values. 2. Patients and methods

performed in the ON state. We also noted the duration of the disease (from first motor symptoms), and the concurrent occurrence of nonmotor symptoms (smell loss, RBD, obstipation, depression and anxiety) using the NMSS scale (Chaudhuri et al. 2007) [18], which also includes the assessment of cognitive functions. Above all, we similarly recorded antiparkinson treatment with a recalculation to the total daily equivalent levodopa dose (LED) according to Tomlinson et al. (2010) [19].

2.2. Data collection and assessments We measured BRS using a Finometer device (FMS, Finapres Medical Systems BV, Amsterdam, Netherlands). This device uses a volume clamp method for continuous recording of blood pressure and pulse frequency from a finger artery (beat-to-beat). In this case, we used the methodology of spontaneous fluctuations in time domain. The inclination of the regression curve based on the relation between systolic pressure and cardiac intervals reflects the cardiac baroreflex sensitivity index [20]. BRS values are expressed in ms/mmHg. The analysis was carried out using the software of FMS (Finapres Medical Systems BV, Amsterdam, Netherlands). We placed a snugly fitted ring cup on the middle finger of the examinant's right or left hand. Patients were measured under relaxed conditions, in a quiet room, in sitting position, with spontaneous breathing. The duration of the BRS measurement depended on the stabilization of balanced BRS values as recorded by the device, the approximate duration was 10 min. Supine blood pressure was measured after 10 min of supine rest, while standing blood pressure was measured three times: after one, two and three minutes of upright posture. The lowest standing BP was recorded. Based on the agreement of the Consensus Committee of the American Autonomic Society and the American Academy of Neurology, OH has been defined as a sustained fall of ≥20 mmHg in systolic or ≥10 mmHg in diastolic blood pressure within 3 min of active standing or head-up tilt to at least 60° [21].

2.3. Statistical analysis The statistical analyses were carried out using SPSS version 18 (SPSS Inc., Chicago, IL). Categorical variables were expressed as numbers and proportions (%), and continuous variables as means the ± standard deviation or median, interquartile range (IQR), and minimal and maximal values. For comparing groups, the chi-squared test, Student t-test, and Mann–Whitney test were used for particular variables. Pearson or Spearman correlation coefficients were used to determine relationships between BRS and particular parameters. Stepwise multiple linear regression analysis was used to identify factors that contributed to BRS.

2.1. Study population 3. Results The examined sample was made up of hospitalized patients and outpatients at the 1st and 2nd Neurological clinic of the University Hospital in Bratislava. Patients were examined in the sitting position, under relaxed conditions, in the laboratory. The study included 104 patients altogether, 52 of them had idiopathic Parkinson's disease. They met the criteria for inclusion in the study and signed an informed consent. The study was approved by the ethical committee. After recruiting the group of patients with diagnosed idiopathic Parkinson's disease (based on clinical findings, with the exclusion of secondary Parkinson syndrome), we also selected, based on their profiles (risk factors, age, BMI), an analogical group of 52 patients without proven neurodegenerative disease to be used as the control group. The exclusion criteria for the control group were neurodegenerative disease or other chronic diseases which can cause orthostatic hypotension. We assessed the level of motor disability of the patients with PD based on a modified Hoehn & Yahr scale [17]. The examinations were

3.1. Clinical and demographic characteristics of patients with PD In both groups (PD and control) there were 32 men (61.5%); p = 1.0. The average age of patients with PD was 65.7 ± 9.1 years, while the average age in the control group was 65.6 ± 10.6 years (p = 0.960). The Hoehn & Yahr score was 2.3 ± 0.7, the disease duration 5.0 years, (0.5–15.0), the onset of the disease at 59.9 ± 8.9 years of age. BMI was 27.2 ± 4.6 in the PD group vs. 28.0 ± 3.5 (p = 0.342) in the controls. Ischemic heart disease was diagnosed in 7 (13.5%) patients with PD vs. 7 (13.5%) patients in the control group (p = 1.0), diabetes mellitus in 8 (15.4%) patients with PD vs. 8 (15.4%) patients in the control group (p = 1.0). Patients with PD had significantly lower SBP (125.2 ± 16.1 mmHg vs. 132.4 ± 12.2 mmHg; p = 0.012), and DBP (70.1 ± 13.4 mmHg vs. 74.9 ± 10.7 mmHg; p = 0.044), as compared with the control group.

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Table 2 Correlation between BRS and baseline characteristics in the PD group. Variable

r-Value

p-Value

Age Body mass index Hoehn and Yahr scale Duration of PD

−0.434 −0.186 −0.045 −0.310 −0.253

0.002⁎⁎ 0.206 0.776 0.040⁎ 0.102 b0.001⁎⁎⁎

L-dopa

dose equivalency (LED)

L-dopa

+ COMTI Systolic blood pressure (SBP) Diastolic blood pressure (DBP) Orthostatic hypotension ΔSBP (difference between supine SBP and standing SBP) ΔDBP (difference between supine DBP and standing DBP)

Fig. 1. BRS in population with Parkinson's disease and in the control group (4.0 ± 2.0 vs. 6.4 ± 3.8; mean ± SD; p b 0.001).

−0.512 −0.423 −0.082 −0.278 −0.739 −0.188

0.003⁎⁎ 0.581 0.048⁎ b0.001⁎⁎⁎ 0.201

⁎ p b 0.05. ⁎⁎ p b 0.01. ⁎⁎⁎ p b 0.001.

3.5. Association of baroreflex and other monitored variables 3.2. 4.2 Baroreflex sensitivity We found significantly lower BRS values in the PD patients as compared with the control group (4.0 ± 2.0 vs. 6.4 ± 3.8; p b 0.001; Fig. 1).

3.3. Orthostatic hypotension Orthostatic hypotension (according to criteria of AHA) was found in 9 patients (17.2%). Six patients had orthostatic symptoms, but their ΔSBP (difference between supine SBP and standing SBP) was lower than 20 mmHg (Table 1). Orthostatic hypotension (as a binary variable) was significantly associated with low BRS (p = 0.048), (Table 2). The strongest association, however, was found by a comparison of ΔSBP and low BRS (p b 0.001) (Table 2, Fig. 2). Likewise, a multivariable regression analysis showed a significant association between OH/ΔSBP and a lowered BRS (beta = −0.908; p b 0.001). Patients with OH had a BRS of 3.2 ± 2, patients with orthostatic symptoms 2.4 ± 0.8, and patients without OH 4.5 ± 2 (Table 1).

We identified a negative correlation between BRS and age (r = −0.434, p = 0.002), and duration of the disease (r = −0.310, p = 0.040). A multivariable regression analysis confirmed a significant association between age and a lowered BRS (beta = −0.194; p = 0.030). We did not find any significant correlation between BRS values and BMI (p = 0,206), H&Y score (p = 0.776), DBP (p = 0.581) (Table 2) and non-motor symptoms such as smell loss (p = 0.483), RBD (p = 0.447), obstipation (p = 0.843), depression (p = 0.772), anxiety (p = 0,051) or non-motor score (p = 0.714). The values of BRS in PD patients were not significantly influenced by gender (p = 0.983), diabetes mellitus (p = 0.471), dyslipidemia (p = 0.732) or ischemic heart disease (p = 0.389). 3.6. Influence of antiparkinson treatment on BRS The third goal was the assessment of the influence of antiparkinson treatment (L-dopa, dopamine agonists, MAO B inhibitors, amantadine) on BRS values and also to determine the impact of antiparkinson treatment administered in parallel recalculated to totally equivalent doses of L-dopa – LED to BRS values. The values of BRS were significantly lower in

3.4. Arterial hypertension 22 (42.3%) patients with PD had arterial hypertension vs. 24 (46.2%) patients in the control group (p = 0.693). Values of BRS were significantly lower in PD patients with arterial hypertension (3.3 ± 1.7 vs. 4.5 ± 2.1, p = 0.024), while BRS values in the controls with AH did not differ significantly from the controls without AH (6.0 ± 3.6 vs. 6.8 ± 3.9; p = 0.137). Lower BRS was significantly associated with higher systolic BP in the PD group (r = − 0.423, p = 0.003; Table 2). Likewise, a multivariable regression analysis showed a significant association between SBP and a lowered BRS (beta = 0.241; p = 0.029).

the PD population treated with LDOPA + COMTI as compared to the rest of the PD population (3.0 ± 1.5 vs. 4.8 ± 2.0, p b 0.001; Table 2). The values of BRS in PD patients were not significantly influenced by LDOPA therapy alone (p = 0.790), dopamine agonists (p = 0.974), MAO B inhibitors (p = 0.201), or amantadine (p = 0.773;) even after recalculating to totally equivalent doses of L-dopa. 4. Discussion The first significant observation in this study was that BRS values were significantly lower in the PD group as compared with the control

Table 1 Occurrence of orthostatic hypotension and orthostatic symptoms in the PD group. PD with orthostatic hypotension (OH)

PD with orthostatic symptoms (OS)

PD without OH (WOH)

p-Value

Number of subjects Male sex

9 6

6 2

37 18

Age (years)

67.3 ± 10.4

69.3 ± 4.5

64.6 ± 9.2

BRS (ms/mmHg)

3.2 ± 2

2.4 ± 0.8

4.5 ± 2.0

Disease duration (years)

5.5 ± 3.2

5.7 ± 3.3

5.2 ± 3.7

Delta SBP

21(IQR 4) (−4–26)

17.5 (IQR 2.75) (11–19)

9 (IQR 16) (−20−31)

N/A 0.91 (OHvsWOH) 0.14 (OSvsWOH) 0.23 (OHvsWOH) 0.44 (OSvsWOH) 0.045 (OH vs WOH) 0.007 (OSvsWOH) 0.73 (OHvsWOH) 0.23 (OSvsWOH) 0.23 (OHvsWOH) 0.44 (OSvsWOH)

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Fig. 2. Correlation between BRS and ΔSBP (r = − 0.739, p b 0,001) in the PD group. ΔSBP = systolic blood pressure.

group. This fact confirms the impairment of the regulation mechanisms of the baroreflex in PD. Baroreflex sensitivity is regulated mainly by parasympathetic activity [22]. Reduced baroreflex-cardiovagal gain may indicate dysfunction of the reflex arc from the early stages of PD. The infliction of those structures by an underlying pathology in the early stages of PD has been confirmed by many histopathologic studies [1,5,23]. In addition, impairment of the locus coeruleus and C1 cells of the rostral ventrolateral spinal cord probably also contributes to BR alteration [24,25]. Furthermore, a lesion of striatum in experimental animals caused disturbances in blood pressure and blood pressure lability [26–28]. On the other hand, deafferentation of baroreceptors decreased striatal dopamine concentration and tyrosine hydroxylase activity [29]. Taken together, there is probably a bidirectional influence between basal ganglia and blood pressure regulation. Low BRS was significantly associated with higher SBP in the PD group (p = 0.003; Table 3). In the control group, we did not find a significant association between those values. This is the second considerable observation that points to the fact that parkinsonian patients with arterial hypertension have more severely impaired baroreflex sensitivity than controls with AH. Supine hypertension is part of an “autonomic cardiovascular tetrad” in PD, which also includes orthostatic hypotension, postprandial hypotension and blood pressure lability [14]. Association between the impaired baroreflex and arterial hypertension is therefore a reasonable finding. This observation is consistent with other studies [14,22,30]. The third considerable discovery is the significant association between a lowered BRS and orthostatic hypotension in patients with PD (Table 2). All patients with OH had significantly lower values of BRS as compared to the PD patients without OH (Table 1). Likewise, a multivariable regression analysis showed a significant association between OH/ ΔSBP and a lowered BRS. Nine patients in the PD group had OH, but another six patients also had orthostatic symptoms – but their ΔSBPs (difference between supine SBP and standing SBP), however, were lower than 20 mmHg (Table 1). BP values were measured three times after one, two and three minutes of standing. Not every patient with a low BRS also had OH, but every patient with OH also had a low BRS. Only a few studies dealt with the relationship between baroreflex and OH in PD [4,14,31]. Oka et al. (2006) [31] found that the BRS of PD patients with OH showed a mild but significant association. However, the multivariable regression analysis did not show a significant association between a lowered BRS and OH in this study. Similarly, Oka et al. (2007) reported no association between the fall in SBP on HUT and baroreflex

sensitivity in the comprehensive study [4]. In our study, a lower BRS in the PD group correlated significantly with higher systolic BP, age, disease duration and OH. However, patients without OH also had a lowered BRS but significantly less than patients with OH (4.5 ± 2 versus 3.2 ± 2, p = 0.045). With regard to this observation, we consider the lowered BRS to be a universal phenomenon reflecting presymptomatic or early symptomatic affection of the autonomic nervous system. Orthostatic hypotension represents a more advanced impairment of cardiovascular autonomic regulation by an underlying pathology, and thus is almost necessarily associated with an impaired BRS. A lowering of BRS can contribute to OH, and can be its potential predictor. This hypothesis is also consistent with the observation that patients with PD and OH have a depletion of catecholaminergic neurons in the nucleus tractus solitarius with a subsequent dysfunction of BRS [6,7]. Taken together, three determinants – cardiac noradrenergic denervation, extracordial noradrenergic denervation, and arterial baroreflex failure – work together, resulting not only in OH but in a syndrome that also includes post-prandial hypotension, blood pressure lability, and supine hypertension [14]. In this study, we did not confirm significant correlations between low BRS and the H&Y stage. However, this is in contradiction with certain other studies, in which the correlation was confirmed [15,24,32, 33]. Harnold et al. (2014) [34] also confirmed insignificance between ANS dysfunction and progression of the disease. This was also supported by studies based on MIBG scintigraphy [35]. In our study, there were negative correlations found between BRS values and the duration of the disease. According to the study of Harnold et al. (2014) [34], HRV had significant correlation with the duration of the disease. Mesec et al. (1993) [15] found that OH correlated more with the duration of the disease than with its stage. On the other hand, studies based on MIBG scintigraphy did not support the theory of an association between ANS dysfunction progression and the duration of the disease [35]. Despite the contradictory results of various studies, disease duration is the most accepted risk factor for cardiovascular autonomic dysfunction, which our study has confirmed as well. The effect of antiparkinson treatment has been reviewed by several studies; however, its clear impact on the autonomic nervous system has not been precisely specified as of yet. In our study, BRS values were significantly lower in the PD population treated with LDOPA + COMTI as compared to the rest of the PD population (3.0 ± 1.5 vs. 4.8 ± 2.0, p b 0.001; Table 2). The values of BRS in PD patients were not significantly influenced by LDOPA therapy alone, dopamine agonists, MAO B inhibitors or amantadine even after recalculating to totally equivalent doses of L-dopa. This observation is consistent with the study of Mesec et al. (1993) which reported no influence of the levodopa treatment on BRS and OH [15]. On the other hand, Oka et al. (2001) reported a decrease of BRS during the late IV phase of Valsalva manoeuvre after Levodopa treatment [16]. In the literature, there are only a few reports of an impact of entacapone on blood pressure. However, according to the study of Jordan et al. (2002), COMT inhibitors elicited a moderate, dose-dependent pressor response in the setting of severely impaired MSA patients. In PD patients without OH and in healthy people, this did not have an impact on blood pressure [36]. We did not find any study in the literature dealing with the relationship between LDOPA + COMTI treatment and BRS. Our observation needs to be proven by more comprehensive studies. 5. Limitations This study has the following limitations: a moderate number of participants; the control group was not tested for OH (although nobody from the control group complained of OH); cardiac 123I–MIBG scintigraphy or another confirmatory method could have been helpful for objectivizing cardiac sympathetic functions; postprandial hypotension was not tested precisely. We did not perform the UPDRS III scale because we considered the H-Y scale as more suitable for this study due

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to easier assessment and clear interpretation. Despite these limitations, our study documented valid results on an adequate cohort of patients and controls, which can contribute to the understanding of complicated connections in autonomic regulation in Parkinson's disease. 6. Conclusion In this study, we have documented that BRS values were significantly lower in the PD group than in the control group. A lower BRS was significantly associated with higher supine systolic BP in the PD group, but not in the control group. 17% of PD patients suffered from orthostatic hypotension, which was significantly associated with a low BRS. For the first time, we described a very strong association between orthostatic hypotension by means of ΔSBP and low BRS in patients with PD in the literature. Our results suggest that BRS was also impaired in patients without OH, as an early abnormality in autonomic control in PD. Moreover, a low BRS was significantly associated with older age, longer disease duration and LDOPA + COMTI treatment, but not with the H&Y stage or other antiparkinson treatment. We consider a lowering of baroreflex sensitivity to be an early phenomenon in cardiovascular autonomic dysfunction in PD. A lowered BRS reflects clinical, and also subclinical, cardiovascular autonomic impairment. Its predictive value in preclinical stage testing for further autonomic dysfunction and orthostatic hypotension should be assessed in more comprehensive studies. Conflict of interest statement The autors declare no conflict of interest. Author contribution Stanislav Šutovský, Peter Valkovič and Peter Turčáni designed the study; Andrej Blaho and Stanislav Šutovský performed clinical and paraclinical evaluation; Pavel Šiarnik performed statistical analysis; Andrej Blaho and Stanislav Šutovský wrote the manuscript; Marek Sýkora and Peter Turčáni reviewed the manuscript. Acknowledgements We are grateful to the study participants for their participation. References [1] H. Braak, E. Braak, Pathoanatomy of Parkinson's disease, J. Neurol. 2 (2000) http:// dx.doi.org/10.1007/PL00007758 s. II3-10. [2] M. Asahina, E. Vichayanrat, D.A. Low, V. Iodice, C.J. Mathias, Autonomic dysfunction in parkinsonian disorders: assessment and pathophysiology, J. Neurol. Neurosurg. Psychiatry 84 (2013) 674–680, http://dx.doi.org/10.1136/jnnp-2012-303135. [3] T. Ziemssen, G. Fuchs, W. Greulich, H. Reichmann, M. Schwarz, B. Herting, Treatment of dysautonomia in extrapyramidal disorders, J. Neurol. 258 (Suppl. 2) (2011) S339–S345, http://dx.doi.org/10.1007/s00415-011-5946-8. [4] H. Oka, M. Yoshioka, K. Onouchi, M. Morita, S. Mochio, M. Suzuki, et al., Characteristics of orthostatic hypotension in Parkinson's disease, Brain 130 (2007) 2425–2432, http://dx.doi.org/10.1093/brain/awm174. [5] M. Ebadi, R. Pfeiffer (Eds.), Parkinson's Disease, CRC Press, New York 2004, p. 1020. [6] J.M. Senard, C. Brefel-Courbon, O. Rascol, J.L. Montastruc, Orthostatic hypotension in patients with Parkinson's disease pathophysiology and management, Drugs Aging 18 (2001) 495–505, http://dx.doi.org/10.2165/00002512-200118070-00003. [7] V. Milazzo, C. Di Stefano, S. Servo, M. Zibetti, L. Lopiano, S. Maule, Neurogenic orthostatic hypotension as the initial feature of Parkinson's disease, Clin. Auton. Res. 22 (2012) 203–206, http://dx.doi.org/10.1007/s10286-012-0165-7. [8] N. Nasr, A. Pavy-Le Traon, V. Larrue, Baroreflex sensitivity is impaired in bilateral carotid atherosclerosis, Stroke 36 (2005) 1891–1895, http://dx.doi.org/10.1161/01. STR.0000177890.30065.cb.

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