Abstract
Nocturnal blood pressure (BP) changes are an indicator of autonomic dysfunction. We aim to investigate the correlation between nocturnal blood pressure (BP) variability, vitamin D levels and Parkinson’s disease severity (PD) in this study. Thirty-five patients with PD participated in the study. Disease severity was evaluated by United Parkinson’s Disease Rating Scale (UPDRS) and Hoehn and Yahr Scale (HYS). Equivalent levodopa dose was calculated and 25-hydroxyvitamin D levels were measured. The Non-Motor Symptom Questionnaire (NMSQ) was applied to all patients. Ambulatory BP monitoring for 24 h was established. Patients were divided into three groups according to nocturnal BP results: dippers (normal finding—a decline in mean nighttime BP of more than 10%); non-dippers (pathological—a decline in mean nighttime BP of less than 10%); reverse dippers (pathological—an increase in mean nighttime BP) .The mean score of the NMSQ was higher in the group with HYS > 2 (p = 0.050). Four patients were dipper, 17 patients were non-dipper and 16 patients were reverse dipper. There was no significant difference between the three groups in terms of age, gender, disease duration, age of the disease onset, disease stage, disease duration, dopamine agonist usage, levodopa equivalent dose, vitamin D level and NMSQ scores. NMSQ scores are high in advanced PD. Ambulatory BP monitoring is useful in detecting autonomic dysfunction. The number of patients with non-dipping and reverse dipping is high in PD, independent from PD severity, drug dose, vitamin D and the other NMS symptoms.
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Introduction
The motor symptoms of Parkinson’s disease (PD) are well known, but recently non-motor symptoms (NMS) including cardiovascular, gastrointestinal, urinary and sexual symptoms are of more interest. These symptoms can cause marked disability and affect the quality of life [1]. Especially, cardiac autonomic dysfunction (AD) plays a crucial role in disability and sudden death [2].
The change in blood pressure (BP) is one of the most remarkable findings for AD. In healthy subjects, BP is lower at nighttime which has been described as ‘dipping’ [3]. If BP does not decrease at nighttime, it is called ‘non-dipping’ and BP increase is called ‘reverse dipping’ [4]. In PD, the prevalence of non-dipping is high and goes up to 90% [5, 6].
Abnormal circadian falls in BP occur more often in PD with AD compared to PD without AD [7]. It was believed that the AD is seen in the late phase of the disease, but recent studies showed that it can occur in early phase of the disease, and even before the onset of motor symptoms [8,9,10].
Vitamin D plays a crucial role as it has a neuroprotective effect on autonomic function [11]. A recent study showed that serum vitamin D levels decreased in PD patients with orthostatic hypotension (OH) [12]. Additionally, it was shown that vitamin D level could influence the BP and cardiac autonomy. By this way, vitamin D can play a role in the pathophysiology of OH in PD [13, 14]. But still, there are some controversiesregarding the effect of vitamin D levels on both PD and autonomic system. In this study, we aimed to investigate the correlation between NMS, nocturnal BP changes, vitamin D levels and severity of PD.
Materials and methods
This is a prospective study; including 35 patients with idiopathic PD. All patients were recruited from Istanbul Medipol University, Faculty of Medicine, Neurology Department from January 2016 to March 2017. The diagnosis of PD was confirmed by a movement disorders specialist (N.H.Y.), according to the United Kingdom Parkinson’s Disease Society Brain Bank Criteria [15]. The exclusion criteria were: age below 18, patients with cognitive impairment, pyramidal, cerebellar and vertical gaze abnormality, a medical condition which can affect BP (malignancy, coronary heart disease, uncontrolled hypertension), taking drugs such as alpha-1- blockers and vitamin D supplement. Disease severity was evaluated by United Parkinson’s Disease Rating Scale (UPDRS) and Hoehn and Yahr Scale (HYS). Equivalent levodopa dose was calculated for each patient [16]. The cardiological examination of the patients, evaluated by electrocardiography and transthoracic echocardiography, was all normal.
The Non-Motor Symptom Questionnaire (NMSQ) containing 30 items was used to evaluate AD. It was applied to all the participants and the participants answered the questions as present or absent. Scoring range was 0–30 (0 = no AD, 1–5 = mild AD, 6–9 = medium AD, 10–13 = severe AD, ≥ 14 AD). The answer to the 20th question evaluating OH was also noted (Question 20: do you feel drowsiness or weakness when sitting or standing up from the supine position?).
Peripheral blood samples for 25-hydroxyvitamin D were collected from patients at 9 am after a 12-h fasting. The 25-hydroxyvitamin D levels were analyzed using electrochemiluminescence. Levels under 20 ng/ml were accepted as vitamin D deficiency.
All participants underwent 24-h ambulatory BP monitoring (ABPM) by automated, validated and calibrated oscillometric portable monitor. The ambulatory BP was measured every 15 min at daytime, every 30 min at nighttime. Blood pressure recording started in the morning and continued for 24 h. During monitoring, patients performed their usual daily activities, when the cuff was inflated, the patient was informed to relax the arm where the cuff was located. Dipping values of 10–20% were considered as normal, while for 0–10% values, dipping was considered as absent and named as ‘non-dipping’ [17]. Mean BP was calculated, for each night and day, as the diastolic pressure plus one-third of systolic pressure minus the diastolic pressure. The percentage difference in nighttime BP was calculated as follows: (mean daytime BP−mean nighttime BP⁄mean daytime BP × 100). Negative values for dipping are considered as reversed dipping. Patients were divided into three groups: dippers (a decline in mean nighttime BP of more than 10%); non-dippers (a decline in mean nighttime BP of less than 10%); reverse dippers (an increase in mean nighttime BP).
The study protocol was approved by the Ethical Committee of the Istanbul Medipol University, Istanbul, Turkey. Informed consent was obtained from all subjects. The study was performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.
Statistical analysis
Descriptive statistics were used to summarize clinical characteristics. Continuous variables were expressed as mean ± standard deviation or median and range. Normal distribution was tested by Kolmogorov–Smirnov test. Kruskal–Wallis test was performed to compare non-normal distributed variables among the groups. Pearson’s Chi-squared test was used for testing categorical variables. p value of < 0.05 was taken significant for all tests. Statistical Package for the Social Sciences (SPSS version 11.0, SPSS Inc., Chicago, IL, USA) was used for analysis.
Results
Twenty-four of the patients were male (68.57%), and 11 were female (31.43%). Two patients were in HYS 1, 14 were in HYS 2, 15 were in HYS 3 and 4 were in HYS 4. Twenty-eight patients were taking dopamine agonist (80.0%), while all of them were taking levodopa with different dosages.
The demographical data and characteristics of the patients are shown in Table 1.
According to the result of NMSQ score: 1–5 points: 4 patients, 6–9 points: 6 patients, 10–13: 10 patients, 14 points and above: 15 patients. Eighteen of the patients (51.43%) answered ‘yes’ to the question 20. Four patients were dipper (11.43%), 17 (48.57%) patients were non-dipper and 16 (45.71%) patients were reverse dipper. There were 21 people (60.00%) with vitamin D levels below 20, 14 people (40.00%) with 20 or more.
When the patients were divided into two subgroups according to disease stages, the ages of patients with HYS > 2 were significantly higher and the duration of the disease was longer (p = 0.014, 0.007, respectively). The mean score of the NMSQ score was higher in the group with HYS > 2 (p = 0.050). (Table 2).
When the patients were divided into three groups as dipper, dipper and reverse dipper according to the results of ABPM, there was no significant difference between the three groups in terms of age, gender, disease duration, age of the disease onset, disease stage, disease duration, dopamine agonist usage, levodopa equivalent dose, vitamin D level and NMSQ scores. (Table 3).
Discussion
Autonomic dysfunction is common in PD. It occurs before the onset of the disease, and present as varying intensities in each stage and sometimes cause more functional disability than motor symptoms [18]. NMSQ is a method that allows evaluating AD in PD patients rapidly and presents the symptoms that the patients subjectively reported [19]. Only one question in the questionnaire examines the presence of cardiovascular dysfunction. Approximately half of the participants answered ‘yes’ to this question in our study. In epidemiological studies using the NMSQ questionnaire, at least one NMS finding is seen in 99% of the patients during the disease course [20], while the rate of cardiovascular findings varies between 14–36% [20,21,22]. NMSQ scores were found to be higher in patients with long disease duration and more severe disease. Similar to previous studies, in our study, NMSQ scores were significantly higher in the patient group with HYS of > 2.
Altered circadian BP changes can be presented in left ventricular hypertrophy, heart failure, myocardial infarction, microalbuminuria, cerebrovascular and vascular dementia [23]. Ambulatory BP monitoring is a method used to detect the existence of the cardiac dysautonomia (non-dipping/reverse dipping, OH and post-prandial hypotension and elevated BP variability) [24]. On the other hand, reverse dipping is a more risky clinical entity that causes stroke and cardiovascular mortality in patients with essential hypertension more common than non-dipping [25,26,27]. In PD, non-dipping/reverse dipping, OH and BP changes are common both because of the disease itself and the medication used for the treatment. Ejaz et al. found that 93% of the patients have circadian BP disorder, while the rate of 88% was reported by Sommer et al. and 80% by Oh et al. [5, 28, 29]. The rate of reverse dipper in PD was 33% in a single study and it was reported as a more accurate finding of cardiac dysautonomia compared to other parameters [30]. In our study, 31 patients (88.57%) had a circadian BP disorder, while 50% of these 35 patients had reverse dipping. Therefore, it was thought that the presence of reverse dipping was an important finding for cardiac dysautonomia and PD patients should be screened for this reason.
In this study, non-dippers were found to be lower than other studies (39%), but less frequently observed reverse dippers was higher. It was thought that reverse dipper blood pressure changes may be important in this type of patients.
The effects of anti-PD drugs on BP are variable. In one study, the administration of levodopa significantly lowered mean arterial BP [31], whereas, in other studies, OH was not found to be associated with levodopa treatment [32, 33]. Dopamine agonists have been shown to cause acute asymptomatic OH [34]. Increasing drug doses and combined therapies increase the risk of OH development, but in the long term, tolerance to these drugs occurs [35]. In this study, patients were grouped into three groups: reverse dipper, non-dipper, dipper; and these groups had shown no significant differences in terms of PD treatment. On this basis, the use of dopamine agonists in PD and equivalent dose of levodopa were thought to have no effect on changes in BP.
Like PD, circadian blood pressure changes can occur with many diseases. Nocturnal movement, sleep disorders like obstructive sleep apnea syndrome or getting up at night for urinary problems are some of these (36,37). However, one of the limiting aspects of this study was the lack of including disorders other than PD which can cause nocturnal blood pressure changes.
The reason for cardiac changes in PD is mostly AD [9]. As a result of affected sympathetic noradrenergic neurons independent of dopaminergic effect, cardiac and extra-cardiac noradrenergic denervation are responsible for the presence of cardiac dysautonomia [35]. Oh et al. showed that sympathetic noradrenergic dysfunction occurs independent of striatal dopamine uptake in Positron Emission Tomography [29]. In our study, when we compared nocturnal BP changes with PD severity, stage of disease duration, age at onset, we observed no significant difference. Therefore, our work supported the hypothesis that AD in PD has a different pathogenesis from cardinal motor findings.
When we looked at the relationship between NMSQ score and nocturnal BP changes, considering the NMSQ score to have an association with cardiac dysautonomia, the patients who have dipper hypertension had higher mean NMSQ score. But the difference was insignificant between the groups. The reason for this was thought to be that cardiac AD was represented with only one question in NMSQ and that the cardiac AD that presented in patients was frequently subclinical.
Vitamin D is a neuroprotective molecule [39]. Vitamin D levels were found to be low in studies conducted with PD [40, 41]. While there are findings showing that low vitamin D levels have an effect on the pathogenesis and progression of PD [42], there are also researchers who think that this relationship is not significant [43]. It is observed that the HYS remained stable in PD patients who were given vitamin D for 12 months and their daily activities were better [44]. Low vitamin D levels are another risk factor of arterial hypertension [45], as it can cause cardiac structural changes that can lead systolic and diastolic dysfunction [46]. In PD, low levels of vitamin D were found to be associated with AD [39], but the relationship between non-dipping and reverse dipping has not been researched before. In our study, when we compare, dipper, non-dipper, and reverse dipper patient groups showed no significant difference according to vitamin D levels. Therefore, vitamin D was not considered to be effective for nocturnal BP changes and its subtypes which is a marker of AD in PD.
As a result, NMSQ scores are high in advanced PD, and a limited number of patients report their symptoms subjectively in NMSQ. ABPM is a valuable tool for determining subclinic cardiac AD findings in PD. However, non-dipping and reverse dipping ratios are high in PD, this is independent of age, gender, disease duration, age at onset, the severity of the disease, the use of anti-PD drugs and vitamin D level. Prospective studies conducted on this subject with more number of patients are needed.
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Arici Duz, O., Helvaci Yilmaz, N. Nocturnal blood pressure changes in Parkinson’s disease: correlation with autonomic dysfunction and vitamin D levels. Acta Neurol Belg 120, 915–920 (2020). https://doi.org/10.1007/s13760-019-01113-7
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DOI: https://doi.org/10.1007/s13760-019-01113-7