24‐hour ambulatory blood pressure alterations in patients with Parkinson's disease

Abstract Objects Abnormal blood pressure (BP) regulation is a feature of autonomic dysfunction in Parkinson's disease (PD) patients. The present study was to analyze the BP alterations by 24‐h ambulatory BP monitoring in PD patients with different disease stages and subtypes. Methods 32 consecutive patients PD patients and 43 control patients in our hospital from 2017 to 2020 were included. The circadian BP rhythm was divided into three types according to the 24‐h ambulatory BP monitoring. Dipping was defined as an average systolic BP (SBP) reduction during night‐time of 10%–19%. Reverse dipping was defined as an average increase in night‐time SBP values. The differences of the circadian BP rhythm and BP variability (BPV) were analyzed between PD group and the control group, the early PD group and the advanced PD group, as well as the tremor‐dominant group and the nontremor‐dominant group. Results There was statistical difference in circadian BP rhythm between PD group and control group (p < .05). There were statistical differences in circadian BP rhythm between the early PD group and the advanced PD group (p < .05). The mean values of night‐time SBP and diastolic BP (DBP) in the advanced PD group were higher than those in the control group and the early PD group (p < .05). The DBP CV in the advanced PD group was higher than that in the control group and the early PD group (p < .05). There was no significant difference of circadian BP rhythm, mean BP, and BPV between the tremor‐dominant and the nontremor‐dominant PD group after matching the disease duration. Conclusions Reverse dipping was more common in PD patients in this study, especially in the advanced PD patients. 24‐h ambulatory BP monitoring is an important method to evaluate the BP alterations in PD patients. Clinicians should be alert to reverse dipping in PD patients and intervene to prevent serious clinical events.


INTRODUCTION
Parkinson's disease (PD) is common degeneration disease of central nervous system. The clinical features of PD include motor symptoms such as bradykinesia, rigidity, tremor, postural instability, and nonmotor symptoms such as hyposmia, depression, sleep disorders, and autonomic dysfunction. Some non-motor symptoms can precede the onset of motor symptoms several years. Autonomic dysfunction is a common non-motor feature in PD patients, whose prevalence is 30%-40% (Duz & Yilmaz, 2020). Although autonomic dysfunction includes different features in PD, cardiovascular autonomic dysfunction is a common feature in PD, which is often characterized by blood pressure abnormalities, such as orthostatic hypotension (OH), supine hypertension, and postprandial hypotension. Since degeneration of the cardiac sympathetic nerve begins in the early stage of PD (Asahina et al., 2013), abnormal blood pressure may appear early in the disease duration. As we know, PD can be divided into two types according to the tremor symptom (Asahina et al., 2013). The nontremor-dominant PD is associated with more non-motor symptoms, such as depression, dementia, and autonomic dysfunction than the tremor-dominant PD (Ejaz et al., 2006). Blood pressure abnormalities may be more common in the nontremor-dominant PD. Therefore, detection of blood pressure abnormalities may be helpful to diagnose PD in the early motor or premotor stages.
Blood pressure abnormalities lead to a decrease in cerebral perfusion and the characteristic symptoms include dizziness, blurred vision, even fall, and syncope (Espay et al., 2016). Long-term blood pressure abnormalities can increase the risk of cardiovascular events (Fanciulli et al., 2014). So it is also important to detect the blood pressure abnormalities in order to prevent the development of some serious symptoms.
Although there were some studies detecting the blood pressure abnormalities in PD patients (Hawkes et al., 2010;Hughes et al., 1992;Kanegusuku et al., 2017;Luis & Felix, 2017), few studies have focused on the BP abnormalities of different PD disease stages or subtypes.
24-h ambulatory blood pressure monitoring (ABPM) is a useful tool to evaluate blood pressure alterations. It can be used to evaluate circadian blood pressure rhythm and blood pressure variability (BPV) with the advantages such as noninvasive, intermittent, etc. This study intended to analyze the blood pressure alterations and BPV in PD patients with different disease stages and subtypes by 24-h ABPM in order to find potential markers which can be used to help the early diagnosis of autonomic dysfunction and provide basis for the treatment of blood pressure abnormalities.

Study population
The study was approved by the ethical committee of the Shanghai Fifth People's hospital, and informed consent were signed from patients or their representatives. The study was performed in accordance with the Patients with benign paroxysmal positional vertigo (BPPV) and chronic subjective dizziness in the hospital at the same time were included as control group. There were no significant differences of the proportion of hypertension, diabetes mellitus, dyslipidemia, and coronary artery disease between PD group and control group.

24-h ambulatory blood pressure monitoring
The 24-h ambulatory blood pressure (BP) monitors were produced by A&D Company Limited. Patients were measured BP and heart rate (HR) every 30 min during 6:00 a.m. to 10:00 p.m. and every 60 min during 10:00 p.m. to 6:00 a.m. the next day. The mean blood pressure from 6:00 a.m. to 10:00 p.m. is the mean daytime blood pressure. The mean blood pressure from 10:00 pm to 6:00 a.m. the next day is the mean night-time blood pressure. We chose the nontremor arm or the less tremor arm of the patient for ABPM.  (Milazzo et al., 2018). We used the coefficient of variation (CV) and ARV as indicators of BPV. Calculation formula as follows:

Comparison of circadian BP rhythm, mean BP, and BPV between PD group and control group
The circadian BP rhythm in PD group was significantly different from that in the control group (p < .05). The proportion of reverse dipping was the highest in PD group (21 cases, 65.6%), and the proportion of non-dipping was the highest in the control group (22 cases, 51.2%). The night-time SBP of PD group was 140.2 ± 26.9 mmHg, which was higher than that of the control group 127.5 ± 21.8 mmHg (p < .05), Table 2.

Comparison of circadian BP rhythm, mean BP, and BPV between the early PD group, advanced PD group, and the control group
The disease duration in the advanced PD group was longer than that in the early PD group (p < .05). There was no significant difference of the circadian BP rhythm between the early PD group and the control group. There was statistical difference of the circadian BP rhythm between the advanced PD group and the early PD group (p < .05).
The proportion of non-dipping was the highest (63.6%) in the early PD group, while the proportion of reverse dipping was the highest in the advanced PD group (81.0%). There was statistically significant difference in the circadian BP rhythm between the control group and the advanced PD group (p < .05), Abbreviations: ARV, average real variability; BP, blood pressure; CV, coefficient of variation; DBP, diastolic blood pressure (value in mmHg); SBP, systolic blood pressure (value in mmHg). a Chi-square value. SBP and diastolic BP (DBP) in the advanced PD group were higher than those in the control group and the early PD group (p < .05). The DBP CV in the advanced PD group was higher than that in the control group and the early PD group (p < .05), but no difference of DBP ARV between the control group and the early PD group, Table 4.
In order to adjust the influence of the disease duration between the early and advanced PD groups, we used PSM method to match disease duration, 7 early PD patients and 21 advanced PD patients were included after PSM. There was statistical difference of the circadian BP rhythm between the two groups after PSM (p < .05).There was also significant difference of night-time SBP and DBP, SBP, and DBP CV between the two groups after PSM (p < .05), Table 5.

Comparison of circadian BP rhythm, mean BP, and BPV in tremor-dominant and nontremor-dominant PD patients
The disease duration of the tremor-dominant PD patients was longer than that in the nontremor-dominant PD patients (p < .05). There was no significant difference of circadian BP rhythm, mean BP, and BPV between the two groups, Table 6.
We used PSM method to match the disease duration.7 tremordominant PD patients and 12 nontremor-dominant PD patients were included after PSM. There was no significant difference of circadian BP rhythm, mean BP, and BPV between the two groups after PSM, Table 7.

Comparison of risk factors affecting circadian BP rhythm between PD reverse dipping group and non-dipping group
There was no significant difference of age, disease duration, gender, proportion of hypertension, proportion of diabetes mellitus, and H&Y stage between PD reverse dipping group and non-dipping group,

DISCUSSION
This study analyzed the circadian BP rhythm and BPV in PD patients.
We found that the constituent ratio of the circadian BP rhythm in PD patients were different from those in the control group (p < .001) .The  (Hughes et al., 1992).
While there were some studies that were different from our study.
Schmidt first found that 23 patients with PD and other extrapyramidal diseases had no significant drop or even increase of blood pressure at night, among which the proportion of reverse dipping in PD patients was 22%, while non-dipping was 48% (Kanegusuku et al., 2017). Sommer found 43% reverse dipping and 45% non-dipping in 40 PD patients (Luis & Felix, 2017 between those studies and our study is the younger average age of PD patients in those studies than the present study. Another possible reason is the small sample size of these studies that produced different results. All of these studies indicated that PD patients presented with a pathological BP regulation. The mechanisms of pathological nocturnal BP regulation include impaired baroreflex activity, inappropriate sympathetic tone while lying supine at night (Orimo et al., 2007).
In this study, the PD group was divided into the early PD group and the advanced PD group. We found the proportion of reverse dipping in the advanced PD group (81.0%) was higher than that in the early PD group (36.4%). Night-time SBP and DBP in advanced PD group was higher than that in the early PD group and the control group. The seriously impaired autonomic nervous system in the advanced PD patients may contribute to this result. Abbreviations: ARV, average real variability; BP, blood pressure; CV, coefficient of variation.; DBP, diastolic blood pressure (value in mmHg); SBP, systolic blood pressure (value in mmHg). a Median expressed as M(P25, P75). b Mann-Whitney u test u value.
PD patients can be divided into tremor-dominant and nontremordominant subtype. In our study, we only found the disease duration of tremor-dominant PD was longer than nontremor-dominant PD.
Although the nontremor-dominant PD is associated with more nonmotor symptoms, there were no significant differences of circadian BP rhythm and BPV between the two subtypes in our studies. After matching the disease duration there were still no significant differences between the two groups. Although the result indicated no differences of ambulatory blood pressure between the two subtypes, we should do further research to confirm it with a larger sample size.
In this study, we used CV and ARV to evaluate BPV. We found DBP CV in advanced PD group was higher than that in the early PD group and the control group, SBP CV in advanced PD group was also higher than that in the early PD group after PSM. But there were no significant differences of SBP and DBP ARV between these groups. BPV reflects 24-h blood pressure fluctuation. An initial increase in BPV is an independent predictor of cardiovascular events (Prodoehl et al., 2013). The indices of BPV include the standard deviation (SD) of 24-h ambulatory blood pressure, the CV of blood pressure, ARV, and SD dn . SD dn is the average of daytime and night-time SDs weighted by the duration of the daytime and night-time intervals. SD dn and ARV are less affected by the measuring time during day and night, both of these indices are better than classical indices (SD and CV) (Rajput & Rozdilsky, 1976).
Few studies have investigated BPV in patients with PD. Schmidt compared BPV between PD patients and control or other extrapyramidal syndromes, and reported no difference (Kanegusuku et al., 2017); while Kanegusuku found 21 PD patients presented higher daytime systolic/diastolic CV and SD than 21 controls as well as higher systolic/diastolic SD dn and ARV (Rajput & Rozdilsky, 1976 Abnormal blood pressure regulation is associated with cardiovascular dysautonomia in PD patients. The pathophysiological mechanism of cardiovascular dysautonomia in PD patients includes cardiac noradrenergic sympathetic denervation, central and peripheral norepinephrine deficiency, and arterial baroreflex failure (Muller et al., 2011). Pathological researches showed α-synuclein deposition in the sympathetic and parasympathetic plexus of the heart of PD patients (Sommer et al., 2011). Degeneration of the cardiac sympathetic nerve begins in the early disease process of PD (Asahina et al., 2013). The Braak hypothesis suggests that PD patients have Lewy body pathology in autonomic centers and nerves that include the dorsal motor nucleus of the glossopharyngeal and vagal nerves before nigral involvement (Stuebner et al., 2013;Thenganatt & Jankovic, 2014). Some research found that autonomic dysfunction can occur at the early stage of PD, and before the occurrence of typical motor symptoms (Tsukamoto et al., 2013;Vallelonga et al., 2019). Therefore, cardiovascular dysautonomia in PD patients may occur at the prodrome stage of PD.
So clinicians should pay more attention to the blood pressure monitoring and management in PD patients. All the patients with PD should carry out 24-h ABPM, which is noninvasive and easy to operate and available in the primary hospitals. Clinicians should be alert to PD patients with reverse dipping who may already have cardiovascular dysautonomia. Proper management of BP in PD patients may reduce the risk of syncope, fall, cardiovascular and stroke event.
There were some limitations in the present study. Small sample size may reduce the statistical power and lead to no statistical difference of some observation indicators. We did not compare our result with other parkinsonism such as multiple system atrophy. Other limitations included that our data was only from one medical center and patients were not repeatedly measured by 24-h ABPM in different periods. In the future, we will do further research to get more valuable results of the BP regulation in PD patients.

CONCLUSIONS
Reverse dipping was more common in PD patients rather than the control patients in this study, especially in advanced PD patients. 24-h ambulatory BP monitoring is an important method to evaluate the BP alterations in PD patients. Clinicians should be alert to PD patients with reverse dipping who may already have cardiovascular dysautonomia and pay more attention to the management of blood pressure in PD patients. Abnormal blood pressure regulation in PD patients should be found in time and intervention should be given to prevent serious clinical events.

ACKNOWLEDGMENTS
We sincerely thank the medical staff who participated in the study.