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High norepinephrinergic orthostatic hypotension in early Parkinson's disease
Parkinsonism and Related Disorders xxx (xxxx) xxx–xxx
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Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
High norepinephrinergic orthostatic hypotension in early Parkinson's disease Tadashi Umeharaa,b,∗, Hisayoshi Okaa,∗∗, Atsuo Nakaharaa, Hiromasa Matsunob, Chizuko Toyodab a b
Department of Neurology, Daisan Hospital, The Jikei University School of Medicine, Tokyo, Japan Department of Neurology, The Jikei University School of Medicine, Tokyo, Japan
A R T I C LE I N FO
A B S T R A C T
Keywords: Autonomic failure Orthostatic hypotension Vasopressin Norepinephrine concentration Cognition Central sympathetic denervation Parkinson's disease
Introduction: Plasma norepinephrine concentration reflects lesions causing OH. We investigate whether patients with high norepinephrinergic orthostatic hypotension (OH) whose supine plasma norepinephrine concentration (NEsupine) is above the mean value in all patients with Parkinson's disease (PD) have central sympathetic denervation. Methods: We analyzed data from 110 non-demented patients with early de novo PD who underwent cardiovascular examinations. We divided the patients into three groups according to the presence or absence of orthostatic hypotension and NEsupine: patients without OH, patients with OH+high NEsupine, and patients with OH +low NEsupine. Results: The mean NEsupine in all patients was 251.6 pg/ml. Twelve patients (10.9%) had OH+high NEsupine (≥251.6 pg/ml), and 45 patients (40.9%) had OH+low NEsupine (< 251.6 pg/ml). OH was more pronounced in patients with OH+high NEsupine than in those with OH+low NEsupine (p = 0.024). Vasopressin release and percent increase of NE after orthostatic stress were well preserved in patients with OH+low NEsupine, but not in patients with OH+high NEsupine. Cognition was lower in patients with OH+high NEsupine than in patients with OH+low NEsupine (p = 0.019) and was associated with vasopressin release during orthostatic stress on multiple regression analysis. The degree of cardiac sympathetic denervation did not differ between two groups with OH. Conclusions: Patient with PD and high norepinephrinergic OH are a subset of patients who have early cognitive decline and impaired vasopressin release. Vasopressin release after orthostatic stress was closely related to global cognition in PD.
1. Introduction Neurogenic orthostatic hypotension (OH) is the most prominent type of autonomic failure observed in a -synucleinopathies. However, supine plasma norepinephrine concentration (NEsupine) and vasopressin (also called antidiuretic hormone) release in response to orthostatic stress differ according to the type of α–synucleinopathy [1,2]. Low NEsupine and a pronounced increase in vasopressin concentration after orthostatic stress are observed in patients with pure autonomic failure (PAF), whereas high NEsupine and a little or no increase in vasopressin concentration are observed in patients with multiple system atrophy (MSA) [1,3]. Previous studies suggest main lesion causing OH in patients with PAF is peripheral sympathetic nerves, whereas that in patients with MSA is central sympathetic nerves [4–7]. Vasopressin concentration after orthostatic stress increases in patients with peripheral (postganglionic) sympathetic denervation, but
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not in patients with central (preganglionic) sympathetic denervation [3,8,9]. Patients with Parkinson's disease (PD) has aggregated α-synuclein proteins in central sympathetic nervous systems such as intermediolateral column cell, rostral ventrolateral medulla and medullary raphe neurons as well as peripheral sympathetic nervous systems [10–12], which suggest both sympathetic nervous systems contribute to the development of OH. In general, patients with PD and OH have low NEsupine, which suggests main lesions causing OH are peripheral sympathetic nerves [1]. However, patients whose sympathetic denervation is severe in central regions as well as in peripheral regions may have high NEsupine and impaired vasopressin release. To clarify this hypothesis, we investigated baseline characteristics and hemodynamic changes in patients with high norepinephrinergic OH whose NEsupine is above the mean value in all patients with PD.
Corresponding author. Department of Neurology, Daisan Hospital, The Jikei University School of Medicine, 4-11-1 Izumihoncho, Komae-shi, Tokyo, 201-8601, Japan. Corresponding author. Department of Neurology, Daisan Hospital, The Jikei University School of Medicine, 4-11-1 Izumihoncho, Komae-shi, Tokyo, 201-8601, Japan. E-mail addresses: [email protected] (T. Umehara), [email protected] (H. Oka).
∗∗
https://doi.org/10.1016/j.parkreldis.2018.05.025 Received 5 December 2017; Received in revised form 18 May 2018; Accepted 27 May 2018 1353-8020/ © 2018 Elsevier Ltd. All rights reserved.
Please cite this article as: Umehara, T., Parkinsonism and Related Disorders (2018), https://doi.org/10.1016/j.parkreldis.2018.05.025
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2. Methods
2.3. Cardiac variability
123
I-metaiodobenzylguanidine scintigraphy & heart rate
2.1. Patients To evaluate cardiac sympathetic and parasympathetic denervation, cardiac 123I-metaiodobenzylguanidine (MIBG) scintigraphy and heart rate variability (HRV) were evaluated, respectively. The ratio of the average pixel count in the heart (H) to that in the mediastinum (M) (H/ M ratio) after 15 min (early) and after 3 h (delayed) of injection of 111 MBq 123I-MIBG (FUJIFILM RI Pharma Co., Ltd. Tokyo, Japan) was calculated. The normal range is 2.3 for early H/M, 2.1 for delayed H/M [16]. To evaluate HRV, RR intervals were measured on electrocardiograms (ECG), recorded with the use of an ECG recorder equipped with an automated analyzer (FCP-4731, FX-7192, Fukuda-Denshi Co., Ltd., Tokyo, Japan) after 5 min of rest. All RR intervals during 1 min or 100 R R intervals were measured with the patient at rest in the supine position and breathing normally, and HRV was analyzed. HRV was automatically calculated as the percentage of the standard deviation of the RR intervals divided by their mean [17].
A total of 110 non-demented patients with newly diagnosed PD were enrolled in this study for about five years (from January 2012 through January 2017). All patients have Mini-Mental State Examination (MMSE) score of 24 or higher. None of the patients had received levodopa, other anti-Parkinson drugs, or treatment for OH. PD was diagnosed clinically according to the diagnostic criteria of the UK Parkinson's Disease Society Brain Bank by at least two neurologists [13]. All patients received levodopa or a dopamine agonist after this study, and had good response. No patient had atrophy on brain magnetic resonance imaging of putamen, brainstem or cerebellum. To evaluate neurogenic OH, we excluded patients affected by diseases and conditions with potential effects on the autonomic nervous system, such as overt diabetes, neuropathy, clinically relevant cardiac disease, cirrhosis, end-stage renal failure, anemia and dehydration on blood tests or physical examinations. If patients were already receiving antihypertensive drugs, such drugs were withdrawn at least 48 h before they were evaluated orthostatic intolerance. The motor severity of PD was assessed according to Hoehn-Yahr stage and the Unified Parkinson's Disease Rating Scale (UPDRS) motor score. The patients were divided into tremor-dominant type (TDT), akinetic-rigid type (ART), and mixed type (MXT) subgroups on the basis of the tremor and non-tremor scores, estimated with the use of part III of the UPDRS, as described by Spiegel and colleagues [14]. We calculated the mean NEsupine in all patients with PD. According to the presence of OH and NEsupine, patients were divided into three groups; patients with no OH, patients with OH+low NEsupine whose NEsupine were less than or equal to the mean value in all patients, and patients with OH+high NEsupine whose NEsupine were above the mean value in all patients. This study was approved by the Ethics Committee of Jikei University School of Medicine, and all subjects gave written informed consent before enrollment.
2.4. Constipation Constipation was defined by the presence of at least 1 of 2 criteria: (1) absence of everyday defecation, or (2) the use of drugs to treat constipation. 2.5. Olfactory assessment Olfactory function was assessed by the odor stick identification test Japan (OSIT-J) (Daiichi Yakuhin Sangyo Co. Ltd., Tokyo, Japan). The procedure of olfactory assessment was performed in the same way as was done in our previous study [18]. The total number of correct responses for the 12 odorants was defined as the OSIT-J score which has been shown to significantly correlate with that on University of Pennsylvania Smell Identification Test (UPSIT) and cross-cultural, smell identification test (CC-SIT) CC-SIT [19,20]. The normal threshold of OSIT-J score is 9 [18].
2.2. Head-up tilt-table testing (HUT)
2.6. Statistical analyses
All subjects underwent HUT in a silent room, maintained at an ambient temperature of 23 °C–26 °C. After an overnight fast, the studies commenced at 9:00 a.m. After resting for 20 min in the supine position, the subject was tilted to a 60° upright position for 10 min. Brachial systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured by an automated sphygmomanometer after 20 min of rest in the supine position (SBPsupine, DBPsupine) and every 1 min after the subject was tilted for up to 10 min. The maximum decreases in SBP and DBP during tilt (⊿SBP and ⊿DBP) were evaluated. OH was defined as ⊿SBP ≥20 mmHg and/or ⊿DBP ≥10 mmHg. OH developed beyond 3 min of upright tilt-table testing, which is called “delayed OH”, is also examined [15]. Venous blood was drawn through an indwelling catheter. The NE and vasopressin concentrations were measured after 20 min of rest in the supine position (NEsupine and vasopressinsupine) and after 10 min tilt, and the differences in the NE and vasopressin concentrations between two positions (⊿NE and ⊿vasopressin) were also calculated. We defined an increase in ⊿vasopressin as any change above 0.0 pg/ml. Both hormones were measured by SRL, Inc. with use of high performance liquid chromatography for NE and radioimmunoassay for vasopressin. We could not have obtained the data of vasopressin concentrations from 31st, March 2012 to 31st, July 2014 because of discontinued production of reagent for measuring this hormone. According to the manufacturer's instruction, the normal range is 100–450 pg/ml for NE and 3.8 pg/ml or less for vasopressin.
Statistical analyses were performed using a statistical data analysis system (Esumi Co., Ltd., Tokyo, Japan). Differences between groups were compared with the use of Welch's t-test for continuous variables such as age, disease duration, UPDRS motor score. Pairwise comparisons were made using χ2 tests for binary variables such as gender and motor subtype. The significant differences between the three groups were determined by two-tailed multiple t-tests with a Bonferroni correction following analysis of variance (ANOVA). Correlations of ⊿SBP with NEsupine were assessed with the use of Spearman correlation coefficients. Correlations of ⊿SBP or ⊿vasopressin with potential associated factors were also evaluated by multiple regression analysis with adjustment for risk factors such as age, sex, symptom duration, UPDRS motor score, motor subtype, presence of preexistent hypertension, olfaction, presence of constipation, MMSE, SBPsupine, NEsupine, ⊿NE, vasopressinsupine, ⊿vasopressin, cardiac uptake of MIBG and HRV. P values of < 0.05 were considered to indicate statistical significance. 3. Results 3.1. Baseline results The mean NEsupine in the 110 patients was 251.6 pg/ml. The mean age was 72 ± 8 (mean ± standard deviation) years, 37 patients (33.6%) were male, the symptom duration was 1.6 ± 1.6 years, 68 patients (61.8%) had ART PD and 50 patients (45.4%) had preexistent hypertension. Vasopressin concentrations were evaluated in 70 patients 2
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Table 1 Clinical characteristics of patients with early Parkinson's disease. PD with no OH (n = 53)
Age (years) Sex (male/female) Symptom duration (years) Hoehn-Yahr stage UPDRS motor score Subtype (ART/TDT or MT) Preexistent hypertension n (%) Olfaction Constipation, n (%) MMSE Supine position Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Norepinephrine (pg/ml) Vasopressin (pg/ml) Upright position ⊿Systolic blood pressure (mmHg) ⊿Diastolic blood pressure (mmHg) ⊿Norepinephrine (pg/ml) % increase of Norepinephrine (%) ⊿Vasopressin (pg/ml) % increase of Vasopressin (%) Delayed OH n (%) Cardiac MIBG scintigraphy H/M ratio Early H/M ratio Delay Heart rate variability (%)
PD with OH (n = 57)
p value
Low NEsupine (n = 45)
High NEsupine (n = 12)
71 ± 9 17/36 1.5 ± 1.8 2.3 ± 0.8 18 ± 8 28/25 26 (49) 4.6 ± 2.7 25 (49.0) b 28 ± 2
74 ± 7 16/29 1.7 ± 1.4 2.6 ± 0.6 21 ± 10 31/14 19 (42) 3.3 ± 2.6 a 37 (82.2) 28 ± 1
74 ± 6 4/8 1.8 ± 1.7 2.8 ± 0.7 a 24 ± 13 9/3 5 (41) 4.0 ± 2.9 10 (83.3) 26 ± 2 c
0.168 0.935 0.754 0.044 0.145 0.161 0.764 0.052 0.001 0.019
126 ± 17 d 72 ± 11 e 292 ± 113 f 2.50 ± 1.53 (n = 31)
138 ± 22 78 ± 13 174 ± 41 3.07 ± 2.62 (n = 29)
144 ± 20 82 ± 11 362 ± 100 g 3.23 ± 3.06 (n = 10)
0.002 0.008 < 0.0001 0.535
−6 ± 8 f 1 ± 6d 189 ± 79 73 ± 41 0.73 ± 1.04 (n = 31) 36 ± 52 (n = 31)
−31 ± 15 −14 ± 10 139 ± 67 i 83 ± 42 4.55 ± 13.29 (n = 29) 151 ± 462 (n = 29) 16 (35.5)
−44 ± 16 h −18 ± 12 197 ± 178 50 ± 34 j 0.71 ± 2.69 (n = 10) 18 ± 68 (n = 10) 2 (16.6)
< 0.0001 < 0.0001 0.015 0.052 0.198
1.54 ± 0.20 1.27 ± 0.15 1.85 ± 1.14
1.51 ± 0.19 1.27 ± 0.26 1.62 ± 0.42
0.0001 < 0.0001 0.292
1.77 ± 0.35 d 1.56 ± 0.37 d 2.08 ± 1.03
0.268 0.221
PD Parkinson's disease, OH orthostatic hypotension, NEsupine plasma norepinephrine at supine rest, UPDRS Unified Parkinson's Disease Rating Scale, ART AkineticRigid Type, TDT Tremor-Dominant Type, MT Mixed Type, MMSE Mini-Mental State Examination, ⊿Systolic blood pressure the maximum decreases in systolic blood pressure (mmHg) during tilt, ⊿Diastolic blood pressure the maximum decreases in diastolic blood pressure (mmHg) during tilt, ⊿Norepinephrine the differences in the NE concentration between two positions, ⊿Vasopressin the differences in the vasopressin concentration between two positions, H/M ratio of the average pixel count in the heart (H) to that in the mediastinum (M), MIBG 123I-metaiodobenzylguanidine. a: p < 0.05 vs patients with no OH. b: p < 0.01vs patients with OH and low NEsupine, p < 0.05 vs patients with OH and high NEsupine. c: p < 0.01 vs patients with no OH, p < 0.05 vs patients with OH and low NEsupine. d: p < 0.01 vs patients with OH and low NEsupine, p < 0.01vs patients with OH and high NEsupine. e: p < 0.05 vs patients with OH and low NEsupine, p < 0.05 vs patients with OH and high NEsupine. f: p < 0.01 vs patients with OH and low NEsupine. g: p < 0.05 vs patients with no OH, p < 0.01 vs patients with OH and low NEsupine. h: p < 0.01 vs patients with no OH, p < 0.01 vs patients with OH and low NEsupine. i: p < 0.01vs patients with no OH. j: p < 0.05 vs patients with OH and low NEsupine.
UPDRS motor score, motor subtype, prevalence of preexistent hypertension, olfaction, prevalence of constipation, H/M ratio on cardiac 123 I-MIBG scintigraphy, and HRV did not differ between these two groups. The only baseline difference between these two groups was cognition. Patients with OH+high NEsupine had a significantly lower MMSE score than did patients with OH+low NEsupine (p = 0.019).
during HUT. Fifty-three (48.1%) patients did not have OH, 57 (51.8%) patients had OH. Forty-five patients (40.9%) had OH+low NEsupine (≤251.6 pg/ml) (16 out of 45 patients had delayed OH), and 12 patients (10.9%) had OH+high NEsupine (> 251.6 pg/ml) (2 out of 12 patients had delayed OH). The prevalence of OH without delayed OH was 35.4%. The clinical characteristics and laboratory data are summarized in Table 1. Patients with no OH tended to have milder Hoehn-Yahr stage than those with OH (p = 0.044). Patients with no OH also had a lower prevalence of constipation (p = 0.001) and higher H/M ratio on cardiac MIBG scintigraphy than did patients with OH+low NEsupine and patients with OH+high NEsupine (early, p = 0.0001; delayed, p < 0.0001). Olfaction was higher in patients with no OH than in patients with OH+low NEsupine (p = 0.01). As for HRV, no statistical difference between 3 groups was observed (p > 0.05). Comparison between patients with OH+low NEsupine and patients with OH+high NEsupine revealed that age, sex, symptom duration,
3.2. HUT results Patients with no OH had a lower SBP and DBP at supine rest than did patients with OH+low NEsupine and patients with OH+high NEsupine (SBP; p = 0.002, DBP; p = 0.008, respectively). NEsupine was 292 ± 113 pg/ml in patients with no OH, 174 ± 41 pg/ml in patients with OH+ low NEsupine, and 362 ± 100 in patients with OH+high NEsupine. And its level was significantly higher in patients with OH +high NEsupine than in patients with no OH and in patients with OH + low NEsupine (p < 0.0001). Patients with OH+high NEsupine had a greater decrease in SBP during HUT than did patients with no OH and 3
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Fig. 1. (A): Title: The correlation between NE at supine rest and the degree of orthostatic hypotension (⊿SBP) (B): Title: The paradoxical change (no change or decrease) in vasopressin concentration after tilt. Description: Paradoxical change in vasopressin concentration after tilt was more frequently observed in patients with high norepinephrinergic OH than in those with low norepinephrinergic OH. *p < 0.05, ***p < 0.001.
concentration after tilt was observed in a significantly higher proportion of patients with OH+high NEsupine than in patients with OH+low NEsupine (50% vs. 6.8%, p = 0.0021) (Fig. 1B).
patients with OH+low NEsupine (p < 0.0001). There was a negative correlation between the NEsupine and the decrease in SBP during HUT in the study group as a whole (r = −0.322, p = 0.0004) (Fig. 1A). However, an analysis including only patients with OH showed no correlation between the NEsupine and the decrease in systolic blood pressure during HUT (p > 0.05). ⊿NE during HUT was significantly smaller in patients with OH +low NEsupine than in patients with no OH and in patients with OH +high NEsupine (p = 0.015). However, the percent increase of NE during HUT was lower in patients with OH+high NEsupine than in patients with OH+low NEsupine (50 ± 34% vs 83 ± 42%, p = 0.0069). There was no difference in vasopressinsupine between three groups. The results of ⊿vasopressin and percent increase of vasopressin during HUT were following descending order: patients with OH+low NEsupine, patients with no OH, patients with OH+high NEsupine, whereas the difference between three groups did not reach statistical significance (⊿vasopressin; p = 0.198, percent increase of vasopressin; p = 0.268). As a paradoxical change, no change or a decrease in the ⊿vasopressin
3.3. Multiple regression analysis conducted in 70 patients with assessment of the vasopressin concentration On multiple regression analysis in which the degree of orthostatic hypotension was used as a dependent variable and age, sex, symptom duration, UPDRS motor score, subtype, presence of preexistent hypertension, olfaction, presence of constipation, MMSE, systolic blood pressure at supine rest, NEsupine, ⊿NE, H/M ratio delayed, HRV, vasopressinsupine and ⊿vasopressin were used as independent variables, the degree of orthostatic hypotension was negatively associated with MMSE and H/M ratio delayed, and positively associated with ⊿vasopressin (MMSE: β = −0.3059, p = 0.0275, H/M ratio delayed: β = −0.3454, p = 0.0095, ⊿vasopressin: β = 0.3691, p = 0.0013, R2 = 0.477) (Table 2). 4
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⊿vasopressin was positively associated with MMSE and degree of orthostatic hypotension (MMSE: β = 0.3616, p = 0.0225, the degree of orthostatic hypotension: β = 0.4828, p = 0.0013, R2 = 0.316) (Table 3).
Table 2 Multiple regression analysis of the correlation between the degree of orthostatic hypotension and potential covariables. ⊿Systolic blood pressure
Parameter estimate
Standard error
p value
Age Sex Symptom duration UPDRS motor score Subtype Preexistent hypertension Olfaction Constipation MMSE Systolic blood pressure at supine rest Norepinephrine at supine rest ⊿Norepinephrine Vasopressin at supine rest ⊿Vasopressin H/M ratio delayed Heart rate variability
−0.2220 0.1085 0.0349 0.0239 −0.0343 0.0184 0.0946 0.0665 −0.3059 0.2018
0.3370 5.1404 1.4716 0.2766 5.1529 5.8098 0.9341 5.2266 1.5069 0.1261
0.1447 0.3589 0.7724 0.8684 0.7753 0.8946 0.4516 0.5757 0.0275 0.1362
−0.0898 0.0635 −0.1053 0.3691 −0.3454 −0.1115
0.0274 0.0264 1.1138 0.2630 8.4155 2.4110
0.5163 0.6320 0.3808 0.0013 0.0095 0.3546
4. Discussion Our study showed that about 10% of patients with early de novo PD had OH with preserved (high) NEsupine for the first time. Despite the high norepinephrine concentrations at supine rest, these patients had a greater decrease in blood pressure during orthostatic stress and a greater decrease in cognition than did patients with OH+low NEsupine. Patients with OH+high NEsupine also had decreased percent increase of NE after orthostatic stress. In addition, the percentage of patients who had impaired vasopressin release during HUT was significantly higher in patients with OH+high NEsupine than in patients with OH+low NEsupine. Conversely, accentuated vasopressin response during HUT was observed in most patients with OH+low NEsupine. Both patients with OH+low NEsupine and patients with OH+high NEsupine had severer cardiac sympathetic denervation than those with no OH. Multiple regression analysis also revealed that the vasopressin release during orthostatic stress was positively associated with cognition as well as with the degree of OH. Based on our results, patients with OH+high NEsupine seem to be a subset of patients with PD who have early cognitive decline and central sympathetic denervation. The prevalence of OH was 51.8%, which seems to be a bit high as compared with previous studies, even though this prevalence was within the previously reported range [21]. This high prevalence may be due to advanced age in our study population and counting delayed OH [15,22]. Patients with OH+high NE group have severe OH despite a high absolute change in NE during HUT perhaps because two major factors. One is relative insufficient release of vasopressin despite great fall in blood pressure. The other is decreased % increase of NE caused by peripheral sympathetic denervation during orthostatic stress. Percent increase of NE during orthostatic stress in patients with OH+high NEsupine was smallest among three groups. We consider % increase of NE is more important to prevent OH than actual measurement value of NE. High actual measurement value of NE may be due to not only increased NE release but also accentuated decrease in NE reuptake because denervation would produce concurrent decreases in both release and reuptake [23]. Increasing pathological evidence suggests that OH in PD is caused by both peripheral and central sympathetic denervation, even though the degree of central neuronal loss is milder than that of MSA [10–12,24]. It has documented that there are three patterns of pathologic process of LB neuritis. First pattern is that LB starting in the dorsal medulla oblongata is postulated to progress to the substantia nigra and then to cerebral cortical areas via caudal-to-rostral propagation in the brain, which is known as Braak hypothesis. Second pattern is LB starting in the amygdala spreads to entorhinal cortex and midbrain/brainstem regions, or both. Third pattern is LB originated in the cerebral cortex spreads descendingly to midbrain/brainstem regions [25]. The relatively low cognitive status in patients with early PD and OH +high NEsupine suggests the central propagation of LB in these patients may correspond to the second or third. Initial emergence of LB in cognition associated areas and consequent descending spreading to brainstem may cause low cognitive status and motor symptoms. The pathological change in these patients may be, therefore, similar to that in patients with Dementia with Lewy Bodies (DLB). In the baroreflex, the centripetal hemodynamic information is transmitted to vasopressin neurons in the hypothalamus [26]. The hypothalamus has been considered the integration center of the autonomic nervous system and is under the influence of the limbic system [27]. This may be the reason why cognition was associated with
R2 = 0.477. ⊿Systolic blood pressure the maximum decreases in systolic blood pressure (mmHg) during tilt, UPDRS Unified Parkinson's Disease Rating Scale, MMSE Mini-Mental State Examination, ⊿Norepinephrine the differences in the plasma norepinephrine concentration between two positions, ⊿Vasopressin the differences in the plasma vasopressin concentration between two positions, H/M ratio of the average pixel count in the heart (H) to that in the mediastinum (M). Sex; male = 1, female = 0, Subtype; ART = 1, TDT or MT = 0, Preexistent hypertension and Constipation; presence = 1, absence = 0. Table 3 Multiple regression analysis of the correlation between ⊿Vasopressin and potential covariables. ⊿Vasopressin
Parameter estimate
Standard error
p value
Age Sex Symptom duration UPDRS motor score Subtype Preexistent hypertension Olfaction Constipation MMSE Systolic blood pressure at supine rest ⊿Systolic blood pressure Norepinephrine ⊿Norepinephrine Vasopressin at supine rest H/M ratio delayed Heart rate variability
0.2744 −0.0916 0.0924 0.0148 0.1487 −0.2152 0.0629 0.0203 0.3616 0.0962
0.1590 2.4427 0.6943 0.1310 2.4142 2.7026 0.4439 2.4815 0.7111 0.0608
0.1143 0.4989 0.5026 0.9283 0.2761 0.1711 0.6625 0.8815 0.0225 0.5379
0.4828 −0.0636 −0.0738 0.1780 0.1754 0.1564
0.0590 0.0130 0.0125 0.5227 4.1972 1.1368
0.0013 0.6883 0.6263 0.1933 0.2619 0.2553
R2 = 0.316. ⊿Vasopressin the differences in the plasma vasopressin concentration between two positions, UPDRS Unified Parkinson's Disease Rating Scale, MMSE MiniMental State Examination, ⊿Systolic blood pressure the maximum decreases in systolic blood pressure (mmHg) during tilt, ⊿Norepinephrine the differences in the plasma norepinephrine concentration between two positions, H/M ratio of the average pixel count in the heart (H) to that in the mediastinum (M). Sex; male = 1, female = 0, Subtype; ART = 1, TDT or MT = 0, Preexistent hypertension and Constipation; presence = 1, absence = 0.
On multiple regression analysis in which ⊿vasopressin was used as a dependent variable and age, sex, symptom duration, UPDRS motor score, subtype, presence of preexistent hypertension, olfaction, presence of constipation, MMSE, systolic blood pressure at supine rest, degree of orthostatic hypotension, NEsupine, ⊿NE, vasopressinsupine, H/ M ratio delayed and HRV were used as independent variables, 5
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vasopressin release during tilt on multiple regression analysis. In a pathological study of patients with PD, LB was identified in every hypothalamic nucleus [28]. Because vasopressin is secreted by paraventricular nuclei and supraoptic nuclei located in the lateral area of the hypothalamus [29], the presence of lesions in this region, lesions associated with central regulatory areas of vasopressin release, or both would explain the impaired vasopressin release after orthostatic stress. Conversely, patients with OH+low NEsupine had appropriate vasopressin release in response to orthostatic stress, suggesting these patients had peripheral sympathetic denervation and a relatively small accumulation of LB in central sympathetic pathway. The pronounced vasopressin release during tilt in these patients might be a compensatory mechanism for the inadequate sympathetic response mediated though NE, as circulating vasopressin can increase the blood pressure though water reabsorption and vasoconstriction [29]. A decreased H/M ratio means clinically reduced cardiac output and vasoconstriction after tilt, and is involved in the mechanism of baroreflex failure in patients with PD and OH [30]. Limitation of our study is HRV measurements were obtained from a 1-min electrocardiogram, which may be insufficient to characterize adequately variability [17]. Second is that we should have used more sensitive scale such as Montreal Cognitive Assessment and Clinical Dementia Rating as well as MMSE to indicate a sensitive spectrum of cognitive decline. In conclusion, vasopressin release after orthostatic stress was closely related to global cognition in PD patients with OH and altered supine NE levels. Specifically, PD patients with OH+high NEsupine were a subset of patients having impaired vasopressin release and early cognitive decline in contrast to PD patients with OH+low NEsupine who exhibit accentuated vasopressin release and preserved cognitive function. The propagational pattern of LB in patients with OH+high NEsupine may be different from the typical Braak's hypothesis.
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Acknowledgements We thank our residents.
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Contents lists available at ScienceDirect
Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
High norepinephrinergic orthostatic hypotension in early Parkinson's disease Tadashi Umeharaa,b,∗, Hisayoshi Okaa,∗∗, Atsuo Nakaharaa, Hiromasa Matsunob, Chizuko Toyodab a b
Department of Neurology, Daisan Hospital, The Jikei University School of Medicine, Tokyo, Japan Department of Neurology, The Jikei University School of Medicine, Tokyo, Japan
A R T I C LE I N FO
A B S T R A C T
Keywords: Autonomic failure Orthostatic hypotension Vasopressin Norepinephrine concentration Cognition Central sympathetic denervation Parkinson's disease
Introduction: Plasma norepinephrine concentration reflects lesions causing OH. We investigate whether patients with high norepinephrinergic orthostatic hypotension (OH) whose supine plasma norepinephrine concentration (NEsupine) is above the mean value in all patients with Parkinson's disease (PD) have central sympathetic denervation. Methods: We analyzed data from 110 non-demented patients with early de novo PD who underwent cardiovascular examinations. We divided the patients into three groups according to the presence or absence of orthostatic hypotension and NEsupine: patients without OH, patients with OH+high NEsupine, and patients with OH +low NEsupine. Results: The mean NEsupine in all patients was 251.6 pg/ml. Twelve patients (10.9%) had OH+high NEsupine (≥251.6 pg/ml), and 45 patients (40.9%) had OH+low NEsupine (< 251.6 pg/ml). OH was more pronounced in patients with OH+high NEsupine than in those with OH+low NEsupine (p = 0.024). Vasopressin release and percent increase of NE after orthostatic stress were well preserved in patients with OH+low NEsupine, but not in patients with OH+high NEsupine. Cognition was lower in patients with OH+high NEsupine than in patients with OH+low NEsupine (p = 0.019) and was associated with vasopressin release during orthostatic stress on multiple regression analysis. The degree of cardiac sympathetic denervation did not differ between two groups with OH. Conclusions: Patient with PD and high norepinephrinergic OH are a subset of patients who have early cognitive decline and impaired vasopressin release. Vasopressin release after orthostatic stress was closely related to global cognition in PD.
1. Introduction Neurogenic orthostatic hypotension (OH) is the most prominent type of autonomic failure observed in a -synucleinopathies. However, supine plasma norepinephrine concentration (NEsupine) and vasopressin (also called antidiuretic hormone) release in response to orthostatic stress differ according to the type of α–synucleinopathy [1,2]. Low NEsupine and a pronounced increase in vasopressin concentration after orthostatic stress are observed in patients with pure autonomic failure (PAF), whereas high NEsupine and a little or no increase in vasopressin concentration are observed in patients with multiple system atrophy (MSA) [1,3]. Previous studies suggest main lesion causing OH in patients with PAF is peripheral sympathetic nerves, whereas that in patients with MSA is central sympathetic nerves [4–7]. Vasopressin concentration after orthostatic stress increases in patients with peripheral (postganglionic) sympathetic denervation, but
∗
not in patients with central (preganglionic) sympathetic denervation [3,8,9]. Patients with Parkinson's disease (PD) has aggregated α-synuclein proteins in central sympathetic nervous systems such as intermediolateral column cell, rostral ventrolateral medulla and medullary raphe neurons as well as peripheral sympathetic nervous systems [10–12], which suggest both sympathetic nervous systems contribute to the development of OH. In general, patients with PD and OH have low NEsupine, which suggests main lesions causing OH are peripheral sympathetic nerves [1]. However, patients whose sympathetic denervation is severe in central regions as well as in peripheral regions may have high NEsupine and impaired vasopressin release. To clarify this hypothesis, we investigated baseline characteristics and hemodynamic changes in patients with high norepinephrinergic OH whose NEsupine is above the mean value in all patients with PD.
Corresponding author. Department of Neurology, Daisan Hospital, The Jikei University School of Medicine, 4-11-1 Izumihoncho, Komae-shi, Tokyo, 201-8601, Japan. Corresponding author. Department of Neurology, Daisan Hospital, The Jikei University School of Medicine, 4-11-1 Izumihoncho, Komae-shi, Tokyo, 201-8601, Japan. E-mail addresses: [email protected] (T. Umehara), [email protected] (H. Oka).
∗∗
https://doi.org/10.1016/j.parkreldis.2018.05.025 Received 5 December 2017; Received in revised form 18 May 2018; Accepted 27 May 2018 1353-8020/ © 2018 Elsevier Ltd. All rights reserved.
Please cite this article as: Umehara, T., Parkinsonism and Related Disorders (2018), https://doi.org/10.1016/j.parkreldis.2018.05.025
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2. Methods
2.3. Cardiac variability
123
I-metaiodobenzylguanidine scintigraphy & heart rate
2.1. Patients To evaluate cardiac sympathetic and parasympathetic denervation, cardiac 123I-metaiodobenzylguanidine (MIBG) scintigraphy and heart rate variability (HRV) were evaluated, respectively. The ratio of the average pixel count in the heart (H) to that in the mediastinum (M) (H/ M ratio) after 15 min (early) and after 3 h (delayed) of injection of 111 MBq 123I-MIBG (FUJIFILM RI Pharma Co., Ltd. Tokyo, Japan) was calculated. The normal range is 2.3 for early H/M, 2.1 for delayed H/M [16]. To evaluate HRV, RR intervals were measured on electrocardiograms (ECG), recorded with the use of an ECG recorder equipped with an automated analyzer (FCP-4731, FX-7192, Fukuda-Denshi Co., Ltd., Tokyo, Japan) after 5 min of rest. All RR intervals during 1 min or 100 R R intervals were measured with the patient at rest in the supine position and breathing normally, and HRV was analyzed. HRV was automatically calculated as the percentage of the standard deviation of the RR intervals divided by their mean [17].
A total of 110 non-demented patients with newly diagnosed PD were enrolled in this study for about five years (from January 2012 through January 2017). All patients have Mini-Mental State Examination (MMSE) score of 24 or higher. None of the patients had received levodopa, other anti-Parkinson drugs, or treatment for OH. PD was diagnosed clinically according to the diagnostic criteria of the UK Parkinson's Disease Society Brain Bank by at least two neurologists [13]. All patients received levodopa or a dopamine agonist after this study, and had good response. No patient had atrophy on brain magnetic resonance imaging of putamen, brainstem or cerebellum. To evaluate neurogenic OH, we excluded patients affected by diseases and conditions with potential effects on the autonomic nervous system, such as overt diabetes, neuropathy, clinically relevant cardiac disease, cirrhosis, end-stage renal failure, anemia and dehydration on blood tests or physical examinations. If patients were already receiving antihypertensive drugs, such drugs were withdrawn at least 48 h before they were evaluated orthostatic intolerance. The motor severity of PD was assessed according to Hoehn-Yahr stage and the Unified Parkinson's Disease Rating Scale (UPDRS) motor score. The patients were divided into tremor-dominant type (TDT), akinetic-rigid type (ART), and mixed type (MXT) subgroups on the basis of the tremor and non-tremor scores, estimated with the use of part III of the UPDRS, as described by Spiegel and colleagues [14]. We calculated the mean NEsupine in all patients with PD. According to the presence of OH and NEsupine, patients were divided into three groups; patients with no OH, patients with OH+low NEsupine whose NEsupine were less than or equal to the mean value in all patients, and patients with OH+high NEsupine whose NEsupine were above the mean value in all patients. This study was approved by the Ethics Committee of Jikei University School of Medicine, and all subjects gave written informed consent before enrollment.
2.4. Constipation Constipation was defined by the presence of at least 1 of 2 criteria: (1) absence of everyday defecation, or (2) the use of drugs to treat constipation. 2.5. Olfactory assessment Olfactory function was assessed by the odor stick identification test Japan (OSIT-J) (Daiichi Yakuhin Sangyo Co. Ltd., Tokyo, Japan). The procedure of olfactory assessment was performed in the same way as was done in our previous study [18]. The total number of correct responses for the 12 odorants was defined as the OSIT-J score which has been shown to significantly correlate with that on University of Pennsylvania Smell Identification Test (UPSIT) and cross-cultural, smell identification test (CC-SIT) CC-SIT [19,20]. The normal threshold of OSIT-J score is 9 [18].
2.2. Head-up tilt-table testing (HUT)
2.6. Statistical analyses
All subjects underwent HUT in a silent room, maintained at an ambient temperature of 23 °C–26 °C. After an overnight fast, the studies commenced at 9:00 a.m. After resting for 20 min in the supine position, the subject was tilted to a 60° upright position for 10 min. Brachial systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured by an automated sphygmomanometer after 20 min of rest in the supine position (SBPsupine, DBPsupine) and every 1 min after the subject was tilted for up to 10 min. The maximum decreases in SBP and DBP during tilt (⊿SBP and ⊿DBP) were evaluated. OH was defined as ⊿SBP ≥20 mmHg and/or ⊿DBP ≥10 mmHg. OH developed beyond 3 min of upright tilt-table testing, which is called “delayed OH”, is also examined [15]. Venous blood was drawn through an indwelling catheter. The NE and vasopressin concentrations were measured after 20 min of rest in the supine position (NEsupine and vasopressinsupine) and after 10 min tilt, and the differences in the NE and vasopressin concentrations between two positions (⊿NE and ⊿vasopressin) were also calculated. We defined an increase in ⊿vasopressin as any change above 0.0 pg/ml. Both hormones were measured by SRL, Inc. with use of high performance liquid chromatography for NE and radioimmunoassay for vasopressin. We could not have obtained the data of vasopressin concentrations from 31st, March 2012 to 31st, July 2014 because of discontinued production of reagent for measuring this hormone. According to the manufacturer's instruction, the normal range is 100–450 pg/ml for NE and 3.8 pg/ml or less for vasopressin.
Statistical analyses were performed using a statistical data analysis system (Esumi Co., Ltd., Tokyo, Japan). Differences between groups were compared with the use of Welch's t-test for continuous variables such as age, disease duration, UPDRS motor score. Pairwise comparisons were made using χ2 tests for binary variables such as gender and motor subtype. The significant differences between the three groups were determined by two-tailed multiple t-tests with a Bonferroni correction following analysis of variance (ANOVA). Correlations of ⊿SBP with NEsupine were assessed with the use of Spearman correlation coefficients. Correlations of ⊿SBP or ⊿vasopressin with potential associated factors were also evaluated by multiple regression analysis with adjustment for risk factors such as age, sex, symptom duration, UPDRS motor score, motor subtype, presence of preexistent hypertension, olfaction, presence of constipation, MMSE, SBPsupine, NEsupine, ⊿NE, vasopressinsupine, ⊿vasopressin, cardiac uptake of MIBG and HRV. P values of < 0.05 were considered to indicate statistical significance. 3. Results 3.1. Baseline results The mean NEsupine in the 110 patients was 251.6 pg/ml. The mean age was 72 ± 8 (mean ± standard deviation) years, 37 patients (33.6%) were male, the symptom duration was 1.6 ± 1.6 years, 68 patients (61.8%) had ART PD and 50 patients (45.4%) had preexistent hypertension. Vasopressin concentrations were evaluated in 70 patients 2
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Table 1 Clinical characteristics of patients with early Parkinson's disease. PD with no OH (n = 53)
Age (years) Sex (male/female) Symptom duration (years) Hoehn-Yahr stage UPDRS motor score Subtype (ART/TDT or MT) Preexistent hypertension n (%) Olfaction Constipation, n (%) MMSE Supine position Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Norepinephrine (pg/ml) Vasopressin (pg/ml) Upright position ⊿Systolic blood pressure (mmHg) ⊿Diastolic blood pressure (mmHg) ⊿Norepinephrine (pg/ml) % increase of Norepinephrine (%) ⊿Vasopressin (pg/ml) % increase of Vasopressin (%) Delayed OH n (%) Cardiac MIBG scintigraphy H/M ratio Early H/M ratio Delay Heart rate variability (%)
PD with OH (n = 57)
p value
Low NEsupine (n = 45)
High NEsupine (n = 12)
71 ± 9 17/36 1.5 ± 1.8 2.3 ± 0.8 18 ± 8 28/25 26 (49) 4.6 ± 2.7 25 (49.0) b 28 ± 2
74 ± 7 16/29 1.7 ± 1.4 2.6 ± 0.6 21 ± 10 31/14 19 (42) 3.3 ± 2.6 a 37 (82.2) 28 ± 1
74 ± 6 4/8 1.8 ± 1.7 2.8 ± 0.7 a 24 ± 13 9/3 5 (41) 4.0 ± 2.9 10 (83.3) 26 ± 2 c
0.168 0.935 0.754 0.044 0.145 0.161 0.764 0.052 0.001 0.019
126 ± 17 d 72 ± 11 e 292 ± 113 f 2.50 ± 1.53 (n = 31)
138 ± 22 78 ± 13 174 ± 41 3.07 ± 2.62 (n = 29)
144 ± 20 82 ± 11 362 ± 100 g 3.23 ± 3.06 (n = 10)
0.002 0.008 < 0.0001 0.535
−6 ± 8 f 1 ± 6d 189 ± 79 73 ± 41 0.73 ± 1.04 (n = 31) 36 ± 52 (n = 31)
−31 ± 15 −14 ± 10 139 ± 67 i 83 ± 42 4.55 ± 13.29 (n = 29) 151 ± 462 (n = 29) 16 (35.5)
−44 ± 16 h −18 ± 12 197 ± 178 50 ± 34 j 0.71 ± 2.69 (n = 10) 18 ± 68 (n = 10) 2 (16.6)
< 0.0001 < 0.0001 0.015 0.052 0.198
1.54 ± 0.20 1.27 ± 0.15 1.85 ± 1.14
1.51 ± 0.19 1.27 ± 0.26 1.62 ± 0.42
0.0001 < 0.0001 0.292
1.77 ± 0.35 d 1.56 ± 0.37 d 2.08 ± 1.03
0.268 0.221
PD Parkinson's disease, OH orthostatic hypotension, NEsupine plasma norepinephrine at supine rest, UPDRS Unified Parkinson's Disease Rating Scale, ART AkineticRigid Type, TDT Tremor-Dominant Type, MT Mixed Type, MMSE Mini-Mental State Examination, ⊿Systolic blood pressure the maximum decreases in systolic blood pressure (mmHg) during tilt, ⊿Diastolic blood pressure the maximum decreases in diastolic blood pressure (mmHg) during tilt, ⊿Norepinephrine the differences in the NE concentration between two positions, ⊿Vasopressin the differences in the vasopressin concentration between two positions, H/M ratio of the average pixel count in the heart (H) to that in the mediastinum (M), MIBG 123I-metaiodobenzylguanidine. a: p < 0.05 vs patients with no OH. b: p < 0.01vs patients with OH and low NEsupine, p < 0.05 vs patients with OH and high NEsupine. c: p < 0.01 vs patients with no OH, p < 0.05 vs patients with OH and low NEsupine. d: p < 0.01 vs patients with OH and low NEsupine, p < 0.01vs patients with OH and high NEsupine. e: p < 0.05 vs patients with OH and low NEsupine, p < 0.05 vs patients with OH and high NEsupine. f: p < 0.01 vs patients with OH and low NEsupine. g: p < 0.05 vs patients with no OH, p < 0.01 vs patients with OH and low NEsupine. h: p < 0.01 vs patients with no OH, p < 0.01 vs patients with OH and low NEsupine. i: p < 0.01vs patients with no OH. j: p < 0.05 vs patients with OH and low NEsupine.
UPDRS motor score, motor subtype, prevalence of preexistent hypertension, olfaction, prevalence of constipation, H/M ratio on cardiac 123 I-MIBG scintigraphy, and HRV did not differ between these two groups. The only baseline difference between these two groups was cognition. Patients with OH+high NEsupine had a significantly lower MMSE score than did patients with OH+low NEsupine (p = 0.019).
during HUT. Fifty-three (48.1%) patients did not have OH, 57 (51.8%) patients had OH. Forty-five patients (40.9%) had OH+low NEsupine (≤251.6 pg/ml) (16 out of 45 patients had delayed OH), and 12 patients (10.9%) had OH+high NEsupine (> 251.6 pg/ml) (2 out of 12 patients had delayed OH). The prevalence of OH without delayed OH was 35.4%. The clinical characteristics and laboratory data are summarized in Table 1. Patients with no OH tended to have milder Hoehn-Yahr stage than those with OH (p = 0.044). Patients with no OH also had a lower prevalence of constipation (p = 0.001) and higher H/M ratio on cardiac MIBG scintigraphy than did patients with OH+low NEsupine and patients with OH+high NEsupine (early, p = 0.0001; delayed, p < 0.0001). Olfaction was higher in patients with no OH than in patients with OH+low NEsupine (p = 0.01). As for HRV, no statistical difference between 3 groups was observed (p > 0.05). Comparison between patients with OH+low NEsupine and patients with OH+high NEsupine revealed that age, sex, symptom duration,
3.2. HUT results Patients with no OH had a lower SBP and DBP at supine rest than did patients with OH+low NEsupine and patients with OH+high NEsupine (SBP; p = 0.002, DBP; p = 0.008, respectively). NEsupine was 292 ± 113 pg/ml in patients with no OH, 174 ± 41 pg/ml in patients with OH+ low NEsupine, and 362 ± 100 in patients with OH+high NEsupine. And its level was significantly higher in patients with OH +high NEsupine than in patients with no OH and in patients with OH + low NEsupine (p < 0.0001). Patients with OH+high NEsupine had a greater decrease in SBP during HUT than did patients with no OH and 3
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Fig. 1. (A): Title: The correlation between NE at supine rest and the degree of orthostatic hypotension (⊿SBP) (B): Title: The paradoxical change (no change or decrease) in vasopressin concentration after tilt. Description: Paradoxical change in vasopressin concentration after tilt was more frequently observed in patients with high norepinephrinergic OH than in those with low norepinephrinergic OH. *p < 0.05, ***p < 0.001.
concentration after tilt was observed in a significantly higher proportion of patients with OH+high NEsupine than in patients with OH+low NEsupine (50% vs. 6.8%, p = 0.0021) (Fig. 1B).
patients with OH+low NEsupine (p < 0.0001). There was a negative correlation between the NEsupine and the decrease in SBP during HUT in the study group as a whole (r = −0.322, p = 0.0004) (Fig. 1A). However, an analysis including only patients with OH showed no correlation between the NEsupine and the decrease in systolic blood pressure during HUT (p > 0.05). ⊿NE during HUT was significantly smaller in patients with OH +low NEsupine than in patients with no OH and in patients with OH +high NEsupine (p = 0.015). However, the percent increase of NE during HUT was lower in patients with OH+high NEsupine than in patients with OH+low NEsupine (50 ± 34% vs 83 ± 42%, p = 0.0069). There was no difference in vasopressinsupine between three groups. The results of ⊿vasopressin and percent increase of vasopressin during HUT were following descending order: patients with OH+low NEsupine, patients with no OH, patients with OH+high NEsupine, whereas the difference between three groups did not reach statistical significance (⊿vasopressin; p = 0.198, percent increase of vasopressin; p = 0.268). As a paradoxical change, no change or a decrease in the ⊿vasopressin
3.3. Multiple regression analysis conducted in 70 patients with assessment of the vasopressin concentration On multiple regression analysis in which the degree of orthostatic hypotension was used as a dependent variable and age, sex, symptom duration, UPDRS motor score, subtype, presence of preexistent hypertension, olfaction, presence of constipation, MMSE, systolic blood pressure at supine rest, NEsupine, ⊿NE, H/M ratio delayed, HRV, vasopressinsupine and ⊿vasopressin were used as independent variables, the degree of orthostatic hypotension was negatively associated with MMSE and H/M ratio delayed, and positively associated with ⊿vasopressin (MMSE: β = −0.3059, p = 0.0275, H/M ratio delayed: β = −0.3454, p = 0.0095, ⊿vasopressin: β = 0.3691, p = 0.0013, R2 = 0.477) (Table 2). 4
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⊿vasopressin was positively associated with MMSE and degree of orthostatic hypotension (MMSE: β = 0.3616, p = 0.0225, the degree of orthostatic hypotension: β = 0.4828, p = 0.0013, R2 = 0.316) (Table 3).
Table 2 Multiple regression analysis of the correlation between the degree of orthostatic hypotension and potential covariables. ⊿Systolic blood pressure
Parameter estimate
Standard error
p value
Age Sex Symptom duration UPDRS motor score Subtype Preexistent hypertension Olfaction Constipation MMSE Systolic blood pressure at supine rest Norepinephrine at supine rest ⊿Norepinephrine Vasopressin at supine rest ⊿Vasopressin H/M ratio delayed Heart rate variability
−0.2220 0.1085 0.0349 0.0239 −0.0343 0.0184 0.0946 0.0665 −0.3059 0.2018
0.3370 5.1404 1.4716 0.2766 5.1529 5.8098 0.9341 5.2266 1.5069 0.1261
0.1447 0.3589 0.7724 0.8684 0.7753 0.8946 0.4516 0.5757 0.0275 0.1362
−0.0898 0.0635 −0.1053 0.3691 −0.3454 −0.1115
0.0274 0.0264 1.1138 0.2630 8.4155 2.4110
0.5163 0.6320 0.3808 0.0013 0.0095 0.3546
4. Discussion Our study showed that about 10% of patients with early de novo PD had OH with preserved (high) NEsupine for the first time. Despite the high norepinephrine concentrations at supine rest, these patients had a greater decrease in blood pressure during orthostatic stress and a greater decrease in cognition than did patients with OH+low NEsupine. Patients with OH+high NEsupine also had decreased percent increase of NE after orthostatic stress. In addition, the percentage of patients who had impaired vasopressin release during HUT was significantly higher in patients with OH+high NEsupine than in patients with OH+low NEsupine. Conversely, accentuated vasopressin response during HUT was observed in most patients with OH+low NEsupine. Both patients with OH+low NEsupine and patients with OH+high NEsupine had severer cardiac sympathetic denervation than those with no OH. Multiple regression analysis also revealed that the vasopressin release during orthostatic stress was positively associated with cognition as well as with the degree of OH. Based on our results, patients with OH+high NEsupine seem to be a subset of patients with PD who have early cognitive decline and central sympathetic denervation. The prevalence of OH was 51.8%, which seems to be a bit high as compared with previous studies, even though this prevalence was within the previously reported range [21]. This high prevalence may be due to advanced age in our study population and counting delayed OH [15,22]. Patients with OH+high NE group have severe OH despite a high absolute change in NE during HUT perhaps because two major factors. One is relative insufficient release of vasopressin despite great fall in blood pressure. The other is decreased % increase of NE caused by peripheral sympathetic denervation during orthostatic stress. Percent increase of NE during orthostatic stress in patients with OH+high NEsupine was smallest among three groups. We consider % increase of NE is more important to prevent OH than actual measurement value of NE. High actual measurement value of NE may be due to not only increased NE release but also accentuated decrease in NE reuptake because denervation would produce concurrent decreases in both release and reuptake [23]. Increasing pathological evidence suggests that OH in PD is caused by both peripheral and central sympathetic denervation, even though the degree of central neuronal loss is milder than that of MSA [10–12,24]. It has documented that there are three patterns of pathologic process of LB neuritis. First pattern is that LB starting in the dorsal medulla oblongata is postulated to progress to the substantia nigra and then to cerebral cortical areas via caudal-to-rostral propagation in the brain, which is known as Braak hypothesis. Second pattern is LB starting in the amygdala spreads to entorhinal cortex and midbrain/brainstem regions, or both. Third pattern is LB originated in the cerebral cortex spreads descendingly to midbrain/brainstem regions [25]. The relatively low cognitive status in patients with early PD and OH +high NEsupine suggests the central propagation of LB in these patients may correspond to the second or third. Initial emergence of LB in cognition associated areas and consequent descending spreading to brainstem may cause low cognitive status and motor symptoms. The pathological change in these patients may be, therefore, similar to that in patients with Dementia with Lewy Bodies (DLB). In the baroreflex, the centripetal hemodynamic information is transmitted to vasopressin neurons in the hypothalamus [26]. The hypothalamus has been considered the integration center of the autonomic nervous system and is under the influence of the limbic system [27]. This may be the reason why cognition was associated with
R2 = 0.477. ⊿Systolic blood pressure the maximum decreases in systolic blood pressure (mmHg) during tilt, UPDRS Unified Parkinson's Disease Rating Scale, MMSE Mini-Mental State Examination, ⊿Norepinephrine the differences in the plasma norepinephrine concentration between two positions, ⊿Vasopressin the differences in the plasma vasopressin concentration between two positions, H/M ratio of the average pixel count in the heart (H) to that in the mediastinum (M). Sex; male = 1, female = 0, Subtype; ART = 1, TDT or MT = 0, Preexistent hypertension and Constipation; presence = 1, absence = 0. Table 3 Multiple regression analysis of the correlation between ⊿Vasopressin and potential covariables. ⊿Vasopressin
Parameter estimate
Standard error
p value
Age Sex Symptom duration UPDRS motor score Subtype Preexistent hypertension Olfaction Constipation MMSE Systolic blood pressure at supine rest ⊿Systolic blood pressure Norepinephrine ⊿Norepinephrine Vasopressin at supine rest H/M ratio delayed Heart rate variability
0.2744 −0.0916 0.0924 0.0148 0.1487 −0.2152 0.0629 0.0203 0.3616 0.0962
0.1590 2.4427 0.6943 0.1310 2.4142 2.7026 0.4439 2.4815 0.7111 0.0608
0.1143 0.4989 0.5026 0.9283 0.2761 0.1711 0.6625 0.8815 0.0225 0.5379
0.4828 −0.0636 −0.0738 0.1780 0.1754 0.1564
0.0590 0.0130 0.0125 0.5227 4.1972 1.1368
0.0013 0.6883 0.6263 0.1933 0.2619 0.2553
R2 = 0.316. ⊿Vasopressin the differences in the plasma vasopressin concentration between two positions, UPDRS Unified Parkinson's Disease Rating Scale, MMSE MiniMental State Examination, ⊿Systolic blood pressure the maximum decreases in systolic blood pressure (mmHg) during tilt, ⊿Norepinephrine the differences in the plasma norepinephrine concentration between two positions, H/M ratio of the average pixel count in the heart (H) to that in the mediastinum (M). Sex; male = 1, female = 0, Subtype; ART = 1, TDT or MT = 0, Preexistent hypertension and Constipation; presence = 1, absence = 0.
On multiple regression analysis in which ⊿vasopressin was used as a dependent variable and age, sex, symptom duration, UPDRS motor score, subtype, presence of preexistent hypertension, olfaction, presence of constipation, MMSE, systolic blood pressure at supine rest, degree of orthostatic hypotension, NEsupine, ⊿NE, vasopressinsupine, H/ M ratio delayed and HRV were used as independent variables, 5
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vasopressin release during tilt on multiple regression analysis. In a pathological study of patients with PD, LB was identified in every hypothalamic nucleus [28]. Because vasopressin is secreted by paraventricular nuclei and supraoptic nuclei located in the lateral area of the hypothalamus [29], the presence of lesions in this region, lesions associated with central regulatory areas of vasopressin release, or both would explain the impaired vasopressin release after orthostatic stress. Conversely, patients with OH+low NEsupine had appropriate vasopressin release in response to orthostatic stress, suggesting these patients had peripheral sympathetic denervation and a relatively small accumulation of LB in central sympathetic pathway. The pronounced vasopressin release during tilt in these patients might be a compensatory mechanism for the inadequate sympathetic response mediated though NE, as circulating vasopressin can increase the blood pressure though water reabsorption and vasoconstriction [29]. A decreased H/M ratio means clinically reduced cardiac output and vasoconstriction after tilt, and is involved in the mechanism of baroreflex failure in patients with PD and OH [30]. Limitation of our study is HRV measurements were obtained from a 1-min electrocardiogram, which may be insufficient to characterize adequately variability [17]. Second is that we should have used more sensitive scale such as Montreal Cognitive Assessment and Clinical Dementia Rating as well as MMSE to indicate a sensitive spectrum of cognitive decline. In conclusion, vasopressin release after orthostatic stress was closely related to global cognition in PD patients with OH and altered supine NE levels. Specifically, PD patients with OH+high NEsupine were a subset of patients having impaired vasopressin release and early cognitive decline in contrast to PD patients with OH+low NEsupine who exhibit accentuated vasopressin release and preserved cognitive function. The propagational pattern of LB in patients with OH+high NEsupine may be different from the typical Braak's hypothesis.
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