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Reduced hypoxic sympathetic response in mild Parkinson's disease: Further evidence of early autonomic dysfunction
Parkinsonism and Related Disorders 19 (2013) 1066–1068
Contents lists available at ScienceDirect
Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
Letter to the Editor
Reduced hypoxic sympathetic response in mild Parkinson’s disease: Further evidence of early autonomic dysfunction Keywords: Parkinson’s disease Ventilatory control Dopaminergic therapy Autonomic dysfunction
The Braak staging hypothesis in Parkinson’s disease (PD) suggests that non-motor dysfunction may precede the classical motor symptoms, and this is supported by observations of postural hypotension, cardiac denervation, bowel dysmotility and hyposmia early in disease [1]. However, the effects of this process on the respiratory system, whose central control system resides mainly in the medulla, have been largely ignored. The dorsal motor nucleus of the vagus in the medulla is one of the earliest regions to accumulate alpha synuclein pathology. The dorsal medullary respiratory centre including the nucleus of the tractus solitarius receives afferent input from carotid and aortic chemoreceptors, which respond to a reduction in arterial oxygen tension and to an increase in arterial carbon dioxide. A reduced ventilatory response to hypoxia [2] and hypercapnia [3] has been reported in those with moderate PD, which was not related to peripheral muscle weakness or impairment in lung function. Dopaminergic therapy is standard in PD and its action on the dopamine receptors within the carotid body is not totally understood, but may affect both ventilatory and sympathetic control [4]. There is strong evidence that low-dose dopamine infusions reduce the ventilatory response to hypoxia in healthy normals and in those with heart failure [5,6]. This raises the question as to whether PD or the dopaminergic treatment was responsible for the previously observed reduced ventilatory drive in moderately advanced PD. We hypothesise that abnormalities in central respiratory control may be identifiable in mild PD due to the early pathological involvement of the medulla. We sought to assess the ventilatory and sympathetic response to hypoxia and hypercapnia before and after dopaminergic medication in patients with mild PD and compare to healthy normals. Patients with mild idiopathic PD were recruited from a hospitalbased PD outpatient clinic. Patients were excluded if they had any clinically significant respiratory or cardiovascular disease or a significant smoking history (>10 pack years). A history, including current medications and disease severity classifications off medications were documented. Ventilatory and sympathetic responses to progressive poikilocapnic hypoxia and isoxic hypercapnia were assessed via rebreathing methods (Vmax Encore, Sensormedics, Yorba Linda, 1353-8020/$ – see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.parkreldis.2013.07.006
CA). Five-lead electrocardiography and finger probe pulse oximetry determined pulse transit time (PTT) and heart rate (HR) (Alice PDX, Respironics, Murrysville, PA). To express minute ventilation (VE) and PTT changes as a linear function of the hypoxic stimulus, oxygen saturation (SCO2) was calculated from the pressure of end-tidal oxygen. VE, PTT and HR were plotted against SCO2 and linear response curves were generated. VE and occlusion pressure (P100) were sequentially measured and plotted against the pressure of end-tidal carbon dioxide, with linear response curves generated. Patients were tested before and more than 1 h after their first morning standard dopaminergic therapy (>12 h withdrawal). Healthy normal subjects were recruited from associates from Concord Hospital and performed rebreathing tests at least 1 h apart. The study was reviewed and approved by the Ethics Review Board of the Sydney Local Health District (New South Wales, Australia). Each subject gave written informed consent. Twelve (two female) subjects with PD were studied (mean SD 63 5 years). Disease severity classifications averaged the group as very mild; H&Y 1.5 0.7, UPDRS Part III 9.3 4.6, Schwab and England 90% 10, time since diagnosis was 5.7 3.0 years. All subjects were currently taking levodopa, mean dose 430 176 mg (range 150–750 mg). Supplementary PD medications included dopamine agonists (n ¼ 7), anti-cholinergics (n ¼ 1) and MAO-B inhibitors (n ¼ 2). Twenty-four (eight female) healthy normal subjects were studied (42 15 years). Height, weight and lung function measurements for the PD subjects were not different to the normal group. Resting ventilatory parameters were not different between or within groups prior to the rebreathing tests (p > 0.15). The mean and individual regression slopes for VE, HR and PTT during progressive hypoxia are presented in Fig. 1. A graphical representation of the mean group response is presented in Fig. 2. Ventilatory responses were not different, but there was a significantly reduced HR (p < 0.01) and PTT (p < 0.001) response, both markers of sympathetic activity, in the PD group as compared to the normals. There was no difference in these parameters before and after dopaminergic therapy in the PD group. No age effect was identified using a selection of the normal group that matched the PD group in age (n ¼ 9). The trends remained for both for HR and PTT (p < 0.003). A strong correlation of the VE and HR response was seen in the normal group (R2 ¼ 0.56, p < 0.0001), but not the PD group, either before (R2 ¼ 0.01, p ¼ 0.55) or after dopaminergic therapy (R2 ¼ 0.07, p ¼ 0.4). There were no significant differences for VE or P100 response to hypercapnia in the PD group as compared to the normal group
Letter to the Editor / Parkinsonism and Related Disorders 19 (2013) 1066–1068
1067
25
0.2
20
VE (L.min)
VE L.min.%SCO2
0 -0.2 -0.4 -0.6 -0.8
15
Normal 10 5
-1 -1.2
PD Pre PD Post
0
0 140
-0.4
*
-0.6 -0.8 -1 -1.2
120
HR (bpm)
HR bpm.%SCO2
-0.2
100
* *
80 60 40
-1.4 -1.6
20
-1.8
0
-2
300
2.5
250
1.5 1
*
0.5
PTT (msec)
PTT msec.%SCO2
2
200
* *
150 100 50 0
75
0
Healthy Normal
Mild Parkinson's disease
V , minute ventilation; HR, heart rate; PTT, pulse transit time. Horizontal bars indicate mean values. * Vs Healthy normal (unpaired t-test, p<0.01) N=12 PTT healthy normal.
Fig. 1. Mean and individual regression slopes for minute ventilation (VE), heart rate (HR) and pulse transit time (PTT) during progressive hypoxia in 12 subjects with mild Parkinson’s disease and 24 healthy normals.
(p ¼ 0.92) and no difference before or after dopaminergic therapy (p ¼ 0.44). Our finding of a significantly reduced sympathetic response to hypoxia in mild PD has not been previously reported. This is likely to be a consequence of the post-ganglionic sympathetic cardiac denervation observed in mild PD, and utilised in MIBG scintigraphy for the diagnosis of Lewy body-related disorders [7]. In healthy normals, the cardiovascular and ventilatory responses during progressive hypoxia are strongly linked. Our finding of discordance between HR and VE responses during progressive hypoxia in mild PD is consistent with early autonomic cardiac changes prior to any impairment in central ventilatory control. Reduced ventilatory chemosensitivity to hypoxia and hypercapnia has been previously demonstrated in more severe PD [2,3]. These studies did not discount an effect from dopaminergic therapy. In our previous study, patients were tested on dopaminergic medication due to ethical and technical reservations about testing those with moderate PD off dopamine [3]. Ventilatory parameters and sympathetic markers before and after dopaminergic therapy in this study were unchanged and therefore do not have an effect on chemosenstivity at the doses used in mild disease. In conclusion, sympathetic response to progressive hypoxia was reduced in subjects with mild PD and these markers appear to be more sensitive than ventilation response in detecting autonomic
SCO2 (%)
100
V , minute ventilation; HR, heart rate; PTT, pulse transit time; S O , calculated oxygen saturation. * Vs Healthy normal (unpaired t-test, p<0.01). N=12 PTT healthy normal.
Fig. 2. Mean group response for minute ventilation (VE), heart rate (HR) and pulse transit time (PTT) during progressive hypoxia in 12 subjects with mild Parkinson’s disease and 24 healthy normals.
cardio-respiratory dysfunction in mild PD. Dopaminergic therapy used in mild PD does not affect ventilatory responses to hypoxia or hypercapnia, and is unlikely to be the explanation for the reduced ventilatory drive seen in more severe PD.
References [1] Braak H, Braak E. Pathoanatomy of Parkinson’s disease. J Neurol 2000;247(Suppl. 2):II3–10. [2] Onodera H, Okabe S, Kikuchi Y, Tsuda T, Itoyama Y. Impaired chemosensitivity and perception of dyspnoea in Parkinson’s disease. Lancet 2000;356:739–40. [3] Seccombe LM, Giddings HL, Rogers PG, Corbett AJ, Hayes MW, Peters MJ, et al. Abnormal ventilatory control in Parkinson’s disease-further evidence for nonmotor dysfunction. Respir Physiolo Neurobiol 2011;179:300–4. [4] Ciarka A, Vincent JL, van de Borne P. The effects of dopamine on the respiratory system: friend or foe? Pulm Pharmacol Ther 2007;20:607–15. [5] Ward DS, Bellville JW. Reduction of hypoxic ventilatory drive by dopamine. Anesth Analg 1982;61:333–7. [6] van de Borne P, Oren R, Somers VK. Dopamine depresses minute ventilation in patients with heart failure. Circulation 1998;98:126–31. [7] Orimo S, Suzuki M, Inaba A, Mizusawa H. 123I-MIBG myocardial scintigraphy for differentiating Parkinson’s disease from other neurodegenerative parkinsonism: a systematic review and meta-analysis. Parkinsonism Relat Disord 2012;18:494–500.
Leigh M. Seccombe* Australian School of Advanced Medicine, Macquarie University, Sydney, Australia Department of Thoracic Medicine, Concord Hospital, Sydney, Australia
1068
Letter to the Editor / Parkinsonism and Related Disorders 19 (2013) 1066–1068
Peter G. Rogers Department of Thoracic Medicine, Concord Hospital, Sydney, Australia Michael W. Hayes Department of Neurology, Concord Hospital, Sydney, Australia Claude S. Farah Australian School of Advanced Medicine, Macquarie University, Sydney, Australia
Matthew J. Peters Australian School of Advanced Medicine, Macquarie University, Sydney, Australia Department of Thoracic Medicine, Concord Hospital, Sydney, Australia Sydney Medical School, Sydney University, Sydney, Australia
Sydney Medical School, Sydney University, Sydney, Australia
* Corresponding author. Department of Thoracic Medicine, Concord Hospital, Hospital Rd, Concord, Sydney 2139, Australia. E-mail address: [email protected] (L.M. Seccombe)
Elizabeth M. Veitch Department of Thoracic Medicine, Concord Hospital, Sydney, Australia
23 April 2013
Department of Thoracic Medicine, Concord Hospital, Sydney, Australia
Contents lists available at ScienceDirect
Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
Letter to the Editor
Reduced hypoxic sympathetic response in mild Parkinson’s disease: Further evidence of early autonomic dysfunction Keywords: Parkinson’s disease Ventilatory control Dopaminergic therapy Autonomic dysfunction
The Braak staging hypothesis in Parkinson’s disease (PD) suggests that non-motor dysfunction may precede the classical motor symptoms, and this is supported by observations of postural hypotension, cardiac denervation, bowel dysmotility and hyposmia early in disease [1]. However, the effects of this process on the respiratory system, whose central control system resides mainly in the medulla, have been largely ignored. The dorsal motor nucleus of the vagus in the medulla is one of the earliest regions to accumulate alpha synuclein pathology. The dorsal medullary respiratory centre including the nucleus of the tractus solitarius receives afferent input from carotid and aortic chemoreceptors, which respond to a reduction in arterial oxygen tension and to an increase in arterial carbon dioxide. A reduced ventilatory response to hypoxia [2] and hypercapnia [3] has been reported in those with moderate PD, which was not related to peripheral muscle weakness or impairment in lung function. Dopaminergic therapy is standard in PD and its action on the dopamine receptors within the carotid body is not totally understood, but may affect both ventilatory and sympathetic control [4]. There is strong evidence that low-dose dopamine infusions reduce the ventilatory response to hypoxia in healthy normals and in those with heart failure [5,6]. This raises the question as to whether PD or the dopaminergic treatment was responsible for the previously observed reduced ventilatory drive in moderately advanced PD. We hypothesise that abnormalities in central respiratory control may be identifiable in mild PD due to the early pathological involvement of the medulla. We sought to assess the ventilatory and sympathetic response to hypoxia and hypercapnia before and after dopaminergic medication in patients with mild PD and compare to healthy normals. Patients with mild idiopathic PD were recruited from a hospitalbased PD outpatient clinic. Patients were excluded if they had any clinically significant respiratory or cardiovascular disease or a significant smoking history (>10 pack years). A history, including current medications and disease severity classifications off medications were documented. Ventilatory and sympathetic responses to progressive poikilocapnic hypoxia and isoxic hypercapnia were assessed via rebreathing methods (Vmax Encore, Sensormedics, Yorba Linda, 1353-8020/$ – see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.parkreldis.2013.07.006
CA). Five-lead electrocardiography and finger probe pulse oximetry determined pulse transit time (PTT) and heart rate (HR) (Alice PDX, Respironics, Murrysville, PA). To express minute ventilation (VE) and PTT changes as a linear function of the hypoxic stimulus, oxygen saturation (SCO2) was calculated from the pressure of end-tidal oxygen. VE, PTT and HR were plotted against SCO2 and linear response curves were generated. VE and occlusion pressure (P100) were sequentially measured and plotted against the pressure of end-tidal carbon dioxide, with linear response curves generated. Patients were tested before and more than 1 h after their first morning standard dopaminergic therapy (>12 h withdrawal). Healthy normal subjects were recruited from associates from Concord Hospital and performed rebreathing tests at least 1 h apart. The study was reviewed and approved by the Ethics Review Board of the Sydney Local Health District (New South Wales, Australia). Each subject gave written informed consent. Twelve (two female) subjects with PD were studied (mean SD 63 5 years). Disease severity classifications averaged the group as very mild; H&Y 1.5 0.7, UPDRS Part III 9.3 4.6, Schwab and England 90% 10, time since diagnosis was 5.7 3.0 years. All subjects were currently taking levodopa, mean dose 430 176 mg (range 150–750 mg). Supplementary PD medications included dopamine agonists (n ¼ 7), anti-cholinergics (n ¼ 1) and MAO-B inhibitors (n ¼ 2). Twenty-four (eight female) healthy normal subjects were studied (42 15 years). Height, weight and lung function measurements for the PD subjects were not different to the normal group. Resting ventilatory parameters were not different between or within groups prior to the rebreathing tests (p > 0.15). The mean and individual regression slopes for VE, HR and PTT during progressive hypoxia are presented in Fig. 1. A graphical representation of the mean group response is presented in Fig. 2. Ventilatory responses were not different, but there was a significantly reduced HR (p < 0.01) and PTT (p < 0.001) response, both markers of sympathetic activity, in the PD group as compared to the normals. There was no difference in these parameters before and after dopaminergic therapy in the PD group. No age effect was identified using a selection of the normal group that matched the PD group in age (n ¼ 9). The trends remained for both for HR and PTT (p < 0.003). A strong correlation of the VE and HR response was seen in the normal group (R2 ¼ 0.56, p < 0.0001), but not the PD group, either before (R2 ¼ 0.01, p ¼ 0.55) or after dopaminergic therapy (R2 ¼ 0.07, p ¼ 0.4). There were no significant differences for VE or P100 response to hypercapnia in the PD group as compared to the normal group
Letter to the Editor / Parkinsonism and Related Disorders 19 (2013) 1066–1068
1067
25
0.2
20
VE (L.min)
VE L.min.%SCO2
0 -0.2 -0.4 -0.6 -0.8
15
Normal 10 5
-1 -1.2
PD Pre PD Post
0
0 140
-0.4
*
-0.6 -0.8 -1 -1.2
120
HR (bpm)
HR bpm.%SCO2
-0.2
100
* *
80 60 40
-1.4 -1.6
20
-1.8
0
-2
300
2.5
250
1.5 1
*
0.5
PTT (msec)
PTT msec.%SCO2
2
200
* *
150 100 50 0
75
0
Healthy Normal
Mild Parkinson's disease
V , minute ventilation; HR, heart rate; PTT, pulse transit time. Horizontal bars indicate mean values. * Vs Healthy normal (unpaired t-test, p<0.01) N=12 PTT healthy normal.
Fig. 1. Mean and individual regression slopes for minute ventilation (VE), heart rate (HR) and pulse transit time (PTT) during progressive hypoxia in 12 subjects with mild Parkinson’s disease and 24 healthy normals.
(p ¼ 0.92) and no difference before or after dopaminergic therapy (p ¼ 0.44). Our finding of a significantly reduced sympathetic response to hypoxia in mild PD has not been previously reported. This is likely to be a consequence of the post-ganglionic sympathetic cardiac denervation observed in mild PD, and utilised in MIBG scintigraphy for the diagnosis of Lewy body-related disorders [7]. In healthy normals, the cardiovascular and ventilatory responses during progressive hypoxia are strongly linked. Our finding of discordance between HR and VE responses during progressive hypoxia in mild PD is consistent with early autonomic cardiac changes prior to any impairment in central ventilatory control. Reduced ventilatory chemosensitivity to hypoxia and hypercapnia has been previously demonstrated in more severe PD [2,3]. These studies did not discount an effect from dopaminergic therapy. In our previous study, patients were tested on dopaminergic medication due to ethical and technical reservations about testing those with moderate PD off dopamine [3]. Ventilatory parameters and sympathetic markers before and after dopaminergic therapy in this study were unchanged and therefore do not have an effect on chemosenstivity at the doses used in mild disease. In conclusion, sympathetic response to progressive hypoxia was reduced in subjects with mild PD and these markers appear to be more sensitive than ventilation response in detecting autonomic
SCO2 (%)
100
V , minute ventilation; HR, heart rate; PTT, pulse transit time; S O , calculated oxygen saturation. * Vs Healthy normal (unpaired t-test, p<0.01). N=12 PTT healthy normal.
Fig. 2. Mean group response for minute ventilation (VE), heart rate (HR) and pulse transit time (PTT) during progressive hypoxia in 12 subjects with mild Parkinson’s disease and 24 healthy normals.
cardio-respiratory dysfunction in mild PD. Dopaminergic therapy used in mild PD does not affect ventilatory responses to hypoxia or hypercapnia, and is unlikely to be the explanation for the reduced ventilatory drive seen in more severe PD.
References [1] Braak H, Braak E. Pathoanatomy of Parkinson’s disease. J Neurol 2000;247(Suppl. 2):II3–10. [2] Onodera H, Okabe S, Kikuchi Y, Tsuda T, Itoyama Y. Impaired chemosensitivity and perception of dyspnoea in Parkinson’s disease. Lancet 2000;356:739–40. [3] Seccombe LM, Giddings HL, Rogers PG, Corbett AJ, Hayes MW, Peters MJ, et al. Abnormal ventilatory control in Parkinson’s disease-further evidence for nonmotor dysfunction. Respir Physiolo Neurobiol 2011;179:300–4. [4] Ciarka A, Vincent JL, van de Borne P. The effects of dopamine on the respiratory system: friend or foe? Pulm Pharmacol Ther 2007;20:607–15. [5] Ward DS, Bellville JW. Reduction of hypoxic ventilatory drive by dopamine. Anesth Analg 1982;61:333–7. [6] van de Borne P, Oren R, Somers VK. Dopamine depresses minute ventilation in patients with heart failure. Circulation 1998;98:126–31. [7] Orimo S, Suzuki M, Inaba A, Mizusawa H. 123I-MIBG myocardial scintigraphy for differentiating Parkinson’s disease from other neurodegenerative parkinsonism: a systematic review and meta-analysis. Parkinsonism Relat Disord 2012;18:494–500.
Leigh M. Seccombe* Australian School of Advanced Medicine, Macquarie University, Sydney, Australia Department of Thoracic Medicine, Concord Hospital, Sydney, Australia
1068
Letter to the Editor / Parkinsonism and Related Disorders 19 (2013) 1066–1068
Peter G. Rogers Department of Thoracic Medicine, Concord Hospital, Sydney, Australia Michael W. Hayes Department of Neurology, Concord Hospital, Sydney, Australia Claude S. Farah Australian School of Advanced Medicine, Macquarie University, Sydney, Australia
Matthew J. Peters Australian School of Advanced Medicine, Macquarie University, Sydney, Australia Department of Thoracic Medicine, Concord Hospital, Sydney, Australia Sydney Medical School, Sydney University, Sydney, Australia
Sydney Medical School, Sydney University, Sydney, Australia
* Corresponding author. Department of Thoracic Medicine, Concord Hospital, Hospital Rd, Concord, Sydney 2139, Australia. E-mail address: [email protected] (L.M. Seccombe)
Elizabeth M. Veitch Department of Thoracic Medicine, Concord Hospital, Sydney, Australia
23 April 2013
Department of Thoracic Medicine, Concord Hospital, Sydney, Australia