Cardiac parasympathetic dysfunction concurrent with cardiac sympathetic denervation in Parkinson's disease

We aimed to characterize the relationship between cardiac sympathetic and parasympathetic dysfunction employing cardiac (123)I-meta-iodobenzylguanidine (MIBG) uptake and other autonomic function parameters in Parkinson's disease (PD). 79 PD patients were studied. We performed (123)I-MIBG myocardial scintigraphy to assess the extent of cardiac sympathetic denervation. Electrocardiogram readings at rest and postural change in blood pressure were also examined. Coefficient variation of RR intervals (CVR-R) was used as an index for cardiac parasympathetic activity. Cardiac (123)I-MIBG uptake did not vary significantly among the Hoehn-Yahr (H-Y) stages. There was a significant correlation between cardiac (123)I-MIBG uptake and CVR-R (early, r=0.457, p<0.001; late, r=0.442, p<0.001). While the correlation was present among the patients who had had the disease less than two years (early, r=0.558, p<0.001; late, r=0.530, p<0.001), the patients with the disease duration longer than two years did not have such a significant correlation. Age, disease duration, corrected QT interval, or postural blood pressure change did not correlate with cardiac (123)I-MIBG uptake. Orthostatic hypotension was observed in 13 out of 72 subjects, and reduced CVR-R was a major determinant for the development of orthostatic hypotension. We conclude that cardiac parasympathetic dysfunction occurs concurrent with sympathetic denervation as revealed by (123)I-MIBG myocardial scintigraphy in PD and contributes to the development of orthostatic hypotension.     

Cardiac sympathetic denervation and its association with cognitive deficits in Parkinson's disease

BackgroundThere is growing evidence to suggest that cognitive decline in patients with Parkinson's disease (PD) is associated with autonomic involvement, although the clinical and pathological correlations have not been firmly established.ObjectiveWe prospectively investigated the pattern of myocardial sympathetic denervation deficits in PD and its correlation with cognitive decline.MethodsTwenty-eight patients with PD who underwent myocardial ¹²³I-metaiodobenzylguanidine (MIBG) scintigraphy, clinical assessment of stage and severity of PD and detailed neuropsychological investigation were included in the study.ResultsThere were significant differences in the MIBG uptake between the PD patients with cognitive deficits and those who did not have cognitive deficits.ConclusionThese findings confirm that cognitive decline in patients with PD is associated with autonomic involvement and raises the possibility that the topographical spread of synuclein pathology involving the neocortical areas might be linked to the autonomic system in PD.     

Cardiac sympathetic denervation correlates with clinical and pathologic stages of Parkinson's disease

Attention has been drawn to cardiac sympathetic denervation in Parkinson's disease (PD) based on clinical studies using [123I] metaiodobenzylguanidine scintigraphy; however, the histologic correlates and time course of cardiac sympathetic denervation are poorly understood. To address these issues, we used tyrosine hydroxylase (TH) immunohistochemistry to detect cardiac sympathetic nerve fibers in the epicardium of 4 normal controls, 11 cases with incidental Lewy bodies (iLBs), and 14 cases of PD. Cardiac sympathetic innervation was significantly less in PD than in normal controls and cases with iLBs (P < 0.05). There was also a decrease in TH‐immunoreactive fibers in iLB cases compared to normal controls (P < 0.01). TH‐immunoreactive fibers correlated with the PD stage (r = ?0.75, P < 0.001), as well as with Hoehn & Yahr clinical stage (r = ?0.61, P < 0.001), and disease duration (r = ?0.63, P < 0.001). Immunohistochemistry for α‐synuclein showed neurites in epicardium in PD and iLB cases, but not in normal controls. The density of α‐synuclein neurites correlated with Braak PD stage (r = 0.38, P < 0.05), Hoehn & Yahr clinical stage (r = 0.44, P < 0.05), and disease duration (r = 0.42, P < 0.05). This study demonstrates that cardiac sympathetic degeneration and α‐synuclein pathology is present in presymptomatic phase of PD, and that both increase with disease duration and severity. © 2008 Movement Disorder Society.     

Orthostatic hypotension from sympathetic denervation in Parkinson's disease

BACKGROUND: Patients with PD often have signs or symptoms of autonomic failure, including orthostatic hypotension. Cardiac sympathetic denervation occurs frequently in PD, but this has been thought to occur independently of autonomic failure. METHODS: Forty-one patients with PD (18 with and 23 without orthostatic hypotension) and 16 age-matched healthy volunteers underwent PET scanning to visualize sympathetic innervation after injection of 6-[(18)F]fluorodopamine. Beat-to-beat blood pressure responses to the Valsalva maneuver were used to identify sympathetic neurocirculatory failure and plasma norepinephrine to indicate overall sympathetic innervation. RESULTS: All patients with PD and orthostatic hypotension had abnormal blood pressure responses to the Valsalva maneuver and septal and lateral ventricular myocardial concentrations of 6-[(18)F]fluorodopamine-derived radioactivity >2 SD below the normal mean. In contrast, only 6 of the 23 patients without orthostatic hypotension had abnormal Valsalva responses (p < 0.0001 compared with patients with orthostatic hypotension), and only 11 had diffusely decreased 6-[(18)F]fluorodopamine-derived radioactivity in the left ventricular myocardium (p = 0.0004). Of the 12 remaining patients without orthostatic hypotension, 7 had locally decreased myocardial radioactivity. Supine plasma norepinephrine was lower in patients with than in those without orthostatic hypotension (1.40 +/- 0.15 vs 2.32 +/- 0.26 nmol/L, p = 0.005). 6-[(18)F]fluorodopamine-derived radioactivity was less not only in the myocardium but also in the thyroid and renal cortex of patients with PD than in healthy control subjects. CONCLUSIONS: In PD, orthostatic hypotension reflects sympathetic neurocirculatory failure from generalized sympathetic denervation.     

Neurotransmitter specificity of sympathetic denervation in Parkinson's disease

In PD, orthostatic hypotension reflects sympathetic noradrenergic denervation. The authors assessed sympathetic cholinergic innervation by the quantitative sudomotor axon reflex test (QSART) in 12 patients who had sympathetic neurocirculatory failure, markedly decreased cardiac 6-[18F] fluorodopamine-derived radioactivity, and subnormal plasma norepinephrine increments during standing. All 12 had normal QSART results. The sympathetic nervous system lesion in PD involves loss of postganglionic catecholaminergic but not cholinergic nerves.     

Cardiac sympathetic denervation preceding motor signs in Parkinson disease

There is substantial interest in identifying biomarkers to detect early Parkinson disease (PD). Cardiac noradrenergic denervation and attenuated baroreflex-cardiovagal function occur in de novo PD, but whether these abnormalities can precede PD has been unknown. Here we report the case of a patient who had profoundly decreased left ventricular myocardial 6-[¹⁸F]fluorodopamine-derived radioactivity and low baroreflex-cardiovagal gain, 4 years before the onset of symptoms and signs of PD. The results lead us to hypothesize that cardiac noradrenergic denervation and decreased baroreflex-cardiovagal function may occur early in the pathogenesis of PD.     

Cardiac MIBG scintigraphy is a sensitive tool for detecting cardiac sympathetic denervation in Parkinson's disease.

[(123)I]Metaiodobenzylguanidine ([(123)I]MIBG) cardiac scintigraphy could be helpful to differentiate Parkinson's disease (PD) from multiple system atrophy (MSA), demonstrating that, in PD with autonomic failure but not in MSA, there is a myocardial postganglionic sympathetic dysfunction. To investigate whether this method is more sensitive than standard autonomic testing to detect early involvement of sympathetic cardiac efferent, we analyse MIBG myocardial uptake in 8 PD patients with normal autonomic testing (nondysautonomia PD group, NDPD) in comparison with 10 PD patients with abnormal autonomic testing (dysautonomia PD group, DPD) and 10 MSA patients. Global MIBG uptake was assessed using the ratio of [(123)I]MIBG uptake in the heart to the upper mediastinum (H/M) on planar scintigraphic data. Regional MIBG uptake was determined on two single photon emission tomography scans in regions of the left ventricle. The mean H/M ratios were significantly different among the three groups (P < 0.0001). H/M ratios of both NDPD and DPD patients groups (H/M = 1.83 +/- 0.50 and 1.24 +/- 0.40, respectively) were significantly lower than in MSA patients (H/M = 2.52 +/- 0.60). However, in NDPD patients, H/M was significantly higher than in DPD patients. When compared to MSA patients, NDPD patients showed a regional reduction in MIBG uptake in all left ventricle regions markedly in the apex and the inferior wall. Our results suggest that MIBG myocardial scintigraphy (analysis of both H/M ratio and regional MIBG uptake) may be more sensitive than standard autonomic testing for the early detection of silent autonomic dysfunction in PD.     

Dobutamine stress test unmasks cardiac sympathetic denervation in Parkinson's disease

OBJECTIVE: Cardiac uptake of [(123)I]metaiodobenzyl guanidine (MIBG) is reduced in patients with Parkinson's disease (PD). However, the cardiac sympathetic abnormality associated with this reduction is unclear. To unmask this abnormality in PD patients we examined the functional consequences of cardiac beta-receptor activation. METHODS: Cardiovascular responses to stepwise administration of the beta1-receptor agonist, dobutamine (DOB), were assessed in 25 PD patients and 12 age-matched controls. Changes in blood pressure were compared to determine the optimal dose at which to detect denervation supersensitivity, and cardiac contractility was measured by DOB echocardiography, based on peak aortic flow velocity. The relations of these cardiovascular responses to the ratio of MIBG uptake into the heart vs. that into the mediastinum (H/M ratio) were analyzed. RESULTS: At 4 microg/kg/min DOB, systolic blood pressure increased more in PD patients than in controls (PD, 17.5+/-12.3 mm Hg; control, 7.2+/-6.2 mm Hg, p<0.01), suggesting the presence of denervation supersensitivity. At this DOB dose cardiac contractility also increased more in PD than in controls (PD, 39.0+/-15.7%; control, 23.5+/-5.2%, p<0.005) and this hyperdynamic response was significantly correlated with reduced H/M ratios (early: r=-0.63, p<0.01, delayed: r=-0.66, p<0.01). CONCLUSION: Low-dose DOB unmasks cardiac sympathetic denervation in PD patients, and decreased MIBG uptake indicates the presence of denervation supersensitivity within the heart, resulting in hyperdynamic cardiac contractility in response to a beta 1-stress condition.     

Cardiac sympathetic denervation precedes neuronal loss in the sympathetic ganglia in Lewy body disease

Decreased cardiac uptake of meta-iodobenzylguanidine (MIBG) on [¹²³I]MIBG myocardial scintigraphy has been reported in Parkinsons disease (PD) and dementia with Lewy bodies (DLB). We hypothesized that cardiac sympathetic denervation might account for the pathomechanism. To elucidate the extent, frequency and pattern of cardiac sympathetic nerve involvement in Lewy body disease and related neurodegenerative disorders, we immunohistochemically examined heart tissues from patients with PD (n=11), DLB (n=7), DLB with Alzheimers disease (DLB/AD; n=4), multiple system atrophy (MSA; n=8), progressive supranuclear palsy (PSP; n=5), pure AD (n=10) and control subjects (n=5) together with sympathetic ganglia from patients with PD (n=5) and control subjects (n=4), using an antibody against tyrosine hydroxylase (TH). TH-immunoreactive nerve fibers in the hearts had almost entirely disappeared in nearly all the patients with PD, DLB and DLB/AD, whereas they were well preserved in all the patients with PSP and pure AD as well as in all except for one patient with MSA. In PD, neurons in the sympathetic ganglia were preserved in all except for one patient. Decreased cardiac uptake of MIBG in Lewy body disease reflects actual cardiac sympathetic denervation, which precedes the neuronal loss in the sympathetic ganglia.     

Cardiac sympathetic degeneration correlates with olfactory function in Parkinson's disease

Autonomic and olfactory dysfunctions are considered markers for preclinical diagnosis in Parkinson's disease (PD), because pathological changes in these systems can start before motor symptoms develop. We investigated whether cardiac sympathetic function and olfactory function are associated in PD. Participants comprised 40 nondemented patients with idiopathic PD, and age‐matched controls. Cardiac sympathetic function was evaluated by ¹²³ I‐metaiodobenzylguanidine (MIBG) uptake, in terms of the heart to mediastinum (H/M) ratio in both early and delayed images, and the washout rate (WR). Olfactory function was evaluated using the Odor Stick Identification Test for Japanese, which evaluates the detection of 12 odorants familiar to Japanese participants. Smell identification scores were significantly lower (P < 0.001) in patients with PD than in controls. Smell identification scores correlated positively with early (P < 0.05) and delayed H/M ratios (P < 0.01), and inversely with the WR (P < 0.005) especially in patients with early PD (below 5 years of the start of motor symptoms), whereas smell identification scores did not correlate with any parameters of MIBG in the advanced PD (above 5 years of the start of motor symptoms). There was no correlation between motor symptom scores and smell identification scores, H/M ratios, or WR. The results suggest that the cardiac sympathetic nervous system might degenerate in parallel with the olfactory system in patients with early PD, and that these two systems might degenerate at a different rate of speed in advanced PD. © 2010 Movement Disorder Society     

Cardiac denervation and dysautonomia in Parkinson's disease: a review of screening techniques

Parkinson's disease (PD) has classically been characterized by features of motor dysfunction, but these may manifest only after the nigrostriatal system has incurred significant damage. However, recent evidence suggests that cardiac sympathetic denervation occurs early on in PD. This may trigger a shift in physicians' attention to features of cardiovascular dysautonomia and allow for the evolution of earlier screening techniques. MIBG and PET (6F-DA) scans have demonstrated the functional loss of postganglionic sympathetic cardiac neurons, while immunohistochemical stains have revealed signs of morphological degeneration. Given this information, various screening techniques have been proposed, though most are particular to PD patients with orthostatic hypotension (OH). This is a considerable drawback given that the prevalence of OH in PD patients is estimated to be 41%. We present the argument that a shift in focus is needed; investigators should look for other manners by which to screen patients that are not reliant upon blood pressure. In our point of view, the problem with using blood pressure as a measurement is that it can be affected by many other factors unrelated to cardiac denervation. This may be why many patients with PD cannot be detected using these techniques. In order to make further progress on this front, we believe that investigators should start looking for variables that are more purely dependent upon cardiac denervation. We give one possible example of such a variable in this paper using heart transplant patients as a model.     

Cardiac sympathetic denervation in Ross syndrome demonstrated by MIBG-SPECT.

We investigated cardiac sympathetic innervation by metaiodobenzylguanidine (MIBG) imaging in a patient with tonic pupils, loss of tendon reflexes, and segmental anhidrosis (Ross syndrome). Despite normal cardiovascular reflex tests, we observed a reduced global myocardial MIBG uptake as well as a regional uptake defect over the posterolateral cardiac territory indicating left ventricular peripheral sympathetic denervation. MIBG imaging seems to be a useful noninvasive diagnostic method for detection of early--possibly subclinical--cardiac autonomic impairment in Ross syndrome and provides further evidence of injury to postganglionic autonomic neurons as the underlying pathological mechanism of the disease.     

Cardiac sympathetic index identifies patients with Parkinson's disease and REM behavior disorder

ObjectiveTo compare circadian autonomic fluctuations in patients with Parkinson's Disease (PD) with or without REM sleep behavior disorder (RBD) by using heart rate variability (HRV) analysis.MethodsThis is a case-control study including 20 PD patients with RBD (PD-RBD) and 20 PD patients without RBD (PD). In all patients, we measured the components of HRV in the frequency domain during 24-h with daytime and night time recordings. Selected variables considered were low-frequency (LF) influenced by the sympathetic system and high-frequency (HF) influenced by the parasympathetic system. Moreover, we calculated night-to-day ratio for both LF (cardiac sympathetic index) and HF (cardiac parasympathetic index) spectral components. Video-polysomnography was performed in all patients to diagnose RBD.ResultsBoth nocturnal LF and HF spectral power values were significantly higher in PD-RBD patients than in PD patients (P < 0.001 and P = 0.004 respectively). Moreover, in PD-RBD patients LF and HF values were higher at night than during the day while no difference between night time and daytime values was observed in patients with PD. Cardiac sympathetic index value was significantly higher in PD-RBD patients (median 1.83, range 1.65–3.66) than in PD patients (median 0.93, range 0.44–1.3) without overlap of individual values between groups (accuracy 100%). By contrast, cardiac parasympathetic index had sensitivity of 45% and specificity of 100% for differentiating between PD groups.ConclusionsCardiac sympathetic index distinguishes PD-RBD patients from those with PD on an individual basis, thus representing a valid help in everyday clinical practice for screening of RBD in PD patients.     

Cardiac denervation occurs independent of orthostatic hypotension and impaired heart rate variability in Parkinson's disease

Patients with idiopathic Parkinson's disease (PD) have impaired sympathetically mediated neurocirculatory innervation. Here we analyzed the correlation between cardiac (123)I-metaiodobenzylguanidine (MIBG) uptake, orthostatic hypotension and heart rate variability in treated patients with PD. Orthostatic hypotension (OH) as a hallmark of sympathetic neurocirculatory failure was found with a high prevalence in PD. PD is known to affect cardiac innervation, resulting in a suppressed heart rate variability and a postganglionic noradrenergic lesion. We measured continuous arterial blood pressure in rest and 70 degrees head-up tilt for at least 20 min, heart rate variability in the supine position, standing, deep respiration and Valsalva manoeuvre in 58 patients with PD (27 male, 31 female; mean age 71 years, mean PD duration 5.1 years, Hoehn and Yahr 3.1+/-0.8). Sympathovagal balance was estimated by the low-frequency (LF: 0.04-0.15Hz) and high-frequency bands (HF: 0.15-0.4Hz) ratio in the analysis of heart rate variability in each condition. Myocardial adrenergic function was analyzed by imaging MIBG using the single-photon emission computed tomography technique. MIBG uptake expressed as heart-to-mediastinum ratio was reduced in all PD patients (H/M-ratio: 1.14+/-0.16). We found no correlation between myocardial MIBG uptake and sympathovagal balance, blood pressure or other autonomic findings. The LF/HF ratio in tilt-table testing was significantly more reduced in PD with OH than without OH (2.18 vs. 1.49, p=0.022). MIBG uptake did not differ. It is concluded that scintigraphy with MIBG appears to be a highly sensitive and useful tool to demonstrate sympathetic postganglionic cardiac nerve disturbances. Loss of sympathetic innervation of the heart seems to occur early and independent of orthostatic hypotension, baroreflex failure and impaired heart rate variability in PD.     

Heterogeneity of cholinergic denervation in Parkinson's disease without dementia

Parkinson's disease (PD) is a multisystem neurodegenerative disorder. Heterogeneous clinical features may reflect heterogeneous changes in different brain regions. In contrast to the pronounced nigrostriatal denervation characteristic of PD, cholinergic changes are less marked. We investigated cholinergic innervation activity in PD subjects relative to normal subjects. Nondemented PD subjects (n=101, age 65.3±7.2 years) and normal subjects (n=29, age 66.8±10.9 years) underwent clinical assessment and [(11)C]methyl-4-piperidinyl propionate acetylcholinesterase and [(11)C]dihydrotetrabenazine monoaminergic positron emission tomography (PET) imaging. Cholinergic projection changes were heterogeneous for 65 out of 101 PD subjects who had neocortical and thalamic acetylcholinesterase activity within the normal range. The remainder had combined neocortical and thalamic (13/101), isolated neocortical (18/101), or isolated thalamic (5/101) acetylcholinesterase activity below the normal range. The low neocortical acetylcholinesterase activity subgroup had significantly lower global cognitive performance compared with the normal range subgroup (F=7.64, P=0.0069) with an independent effect for nigrostriatal denervation (F=7.60, P=0.0074). The low thalamic acetylcholinesterase activity subgroup did not differ from the normal thalamic acetylcholinesterase activity subgroup in cognitive performance or motor impairments except for a history of falls (P=0.0023). Cholinergic denervation is heterogeneous with reduced neocortical and/or thalamic acetylcholinesterase activity in 36% of nondemented PD subjects with corresponding clinical phenotypic variation. Results also show independent cognitive effects for both cholinergic and dopaminergic system changes in nondemented PD subjects.     

Evaluation of sympathetic skin response in Parkinson's disease

There is no clear definition on the role of sympathetic skin response (SSR) in the evaluation of patients with Parkinson's disease (PD). We recorded the SSR of the palms of 64 controls and 46 patients with PD to electrical stimulation of the median nerve at the wrist. We analyzed onset latency and peak-to-peak amplitude. A study of parasympathetic function (R–R interval analysis) was also undertaken. We found that patients with PD had more absent SSRs than controls. The mean amplitude of the SSR was significantly reduced in both lower and upper limbs of PD patients in comparison with control subjects (p<0.001). The onset latency was longer in the lower limbs of these patients in respect to the control group (p<0.003). There was a significant inverse correlation between SSR amplitudes and age, severity and late onset of the disease. There was no association of these parameters with dysautonomic symptoms or R–R interval variation. In conclusion, there is a significant association between altered SSR and PD and an inverse correlation in this group of patients between SSR values and older age, greater severity and later onset of disease. Therefore, the study of SSR may provide valuable information on cholinergic sympathetic function in patients with PD.     

交感神经皮肤反应在帕金森病中的应用

目的探讨交感神经皮肤反应(SSR)在帕金森病(PD)患者自主神经损害中的评价作用。方法选用36例PD患者和30例健康对照者作为研究对象,行SSR检测,并对患者进行SCOPA-AUT评分及H-Y分级,评价SSR与PD自主神经损害的相关性。结果 PD患者SSR总异常率61.1%;H-Y评分0~1.5分者,SSR异常率为35.7%,H-Y评分2.0分者,SSR异常率77.3%;伴随自主神经症状的PD患者中(PD-AS),SSR异常率85.7%;不伴随自主神经症状者(PD-NAS),SSR异常率26.7%。结论 SSR可客观评价PD患者自主神经功能障碍,并检测PD自主神经的亚临床损害,且随患者运动症状加重,SSR异常越明显。     

Cardiac involvement in malignant syndrome in Parkinson's disease

Little is known about cardiac abnormalities in neuroleptic malignant syndrome (NMS) in Parkinson's disease (PD), although high levels of serum creatine kinase (CK) suggest the presence of cardiac involvement. We have also been aware of elevated serum myosin light chain I (MLCI) in these patients with no clear evidence of an acute coronary syndrome. To evaluate cardiac involvement in NMS in PD, we recorded the electrocardiogram (ECG) and measured serum MLCI and CK-MB levels. Plasma levels of noradrenaline and adrenaline were also determined. The patients were classified based on the in-hospital outcome into 55 survivors and 5 nonsurvivors. Age- and gender-matched PD patients without NMS served as controls (n = 51). All patients had high serum concentrations of CK-MB and MLCI. The mean values of CK, CK-MB, MLCI, adrenaline and noradrenaline were higher in both patient groups as compared to control subjects, and the values in nonsurvivors were significantly higher than those in survivors. A positive correlation was observed between serum MLCI and CK levels (p < 0.01), and between serum MLCI levels and plasma noradrenaline concentrations (p < 0.01). ECG abnormalities such as prolonged QTc interval, abnormal Q wave, ST elevation and T wave inversion were observed in all nonsurvivors and 32 (58.2%) survivors. We conclude that myocardial involvement is common in patients with NMS even when they have no symptoms suggestive of myocardial injury, and MLCI and CK-MB as well as ECG are useful indicators of mortality.