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.     

Pandysautonomia associated with impaired ganglionic neurotransmission and circulating antibody to the neuronal nicotinic receptor

We report the case of a patient with chronic autonomic failure who had evidence of decreased postganglionic traffic to intact sympathetic nerve terminals. The patient complained mainly of decreased salivation, constipation, dry skin, and orthostatic intolerance. There was no evidence of central neurodegeneration. Autonomic function testing showed orthostatic hypotension without tachycardia and abnormal blood pressure and pulse rate responses to the Valsalva maneuver, indicating combined sympathetic and parasympathetic neurocirculatory failure. In contrast to patients with pure autonomic failure, the patient had normal left ventricular myocardial concentrations of 6-[¹⁸F]fluorodopamine-derived radioactivity, establishing intact postganglionic sympathetic innervation; and in contrast to patients with multiple system atrophy or baroreflex failure, the patient had a low plasma norepinephrine concentration and brisk norepinephrine response to orthostasis. These findings indicated an impediment to ganglionic neurotransmission. Serologic testing demonstrated a circulating antibody to the ganglionic nicotinic acetylcholine receptor. The findings in this case support the concept that circulating antibodies to this receptor can interfere with ganglionic neurotransmission and produce autoimmune autonomic neuropathy. Received: 28 January 2001, Accepted: 21 March 2002     

Sympathetic innervation and function in reflex sympathetic dystrophy

Patients with reflex sympathetic dystrophy have posttraumatic pain disproportionate to the injury and spreading beyond the distribution of any single peripheral nerve. We examined sympathetic neurocirculatory function and the role of sympathetic postganglionic nerve traffic in maintaining the pain in 30 patients with reflex sympathetic dystrophy. Most had had the condition for more than 1 year, and 14 had undergone sympathectomy for the pain. Positron emission tomographic scanning after administration of 13N-ammonia was used to assess local perfusion, and 6-[18F]fluorodopamine was used to assess sympathetic innervation. Rates of entry of norepinephrine in the regional venous drainage (spillovers) and regional plasma levels of L-dihydroxyphenylalanine (the immediate product of the rate-limiting enzymatic step in norepinephrine biosynthesis) and dihydroxyphenylglycol (the main neuronal metabolite of norepinephrine) were measured with and without intravenous trimethaphan for ganglion blockade. 13N-Ammonia-derived radioactivity was less on the affected side than on the unaffected side, whereas 6-[18F]fluorodopamine-derived radioactivity was symmetrical. Thus, perfusion-adjusted 6-[18F]fluorodopamine-derived radioactivity was higher on the affected side. Norepinephrine spillover and arteriovenous increments in plasma levels of L-dihydroxyphenylalanine and dihydroxyphenylglycol did not differ significantly between affected and unaffected limbs, although 4 patients had noticeably less norepinephrine spillover and smaller arteriovenous increments in plasma dihydroxyphenylglycol on the affected side. Trimethaphan decreased the pain in only 2 of 12 nonsympathectomized patients. The results indicate that patients with chronic unilateral reflex sympathetic dystrophy have decreased perfusion of the affected limb, symmetrical sympathetic innervation and norepinephrine synthesis, variably decreased release and turnover of norepinephrine in the affected limb, and failure of ganglion blockade to improve the pain in most cases. These findings suggest augmented vasoconstriction, intact sympathetic terminal innervation, possibly impaired sympathetic neurotransmission, and pain usually independent of sympathetic neurocirculatory outflows.     

Progressive loss of cardiac sympathetic innervation in Parkinson's disease

This study addressed whether cardiac sympathetic denervation progresses over time in Parkinson's disease. In 9 patients without orthostatic hypotension, 6-[(18)F]fluorodopamine positron emission tomography scanning was repeated after a mean of 2 years from the first scan. 6-[(18)F]fluorodopamine-derived radioactivity was less in the second scan than in the first scan, by 31% in the left ventricular free wall and 16% in the septum. In Parkinson's disease, loss of cardiac sympathetic denervation progresses in a pattern of loss suggesting a dying-back mechanism.     

Cardiac sympathetic hypo-innervation in familial dysautonomia

OBJECTIVE: Familial dysautonomia (FD) involves incomplete development of the sympathetic nervous system. Whether such loss extends to sympathetic innervation of the heart has been unknown. This study used 6-[(18)F]fluorodopamine neuroimaging to assess cardiac sympathetic innervation and function in FD. METHODS: Six adult FD patients underwent thoracic PET scanning for 30 minutes after i.v. 6-[(18)F]fluorodopamine injection, as did healthy volunteers without (N = 21) or with (N = 10) pre-treatment by desipramine, which interferes with neuronal uptake and thereby simulates effects of noradrenergic denervation. Effective rate constants for uptake and loss were calculated using a single compartment pharmacokinetic model. RESULTS: FD patients had decreased uptake and accelerated loss of 6-[(18)F]fluorodopamine-derived radioactivity in the interventricular myocardial septum (P = 0.009, P = 0.05) and ventricular free wall (P = 0.007, P < 0.001), compared to untreated controls. Desipramine-treated subjects had decreased uptake but normal loss of 6-[(18)F]fluorodopamine-derived radioactivity. CONCLUSIONS: FD involves cardiac noradrenergic hypo-innervation. Since accelerated loss of 6-[(18)F]fluorodopamine-derived radioactivity cannot be explained by decreased neuronal uptake alone, FD may also involve augmented NE loss from extant terminals.     

Neuropharmacologic distinction of neurogenic orthostatic hypotension syndromes

BACKGROUND: Neurogenic orthostatic hypotension (OH) characterizes pure autonomic failure (PAF), multiple system atrophy (MSA), and Parkinson disease (PD) with autonomic failure. We used neuropharmacologic probes that might distinguish these diseases based on loss of sympathetic noradrenergic nerves in PAF and PD + OH but not in MSA, and related the results to neurochemical and neuroimaging findings in the same patients. METHODS: Patients with neurogenic OH (PD + OH; N = 35), MSA (N = 41), and PAF (N = 12) received iv trimethaphan (TRI), which inhibits sympathetic nerve traffic, or yohimbine (YOH), which stimulates sympathetic traffic. Dependent measures included blood pressure, plasma norepinephrine (NE) levels, and interventricular septal myocardial radioactivity after iv injection of the sympathoneural imaging agent, 6-[F]fluorodopamine. RESULTS: The PD + OH and PAF groups had smaller pressor responses to YOH (12 +/- 8 and 13 +/- 1 mm Hg) and depressor responses to TRI (-14 +/- 8 and -17 +/- 7 mm Hg) than did the MSA group (43 +/- 8 mm Hg, -57 +/- 8 mm Hg; P = 0.01, P = 0.03). The PD + OH and MSA groups did not differ in NE responses to YOH and TRI. The depressor response to TRI, the pressor response to YOH, and the blood pressure difference between YOH and TRI all correlated positively with myocardial 6-[F]fluorodopamine-derived radioactivity. CONCLUSIONS: The PD + OH resembles PAF and differs from MSA in hemodynamic responses to drugs that alter NE release from sympathetic nerves. The results fit with sympathetic noradrenergic denervation in PD + OH and PAF but not in MSA.     

Autonomic dysfunction in PD: a window to early detection?

It has been suggested that autonomic dysfunction constitutes a biomarker for early detection of the disease process in Parkinson disease (PD). Recent findings based on cardiac sympathetic and striatal dopaminergic imaging in the same patients indicate that this view is overly simple. Although evidence of cardiac sympathetic denervation is associated with other non-motor manifestations such as anosmia, REM behavior disorder, dementia, baroreflex failure, and orthostatic hypotension (OH), across individual patients the severities of OH and of the cardiac sympathetic lesion (indicated by thoracic 6-[(18)F]fluorodopamine PET scanning) are unrelated to the severity of the putamen dopaminergic lesion (indicated by brain 6-[(18)F]fluorodopa PET scanning). Moreover, whereas cases have been reported with neuroimaging evidence of cardiac sympathetic denervation several years before motor onset of PD, in other cases loss of cardiac sympathetic innervation progresses approximately concurrently with the movement disorder or can even occur as a late finding. Bases for independent sympathetic noradrenergic and striatal dopaminergic lesions in Lewy body diseases remain poorly understood. In elderly patients with unexplained OH or other evidence of autonomic failure, it is reasonable for clinicians to look for subtle signs of parkinsonism, such as masked facies, cogwheel rigidity, and shuffling gate.     

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.     

Beat-to-beat blood pressure and heart rate responses to the Valsalva maneuver

Measurement of beat-to-beat blood pressure and heart rate responses to the Valsalva maneuver is the basis for a highly informative autonomic function test. Whereas in the past this measurement required intra-arterial cannulation, the development of finger cuff devices that acquire arterial pressure waveforms indistinguishable from those recorded intra-arterially has made it possible to obtain accurate measurements noninvasively. In a patient with orthostatic hypotension, the pattern of blood pressure responses during and after the release of the maneuver can identify a neurogenic basis: sympathetic neurocirculatory failure. The quantifiable change in cardiac interbeat interval per unit change in systolic pressure during the maneuver can identify baroreflex-cardiovagal failure.     

Noninvasive detection of sympathetic neurocirculatory failure

In sympathetic neurocirculatory failure (SNF), reflexive sympathetically mediated cardiovascular stimulation does not compensate for decreased cardiac filling. This explains orthostatic hypotension in chronic primary autonomic failure (CPAF). During phase 2 of the Valsalva maneuver (phase 2_L), blood pressure increases from its peak. During phase 4, blood pressure normally overshoots the baseline. Because these changes depend on sympathetically mediated cardiovascular stimulation, a progressive decrease in pressure during phase 2 and absence of the overshoot in phase 4 may indicate SNF. Moreover, because beat-to-beat blood pressure can be measured noninvasively using a photoplethysmographic or tonometric device, evaluating reflexive pressure responses might enable noninvasive diagnosis of SNF. This study assessed the relative frequencies of abnormal phase 2_L and phase 4 blood pressure in patients with CPAF and orthostatic hypotension and whether noninvasive measurement of beat-to-beat blood pressure can be used to diagnose SNF in patients. Twenty patients with chronic primary autonomic failure and orthostatic hypotension and 50 comparison patients, including several with CPAF but lacking orthostatic hypotension, underwent arterial pressure monitoring during performance of the Valsalva maneuver. Of the 20 patients with CPAF and orthostatic hypotension, all had an abnormal phase 2_L or phase 4 pressure response (sensitivity 100%), whereas only 3 of the 50 comparison patients had an abnormal response in either phase (specificity 94%). Seventeen patients with CPAF and orthostatic hypotension had abnormal responses in both phases (sensitivity 85%), but none of the comparison patients had such findings in both phases (specificity 100%). Of 13 patients in whom beat-to-beat blood pressure was recorded simultaneously invasively and noninvasively, all had abnormal blood pressure responses during phase 2_L and phase 4, whereas none of 29 comparison patients had such symptoms. Detection of abnormal blood pressure responses during phase 2_L or phase 4 of the Valsalva maneuver is a highly sensitive test for SNF. Abnormal pressure during these phases appears to identify SNF specifically. Noninvasive measurements can detect both of these abnormalities.     

Cardiovascular autonomic dysfunction in dementia with Lewy bodies and Parkinson's disease

OBJECTIVE: We estimated the extent and pattern of cardiovascular autonomic dysfunction in dementia with Lewy bodies (DLB) as compared with that in Parkinson's disease (PD). METHODS: We performed meta-iodobenzylguanidine ((123)I-MIBG) scintigraphy of the heart and hemodynamic autonomic function testing using the Valsalva maneuver in 27 patients with DLB, 46 with PD, and 20 controls. RESULTS: (123)I-MIBG uptakes in DLB were reduced as compared with those in control and PD. Hemodynamic studies revealed that DLB had decreased baroreceptor reflex and reduced responses of SBP in phases II and IV as compared with PD and control. SBP responses on standing and the difference in plasma norepinephrine (NE) concentrations between supine and standing positions were reduced in PD as compared with those in control. Furthermore, SBP responses on standing, plasma NE concentrations in supine and standing positions, and the difference in plasma NE concentrations between these positions were significantly lower in DLB than in PD and control. Plasma NE concentrations in DLB with orthostatic hypotension (OH) were lower than that in DLB without OH, although some patients who had DLB with orthostatic hypotension had relatively normal plasma NE levels. CONCLUSION: Cardiovascular autonomic dysfunction is more severe in DLB than in PD and is usually caused by the loss of postganglionic sympathetic nervous function, although dysautonomia in some patients with DLB may result from preganglionic dysfunction.     

Cardiovascular dysautonomia in de novo Parkinson’s disease without orthostatic hypotension

Background: Clinical symptoms of Parkinson’s disease (PD) include not only motor distress, but also autonomic dysfunction. Objective: To study the characteristics of subclinical autonomic nervous dysfunction in de novo PD without orthostatic hypotension (OH). Methods: Autonomic nervous function including cardiac sympathetic gain was evaluated on the basis of cardiac radioiodinated metaiodobenzylguanidine (MIBG) uptake, the response to the Valsalva maneuver, and spectral analyses of the RR interval and blood pressure in 20 patients with de novo PD without OH. Results: Decreased cardiac MIBG uptake was found even in patients with PD without OH. Hemodynamic studies using the Valsalva maneuver revealed that patients with PD without OH had preserved baroreceptor reflex sensitivity in phase II and phase IV. Blood pressures normally responded in early and late phase II, but not in phase IV. Blood pressure recovery time was slightly reduced in patients with PD without OH when compared with the value in controls. The low frequency component of the RR interval and systolic blood pressure and the ratio of RR‐LF to RR‐HF in de novo PD without OH were significantly reduced when compared with the control values, whereas the high frequency component of the RR interval did not differ significantly. Conclusion: These results show that latent cardiac and vasomotor sympathetic dysfunction but not parasympathetic dysfunction is already present in early stage de novo PD, even without orthostatic hypotension.     

Parasympathetic denervation of the iris in Chagas' disease

The parasympathetic innervation of the iris along with cardiovascular reflexes involving parasympathetic and sympathetic function were studied in 45 patients with Chagas' disease and in 36 controls. The autonomic features in Chagas' disease included 15 with cardiomyopathy, three with megaoesophagus and five with megacolon. None of the patients had orthostatic hypotension. Parasympathetic cardiac reflexes (deep breathing 30:15 ratio, Valsalva) were abnormal. There were exaggerated pupillary responses to dilute pilocarpine. These studies suggest iris parasympathetic denervation and favour more widespread cholinergic involvement in patients with Chagas' disease, than previously recognized.     

A case of autoimmune autonomic neuropathy with marked orthostatic hypotension, decreased salivation, constipation, and Adie pupil]

We report a 68-year-old man with subacute autonomic failure who developed orthostatic hypotension, decreased salivation, constipation, and Adie pupil. There was no evidence of central neurodegeneration, sensory and motor dysfunction. Head-up tilt test showed marked orthostatic hypotension without tachycardia. The patient had a low plasma noradrenaline concentration while supine and a poor noradrenaline response to head-up. Adie pupil responded to 0.125% pilocarpine, establishing denervation hypersensitivity of the parasympathetic nerve. Blood pressure, However, did not show a remarkable response to 0.05-0.2gamma noradrenaline, demonstrating the absence of denervation hypersensitivity of the sympathetic nerve. In contrast to patients with pure autonomic failure, the patient showed normal uptake of I-123-MIBG in the myocardium, indicating intact postganglionic sympathetic innervation. Serologic testing demonstrated circulating antibody to the ganglionic acetylcholine receptor (AchR). Because of subacute clinical course, autonomic symptoms and presence of anti-ganglionic AchR antibody, autoimmune autonomic neuropathy was diagnosed.     

Functional effects of cardiac sympathetic denervation in neurogenic orthostatic hypotension

BackgroundDiseases characterized by neurogenic orthostatic hypotension (NOH), such as Parkinson disease (PD) and pure autonomic failure (PAF), are associated with cardiac sympathetic denervation, as reflected by low myocardial concentrations of 6-[¹⁸F]fluorodopamine-derived radioactivity. We studied the impact of such denervation on cardiac chronotropic and inotropic function.MethodsCardiac inotropic function was assessed by the pre-ejection period index and the systolic time ratio index in response to the directly acting beta-adrenoceptor agonist, isoproterenol, and to the indirectly acting sympathomimetic amine, tyramine, in patients with PD + NOH or PAF (PD + NOH/PAF group, N = 13). We compared the results to those in patients with multiple system atrophy, which usually entails NOH with normal cardiac sympathetic innervation (MSA, N = 15), and in normal control subjects (N = 5).ResultsThe innervated and denervated groups did not differ in baseline mean pre-ejection period index or systolic time ratio index. Tyramine increased cardiac contractility in the MSA patients and controls but not in the PD + NOH/PAF group. For similar heart rate responses, the PD + NOH/PAF group required less isoproterenol (p < 0.01) and had lower plasma isoproterenol levels (p < 0.01) than did the MSA group.ConclusionsAmong patients with NOH those with cardiac sympathetic denervation have an impaired inotropic response to tyramine and exaggerated responses to isoproterenol. This pattern suggests that cardiac denervation is associated with decreased ability to release endogenous norepinephrine from sympathetic nerves and with supersensitivity of cardiac beta-adrenoreceptors.     

Beat-to-beat blood pressure analysis after premature ventricular contraction indicates sensitive baroreceptor dysfunction in Parkinson's disease.

Extrasystoles occur in normal subjects but are significant more frequently (16.25% vs. 55%; chi(2) = 19.3; P < 0.001) seen in Parkinson's disease (PD) patients. The extrasystolic decreases in stroke volume and systolic pressure activate sympathetic vasomotor innervation and lead to a blood pressure increase for a few heartbeats. The purpose of this study was to prove whether the short time analysis of this blood pressure regulation allows the assessment of sympathetic neurocirculatory function. Records of noninvasive blood pressure monitoring were reviewed from 40 PD patients and 80 controls. A battery of cardiovascular autonomic tests, including Valsalva maneuver, tilt-table testing, echocardiography, and cardiac scintigraphy with [(123)I]meta-iodobenzylguanidine were performed. Fifty-five percent of the PD patients had at least one premature ventricular contraction (PVC) in 10 minutes lying supine at rest. After every PVC (13 PVCs) recorded from normal subjects, we found an increase in systolic blood pressure above base line with a maximum at the seventh heart beat. In all of the 22 PD patients, the systolic blood pressure was significantly decreased less than baseline in every PVC from the second to the ninth postextrasystolic beat (P < 0.001). In both groups, the extrasystolic fall in blood pressure was on average approximately 22%. The postextrasystolic potentiation did not differ (5.3% vs. 4.4%, not significant). If a PVC occurs, the analysis of short-time blood pressure regulation is a sensitive tool for baroreceptor reflex function. The advantage of this method results from the independence of patients cooperation and the high sensitivity to prove a sympathetic neurocirculatory failure within 10 heart beats.     

Orthostatic hypotension, non-dipping and striatal dopamine in Parkinson disease

Orthostatic hypotension and non-dipping are relatively common autonomic dysfunctions in patients with Parkinson disease (PD). These abnormalities have been thought to occur independently of striatal dopaminergic depletion; however, only little preliminary information is available. In this study, we investigated the association of neurocirculatory changes with striatal dopamine transporter status in 69 patients with early PD. Seventeen patients had orthostatic hypotension and 55 patients were non-dippers. A comparison between cases with and without orthostatic hypotension was insignificant for striatal dopamine transporter uptake. These insignificances continued in a comparison of dippers and non-dippers. These results suggest that sympathetic noradrenergic dysfunctions in PD are independent of striatal dopamine transporter depletion.     

Orthostatic hypotension as an early finding in Parkinson’s disease

Abstract Patients with Parkinson’s disease (PD) commonly have clinically significant orthostatic hypotension (OH). In such patients PD+OH might be confused with multiple system atrophy (MSA), in which OH is a frequent finding, or with pure autonomic failure (PAF), if OH preceded clinical manifestations of the movement disorder. This study addressed whether OH can occur as an early finding in PD+OH.Historical data were analyzed from 35 patients with PD+OH evaluated at the NIH. OH was considered early if the patient had OH before, concurrent with, or starting within 1 year after onset of a symptomatic movement disorder. MSA was excluded by myocardial 6-[¹⁸F]fluorodopamine-derived radioactivity more than 2 standard deviations below the normal mean. Among the 35 PD+OH patients, 21 (60 %) had documentation of OH as an early finding. In 4 such patients, OH had preceded parkinsonism, and in 4 others, OH had dominated the early clinical picture, even after cessation of levodopa treatment for the movement disorder. In PD, OH can occur early in the disease, occasionally preceding or overshadowing the movement disorder.     

Olfactory dysfunction in pure autonomic failure: Implications for the pathogenesis of Lewy body diseases

BackgroundPure autonomic failure (PAF) and Parkinson disease (PD) both are Lewy body diseases, and both entail substantia nigra dopaminergic, locus ceruleus noradrenergic, and cardiac sympathetic denervation. Multiple system atrophy (MSA) is a non-Lewy body disease in which alpha-synuclein accumulates in glial cells, with central catecholamine deficiency but preserved cardiac sympathetic innervation in most patients. PD is associated with more severe and consistent olfactory dysfunction than in MSA; whether PAF entails olfactory dysfunction has been unknown. In this study we assessed olfactory function in PAF in comparison with the two other synucleinopathies and whether olfactory dysfunction correlates with neuroimaging evidence of cardiac noradrenergic or nigrostriatal dopaminergic denervation.MethodThe University of Pennsylvania Smell Identification Test (UPSIT) was administered to 8 patients with PAF, 23 with PD, and 20 with MSA. 6-[¹⁸F]Fluorodopamine positron emission tomographic (PET) scanning was used to indicate cardiac noradrenergic innervation and the putamen:occipital cortex (PUT:OCC) and substantia nigra (SN):OCC ratios of 6-[¹⁸F]fluorodopa-derived radioactivity to indicate nigrostriatal dopaminergic innervation.ResultsThe PAF group had a low mean UPSIT score (22 ± 3), similar to that in PD (20 ± 2) and lower than in MSA (31 ± 2, p = 0.004). Individual UPSIT scores correlated positively with cardiac 6-[¹⁸F]fluorodopamine-derived radioactivity (r = 0.63 in the septum, p < 0.0001; r = 0.64 in the free wall, p < 0.0001) but not with PUT:OCC or SN:OCC ratios of 6-[¹⁸F]fluorodopa-derived radioactivity.DiscussionIn synucleinopathies, olfactory dysfunction is related to Lewy body pathology and cardiac sympathetic denervation, independently of parkinsonism or striatal dopamine deficiency.     

Cardiac sympathetic denervation in symptomatic and asymptomatic carriers of the E46K mutation in the α synuclein gene

ObjectiveThe aim of this study was to analyze autonomic function and cardiac sympathetic innervation in symptomatic and asymptomatic carriers of the E46K alpha-synuclein gene (SNCA) mutation.Patients and methodsAutonomic function tests were performed in six patients, four of whom were symptomatic carriers (ages: 46, 59, 52 and 28-years) and two who were asymptomatic carriers (ages: 52 and 29 years). Autopsy studies were performed on an additional two symptomatic carriers not eligible for autonomic testing.Patients completed the SCOPA autonomic questionnaire, and underwent the head-up tilt test accompanied by measurements of plasma norepinephrine. Valsalva maneuver and deep breathing tests, along with recording of sympathetic skin response (SSR) and cardiac MIBG scintigraphy were carried out. Myocardial tissue sections removed from the two autopsied cases were subjected to routine histological staining and immunohistochemical processing with monoclonal antibodies against tyrosine hydroxylase and alpha-synuclein.ResultsBoth the four symptomatic and the older asymptomatic carriers reported abnormalities in the SCOPA questionnaire and had markedly diminished cardiac MIBG uptake. Plasma norepinephrine in the supine and tilted positions was normal in all subjects. Only one patient had significant orthostatic hypotension. There was a complete absence of tyrosine hydroxylase immunostaining in the myocardium of the two autopsied cases.InterpretationWe have found imaging and histological evidence of cardiac sympathetic denervation in symptomatic and asymptomatic carriers of the E46K alpha-synuclein gene mutation. The sympathetic denervation appears to be organ-specific, with selective affectation of the heart given that plasma norepinephrine levels and blood pressure were normal.