Pattern of Cardiac Sympathetic Denervation in Idiopathic Parkinson Disease Studied with 11C Hydroxyephedrine PET.
ABSTRACT Purpose: To determine whether cardiac sympathetic denervation in idiopathic Parkinson disease (IPD) affects the left ventricle in a distinct regional pattern versus a more global pattern with use of carbon 11 ((11)C) meta-hydroxyephedrine (HED) positron emission tomography (PET). Materials and Methods: This prospective study was approved by the institutional review board and was compliant with HIPAA. Informed consent was obtained from all subjects. Cardiac PET was performed with (11)C HED in 27 patients with IPD (20 men and seven women aged 50-74 years; mean age, 62 years ± 6 [standard deviation]). (11)C HED retention indexes (RIs), which reflect nerve density and integrity, were determined. RIs for 33 healthy control subjects (15 men and 18 women aged 20-78 years; mean age, 47 years ± 17) were used as a control database. Patients with IPD were compared with control subjects by using z score analysis. Global and segmental measurements of sympathetic denervation were expressed as percentage extent, z score severity, and severity-extent product (SEP). Group comparisons were performed with the Student t test. Results: The mean (11)C HED RI was 0.086 mL of blood per minuteper milliliter tissue ± 0.015 for control subjects and 0.043 mL of blood per minute per milliliter tissue ± 0.016 for patients with IPD (P < 0001). When compared with normative data from the control database, profound cardiac denervation (global extent >50%) was seen in most patients (19 of 27 patients, 70%). Four patients had normal (11)C HED studies and four had mild denervation (global extent <25%). The mean global denervation extent was 62% ± 38, the mean severity z score was -2.7 ± 1.2, and the mean SEP was -202 ± 131 (range, -358 to 0). Segmental analysis revealed relative sparing of anterior and proximal septal segments (mean extent, 48%-51%; mean severity z score, -2.47 to -2.0; mean SEP, -167 to -139), with lateral and proximal inferior segments more severely affected (mean extent, 68%-73%; mean severity z score, -2.8 to -2.62; mean SEP, -271 to -230). Patients with normal findings or preserved denervation did not significantly differ in mean age (t = 1.09) or disease duration (t = 0.44) compared to patients with severe sympathetic denervation. Conclusion: Cardiac sympathetic denervation in IPD is extensive, with a segmental pattern that involves the proximal lateral left ventricular wall most severely, with relative sparing of the anterior and proximal septal walls. © RSNA, 2012 Supplemental material: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.12112723/-/DC1.
- SourceAvailable from: Valerie Joers[Show abstract] [Hide abstract]
ABSTRACT: Cardiac sympathetic neurodegeneration and dysautonomia affect patients with sporadic and familial Parkinson's disease (PD) and are currently proposed as prodromal signs of PD. We have recently developed a nonhuman primate model of cardiac dysautonomia by iv 6-hydroxydopamine (6-OHDA). Our in vivo findings included decreased cardiac uptake of a sympathetic radioligand and circulating catecholamines; here we report the postmortem characterization of the model. Ten adult rhesus monkeys (5-17 yrs old) were used in this study. Five animals received 6-OHDA (50 mg/kg iv) and five were age-matched controls. Three months post-neurotoxin the animals were euthanized; hearts and adrenal glands were processed for immunohistochemistry. Quantification of immunoreactivity (ir) of stainings was performed by an investigator blind to the treatment group using NIH ImageJ software (for cardiac bundles and adrenals, area above threshold and optical density) and MBF StereoInvestigator (for cardiac fibers, area fraction fractionator probe). Sympathetic cardiac nerve bundle analysis and fiber area density showed a significant reduction in global cardiac tyrosine hydroxylase-ir (TH; catecholaminergic marker) in 6-OHDA animals compared to controls. Quantification of protein gene protein 9.5 (pan-neuronal marker) positive cardiac fibers showed a significant deficit in 6-OHDA monkeys compared to controls and correlated with TH-ir fiber area. Semi-quantitative evaluation of human leukocyte antigen-ir (inflammatory marker) and nitrotyrosine-ir (oxidative stress marker) did not show significant changes 3 months post-neurotoxin. Cardiac nerve bundle α-synuclein-ir (presynaptic protein) was reduced (trend) in 6-OHDA treated monkeys; insoluble proteinase-K resistant α-synuclein (typical of PD pathology) was not observed. In the adrenal medulla, 6-OHDA monkeys had significantly reduced TH-ir and aminoacid decarboxylase-ir. Our results confirm that systemic 6-OHDA dosing to nonhuman primates induces cardiac sympathetic neurodegeneration and loss of catecholaminergic enzymes in the adrenal medulla, and suggests that this model can be used as a platform to evaluate disease-modifying strategies aiming to induce peripheral neuroprotection.PLoS ONE 08/2014; 9(8):e104850. · 3.53 Impact Factor
- Journal of vascular and interventional radiology: JVIR 04/2014; 25(4):497-509. · 1.81 Impact Factor
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ABSTRACT: Parkinson's disease (PD) is currently recognized as a multisystem disorder affecting several components of the central and peripheral nervous system. This new understanding of PD helps explain the complexity of the patients' symptoms while challenges researchers to identify new diagnostic and therapeutic strategies. Cardiac neurodegeneration and dysautonomia affect PD patients and are associated with orthostatic hypotension, fatigue, and abnormal control of electrical heart activity. They can seriously impact daily life of PD patients, as these symptoms do not respond to classical anti-parkinsonian medications and can be worsened by them. New diagnostic tools and therapies aiming to prevent cardiac neurodegeneration and dysautonomia are needed. In this manuscript we critically review the relationship between the cardiovascular and nervous system in normal and PD conditions, current animal models of cardiac dysautonomia and the application of molecular imaging methods to visualize cardiac neurodegeneration. Our goal is to highlight current progress in the development of tools to understand cardiac neurodegeneration and dysautonomia and monitor the effects of novel therapies aiming for global neuroprotection.American Journal of Nuclear Medicine and Molecular Imaging 01/2014; 4(2):125-159. · 3.25 Impact Factor