Pattern of Cardiac Sympathetic Denervation in Idiopathic Parkinson Disease Studied with 11 C Hydroxyephedrine PET
Division of Nuclear Medicine, Department of Radiology, Department of Neurology, and Functional Neuroimaging, Cognitive and Mobility Laboratory, Departments of Radiology and Neurology, University of Michigan Medical Center, University of Michigan, 1500 E Medical Center Dr, B1G505G, Ann Arbor, MI 48105. Radiology
(Impact Factor: 6.87).
07/2012; 265(1):240-7. DOI: 10.1148/radiol.12112723
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 (11C) 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 11C HED in 27 patients with IPD (20 men and seven women aged 50-74 years; mean age, 62 years±6 [standard deviation]). 11C 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.
The mean 11C HED RI was 0.086 mL of blood per minute per 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 11C 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.
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.
Available from: Valerie Joers
- "Human studies have shown greater TH-positive nerves in the base and epicardium of the left ventricle compared to the apex and the endocardium, respectively . In PD, patterns across levels have not been evaluated by postmortem analysis, however, imaging studies have shown reduced MHED uptake in the more apical segments of the left ventricle lateral wall . Diabetic patients have also shown impaired MHED uptake in nerves terminating near the apex, or the longest nerves in the heart , . "
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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. DOI:10.1371/journal.pone.0104850 · 3.23 Impact Factor
Available from: Qingshan Wang
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ABSTRACT: The striato-nigral projecting pathway contains the highest concentrations of dynorphin in the brain. The functional role of this opioid peptide in the regulation of mesencephalic dopaminergic (DAergic) neurons is not clear. We reported previously that exogenous dynorphin exerts potent neuroprotective effects against inflammation-induced dopaminergic neurodegeneration in vitro. The present study was performed to investigate whether endogenous dynorphin has neuroprotective roles in vivo.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and methamphetamine (MA), two commonly used neurotoxins in rodent models of Parkinson's disease, were administered to wild-type (Dyn⁺/⁺) and prodynorphin-deficient mice (Dyn⁻/⁻). We examined dopaminergic neurotoxicity by using an automated video tracking system, HPLC, immunocytochemistry, and reverse transcription and polymerase chain reaction (RT-PCR).
Treatment with MPTP resulted in behavioral impairments in both strains. However, these impairments were more pronounced in Dyn-l- than in Dyn⁺/⁺. Dyn⁻/⁻ showed more severe MPTP-induced dopaminergic neuronal loss in the substantia nigra and striatum than Dyn⁺/⁺. Similarly, the levels of dopamine and its metabolites in the striatum were depleted to a greater extent in Dyn⁻/⁻ than in Dyn⁺/⁺. Additional mechanistic studies revealed that MPTP treatment caused a higher degree of microglial activation and M1 phenotype differentiation in Dyn⁻/⁻ than in Dyn⁺/⁺. Consistent with these observations, prodynorphin deficiency also exacerbated neurotoxic effects induced by MA, although this effect was less pronounced than that of MPTP.
The in vivo results presented here extend our previous in vitro findings and further indicate that endogenous dynorphin plays a critical role in protecting dopaminergic neurons through its anti-inflammatory effects.
Journal of Neuroinflammation 06/2012; 9(1):124. DOI:10.1186/1742-2094-9-124 · 5.41 Impact Factor
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ABSTRACT: A hallmark of neurodegenerative diseases is impairment of certain aspects of "brain functionality". Brain functionality is defined as the total input and output of the brain's neural circuits and networks. A given brain degenerative disorder does not deregulate total brain functionality but rather the activity of specific circuits in a given network, affecting their organization and topology, their cell numbers, their cellular functionality, and the interactions between neural circuits. Similarly, our concept of neurodegenerative diseases, which for many years revolved around neural survival or death, has now been extended to emphasize the role of glia. In particular, the role of glial cells in neuro-vascular communication is now known to be central to the effect of insults to the nervous system. In addition, a malfunctioning vascular system likely plays a role in the etiology of certain neurodegenerative diseases. Thus, the symptoms of neurodegenerative or more correctly brain degenerative disease are, to a very large extent, a result of impairment in glial cells that lead to pathological neuro-vascular interactions that, in turn, generate a rather "hostile" environment in which the neurons fail to function. These events lead to systematic neural cell death on a scale that appears to be proportional to the severity of the neurological deficit.
DNA repair 05/2013; 12(8). DOI:10.1016/j.dnarep.2013.04.007 · 3.11 Impact Factor
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