Summary: By the time common motor symptoms of Parkinson’s disease prompt diagnosis, roughly 60% of patients already have substantial damage to the heart’s sympathetic nerve connections. Researchers have now mapped where inflammation and oxidative stress occur in the heart and how those processes relate to cardiac problems linked to Parkinson’s.
Source: University of Wisconsin Madison.
New imaging method pinpoints inflammation and oxidative stress in the heart, offering a way to test therapies and to better understand an underrecognized source of falls and hospitalization in Parkinson’s patients.
Many people with Parkinson’s disease develop damage to the sympathetic nerves that control heart rate and blood pressure regulation. These nerves normally cause the heart to speed up or adjust in response to activity and changes in posture. When they are damaged, patients are more likely to experience fatigue, fainting, orthostatic intolerance and falls, which complicate care and increase the risk of injury.
Researchers at the University of Wisconsin–Madison, led by Marina Emborg and graduate student Jeanette Metzger, together with cardiology and medical imaging specialists, developed a refined approach to visualize the biological processes that drive nerve loss in the heart. Their study, conducted in a nonhuman primate model and published in npj Parkinson’s Disease, uses positron emission tomography (PET) with multiple radioligands to track nerve integrity, inflammation and oxidative stress within specific regions of the heart’s left ventricle.
Ten adult male rhesus macaques received systemic doses of the neurotoxin 6-hydroxydopamine (6-OHDA) to reproduce the pattern of cardiac sympathetic neurodegeneration seen in Parkinson’s disease. The animals underwent PET scans before the neurotoxin and at two time points afterward. The team used three different PET tracers to measure distinct biological signals: [11C]meta-hydroxyephedrine (MHED) to identify catecholaminergic nerve terminals, [11C]PBR28 (PBR28) to detect inflammation, and [61Cu]ATSM (ATSM) to indicate oxidative stress.
These radioligands provided spatially resolved images of the left ventricle, allowing researchers to follow changes over time in discrete circumferential regions and axial levels of the heart wall. This level of resolution made it possible to correlate loss of nerve uptake with localized increases in inflammation and oxidative markers and to observe how those patterns evolved after nerve injury.
To test whether a candidate neuroprotective treatment could modify these processes, half of the animals received the PPARγ agonist pioglitazone, a drug known to possess anti-inflammatory and antioxidant effects, while the other half received placebo. One week after 6-OHDA administration, MHED uptake fell sharply in both groups, indicating acute loss of sympathetic nerve terminals. PBR28 and ATSM signals rose, reflecting increased inflammation and oxidative stress, but these rises were blunted in animals treated with pioglitazone.
At 12 weeks, animals treated with pioglitazone showed greater partial recovery of MHED uptake compared with placebo, and that recovery varied by circumferential region and axial level of the left ventricle. The degree of MHED recovery at 12 weeks correlated strongly with cardiac tyrosine hydroxylase immunoreactivity, supporting the tracer’s ability to reflect actual nerve terminal status. In contrast, PBR28 and ATSM signals returned toward baseline by 12 weeks, indicating that the early inflammatory and oxidative responses were transient but linked to the acute phase of neuronal loss.
Metzger, the study’s lead author, explains that this multimodal PET strategy provides a practical way to visualize where inflammatory and oxidative processes are occurring in the heart and how those processes relate to the decline and partial recovery of sympathetic innervation. Emborg notes that the method can detect treatment effects separately for inflammation and oxidative stress, offering a tool to evaluate candidate neuroprotective agents aimed at preserving cardiac autonomic function.
These imaging techniques have two important implications. First, they can serve as in vivo biomarkers to test and optimize therapies intended to protect cardiac sympathetic neurons in Parkinson’s disease. Second, because cardiac sympathetic loss can precede motor symptoms in many patients, such scans might reveal early heart involvement and help clarify mechanisms behind nonmotor cardiovascular symptoms that increase fall and hospitalization risk.
Beyond Parkinson’s disease, similar patterns of nerve damage, inflammation and oxidative stress occur after heart attacks, in diabetes-related cardiac neuropathy and in other disorders. Therefore, the imaging approach described here could be applicable to a wider range of conditions and to the development of protective treatments for cardiac autonomic nerves.
Key contributors from UW–Madison included Jeanette M. Metzger, Marina E. Emborg, Colleen F. Moore, Carissa A. Boettcher, Kevin G. Brunner, Rachel A. Fleddermann, Helen N. Matsoff, Henry A. Resnikoff, Viktoriya Bondarenko, Timothy J. Kamp, Timothy A. Hacker, Todd E. Barnhart, Patrick J. Lao, Bradley T. Christian, R. Jerry Nickles, Catherine L. Gallagher, James E. Holden and others across psychology, cardiovascular medicine, neurology and medical physics departments.
Funding: This research was supported by grants from the National Institutes of Health (P51OD011106, R21NS084158, F31HL136047), the Parkinson’s Foundation, Welton and Trewartha undergraduate honors scholarships, and institutional support from UW–Madison.
Source: Marina Emborg, University of Wisconsin–Madison.
Publisher: Organized by NeuroscienceNews.com.
Image source: Public domain image credited to NeuroscienceNews.com.
Original research: “In vivo imaging of inflammation and oxidative stress in a nonhuman primate model of cardiac sympathetic neurodegeneration” — published in npj Parkinson’s Disease (July 13, 2018). DOI: 10.1038/s41531-018-0057-1.
Abstract
In vivo imaging of inflammation and oxidative stress in a nonhuman primate model of cardiac sympathetic neurodegeneration
Cardiac loss of postganglionic sympathetic innervation is a prominent pathology in Parkinson’s disease that progresses independently of motor symptoms and is not responsive to standard anti-parkinsonian therapies. Systemic dosing with 6-hydroxydopamine (6-OHDA) reproduces this pattern in animal models and is associated with increased inflammation and oxidative stress. To evaluate the feasibility of tracking changes over time in cardiac innervation and the mechanisms driving neurodegeneration, myocardial PET with MHED, PBR28 and ATSM was performed in 6-OHDA-treated rhesus macaques. The PPARγ agonist pioglitazone, which has anti-inflammatory and antioxidant properties, was tested in half of the animals. One week after 6-OHDA, MHED uptake was markedly reduced in all animals while PBR28 and ATSM uptake increased; these increases were attenuated by pioglitazone. At 12 weeks, MHED uptake showed greater recovery in pioglitazone-treated animals and correlated with tyrosine hydroxylase immunoreactivity across cardiac regions, while inflammatory and oxidative signals returned toward baseline. These radioligands therefore offer potential as in vivo biomarkers of cardiac neurodegeneration and neuroprotection.