6 April 2012. Tracers used in positron emission tomography double as imaging tools and therapeutic agents in two new papers on treatment strategies for Parkinson’s disease. In the April 5 Science, researchers led by Paola Piccini of Imperial College London, U.K., use clinical tests and PET imaging to show that dopamine grafts give PD patients lasting motor improvement, yet fail to slow the disease’s non-motor symptoms. And in a paper posted online April 2 in the Journal of Experimental Medicine, Kevin Barnham, University of Melbourne, Australia, and colleagues report that a cancer imaging agent improves motor and cognitive functions in four different PD animal models by scavenging harmful nitrogen radicals.
Though thought of primarily as a movement disorder, advancing Parkinson’s can also afflict mood, sleep, and cognition in ways that are equally, if not more, distressing than the motor symptoms. In the first paper, first author Marios Politis and colleagues asked whether intrastriatal tissue grafts—which can curb motor deficits in PD patients (see Lindvall and Björklund, 2004)—could relieve non-motor difficulties as well. The researchers clinically assessed all symptoms in three young-onset PD patients who received dopamine-rich fetal tissue grafts 13 to 16 years earlier (Hagell et al., 1999; Brundin et al., 2000), and used PET imaging to correlate the clinical symptoms with neuronal function.
The news was mixed. On the one hand, the tissue grafts brought lasting motor improvement—enough for patients to go off L-dopa medication a few years after transplantation and still not need the drug when analyzed for the current study. However, the dopamine grafts did not help with non-motor symptoms. Though the transplant patients’ cognition stayed intact, they battled depression, sleep disturbances, and a host of gastrointestinal and other problems more so than age-matched controls.
In brain scans with the PET ligand 18F-dopa, dopamine levels proved to have been restored to normal not only in the striatum, where the graft was placed, but also in other parts of the basal ganglia. This was also the case in the hypothalamus, insula, prefrontal cortex, thalamus, and locus coeruleus. But when the researchers used another PET marker, 11C-DASB, to measure the function of serotonergic neurons in the transplant recipients, they saw substantial degeneration in the raphe nuclei and other areas innervated by such neurons—including the amygdala, hypothalamus, and prefrontal cortex (see image below). “As expected, PD continues to progress elsewhere, as indicated by the loss of serotonin transporter binding in the raphe,” commented Kenneth Marek of the Institute for Neurodegenerative Disorders in New Haven, Connecticut. In a similar vein, deep-brain stimulation—another therapeutic approach for Parkinson’s—relieves motor impairment in some patients but leaves them with troubling cognitive and behavioral symptoms (see ARF related news story).
Parkinson’s disease patients receiving dopamine cell transplants show non-motor symptoms such as sleep, mood, and appetite disturbances, along with serotonin neuron loss in their brains. View larger image. Image credit: Marios Politis
Acknowledging that the current evidence is “circumstantial,” the authors propose that the low serotonin levels revealed by PET may underlie the non-motor symptoms of the grafted PD patients.
They suggest that additional grafts of serotonin cells in raphe nuclei or forebrain areas may help relieve these problems. This proposal “will be met with great skepticism,” David Grimes of Ottawa Hospital, Ontario, Canada, wrote in an e-mail to the Alzforum. “It is clear that a wide range of cells degenerate in more advanced PD. Targeting just one of these non-dopamine cell types is unlikely to reverse the many problems of advanced PD.” Moreover, Grimes noted, the data should be interpreted with caution, since the transplant patients were atypical in that they developed PD in their thirties and stayed free of dementia for 25 years of disease. (See full comment below.)
Further complicating matters, Politis and colleagues reported previously that contaminating serotonergic neurons contained in dopamine grafts can cause uncontrolled movements called dyskinesias as a side effect of transplantation (ARF related news story on Politis et al., 2010).
In the JEM paper, PET serves quite a different purpose. The Australian researchers stumbled on a PET tracer being developed for cancer imaging, and showed it was neuroprotective and improved behavior in four PD mouse models. The PET ligand, CuII(atsm), has a curious property. It hunts down the harmful nitrogen radical ONOO- (peroxynitrite) and inhibits its toxicity, as does uric acid, one of the body’s natural peroxynitrite scavengers. Epidemiological data suggest that people with high uric acid levels are protected against PD (Alonso et al., 2007; De Vera et al., 2008), whereas those with less uric acid are more susceptible to the disease (Hooper et al., 1998). Furthermore, ONOO- promotes nitration and aggregation of α-synuclein, and Lewy bodies have a lot of nitrated synuclein (Giasson et al., 2000). All this “indicates that nitration events are potentially quite important [in PD],” Barnham said.
First author Lin Hung and colleagues demonstrated in vitro that CuII(atsm) hastens ONOO- degradation, and blocks α-synuclein nitration and oligomerization. They then showed the compound could relieve stress caused by nitrogen free radicals in a neuroblastoma cell line. Finally, they took the approach into PD mouse models and found that oral administration of CuII(atsm) slowed neuronal death, reduced α-synuclein dimerization, rescued motor deficits, and improved memory. They showed the last two effects in hA53T mice overexpressing mutant human α-synuclein, and correlated these benefits with increased dopamine metabolite levels measured in Western blots, immunostaining, or PET imaging. To ensure the compound was truly neuroprotective and not just inhibiting the toxin’s actions in several of the PD models, the researchers were careful not to administer CuII(atsm) until the cell death cascade was well underway.
“This is probably the most rigorous preclinical evaluation of a compound that we’re capable of doing,” Barnham told Alzforum. Furthermore, when Japanese researchers used CuII(atsm) as an oxidative stress marker in a PET study of 15 PD patients (Ikawa et al., 2011), they reported that “the compound accumulates exactly where it’s supposed to—in the striatum,” Barnham said. “And the greater the disease severity, the more drug accumulated in that area.”
The compound looks promising for other neurodegenerative disorders as well. In a prior study (Soon et al., 2011), Barnham and colleagues found that CuII(atsm) extends lifespan and relieves motor deficits in a mouse model for amyotrophic lateral sclerosis (ALS). They are talking with potential commercial partners to advance the compound into clinical testing in PD or ALS. Meanwhile, the team is doing more mechanistic work and trying to design analogs, Barnham said.—Esther Landhuis.
Politis M, Wu K, Loane C, Quinn NP, Brooks DJ, Oertel WH, Björklund A, Lindvall O, Piccini P. Serotonin Neuron Loss and Nonmotor Symptoms Continue in Parkinson’s Patients Treated with Dopamine Grafts. Sci Transl Med. 4 Apr 2012;4(128):1-10. Abstract
Hung LW, Villemagne VL, Cheng L, Sherratt NA, Ayton S, White AR, Crouch PJ, Lim SC, Leong SL, Wilkins S, George J, Roberts BR, Pham CL, Liu X, Chiu FC, Shackleford DM, Powell AK, Masters CL, Bush AI, O’Keefe G, Culvenor JG, Cappai R, Cherny RA, Donnelly PS, Hill AF, Finkelstein DI, Barnham KJ. The hypoxia imaging agent CuII(atsm) is neuroprotective and improves motor and cognitive functions in multiple animal models of Parkinson’s disease. J Exp Med. 2 Apr 2012. Abstract