9 January 2009. Parkinson disease researchers can ring in the new year with a pair of high-profile studies—one bolstering a backburner treatment, the other proposing a molecular pathway that may contribute to disease. In this week’s issue of JAMA, scientists report that deep brain stimulation (DBS) relieved PD symptoms more effectively but also caused more side effects than did state-of-the-art noninvasive therapy in the largest DBS trial to date. This provides some comfort against the disheartening setback last fall of a gene therapy for PD. On the basic research front, a 2 January Science paper describes how α-synuclein could trigger neurodegeneration by binding myocyte enhancer factor 2D (MEF2D) and preventing its degradation.
The primary symptoms of PD result from reduced stimulation of the motor cortex due to inadequate production and action of the neurotransmitter dopamine. Deep brain stimulation aims to restore disrupted dopaminergic nerve circuits by delivering electrical pulses through electrodes implanted into affected brain areas, thereby alleviating PD motor symptoms. Though it has been an accepted PD therapy for about a decade, DBS remains a fallback option—used when drugs and non-pharmacological interventions fail or start to produce troubling side effects. “I get the sense that physicians may sometimes dismiss it pretty quickly, saying ‘I don't know that I want to put my patients through this’—particularly older patients,” said lead investigator Frances Weaver of Hines Veterans Affairs Hospital, Illinois, in an interview with ARF. She hopes the new findings could help change this attitude.
Weaver and collaborators at 13 U.S. sites enrolled 255 moderate to severe PD patients who were responsive to levodopa (an oral drug widely seen as the current gold standard for relieving PD symptoms) but had persistent motor complications despite medication. The participants were randomized to receive bilateral DBS (n = 121) or “best medical therapy” (n = 134) from premier movement disorder neurologists. After six months of treatment, the DBS patients gained an average of 4.6 hours/day of good symptom control whereas the group receiving non-surgical therapy had no change. Nearly a third of the best medical therapy patients did have some motor improvement (five points or greater on the Unified Parkinson Disease Rating Scale score), but these gains showed up in more than twice as many (71 percent) DBS patients. Compared with the medical therapy patients, the DBS group also experienced greater quality of life, reflected as higher six-month change scores on the summary index and in seven of eight subscales of Parkinson Disease Questionnaire 39.
Weaver pointed out that participants in the recent trial spanned a wider age range than those of most previous DBS studies. Compared with the younger subgroup, the 25 percent of patients aged 70 years or older in the new study fared comparably on most outcome measures. “The fact that we had them in our study and they did almost as well as the younger patients was a very positive finding,” Weaver said. “Age itself should not exclude someone from being considered for the DBS surgery.”
In terms of efficacy, the new results echo those of a 2006 DBS trial involving 156 PD patients under 75 years of age with severe motor symptoms (Deuschl et al., 2006). The new study, however, also included careful monitoring of adverse events associated with the DBS procedure—perhaps the key point of concern in the JAMA data. Forty-nine DBS patients experienced at least one serious adverse event during the trial, compared with 15 best medical therapy patients. The 82 serious adverse events in the DBS group included 68 related to the surgical procedure, stimulation device, or stimulation therapy, and one death secondary to cerebral hemorrhage that occurred 24 hours after lead implantation. Older and younger participants experienced these problems at the same rates (26 and 25 percent, respectively). Weaver noted that though 40 percent of the DBS patients had at least one serious adverse event, 99 percent of these issues were resolved by six months. Other groups have been developing less invasive brain stimulation techniques for relieving PD symptoms (see ARF related news story).
In the JAMA study, the investigators had randomized the DBS participants into two subgroups that received bilateral stimulation of the subthalamic nucleus (n = 60) or globus pallidus (n = 61)—brain areas that receive input from dopamine-producing neurons. Most DBS procedures thus far have targeted the former. Data from these subgroups were pooled in the current paper, but forthcoming analysis of data should offer insight into the relative advantages of targeting the two areas. In addition, after the six-month trial, patients who had gotten “best medical therapy” were enrolled to receive DBS at one of the two brain sites in the surgical arm, which now includes about 300 patients, Weaver told ARF. Her team has followed them for at least two years—up to three years for about a third of these patients—and hopes to submit the surgical outcome data for publication within a few months.
In the meantime, the JAMA study may help soften the blow from the disappointing Phase 2 trial of CERE-120, a PD gene therapy approach. Unlike DBS, which can relieve symptoms but does nothing to slow neuronal death, gene therapy strategies aim to rescue dying neurons by delivering growth factors to brain regions affected by disease. Such methods have shown some success in AD (see ARF related conference story).
CERE-120, an adeno-associated viral vector developed by San Diego, California-based Ceregene, Inc., carries the growth factor neurturin to dopamine-producing nigral neurons that degenerate in PD. In a November news release, the company announced that CERE-120 showed no clinical benefit in a Phase 2 study of 58 patients with advanced PD. The trial did have a silver lining. “We saw no product-related side effects at all,” said Ray Bartus, the company’s chief scientific officer, in an interview with ARF.
Based on autopsy data his team has analyzed from two patients in the recent trial, he thinks the gene delivery procedure could be at fault. While it appeared that neurturin DNA was taken up at the injection site—the terminal fields of nigral neurons—the researchers saw no evidence of the target protein in nigral cell bodies. To work in advanced PD patients, Bartus said the therapy should target both terminal fields and cell bodies. Based on this working hypothesis, he hopes the company can launch a trial that includes those adjustments later this year.
Amid these efforts at developing treatments, other researchers have focused on the underlying causes of PD. Writing in Science, researchers led by Zixu Mao at Emory University in Atlanta, Georgia, report that both wild-type and PD-mutant forms of α-synuclein may spur neurodegeneration by disrupting cellular recycling of the neuronal survival factor MEF2D. Using a mouse dopaminergic cell line (SN4741), first author Qian Yang and colleagues showed that MEF2D levels are controlled by chaperone-mediated autophagy (CMA), a key mechanism for degrading cytosolic proteins. They showed that MEF2D binds to heat shock protein 70 (Hsc70) and that wild-type and mutant α-synuclein disrupt this interaction, resulting in accumulation of inactive MEF2D in the cytoplasm, leaving the neurons more susceptible to death.—Esther Landhuis.
Weaver FM, Follett K, Stern M, Hur K, Harris C, Marks WJ Jr, Rothlind J, Sagher O, Reda D, Moy CS, Pahwa R, Burchiel K, Hogarth P, Lai EC, Duda JE, Holloway K, Samii A, Horn S, Bronstein J, Stoner G, Heemskerk J, Huang GD; CSP 468 Study Group. Bilateral deep brain stimulation vs. best medical therapy for patients with advanced Parkinson disease: a randomized controlled trial. JAMA. 2009 Jan 7;301(1):63-73. Abstract
Deuschl G. Neurostimulation for Parkinson disease. JAMA. 2009 Jan 7;301(1):104-5. Abstract
Yang Q, She H, Gearing M, Colla E, Lee M, Shacka JJ, Mao Z. Regulation of Neuronal Survival Factor MEF2D by Chaperone-Mediated Autophagy. Science. 2009 Jan 2;323(5910):124-7. Abstract