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.

References:
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

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  1. Don’t Jeopardize New Therapies With Sham Surgery Control—Placebo Responses May Be Part of Therapies
    I was the patient representative on the FDA advisory panel that reviewed deep brain stimulation (DBS) in March of 2000, and later I participated in the Medicare National Coverage decision for DBS on behalf of the requester (not Medtronics but an individual person with Parkinson's). From these engagements, I recall this treatment was shown to be very effective (upwards of 85 percent have 50 percent improvement in motor symptoms). Such dramatic and lasting improvements would need to be expected to offer a treatment that makes it worthwhile to take the risk of brain surgery. After a delay of more than four years from the initial advisory group, DBS has been available to patients, as a near breakthrough option once first-line treatment fails. Indeed, it is the only major new therapy for PD in the 40 years since levodopa was discovered. Now the recent study published in JAMA continues to show efficacy and also shows that its adverse side effects for important functions like cognition are greater for DBS than with standard drug therapy. The DBS experience can be instructive for other surgical treatments for PD.

    The question I want to raise regards the Ceregene 120 study, a gene therapy application of the nerve growth factor neurturin, NTN. The Phase 2 study "failed to meet primary endpoints" in comparison to a sham surgery placebo control. Similar to experiences with other surgically installed treatments, such as GDNF infusion pump and implantation of spheramine, a cell-based therapy using retinal dopaminergic cells, this latest placebo-controlled trial did not replicate the gains from the Phase 1 open-label study. The results of all of these studies are clouded from methodological issues such as differences in dosing between Phase 1 and Phase 2, dislodgement of pump connections, and differences in the use of other PD medications during the studies that may have affected the results. Even so, the fact remains that some study participants have experienced dramatic improvements lasting as long as six years and counting, and some have reduced their PD medications to near zero, being almost symptom-free after decades of increasing disability. A brain autopsy of one GDNF patient showed nerve growth in the side of the brain in which the treatment was administered during the trial. For all of these treatments, data point to improvements well beyond reasonable estimates of placebo effects.

    Clearly placebo effects are very strong. Research on placebo response for a range of medical conditions including PD attributes these real physiological effects to expectations of benefit and conditioning established in the social context of administering a treatment. The greater the risk and notoriety of the intervention, and the more certain and authoritative the source, a greater placebo effect is produced. Maximum placebo effects, as would be expected, are found from brain surgery as well as from the safest form of sham brain surgery, where the brain is not penetrated but the patient goes through the same process including lengthy anesthesia. DBS patients report vast improvements in symptoms even before the stimulators are turned on. Clinical brain researchers (including more than 90 percent of the Parkinson's Study Group) agree that sham brain surgery is necessary to prove that improvements are attributable to the treatment beyond the placebo. On the other hand, an online survey of activist PD patients found that only 37 percent would participate in a sham surgery study. Closing this gap raises practical as well as ethical issues.

    DBS was approved without sham surgery as a placebo control. So why aren't DBS's gains in motor scores attributed in part to a learned placebo response? Shouldn't the placebo effects that last multiple years be counted as part of the treatment, as they effectively are with DBS, and not written off as bias? The recent JAMA publication improved the evidence of efficacy for DBS by randomization to best medical treatment versus surgery. Why isn't random assignment to best medical practice a sufficient comparison for other surgical interventions?

    Sham surgery is not a sugar pill; it is a powerful intervention, although you would probably be charged with fraud if you tried to sell it. Placebo studies on the experience of pain in fact demonstrate that the "bias" from patient hopes and expectations, a central element of all healing, is opposite of what has been assumed by science in experimental settings. That is, treatment effects are reduced and placebo effects are increased. That is so because random assignment dilutes positive effect of patients’ expectation that they will improve from the ongoing uncertainty about whether they are on the real thing, and conversely it elevates the placebo group’s expectation that they may be on the real thing. This biases the results toward type II errors (false negative), which are more important to patients with serious illness than are type I errors (false positive) that are the target of statistical models. The pain studies suggest that the placebo mechanism may be necessary to trigger the therapeutic effects of treatment. Elaborate deception to control this effect could be undermining its evaluation.

    Sure, we need to control bias. But variability and bias can come from many sources, including, importantly the selection of participants and the variability of raters on subjective scales such as UPDRS. For example, are all study participants diagnosed correctly? And do they represent homogeneous types of patients? Depression medication trials, which also fail at high rates, have taught us that clearer distinction between treatment and placebo results from higher-quality central rating of subjective measurement scales. Multiple ratings of key measures reduce noise in data when averaged. Patients who have participated in PD clinical trials know that UPDRS "off" may describe different behavior on different days, and are not totally determined by the time since the last dose. Better understanding of these factors from the patient perspective is necessary to control this source of variability in the data.

    Alternatively, where the sources of variability are unbiased, the problem can be fixed by increasing sample size to account for random fluctuations in the calculations of confidence of the result. This not only costs more, but it also may bump up against practical limitations including recruitment and FDA statisticians.

    New Directions for the Twenty-first Century

    As science progresses, we need to re-examine our assumptions about the standards for evidence in the assessment of safety and effectiveness. The gold standard of the randomized, prospective, double-blind placebo-controlled study cannot be applied as a one-size-fits-all to conditions on the cutting edge of medical science.

    Medical miracles of the twentieth century mostly pertain to acute conditions, where linear assumptions of statistical models for hypothesis testing more closely approximate the relatively short-term interventions. As we deal with longer-term degenerative processes involving dynamic interaction and feedback to our conscious brain processes, assumptions from the experimental model become questionable. This is true even where all orthodoxies of statistics are followed and statistical significance is achieved.

    Recent FDA law offers greater flexibility to align methods to the parameters of the specific case. Such alternative methods need to be qualified and used. Examples include Bayesian statistics for application to dose-finding tasks, or mathematical models of disease progression as historical controls. Crossover designs can detect differences in symptomatic benefits, and delayed start designs have shown promise to detect neuroprotection.

    FDA law requires well-controlled randomized studies, not placebos. New policies put more emphasis on life cycle monitoring of treatments in real practice settings, and provide reimbursement coverage for access to new treatments while evidence of long-term safety and efficacy are established with greater certainty. Following patients more closely for a number of years to see the lasting effects can establish whether the treatment effects are purely placebo, at the same time that long-term safety is tracked.

    Continuing failure of studies based on faulty assumptions about human behavior is not a viable option. A better understanding of placebo responses in the design of clinical trials points to new approaches in collaboration with patient advocates and communications to FDA.

    Perry D. Cohen directs the Parkinson Pipeline Project.

References

News Citations

  1. Parkinson Therapies Go Deep and Shallow
  2. Madrid: Clinical Trials Update—Where Do Things Stand?

Paper Citations

  1. . A randomized trial of deep-brain stimulation for Parkinson's disease. N Engl J Med. 2006 Aug 31;355(9):896-908. PubMed.
  2. . 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. PubMed.
  3. . Neurostimulation for Parkinson disease. JAMA. 2009 Jan 7;301(1):104-5. PubMed.
  4. . Regulation of neuronal survival factor MEF2D by chaperone-mediated autophagy. Science. 2009 Jan 2;323(5910):124-7. PubMed.

External Citations

  1. news release

Further Reading

Papers

  1. . A randomized trial of deep-brain stimulation for Parkinson's disease. N Engl J Med. 2006 Aug 31;355(9):896-908. PubMed.
  2. . Five-year follow-up of bilateral stimulation of the subthalamic nucleus in advanced Parkinson's disease. N Engl J Med. 2003 Nov 13;349(20):1925-34. PubMed.
  3. . 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. PubMed.

Primary Papers

  1. . A randomized trial of deep-brain stimulation for Parkinson's disease. N Engl J Med. 2006 Aug 31;355(9):896-908. PubMed.
  2. . Five-year follow-up of bilateral stimulation of the subthalamic nucleus in advanced Parkinson's disease. N Engl J Med. 2003 Nov 13;349(20):1925-34. PubMed.
  3. . 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. PubMed.