BETHESDA, MD—Just what should be priority areas for research in Parkinson's disease (PD), particularly at a time when funding is scarce? That was the focus for a two-day meeting here in January, “Parkinson's Disease 2014: Advancing Research, Improving Lives,” sponsored by the National Institute of Neurological Disorders and Stroke (NINDS). Scientists, clinicians, as well as PD patients and advocates convened to comment on 30 draft research priorities that had been prepared for NINDS by panels of specialists.
Conference Chair Thomas J. Montine, MD, PhD, Alvord professor and chair of the department of pathology at the University of Washington, told Neurology Today, the 30 recommendations for research priorities fell into four broad categories: precision medicine for the molecular and clinical heterogeneity of PD; use of innovative technologies and tools to fuel scientific discovery at all levels; increasing scientific understanding of the genetic, environmental, and lifestyle factors that contribute to the variation among PD patients; and improving the infrastructure that supports clinical, translational, and basic research on PD in order to bring better care and an improved quality of life to patients, and the hope of prevention or delay to those at risk of PD.
NINDS Director Story C. Landis, PhD, praised the depth and breadth of the draft research recommendations, adding that they will be revised to incorporate comments made at the conference, polished, and presented to the NINDS advisory council; portions may also be made publicly available.
She said NINDS would share the document with the National Institute on Aging, and both NIH institutes would then review their research portfolios to see if there are recommended projects that are already being funded. Dr. Landis told Neurology Today that, given the reality of budget constraints, the recommendations would have to be winnowed down. Ultimately, she said, the recommendations will be prioritized and used to help evaluate future NINDS research applications.
Among the key draft research recommendations made at the two-day conference was a proposal to conduct proof-of-principle prevention trials targeting high-risk and prodromal populations, including biomarker assessment. The recommendation included a data and tissue resource for future clinical and laboratory investigations.
In the absence of a screening test for PD and given the typically long period of neurodegeneration without symptoms, researchers said it is vitally important to find ways of identifying high-risk populations before significant loss of neurons has occurred.
Such populations may include those at risk of inherited PD due to mutations; those with duplications of the protein alpha-synuclein, the primary constituent of Lewy bodies; those with prodromal symptoms such as REM sleep behavior disorder; and those with hyposmia. “Prevention could be defined as ‘delaying onset,’” said Werner Poewe, MD, director of the department of neurology at Innsbruck Medical University, Austria. “A proof-of-concept trial would be very valuable.”
“Ideally, we need a biomarker for PD that changes over time,” said Caroline M. Tanner, MD, PhD, director of clinical research at the Parkinson's Institute in Sunnyvale, CA. But, “we have to validate our biomarkers,” cautioned Steven Finkbeiner, MD, PhD, associate director and senior investigator at the Gladstone Institute of Neurological Disease at the University of California San Francisco.
Another recommendation supported the development of novel and specific alpha-synuclein PET imaging agents and assays to measure the alpha-synuclein burden in both animal models and human tissue.
Several conference participants made the analogy between alpha-synuclein as a pathological hallmark of PD and amyloid-beta as a signature pathology of Alzheimer's disease, stressing the need for alpha-synuclein tracers. The draft document noted that PET imaging is well suited for detecting alpha-synuclein in the living brain using a suitable PET ligand. (NINDS has a Parkinson's Disease Biomarkers Program aimed at identifying validated biomarkers for PD.)
The draft document noted that currently available high-resolution metabolomics tools can be used to analyze blood, urine, and cerebrospinal fluid samples from extensively phenotyped PD patients to indicate slow and rapid disease progression. These tools could help to determine metabolic sub-classifications of patients, according to the report.
“We need an environmental stratification as well as a genetic stratification,” emphasized Dean P. Jones, PhD, professor in the department of medicine (Pulmonary Division) at Emory University and director of the Emory Clinical Biomarkers Laboratory. He pointed out the likely interaction between genes and the environment in some subsets of PD patients.
PD causes a “huge social and economic burden,” one that will only grow worse as the population ages, according to the draft report. The good news is that “PD has a long prodromal phase, providing a window of opportunity for disease modifying interventions.” But many “knowledge gaps” ripe for research now serve as barriers to developing interventions to prevent PD onset or slow its progression.
Quality-of-life tools to measure benefit to patients from interventions are critically important, said Lisa M. Shulman, MD, professor of neurology and co-director of the Maryland Parkinson's Disease and Movement Disorders Center at the University of Maryland School of Medicine. In trials, “we need to link efficacy outcome to what is a meaningful clinical difference, not just a statistical difference,” she said. “There is no question that we need to be including patient-centered outcome measures” in clinical trials.
The draft document stated that non-motor symptoms are the new “cardinal features” of PD, are associated with substantial morbidity and mortality, may represent broad neurodegenerative vulnerability, and may occur decades before diagnosis of the disease. While the motor symptoms of Parkinson's disease have been well defined, “substantial knowledge gaps remain” related to non-motor symptoms and very few clinical trials have been conducted on them, states the document.
The promise of induced pluripotent stem cells (iPSCs), which can be coaxed into becoming neurons, was discussed in detail at the conference. The draft document recommended that iPSC technology be integrated into all translational efforts for PD.
It is likely that iPSCs will lead to “innovative, personalized therapies,” said Clive Svendsen, PhD, director of the Cedars-Sinai Regenerative Medicine Institute in Los Angeles. But, he cautioned, the jury is still out on neural transplantation as a therapeutic strategy. One key question: can the transplanted neural cells produce the right signals? He pointed out that iPSCs probably need a maturation step to be able to communicate fully via synapses like real neurons.
The draft document underscored the point that current clinical trials for disease modification in PD “are expensive and require long periods of study and large numbers of patients.” Therefore, intermediate markers of drug efficacy could shorten the process and ensure a continued investment in the therapeutic development process for PD. Along these lines, researchers can learn valuable information from their drug failures as well as their successes, emphasized John Dunlop, PhD, vice president for neuroscience at AstraZeneca and a member of an NINDS study section that reviews translational grant applications in neurological disorders.
Speakers repeatedly advocated research that takes advantage of new technologies as a platform for the development of innovative therapies. For example, the draft report cites the clear potential of deep brain stimulation (DBS) for PD patients. But it noted, “further refinement of our understanding of the mechanism of DBS is critical to enable the optimization of DBS [and the next-generation therapeutic devices] for patients with PD.”