A recent study in the journal Lancet Neurology announced the discovery of new biomarker for Parkinson’s disease. The assay, which targets a protein found in the nervous system called alpha synuclein, can detect the disease in both people with Parkinson’s and individuals not yet diagnosed or exhibiting symptoms of the disease, but who are at a high risk of developing it.
The discovery emerged from the Parkinson’s Progression Markers Initiative (PPMI), a decade-long longitudinal study led by the Michael J. Fox Foundation for Parkinson’s Research (MJFF) with support from more than 40 other organizations. More than 1,400 participants, both with and without Parkinson’s, participated in the PPMI study.
Irene Richard, MD, a professor of Neurology and Psychiatry at the University of Rochester Medical Center (URMC), was involved in the development and planning of the PPMI study in her role as senior medical advisor to MJFF, a position she held from 2008-2011. Richard continued her work with the organization as a member of the scientific advisory committee and was the principal investigator for the Rochester site of the PPMI study, overseeing the enrollment, evaluations, and follow up the initial cohort of study participants. We asked Richard why this new finding is important and what it means for future research efforts.
Describe alpha synuclein and the role it plays in Parkinson’s disease.
Abnormalities in alpha synuclein, a protein normally found in the nervous system, is associated with damage to neurons. Aggregates of misfolded and clumping of alpha synuclein that accumulate in the nervous system have been considered a hallmark of Parkinson’s disease (PD), but until now have only been detectable post-mortem. This new assay enables the detection of abnormal alpha synuclein during a patient’s life–and years before the clinical features of the PD appear.
While the assay was remarkably good at detecting PD pathology and doing it at very early stages, it did not pick up abnormal alpha synuclein in some patients with PD, mainly those with certain genetic forms of the disease. This provides support for the notion that there may be “subtypes” of PD that, while manifesting the same signs and symptoms, likely have differing underlying pathophysiology. This aspect will facilitate the development of targeted therapies and precision medicine approaches.
Why is it important to diagnose Parkinson’s early?
To date, we have only been able to treat the symptoms of the disease. Since PD is a progressive, neurodegenerative disease, a major goal has been to develop an intervention that could slow, or even stop progression. The sooner in the disease course one could do that, the better off the patient would be. Of course, the “holy grail” would be to actually prevent the disease from taking hold in the first place.
Traditionally, PD is diagnosed when patients develop the characteristic motor symptoms such as tremor and slowness. However, we have learned that the disease process has already begun long before these motor symptoms even manifest. For example, we now know that patients may have what we refer to as “pre-motor” symptoms such as diminished sense of smell, constipation, and a sleep disturbance known as “REM behavior disorder” wherein patients act out their dreams.
It is likely that, even if an intervention that was able to slow disease progression was developed, by the time someone has motor symptoms it may be too late. The disease process has silently been causing neuronal loss for years, the “horse is already out of the barn,” and saving the limited number of neurons left may not suffice. In the event we discover a disease modifying intervention, the earlier it can be given, the more likely it is to be effective–which is why there has been such a push to find ways to detect the disease at its earliest stages.
What more needs to be done before this is widely used to screen for Parkinson’s disease?
This is a first step, but it is a big one–think Neil Armstrong. At this point, the assay has been used on spinal fluid, obtained through a lumbar puncture or “spinal tap”. However, it seems only a matter of time before further developments and refinement will enable it to be performed on fluids more readily accessible, such as blood, saliva, nasal secretions or potentially using a skin biopsy.
How will this discovery help advance new treatments?
This assay will enable us to establish objective endpoints for clinical trials of PD treatments, ensure study participants exhibit appropriate pathology, and detect therapy induced changes in their status. All of these factors will significantly decrease the risk to industry to invest in the development of potential “blockbuster” therapies, including preventative agents, and increase the speed with which they can be developed, tested, and brought to market.
One of the great challenges has been to find a way to actually measure disease progression. To date, we have relied on clinical measurements, using a standardized rating scale, which while validated is far from an ideal objective measure of progression. This is, in part, because one of the rather unique aspects of the disease is that the clinical features vary among and within patients, are affected by symptomatic medications, and can fluctuate, even within the course of a day.
We knew that we must find an objective way to measure disease progression in parallel with seeking an intervention that could modify it. A lack of such a measure has resulted numerous clinical trials yielding results that were difficult to interpret. Complex clinical trial designs were a step forward, but have not been able to compensate for the lack of an objective and reliable biomarker. This assay represents a big step forward in meeting that need.
What does this discovery mean to the Parkinson’s research community?
I have spent my entire academic career at the University of Rochester and have focused on PD, both clinical care of patients and clinical research. To witness the growth and be part of this worldwide effort has been inspiring and I am thrilled with this breakthrough. There is a unique sense of energy and commitment that comes from being part of something greater than ourselves—a collective desire by everyone involved to alleviate the suffering of those living with PD now, with the hope of a future in which the disease will be a thing of the past.