Currently there is no definitive diagnostic test for Parkinson’s disease (PD) in a live patient, and no way to track disease progression on a biological level. These gaps have ramifications on personal disease management and on drug development. Findings from trials testing new PD therapeutics rely predominantly on outcomes measured through clinical observation, and there are limits on stratifying patients for trials. Reliable and well-validated biological markers of the disease would dramatically improve patient care and accelerate our understanding of PD, speeding therapeutic development.
During the past two decades much progress has been made in identifying and assessing PD biomarkers, but as yet, no fully validated biomarker for PD is currently available. Given the recent advances in the studies of molecular genetics, neurobiology, imaging technology and radiochemistry and the recognition that the lack of PD biomarkers has created a roadblock for further studies of disease-modifying therapies, there has been increasing consensus that a major initiative to develop PD progression biomarkers is both necessary and feasible.
In response, in 2010, The Michael J. Fox Foundation (MJFF) launched a longitudinal, multi-center clinical study — the Parkinson’s Progression Markers Initiative (PPMI) — to collect clinical, imaging and biologic data to identify and validate biomarkers of Parkinson’s disease (PD) progression.
This study focuses on de novo (recently diagnosed) PD patients and control volunteers. Researchers will collect data over three to five years, including motor and non-motor clinical data, dopamine scans and biologic fluid (blood, urine, cerebral spinal fluid) collection. Clinical and imaging data will be made available to the PD research community; researchers will be able to apply for access to the stored biologic samples.
A portion of collected samples will be used to verify promising biologic analytes (biologics of interest). As part of the preparatory phase of PPMI, MJFF worked closely with the company Covance to test and optimize one of the analytes. Covance successfully increased the specificity and sensitivity of an assay (laboratory experiment set-up) that measures levels of alpha-synuclein in human blood and cerebral spinal fluid (CSF). MJFF also prioritized identifying the correct test to measure the DJ-1 protein in blood and CSF by working with Dr. Un Kang from the University of Chicago.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Progression markers of Parkinson’s disease are critical in effectively testing a disease-modifying therapy in the clinic. Currently, there is no objective way to measure how PD progresses, which makes it difficult to determine if a therapy is slowing or halting the disease’s progression. PPMI is the first study of its kind to closely follow early PD and control subjects to determine whether collected data and/or biosamples can be used either alone or together as a tool to track disease progression. Finding such a tool that can be used in clinical testing of drugs would accelerate clinical development of therapies and improve the ability of trial sponsors to determine a drug’s success in meeting its goals.
PPMI seeks to achieve the following goals:
- Establish standardized protocols for acquisition, transfer and analysis of clinical, imaging, and biologic data that can be used by the PD research community. Access to data and biospecimens will occur through the study website (www.ppmi-info.org).
- Compile a comprehensive and uniformly acquired clinical and imaging dataset and biological samples that can be used to estimate the mean rates of change and the variablilty around the mean of clinical, imaging, and biologic outcomes in early PD patients.
- Investigate existing and identify novel clinical, imaging, and biologic Parkinson’s disease progression markers to identify quantitative individual measures or combination of measures that demonstrate optimum interval change in PD patients in comparison to healthy controls. Conduct preliminary verification studies on promising biological markers using stored collected samples.
Interim Progress Report:
In April 2013, PPMI completed enrollment of its initial cohort with 423 de novo Parkinson’s patients, 196 control subjects and 64 SWEDD individuals (people consented as PD subjects but who do not show dopamine deficit on DaTscan). That month the study launched a pre-motor arm, enrolling patients with known Parkinson’s risk factors: REM sleep behavior disorder, smell loss and certain genetic mutations). The genetic component has grown into its own arm, now recruiting cohorts of PD patients and people without PD who have a mutation of either the LRRK2 or the SNCA gene. The successful infrastructure of the original PPMI cohort allowed for these expansions. Additionally, the availability of PPMI data and biospecimens has been well received by the PD research community, with more than 110,000 data downloads and 28 specimen requests. Findings from the initial cohort—differences in protein levels in CSF of PD patients and controls—have been published, and researchers are testing those findings in the entire original group. Baseline data from that cohort will be published in early 2014.
Weintraub D; Papay K; Siderowf A; Parkinson's Progression Markers Initiative; "Screening for impulse control symptoms in patients with de novo Parkinson disease: a case-control study." Neurology 2013 Jan;80(2):176-80
Kang JH, Irwin DJ, Chen-Plotkin AS, Siderowf A, Caspell C, Coffey CS, Waligórska T, Taylor P, Pan S, Frasier M, Marek K, Kieburtz K, Jennings D, Simuni T, Tanner CM, Singleton A, Toga AW, Chowdhury S, Mollenhauer B, Trojanowski JQ, Shaw LM; and the Parkinson’s Progression Markers Initiative. "Association of Cerebrospinal Fluid B-Amyloid 1-42, T-tau, P-tau181, and a-Synuclein Levels With Clinical Features of Drug-Naive Patients With Early Parkinson Disease." JAMA Neurol. 2013 Aug 26. doi: 10.1001/jamaneurol.2013.3861. [Epub ahead of print]
Parkinson Progression Marker Initiative. "The Parkinson Progression Marker Initiative (PPMI)." Prog. Neurobiol. 2011 Dec;95(4):629-35