Parkinson’s Study Looks for Prodromal and Disease Progression Biomarkers

WEB FIRST LOOK: A Summary by the Parkinson’s Progression Marker’s Initiative*

 

Identifying therapies that can slow or halt the progression of Parkinson’s disease (PD) is a crucial challenge facing PD researchers. A significant obstacle to effectively testing possible disease modifying therapies is the lack of objective biomarkers to accurately diagnose PD, identify subsets of PD patients, monitor the course of illness and establish the effect of therapies on disease progression.1 The goal of the Parkinson’s Progression Marker Initiative (PPMI) is to identify clinical, imaging, and biospecimen biomarkers of PD progression, establish standardized methods of acquisition and analysis of biomarker data that could be utilized in multi-center clinical trials and provide rapid ongoing public access to PPMI data and biospecimen (Fig 1).2

The initiative is sponsored by The Michael J. Fox Foundation for Parkinson’s Research (MJFF) and co-funded by MJFF and 13 pharmaceutical and biotech industry partners. PPMI serves as a large collaboration amongst various stakeholders in the PD research arena: MJFF, industry, academic research centers in the US, Europe and Australia and the patients and individuals who are participating in the study. Recognizing the value of the data and samples that are collected through this study, all study participants have agreed to the principle of open data access; researchers throughout the world can access collected data in ‘real time’ through the study’s website (www.ppmi-info.org). Since the PPMI website launch in March 2011, over 70,000 data downloads and 23 requests for biosamples have been made.

PPMI subjects have been enrolled at 24 sites worldwide. The PD, healthy subjects and SWEDD cohorts have been fully enrolled and longitudinal assessments are underway. Comparison of baseline data in PD healthy subjects demonstrates expected marked differences in both motor and behavioral, and cognitive tests. The study design includes subject evaluation every three months during the first year and then every six months thereafter. Sites have been trained to collect clinical, biologic, and imaging data according to standardized protocols (available at the PPMI website). Blood is collected at each study visit. All subjects are also required to undergo lumbar puncture (LP) at baseline and then at six month intervals during year one and then yearly thereafter. Most of the LPs have been conducted using non-traumatic needles and approximately 15mls have been obtained at each spinal tap. The LPs have been well tolerated and approximately 85-90 percent of all subjects reaching the one-year study visit have completed three LPs. Pilot studies (n=102) of collected CSF at baseline have already demonstrated reduction in Tau, phosphor-Tau and alpha-synuclein in PD subjects compared to control subjects. All biospecimen are quality controlled and stored at biorepositories in the US or Europe. These samples are available to the scientific community for biomarker research through application to the PPMI Biospecimen Review Committee (instructions on PPMI website). The focus of PPMI is on validation of biomarkers with existing preliminary or proof of concept data with relevance to PD.

PPMI subjects undergo DaT imaging at study entry as an eligibility criteria and then PD subjects will undergo repeat DaT imaging at yearly intervals during the study. Early imaging data indicates that PD subjects demonstrate approximately a 50 percent loss of dopamine transporter binding at baseline compared to controls. All sites have undergone extensive imaging acquisition training and a specially designed phantom is acquired with each scan in an attempt to improve the standardization among sites. All imaging data is quality controlled and analyzed by a central imaging core. A subset of PPMI subset will undergo Diffusion Tensor imaging and Resting State imaging. The sites participating in these studies have similarly been trained and data will be centrally quality controlled and analyzed.

With enrollment of the PPMI PD and healthy subject cohorts complete and analysis of baseline PPMI data underway, the first paper summarizing aggregated data from the cohort is expected by the end of the 2013. In parallel with the ongoing longitudinal follow up of the PD, control and SWEDD subjects, PPMI has recently initiated enrollment of a prodromal cohort. The goal of this additional cohort is to identify PD biomarkers prior to the onset of typical motor symptoms when existing pathology and imaging has shown that neurodegeneration is long underway. The study aims to enroll 100 subjects with hyposmia and/or REM Sleep Behavior Disorder (RBD) who also show evidence of dopaminergic deficit through DaTSCAN imaging. RBD subjects will be enrolled at sites that have ongoing collaborations with sleep centers. MJFF and study sites are engaging in broad outreach across the general population to identify individuals who may be hyposmic by driving people to take a brief smell survey (www.michaeljfox.org/takethesmellsurvey). A major component of the study is to establish definitions for the onset of clinical PD as these individual phenoconvert from prodromal to manifest PD.3 Finally, most recently PPMI has further expanded and will include a genetic cohort of 600 PD subjects and at risk family members with the most LRRK2 and SNCA mutations, both to further identify individuals prior to the onset of typical PD and to compare the biomarker signature in PD subjects with a known genetic mutation to idiopathic PD (Fig 2).

In both AD and PD, there are large-scale collaborative efforts underway: PPMI for Parkinson’s, the Alzheimer’s Disease NeuroImaging Initiative (ADNI), and the Dominantly Inherited Alzheimer Network (DIAN) in Alzheimer’s. ADNI–which started in 2004–served as a model for PPMI, especially in its approach toward open data access. There are similarities across both in the type of clinical and imaging information and biosamples being collected. Many of the same analyses are being carried out in both studies including measurement of CSF levels of beta amyloid, tau, and alpha-synuclein that appear to be relevant biomarkers in both AD and PD. In addition to overlapping biomarkers, researchers are appreciating the overlapping pathologies that occur in both disorders including beta amyloid and alpha-synuclein deposition that may contribute to the cognitive dysfunction observed in both diseases. Full genomic sequencing of the PPMI and ADNI cohorts may illuminate additional common pathways that are responsible for neurodegeneration. As we increase our knowledge of both diseases, it is clear that there are learnings to be leveraged in each of the fields and we expect to accelerate biomarker discovery for both disorders through closer collaboration between the ADNI and PPMI studies.

* For complete list of PPMI Study Investigators, visit www.ppmi-info.org/authorslist

  1. Schapira, A.H. and C.W. Olanow, Neuroprotection in Parkinson disease: mysteries, myths, and misconceptions. Jama, 2004. 291(3): p. 358-64.
  2. The Parkinson Progression Marker Initiative (PPMI). Progress in neurobiology, 2011. 95(4): p. 629-35.
  3. Berg, D., et al., Defining at-risk populations for Parkinson's disease: lessons from ongoing studies. Movement disorders : official journal of the Movement Disorder Society, 2012. 27(5): p. 656-65.
 

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