20 October 2010. The Parkinson’s Progression Markers Initiative (PPMI) was launched in July with hopes of identifying a biomarker, or set of markers, that tracks the natural course of Parkinson disease in 400 newly diagnosed PD patients and 200 healthy controls. Modeled after the Alzheimer’s Disease Neuroimaging Initiative (ADNI), but with more initial emphasis on fluid biomarkers (see Part 1), PPMI also includes brain imaging—not only as part of the longitudinal data, but also to determine who is eligible to enroll. The study seeks people at the earliest stage of PD, namely, those diagnosed less than a year ago who have not yet gone on medication. In addition, study volunteers must have abnormal dopamine transporter (DAT) imaging at baseline. This means their brain scan needs to show evidence of dopaminergic neuron loss, as detected by single photon emission computed tomography (SPECT) imaging using a radiolabeled DAT ligand (DaTSCAN).

DaTSCAN is made by GE and has been used as a diagnostic agent in Europe since 2000, mainly to distinguish PD from other disorders with overlapping symptoms, such as essential tremor. In the U.S., the imaging agent could have gained approval by the Food and Drug Administration (FDA) in 2009, but only as a Schedule II drug, according to John Seibyl of the Institute of Neurodegenerative Disorders in New Haven, Connecticut. Schedule II drugs have safe and accepted medical uses, but face tighter distribution because they carry a risk of abuse. “GE decided it would be difficult for some sites to handle the burden of the extra paperwork and drug accountability associated with a Schedule II drug,” said Seibyl, who directs PPMI’s imaging core. The regulation does not consider that the radiopharmaceutical is administered at mass doses several orders of magnitude below the threshold required to approach a pharmacologic range, he noted.

Seibyl’s group did much of the early work characterizing DAT tracers and applying them as imaging biomarkers in PD. He performed those studies in collaboration with PPMI’s principal investigator, Ken Marek, Institute of Neurodegenerative Disorders, when both were at Yale University (Seibyl et al., 1998). Even though DaTSCAN has not yet gained FDA approval as a diagnostic, U.S. scientists can use the imaging agent for research purposes. However, delivery of the ligand to Canada is problematic, according to Sohini Chowdhury of the Michael J. Fox Foundation for Parkinson’s Research, which is sponsoring the $40 million PD biomarkers study. As a result, Canadian sites, though well represented in ADNI, are not included in PPMI.

Seibyl and coworkers at the Institute of Neurodegenerative Disorders have tweaked DaTSCAN (aka “FP-CIT”) to produce a related compound, “beta-CIT.” This SPECT tracer has higher signal-to-noise ratio, which is desirable, but on the downside, it requires 16-18 hours (compared to DaTSCAN’s three to four) to achieve a strong quantitative signal in the brain, Seibyl said. In practice, this means the patient can’t receive the scan on the day of the injection, but must return to the clinic the next day.

Seibyl’s studies with this agent indicate that SPECT imaging is sensitive enough to pick up striatal dopamine transporter abnormalities in the area corresponding to the side of the body that does not yet show clinical signs. “Imaging is very sensitive to changes in the brain even prior to motor symptoms,” said Seibyl, noting that SPECT could be useful to screen for patients who are on the verge of PD. Though PPMI itself is not designed to evaluate biomarkers in at-risk populations, future phases of the study may look more closely at pre-motor stages. Similarly, the second ADNI study applies the results of the first ADNI study to place much greater emphasis on earlier, pre-dementia stages.

In the current phase of PPMI, participants will receive two types of brain imaging once a year—SPECT to gauge dopaminergic abnormalities, and diffusion tensor magnetic resonance imaging (DT-MRI). By quantifying the degree of randomness in water molecules moving through the brain, DT-MRI can pick up disturbances in the integrity of neural networks. “Water molecules move in a non-random fashion when traveling on nerve fibers,” Seibyl explained. “You see more randomness in those pathways when there is a lesion. You can put a number on it.” DT-MRI is being tested as an exploratory measure in eight of PPMI’s 18 sites; they are Northwestern University (Chicago, Illinois), Johns Hopkins University (Baltimore, Maryland), Emory University (Atlanta, Georgia), Baylor College of Medicine (Houston, Texas), Federico II University (Naples, Italy), University of Marburg (Kassel, Germany), University of Tuebingen (Germany), and the Parkinson’s Institute (Sunnyvale, California). ADNI also includes diffusion tensor imaging.

Transcranial ultrasound, a different imaging technique developed in Germany that detects areas of increased iron deposition in the brain, was also considered for PPMI. However, the data on this method have shown great variability. “Some sites are very good and very reliable. But some studies we have not been able to corroborate,” Seibyl said. Ultimately, the technique was ousted because of “technical difficulties in getting consistency in a multicenter study,” he said. “We thought it would be hard to achieve the rigor for standardization.” Transcranial sonography and SPECT did look promising as markers in a recent study of people with a rare sleep disorder associated with elevated risk of PD and other synucleinopathies (Iranzo et al., 2010 and ARF related news story).

In the future, Seibyl sees physicians using neuroimaging to confirm predictions of elevated risk in people with sleep problems and/or lost sense of smell (aka hyposnia). The ongoing Parkinson’s Associated Risk Study (PARS) aims to see whether low scores on a scratch-and-sniff smell test can reliably predict who faces elevated PD risk. Olfaction and sleep tests are included in the clinical workup done on PPMI participants. These results may be especially informative for control participants, some of whom may end up developing PD years later. “The [controls] may be the jewel in this whole study,” Seibyl said. “The problem is, we’ve biased ourselves a little bit. By excluding people with an abnormal DaTSCAN, we’ve made the normal population pretty pristine.” Nevertheless, if PPMI achieves its goal of validating a biomarker profile for just-diagnosed PD patients, it might be possible to “work backward and apply it to at-risk individuals to predict who is most likely to progress to PD,” said PPMI steering committee member Andrew Siderowf, University of Pennsylvania, Philadelphia.—Esther Landhuis.

This is Part 2 of a two-part series. See also Part 1. View PDF of entire series.