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Parkinson's Progression Markers Initiative Publishes First Study, IDs Four Potential Disease Markers

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Researchers from the Parkinson's Progression Markers Initiative have identified an association between four cerebrospinal fluid protein markers and clinical features in patients with early Parkinson's disease.

In a study published this week in JAMA Neurology, the researchers found that CSF α-synuclein, β-amyloid 1-42, tau, and phospho-tau have potential as prognostic and diagnostic markers for Parkinson's. Most notably, they found that β-amyloid 1-42 and phospho-tau were significantly linked to the postural instability-gait disturbance, or PIGD, subtype of Parkinson's, which has been associated with quicker and more severe cognitive decline and functional disability than other varieties of the disease.

Launched in 2010 with funding from the Michael J. Fox Foundation, the PPMI is a collaboration between academic, government, and industry aimed at verifying progression markers for Parkinson's disease. The initiative's research is taking place at 24 clinical sites across the US, Europe, and Australia, and aims to establish a comprehensive, standardized, longitudinal Parkinson's data and sample repository for use by researchers investigating the disease.

This week's JAMA Neurology paper marks a milestone for the group as its first publication, John Trojanowski, a University of Pennsylvania researcher and head of the PPMI Bioanalytics Core, told ProteoMonitor.

In the study, the researchers examined 63 patients and 39 health controls, finding, they wrote, "slightly, but significantly, lower levels" of the four markers in Parkinson's cases compared to controls and significantly lower levels of β-amyloid 1-42 and phospho-tau in the PIGD subtype as compared to other patient subtypes or controls.

Three of the markers investigated in the study — β-amyloid 1-42, tau, and phospho-tau — have been traditional areas of focus in Alzheimer's biomarker research. They are considered potential Parkinson's markers, as well, Trojanowski said, due to the fact that many Parkinson's patients develop cognitive impairment similar to that seen in Alzheimer's sufferers.

"About 80 percent of Parkinson's patients will develop dementia over the course of their illness," he said. "Some of it is attributable to Lewy bodies in the cortical area, but about a third of patients will develop Alzheimer's pathology to account for their cognitive impairment."

While there have been some previous studies looking at the four markers in Parkinson's patients, the PPMI effort is the first, Trojanowski said, to look at CSF biomarkers in unmedicated Parkinson's sufferers at a very early stage in the disease.

He noted that, while the markers did show potential usefulness for early identification of Parkinson's sufferers and, in particular, patients in the PIGD subtype, the researchers "still have a ways to go to developing an algorithm or formula for predicting who will progress to dementia based on these biomarkers or those who are asymptomatic who will progress to Parkinson's disease."

The researchers plan to follow the JAMA Neurology work with a larger study analyzing around 1,000 additional CSF samples from the same set of patients. Trojanowski added that the PPMI group also hopes to launch a follow-up study late this year or early 2014 with a significantly larger number of subjects.

In addition to looking at patients in the early stage of the disease, the PPMI researchers also hope to study pre-symptomatic subjects. As in Alzheimer's, it is hoped that therapy for Parkinson's can be made more effective by delivering it early in the disease's progression, Trojanowski said.

"We assume that Parkinson's patients will respond better to disease modifying drugs at the earliest stage of the disease," he said. "So we would like to identify patients earlier in the disease course. We're trying to move upstream to identify people at the stage at which the pathology is there but before they become impaired in their movements or develop other impairments."

To do this, Trojanowski said, the PPMI is looking at subjects who exhibit certain characteristics known to predispose them to developing Parkinson's at a higher rate — specifically, REM Sleep Behavior Disorder, hyposmia, or the reduced ability to smell odors, and mutations in the LRRK2 gene. The initiative has set a goal of enrolling 100 such patients.

The researchers are also looking for blood-based biomarkers, which, Trojanowski noted, would allow patients to avoid the lumbar puncture procedure needed to obtain CSF. His UPenn colleague Alice Chen-Plotkin — a co-author on the JAMA Neurology paper — is currently looking at several potential plasma markers including epidermal growth factor and apolipoprotein A1, he said.

With UPenn researcher and PPMI participant Leslie Shaw, Trojanowski is also co-director of the National Institute on Aging's Alzheimer's Disease Neuroimaging Initiative. In the course of that work, he has done considerable research into β-amyloid 1-42, tau as biomarkers for Alzheimer's disease. This work has included extensive research into standardizing measurements of the markers across clinical sites, research, he noted, that is now facilitating use of these markers in multi-site Parkinson's projects like the PPMI.

"Standardization is absolutely critical, and we are making excellent progress in that direction," he said, noting that the β-amyloid 1-42 and tau assays have become highly reliable, achieving over 95 percent accuracy. The α-synuclein assays "require, I think, more attention," he said. "But they are moving along in a very positive direction toward becoming more standardized."

The Michael J. Fox Foundation is currently soliciting researcher requests for funding to analyze the PPMI data and samples. Researchers may request up to two years and $250,000 in total costs. Review of requests is slated to take place in October and December of this year. The MJFF will hold a conference call at noon on Sept. 17 to further explain the initiative and answer researcher questions.

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