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Pilot Study Points to Circulating miRNAs as Potential Parkinson's Biomarkers

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Researchers from the Van Andel Institute and the University of Colorado last month reported on the identification of a series of plasma-based microRNAs that could potentially be used as biomarkers for Parkinson's disease.

The data weren't all positive, with the robust results achieved in one set of patients failing to be replicated in a different set. Still, the study suggests that blood-borne miRNAs may offer a means to diagnose Parkinson's disease earlier than current approaches, which rely on subjective analyses of motor function impairment that typically occurs when the disease has progressed significantly.

"A diagnostic test to determine the status of a patient's disease onset would provide crucial data for more timely, efficient, and successful therapeutic interventions," Patrik Brundin, director of the Van Andel Institute's Center for Neurodegenerative Science, said in a statement. "There is an urgent need to develop objective, measureable biomarkers to improve PD diagnostics and help define its subtypes, and [the recent] study is an important step in that direction."

According to the paper, which appeared in the Journal of Parkinson's Disease, current PD candidate biomarkers are primarily based on individual proteins related to the pathogenesis of the disease in cerebral spinal fluid and brain tissue, which makes obtaining samples from patients difficult or impossible.

Moreover, conflicting results from studies in cerebral spinal fluid proteins have been reported due to assay differences and/or blood contamination, the study's authors wrote. “In contrast, blood is an ideal source for biomarkers due to its propensity to contain biological and chemical signals from relevant sources such as cells associated with a disease,” and sample collection is simple and inexpensive.

Noting that miRNAs are abundant, tissue-specific, and quantifiable in plasma, the researchers hypothesized that certain of the non-coding RNAs might serve as biomarkers for PD. In an initial study, the team collected blood samples from 32 PD patients and 32 normal individuals, and identified nine pairs of PD-predictive classifiers and 13 differentially expressed miRNAs as potential biomarkers that could distinguish between healthy and diseased people.

RT-qPCR was then used to validate these biomarkers in plasma in a set of 42 additional PD patients and 30 controls from the same clinical site. They found that a panel comprised of four miRNAs — miR-1862, miR-450b-3p, miR-626, and miR-505 — achieved the highest predictive biomarker performance: 91 percent sensitivity, 100 specificity, 100 percent positive predicted value, and 88 percent negative predicted value.

The scientists then tested the performance of this panel in a new, independent set of 30 PD patients from a different site, but were unable to replicate their earlier findings since miR-450b-3p could not be detected.

“However, interestingly … miR-626 showed high specificity but poor sensitivity, while miR-505 showed the reverse,” the team wrote. “We also examined the associations between age, gender, and treatment of these biomarkers, but there were no significant statistical differences between these groups.”

They noted that certain limitations to the study should be considered when interpreting the findings, including the influence of medication and medical co-morbidities on miRNA expression. “Xenobiotic drugs have been known to alter miRNA expression in human cancer cell lines,” the researchers stated. “In peripheral blood, differentially expressed miRNAs were found in levodopa treated versus untreated patients.”

They did not perform global miRNA profiling on the treated and untreated PD patients, but the RT-qPCR results showed no statistical significance in the plasma miRNA expression of the non-medicated versus medicated Parkinson's patients examined, “suggesting that variable miRNA expression may be due to disease severity or medical co-morbidity.”

The second important limitation, they added, was the number of individuals who participated in the research. “Our studies can be strengthened with a larger number of patients in the discovery phase to increase the power of statistical analyses and obtain statistically significant results in various subtypes of PD,” they wrote.

The investigators added that, ideally, patients in future studies would be recruited using standardized clinical and biological protocols from multiple centers. “However, to eventually test biomarker candidates in practicing clinical settings, non-standardization of clinical and biological procedures is probably unavoidable and may remain a challenge.”

At the same time, TaqMan RT-qPCR may not be the most sensitive technology to validate the expression of all miRNAs, the team stated, pointing out that they came across examples of miRNA non-expression using the platform. “Direct measurement of miRNA expression without enzymatic reactions or bias using the NanoString technology may be an alternate approach to validate the biomarkers.”

In the end, the work represents a pilot study, offering “new opportunities to the exploration of circulating miRNAs for diagnostic, prognostic, and therapeutic interventions for PD and possibly other neurodegenerative diseases,” the paper's authors concluded.

“Our future plans include cross-platform re-discovery and re-validation using next-generation sequencing of miRNAs and miRNA microarrays in larger and independent multi-center standardized samples,” they wrote. “In order to achieve the ultimate goal of developing a quantifiable clinical diagnostic test that can better define PD risk, an integrated and multi-disciplinary approach such as coupling plasma-based biomarkers with imaging technology may be necessary to develop a powerful next-generation diagnostic tool for PD.”

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