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Developing Biomarkers for Parkinson's Disease


 

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A blood test that can differentiate patients with early-stage Parkinson’s disease from healthy patients or those with Parkinson’s disease–like symptoms but without dopaminergic deficit would revolutionize diagnosis and treatment of, as well as research on, the disease. Mikhail Bogdanov, MD, from Weill Cornell Medical College in New York City, and colleagues may have developed the prototype for such a test.

Regarding pilot data reported in the February Brain, “We discovered a clear differentiation between the metabolomic profiles of the Parkinson’s disease patients versus those of the controls,” said coauthor M. Flint Beal, MD, Chairman of the Department of Neurology at Weill Cornell Medical College and Neurologist-in-Chief at New York Presbyterian Hospital.

The study further implicates oxidative stress as a factor in Parkinson’s disease, Dr. Beal told Neurology Reviews. Metabolomic profiling showed increased levels of 8-hydroxy-2-­deoxyguanosine (8-OHdG), a marker of oxidative damage to DNA, in patients with Parkinson’s disease, as well as reduced levels of uric acid and increased levels of glutathione, both of which are associated with oxidative stress.

Developing a Profile for Parkinson’s Disease
The metabolomic profile was developed by examining differences in small molecules in the plasma from 66 patients with Parkinson’s disease and 25 controls. The researchers used high-performance liquid chromatography coupled with electrochemical coulometric array detection ­(LCECA) to screen for potentially useful biomarkers among more than 2,000 small molecules. They then used the smaller number of candidate markers to generate quantitative profiles that could be compared between patients and controls. “A metabolomic biomarker that predicts disease, measures progression, or monitors therapy potentially could be a single molecule, as well as a pattern of several molecules,” explained the researchers. “If the relevant species are defined and identified, there are several technologies that can be used to develop rapid targeted assays suitable for clinical use.”

According to Dr. Beal, the profile developed in this study was able to differentiate patients with Parkinson’s disease from those without the disease. “We found a complete separation of the two groups,” he said. “No one molecule was definitive, but a pattern of about 160 compounds emerged that was highly specific to Parkinson’s patients.”

Profiling based on changes in metabolism is a reasonable strategy in Parkinson’s disease, because a number of genetic mutations associated with Parkinson’s disease are likely to disarrange cellular metabolism. These mutations include α-synuclein, parkin, DJ1, PINK1, and LRRK2. “Strong evidence relates mutations in these genes to protein aggregation, mitochondrial dysfunction, and oxidative damage. It is, therefore, quite feasible that mutations in these genes may lead to metabolic abnormalities, which are detectable in peripheral tissues,” Dr. Beal said.

A subgroup comparison showed that the changes were not the result of Parkinson’s disease treatment, because the profiles were able to distinguish between controls and patients with Parkinson’s disease treated with either carbidopa-levodopa or the combination of carbidopa-levodopa with dopamine receptor agonists.

These findings are of great importance, as current Parkinson’s disease diagnosis is based on asymmetric parkinsonism, rest tremor, and levodopa response, according to Dr. Beal. The general assumption, he noted, is that clinical diagnosis is 90% accurate at best. “This can cause real problems, because that remaining 10% of patients—who may have look-alike conditions such as multisystem atrophy or progressive supranuclear palsy—end up getting treated with Parkinson’s drugs,” he said. Such conditions are generally unresponsive to pharmacotherapy and surgical treatment.

A Benchmark for Disease Progression?
The findings have implications for early intervention in patients with true Parkinson’s disease and for clinical trials of potential neuroprotective therapies. In the Earlier versus Later L-DOPA (ELLDOPA) study, 21 of 142 subjects had no evidence of dopaminergic deficit when examined by bCIT single-photon emission CT imaging. Ten of these 21 patients were followed for 48 months, and all 10 continued to have normal scans, suggesting that at least 7% of the subjects did not have Parkinson’s disease.

Dr. Beal said that LCECA, as used in this study, is currently only a research tool. His group is extending these studies to include more patients and will be evaluating subjects at serial intervals to see if this test might also serve as a benchmark for disease progression. “We are also looking at people who carry a gene for a familial form of Parkinson’s but who do not have the illness now,” Dr. Beal said.

—Janis Kelly


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