Biomarker for Parkinson's disease found in urine

Researchers have identified a biomarker in the urine of certain patients with Parkinson’s disease. The biomarker predicted disease risk in people who had the leucine-rich repeat kinase (LRRK2) gene mutation—the most common known genetic cause of Parkinson’s disease.

The researchers reported their findings in two recent articles, one published in Neurology and one in Movement Disorders.

No validated biomarkers currently exist for diagnosing Parkinson’s disease or measuring its severity. So, identifying LRRK2 mutation carriers and finding biological markers of Parkinson’s are important because this could mean early or even preventive treatment of the disease.

For this research, neurologists at University of Alabama at Birmingham (UAB) in Birmingham, AL, and at Columbia University in New York, NY, found that the protein produced by LRRK2, and other proteins linked genetically and pathologically to Parkinson’s, could be detected in exosomes isolated from human biofluids, such as urine. Exosomes are nanovesicles—containing protein, mRNA, and microRNA markers—that are released from most viable cells.

Up to this point, researchers have had difficulty obtaining such proteins due to the limited availability of disease-susceptible tissue, and because specimens for studying Parkinson’s disease have to be obtained post-mortem. This research marks a turning point because the investigators found a way to purify exosomes from patients’ urine samples, and then they measured amounts of phosphorylated LRRK2 in those exosomes.

“Nobody thought we’d be able to measure the activity of this huge protein called LRRK2 in biofluids since it is usually found inside neurons in the brain,” said lead investigator Andrew West, PhD, co-director of UAB’s Center for Neurodegeneration and Experimental Therapeutics.

“New biochemical markers like the one we’ve discovered, together with new neuroimaging approaches, are going to be the key to successfully stopping Parkinson’s disease in its tracks,” added Dr. West, who is also John A. and Ruth R. Jurenko Professor of Neurology at UAB.

In the Neurology study, the researchers found that LRRK2-mutation carriers with Parkinson’s had more than double the level of the biomarker (phosphorylated LRRK2) in their urine when compared with LRRK2-mutation carriers who didn’t have Parkinson’s (yet).

Also in this study, when the researchers tested LRRK2 kinase inhibitors in cell culture, they found that the inhibitors diminished phosphorylated LRRK2 levels. This seems to suggest that the urine biomarker test could be used to monitor potential Parkinson’s drugs that work by this mechanism.

“I think the days of blindly testing new therapies for complex diseases like Parkinson’s without having active feedback both for ‘on-target’ drug effects and for effectiveness in patients are thankfully coming to an end,” Dr. West said.

In the follow-up study in Movement Disorders, the researchers obtained urine samples from 79 patients diagnosed with Parkinson’s disease and from 79 neurologically healthy controls enrolled at the UAB Movement Disorder Clinic. None of the participants carried a LRRK2 mutation.

The researchers found that levels of the urinary biomarker were about 1.5 times higher in Parkinson’s patients than in healthy controls. Phosphorylated LRRK2 levels also correlated with cognitive impairment severity and difficultly in accomplishing activities of daily living.

With LRRK2-targeted therapeutics on the horizon, biomarkers for Parkinson’s deserves further study, the authors concluded. However, questions still remain. For instance, none of the patients in the follow-up study had the LRRK2 mutation, yet many of the urine samples showed elevated levels of phosphorylated LRRK2—where it derived from remains undetermined, the researchers acknowledged.