The Search for Biomarkers in PARKINSON’S DISEASE – Part I
PARKINSON’S DISEASE is very complex. Making an accurate diagnosis depends on the observational skill of the physician doing a neurological exam and the types of symptoms exhibited by the patient. By the time symptoms have appeared, the disease is well established, the symptoms merely a marker of the progression of the disease. . Physicians and researchers have long sought some type of diagnostic test to define unique biomarkers that can accurately determine the presence or absence of this disease. The search for a biomarker is complicated by the fact that the motor and non-motor symptoms of PARKINSON’S DISEASE present at different times and affect different regions in the brain and therefore involve different biological processes. A disease with so many aspects as PARKINSON’S makes finding a unique, specific biomarker a bit like the proverbial search for the needle in a haystack. And additionally, the ideal test should also be able to measure the progression of the disease or predict development of certain symptoms.
Research has made tremendous progress in analyzing and understanding the biological processes involved in PARKINSON’S DISEASE, but usually, the analyses involve animal models of the disease, not actual humans. Research on humans can only be accomplished in individual brains after the patient has died. Some recent research has shown good results for biomarkers in cerebral spinal fluid (CSF), however that requires a lumbar puncture, a potentially painful procedure for a patient that may not have developed symptoms and also expensive to perform. Finding a reliable test using bodily fluids obtained less invasively, such as by a simple blood sample, has been the goal of some researchers using the newest “omics” research methods (proteomics, metabolomics, transcriptomics, genomics).
Proteomics is a study of proteins, and involves understanding the functions and structures as well as the complexities of the interactions of proteins involved in biological, pathological or pharmacological processes. Proteins are composed of peptides, strings of basic amino acid building blocks, and it is the combination of peptides that determine the nature of the protein. A collaboration of research institutions based at Washington State University in Seattle had done previous research in identifying proteins and peptides. A vast array of proteins can be found in human blood, proteins that come from all the organ systems in the human body found specifically in neurological diseases such as PARKINSON’S. Bringing their prior knowledge to a new proteomic research study, they narrowed the search down to the specific proteins found to be associated with functions of the central nervous system (CNS). These proteins are found in significantly smaller numbers, compared to proteins from other organs. From those CNS proteins, the research team then compared samples obtained from healthy controls to people previously diagnosed with PARKINSON’S DISEASE, and found the PARKINSON samples to have a distinctly altered profile.
Focusing on glycoproteins that have a previously explored relationship to PARKINSON’S, they then examined the peptides that compose the proteins. From an initial pool of 50 peptides, they found that 12 of them were consistently found in the plasma of people with PARKINSON’S, and further, that three of them correlated to specific diagnostic differences. A combination of two specific peptides showed a strong association with the severity of symptoms as diagnosed using the Unified Parkinson’s Disease Rating Scale (UPDRS). A combination of four specific peptides appears to be possible significant markers of PARKINSON’S DISEASE.
The researchers used a laboratory analysis method called selected reaction monitoring (SRM), which has a benefit of being fast, cost effective and is reproducible in different laboratories using different instruments. It is highly sensitive and can identify and quantify multiple proteins with high accuracy. They also used a particular technique that does not require the use of expensive antibodies, which again, would increase the efficiency for screening samples in clinical situations.
This research drew from a relatively large pool of subjects, 282, to be precise. It was successful in using easily obtained blood samples and a sensitive and cost efficient method for screening those samples for proteins and specific peptides. This research project brings the search for a unique diagnostic test for biomarkers to diagnose PARKINSON’S DISEASE many steps closer to reality. The results will need to be replicated and validated in many other independent studies and other researchers will add insights and refinement. This study does show the way to the development of diagnostic tests which can be done economically early and often to assist in diagnosis, follow disease progression and even track the effectiveness of treatments for PARKINSON’S DISEASE.
The principal investigator for this study was Jing Zhang, M.D., Ph.D. He is the Director and Shaw Professor of Neuropathology at the University of Washington, School of Medicine in Seattle, Washington. He received research assistance from The Veteran’s Affairs Puget Sound Health Care System, Department of Neurology, Oregon Health and Science University in Portland, OR and also from Department of Neurosciences, University of California at San Diego, La Jolla, CA. A total of 12 research assistants helped with this study.
Pan C, Zhou Y, Dator R, Ginghina C, ZhaoY, Movius J, Peskind, E, Zabetian C.P, Quinn J, Galasko D, Stewart T, Shi M, Zhang J. Targeted Discovery and Validation of Plasma Biomarkers of Parkinson’s Diseas J. Proteome Res., DOI: 10.1021/pr500421v pub. date May 22, 2014
Review by Marcia McCall