Andrew West, Ph.D., and colleagues at the University of Alabama at Birmingham (UniAlB) discovered a brand-new type of biomarker - a phosphorylated protein that correlates with the presence and severity of Parkinson’s disease (lat. Parkinson scriptor morbus). Scientists with support from the National Institutes of Health, the Michael J. Fox Foundation for Parkinson’s Disease Research and the Parkinson’s Disease Foundation, are digging deeper into these biobanked samples, to validate the biomarker as a possible guide for future clinical treatments and a monitor of the efficacy of potential new Parkinson’s drugs in real time during treatment.
New biochemical markers like the one scientists have discovered together with new neuroimaging approaches are going to be the key to successfully stopping Parkinson’s disease in its tracks. Scientists 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. In the Neurology study, scientists found that elevated phosphorylated LRRK2 predicted the risk for onset of Parkinson’s disease for people carrying a mutation in LRRK2, which is about 2-3 percent of all Parkinson’s disease patients. These findings were first tested with a preliminary, 14-person cohort of urine samples from the Columbia University Movement Disorders Center. That was followed by a larger replication study of 72 biobanked urine samples from the Michael J. Fox Foundation LRRK2 Cohort Consortium. All samples were provided to UAB in a blinded fashion to ensure the approach was rigorous.
The follow-up Movement Disorders paper - the first study of its type - expanded the scope to people without LRRK2 mutations, which is most Parkinson’s disease patients. Using 158 urine samples from Parkinson’s disease patients and healthy controls enrolled in the UAB Movement Disorder Clinic as part of the NIH Parkinson’s Disease Biomarker Program, Andrew West and colleagues found that approximately 20 percent of people without LRRK2 mutations but with Parkinson’s disease also showed highly elevated phosphorylated LRRK2 similar to people with LRRK2 mutations, and this was not present in healthy controls. The study speculates that people with elevated phosphorylated LRRK2 may be particularly good candidates for future drugs that reduce phosphorylated LRRK2.
Questions remain for this evidence of biochemical changes in LRRK2 in idiopathic Parkinson’s disease. One is finding out where the urinary exosomes come from. Given a suspected role for inflammation in Parkinson’s disease, it is interesting that LRRK2 is highly expressed in cells of the innate immune system. A possible explanation for the phosphorylated LRRK2 in patients with more severe disease may be an increased inflammation in those patients who have an aggressive progression of a disease. Andrew West was awarded a new collaborative grant from the National Institute of Neurological Disorders and Stroke to further explore urinary exosomes and extend the observations to cerebral-spinal fluid as a marker for disease prediction and prognosis.