Increased Dopamine Turnover as a Manifestation of LRRK2 Mutation
Pharmacodynamic Biomarkers of LRRK2 Activity, 2010
Mutations in LRRK2 represent the single most important cause of dominantly inherited Parkinson’s. We have previously shown that people with LRRK2 mutations have abnormal dopamine function prior to clinical disease, but the most striking abnormality is an increase in dopamine turnover, which is present in early adulthood, many years before other abnormalities. This suggests not only a very sensitive biomarker in LRRK2 carriers, but also a mechanism by which dopamine cells may undergo progressive degeneration.
We will use positron emission tomography (PET) to study the dopamine system in detail in people from families with different LRRK2 mutations. We will study dopamine innervation by assessing vesicular monoamine transporter type 2 (VMAT2) and dopamine transporter (DAT) binding. Dopamine turnover will be assessed by performing prolonged scans with 6-fluorodopa (FD) using methods developed at our centre. This method also provides another indirect measure of dopamine innervation but is particularly sensitive to the relationship between the rate at which dopamine is lost from storage packets and the rate at which it is synthesized. The related property of dopamine release will be studied by measuring changes in dopamine receptor binding in response to amphetamine, which stimulates dopamine release. These measures will be compared in families with different mutations in LRRK2 and the results will be related to those derived from parallel studies conducted in pre-clincal models in our centre.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Functional imaging using PET, although primarily used for research purposes, is already well established as a diagnostic tool for PD. Although its utility for detecting pre-clinical disease has been recognized for many years, it is an impractical approach for broad population screening. People with aSymptoms & Side Effects LRRK2 mutations represent an ideal population to study, as they have a known abnormality predisposing them to PD but can be studied long before disease occurs. In addition to establishing a non-invasive biomarker to use in future studies of treatments designed to slow or halt LRRK2 parkinsonism, these studies may reveal a mechanism by which disease progression occurs and therefore suggest potential new strategies for protection against disease in at-risk individuals.
We anticipate that the studies performed here will demonstrate (i) that dopamine turnover is affected many years before other markers of dopamine function and before disease onset; (ii) that this abnormality will affect people from multiple different families with LRRK2 mutations, irrespective of mutation; (iii) that dopamine release will be altered in mutation carriers and (iv) that dopamine turnover will ultimately prove to be a sensitive readout for the effects of disease modifying agents in LRRK2 parkinsonism.
Professor and Head of Neurology, and Director of the Pacific Parkinsonís Research Centre at University of British Columbia
Location: Vancouver, Canada