DAT Imaging in Ashkenazi Jews (AJ) LRRK2 Gene Carriers - a consortium proposal

Objective/Rationale:
While most PD is not associated with a specific genetic cause, in some ethnic populations such as Ashkenazi Jews there is a high prevalence of a genetic cause for PD affecting a specific gene called LRRK2. We plan to conduct brain imaging in unaffected family members of Ashkenazi Jewish PD patients with the LRRK2 gene to investigate whether it is possible to detect changes in the brain even before any PD symptoms occur. Early detection of brain imaging changes will help to understand how LRRK2 results in PD and, ultimately, how to best develop medication to prevent the onset of symptoms.
Project Description: 
This study is part of a consortium of PD investigators in New York and Israel to evaluate patients and unaffected family members of Ashkenazi Jewish PD families. We will conduct the brain imaging component of the study. Patients and unaffected family members of Ashkenazi Jewish PD will undergo single photon emission computerized tomography (SPECT) imaging using a radioactive isotope to tag the dopamine transporter (Datscan), a protein on nerve cells that is reduced in PD. This method is a standard technique that is commonly used to diagnose PD. Using this technique it is possible to determine whether there has been a reduction in dopamine imaging activity even before any PD symptoms might arise. We plan to study whether those family members of PD patients with a LRRK2 gene mutation are more likely to show a reduction in Datscan compared to those without the gene mutation.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Utilizing DAT SPECT imaging to detect changes in unaffected family members carrying the gene for LRRK2 enables us to study the stage of PD before symptoms occur called the pre-diagnostic period. Identifying and ultimately monitoring the reduction in dopamine imaging in these ‘at risk’ family members will provide a unique opportunity to study how PD begins in LRRK2 patients and to eventually develop a strategy to develop medications to prevent the onset of PD in LRRK2 gene carriers and potentially for other causes of PD. 
Anticipated Outcome:
In collaboration with the AJ LRRK2 consortium we will assess the pre-diagnostic period for PD family members of LRRK2 PD patients. The imaging results will be correlated with comprehensive clinical testing to better understand the earliest phase of PD and ultimately to develop medications that might prevent the onset of PD symptoms. The lessons learned from these LRRK2 families also will likely provide crucial clues to the causes and treatment of both genetic and non-genetic PD.