Investigation of Neuroinflammation in LRRK2 Mutation Carriers Using Positron Emission Tomography

Objective/Rationale:             
There is evidence that LRRK2 mutation may alter the immune response in such as way as to potentiate neuroinflammatory responses to external triggers, with a downstream selective impact on the dopaminergic system. It is thus reasonable to surmise that the primary, or at least a very important, mechanism by which LRRK2 mutations induce PD, is related to the link between LRRK2 function and the immune system.

 Project Description:             
The first goal is to determine whether neuroinflammation is present in LRRK2 mutation carriers that are at risk of developing PD. Positron emission tomography (PET) imaging studies will be performed in asymptomatic and early symptomatic mutation carriers using ¹¹C-PBR28 (PBR28) as a marker of inflammation, ¹¹C-DTBZ (DTBZ) as a marker of dopaminergic neuronal integrity and ¹⁸Fdopa (FD) as a marker of turnover and dopamine synthesis. If evidence of neuroinflammation is found, a larger study will be undertaken to investigate the temporal relationship between dopaminergic deficit and neuroinflammation.

Relevance to Diagnosis/Treatment of Parkinson’s Disease:                     
This study could help unravel one of the mechanisms leading to PD onset. If an exaggerated response to inflammatory triggers is indeed found to lead to PD, novel treatment targets can be identified. Most importantly, if treatment targeting the immune system is administered early in a subject-at-risk life, it might decrease the probability of PD occurrence.

Anticipated Outcome:          
This study will ascertain if neuroinflammation is present in LRRK2 mutation carriers and will provide preliminary insights into its relation to dopaminergic deficit and will inform whether further studies are warrantied. If so, it will also help define at what stage of a subject life the collection of imaging data will be most informative to conclusively unravel if neuroinflammation precedes dopaminergic deficit. If evidence of early neuroinflammation is found, similar studies could be extended to other conditions that are known risk factors for PD, to ascertain if neuroinflammation in the premotor stage is LRRK2-mutation specific or is common to other forms of parkinsonism.