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Funded Studies

Imaging Neuroinflammation in LRRK2 Models of Parkinson’s Disease

The mechanisms for the initiation and progression of the loss of dopamine (DA) neurons in Parkinson’s disease (PD) are still largely unknown. Increasing evidence indicates that neuroinflammation may be a likely contributor to PD origin and its progression and that genetic mutations might predispose subjects to increased neuroinflammation. We will use transgenic models and novel imaging markers to investigate this hypothesis.

Project Description:
We will investigate microglial responses to an inflammatory stressor in the G2019S LRRK2 mutation model and assess their long-term impact on the dopaminergic system. An optimal approach to these studies is to use imaging markers, since: (i) longitudinal studies can be performed on the same models, thus significantly reducing the variability in the data, (ii) such studies can be performed in models, thus subject to potential naturally occurring regulatory mechanisms and (iii) imaging studies can be easily performed in humans, thus providing a common readout between the models and human genetically-related PD.

Longitudinal positron emission tomography (PET) imaging will be used with 11C-PBR28 as a marker of inflammation and 11C-DTBZ as a marker of dopaminergic neuronal integrity. PET imaging will be complemented by high-resolution autoradiography, post- mortem staining and behavioral measures.

Relevance to Diagnosis/Treatment of Parkinson’s Disease:
A synergic ability of neuroinflammation and LRRK2 mutation to induce or potentiate neurodegeneration could at least partially explain the limited and varying penetrance of the LRRK2-mutation related PD. In addition, the imaging protocols developed as part of this study will be immediately applicable to studies of human LRRK2 mutation carriers. If inflammation proves to be an important triggering factor for neurodegeneration in human mutation carriers, proper management of any inflammatory episode will become of utmost relevance.

Anticipated Outcome:
This will be, to our knowledge, the first longitudinal study that will explore LRRK2 regulation of the inflammatory process, influence of the LRRK2 mutations on this process and its relation to loss of dopaminergic function. The study will help to establish if subjects with LRRK2 mutations are particularly sensitive to inflammatory triggers and react with sustained neuroinflammation leading to the degeneration of the dopaminergic system. Such knowledge will be relevant to the understanding of genetically-related PD and hopefully decreasing its prevalence.


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