Advanced MRI studies of cerebrovascular and lymphatic abnormalities in LRRK2 mouse models of Parkinson's disease

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Abstract: Parkinson’s disease (PD) is the second-most common neurodegenerative disease. Currently there is no curative therapy. Clinical evaluation of PD has been limited to psychophysical assessment, which is subjective and uninformative with regard to brain neuropathological abnormalities. Developing biomarkers for early diagnostics and treatment evaluation is critical for disease prognosis. PD cases display brain cerebrovascular, lymphatic system and structural abnormalities which contribute to the loss of dopaminergic neurons and movement disorders. Small pial arteries and arterioles are the primary controls of local brain tissue perfusion for delivery of nutrients and oxygen to supply the metabolic needs of neurons, and other cells, while lymphatic vessels play a crucial role in the clearance of waste products from brain tissues. The arterial pulsation wave from small blood vessels is the primary driving force for the fluid in lymphatic vessels and the perivascular space. Imbalance in the interaction between the two systems may have implications for PD pathogenesis. We recently developed several new MRI (Magnetic resonance imaging) techniques that can be used to measure brain cerebrovascular and lymphatic system abnormalities in both humans and animal models. We propose to test the hypothesis that abnormalities in brain microvascular and lymphatic vessels can be measured by novel MRI techniques through PD development and progression, and that those abnormalities can serve as potential indicators for pathogenic processes and treatment evaluation. Mutations in LRRK2 (Leucine Rich Repeat Kinase 2) cause genetic PD and contribute to sporadic PD. We recently generated a LRRK2 mouse model that displayed a robust PD-like phenotype and provided an excellent model for MRI assessment. MRI measures can be validated with invasive techniques in LRRK2 mouse models using histological methods. The longitudinal study and therapeutic testing can be done in a relatively short time period in these mice. Our pilot study found that mutant G2019S-LRRK2 mice display cerebrovascular abnormalities. Thus, we propose to use new MRI methods to study brain pathophysiological changes in cerebrovascular and lymphatic vessels underlying PD using LRRK2 mouse models with or without MPTP (a toxin to speed disease progression) and lipopolysaccharide (a preinflammatory agent) challenge by combining behavioral testing and brain histochemical studies. Aim 1. We will assess abnormalities in brain small blood vessels in LRRK2 mouse models. Aim 2. We will assess abnormalities in the perivascular space and cerebral lymphatic vessels in the brain in LRRK2 mouse models. Aim 3. We will characterize the abnormalities in the interactions between brain microvascular and lymphatic vessels, and assess whether cerebrovascular and lymphatic measures can be used to evaluate treatment efficacy of L-DOPA, LRRK2 kinase and GTP binding inhibitors. These studies will advance our understanding of the neuropathological changes underlying PD pathogenesis, which may facilitate the development of biomarkers for diagnostics and PD intervention.