Advanced MRI Studies of Cerebrovascular and Lymphatic Abnormalities in LRRK2 mouse models of Parkinson's disease

Johns Hopkins University, Baltimore MD

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Abstract

This is a supplemental proposal to 1R01NS120879-01, “Advanced MRI studies of cerebrovascular and lymphatic abnormalities in LRRK2 mouse models of Parkinson’s disease”. The goal of this RO1 is to establish and evaluate neurophysiological abnormalities measured by advanced MRI techniques as progression markers for Parkin- son’s disease (PD). Cognitive impairment has now been widely recognized in PD. Approximately 30% of indi- viduals with PD have PD dementia (PDD), and upwards of 80% of individuals with PD will develop PDD within 15 years of motor symptom onset. The cognitive change that occurs in patients with PD greatly contributes to morbidity, mortality, and caregiver burden above PD alone. It is of importance to investigate and compare the functional and neurophysiological changes underlying PD and dementia. Thus, we propose to use the MRI and other techniques established in the parent R01 to test the hypothesis that abnormalities in brain microvascular and lymphatic vessels can be measured with novel MRI techniques through Alzheimer’s disease (AD) develop- ment and progression, and that those abnormalities can serve as potential indicators for pathogenic processes using the 3xTg-AD mouse model. Although AD dementia is different from PD dementia, the two types of de- mentia do have many common behavioral, functional, and physiological changes in the brain. The 3xTg-AD mice are overexpressed three familial AD-linked mutations (APP lSwedish, MAPT P301L, and PSEN1 M146V) in the brain, and display key features of human AD including cognitive impairment, Aβ deposits, gliosis and tau pathol- ogy. Thus, it is an ideal model for our MRI studies of blood and lymphatic vessel changes at the early stage of the disease, and their correlation with cognitive impairment, Aβ deposits and tau pathology. The early-stage biomarkers are of utmost importance for early diagnosis and for determining the prognosis from early treatment. Thus, we will use normal and 3xTg-AD mice at 3, 6, 9 and 12 months of age to study cerebrovascular abnormal- ities in the disease progression, especially in the early stage. Using the methods established in the parent R01, we have performed a pilot study of 3xTg-AD mice at 3 months of age to show the feasibility and we are confident that the proposed studies can be completed within one year via three specific aims. Aim.1. We will assess whether brain neurovascular abnormalities can be identified in 3xTg-AD mice. Aim 2. we will assess whether abnormalities in the perivascular space and cerebral lymphatic vessels can be identified in 3xTg-AD mice. Aim 3. we will study the interactions among brain neurovascular and lymphatic abnormalities in 3xTg-AD mouse model. The outcomes will be compared with the PD mouse studies in the parent R01 using the same analytical methods. This is a natural extension of the parent R01, and a highly effective way to utilize the resource provided by the parent R01 and to maximize the impact of the research. These studies will provide novel understanding of neurovascular abnormalities corresponding to AD and PD related pathology and dementia and may provide novel biomarkers for disease progression.