Noninvasive assessment of alcoholic hepatitis effects in promoting age-related cognitive decline with multiparametric magnetic resonance elastography (MRE) imaging

Project: Research project

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ABSTRACT: ADMINISTRATIVE SUPPLEMENT Aging is the most important risk factor for the development of dementia, and the leading etiology underlying most cases of dementia is Alzheimer?s disease (AD). The age-related continuous inflammation may be related to pathological processes that promote AD. Alcoholic hepatitis (AH) may also add to the effects of AD or other pathology in promoting age-related cognitive decline. In this proposal, we will develop MRE imaging techniques to detect tissue abnormalities in both brain and liver tissues in rat models with aging and AH. This may provide novel measurements to understand the systemic inflammatory mechanism, alcoholic toxicity and their possible contributions to AD in promoting age-related cognitive decline. Aim 1. Develop MRE methods for assessing multiple mechanical parameters in the brain and liver. An advanced 3D multifrequency liver and brain MRE technique will be secondarily utilized for characterizing multiple mechanical properties in vivo in small animals. We will use two different approaches to deliver multiple frequency motions externally to induce shear waves in the liver and brain tissues respectively (80-1200Hz). 3D direct inversion of a Helmholtz equation will be applied to calculate multiple mechanical properties, including storage modulus, loss modulus, shear stiffness, damping ratio, and volumetric strain. Aim 2. Establish a rat model for MRE assessment of AH and age-related brain and liver change. We will use a chronic-plus-binge alcohol feeding rat model with varying ethanol feeding duration and binge number to create different extent of liver and brain injury. Age effect will be assessed by using young, middle-aged and old rats. Aim 3. Evaluate MRE biomarkers for AH and age-related systemic inflammation and cognitive decline. We will perform liver/brain MRE on a rat model with AH and aging. The diagnostic performance will be assessed by comparing multiple in vivo imaging biomarkers with histologic measures of hepatic inflammation and neurodegeneration (i.e., neuron counts and synaptophysin measures as a primary outcome), and behavior tests (i.e., anxiety, fear, learning and memory as a secondary outcome) respectively. We will also develop statistical models to evaluate systemic inflammation and cognitive decline with multiple MRE parameters. We anticipate that this 1-year program will provide an initial evaluation of multiparametric MRE and derived systemic inflammation surrogate to detect early onset of AH and cognitive decline. This proposed study?s success will maximize clinically relevant MRE-provided information to substantially advance our understanding and ability to diagnose liver disease severity in relation to the cognitive decline with a broad pathophysiologic spectrum of the aging process. Also, the proposed multi-parametric brain MRE can further stimulate additional research on AD and related dementias. The success of this study may help establish a basis for future R01-level studies that monitor aging and age-related diseases with altered liver and brain imaging parameters.
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