To Study Mechanisms of a Non-Pharmacological Treatment Strategy for Alzheimer’s disease - Project Summary/Abstract: Accumulation of brain derived metabolic waste is the major pathophysiological feature of Alzheimer’s disease. We hypothesize that brain waste clearance can be accelerated by a mechanoceutics treatment known as cranial osteopathic manipulation (COM). COM has been successfully used in the outpatient setting for various neurological disorders and has been proven effective by cross disciplinary studies. Although in clinical practice since 1930’s, lack of understanding of COM molecular mechanisms limit public awareness and interest on this non-invasive treatment which has potential to improve the symptoms of Alzheimer’s disease. Therefore, it is critical to understand the biological effect of COM treatment using experimental animal models of Alzheimer’s disease. Here, we propose to study the molecular mechanisms of COM induced improvement in cognitive function, CNS fluid circulation and relevant changes in protein expression using aged and transgenic rat model of Alzheimer’s disease. In this research work, we will carry out the following specific aims to understand the mechanisms of COM: Aim 1. To determine the influence of COM on spatial learning and memory in transgenic and naturally aged rat model of Alzheimer’s disease. Osteopathic physicians with expertise in COM will, by wearing custom made tactile pressure monitoring nano-sensor gloves, apply quantifiable mechanical pressure around the fourth ventricle with the goal of improving fluid circulation in the rat brain. This treatment induced improvement in learning and memory will be studied by two independent behavioral assays. These experiments will reveal the changes in cognitive function produced by transferring COM to an experimental animal model of Alzheimer’s disease. Aim 2. To demonstrate COM induced improvement in brain fluid circulation in live rats. We will study the changes in the kinetics of radioactive tracer fluorodeoxyglucose movement through cisterna magna, deep cervical lymph nodes and heart using dynamic positron emission tomography imaging. Further a dynamic contrast-enhanced magnetic resonance imaging will be performed to study spatiotemporal changes in gadolinium signal intensity to determine solute movement velocity. These live animal imaging studies will report COM mediated effects in CNS fluid circulation. Aim.3 To identify molecular level changes in substrates of learning and memory and brain fluid circulation in COM treated animals. Quantitative immunoassays will be carried out to study the expression of macromolecules including amyloid and markers of lymphangiogenesis, water homeostasis and synaptic substrates of learning and memory. Collectively, these findings will provide insights on the molecular mechanism of COM effects observed in aim 1 and 2. Overall, this proposal seeks to study the biology of a medical practice that is not generally considered as part of conventional medicine. The outcome of this study will generate public awareness and interest in a low cost, non-invasive adjunct treatment strategy for Alzheimer’s disease. 1
