RESEARCH

Introduction

Injuries and diseases of the brain lead to activation of resident brain macrophages (microglia). In neurodegenerative diseases (ND) such as Alzheimer’s and Parkinson’s disease (AD, PD) it is still unclear whether altered protein metabolism or activation of a microglial response drives disease progression. Activated microglia exists in various phenotypes depending on the nature and stage of disease. Microglial responsiveness to injury suggests that they may serve as diagnostic marker for disease activity and progression (Perry et al. 2010). This project focuses on the assessment of the dynamic in vivo pattern of microglial activation at various disease stages (early, late, under therapy) in AD, PD, Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS) with the dual aim of developing novel assessment and treatment paradigms based on new knowledge on microglial activity and regulation in model systems and patients in vivo. Moreover, the systemic immune system modulates various brain functions including glial reactivity following neuronal injury as well as microglia subpopulations originating from blood progenitor cells. The development of strategies for safe modulation of the systemic immune system to prevent or repair neuronal dysfunction is a major challenge. In a series of preclinical and clinical studies, our group has developed non-invasive tools to assess and quantify the dynamics of activated microglia in vivo in response to hormones and cytokines, in various disease states, and in response to anti-inflammatory treatments. In this project we will focus on the study of molecular mechanisms of neuroinflammation (NI) in ND to identify novel biomarkers for activated microglial cells for both diagnostic and therapeutic purposes. More specifically we will (i) identify basic mechanisms of microglial activation and new molecular targets for activated microglia which may serve as imaging as well as therapeutic targets; (ii) generate improved animal models to study NIND; (iii) design new contrast media and radiotracers for the assessment of activated microglia in vivo; (iv) implement and test novel compounds in animal models with various ND pathophysiologies; (v) provide quantification of microglial activity in vivo; (vi) set-up clinical studies in ND to pool in vivo measures of NI, including a Phase I/II immune therapy trial for PIB-positive patients with mild cognitive impairment (MCI).


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