In Vivo Imaging of Cortical Glial Activation Using Advanced Diffusion Magnetic Resonance Imaging

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Project Summary Neuroinflammation by means of glial (microglia and astrocytes) activation is thought to play a key role in the pathogenesis of several psychiatric and neurodegenerative disorders of different etiology including depression, schizophrenia, Alzheimer’s disease and multiple sclerosis (MS). Still, current noninvasive methods to detect and characterize neuroinflammation in vivo are limited. Positron emission tomography (PET)- based targeting of the 18kDa translocator protein (TSPO), which is overexpressed in activated glial cells but otherwise present at very low levels in the healthy brain, is the current gold-standard for imaging in vivo glial activation in the human brain. PET imaging, however, is associated with radiation exposure, which limits its use in children and child-bearing women, and over time. Microglia and astrocytes are dynamic cells able to change morphology and function following “activation” from a variety of pathological insults. Advanced magnetic resonance (MR) diffusion weighted imaging (DWI) is a sensitive approach for non- invasive measurement of intra- and extra-cellular microstructural changes associated with glial activation. We have developed a novel DWI multi-compartment microstructural model (MCM) for imaging microglia and astrocyte activation, which we validated in an experimental rat model of grey matter (GM) inflammation. Here, we propose to translate this model to the study of cortical glial activation in healthy controls and patients with MS, and to validate in vivo findings in post-mortem MS brain tissue. MS is a chronic inflammatory and neurodegenerative disorder of the central nervous system that represents the leading cause of non-traumatic neurological disability in young adults in the US. There is solid evidence that extensive microglia activation is a main pathological feature of cortical pathology in MS. Our overall hypothesis is that MCM-derived indices are sensitive to cortical microstructural changes related to glial activation as evidenced by a strong correlation with TSPO levels on PET with 11C-PBR28, a second generation TSPO radioligand, and by neuropathological verification. A non-invasive methodology that allows investigating and characterizing the contribution of neuroinflammation in the GM will have a tremendous impact in clarifying disease mechanisms in MS, as well as in a wide- spectrum of neurological and psychiatric conditions.