Pathophysiological studies and treatment development in schizophrenia (SZ) have mainly focused on modulating neurotransmitters. Currently available antipsychotics that affect neurotransmitters fail to significantly improve long term social/functional outcomes. Therefore, there is an urgent need to characterize alternative pathophysiological models to design novel treatments. Mounting evidence over the last 5 decades suggest that neuroinflammation may be fruitfully targeted for pathophysiological studies and novel treatment development. Neuroinflammation was relegated to be unimportant in the pathophysiology of SZ. Emerging evidence strongly suggest reciprocal regulation between the immune and the central nervous systems. Immune mediators, e.g. cytokines that are expressed on neurons and glia modulate neuronal development, programmed cell death, neuronal signal transduction, neuroplasticity and neurotransmission through dopamine, serotonin, glutamate, and norepinephrine. Abnormalities of these neurotransmitters are implicated in the pathophysiology of SZ. Likewise, neurotransmitters secreted from nerve terminals modulate immune cell activity supporting an intricate reciprocal relationship between the two apparently disparate systems. Hence, systematic studies on neuroinflammation would provide a meaningful alternative pathophysiological model for novel treatment designs. Although extant literature provides ample suggestive data on neuroinflammation, there is a paucity of direct in vivo evidence of neuroinflammation and its clinical and neurobiological correlates. This proposal aims to systematically gather convergent preliminary in vivo multimodal neuroimaging data on neuroinflammation in SZ and healthy controls (HC) on two distinct aspects of neuroinflammation, namely activated inflammatory cells and microvascular changes. Positron Emission Tomography (PET) using highly specific radioligand ([11C]PBR28]) that binds to a receptor called the Translocator Protein 18 kDa (TSPO) in the mitochondria of activated microglia/ macrophage collects in vivo data on activated immune cells. Concurrently obtaining high-resolution (32-channel head coil that improves sensitivity by 4 times), high-field (7 Tesla) susceptibility weighted imaging (SWI) reliably captures changes in cerebral microvasculature (small venules/arterioles, and branching of venules/arterioles called arborizations) and local iron content due to accumulation of activated microglia/macrophages. We predict an increased [11C]PBR28 binding, increased density of venules/arterioles and arborizations, and local iron levels among SZ subjects compared to HC, specifically in the prefrontal cortex and hippocampus (aim 1). We will also test if the [11C]PBR28 binding, venluar density, arborizations and local iron levels are correlated with each other (aim 2). We will explore if these neuroinflammatory measures will correlate with brain connectivity, cognitive impairments and psychopathology (exploratory aim). Such convergent in vivo evidence on neuroinflammation could be further evaluated for biomarker characterization, targeting SZ subjects for anti-inflammatory drugs, finding specific immune pathways relevant for SZ and developing novel drugs that target identified pathways.

Public Health Relevance

Schizophrenia is a severe chronic debilitating disorder that is identified as the 5th leading cause of disability in the world, costing more than $60 billion annually in the US, according to 1996 estimates. Currently available treatments do not provide lasting remission or considerably improved social functions for majority of subjects with schizophrenia, and are associated with side effects such as increased risk for diabetes and metabolic syndrome that further add to the health care costs. These drawbacks compel us to examine viable alternative models of pathophysiology, namely neuroinflammation, to identify novel molecular targets for new therapeutic strategies. Proposed study is designed to obtain in vivo data on neuroinflammation, and examine the clinical and neurobiological correlates of neuroinflammation.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Exploratory/Developmental Grants (R21)
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Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section (NPAS)
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Rumsey, Judith M
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University of Pittsburgh
Schools of Medicine
United States
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