[C-11]DAC-PET for Noninvasively Monitoring Neuroinflammation and Immunosuppressive Therapy Efficacy in Rat Experimental Autoimmune Encephalomyelitis Model
ABSTRACT Neuroimaging measures have potential for monitoring neuroinflammation to guide treatment before the occurrence of significant functional impairment or irreversible neuronal damage in multiple sclerosis (MS). N-Benzyl-N-methyl-2-(7-[(11)C]methyl-8-oxo-2-phenyl-7,8-dihydro-9H-purin-9-yl) acetamide ([(11)C]DAC), a new developed positron emission tomography (PET) probe for translocator protein 18 kDa (TSPO), has been adopted to evaluate the neuroinflammation and treatment effects of experimental autoimmune encephalomyelitis (EAE), an animal model of MS. [(11)C]DAC-PET enabled visualization of neuroinflammation lesion of EAE by tracing TSPO expression in the spinal cords; the maximal uptake value reached in day 11 and 20 EAE rats with profound inflammatory cell infiltration compared with control, day 0 and 60 EAE rats. Biodistribution studies and in vitro autoradiography confirmed these in vivo imaging results. Doubling immunohistochemical studies showed the infiltration and expansion of CD4+ T cells and CD11b+ microglia; CD68+ macrophages were responsible for the increased TSPO levels visualized by [(11)C]DAC-PET. Furthermore, mRNA level analysis of the cytokines by quantitative reverse-transcription polymerase chain reaction (qRT-PCR) revealed that TSPO+/CD4 T cells, TSPO+ microglia and TSPO+ macrophages in EAE spinal cords were activated and secreted multiple proinflammation cytokines to mediate inflammation lesions of EAE. EAE rats treated with an immunosuppressive agent: 2-amino-2-[2-(4-octylphenyl)ethyl] propane-1,3-diolhydrochloride (FTY720), which exhibited an absence of inflammatory cell infiltrates, displaying a faint radioactive signal compared with the high accumulation of untreated EAE rats. These results indicated that [(11)C] DAC-PET imaging is a sensitive tool for noninvasively monitoring the neuroinflammation response and evaluating therapeutic interventions in EAE.
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ABSTRACT: Mitochondrial dysfunction is responsible for liver damage and disease progression in non-alcoholic fatty liver disease (NAFLD). Translocator protein (18kDa) (TSPO), a mitochondrial transmembrane protein, plays important roles in modulating mitochondrial function. This study explored whether TSPO can be used as an imaging biomarker of non-invasive diagnosis and staging of NAFLD, monitored using positron emission tomography (PET) with a TSPO radioligand [(18)F]FEDAC. PET with [(18)F]FEDAC, non-enhanced computerized tomography (CT), autoradiography, histopathology, and gene analysis were performed to evaluate and quantify TSPO levels and NAFLD progression in methionine and choline-deficient diet-fed mice. Correlations were analyzed between uptake ratio of radioactivity and NAFLD activity score (NAS) in the liver. Uptake of [(18)F]FEDAC obviously increased with disease progression from simple steatosis to non-alcoholic steatohepatitis (NASH) (p<0.01). A close correlation was identified between [(18)F]FEDAC uptake ratio and NAS in the liver (Pearson's r=0.922, p=0.000). Specific binding of [(18)F]FEDAC to TSPO in the NAFLD livers was assessed in competition studies with the unlabelled TSPO-selective ligand PK11195. Autoradiography and histopathology confirmed the PET imaging results. Further, the mRNA levels of the functional macromolecular signaling complex composed of TSPO were obviously higher compared to controls. TSPO expression increases in NAFLD and closely correlates with NAFLD progression. TSPO as a specific molecular imaging biomarker may open a novel avenue for non-invasive, reliable, and quantitative diagnosis and staging of NAFLD.Journal of Hepatology 07/2012; 57(5):1076-82. DOI:10.1016/j.jhep.2012.07.002 · 10.40 Impact Factor
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ABSTRACT: Cells of the innate immune system including monocytes and macrophages are the first line of defence against infections and are critical regulators of the inflammatory response. These cells express toll-like receptors (TLRs), innate immune receptors which govern tailored inflammatory gene expression patterns. Monocytes, which produce pro-inflammatory mediators, are readily recruited to the central nervous system (CNS) in neurodegenerative diseases. This study explored the expression of receptors (CD11b, TLR2 and TLR4) on circulating monocyte-derived macrophages (MDMs) and peripheral blood mononuclear cells (PBMCs) isolated from healthy elderly adults who we classified as either IQ memory-consistent (high-performing, HP) or IQ memory-discrepant (low-performing, LP). The expression of CD11b, TLR4 and TLR2 was increased in MDMs from the LP group when compared to HP cohort. MDMs from both groups responded robustly to treatment with the TLR4 activator, lipopolysaccharide (LPS), in terms of cytokine production. Significantly, MDMs from the LP group displayed hypersensitivity to LPS exposure. Overall these findings define differential receptor expression and cytokine profiles that occur in MDMs derived from a cohort of IQ memory-discrepant individuals. These changes are indicative of inflammation and may be involved in the prodromal processes leading to the development of neurodegenerative disease.PLoS ONE 05/2013; 8(5):e63194. DOI:10.1371/journal.pone.0063194 · 3.53 Impact Factor
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ABSTRACT: Inflammation plays a significant role in many disease processes. Development in molecular imaging in recent years provides new insight into the diagnosis and treatment evaluation of various inflammatory diseases and diseases involving inflammatory process. Positron emission tomography using (18)F-FDG has been successfully applied in clinical oncology and neurology and in the inflammation realm. In addition to glucose metabolism, a variety of targets for inflammation imaging are being discovered and utilized, some of which are considered superior to FDG for imaging inflammation. This review summarizes the potential inflammation imaging targets and corresponding PET tracers, and the applications of PET in major inflammatory diseases and tumor associated inflammation. Also, the current attempt in differentiating inflammation from tumor using PET is also discussed.Theranostics 06/2013; 3(7):448-466. DOI:10.7150/thno.6592 · 7.83 Impact Factor