Examples of progress made during the prior year are summarized below. 1) We investigated a genetic polymorphism for translocator protein (TSPO) (18 kDa)a putative biomarker of neuroinflammationand found that it affects both in vitro and in vivo radioligand binding in human brain (Kreisl, et al. J Cereb Blood Flow Metab. 33: 53-58, 2013a). NCT00696371 We continued our investigation into TSPO, a marker of inflammation. Notably, second-generation radioligands for TSPO have been confounded by the co-dominant rs6971 polymorphism that affects binding affinity. The resulting three groups are homozygous for high affinity state (HH), homozygous for low affinity state (LL), or heterozygous (HL). This study investigated whether in vitro binding to lymphocytes distinguished TSPO genotypes, and whether genotype could affect clinical studies using the TSPO radioligand 11C-PBR28. In vitro binding to lymphocytes and 11C-PBR28 brain imaging was performed in 27 human subjects with known TSPO genotype. Specific 3H-PBR28 was measured in the prefrontal cortex of 45 patients with schizophrenia and 47 healthy controls. Lymphocyte binding to PBR28 predicted genotype in all subjects. Brain uptake was 40% higher in HH than HL subjects. Specific 3H-PBR28 binding in LL controls was negligible, while HH controls had 80% higher binding than HL controls. Notably, specific binding was 16% greater in schizophrenics than controls after LL subjects were excluded. This difference was insignificant by itself (p = 0.085), but was significant after correcting for TSPO genotype (p = 0.011). Thus, the results show that TSPO genotype influences PBR28 binding in vitro and in vivo. Correcting for this genotype increased statistical power in our postmortem study and is recommended for in vivo PET studies. 2) We further measured translocator protein (TSPO), a putative marker of inflammation, in patients with Alzheimers disease (AD), patients with mild cognitive impairment (MCI), and older controls (Kreisl, et al. Brain, 2013b. Doi: 10.1093/brainawt145). PET scans with 11C-PBR28 were used to measure TSPO levels;patients were also scanned with 11C-Pittsburgh Compound B to measure amyloid burden. NCT00613119 Amyloid-positive patients (19 with AD, 10 with MCI) and 13 amyloid-negative control subjects were studied. The primary goal was to determine whether TSPO binding is elevated in patients with AD, and the secondary goal was to determine whether TSPO binding correlates with neuropsychological measures, grey matter volume, 11C-Pittsburgh Compound B binding, or age of onset. AD patients, but not those with MCI, had greater 11C-PBR28 binding in cortical brain regions than controls. The largest differences were seen in the parietal and temporal cortices;no difference was observed in subcortical regions or cerebellum. 11C-PBR28 binding inversely correlated with performance on a number of neurocognitive tasks. The largest correlations were observed in the inferior parietal lobule. 11C-PBR28 binding also inversely correlated with grey matter volume. Early-onset (<65 years) patients had greater 11C-PBR28 binding than late-onset patients;in parietal cortex and striatum, 11C-PBR28 binding correlated with lower age of onset. Partial volume corrected and uncorrected results were generally in agreement;however, the correlation between 11C-PBR28 and 11C-Pittsburgh Compound B binding was seen only after partial volume correction. The results suggest that neuroinflammation, indicated by increased 11C-PBR28 binding to TSPO, occurs after conversion of MCI to AD and worsens with disease progression. Greater inflammation may contribute to the precipitous disease course typically seen in early-onset patients. Furthermore, 11C-PBR28 may be useful in longitudinal studies to mark the conversion from MCI or to assess response to experimental treatments of AD. 3) We sought to quantify the binding of 11C-(R)-rolipram, a phosphodiesterase type IV (PDE4) inhibitor, as an indirect measure of this enzymes activity in the brain of individuals with major depressive disorder (MDD) compared with healthy controls (Fujita, et al. Biol Psychiatry 72: 548-554, 2012). NCT00369798 PDE4, an important component of the cyclic adenosine monophosphate (cAMP) cascade, selectively metabolizes cAMP in the brain to the inactive monophosphate. Studies suggest that PDE4 mediates the effects of several antidepressants. To quantify the binding of 11C-(R)-rolipram as an indirect measure of this enzymes activity in the brain of individuals with MDD, we performed 11C-(R)-rolipram brain PET scans in 28 moderately depressed MDD subjects and 25 age- and gender-matched healthy controls;roughly half of patients were treatment-naive. 11C-(R)-rolipram binding in brain was measured using arterial 11C-(R)-rolipram levels to correct for the influence of cerebral blood flow. MDD subjects showed a widespread, 20% reduction in 11C-(R)-rolipram binding (p=.002), which was not caused by different volumes of gray matter. Decreased rolipram binding of similar magnitude was observed in most brain areas. Rolipram binding did not correlate with the severity of depressive or anxiety symptoms. The results demonstrate that brain levels of PDE4 are decreased in unmedicated individuals with MDD in vivo. These results are in line with human postmortem and rodent studies demonstrating downregulation of the cAMP cascade in MDD, and supported the hypothesis that PDE4 inhibitors, which increase cAMP cascade activity, may have antidepressant effects.

Project Start
Project End
Budget Start
Budget End
Support Year
9
Fiscal Year
2013
Total Cost
$3,101,412
Indirect Cost
Name
U.S. National Institute of Mental Health
Department
Type
DUNS #
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Zanotti-Fregonara, Paolo; Xu, Rong; Zoghbi, Sami S et al. (2016) The PET Radioligand 18F-FIMX Images and Quantifies Metabotropic Glutamate Receptor 1 in Proportion to the Regional Density of Its Gene Transcript in Human Brain. J Nucl Med 57:242-7
Brouwer, Chad; Jenko, Kimberly J; Zoghbi, Sami S et al. (2016) Translocator protein ligands based on N-methyl-(quinolin-4-yl)oxypropanamides with properties suitable for PET radioligand development. Eur J Med Chem 124:677-688
Kreisl, William C; Lyoo, Chul Hyoung; Liow, Jeih-San et al. (2016) (11)C-PBR28 binding to translocator protein increases with progression of Alzheimer's disease. Neurobiol Aging 44:53-61
Veronese, Mattia; Zanotti-Fregonara, Paolo; Rizzo, Gaia et al. (2016) Measuring specific receptor binding of a PET radioligand in human brain without pharmacological blockade: The genomic plot. Neuroimage 130:1-12
Liow, Jeih-San; Zoghbi, Sami S; Hu, Shuo et al. (2016) (18)F-FCWAY, a serotonin 1A receptor radioligand, is a substrate for efflux transport at the human blood-brain barrier. Neuroimage 138:134-40
Kreisl, William C; Bhatia, Ritwik; Morse, Cheryl L et al. (2015) Increased permeability-glycoprotein inhibition at the human blood-brain barrier can be safely achieved by performing PET during peak plasma concentrations of tariquidar. J Nucl Med 56:82-7
Lyoo, Chul Hyoung; Ikawa, Masamichi; Liow, Jeih-San et al. (2015) Cerebellum Can Serve As a Pseudo-Reference Region in Alzheimer Disease to Detect Neuroinflammation Measured with PET Radioligand Binding to Translocator Protein. J Nucl Med 56:701-6
Gershen, Leah D; Zanotti-Fregonara, Paolo; Dustin, Irene H et al. (2015) Neuroinflammation in Temporal Lobe Epilepsy Measured Using Positron Emission Tomographic Imaging of Translocator Protein. JAMA Neurol 72:882-8
Lyoo, Chul Hyoung; Zanotti-Fregonara, Paolo; Zoghbi, Sami S et al. (2014) Image-derived input function derived from a supervised clustering algorithm: methodology and validation in a clinical protocol using [11C](R)-rolipram. PLoS One 9:e89101
Lohith, Talakad G; Zoghbi, Sami S; Morse, Cheryl L et al. (2014) Retest imaging of [11C]NOP-1A binding to nociceptin/orphanin FQ peptide (NOP) receptors in the brain of healthy humans. Neuroimage 87:89-95

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