Examples of progress made during the prior year are summarized below. 1) We used the novel radioligand 11C-PBR28 to determine whether in vivo expression of translocator protein (TSPO), an inflammatory marker, is increased ipsilateral to the seizure focus in patients with temporal lobe epilepsy and found that in vivo expression of TSPO was indeed increased in subjects with this disorder (Hirvonen et al, 2012). Animal studies and clinical observations suggest that epilepsy is associated with inflammation. TSPO (18 kDa), a marker of inflammation, is increased in vitro in surgical samples from patients with temporal lobe epilepsy. In this study, we sought to determine whether in vivo expression of TSPO was increased ipsilateral to the seizure focus in patients with temporal lobe epilepsy using PET imaging with the novel radioligand 11C-PBR28 to measure TSPO in the living human brain. In this study, 16 patients with unilateral temporal lobe epilepsy and 30 healthy subjects were studied with 11C-PBR28 PET and magnetic resonance imaging (MRI). Uptake of radioactivity after injection of 11C-PBR28 was measured from regions of interest drawn bilaterally onto MR images. Brain uptake from ipsilateral and contralateral hemispheres was compared using a paired-samples t-test. Brain uptake was found to be higher ipsilateral to the seizure focus in the hippocampus, parahippocampal gyrus, amygdala, fusiform gyrus, and choroid plexus but not in other brain regions. This asymmetry was more pronounced in patients with hippocampal sclerosis than in those without. The results indicate increased uptake of radioactivity after injection of 11C-PBR28 ipsilateral to the seizure focus in patients with temporal lobe epilepsy, suggesting increased expression of TSPO. Given the important clinical implications of this finding, future studies with larger sample sizes are required to confirm the results and determine the clinical utility of imaging TSPO in temporal lobe epilepsy. 2) 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, in press). Building on our previous work, 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. We found that 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. Another notable finding of the study was that specific binding was 16% greater in patients with schizophrenia 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.

Project Start
Project End
Budget Start
Budget End
Support Year
8
Fiscal Year
2012
Total Cost
$2,547,877
Indirect Cost
Name
U.S. National Institute of Mental Health
Department
Type
DUNS #
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Kreisl, William C; Lyoo, Chul Hyoung; Liow, Jeih-San et al. (2017) Distinct patterns of increased translocator protein in posterior cortical atrophy and amnestic Alzheimer's disease. Neurobiol Aging 51:132-140
Kreisl, William C; Lawrence, Robin; Page, Emily et al. (2017) 11C-PBR28 PET detects translocator protein in a patient with astrocytoma and Alzheimer disease. Neurology 88:1001-1004
Ikawa, Masamichi; Lohith, Talakad G; Shrestha, Stal et al. (2017) 11C-ER176, a Radioligand for 18-kDa Translocator Protein, Has Adequate Sensitivity to Robustly Image All Three Affinity Genotypes in Human Brain. J Nucl Med 58:320-325
Kobayashi, Masato; Jiang, Teresa; Telu, Sanjay et al. (2017) (11)C-DPA-713 has much greater specific binding to translocator protein 18?kDa (TSPO) in human brain than (11)C-( R)-PK11195. J Cereb Blood Flow Metab :271678X17699223
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
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
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
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 138:134-140
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
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

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