A Genetic Polymorphism for Translocator Protein 18 Kda Affects bothin Vitroandin VivoRadioligand Binding in Human Brain to this Putative Biomarker of Neuroinflammation

Abstract

Second-generation radioligands for translocator protein (TSPO), an inflammation marker, are confounded by the codominant 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). We tested if in vitro binding to leukocytes distinguished TSPO genotypes and if genotype could affect clinical studies using the TSPO radioligand [(11)C]PBR28. In vitro binding to leukocytes and [(11)C]PBR28 brain imaging were performed in 27 human subjects with known TSPO genotype. Specific [(3)H]PBR28 binding was measured in prefrontal cortex of 45 schizophrenia patients and 47 controls. Leukocyte binding to PBR28 predicted genotype in all subjects. Brain uptake was ∼40% higher in HH than HL subjects. Specific [(3)H]PBR28 binding in LL controls was negligible, while HH controls had ∼80% higher binding than HL controls. After excluding LL subjects, specific binding was 16% greater in schizophrenia patients than controls. This difference was insignificant by itself (P=0.085), but was significant after correcting for TSPO genotype (P=0.011). Our 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 positron emission tomography studies.

Imaging robust microglial activation after lipopolysaccharide administration in humans with PET

“…[ 11 C]PBR28 volume of distribution (V T ), which is proportional to the availability of TSPO binding sites, was measured in regions of interest for baseline and LPS challenge scans, and the change in V T (%ΔV T ) was calculated and reported as mean ± SEM (Table 1). Baseline V T values were two times higher in HAB compared with MAB subjects, consistent with results from other studies (34,35). However, there was no significant difference in %Δ V T between HAB (39 ± 12%, n = 3) and MAB (50 ± 10%, n = 5) subjects (F 1,6 = 0.70, P = 0.43); therefore all subjects were combined for further analysis.…”

“…An important caveat to performing studies with [ 11 C]PBR28 is that the binding affinity of [ 11 C]PBR28 is dependent on the presence of a single nucleotide polymorphism rs6971 on the TSPO gene (34,35). Thus, subjects must be genotyped before the PET scan to determine binding phenotypes, classified as HABs, MABs, or low-affinity binders (LABs); LABs were not included in the study due to negligible specific binding for [ 11 C]PBR28 (Materials and Methods).…”

Kinetic Modeling without Accounting for the Vascular Component Impairs the Quantification of [11C]PBR28 Brain PET Data

“…Data were obtained from the database of healthy subjects of the Molecular Imaging Branch at the National Institute of Mental Health. In particular two different data sets of healthy subjects (some of them were also included in previous studies 24,25 ) have been provided: one data set of 11 young healthy subjects (6 men and 5 women; age, 33 ± 9 years); another data set of 8 elderly healthy subjects was used (6 men and 2 women; age, 65 ± 4 years). The protocol was approved by the Ethics Committee of the National Institutes of Health (NIH); all subjects gave written informed consent.…”

Positron Emission Tomography Studies of the Glial Cell Marker Translocator Protein in Patients With Psychosis: A Meta-analysis Using Individual Participant Data

“…In addition, TSPO radioligands display substantial within-and betweensubject variability (12,27) even after accounting for the TSPO rs6971 polymorphism that is known to affect radioligand binding in vivo (28)(29)(30). This has important implications for sensitivity and the power to detect differences between patients with psychosis and control subjects.…”