Influence of <i>TSPO</i> Genotype on <sup>11</sup>C-PBR28 Standardized Uptake Values

Yoder, Karmen K.; Nho, Kwangsik; Risacher, Shannon L.; Kim, Sungeun; Shen, Li; Saykin, Andrew J.

doi:10.2967/jnumed.112.118885

Cited by 61 publications

(58 citation statements)

References 18 publications

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“…This difference is larger than what was found in recent studies on Standardized Uptake Values (30 % difference, [29]) and V T (30-40 % difference [30,31], although the discrepancy was highly influenced by the outlier individual in the HAB group. Importantly, we could not show an effect of genotype on test-retest reproducibility, suggesting that genotype does not have to be controlled for in clinical studies with a within-subject experimental design.…”

Section: Discussioncontrasting

confidence: 71%

Test–retest reproducibility of [11C]PBR28 binding to TSPO in healthy control subjects

Collste

Forsberg

Varrone

et al. 2015

Eur J Nucl Med Mol Imaging

108

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Here, we examined reproducibility of [ 11 C]PBR28 binding in healthy subjects as quantified on a regional and voxel-by-voxel basis. In addition, a preliminary analysis of diurnal changes in TSPO availability was performed. MethodsTwelve subjects were examined with HRRT PET and [ 11 C]PBR28, six in the morning and afternoon on the same day, and six in the morning of two separate days. Regional Volume of distribution (V T ) values were derived using a region-of-interest based two-tissue compartmental analysis (2TCM), as well as a parametric approach. Metabolite-corrected arterial plasma was used as input function. ResultsFor the whole sample, the mean absolute variability of V T in gray matter (GM) was 18.3 ± 12.7 %. Intraclass Correlation Coefficient values in GM regions ranged from 0.90 to 0.94. Reducing the time of analysis from 91 to 63 minutes yielded a variability of 16.9 ± 14.9%. There was a strong correlation between the parametric and 2TCM-derived GM values (r=0.99). A significant increase in GM V T was observed between morning and afternoon examinations when using secondary methods of quantification (p=0.028). For the subjects examined at the same time of the day, the absolute variability was 15.9 ± 12.2 % for the 91 minute 2TCM data. [15,16], the study was designed so that six subjects were examined in the morning and afternoon on the same day, and six subjects at the same time point on two different days. Conclusions Methods SubjectsThe study was conducted at the Karolinska University Hospital, Solna, Sweden and was approved by the regional Ethics Committee in Stockholm and the Radiation Safety Committee at the Karolinska University Hospital, Stockholm.Subjects were recruited by advertisement and provided written informed consent. They were healthy according to medical history, clinical examination and routine laboratory tests in blood and urine. All subjects were assessed by a senior psychiatrist (K.C.), using the Mini International Neuropsychiatric Interview (MINI) for psychiatric diagnoses. None of the subjects had previously been exposed to psychopharmacological medication. Furthermore, a negative illegal drug screening test was ascertained in all subjects, prior to PET examination. None of the subjects were on any medication at the time of the study. No brain abnormality was detected on magnetic resonance imaging (MRI), as evaluated by a neuroradiologist at the MR-centre, Karolinska University Hospital, Solna.As demonstrated both in vitro and in vivo, [ 11 C]PBR28 binding is influenced by an identified single point mutation in the TSPO gene [8,17]. At screening, a blood sample was collected and genotyping was performed according to the description below. In total, 15 subjects were recruited. Of these, one was a low affinity binder (LAB) and was therefore excluded from the analysis. Two additional subjects were excluded due to technical issues with the PET measurements. The remaining twelve subjects were six men and six women, with a mean age of 23.9 SD ± 3.1 years. Six were high affinity binders ...

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Section: Discussioncontrasting

confidence: 71%

Test–retest reproducibility of [11C]PBR28 binding to TSPO in healthy control subjects

Collste

Forsberg

Varrone

et al. 2015

Eur J Nucl Med Mol Imaging

108

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“…and [(18)F]-FEPPA for imaging brain inflammation have been linked to this polymorphism (88,(93)(94)(95)(96). However, structural analyses have shown that A147T TSPO is able to retain the same structural profile as the wild-type protein, and binds the first generation TSPO ligand, PK 11195, with comparable affinity (97).…”

Section: Complications In the Application Of Certain Tspo Pet Ligandsmentioning

confidence: 99%

TSPO: kaleidoscopic 18-kDa amid biochemical pharmacology, control and targeting of mitochondria

Gatliff

Campanella

2016

Biochemical Journal

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The 18-kDa translocator protein (TSPO) localizes in the outer mitochondrial membrane (OMM) of cells and is readily up-regulated under various pathological conditions such as cancer, inflammation, mechanical lesions and neurological diseases. Able to bind with high affinity synthetic and endogenous ligands, its core biochemical function resides in the translocation of cholesterol into the mitochondria influencing the subsequent steps of (neuro-)steroid synthesis and systemic endocrine regulation. Over the years, however, TSPO has also been linked to core cellular processes such as apoptosis and autophagy. It interacts and forms complexes with other mitochondrial proteins such as the voltage-dependent anion channel (VDAC) via which signalling and regulatory transduction of these core cellular events may be influenced. Despite nearly 40 years of study, the precise functional role of TSPO beyond cholesterol trafficking remains elusive even though the recent breakthroughs on its high-resolution crystal structure and contribution to quality-control signalling of mitochondria. All this along with a captivating pharmacological profile provides novel opportunities to investigate and understand the significance of this highly conserved protein as well as contribute the development of specific therapeutics as presented and discussed in the present review.

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“…The Ala/Ala TSPO genotype (wild-type) results in high-affinity binding, whereas Ala/Thr results in mixed-affinity binding, and Thr/Thr results in low-affinity binding. MABs have 40%-50% lower binding potential for TSPO than do HABs (10)(11)(12). Because of the lack of binding in LABs, they are unsuitable for evaluation.…”

mentioning

confidence: 99%

“…However, their uptake is dependent on TSPO phenotype-high-affinity binders (HABs), low-affinity binders (LABs), and mixed-affinity binders (MABs) (10,11)-with a 40%-50% increase in binding potential for HABs compared with MABs, whereas LABs are unsuitable for evaluation. It is now clear that a nonsynonymous polymorphism of TSPO, coded by the rs6971 single-nucleotide polymorphism, affects the binding affinity of these tracers (10,11). This single-nucleotide polymorphism in exon 4 of the TSPO gene causes an alanine-tothreonine substitution in position 147.…”

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confidence: 99%

Can Studies of Neuroinflammation in a TSPO Genetic Subgroup (HAB or MAB) Be Applied to the Entire AD Cohort?

et al. 2015

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Neuroinflammation plays a significant role in Alzheimer disease (AD), and translocator protein (TSPO) PET imaging allows us to quantify this process. However, the binding of second-generation TSPO tracers depends on the TSPO genotype coded by the rs6971 single-nucleotide polymorphism, with a 40%-50% increase in BP in high-affinity binders (HABs) compared with mixed-affinity binders (MABs), whereas low-affinity binders (LABs) are unsuitable for evaluation. Hence, several studies are using either HAB alone or HAB and MAB subjects. To translate the findings of neuroinflammation studies to the entire population, it is crucial to establish the influence of TSPO genotypes on AD. Here, we investigated whether different TSPO genotypes influence cognitive function, amyloid load, and disease progression over time. Methods: We evaluated 798 subjects (225 control, 388 with mild cognitive impairment [MCI], and 185 with AD) from the Alzheimer's Disease Neuroimaging Initiative database at baseline and during follow-up. All subjects were screened for TSPO genotype and underwent detailed clinical and neuropsychologic assessments yearly for 4 y. Of the 798 subjects, 255 also had T1-and T2-weighted MR imaging and amyloid PET with 11 C-Pittsburgh compound B or 18 F-florbetapir. Results: We demonstrated that all TSPO binding groups (HAB, MAB, and LAB) have same level of amyloid load in AD and MCI subjects. We also demonstrated that the prevalence is 50.3% for HAB, 41.2% for MAB, and 8.5% for LAB, without a statistical difference among the AD, MCI, and control groups. During longitudinal follow-up, the mean change in neuropsychometric test scores on the MiniMental State Examination, the cognitive and modified Alzheimer Disease Assessment Scales (ADASs), and the Geriatric Depression Scale over time were similar in AD and MCI subjects among the 3 TSPO binding groups. Analysis of the covariates showed that diagnostic group (control, MCI, AD), apolipoprotein E4 status, and sex had a significant effect on decline on the modified Alzheimer Disease Assessment Scale (.3 points of the scale), but age and TSPO genotype did not. Conclusion: This study suggests that information obtained from evaluating a subgroup of AD or MCI subject using second-generation TSPO tracers can be translated to the entire AD and MCI population. Thus, we can study fewer AD subjects in evaluating new antineuroinflammatory and antimicroglial agents in intervention studies and in observational studies evaluating the role of neuroinflammation.

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Influence of TSPO Genotype on ¹¹C-PBR28 Standardized Uptake Values

Cited by 61 publications

References 18 publications

Test–retest reproducibility of [11C]PBR28 binding to TSPO in healthy control subjects

Test–retest reproducibility of [11C]PBR28 binding to TSPO in healthy control subjects

TSPO: kaleidoscopic 18-kDa amid biochemical pharmacology, control and targeting of mitochondria

Can Studies of Neuroinflammation in a TSPO Genetic Subgroup (HAB or MAB) Be Applied to the Entire AD Cohort?

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Influence of TSPO Genotype on 11C-PBR28 Standardized Uptake Values

Cited by 61 publications

References 18 publications

Test–retest reproducibility of [11C]PBR28 binding to TSPO in healthy control subjects

Test–retest reproducibility of [11C]PBR28 binding to TSPO in healthy control subjects

TSPO: kaleidoscopic 18-kDa amid biochemical pharmacology, control and targeting of mitochondria

Can Studies of Neuroinflammation in a TSPO Genetic Subgroup (HAB or MAB) Be Applied to the Entire AD Cohort?

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Influence of TSPO Genotype on ¹¹C-PBR28 Standardized Uptake Values