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Nondisplaceable Binding Is a Potential Confounding Factor in ¹¹C-PBR28 Translocator Protein PET Studies.

ABSTRACT: The PET ligand ¹¹C-PBR28 (N-((2-(methoxy-¹¹C)-phenyl)methyl)-N-(6-phenoxy-3-pyridinyl)acetamide) binds to the 18-kDa translocator protein (TSPO), a biomarker of glia. In clinical studies of TSPO, the ligand total distribution volume, V_T, is frequently the reported outcome measure. Since V_T is the sum of the ligand-specific distribution volume (V_S) and the nondisplaceable-binding distribution volume (V_ND), differences in V_ND across subjects and groups will have an impact on V_T Methods: Here, we used a recently developed method for simultaneous estimation of V_ND (SIME) to disentangle contributions from V_ND and V_S Data from 4 previously published ¹¹C-PBR28 PET studies were included: before and after a lipopolysaccharide challenge (8 subjects), in alcohol use disorder (14 patients, 15 controls), in first-episode psychosis (16 patients, 16 controls), and in Parkinson disease (16 patients, 16 controls). In each dataset, regional V_T estimates were obtained with a standard 2-tissue-compartment model, and brain-wide V_ND was estimated with SIME. V_S was then calculated as V_T - V_ND V_ND and V_S were then compared across groups, within each dataset. Results: A lower V_ND was found for individuals with alcohol-use disorder (34%, P = 0.00084) and Parkinson disease (34%, P = 0.0032) than in their corresponding controls. We found no difference in V_ND between first-episode psychosis patients and their controls, and the administration of lipopolysaccharide did not change V_ND Conclusion: Our findings suggest that in TSPO PET studies, nondisplaceable binding can differ between patient groups and conditions and should therefore be considered.

SUBMITTER: Laurell GL

PROVIDER: S-EPMC8049343 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Alzheimer's disease is associated with chronic response of innate immune system, referred as neuroinflammation. PET radioligands binding to the 18 kDa translocator protein are potential biomarkers of neuroinflammation. Translocator protein PET studies in mild cognitive impairment and Alzheimer's disease have indicated controversial results, possibly reflecting interindividual variation and heterogeneity of study populations. We controlled for genetic and environmental effects by studying twin pairs discordant for episodic memory performance. Episodic memory impairment is a well-known cognitive hallmark of early Alzheimer's disease process. Eleven same-sex twin pairs (four monozygotic pairs, six female pairs, age 72-77 years) underwent [11C]N-acetyl-N-(2-methoxybenzyl)-2-phenoxy-5-pyridinamine ([11C]PBR28) PET imaging, structural magnetic resonance imaging and neuropsychological testing in 2014-17. Main PET outcome was the volume-weighted average standardized uptake value of cortical regions vulnerable to Alzheimer's disease pathology. Ten pairs were discordant for episodic memory performance. In the eight pairs with identical translocator protein genotype, twins with poorer episodic memory had ∼20% higher cortical [11C]PBR28 binding compared with their better-performing co-twins (mean intra-pair difference 0.21 standardized uptake value, 95% confidence interval 0.05-0.37, P = 0.017). The result remained the same when including all discordant pairs and controlling for translocator protein genotype. Increased translocator protein PET signal suggests that increased microglial activation is associated with poorer episodic memory performance. Twins with worse episodic memory performance compared with their co-twins had on average 20% higher uptake of the neuroinflammatory marker translocator protein PET tracer 11[11C]PBR28. The findings support a negative association between neuroinflammation and episodic memory and the use of translocator protein positron emission tomography as a useful indicator of Alzheimer's disease process.

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Nondisplaceable Binding Is a Potential Confounding Factor in ¹¹C-PBR28 Translocator Protein PET Studies.

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Nondisplaceable Binding Is a Potential Confounding Factor in 11C-PBR28 Translocator Protein PET Studies.

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OmicsDI is part of the ELIXIR infrastructure

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Nondisplaceable Binding Is a Potential Confounding Factor in ¹¹C-PBR28 Translocator Protein PET Studies.