Dataset Information

Patterns of Mitochondrial TSPO Binding in Cerebral Small Vessel Disease: An in vivo PET Study With Neuropathological Comparison.

ABSTRACT: Small vessel disease (SVD) is associated with cognitive impairment in older age and be implicated in vascular dementia. Post-mortem studies show proliferation of activated microglia in the affected white matter. However, the role of inflammation in SVD pathogenesis is incompletely understood and better biomarkers are needed. We hypothesized that expression of the 18 kDa translocator protein (TSPO), a marker of microglial activation, would be higher in SVD. Positron emission tomography (PET) was performed with the second-generation TSPO ligand [11C]PBR28 in 11 participants with SVD. TSPO binding was evaluated by a two-tissue compartment model, with and without a vascular binding component, in white matter hyperintensities (WMH) and normal-appearing white matter (NAWM). In post-mortem tissue, in a separate cohort of individuals with SVD, immunohistochemistry was performed for TSPO and a pan-microglial marker Iba1. Kinetic modeling showed reduced tracer volume and blood volume fraction in WMH compared with NAWM, but a significant increase in vascular binding. Vascular [11C]PBR28 binding was also increased compared with normal-appearing white matter of healthy participants free of SVD. Immunohistochemistry showed a diffuse increase in microglial staining (with Iba1) in sampled tissue in SVD compared with control samples, but with only a subset of microglia staining positively for TSPO. Intense TSPO staining was observed in the vicinity of damaged small blood vessels, which included perivascular macrophages. The results suggest an altered phenotype of activated microglia, with reduced TSPO expression, in the areas of greatest white matter ischemia in SVD, with implications for the interpretation of TSPO PET studies in older individuals or those with vascular risk factors.

SUBMITTER: Wright P

PROVIDER: S-EPMC7596201 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Patterns of Mitochondrial TSPO Binding in Cerebral Small Vessel Disease: An <i>in vivo</i> PET Study With Neuropathological Comparison.

Wright Paul P Veronese Mattia M Mazibuko Ndabezinhle N Turkheimer Federico E FE Rabiner Eugenii A EA Ballard Clive G CG Williams Steven C R SCR Hari Narayanan Avinash Kumar AK Osrah Bahiya B Williams Ricky R Marques Tiago R TR Howes Oliver D OD Roncaroli Federico F O'Sullivan Michael J MJ

Frontiers in neurology 20201016

Small vessel disease (SVD) is associated with cognitive impairment in older age and be implicated in vascular dementia. Post-mortem studies show proliferation of activated microglia in the affected white matter. However, the role of inflammation in SVD pathogenesis is incompletely understood and better biomarkers are needed. We hypothesized that expression of the 18 kDa translocator protein (TSPO), a marker of microglial activation, would be higher in SVD. Positron emission tomography (PET) was ...[more]

PMID: 33178101

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Project description:To date, ¹¹C-(R)-PK11195 has been the most widely used TSPO PET imaging probe, although it suffers from high non-specific binding and low signal to noise. A significant number of 2nd generation TSPO radioligands have been developed with higher affinity and/or lower non-specific binding, however there is substantial inter-subject variation in their affinity for the TSPO. TSPO from human tissue samples binds 2nd generation TSPO radioligands with either high affinity (high affinity binders, HABs), or low affinity (LABs) or expresses both HAB and LAB binding sites (mixed affinity binders, MABs). The expression of these different TSPO binding sites in human is encoded by the rs6971 polymorphism in the TSPO gene. Here, we use a predictive biomathematical model to estimate the in vivo performances of three of these 2nd generation radioligands (¹?F-PBR111, ¹¹C-PBR28, ¹¹C-DPA713) and ¹¹C-(R)-PK11195 in humans. The biomathematical model only relies on in silico, in vitro and genetic data (polymorphism frequencies in different ethnic groups) to predict the radioactivity time course in vivo. In particular, we provide estimates of the performances of these ligands in within-subject (e.g. longitudinal studies) and between-subject (e.g. disease characterisation) PET studies, with and without knowledge of the TSPO binding class. This enables an assessment of the different radioligands prior to radiolabelling or acquisition of any in vivo data. The within-subject performance was characterised in terms of the reproducibility of the in vivo binding potential (%COV[BP(ND)]) for each separate TSPO binding class in normal and diseased states (50% to 400% increase in TSPO density), whilst the between-subject performance was characterised in terms of the number of subjects required to distinguish between different populations. The results indicated that the within-subject variability for ¹?F-PBR111, ¹¹C-PBR28 and ¹¹C-DPA713 (0.9% to 2.2%) was significantly lower than ¹¹C-(R)-PK11195 (16% to 36%) for HABs and MABs in both normal and diseased states. For between-subject studies, sample sizes required to detect 50% differences in TSPO density with the 2nd generation tracers are approximately half that required with ¹¹C-(R)-PK11195 when binding class information is known a priori. As binding class can be identified using a simple genetic test or from peripheral blood assays, the combination of binding class information with 2nd generation TSPO imaging data should provide superior tools to investigate inflammatory processes in humans in vivo.

Dataset Information

Patterns of Mitochondrial TSPO Binding in Cerebral Small Vessel Disease: An in vivo PET Study With Neuropathological Comparison.

Publications

Patterns of Mitochondrial TSPO Binding in Cerebral Small Vessel Disease: An <i>in vivo</i> PET Study With Neuropathological Comparison.

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