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BACKGROUND: The need for arterial blood data in quantitative PET research limits the wider usability of this imaging method in clinical research settings. Image-derived input function (IDIF) approaches have been proposed as a cost-effective and non-invasive alternative to gold-standard arterial sampling. However, this approach comes with its own limitations-partial volume effects and radiometabolite correction among the most important-and varying rates of success, and the use of IDIF for brain PET has been particularly troublesome. MAIN BODY: This paper summarizes the limitations of IDIF methods for quantitative PET imaging and discusses some of the advances that may make IDIF extraction more reliable. The introduction of automated pipelines (both commercial and open-source) for clinical PET scanners is discussed as a way to improve the reliability of IDIF approaches and their utility for quantitative purposes. Survey data gathered from the PET community are then presented to understand whether the fields opinion of the usefulness and validity of IDIF is improving. Finally, as the introduction of next-generation PET scanners with long axial fields of view, ultra-high sensitivity, and improved spatial and temporal resolution, has also brought IDIF methods back into the spotlight, a discussion of the possibilities offered by these state-of-the-art scanners-inclusion of large vessels, less partial volume in small vessels, better description of the full IDIF kinetics, whole-body modeling of radiometabolite production-is included, providing a pathway for future use of IDIF. CONCLUSION: Improvements in PET scanner technology and software for automated IDIF extraction may allow to solve some of the major limitations associated with IDIF, such as partial volume effects and poor temporal sampling, with the exciting potential for accurate estimation of single kinetic rates. Nevertheless, until individualized radiometabolite correction can be performed effectively, IDIF approaches remain confined at best to a few tracers.

Introduction: Recent evidence suggests the blood-to-brain influx rate (K1) in TSPO PET imaging as a promising biomarker of blood-brain barrier (BBB) permeability alterations commonly associated with peripheral inflammation and heightened immune activity in the brain. However, standard compartmental modeling quantification is limited by the requirement of invasive and laborious procedures for extracting an arterial blood input function. In this study, we validate a simplified blood-free methodologic framework for K1 estimation by fitting the early phase tracer dynamics using a single irreversible compartment model and an image-derived input function (1T1K-IDIF). Methods: The method is tested on a multi-site dataset containing 177 PET studies from two TSPO tracers ([11C]PBR28 and [18F]DPA714). Firstly, 1T1K-IDIF K1 estimates were compared in terms of both bias and correlation with standard kinetic methodology. Then, the method was tested on an independent sample of [11C]PBR28 scans before and after inflammatory interferon-α challenge, and on test-retest dataset of [18F]DPA714 scans. Results: Comparison with standard kinetic methodology showed good-toexcellent intra-subject correlation for regional 1T1K-IDIF-K1 (ρintra = 0.93 ± 0.08), although the bias was variable depending on IDIF ability to approximate blood input functions (0.03-0.39 mL/cm3/min). 1T1K-IDIF-K1 unveiled a significant reduction of BBB permeability after inflammatory interferon-α challenge, replicating results from standard quantification. High intra-subject correlation (ρ = 0.97 ± 0.01) was reported between K1 estimates of test and retest scans. Discussion: This evidence supports 1T1K-IDIF as blood-free alternative to assess TSPO tracers' unidirectional blood brain clearance. K1 investigation could complement more traditional measures in TSPO studies, and even allow further mechanistic insight in the interpretation of TSPO signal. [ABSTRACT FROM AUTHOR]

Although both central and peripheral inflammation have been observed consistently in depression, the relationship between the two remains obscure. Extra-axial immune cells may play a role in mediating the connection between central and peripheral immunity. This study investigates the potential roles of calvarial bone marrow and parameningeal spaces in mediating interactions between central and peripheral immunity in depression. PET was used to measure regional TSPO expression in the skull and parameninges as a marker of inflammatory activity. This measure was correlated with brain TSPO expression and peripheral cytokine concentrations in a cohort enriched for heightened peripheral and central immunity comprising 51 individuals with depression and 25 healthy controls. The findings reveal a complex relationship between regional skull TSPO expression and both peripheral and central immunity. Facial and parietal skull bone TSPO expression showed significant associations with both peripheral and central immunity. TSPO expression in the confluence of sinuses was also linked to both central and peripheral immune markers. Group-dependent elevations in TSPO expression within the occipital skull bone marrow were also found to be significantly associated with central inflammation. Significant associations between immune activity within the skull, parameninges, parenchyma and periphery highlight the role of the skull bone marrow and venous sinuses as pivotal sites for peripheral and central immune interactions., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)