AUTHOR=Maccioni Lucia , Michelle Carranza Mellana , Brusaferri Ludovica , Silvestri Erica , Bertoldo Alessandra , Schubert Julia J. , Nettis Maria A. , Mondelli Valeria , Howes Oliver , Turkheimer Federico E. , Bottlaender Michel , Bodini Benedetta , Stankoff Bruno , Loggia Marco L. , Veronese Mattia 

TITLE=A blood-free modeling approach for the quantification of the blood-to-brain tracer exchange in TSPO PET imaging

JOURNAL=Frontiers in Neuroscience

VOLUME=18

YEAR=2024

URL=https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2024.1395769

DOI=10.3389/fnins.2024.1395769

ISSN=1662-453X

ABSTRACT=<sec id="sec1"><title>Introduction</title><p>Recent evidence suggests the blood-to-brain influx rate (<italic>K<sub>1</sub></italic>) in <italic>TSPO PET</italic> imaging as a promising biomarker of blood–brain barrier (<italic>BBB</italic>) 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 <italic>K<sub>1</sub></italic> estimation by fitting the early phase tracer dynamics using a single irreversible compartment model and an image-derived input function (<italic>1T1K-IDIF</italic>).</p></sec><sec id="sec2"><title>Methods</title><p>The method is tested on a multi-site dataset containing 177 <italic>PET</italic> studies from two <italic>TSPO</italic> tracers ([<sup>11</sup>C]PBR28 and [<sup>18</sup>F]DPA714). Firstly, <italic>1T1K-IDIF K<sub>1</sub></italic> estimates were compared in terms of both bias and correlation with standard kinetic methodology. Then, the method was tested on an independent sample of [<sup>11</sup>C]PBR28 scans before and after inflammatory interferon-<italic>α</italic> challenge, and on test–retest dataset of [<sup>18</sup>F]DPA714 scans.</p></sec><sec id="sec3"><title>Results</title><p>Comparison with standard kinetic methodology showed good-to-excellent intra-subject correlation for regional <italic>1T1K-IDIF-K<sub>1</sub></italic> (<italic>ρ<sub>intra</sub></italic> = 0.93 ± 0.08), although the bias was variable depending on <italic>IDIF</italic> ability to approximate blood input functions (0.03–0.39 mL/cm<sup>3</sup>/min). <italic>1T1K-IDIF-K<sub>1</sub></italic> unveiled a significant reduction of <italic>BBB</italic> permeability after inflammatory interferon-<italic>α</italic> challenge, replicating results from standard quantification. High intra-subject correlation (<italic>ρ</italic> = 0.97 ± 0.01) was reported between <italic>K<sub>1</sub></italic> estimates of test and retest scans.</p></sec><sec id="sec4"><title>Discussion</title><p>This evidence supports <italic>1T1K-IDIF</italic> as blood-free alternative to assess <italic>TSPO</italic> tracers’ unidirectional blood brain clearance. <italic>K<sub>1</sub></italic> investigation could complement more traditional measures in <italic>TSPO</italic> studies, and even allow further mechanistic insight in the interpretation of <italic>TSPO</italic> signal.</p></sec>