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

Introduction: Recent evidence suggests the blood-to-brain influx rate ( K ₁ ) 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 K ₁ 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 ([ ¹¹ C]PBR28 and [ ¹⁸ F]DPA714). Firstly, 1T1K-IDIF K ₁ estimates were compared in terms of both bias and correlation with standard kinetic methodology. Then, the method was tested on an independent sample of [ ¹¹ C]PBR28 scans before and after inflammatory interferon- α challenge, and on test-retest dataset of [ ¹⁸ F]DPA714 scans.
Results: Comparison with standard kinetic methodology showed good-to-excellent intra-subject correlation for regional 1T1K-IDIF-K ₁ ( ρ _intra  = 0.93 ± 0.08), although the bias was variable depending on IDIF ability to approximate blood input functions (0.03-0.39 mL/cm ³ /min). 1T1K-IDIF-K ₁ 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 K ₁ estimates of test and retest scans.
Discussion: This evidence supports 1T1K-IDIF as blood-free alternative to assess TSPO tracers' unidirectional blood brain clearance. K ₁ investigation could complement more traditional measures in TSPO studies, and even allow further mechanistic insight in the interpretation of TSPO signal.
Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.
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