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

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

doi:10.3389/fnins.2024.1395769

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

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

University of Padova
Harvard Medical School
Institute of Psychiatry, Psychology and Neuroscience (IoPPN)
King's College London
INSERM
ICM Institut du cerveau et de la moelle épinière
University of Padua

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9 Citations (Scopus)

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Abstract

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 ([ 11C]PBR28 and [ 18F]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 [ 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-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.

Original language	English
Article number	1395769
Pages (from-to)	1395769
Journal	Frontiers in Neuroscience
Volume	18
Early online date	22 Jul 2024
DOIs	https://doi.org/10.3389/fnins.2024.1395769
Publication status	Published - 2024

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Maccioni, L., Michelle, C. M., Brusaferri, L., Silvestri, E., Bertoldo, A., Schubert, J. J., Nettis, M. A., Mondelli, V., Howes, O., Turkheimer, F. E., Bottlaender, M., Bodini, B., Stankoff, B., Loggia, M. L., & Veronese, M. (2024). A blood-free modeling approach for the quantification of the blood-to-brain tracer exchange in TSPO PET imaging. Frontiers in Neuroscience, 18, 1395769. Article 1395769. https://doi.org/10.3389/fnins.2024.1395769

@article{df382581e2934134ab914757bb9f4a5c,

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

abstract = "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 ([ 11C]PBR28 and [ 18F]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 [ 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-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. ",

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

note = "Publisher Copyright: Copyright {\textcopyright} 2024 Maccioni, Carranza Mellana, Brusaferri, Silvestri, Bertoldo, Schubert, Nettis, Mondelli, Howes, Turkheimer, Bottlaender, Bodini, Stankoff, Loggia and Veronese.",

year = "2024",

doi = "10.3389/fnins.2024.1395769",

language = "English",

volume = "18",

pages = "1395769",

journal = "Frontiers in Neuroscience",

issn = "1662-4548",

publisher = "Frontiers Media S.A.",

}

Maccioni, L, Michelle, CM, Brusaferri, L, Silvestri, E, Bertoldo, A, Schubert, JJ , Nettis, MA , Mondelli, V , Howes, O , Turkheimer, FE, Bottlaender, M, Bodini, B, Stankoff, B, Loggia, ML & Veronese, M 2024, 'A blood-free modeling approach for the quantification of the blood-to-brain tracer exchange in TSPO PET imaging', Frontiers in Neuroscience, vol. 18, 1395769, pp. 1395769. https://doi.org/10.3389/fnins.2024.1395769

TY - JOUR

T1 - A blood-free modeling approach for the quantification of the blood-to-brain tracer exchange in TSPO PET imaging

AU - Maccioni, Lucia

AU - Michelle, Carranza Mellana

AU - Brusaferri, Ludovica

AU - Silvestri, Erica

AU - Bertoldo, Alessandra

AU - Schubert, Julia J

AU - Nettis, Maria A

AU - Mondelli, Valeria

AU - Howes, Oliver

AU - Turkheimer, Federico E

AU - Bottlaender, Michel

AU - Bodini, Benedetta

AU - Stankoff, Bruno

AU - Loggia, Marco L

AU - Veronese, Mattia

N1 - Publisher Copyright: Copyright © 2024 Maccioni, Carranza Mellana, Brusaferri, Silvestri, Bertoldo, Schubert, Nettis, Mondelli, Howes, Turkheimer, Bottlaender, Bodini, Stankoff, Loggia and Veronese.

PY - 2024

Y1 - 2024

N2 - 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 ([ 11C]PBR28 and [ 18F]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 [ 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-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.

AB - 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 ([ 11C]PBR28 and [ 18F]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 [ 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-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.

UR - https://www.scopus.com/pages/publications/85200392667

U2 - 10.3389/fnins.2024.1395769

DO - 10.3389/fnins.2024.1395769

M3 - Article

C2 - 39104610

SN - 1662-4548

VL - 18

SP - 1395769

JO - Frontiers in Neuroscience

JF - Frontiers in Neuroscience

M1 - 1395769

ER -

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

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