Cerebral and myocardial kinetics of [11C]acetoacetate and [11C]β-hydroxybutyrate: A comparative crossover study in healthy rats

Mette Louise Gram Kjærulff; Thien Vinh Luong; Gabriel Richard; Valérie St-Pierre; Esben Søndergaard; Niels Møller; Lars Christian Gormsen; Sébastien Tremblay; Etienne Croteau; Stephen C. Cunnane

doi:10.1016/j.nucmedbio.2024.108967

Cerebral and myocardial kinetics of [¹¹C]acetoacetate and [¹¹C]β-hydroxybutyrate: A comparative crossover study in healthy rats

Mette Louise Gram Kjærulff^*, Thien Vinh Luong, Gabriel Richard, Valérie St-Pierre, Esben Søndergaard, Niels Møller, Lars Christian Gormsen, Sébastien Tremblay, Etienne Croteau, Stephen C. Cunnane

^*Corresponding author af dette arbejde

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

Abstract

Background: Ketone metabolism has been studied using positron emission tomography (PET) with the radiotracers [¹¹C]acetoacetate and [¹¹C]β-hydroxybutyrate. However, whether these two radiotracers actually yield equivalent estimates of cerebral and myocardial ketone metabolism has not yet been investigated. This study aimed to investigate and compare the kinetics of both tracers in the brain and heart of healthy rats under varying levels of circulating ketones at baseline and after a single-dose exogenous ketone ester (KE) supplement. Methods: Six healthy Sprague-Dawley rats each underwent two scans with each tracer: one following oral KE administration and one with a placebo. Cerebral kinetic parameters (K_i, V_T, and cerebral metabolic rate (CMR)) were obtained using the Patlak method, whereas myocardial kinetic parameters (K₁, k₂, and V_T) were derived using a 1-tissue compartment model. Parameters were compared through mixed-effects, correlation, and Bland-Altman analyses. Results: Global CMR increased 3–4-fold in the KE group versus placebo, with strong positive correlations between CMR and plasma ketone levels for both tracers. Correlations between [¹¹C]acetoacetate and [¹¹C]β-hydroxybutyrate were moderate and non-significant for relative cerebral uptake expressed as K_i (ρ = 0.40) and for V_T (ρ = 0.38) but strongly positive for absolute uptake, CMR (r = 0.84), with a non-significant mean bias of −0.03. In contrast, myocardial kinetics showed only non-significant weak to moderate correlations between the radiotracers (K₁ (r = 0.04), k₂ (r = −0.27), and V_T (ρ = 0.43)), with no systematic biases. Conclusion: [¹¹C]acetoacetate and [¹¹C]β-hydroxybutyrate can be used interchangeably for measuring global CMR in healthy rats but differ in certain cerebral and myocardial kinetics. Whether these findings are generalizable to pathological conditions warrants further studies to explore the kinetics of these tracers in disease models.

Originalsprog	Engelsk
Artikelnummer	108967
Tidsskrift	Nuclear Medicine and Biology
Vol/bind	138-139
Antal sider	11
ISSN	0969-8051
DOI	https://doi.org/10.1016/j.nucmedbio.2024.108967
Status	Udgivet - 1 nov. 2024

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10.1016/j.nucmedbio.2024.108967Licens: CC BY

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Kjærulff, M. L. G., Luong, T. V., Richard, G., St-Pierre, V., Søndergaard, E., Møller, N., Gormsen, L. C., Tremblay, S., Croteau, E., & Cunnane, S. C. (2024). Cerebral and myocardial kinetics of [¹¹C]acetoacetate and [¹¹C]β-hydroxybutyrate: A comparative crossover study in healthy rats. Nuclear Medicine and Biology, 138-139, Artikel 108967. https://doi.org/10.1016/j.nucmedbio.2024.108967

@article{cb39921db6b14558ba6e0dc0cb8328cb,

title = "Cerebral and myocardial kinetics of [11C]acetoacetate and [11C]β-hydroxybutyrate: A comparative crossover study in healthy rats",

abstract = "Background: Ketone metabolism has been studied using positron emission tomography (PET) with the radiotracers [11C]acetoacetate and [11C]β-hydroxybutyrate. However, whether these two radiotracers actually yield equivalent estimates of cerebral and myocardial ketone metabolism has not yet been investigated. This study aimed to investigate and compare the kinetics of both tracers in the brain and heart of healthy rats under varying levels of circulating ketones at baseline and after a single-dose exogenous ketone ester (KE) supplement. Methods: Six healthy Sprague-Dawley rats each underwent two scans with each tracer: one following oral KE administration and one with a placebo. Cerebral kinetic parameters (Ki, VT, and cerebral metabolic rate (CMR)) were obtained using the Patlak method, whereas myocardial kinetic parameters (K1, k2, and VT) were derived using a 1-tissue compartment model. Parameters were compared through mixed-effects, correlation, and Bland-Altman analyses. Results: Global CMR increased 3–4-fold in the KE group versus placebo, with strong positive correlations between CMR and plasma ketone levels for both tracers. Correlations between [11C]acetoacetate and [11C]β-hydroxybutyrate were moderate and non-significant for relative cerebral uptake expressed as Ki (ρ = 0.40) and for VT (ρ = 0.38) but strongly positive for absolute uptake, CMR (r = 0.84), with a non-significant mean bias of −0.03. In contrast, myocardial kinetics showed only non-significant weak to moderate correlations between the radiotracers (K1 (r = 0.04), k2 (r = −0.27), and VT (ρ = 0.43)), with no systematic biases. Conclusion: [11C]acetoacetate and [11C]β-hydroxybutyrate can be used interchangeably for measuring global CMR in healthy rats but differ in certain cerebral and myocardial kinetics. Whether these findings are generalizable to pathological conditions warrants further studies to explore the kinetics of these tracers in disease models.",

keywords = "Acetoacetate, beta-hydroxybutyrate, Ketone bodies, Ketone metabolism, Positron emission tomography, Tracer kinetics",

author = "Kj{\ae}rulff, {Mette Louise Gram} and Luong, {Thien Vinh} and Gabriel Richard and Val{\'e}rie St-Pierre and Esben S{\o}ndergaard and Niels M{\o}ller and Gormsen, {Lars Christian} and S{\'e}bastien Tremblay and Etienne Croteau and Cunnane, {Stephen C.}",

note = "Publisher Copyright: {\textcopyright} 2024 The Authors",

year = "2024",

month = nov,

day = "1",

doi = "10.1016/j.nucmedbio.2024.108967",

language = "English",

volume = "138-139",

journal = "Nuclear Medicine and Biology",

issn = "0969-8051",

publisher = "Elsevier Inc.",

}

Kjærulff, MLG , Luong, TV, Richard, G, St-Pierre, V, Søndergaard, E , Møller, N , Gormsen, LC, Tremblay, S, Croteau, E & Cunnane, SC 2024, 'Cerebral and myocardial kinetics of [¹¹C]acetoacetate and [¹¹C]β-hydroxybutyrate: A comparative crossover study in healthy rats', Nuclear Medicine and Biology, bind 138-139, 108967. https://doi.org/10.1016/j.nucmedbio.2024.108967

Cerebral and myocardial kinetics of [¹¹C]acetoacetate and [¹¹C]β-hydroxybutyrate: A comparative crossover study in healthy rats. / Kjærulff, Mette Louise Gram ; Luong, Thien Vinh; Richard, Gabriel et al.
I: Nuclear Medicine and Biology, Bind 138-139, 108967, 01.11.2024.

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

TY - JOUR

T1 - Cerebral and myocardial kinetics of [11C]acetoacetate and [11C]β-hydroxybutyrate

T2 - A comparative crossover study in healthy rats

AU - Kjærulff, Mette Louise Gram

AU - Luong, Thien Vinh

AU - Richard, Gabriel

AU - St-Pierre, Valérie

AU - Søndergaard, Esben

AU - Møller, Niels

AU - Gormsen, Lars Christian

AU - Tremblay, Sébastien

AU - Croteau, Etienne

AU - Cunnane, Stephen C.

PY - 2024/11/1

Y1 - 2024/11/1

N2 - Background: Ketone metabolism has been studied using positron emission tomography (PET) with the radiotracers [11C]acetoacetate and [11C]β-hydroxybutyrate. However, whether these two radiotracers actually yield equivalent estimates of cerebral and myocardial ketone metabolism has not yet been investigated. This study aimed to investigate and compare the kinetics of both tracers in the brain and heart of healthy rats under varying levels of circulating ketones at baseline and after a single-dose exogenous ketone ester (KE) supplement. Methods: Six healthy Sprague-Dawley rats each underwent two scans with each tracer: one following oral KE administration and one with a placebo. Cerebral kinetic parameters (Ki, VT, and cerebral metabolic rate (CMR)) were obtained using the Patlak method, whereas myocardial kinetic parameters (K1, k2, and VT) were derived using a 1-tissue compartment model. Parameters were compared through mixed-effects, correlation, and Bland-Altman analyses. Results: Global CMR increased 3–4-fold in the KE group versus placebo, with strong positive correlations between CMR and plasma ketone levels for both tracers. Correlations between [11C]acetoacetate and [11C]β-hydroxybutyrate were moderate and non-significant for relative cerebral uptake expressed as Ki (ρ = 0.40) and for VT (ρ = 0.38) but strongly positive for absolute uptake, CMR (r = 0.84), with a non-significant mean bias of −0.03. In contrast, myocardial kinetics showed only non-significant weak to moderate correlations between the radiotracers (K1 (r = 0.04), k2 (r = −0.27), and VT (ρ = 0.43)), with no systematic biases. Conclusion: [11C]acetoacetate and [11C]β-hydroxybutyrate can be used interchangeably for measuring global CMR in healthy rats but differ in certain cerebral and myocardial kinetics. Whether these findings are generalizable to pathological conditions warrants further studies to explore the kinetics of these tracers in disease models.

AB - Background: Ketone metabolism has been studied using positron emission tomography (PET) with the radiotracers [11C]acetoacetate and [11C]β-hydroxybutyrate. However, whether these two radiotracers actually yield equivalent estimates of cerebral and myocardial ketone metabolism has not yet been investigated. This study aimed to investigate and compare the kinetics of both tracers in the brain and heart of healthy rats under varying levels of circulating ketones at baseline and after a single-dose exogenous ketone ester (KE) supplement. Methods: Six healthy Sprague-Dawley rats each underwent two scans with each tracer: one following oral KE administration and one with a placebo. Cerebral kinetic parameters (Ki, VT, and cerebral metabolic rate (CMR)) were obtained using the Patlak method, whereas myocardial kinetic parameters (K1, k2, and VT) were derived using a 1-tissue compartment model. Parameters were compared through mixed-effects, correlation, and Bland-Altman analyses. Results: Global CMR increased 3–4-fold in the KE group versus placebo, with strong positive correlations between CMR and plasma ketone levels for both tracers. Correlations between [11C]acetoacetate and [11C]β-hydroxybutyrate were moderate and non-significant for relative cerebral uptake expressed as Ki (ρ = 0.40) and for VT (ρ = 0.38) but strongly positive for absolute uptake, CMR (r = 0.84), with a non-significant mean bias of −0.03. In contrast, myocardial kinetics showed only non-significant weak to moderate correlations between the radiotracers (K1 (r = 0.04), k2 (r = −0.27), and VT (ρ = 0.43)), with no systematic biases. Conclusion: [11C]acetoacetate and [11C]β-hydroxybutyrate can be used interchangeably for measuring global CMR in healthy rats but differ in certain cerebral and myocardial kinetics. Whether these findings are generalizable to pathological conditions warrants further studies to explore the kinetics of these tracers in disease models.

KW - Acetoacetate

KW - beta-hydroxybutyrate

KW - Ketone bodies

KW - Ketone metabolism

KW - Positron emission tomography

KW - Tracer kinetics

UR - http://www.scopus.com/inward/record.url?scp=85207664476&partnerID=8YFLogxK

U2 - 10.1016/j.nucmedbio.2024.108967

DO - 10.1016/j.nucmedbio.2024.108967

M3 - Journal article

C2 - 39476467

AN - SCOPUS:85207664476

SN - 0969-8051

VL - 138-139

JO - Nuclear Medicine and Biology

JF - Nuclear Medicine and Biology

M1 - 108967

ER -