FDG-PET and [18F]MPPF-PET are brain biomarkers for the creatine transporter Slc6a8 loss of function mutation

Abstract: Pathogenic variants in the creatine transporter gene SLC6A8, reported to represent 2% of all intellectual disabilities in males, result in a spectrum of behavioral abnormalities including developmental delay, intellectual disability, and deficit in speech. While at present there are no effective treatments available, preclinical development and testing of gene therapy and other approaches to increase brain creatine are being actively pursued. In studying a mouse model of the disorder, [¹⁸F]fluorodeoxyglucose ([¹⁸F]FDG)-based positron emission tomography (PET)/computed tomography (CT) was performed to assess brain glucose metabolism in wild type and creatine transporter mutant mice (Slc6a8^-/y). The findings demonstrate marked differences in glucose metabolism in the brains of wild type and Slc6a8^-/y mice. In conducting behavioral phenotyping studies, notable abnormalities in behavior in the murine model led to additional studies in serotonin-mediated activity. Serotonergic signaling differences were detected between wild type and Slc6a8^-/y mice using 4-(2′-methoxyphenyl)-1-[2′-(N-2″-pyridinyl)-p-[¹⁸F]fluorobenzamido]ethylpiperazine ([¹⁸F]MPPF). These data demonstrate that [¹⁸F]FDG-PET and [¹⁸F]-MPPF-PET may serve as appropriate and sensitive biomarkers that could be used to assess the efficacy of not only new approaches in treating mutations of the creatine transporter SLC6A8 and their effectiveness in normalizing brain metabolism but also in enhancing our understanding of the mechanism of brain dysfunction that occurs in this complex brain disorder.

Parent Summary: In this paper, researchers showed that compared to mice without CTD, CTD mice had lower creatine in their blood and brains, had abnormal behavior (increased anxiety-like behavior, impairments in learning and memory, decreased motivation), and had increased brain glucose metabolism. Increased brain glucose metabolism means that their brains used up more glucose (a high energy molecule), suggesting they may be trying to compensate for the energy deficiency created by a lack of creatine. However, there was not a concomitant increase in proteins able to transport glucose or enzymes involved in energy regulation, suggesting a limited ability to adapt to the energy deficit. In addition to differences in glucose metabolism and behavior, the CTD mice also exhibited a difference in serotonin signaling in their brains, which is involved in regulating mood, sleep, appetite, and more. Two positron emission tomography (PET) imaging techniques were used to measure the glucose and serotonin changes in the CTD mice: [18F]FDG and [18F]MPPF. PET is non-invasive and widely available for use in humans. Because these techniques were able to demonstrate changes between the CTD and non-CTD mice, they may be useful as biomarkers to assess the effectiveness of new CTD treatments and to better understand the underlying mechanisms of this disorder.

Link to article:   https://www.nature.com/articles/s41598-025-92022-8

PubMed: https://pubmed.ncbi.nlm.nih.gov/40025148/

Authors: Isabel Day, Mikayla Tamboline, Lindsay Lueptow, Irina Zhuravka, Taryn Diep, Ilona Tkachyova, Shili Xu, Andreas Schulze, Gerald S. Lipshutz

Key Terms: CTD, Animal Study, Mutation Study, Basic Science