Preclinical evaluation of high-resolution CT, 18F-FDG, and 18F-NaF PET imaging for longitudinal monitoring of atherosclerosis - PubMed (original) (raw)

. 2025 Sep;52(11):4256-4267.

doi: 10.1007/s00259-025-07276-1. Epub 2025 Apr 28.

Jeffrey Collins 1 2, William Jackson 3, Wenduo Gu 3, Matthew Worssam 3, Paul Cheng 3 4, John David 5, Richard Taschereau 1 2, Arion F Chatziioannou 1 2 6, Simon Jackson 5, Shili Xu 7 8 9 10, Oluwatayo F Ikotun 11 12 13 14

Affiliations

Preclinical evaluation of high-resolution CT, 18F-FDG, and 18F-NaF PET imaging for longitudinal monitoring of atherosclerosis

Mikayla Tamboline et al. Eur J Nucl Med Mol Imaging. 2025 Sep.

Abstract

Rationale: Detection of atherosclerosis is essential to the management and prevention of life-threatening cardiovascular events. Although non-invasive imaging modalities, such as 18F-sodium fluoride (18F-NaF), 18F-fluorodeoxyglucose (18F-FDG) PET, and CT, visualize distinct hallmarks of atherosclerosis, there has yet to be a singular multi-cohort interrogation of their strengths and limitations. Thus, we focused on identifying the optimal approach for visualizing atherosclerosis at different stages of disease progression.

Methods: In this study, 6-week-old, male, ApoE deficient mice (Apoe-/-) were placed on a high cholesterol diet for 12-20 weeks to induce calcific atherosclerotic disease. Age-matched, male, wildtype (WT) C57BL/6 mice fed with regular chow served as the control group. Mice were imaged at 12, 15, 18, and 20 weeks after starting their respective diets. To follow the progression of calcified atherosclerotic lesions, at each time point, in vivo, 18F-NaF microPET/CT images were acquired 1 h and 3 h post tracer i.v. injection. In a separate cohort, in vivo 18F-FDG PET/CT images were acquired at 3 and 5 h post tracer i.v. injection to follow inflammation as a result of progressive atherosclerotic lesion formation. High-resolution microCT images were acquired for all mice to visualize aorta calcification. After each imaging session, a subset (n = 3) was euthanized from each group and histological analysis of the aorta was performed to confirm disease progression.

Results: In this comparative study, within the same cohort, 18F-NaF PET detected atherosclerotic calcification earlier than microCT. At both 1 and 3 h post-injection (p.i.), calcified lesions were clearly detected by 18F-NaF with a six-fold higher signal in Apoe-/- compared to WT mice. Interestingly, 18F-NaF signal peaked at week 18, whereas aortic CT signal progressively increased with a 13-, 16-, and 29-fold at 15, 18, and 20 weeks, respectively. 18F-FDG arortic accumulation at weeks 12 and 15, were significantly greater in Apoe -/- mice than WT control when images were acquired at 5 h but not at 3 h p.i.. In contrast to histological analysis, at ≥ 16 weeks where inflammation is significantly elevated, 18F-FDG was equivalent in Apoe-/- and WT control mice and significantly reduced with disease progression.

Conclusions: Our results show that 18F-NaF PET and 18F-FDG PET are sensitive imaging modalities for the early detection of atherosclerotic lesions. However, both 18F-NaF PET and high-resolution microCT prove to be effective methods for monitoring late-stage and progressive disease.

Keywords: 18F-FDG; 18F-NaF; Aorta; Atherosclerosis; CT; Calcification; Diagnosis; PET.

© 2025. The Author(s).

PubMed Disclaimer

Conflict of interest statement

Declarations. Ethics approvals: All experimental protocols in this study were reviewed and approved by the Institutional Animal Care and Use Committee of the University of California, Los Angeles. The study was carried out in compliance with the ARRIVE guidelines. This article does not contain any studies with human participants. Consent to participate: No patients or human subjects involved in this study. Consent to publish: No patients or human subjects involved in this study. Competing interests: No potential conflict of interest relevant to this article was reported. Clinical trial number: Not applicable.

Figures

Fig. 1

Fig. 1

Experimental study design and timeline of longitudinal in vivo imaging assays. A Two groups of mice, _Apoe_−/− on a high fat diet (HFD) and C57BL/6 wildtype control mice on a regular diet, were imaged with two microPET tracers: 18F-NaF (n = 20/group) and a separate cohort imaged by 18F-FDG (n = 20/group). MicroCT was performed on both cohorts combined (n = 40/group). B Schematic of the imaging protocol. Each cohort of mice was imaged at weeks 12, 15, 18, and 20 after starting their respective diets

Fig. 2

Fig. 2

Establishment of atherosclerotic disease in an _Apoe_−/− mouse model. A Longitudinal monitoring of the body weight of _Apoe_−/− mice on a high-fat diet (HFD) compared with C57BL/6 control mice fed a regular chow diet for up to 20 weeks. B Representative Sudan IV red staining and (C) quantification of isolated aorta of _Apoe_−/− and C57BL/6 mice after 12, 15, 18, and 20 weeks on respective diets confirms lipid accumulation in _Apoe_−/−/HFD group. Statistical significance was determined by two-way ANOVA, using Tukey’s multiple comparisons test. *p < 0.05; **p < 0.01; *** p < 0.001; ****p < 0.0001

Fig. 3

Fig. 3

Apoe −/−/HFD mouse aortic root plaque histology analysis. A Representative fluorescent images of mouse aortic root plaque histology stained for CD68 in Apoe −/−/HFD mice at 9 and 16 weeks. Higher magnification images highlight CD68+ macrophage infiltration. B Quantification of total CD68+ area (µm2) at 9 and 16 weeks. C Representative images of aortic root sections stained with Ferangi Blue to assess calcification in Apoe −/−/HFD mice at 9 and 16 weeks. D Quantification of total Ferangi Blue-stained area (µm2) at 9 and 16 weeks. E Quantification of total lesion area (µm2) at 9 and 16 weeks of Ferangi Blue stained aortic root sections. Data are mean ± SEM, N = 3–5. Statistical significance was determined by unpaired two-tailed t-test. *, p < 0.05. **, p < 0.01

Fig. 4

Fig. 4

Detection of atherosclerosis by in vivo 18F-NaF microPET. A Representative coronal plane of the co-registered microPET/CT images of the _Apoe_−/− and control mice at week 12, 15, 18, and 20 on their respective diets, 1 h and 3 h post injection of 18F-NaF. White arrows indicate 18F-NaF uptake in the aorta. B Quantitative PET of aortic 18F-NaF uptake in the _Apoe_−/−/HFD and WT control mice at week 12 (n = 20/group), 15 (n = 17/group), 18 (n = 14/group), and week 20 (n = 11/group), 1 h and (C) 3 h post injection of 18F-NaF. Statistical significance was determined by mixed-effect two-way ANOVA using Tukey’s multiple comparisons test. *p < 0.05; **p < 0.01; *** p < 0.001; ****p < 0.0001

Fig. 5

Fig. 5

Detection of atherosclerosis by in vivo 18F-FDG microPET. A Representative transverse plane of the co-registered microPET/CT images of the _Apoe_−/− and control mice at week 12, 15, 18, and 20 on their respective diets, 3 h and 5 h post injection of 18F-FDG. A white arrow indicates 18F-FDG uptake in the aorta. B Quantitative PET analysis obtained 3 h and (C) 5 h post-injection of 18F-FDG in _Apoe_−/−/HFD and WT control mice at week 12 (n = 20/group), 15 (n = 17/group), 18 (n = 14/group), and 20 (n = 11/group). Statistical significance was determined by mixed-effect two-way ANOVA, Tukey’s multiple comparisons test. *p < 0.05; **p < 0.01; *** p < 0.001; ****p < 0.0001; ns, not significant

Fig. 6

Fig. 6

Detection of atherosclerosis by in vivo microCT. A Representative coronal view with maximum-intensity projection of the _Apoe_−/− and control mice at week 12, 15, 18, and 20 on their respective diets. A dashed red circle indicates calcification observed by the microCT. B Quantitative analysis of aortic calcium content in the _Apoe_−/−/HFD and control mice at week 12 (n = 40/group), 15 (n = 34/group), 18 (n = 28/group), and 20 (n = 22/group). Statistical significance was determined by mixed-effect two-way ANOVA, using Tukey’s multiple comparisons test. *p < 0.05; **p < 0.01; *** p < 0.001; ****p < 0.0001; ns, not significant

Fig. 7

Fig. 7

Multi-cohort molecular PET and anatomical CT imaging in an _Apoe_−/−/HFD model of progressive atherosclerosis. A Quantitative 18F-FDG, B 18F-NaF PET SUV, and C microCT in the _Apoe_−/− mice fed a high-fat diet to induce atherosclerosis and monitored during early, mid, late, and terminal disease after 12, 15, 18, and 20 weeks of HFD, respectively. D, E, F Correlative analysis in matched subjects comparing 18F-FDG or 18F-NaF PET or anatomical high-resolution CT with terminal Sudan IV staining. A strong correlation between lipid accumulation (Sudan IV) and 18F-NaF PET or anatomical high-resolution CT was observed, while 18F-FDG did not correlate with %Sudan IV-positive area. G, H, I No correlation was observed with 18F-FDG or 18F-NaF SUVmean, while there was a strong correlation between microCT and 18F-FDG or 18F-NaF. Correlative analysis was conducted using the Pearson’s rank correlation coefficient. Statistical significance was determined by one-way ANOVA, Šídák's multiple comparisons test. *p < 0.05; **p < 0.01; *** p < 0.001; ****p < 0.0001

References

    1. Pahwa R, Jialal I. Atherosclerosis. Treasure Island: StatPearls; 2024.
    1. Ferrara P, Di Laura D, Cortesi PA, Mantovani LG. The economic impact of hypercholesterolemia and mixed dyslipidemia: a systematic review of cost of illness studies. PLoS ONE. 2021;16:e0254631. 10.1371/journal.pone.0254631. -DOI -PMC -PubMed
    1. Cocker MS, Mc Ardle B, Spence JD, Lum C, Hammond RR, Ongaro DC, et al. Imaging atherosclerosis with hybrid [18F]fluorodeoxyglucose positron emission tomography/computed tomography imaging: what Leonardo da Vinci could not see. J Nucl Cardiol. 2012;19:1211–25. 10.1007/s12350-012-9631-9. -DOI -PMC -PubMed
    1. McKenney-Drake ML, Moghbel MC, Paydary K, Alloosh M, Houshmand S, Moe S, et al. (18)F-NaF and (18)F-FDG as molecular probes in the evaluation of atherosclerosis. Eur J Nucl Med Mol Imaging. 2018;45:2190–200. 10.1007/s00259-018-4078-0. -DOI -PMC -PubMed
    1. Ross R. Atherosclerosis–an inflammatory disease. N Engl J Med. 1999;340:115–26. 10.1056/NEJM199901143400207. -DOI -PubMed

MeSH terms

Substances

Grants and funding

LinkOut - more resources