Author + information
- Sytse F. Oudkerk, MD,
- Pim A. de Jong, MD, PhD∗ (, )
- Björn A. Blomberg, MD,
- Asbjørn M. Scholtens, MD,
- Willem P.Th.M. Mali, MD, PhD and
- Wilko Spiering, MD, PhD
- ↵∗Department of Radiology and Nuclear Medicine, University Medical Center Utrecht, Room E01.132, Heidelberglaan 100, 3508 GA Utrecht, the Netherlands
Pseudoxanthoma elasticum (PXE), CD73 deficiency, generalized arterial calcification of infancy, and progeria involve accelerated medial arterial calcification (MAC) leading to premature cardiovascular morbidity and mortality. MAC is also observed in diabetes mellitus, chronic kidney disease, and the elderly (1), and insufficient levels of inorganic pyrophosphate are thought to be involved. Finding a therapy for the genetic syndromes may cure these diseases and provide a model for lowering cardiovascular disease burden in the aging population. Drug discovery would be facilitated by a powerful intermediate endpoint. Positron emission tomography/computed tomography (PET/CT) with radioactive sodium fluoride (18NaF) provides quantitative information on arterial calcification formation. We aimed to provide proof-of-concept that whole-body deregulated calcification metabolism in PXE could be visualized and quantified with 18NaF PET/CT.
In our clinic we investigated 4 female patients with PXE using 18NaF PET/CT. Image acquisition was done on a whole-body LSO PET scanner with a 40-slice CT scanner 90 min after injection of 2.0 MBq/kg 18NaF. Low-dose CT involved 100 to 120 kV, 8 to 155 mA (combined effective dose, 5 mSv). On 18NaF PET/CT, we measured femoral artery and skin findings. Briefly, for arteries, an observer drew regions of interest around the arteries and in the right atrium to derive a corrected maximal standardized uptake value (cSUVmax) and a target-to-blood pool ratio (TBR). On CT, Agatston-like calcium scores of lesions with >130 Hounsfield units (HU) in the arteries and the bone density in the lumbar spine were quantified. Skin abnormalities in the neck, axillar, and inguinal regions were visually scored as absent, mild, moderate, or severe by 1 observer at standard window settings (CT, 1500/450; PET, count per megabecquerel of 459/2,481 [IntelliSpace Portal client version 4.0, Philips Medical Systems, Eindhoven, the Netherlands]). The same regions were evaluated by a physician blinded to the PET/CT images by using the Phenodex classification (2).
The patients were 43, 49, 57, and 67 years of age, respectively. On CT, we visually identified long segments with thin circular calcifications, predominantly in the femoral arteries (Figure 1). Interestingly, the density of these calcifications was <130 HU, and, therefore, the software could not calculate Agatston scores. Visually, especially in the femoral arteries, the arterial 18NaF signal was increased at levels similar to those for cortical bone. In the right femoral artery, the cSUVmax was 0.2, 0.2, 2.1, and 1.1, and the TBR was 1.4, 1.3, 3.3, and 1.9; in the left femoral artery, the cSUVmax was 0.2, 0.1, 2.2, and 1.3; and the TBR was 1.5, 1.1, 3.4, and 2.1 for the 4 patients with increasing age, respectively. On CT, the HU value in the lumbar vertebra 1 was 252, 169, 82, and 122, respectively. Values <120 are considered osteoporosis. Regarding the skin, patient 1 had severe skin abnormalities, both clinically and on PET, patient 2 had mild skin abnormalities both clinically and on PET, patient 3 had moderate skin abnormalities clinically and on PET, and patient 4 had moderate skin abnormalities clinically and severe on PET. Skin abnormalities were identified at all locations, and the severity and location of PET scores corresponded favorably with the clinical classification (RSpearman = 0.44, p = 0.09).
In conclusion, this is the first report showing that 18NaF PET/CT is able to visualize and quantify ectopic calcifications and bone metabolism in PXE and may prove a valuable intermediate mechanistic endpoint for therapeutic studies aiming to slow or remove MAC.
Please note: The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
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