Confirming improved detection of gadolinium in bone using in vivo XRF
Introduction
Gadolinium (Gd) is used in MRI contrast agents, which are commonly administered prior to receiving MRI scans to improve contrast in certain tissues. When Gd-based contrast agents (GBCAs) were first introduced in the early 80's, they were thought to be completely stable and excreted from the body within a matter of hours (Weinmann et al., 2005, Carr et al., 1984). However, in 2006 GBCAs were linked to nephrogenic systemic fibrosis (NSF) in patients with renal disease, suggesting they are accumulating in the body, rather than being excreted (Grobner, 2006, Marckmann et al., 2006, Thomsen et al., 2006). NSF is a painful condition involving hardening of the skin, due to the formation of papules and plaques, for which there is no clear cure (Cowper et al., 2001). Since the association of GBCAs with NSF, extra precautions are being taken to prevent individuals with renal disease from receiving GBCAs prior to an MRI scan. However, Gd accumulation does not only occur in individuals with renal disease, as it has recently been found in patients with normal renal function (McDonald et al., 2015, Quattrocchi et al., 2015, Errante et al., 2014, Kanda et al., 2013, Kanda et al., 2015, Murata et al., 2016), which is why the safety of GBCAs is currently such an important topic in the MRI community.
One of the main sites of interest for Gd accumulation in the body is the brain, specifically the dentate nucleus and the pons. Multiple research groups have carried out image analysis studies, showing an increase in T1 signal intensity with increasing doses of Gd-based contrast agents, which suggests Gd accumulation in the brain (McDonald et al., 2015, Quattrocchi et al., 2015, Errante et al., 2014, Kanda et al., 2013). Inductively coupled plasma mass spectrometry (ICP-MS) was used on autopsy samples by Kanda et al. and demonstrated a correlation between Gd accumulation in the brain and GBCA dose (Kanda et al., 2015). All studies regarding Gd accumulation in the brain were performed on patients with healthy renal function.
Another site of interest for Gd accumulation in the body is bone. Rare earth elements such as Gd are known to be bone seeking, with Gd3+ having a similar radial size to Ca2+ and higher ionic charge, thus leading to competitive inhibition for processes involving Ca2+. It is assumed that Gd incorporates into human bone mineral, as it is the storage site for the majority of Ca in the body (Sherry et al., 2009, Thakral et al., 2007, Darrah et al., 2009, Rogosnitzky and Branch, 2016). Darrah et al. and White et al. found unusually high concentrations of Gd, ranging from 0.42 to 6.02 μg Gd/g bone, in the femoral heads of patients undergoing hip replacement surgery who had previously received GBCA (Darrah et al., 2009, White et al., 2006). Murata et. al measured Gd in brain and bone autopsy samples from patients who had received GBCA, all with healthy renal function. Gd levels measured in bone, ranging from 0.1 to 5.3 μg Gd/g bone, were 23 times higher than levels in brain and showed a significant correlation between concentrations in the bone and brain (Murata et al., 2016). Overall, bone proves to be a main storage site for Gd and would serve as a convenient measurement location to investigate Gd accumulation in the body.
All studies previously discussed used in vitro methods, where the bone sample is removed from the body to be measured by ICP-MS, which is a destructive technique. X-ray fluorescence (XRF) is a non-invasive and non-destructive technique, that allows for in vivo measurements of Gd, through Gd excitation and measurement of produced fluorescent x-rays. A previous study by Lord et al. in our research group investigated the feasibility of using an XRF system to measure Gd by using bone phantoms anthropomorphic to a human tibia. For a single high-purity germanium (HPGe) detector, and a 0.11 GBq Cd-109 excitation source, the minimum detection limit (MDL) was calculated to be 0.87 μg Gd/g plaster for a bare bone phantom, and 1.34 μg Gd/g plaster for a bone phantom with an overlaying tissue thickness of 5.5 mm. Due to the weak activity of the Cd-109 source used, measurement times had to be extended to 20-h to detect the Gd properly (Lord et al., 2016). A 20-h measurement is unrealistic for human in vivo measurements, and MDLs for this system increase to 5.5 μg Gd/g plaster for bare bone and 8.47 μg Gd/g plaster for an overlaying tissue thickness of 5.5 mm for a realistic measurement time of 30-min. It is clear that these values are too large to detect trace amounts of Gd in bone properly, considering previous measurements of Gd in bone range from 0.1 to 6.02 μg Gd/g bone. Therefore it is necessary to update to a stronger source and a new detection system for human measurements.
MDL values in Lord et al. were scaled to create estimated MDLs for a 30-min measurement time with an updated four-detector cloverleaf system and a stronger source of 5 GBq. These values proved to be very promising for in vivo measurements, ranging from 1.49 to 1.52 μg Gd/g plaster for an average overlaying tissue thickness, with an effective dose of approximately 0.13 μSv (Lord et al., 2016). This report presents the experimental methods and data for Gd measurements, including MDLs for a range of tissue overlay thicknesses, for an updated (cloverleaf design) XRF system in preparation for human measurements. In addition, we present data from a cross validation study, performed on a set of autopsy bone samples, and compare our XRF measurements to ICP-MS measurements performed at the Wadsworth Center in Albany, New York.
Section snippets
Measurement location
A measurement location of the tibia was chosen due to the relatively thin layer of overlaying tissue on the tibia, thus reducing attenuation of Gd x-rays exiting the bone. A lower (total body) effective dose is received by the individual being measured since the tibia is located in an extremity of the body and there is no active red bone marrow in the adult tibia. In addition, measuring the leg provides comfort for individuals during a measurement, in terms of physical comfort and in knowing
Peak fitting
Measurements for all samples were carried out in 30-min real time counting intervals. Since the XRF system consists of four HPGe detectors, four spectra were acquired for each sample measured, and four sets of Gd peaks were fit as described in the previous section. All sets of peaks were fit well, resulting in an average χ2 value of 1.04, ranging from 0.88–1.20, for all the samples measured.
Once the Gd peaks were properly fit for phantom measurements, the areas under the peaks were calculated
Estimated MDLs from a single detector system
In our previous Gd study, a single HPGe detector was used with a 0.11 GBq Cd-109 source (Lord et al., 2016). Due to the weak activity of the excitation source, the measurement times had to be approximately 20 h to achieve reasonable MDLs. Therefore MDL values from this study were scaled to give estimated MDL values for a 30-min measurement on the cloverleaf system with a much stronger 5 GBq source. The relationship of MDL was used to scale the time from a 20–30 min measurement. The increase in
Conclusions
An improved XRF system for the detection of Gd in bone proved to have promising detection limits of 1.64–1.72 μg Gd/g plaster for overlying tissue thickness in the normal adult range. These experimentally determined detection limits were close to estimated values of 1.49–1.52 μg Gd/g plaster. These low MDL values suggest that the XRF system is capable of detecting the trace amounts of Gd that may remain in patient's bones after an MR imaging scan, since the published literature suggests retained
Conflicts of interest
The authors affirm that none of them has any conflict of interest.
Acknowledgements
This study was funded by Natural Sciences and Engineering Research Council of Canada Discovery Grants to FEMcN (203611-2012) and DRC (RGPIN06399-15).
References (30)
- et al.
A phantom-based feasibility study for detection of gadolinium in bone in-vivo using x-ray fluorescence
Appl. Radiat. Isot.
(2016) - et al.
Is there a causal relation between the administration of gadolinium based contrast media and the development of nephrogenic systemic fibrosis (NSF)?
Clin. Radiol.
(2006) - et al.
In vivo X-ray fluorescence of lead in bone
Environ. Res.
(1992) - et al.
An interlaboratory comparison of bone lead measurements via K-shell X-ray fluorescence spectrometry: validation against inductively coupled plasma massspectrometry
J. Anal. At. Spectrom.
(2012) - et al.
Gadolinium-DTPA as a contrast agent in MRI: initial clinical experience in 20 patients
Am. J. Roentgenol.
(1984) - et al.
Aslam, The feasibility of in vivo quantification of bone-fluorine in humans by delayed neutron activation analysis: a pilot study
Physiol. Meas.
(2012) - et al.
Lead in bone: sampling and quantitation using KX-rays excited by 109 Cd
Environ. Health Perspect.
(1991) - et al.
Nephrogenic fibrosing dermopathy
Am. J. Dermatopathol.
(2001) - et al.
Incorporation of excess gadolinium into human bone from medical contrast agents
Metallomics
(2009) - et al.
Progressive increase of T1 signal intensity of the dentate nucleus on unenhanced magnetic resonance images is associated with cumulative doses of intravenously administered gadodiamide in patients with normal renal function, suggesting dechelation
Invest. Radiol.
(2014)
The reproducibility of 109Cd-based X-ray fluorescence measurements of bone lead
Environ. Health Perspect.
Gadolinium-a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis?
Nephrol. Dial. Transplant.
High signal intensity in the dentate nucleus and globus pallidus on unenhanced T1-weighted MR images: relationship with increasing cumulative dose of a gadolinium-based contrast material
Radiology
Gadolinium-based contrast agent accumulates in the brain even in subjects without severe renal dysfunction: evaluation of autopsy brain specimens with inductively coupled plasma mass spectroscopy
Radiology
Cited by (15)
Content-based medical image retrieval by spatial matching of visual words
2022, Journal of King Saud University - Computer and Information SciencesCitation Excerpt :Medical image retrieval research has emanated as the chalk horse for doctors and radiologists, particularly due to the prodigious increase in the use of medical images in the recent past. The advancement in medical imaging techniques (Diekhoff et al., 2017; Gherase et al., 2017; Hussain et al., 2017; Lord et al., 2017; Miwa and Otsuka, 2017; Woźniak et al., 2018b; Xie et al., 2018) and automatic diagnosis systems (Muhammad et al., 2017; Wang et al., 2018; Woźniak et al., 2018a; Woźniak and Połap, 2018) cause the accumulation of an extensive collection of medical images in hospitals. Modern hospitals store medical images in DICOM (Digital Imaging and Communications in Medicine) format.
Lanthanides and tissue engineering strategies for bone regeneration
2019, Coordination Chemistry ReviewsCitation Excerpt :More recent reports began to question the safety of gadolinium. The deposition and retention of gadolinium in various tissues of patients, including bone, brain and kidneys were described in the literature [100–103]. The group of Jinchao Zhang showed that Europium (Eu3+)-doped Gd2O3 nanotubes increased bone mineral density in vivo and promoted mineralization in vitro [104].
Standardization of <sup>109</sup>Cd by two methods
2018, Applied Radiation and IsotopesCitation Excerpt :It emits 88 keV γ-rays and an amount of conversion electrons, Auger electrons and X-rays (Bé and Schönfeld, 2014). That makes it quite a useful nuclide for the calibration of X-ray and gamma-ray spectroscopy (IAEA, 2007) or as an excitation source in X-ray fluorescence (Shenberg et al., 1974; Lord et al., 2017); therefore, to standardize this nuclide is meaningful. Though 109Cd emits electrons, X-rays and gamma rays, the 39.7 s half-life of the isomeric state of 109Ag (Bé and Schönfeld, 2014) makes the conversional 4π(e,x)-γ absolute counting method unable to standardize this nuclide.
The feasibility of K XRF bone lead measurements in mice assessed using 3D-printed phantoms
2024, Biomedical Physics and Engineering ExpressA new technique for baseline calibration of soil X-ray fluorescence spectra based on enhanced generative adversarial networks combined with transfer learning
2023, Journal of Analytical Atomic SpectrometryAssociation between bone trace elements and osteoporosis in older adults: a cross-sectional study
2022, Therapeutic Advances in Musculoskeletal Disease