Repeatability and reproducibility of cerebral ²³Na imaging in healthy subjects

Initial reports of ²³Na magnetic resonance imaging (MRI) date back to the 1970s [1]. However, methodological challenges of the technique – low SNR due to low in-vivo sodium concentrations and low available field strengths – hampered its widespread adoption for many years. Recent technical developments such as clinical 3 Tesla MRI, improved coils, and faster gradients have overcome some of these limitations and have led to more optimal conditions for ²³Na-MR imaging. Several recent publications have demonstrated the feasibility of ²³Na-MRI for in-vivo imaging of physiological conditions in the kidney [2‐4], cartilage and musculoskeletal system [5‐8], heart [9‐11], and prostate [12].

The use of ²³Na-MRI for imaging of the brain was first described in 1983 by Hilal et al., who observed changes following an induced stroke in a cat model [13]. In 1987, Turski et al. utilized the technique in patients with a cerebral neoplasm [14]. Since then, several feasibility studies [15, 16] have utilized ²³Na-MRI for the imaging of stroke [17‐19], demyelinating diseases [20], and brain tumors. In the latter case, various brain tumors exhibit increased sodium concentrations relative to normal brain structures [21‐23]. Theoretically, this observation is based on the presence of cell membrane depolarization prior to cell division. Since cell division is increased in neoplasia, intracellular sodium concentration (ISC) is thus increased and consequently the total ²³Na-concentration rises [24]. Therefore, ²³Na-MRI could be useful for predicting therapeutic tumor response in brain [22] or other organs [25].

In order to serve as a reliable tool for the assessment of clinical stroke or brain tumor patients, studies have to investigate the absolute levels and differences of sodium concentrations in healthy volunteers undergoing consecutive MRIs with a dual-tuned (²³Na/¹H) head-coil at different time points. Thus, the objective of this study was to verify the repeatability and reproducibility of cerebral ²³Na-MR imaging in healthy subjects.

This study was performed without any financial or non-financial support from industry. The authors had complete control of the data submitted for publication. The local institutional review board (IRB) and ethics committee (Medical Ethics Committee II Mannheim, Germany; reference number: 2013 566 N – MA) approved this prospective baseline study which was performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.

The potential of ²³Na-MRI for brain imaging in oncological and non-oncological applications remains to be ultimately determined [29]. To further implement ²³Na-MRI in clinical neuroimaging, particularly in the setting of oncological follow-up, certain fundamental requirements are to be fulfilled. One of these is the intra-individual reliability and reproducibility of brain ²³Na-concentrations on consecutive MR examinations. Little published data are available regarding the ²³Na-concentrations of healthy gray and white matter, but the values of the current study are in the range described in the literature [20, 21, 30]. This study showed no significant asymmetries in the ²³Na-concentrations of several predefined areas of the human brain, other than between the left and right caudate head. These differences could be attributed to partial volume effects of the immediately adjacent cerebrospinal fluid (CSF). The relatively narrow head of the caudate nucleus impeded the manual ROI placement, which could explain these differences. One way to potentially solve this problem is by normalization of the data to a reference brain data set, as done in psychiatry studies for hippocampus volume measurements and the use of semi-automatic segmentation tools. Statistically significant intra-individual differences were neither seen between two consecutive MR exams nor between MR exams separated temporally by 8 days. This supports the repeatability and reproducibility of cerebral ²³Na-MRI. However, per-patient differences in sodium concentration were as high as 10%, depending on the anatomic region. This potential bias should be considered in any further longitudinal or follow up study. Nevertheless, future studies may benefit from an intra-individual longitudinal approach, since inter-individual differences at a single time point can reach over 30%. Another important consideration for the clinical implementation of brain ²³Na-MRI would be the development of a simple evaluation method for ²³Na-MRI imaging with sufficient inter-reader reliability. The inter-reader reliability in this study was moderate but not perfect; however, this may be explained in part by the differences in clinical ²³Na-MRI experience between the readers (6 vs. 2 years). As previously mentioned, a semi-automatic segmentation tool could facilitate this assessment and decrease inter-reader variability. In general, several future avenues may benefit from a broader clinical implementation of ²³Na-MRI. Accuracy and quantification of ²³Na concentrations between different research facilities, hospitals, and techniques (e.g. UTE, radial or cones scheme [31]) should be confirmed. Double-tuned coils seem to be the ideal instrument for ²³Na-imaging enabling the appropriate fusion of ¹H- and ²³Na-images. Although the reliability of the current technique appears to be sufficient, this potential (small) for bias should be taken into account within further studies. While intra-individual comparison seems acceptable for assessment of ²³Na concentration, biases may arise due to natural inter-individual differences, and further follow-up studies are necessary. Finally, future semi-automatic segmentation tools as proposed could help to partially overcome biases due to inter-reader interpretative differences.

Our study had a number of limitations. Since it was initiated as a baseline study, the study group was relatively small and young without any known medical conditions. To evaluate the true clinical value of this technique, further evaluations in longitudinal studies will be necessary both in healthy volunteers as well as in patients.

Our study has shown that intra-individual ²³Na-concentrations in healthy subjects do not significantly differ after repeated scans on the same day and a pre-set time interval. This confirms the repeatability and reproducibility of cerebral ²³Na-imaging and serves as a baseline for future studies. However, with manual placement of ROIs in predetermined anatomic landmarks, fluctuations in ²³Na-concentrations can be observed. This must be taken into account if ²³Na-imaging is to be considered as a potential tool for therapeutic monitoring.