Synthetic MRI and MR Fingerprinting–Derived Relaxometry of Antenatal Human Brainstem Myelination: A Postmortem-Based Quantitative Imaging Study

DISCUSSION

This investigation compared 2 different quantitative imaging modalities on the basis of postmortem fetal MR data. Moreover, the relaxometric properties obtained by both imaging techniques were used to study ongoing myelination processes throughout antenatal development. The quantitative results provided by Synthetic MR imaging and MRF revealed good-to-excellent consistency. Furthermore, both MR approaches revealed the feasibility of tracking proceeding myelinogenesis in the fetal period. Thus, this study proves the value of quantitative imaging to obtain insight into the biochemical aspects of brain maturation noninvasively, which are currently difficult to uncover by means of standard-of-reference MR imaging acquisition principles and conventional radiologic evaluation strategies.^3,6,7,11

Myelin is first detectable in the column of Burdach at the beginning of the second trimester and progresses cephalad.^1,9,12 Biochemical changes in myelin composition throughout cerebral development lead to alterations of the physical properties of the brain tissue and, therefore, to white matter signal intensity characteristics on MRI.¹ However, although T1-weighted pulse sequences represent the current criterion standard with which to evaluate ongoing myelin deposition perinatally, the relaxometric changes induced by only small myelin quantities antenatally are too subtle to cause visually perceivable signal intensity changes. This issue currently hinders reliable qualitative assessments of ongoing myelination in fetal imaging settings.^1,13,14 Thus, the direct retrieval of tissue-specific relaxometric properties appears to represent a viable alternative to qualitative evaluations to render tracking of myelin development feasible, even within an antenatal MR-based diagnostic framework.^6,7,15 In accordance with prior descriptions in the literature that focused on quantitative MR imaging in vivo and due to the relative predominance of myelinated tissue infratentorially at early developmental stages, ROI placement for relaxometric analysis was performed in the developing medulla oblongata and the midbrain.^1,5,7,9,12 Synthetic MR imaging and MRF represent the current state-of-the-art in terms of quantitative imaging.^6,11 While both techniques provide tissue-specific relaxation properties, their approach to data acquisition is of a different nature.^6,11 As opposed to Synthetic MR imaging, in which a spin-echo-based acquisition principle is used, MRF operates via a signal-recognition process to determine relaxometric features on the basis of a gradient-echo sequence.^{6,16⇓⇓-19} Therefore, while T1R/T2R are measured directly in Synthetic MR imaging (ie, T2R: obtained via a multiecho technique; T1R: obtained via the application of various 90° radiofrequency pulses at different saturation recovery times), MRF retrieves these metrics via a database with which the obtained signals are matched (ie, SSFP sequences induce evolutions of tissue-specific signals that are then allocated to certain physical/MR-based properties).^{6,11,16⇓⇓-19}

There was considerable consistency between both techniques. These results appear credible, because relaxometric properties are considered relatively robust.²⁰ There is evidence that the accuracy for T1R is slightly higher than that of T2R, which is in line with the presented data.²⁰ This feature may be attributed to potential biases caused by magnetic field inhomogeneity that are considered more pronounced in gradient-echo-based sequence acquisitions and T2R metrics.²¹ Additionally, the impact of temperature on tissue-specific relaxation properties has considerable implications on this study.²² As described by Petrén-Mallmin et al,²² reductions in temperature are associated with decreasing T1R/T2R metrics. Thus, because postmortem MR imaging mandates the need for specimen cooling before imaging, its effects must be considered when interpreting the presented data. However, minor deviations between techniques are in keeping with previous investigations.¹⁸

Both modalities revealed relationships between relaxometric properties and individual developmental stages, with more advanced GA associated with decreases in T1R and T2R. These findings are in line with various descriptions in the literature.^7,23 In a previous fetal imaging study, MDME-based relaxometry was applied in vivo.⁷ Even though this prior study was performed at 1.5T in fetuses older than 23 weeks’ GA, the observed decreases in quantitative MR parameters are comparable with those reported in the presented investigation.⁷ Moreover, similar findings were detected in former preterm neonates, imaged at various stages of postnatal development.⁵ The T1R is believed to have sensitivity even for “premyelination” states.⁵ Before actual fiber ensheathment, myelin building blocks, such as cholesterol, proteins, and glycolipids interact with H₂O (ie, “premyelination” stage).^5,24 Concomitantly, the overall water content of the tissue certainly decreases, resulting in shortening of the T1R.^5,24 With time, there is winding of loose myelin membranes around the neural axons, accompanied by progressive entry of organic compounds into the sheath, further decreasing the T1R and the overall proton density.^1,5,24 As opposed to the T1R, changes of the T2R appear considerably later in the course of myelinogenesis.^1,24 Following development of the bilayer, there is tightening of closely packed wraps of relatively mature myelin sheaths, which causes the T2R to decrease.^1,24 Therefore, detailed observations of quantitative parameter shortening appear to allow approximations of the actual state of myelination and myelin content, respectively, as demonstrated and confirmed by Figs 4 and 5.

On the basis of these considerations, Synthetic MR imaging may be slightly more sensitive than MRF in the early developmental stages, because the latter did not reveal any significant relationships between T1R in the midbrain and GA. Nonetheless, sample size–related issues and variabilities of postprocessing algorithms could also explain these minor differences between techniques.^20,25 Most interesting, there is evidence that the T2R properties may allow a more sophisticated distinction between various states of myelin maturation (ie, completely or incompletely myelinated and unmyelinated tissue), which may explain the highly significant correlations between developmental stages and T2R¹. Thus, overall, both investigated approaches proved feasible for capturing the complexities of biochemical brain maturation on an objective, quantitative basis. Moreover, in this study, an interrater reliability analysis has proved the reproducibility of the quantitative, manually determined measurements and, therefore, the robustness of both techniques.

Both investigated techniques use a single-sequence-based approach with which to derive multiple MR contrasts and relaxometric properties to uncover microstructural aspects of the investigated tissue of interest.^3,5,6 These benefits are of greatest interest for prenatal diagnostics. Nonetheless, sequence acquisition–related drawbacks currently limit the feasibility and application of fetal quantitative MR imaging in a clinical in vivo setting, mandating the need for further optimization (ie, k-space sampling, acceleration techniques, and so forth).⁷ Therefore, this study focused on postmortem MR data to further expand the knowledge of the potential of relaxometric prenatal MR imaging, despite its current limitations. However, technical advances (eg, single sequence–derived 3D-based MR relaxometry) are progressing rapidly and may soon render quantitative MR imaging feasible in clinical fetal imaging practice.²⁶

Certain limitations require consideration. There were slight differences in acquisition parameters for both modalities, which prohibited the investigation of absolute agreement between the quantitative metrics obtained by Synthetic MR imaging and MRF. Nevertheless, despite certain differences in metric data, Synthetic MR imaging and MRF provided comparable results, because the consistency between both techniques was highly satisfactorily, particularly when considering certain frame conditions associated with postmortem imaging and quantitative MR imaging (eg, variability of delays between termination of pregnancy and MR imaging and the accompanied variance in postmortem edema at the time of imaging, as well as computational variability in postprocessing procedures, and so forth).^20,22 As a matter of course, medically indicated termination of pregnancy was performed only in fetuses who revealed serious pathology. Thus, certain conditions may have affected myelin development and, therefore, the presented data do not represent reference values for regular antenatal myelin maturation. Nonetheless, the investigated modalities have the potential to provide such data, which should be further elaborated in the future.

While this study focused on the midbrain and the medulla oblongata, the pontine region was not considered for this investigation, due to its relatively hard contouring (accompanied by the limited discriminability between the pontine tegmentum and the basis pontis) on quantitative postmortem fetal MR data, especially at very early stages of brain development. However, consideration was given to this region when comparing quantitative MR imaging and histology (Fig 5). Nevertheless, even though efforts were made to provide radiologic-pathologic correlations within the presented work, this study lacks a systematic comparison between histology-based myelin assessment and imaging-derived mapping. Foremost, the variability of the timeframe between the initiation of medically indicated termination of pregnancy (accompanied by the differences in the time spent in utero in each individual case) and state-of-the-art specimen work-up (eg, appropriate specimen fixation before onsets of postmortem lysis and, concomitantly, consistency-related issues, and so forth), prohibited high-quality myelin staining and, therefore, the acquisition of sufficient data for extended histologic (versus MR-based) analysis in most included cases. Besides these abovementioned limitations, advanced myelin staining (eg, immunohistochemical detection of myelin basic protein [MBP]) for the evaluation of early maturational stages was not routinely performed in postmortem fetal specimens. Finally, the number of included cases was relatively small. However, the investigated data represent a highly exclusive and rare sample.