In this study, we utilized 3D MRSI to report metabolic ratios of premature newborns with normative outcome. MR spectroscopy has been shown to be a valuable tool for evaluating brain injury in neonates (1
). However the complexity in performing, processing, and analyzing 3D MRSI have largely limited the acquisition to 2D and single voxel studies of the neonatal brain. Also, as noted by McNatt et al (14
), normative 1H MRS data in newborns are not well established and institutions rely on their own experiences and results to determine the severity of the injury. Various groups use LCModel to quantify metabolites (14
), which can be difficult for many institutions to perform routinely in the clinical setting due to computationally intensive post-processing requirements. In addition, absolute metabolite quantitation using modeling also assumes a clear definition of peaks where the beginning and the end of the peak locations are set. This is always a challenge to establish with in vivo spectra. A normal metabolite baseline using simple metabolite ratios would facilitate differentiating between normal and abnormal brains in premature neonates. Only newborns with normal neurological follow-up examination at 1 year of age were included in this study in order to establish a normal baseline, to which proton MRS of future premature newborns and newborns with birth complications can be compared. It is already known that NAA/Cho ratio increases as the brain matures, which has been previously reported at specific time points (1
). This study provides evaluation of metabolite levels for the entire brain in prematurely born neonates with correlation to gestational ages from 27 weeks to full term. Although we recognize that a normal 12-month exam does not guarantee that the child will develop completely normally, it suggests that any subsequently developing abnormalities will be relatively mild (17
). In this normative population, lactate level is barely visible, which confirms previous studies indicating injury with elevated levels of lactate (7
NAA, a marker for neuronal activity, increases with brain maturity. Concurrently, Cho, a marker for membrane turnover and myelination, and LAC, a marker of anaerobic respiration, decrease with age as the rapid brain growth of the neonate slows in infancy; these findings have been reported previously using single voxel techniques (1
). The study demonstrated that NAA/Cho significantly increased with age for all the regions of interest across the entire premature newborn brain. Among the regions, cortical spinal tract’s highest ratio inferred that it had the highest neuronal activity and possibly matured first. In comparison, the temporal visual association pathway showed the lowest ratio, as it is a relatively immature pathway at this age.
Also, the parietal white matter had higher NAA/Cho ratio than the frontal white matter, possibly demonstrating the sensory pathway is quicker to mature compared to the motor pathway (19
). Lac/NAA ratio should decrease with age, as the rapid growth of the newborn brain starts to slow allowing adequate ATP production for growth and metabolism by aerobic respiration and starts rely on glucose for energy (20
). demonstrates that the Lac/NAA ratio decreased over time in all regions, but this was not always statistically significant. The lack of significance is likely due to the limited patient population as individuals have different metabolic rates, which will contribute to the variability of the data. In addition, the provided gestational age is an approximate estimation of the actual age of the newborn; this can contribute to the variability as a few days of neonatal brain development may yield different results. It could also result from the fact that some regions, such as the frontal white matter and temporal visual association tracts, remain relatively immature at 42 weeks (19
); longer follow-up may be necessary to demonstrate this phenomenon. We expect all regions to show significant decreasing Lac/NAA as we continue to build our newborn metabolite database with more premature newborns, particularly as a wider adjusted age range is included.
The variation in Lac/Cho ratio shown in is expected, as Lac and Cho both decrease with maturity, but the precise biochemical changes that underly these decreases are not known and are likely to vary somewhat from region to region. Individuals mature slightly differently, so the decrease in lactate and choline levels will vary, resulting in no correlation with gestational age. The included premature newborns in this study have normative neuromotor outcome are slightly older (approximately 34 weeks post-conception at scan with 28 weeks at birth), which may suggest that newborns with higher gestational age have a better chance of having a normal growth trajectory in comparison to younger premature infants. Further studies are ongoing to investigate the cohorts with poor outcome of newborns with abnormal neuromotor scores, indicative of abnormal growth.
As expected, sedation had no effect on the overall trend of metabolite levels in correlation with age. Unlike previously reported (21
), the metabolite levels for patients with and without sedation did not differ. It is possible that with large amount of data, that variability is not significant.
This study demonstrated the feasibility of the 3D MRSI method to analyze the spatial and temporal variations of brain cellular metabolite levels in preterm infants. This study establishes a baseline for regional metabolite levels, which may be used to assess any association of brain injury with regional metabolite ratios at similar post-conceptual ages and with neurodevelopmental outcome. The current study is still limited by the incomplete coverage of the brain with 8×8×8 matrix at 1cc due to scan time (17 minutes) concerns as demonstrated by missing data points for CST and FWM. Even with this long duration, there were usable spectral data in all exams due the robustness of the technique. Spectroscopy has a small amount of motion correction built into the analysis due to the phase correction algorithm. With the development of newer phased array coil technology and associated parallel imaging (22
) and fast acquisition techniques (23
), it is now possible to obtain similar quality of 3D MRSI with full brain coverage at much shorter scan times of 10 minutes or less and, thus, to assess the value of this technique in clinical practice.