Abnormal White Matter Signal on MR Imaging Is Related to Abnormal Tissue Microstructure

Materials and Methods

DTI Analysis

For each voxel, 3 eigenvalues and eigenvectors of the diffusion tensor and the ADC were calculated. Apparent diffusion was measured according to the Stejskal and Tanner equation,¹⁷ with the diffusion tensor elements estimated for each voxel by nonlinear regression, as suggested by Basser and Pierpaoli.¹⁸

DTI analysis was performed off-line by using XPhase image analysis software (SE Maier, Boston, Mass). ADC, FA, axial (λ1), and radial (λ2 + λ3)/2 diffusivity were calculated in 12 manually selected regions of interest in the brain, located on 2 axial sections. The region-of-interest placement was performed by 1 individual and then checked by another who was experienced in neonatal neuroimaging. The superior axial section was taken at a level just above the lateral ventricles, and regions of interest were located in bilateral frontal, sensorimotor, and occipital white matter regions (Fig 1A). The inferior section was taken at a level through the basal ganglia and posterior limb of the internal capsule (PLIC), and regions of interest were located in the bilateral middle third of the PLICs and the frontal and occipital white matter regions (Fig 1B). The diffusion-weighted, ADC, relative anisotropy, and FA images were viewed simultaneously in the axial plane for region-of-interest placement.

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Fig 1.

A, Axial line scan images obtained at the level just above the superior margins of the lateral ventricles. The 4 images used to determine the regions of interest were the following: 1) FA (top left), 2) relative anisotropy (top right), 3) ADC (bottom left), and 4) diffusion-weighted (bottom right). Six regions of interest were located in the following regions: frontal white matter, sensorimotor white matter, and occipital white matter. B, Axial line scan image obtained at the level of the basal ganglia and PLIC. The 4 images used to determine the regions of interest were the following: 1) FA (top left), 2) relative anisotropy (top right), 3) ADC (bottom left), and 4) diffusion-weighted (bottom right). Six regions of interest were located in the following regions: frontal white matter, middle third of the PLICs, and occipital white matter.

Results

Of the 227 preterm infants who were recruited, 111 had MR imaging examinations at term-corrected age in which all 3 sequences (ie, conventional T1-, T2-weighted, and diffusion-weighted line scan) were obtained and the data were analyzable. The clinical characteristics of the infants are summarized in Table 1. There were no significant differences in any of the clinical characteristics between the subgroup analyzed for this study and the whole preterm cohort (data not shown).

Discussion

This study has demonstrated important associations between a global WMSA score on MR imaging and diffusion parameters. Increased radial diffusivity and decreased FA in the internal capsules and sensorimotor regions of infants with extensive WMSA on MR imaging were the most prominent findings. In addition, ADC was increased in the right superior occipital and bilateral sensorimotor regions, and axial diffusivity was decreased in the right internal capsule and bilateral sensorimotor regions. These findings suggest that extensive WMSA on conventional T1- and T2-weighted MR imaging are associated with important microstructural abnormalities, in particular, radial diffusivity. This implies that the major correlate of extensive WMSA on MR imaging may be the disruption within the premyelinating oligodendroglia rather than axonal pathology. In addition, the results also suggest that there are vulnerable brain regions that display more microstructural derangement on diffusion imaging, including the sensorimotor region and internal capsules.

Altered diffusion parameters have been documented in preterm infants with abnormal white matter on MR imaging and in those with abnormal neurologic outcome. Previous studies have found that mean ADC increased in preterm infants with white matter abnormalities on MR imaging, including diffuse excessive high-signal intensities on MR imaging, and in infants with overt white matter lesions (eg, diffuse or nodular white matter hypo- or hyperintensities and cystic lesions).^14,15 Relative anisotropy was lower in infants with white matter lesions, and it was speculated that this may have been due to a decrease in directionality as a result of fiber tracts that were disrupted. Subsequent to these studies, radial diffusivity and axial diffusivity were also found to be deranged in infants with diffuse excessive WMSA on MR imaging.¹⁶ The authors concluded that the findings may have reflected delayed myelination in infants with white matter abnormalities on MR imaging.

The findings from this study are in keeping with previously published studies. We found abnormal diffusion parameters, in particular radial diffusivity in infants with extensive WMSA on MR imaging. Radial diffusivity describes water ADC perpendicular to axons. Data from studies on mature animals have shown that primary injury to myelin is associated with an increase in radial diffusivity, whereas primary injury to axons, such as wallerian degeneration, is associated with a decrease in axial diffusivity.^19,20 However, our studies are at a stage of brain development in which there is little myelination but an abundance of premyelinating oligodendrocytes in the human cerebral white matter. During this maturational phase, the early differentiating oligodendrocytes are beginning to ensheathe cerebral white matter axons, in preparation for myelination, which happens after term in the human.^21-23 These changes in the oligodendroglia, which subsequently result in changes in axonal size, axonal membranes, and intracellular axonal constituents, are likely to contribute to the normal decreases in the extracellular space and water content in cerebral white matter and thus to the normal decline in ADC and increases in FA and radial anisotropy.^24-26 Thus, 1 hypothesis to explain the changes demonstrated in this study and previous studies for the failure of the reduction in ADC from higher levels in the premature infant to the lower levels of the term infant in the presence of WMSA on MR imaging may relate to prior injury to premyelinating oligodendrocytes and the subsequent failure of their development and ensheathment of axons.²⁷

In addition, there were inconsistent findings in relation to axial diffusivity, with a reduction in the internal capsule but an increase in the sensorimotor cortex regions. The internal capsule is a very tightly packed cabling network; thus, it is plausible that there may be a lack of sensitivity for the measures in these densely packed fiber tracts. The infants in this study were imaged at term-corrected age, many weeks after birth and presumed time of insult. Thus, chronic alterations in axial diffusivity consistent with axonal loss may be more visible in the less densely packed fibers as they emerge and spread into the sensorimotor region.

There were no significant differences in any of the diffusion parameters in infants with normal and focal WMSA. This would suggest that less extensive WMSA changes on conventional T1- and T2-weighted MR imaging in ex-preterm infants were not associated with significant MR imaging−detectable microstructural disruption on these diffusion analyses during this period of brain development. There are, however, limitations in the diffusion data that were acquired in this study that may have led to a reduction in sensitivity to milder forms of microstructural disruption. The data were obtained at a low field strength (1.5T) with a large section thickness (4–6 mm) and a very limited number of 6 directions. Newer diffusion imaging techniques with more directions and higher resolution in higher field magnets may have greater sensitivity for milder forms of white matter microstructural disturbance.

Another notable finding from this study relates to the fact that altered diffusivity was region-specific, involving particularly the sensorimotor pathways of the brain. Severe white matter abnormality on MR imaging is known to be most strongly associated with motor dysfunction.⁶ We found that many of the diffusion alterations involved the sensorimotor regions and the internal capsules, which are areas of increased white matter maturity in the neonate. This may partly explain the strong relationship between qualitative extensive white matter abnormalities in ex-preterm infants and poor neuromotor outcome.

In comparison with previous studies, which have been on smaller cohorts (<50 infants), our findings have been based on a much larger cohort. The consistent finding that abnormal diffusion parameters are associated with WMSA further adds weight to existing evidence that WMSA on MR imaging are related to abnormal tissue microstructure and are not solely explained by image artifacts or windowing.

One of the drawbacks of the current study is that the diffusion information was obtained from prespecified regions of interest within the brain. It would be useful to obtain diffusion information from “diffusion maps” encompassing the whole brain to be able to further define the abnormal areas within the brain in ex-preterm infants with WMSA. With technical advancements in postacquisition diffusion analysis, it may be possible to derive diffusion maps from similar cohorts in the future.

Future directions in this research area would also include MR tractography to explore the associations between altered diffusivity and altered fiber tract development in these infants. The infants in this study are being longitudinally evaluated for neurodevelopmental outcomes; thus, evaluation of the relationships between diffusion measures, WMSA, and childhood outcomes will be possible.

Conclusions

Signal-intensity abnormalities in the white matter on MR imaging in ex-preterm infants at term-corrected age are associated with derangement in all diffusion parameters, with radial diffusivity being the most prominent. The severity of the derangement is related to the severity of the regional involvement of WMSA. These findings in vivo concur with in vitro and experimental studies that imply disruption of premyelinating oligodendroglia as the major correlate with extensive WMSA in the preterm neonate.