Diffusion tensor imaging (DTI) has been widely applied to investigate injuries in the central nervous system (CNS) white matter (WM). However, the underlying pathological correlates of diffusion changes have not been adequately determined. In this study the coregistration of histological sections to MR images and a pixel-based receiver operating characteristic (ROC) analysis were used to compare the axial ( ሻ ) and radial ( Ќ ) diffusivities derived from DTI and histological markers of axon (phosphorylated neurofilament, SMI-31) and myelin (Luxol fast blue (LFB)) integrity, respectively, in two different patterns of injury to mouse spinal cord (SC) WM. In contusion SC injury (SCI), a decrease in ሻ matched the pattern of axonal damage with high accuracy, but Ќ did not match the pattern of demyelination detected by LFB. In a mouse model of multiple sclerosis (MS), Ќ and ሻ did not match the patterns of demyelination or axonal damage, respectively. However, a region of interest (ROI) analysis suggested that Ќ -detected demyelination paralleled that observed with LFB, and ሻ decreased in both regions of axonal damage and normal-appearing WM ( Key words: diffusion tensor imaging; axial diffusivity; radial diffusivity; experimental autoimmune encephalomyelitis; spinal cord injury White matter (WM) dysfunction is a common finding in neurological disorders. The underlying pathology of neurological disability may involve axonal injury, myelin damage, or both. However, the routine neurological examination is not capable of differentiating these pathological entities. An accurate and noninvasive evaluation of the underlying WM pathology is crucial for diagnosing and assessing the efficacy of therapeutic interventions. Although relaxation-based magnetic resonance imaging (MRI) is routinely used to diagnose central nervous system (CNS) injuries and diseases, it has not been shown to be specific to the underlying WM pathology.The development of diffusion tensor imaging (DTI) has enabled a more sensitive investigation of CNS WM diseases and injuries. However, current approaches that exploit the mean diffusivity or anisotropy indices have not resulted in improved specificity for the underlying pathology in WM disorders. In a promising strategy for improving the specificity, the directional diffusivities derived from DTI measurements are separated into components parallel ( 1 ) and perpendicular ( 2 and 3 ) to the WM tract. These components are referred to as the axial diffusivity, , and radial diffusivity, Ќ ϭ ( 2 ϩ 3 )/2, respectively. It was previously demonstrated, through side-by-side visual examinations of the correspondence between DTI parameter maps and histology staining, that decreased is associated with axonal injury and dysfunction, and increased Ќ is associated with myelin injury in mouse models of WM injury (1,2).Diffusion MRI is widely used to investigate WM integrity following many different injuries and diseases. Among these, considerable efforts have been focused on spinal cord injury (SCI) and multiple sclerosis...

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Purpose To propose and evaluate a novel multidimensional approach for imaging sub-voxel tissue compartments called Diffusion-Relaxation Correlation Spectroscopic Imaging (DR-CSI). Theory and Methods Multi-exponential modeling of MR diffusion or relaxation data is commonly used to infer the many different microscopic tissue compartments that contribute signal to macroscopic MR imaging voxels. However, multi-exponential estimation is known to be difficult and ill-posed. Observing that this ill-posedness is theoretically reduced in higher dimensions, DR-CSI uses a novel multidimensional imaging experiment that jointly encodes diffusion and relaxation information, and then uses a novel constrained reconstruction technique to generate a multidimensional diffusion-relaxation correlation spectrum for every voxel. The peaks of the multidimensional spectrum are expected to correspond to the distinct tissue microenvironments that are present within each macroscopic imaging voxel. Results Using numerical simulations, experiment data from a custom-built phantom, and experiment data from a mouse model of traumatic spinal cord injury, DR-CSI is demonstrated to provide substantially better multi-compartment resolving power compared to conventional diffusion- and relaxation-based methods. Conclusion The DR-CSI approach provides powerful new capabilities for resolving the different components of multi-compartment tissue models, and can be leveraged to significantly expand the insights provided by MRI in studies of tissue microstructure.

Recent studies have suggested that axonal damage, and not demyelination, is the primary cause of long-term neurological impairment in Multiple Sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). The axial and radial diffusivities derived from diffusion tensor imaging (DTI) have shown promise as noninvasive surrogate markers of axonal damage, and demyelination, respectively. In the current study, in vivo DTI of the spinal cords from mice with chronic EAE was performed to determine if axial diffusivity correlated with neurological disability in EAE assessed by the commonly used clinical scoring system. Axial diffusivity in the ventrolateral white matter had a significant negative correlation with EAE clinical score and was significantly lower in mice with severe EAE than mice with moderate EAE. Furthermore, the greater decreases in axial diffusivity were associated with greater amounts of axonal damage as confirmed by quantitative staining for non-phosphorylated neurofilaments (SMI-32). Radial diffusivity and relative anisotropy could not distinguish between the groups of mice with moderate EAE and those with severe EAE. The results further the notion that axial diffusivity is a noninvasive marker of axonal damage in white matter and could provide the necessary link between pathology and neurological disability.

We examined in vivo measurements of directional diffusivity derived from diffusion tensor imaging (DTI) to study the evolution of ventrolateral white matter (VWM) changes following contusive spinal cord injury (SCI) in C57BL/6 mice at 1, 3, 7, and 14 days postinjury. Relative anisotropy maps provided excellent gray matter (GM)/white matter (WM) contrast for characterization of evolving WM injury at all time points. Longitudinal DTI measurements clearly demonstrated rostral-caudal injury asymmetry. Axial diffusivity provided a sensitive, noninvasive measure of axonal integrity within the injury epicenter and at remote levels. Quantitative measurements of axial and radial diffusivities in VWM showed a trend of acute primary axonal injury followed by delayed, subacute myelin damage at the impact site, with good histological correlation. Magn Reson Med 58:253-260, 2007.

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"Diffusion tensor imaging predicts hyperacute spinal cord injury severity." Journal of Neurotrauma.24,6. 979-990. (2007 We recently demonstrated that in vivo derived diffusion tensor imaging (DTI) parameters are sensitive and specific biomarkers for spinal cord white matter damage. In this study, non-invasive in vivo DTI was utilized to evaluate the white matter of C57BL/6 mice 3 h after mild (0.3 mm), moderate (0.6 mm), or severe (0.9 mm) contusive SCI. In the hyperacute phase, relative anisotropy maps provided excellent gray-white matter contrast in all degrees of injury. In vivo DTI-derived measurements of axial diffusion differentiated between mild, moderate, and severe contusive SCI with good histological correlation. Cross-sectional regional measurements of white matter injury severity between dorsal columns and VWM varied with increasing cord displacement in a pattern consistent with spinal cord viscoelastic properties.

Chronic traumatic encephalopathy (CTE) is a progressive degenerative disorder associated with repetitive traumatic brain injury. One of the primary defining neuropathological lesions in CTE, based on the first consensus conference, is the accumulation of hyperphosphorylated tau in gray matter sulcal depths. Post-mortem CTE studies have also reported myelin loss, axonal injury and white matter degeneration. Currently, the diagnosis of CTE is restricted to post-mortem neuropathological analysis. We hypothesized that high spatial resolution advanced diffusion MRI might be useful for detecting white matter microstructural changes directly adjacent to gray matter tau pathology. To test this hypothesis, formalin-fixed post-mortem tissue blocks from the superior frontal cortex of ten individuals with an established diagnosis of CTE were obtained from the Veterans Affairs-Boston University-Concussion Legacy Foundation brain bank. Advanced diffusion MRI data was acquired using an 11.74 T MRI scanner at Washington University with 250 × 250 × 500 µm spatial resolution. Diffusion tensor imaging, diffusion kurtosis imaging and generalized q-sampling imaging analyses were performed in a blinded fashion. Following MRI acquisition, tissue sections were tested for phosphorylated tau immunoreactivity in gray matter sulcal depths. Axonal disruption in underlying white matter was assessed using two-dimensional Fourier transform analysis of myelin black gold staining. A robust image co-registration method was applied to accurately quantify the relationship between diffusion MRI parameters and histopathology. We found that white matter underlying sulci with high levels of tau pathology had substantially impaired myelin black gold Fourier transform power coherence, indicating axonal microstructural disruption (r = -0.55, p = 0.0015). Using diffusion tensor MRI, we found that fractional anisotropy (FA) was modestly (r = 0.53) but significantly (p = 0.0012) correlated with axonal disruption, where lower FA was associated with greater axonal disruption in white matter directly adjacent to hyperphosphorylated tau positive sulci. In summary, our findings indicate that axonal disruption and tau pathology are closely associated, and high spatial resolution ex vivo diffusion MRI has the potential to detect microstructural alterations observed in CTE tissue. Future studies will be required to determine whether this approach can be applied to living people.