Orientation Dependent MR Signal Decay Differentiates between People with MS, Their Asymptomatic Siblings and Unrelated Healthy Controls

Abstract

R2* relaxometry of the brain is a quantitative magnetic resonance technique which is influenced by iron and myelin content across different brain regions. Multiple sclerosis (MS) is a common inflammatory, demyelinating disease affecting both white and grey matter regions of the CNS. Using R2*, increased iron deposition has been described in deep gray matter of MS patients. Iron accumulation might promote oxidative stress in the brain, which can lead to cell death and neurodegeneration. However, recent histological work indicates that iron may be reduced within the normal appearing white matter (WM) in MS. In the present study we analyzed the R2* signal across the white matter in 39 patients with MS, 31 asymptomatic age matched siblings of patients and 30 age-matched controls. The measurement of R2* in white matter is affected by the signal's dependency on white matter fibre orientation with respect to the main magnetic field which can be accounted using diffusion tensor imaging. We observed a clear separation of the three study groups in R2*. The values in the MS group were significantly lower compared to the siblings and controls, while the siblings group presented with significantly higher R2* values than both unrelated healthy controls and patients. Furthermore, we found significantly decreased normal-appearing white matter R2* values in patients with more severe disease course. Angle resolved analysis of R2* improves the sensitivity for detecting subtle differences in WM R2* compared to standard histogram based analyses. Our findings suggest that the decreased R2* values in MS are due to diffuse tissue damage and decreased myelin in the normal appearing and diffusely abnormal WM. The increased R2* in unaffected siblings may identify a predisposition to increased iron and the potential for oxidative stress as a risk factor for developing MS.

Mechanisms of T2* anisotropy and gradient echo myelin water imaging

“…Compared with susceptibility tensor imaging , which is another magnetic susceptibility based fiber orientation mapping method, the T 2 * approach measures orientation using intra‐voxel field inhomogeneity information and, therefore, may be less prone to artifacts from nonlocal field inhomogeneity if the voxel size is small. Another approach using the T 2 * anisotropy is combining a single orientation T 2 * map with a DTI fiber orientation map and generating a white matter T 2 * anisotropy plot . This plot does not require multiple head rotations and may provide a good sensitivity to myelination, although spatial information is no longer available.…”

Anisotropic cerebral vascular architecture causes orientation dependency in cerebral blood flow and volume measured with dynamic susceptibility contrast magnetic resonance imaging

“…21 Perfusion maps were registered to DTI using FLIRT. Voxels with orientations within 5 intervals were pooled and averaged and then used to calculate 22 for further details on the use of DTI to measure tissue orientation.…”

The role of iron and myelin in orientation dependent R2* of white matter

“…Furthermore, in MS lesions with profound axonal loss, the tissue orientation is also ill‐defined. However, there was almost no difference in R 2 * (θ) when lesions were included or excluded . This finding suggests that the step of lesion exclusion may be omitted for the investigation of non‐lesional WM in MS using the proposed approach.…”

“…In addition to focal demyelinated WM lesions, diffuse alteration of the non‐lesional WM has been observed when using various MR methodologies, such as proton MR spectroscopy, magnetization transfer ratio, myelin water imaging, or R 2 * in combination with diffusion tensor imaging (DTI). By associating a measured R 2 * with a fibre orientation, θ, computed from DTI, the orientation dependent R 2 * (θ) can be calculated . Histopathological studies have revealed diffuse and extensive damage in the normal appearing white matter (NAWM), encompassing myelin loss, axonal injury, microglia activation, and perivascular inflammatory infiltrates .…”

“…Input parameters for a best fit with the experimental data were determined through a gradient descent based L 2 ‐norm minimization algorithm using MATLAB's lsqcurvefit (NLLS, Matlab 2014b). Weighted fits were performed on previously published experimental R 2 * (θ) data acquired in healthy controls, subjects with MS, and healthy siblings of subjects with MS, with weights corresponding to the number of voxels in a given fibre orientation angle bin . The lowest number of voxels are for fibre bundles parallel to the direction of B 0 (0 o ), with increasing number of voxels for increasing angles.…”