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The Spinal Cord in Multiple Sclerosis: Relationship of High-Spatial-Resolution Quantitative MR Imaging Findings to Histopathologic Results¹

¹ From the Departments of Radiology (J.C.J.B., G.J.L.N., J.A.C., E.B., F.B.), Pathology (W.K.), and Neurology (C.P.), MR Center for MS Research, and Department of Biostatistics and Epidemiology (H.J.A.), VU Medical Center, PO Box 7057, 1007 MB Amsterdam, the Netherlands; Experimental in vivo NMR, Image Sciences Institute, University Medical Center Utrecht, Utrecht, the Netherlands (E.L.A.B.); Department of Biomedical NMR, Faculty of Biomedical Engineering, University of Technology, Eindhoven, the Netherlands (K.N.I.); and Netherlands Brain Bank, Amsterdam, the Netherlands (R.R.). Received September 27, 2003; revision requested December 5; revision received February 6, 2004; accepted March 18. Supported by the Stichting Vrienden MS Research; J.C.J.B. supported by grant no. 97–307 MS from the Stichting Vrienden MS Research. Address correspondence to J.C.J.B. (e-mail: j.bot@vumc.nl).

View larger version (99K): [in a new window]   Figure 1. Transverse MR images and histologic slices of cervical spinal cord specimen acquired postmortem from 41-year-old woman without clinical history of central nervous system disease. Top left: Klüver-stained histologic slice. Top right: NE-14 immunohistochemically stained slice. Photomicrographs A-C at left and right correspond to ROI selections A, B, and C in Klüver- and NE-14-stained histologic slices. Middle column shows corresponding MR images. At top is conventional intermediate-weighted high-spatial-resolution MR image (3000/15; number of signals acquired, eight); below are quantitative MR maps. The T1 map was obtained with >5000/15, two signals acquired, and inversion times of 10, 150, 300, 600, 1200, and 1800 msec. The T2 map was obtained with a repetition time of 4000; a variable echo time of 10, 16, 25, and 40 msec; and four signals acquired. The MTR map was acquired with a gradient-echo sequence (1300/9, four signals acquired, 5° flip angle) performed with and without a Gaussian-shaped off-resonance prepulse (–4.7 kHz off resonance; duration, 12 msec; nominal flip angle, 429°). The intermediate-weighted high-spatial-resolution MR image shows that white matter has homogeneously low signal intensity, which histopathologically corresponds to areas of normal myelination in ROIs A-C. The cord area was 86.8 mm2, and the numbers of axons for each ROI showed small differences compared with each other and were high compared with the number of axons found in an MS specimen, irrespective of the myelin density.

View larger version (110K): [in a new window]   Figure 2. Transverse MR images and histologic slices of cervical spinal cord specimen acquired postmortem from 58-year-old woman who had a diagnosis of secondary progressive MS and a disease duration of 20 years. Top left: Klüver-stained histologic slice. Top right: NE-14 immunohistochemically stained slice. Photomicrographs A-C at left and right correspond to ROI selections A, B, and C in Klüver- and NE-14-stained histologic slices. Middle column shows corresponding MR images. At top is conventional intermediate-weighted high-spatial-resolution MR image (3000/15; number of signals acquired, eight); below are quantitative MR maps that were acquired with the same imaging parameters as the corresponding images in Figure 1. The intermediate-weighted high-spatial-resolution MR image shows two high-signal-intensity lesions in both lateral columns (eg, in ROI A) and NAWM in anterior and partially posterior columns (eg, in ROI B). The center of the posterior portion of the column shows an area of intermediately elevated signal intensity (too high for this location) that was considered to represent an intermediate-signal-intensity lesion (in ROI C). The number of axons differed little between types of MS abnormalities and even between areas of NAWM, although the number was significantly lower than the number in control specimens (Fig 6), irrespective of myelin density. A range of myelin densities, none of which reached normal values, was observed in this specimen. With increasing demyelination, prolonged relaxation times and decreased MTR values can be observed. However, note the extensive loss of axons (in ROI B) in an area of NAWM, without corresponding distinct changes in quantitative MR parameters. The cord area of this specimen was 60.6 mm2.

View larger version (23K): [in a new window]   Figure 3. Box plot shows relationship between appearance of white matter on intermediate-weighted MR images and state of myelination (ie, myelin density) in cervical spinal cord in control specimens and MS specimens. (MS specimens were categorized as showing high-signal-intensity lesions [HISIL], intermediate-signal-intensity lesions [IMSIL], and NAWM). The wide range of myelin density values in the MS specimens and extensive demyelination in NAWM were not clearly detected on conventional intermediate-weighted MR images. * = extreme value. Results of statistical analysis between subgroups are listed in Table 5.

View larger version (22K): [in a new window]   Figure 4. Box plot shows relationship between signal intensity on intermediate-weighted MR images and axonal number (ie, axonal density) in cervical spinal cord in control specimens and MS specimens. (MS specimens were categorized as showing high-signal-intensity lesions [HISIL], intermediate-signal-intensity lesions [IMSIL], and NAWM). NAWM showed extensive axonal loss, although this was not clearly detected on intermediate-weighted MR images. Results of statistical analysis between subgroups are listed in Table 3.

View larger version (16K): [in a new window]   Figure 5. Scatterplot shows relationship between cord area and whole-cord T1 relaxation time ( = –0.78, P < .01). Correlations between cord area and both T2 relaxation time and MTR were less strong (ie, = –0.53, P < .01 for T2 relaxation time and = 0.481, P < .01 for MTR).

View larger version (25K): [in a new window]   Figure 6. Scatterplot shows relationship between T2 relaxation time and state of myelination (as percentage of residual myelin density in an ROI) in cervical spinal cord specimens ( = 0.77, P < .001). Data points are labeled according to tissue classification on intermediate-weighted MR images: HISIL = high-signal-intensity lesions (in MS specimens), IMSIL = intermediate-signal-intensity lesions (in MS specimens), and WM = white matter (in control specimens). (NAWM was classified only for MS specimens.) For correlation coefficient analysis, control specimen data (ie, those for white matter) were excluded. The relationships between myelin density and both T1 relaxation time and MTR showed similar trends, although the correlation coefficients were less strong.

View larger version (31K): [in a new window]   Figure 7. Scatterplot shows relationship between T2 relaxation time and axonal density (as number of axons per square millimeter in an ROI) in cervical spinal cord specimens ( = –0.44, P < .01). Data points are labeled according to tissue classification on intermediate-weighted MR images: HISIL = high-signal-intensity lesions (in MS specimens), IMSIL = intermediate-signal-intensity lesions (in MS specimens), and WM = white matter (in control specimens). (NAWM was classified only for MS specimens.) For correlation coefficient analysis, control specimen data (ie, those for white matter) were excluded. Correlations between number of axons and both T1 relaxation time and MTR were less strong ( = –0.39, P < .01 for T1 relaxation time and = 0.41, P < .01 for MTR).

View larger version (102K): [in a new window]   Figure 8. Transverse MR images and histologic slices of cervical spinal cord specimen acquired postmortem from 71-year-old woman with MS of a phenotype that could not be classified and a disease duration of 23 years. Top left: Klüver-stained histologic slice. Top right: NE-14 immunohistochemically stained slice. Photomicrographs A-C at left and right correspond to ROI selections A, B, and C in Klüver- and NE-14-stained histologic slices. Middle column shows corresponding MR images. At top is conventional intermediate-weighted high-spatial-resolution MR image (3000/15; number of signals acquired, eight); below are quantitative MR maps that were acquired with the same imaging parameters as the corresponding images in Figure 1. Images show an atrophic cervical spinal cord (cord area, 40.1 mm2) with extensive demyelination and a low number of axons throughout almost the entire cord area. Despite the extensive demyelination, the numbers of axons per square millimeter remain relatively unchanged (compared with the number of axons in the MS specimen in Fig 2). Quantitative MR imaging parameters are strongly increased for T1 and T2 relaxation times and decreased for MTR owing to demyelination and, to a lesser extent, axonal loss.