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Research ArticleBrain

Enhanced Axonal Metabolism during Early Natalizumab Treatment in Relapsing-Remitting Multiple Sclerosis

O.T. Wiebenga, A.M. Klauser, M.M. Schoonheim, G.J.A. Nagtegaal, M.D. Steenwijk, J.A. van Rossum, C.H. Polman, F. Barkhof, P.J.W. Pouwels and J.J.G. Geurts
American Journal of Neuroradiology June 2015, 36 (6) 1116-1123; DOI: https://doi.org/10.3174/ajnr.A4252
O.T. Wiebenga
aFrom the Departments of Radiology and Nuclear Medicine (O.T.W., G.J.A.N.†, M.D.S., F.B.)
bAnatomy and Neurosciences (O.T.W., A.M.K., M.M.S., G.J.A.N.†, J.J.G.G.)
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A.M. Klauser
bAnatomy and Neurosciences (O.T.W., A.M.K., M.M.S., G.J.A.N.†, J.J.G.G.)
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M.M. Schoonheim
bAnatomy and Neurosciences (O.T.W., A.M.K., M.M.S., G.J.A.N.†, J.J.G.G.)
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G.J.A. Nagtegaal
aFrom the Departments of Radiology and Nuclear Medicine (O.T.W., G.J.A.N.†, M.D.S., F.B.)
bAnatomy and Neurosciences (O.T.W., A.M.K., M.M.S., G.J.A.N.†, J.J.G.G.)
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M.D. Steenwijk
aFrom the Departments of Radiology and Nuclear Medicine (O.T.W., G.J.A.N.†, M.D.S., F.B.)
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J.A. van Rossum
cNeurology (J.A.v.R., C.H.P.)
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C.H. Polman
cNeurology (J.A.v.R., C.H.P.)
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F. Barkhof
aFrom the Departments of Radiology and Nuclear Medicine (O.T.W., G.J.A.N.†, M.D.S., F.B.)
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P.J.W. Pouwels
dPhysics and Medical Technology (P.J.W.P.), Neuroscience Campus Amsterdam and VU University Medical Center, Amsterdam, the Netherlands.
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J.J.G. Geurts
bAnatomy and Neurosciences (O.T.W., A.M.K., M.M.S., G.J.A.N.†, J.J.G.G.)
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    Fig 1.

    A, The illustration shows axial T2-weighted and sagittal T1-weighted MR images. The pituitary-fastigium axis (dashed line) is used to position the grid (in red) with 64 voxels. B, An example of the WM, GM, and lesion PVE calculated on the MRSI grid and superimposed with the T2 image of the center of the slab. The yellow in the lesion PVE image represents the projection of the lesion content of the slab. C, The allocation of the different regions of GM, NAWM, and LWM based on the rows of the grid and the lesion content is seen.

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    Fig 2.

    Scatterplot of individual measurements of tNAA, tCr, and Glu in LWM (mmol/L) (upper 3 rows) and percentage of lesion volume per LWM voxel (lower row) as a function of the days elapsed since the baseline for the patients treated with natalizumab and IFNb/GA. The asterisk indicates that patients treated with natalizumab show a significant increase of tNAA, tCr, and Glu in the LWM (mmol/L/year ± SD). At each time point (baseline, month 6, month 12, and month 18), the number of subjects in the natalizumab group was, respectively, 18, 25, 23, and 15; in the IFNb/GA group, it was 15, 17, 18, and 16; and in the healthy control group, it was 11, 12, 11, and 8.

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    Table 1:

    Baseline variables of patients and controlsa

    Natalizumab (n = 25)IFNb/GA (n = 18)Healthy Controls (n = 12)P Value
    Age (yr)36.0 ± 8.938.2 ± 5.037.6 ± 8.7.619
    Sex (male/female)9:169:93:9.368
    EDSSb,c3.0 (1.5–6.5)2.5 (1.0–6.5).589
    Duration since onset (yr)7.9 ± 6.18.8 ± 5.3.550
    Prior IFNb/GA duration at baseline (yr)2.6 ± 3.04.4 ± 3.9.121
    Brain volumes
        NGMV (L)0.75 ± 0.040.73 ± 0.050.77 ± 0.04.063
        NWMV (L)0.70 ± 0.030.69 ± 0.030.72 ± 0.04.061
        NBV (L)1.45 ± 0.051.42 ± 0.081.49 ± 0.07.020d
    T2 lesion volume (mL)e6.1 (2.4–14.3)4.9 (2.4–11.9).599
    • Note:—EDSS indicates Expanded Disability Status Scale; NGMV, normalized total GM volume; NWMV, normalized total WM volume; NBV, normalized whole-brain volume.

    • ↵a Data are mean ± SD. When normally distributed, a multivariate general linear model was used with age and sex included as covariates. Nonparametric testing was performed using Kruskal-Wallis and post hoc Mann-Whitney U tests.

    • ↵b χ2 test.

    • ↵c Median and range.

    • ↵d Only significant between patients treated with IFNb/GA and healthy controls.

    • ↵e Median and interquartile range.

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    Table 2:

    Baseline absolute metabolite concentrations in NAWM, LWM, and GMa

    Natalizumab (n = 25)IFNb/GA (n = 18)Controls (n = 12)
    NAWMLWMGMNAWMLWMGMWMGM
    tCr
        Frontal4.86 ± 0.714.35c ± 0.588.70 ± 1.894.93 ± 0.924.95 ± 0.908.70 ± 1.414.93 ± 0.648.48 ± 1.31
        Semiovale4.67 ± 0.634.30c ± 0.814.83 ± 0.754.41b ± 0.774.72 ± 0.60
        Parietal4.52 ± 0.624.42 ± 0.527.78 ± 0.884.72 ± 0.694.57 ± 0.938.24 ± 1.024.58 ± 0.457.48 ± 0.99
    tNAA
        Frontal7.17 ± 1.205.89c ± 0.8111.1 ± 1.747.06 ± 1.166.75 ± 1.5410.93 ± 1.617.62 ± 0.9611.66 ± 1.37
        Semiovale7.96 ± 0.876.70c ± 1.518.25 ± 1.567.05c ± 1.178.51 ± 0.94
        Parietal7.43d ± 1.056.55c ± 0.7410.51 ± 1.087.59 ± 0.987.08 ± 1.2411.52 ± 1.468.22 ± 0.8110.89 ± 1.30
    Cho
        Frontal1.50 ± 0.201.51 ± 0.252.16 ± 0.491.59 ± 0.281.64 ± 0.292.11 ± 0.451.62 ± 0.252.08 ± 0.39
        Semiovale1.44 ± 0.191.42 ± 0.281.53 ± 0.211.49 ± 0.281.49 ± 0.16
        Parietal1.13 ± 0.241.36 ± 0.191.31 ± 0.221.34 ± 0.231.39 ± 0.271.36 ± 0.241.37 ± 0.171.13 ± 0.20
    mIns
        Frontal4.82e ± 1.185.29 ± 1.017.49 ± 1.574.44 ± 0.925.45c ± 1.517.30 ± 1.113.90 ± 0.657.00 ± 1.16
        Semiovale4.47e ± 1.184.76 ± 0.914.27 ± 0.694.71 ± 1.013.56 ± 0.44
        Parietal4.79e ± 0.645.59b ± 1.076.47 ± 0.914.98 ± 0.935.32 ± 1.426.47 ± 0.834.01 ± 0.625.85 ± 0.52
    Glu
        Frontal6.34 ± 1.465.36b ± 1.1312.96 ± 2.985.86 ± 1.186.03 ± 1.4812.71 ± 2.576.25 ± 0.9614.01 ± 2.40
        Semiovale5.38 ± 1.084.73b ± 1.165.50 ± 0.915.11 ± 0.965.49 ± 0.72
        Parietal5.17 ± 1.344.22b ± 0.9412.99 ± 3.875.37 ± 1.574.80 ± 0.6812.68 ± 1.445.31 ± 0.6711.81 ± 1.85
    • ↵a In mmol/L tissue, mean ± SD. Absolute metabolite concentrations (mmol/L) of NAWM, GM, WM, and LWM in the frontal, centrum semiovale, and parietal regions averaged over the subjects at the baseline measurement.

    • ↵b Significant difference within the group between NAWM and LWM in the same region of the baseline measurement (P < .05).

    • ↵c Significant difference within the group between NAWM and LWM in the same region of the baseline (P < .01).

    • ↵d Significant differences between patients treated with natalizumab and healthy controls including all the time points (P < .05).

    • ↵e Significant differences between patients treated with natalizumab and healthy controls including all the time points (P < .01).

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American Journal of Neuroradiology: 36 (6)
American Journal of Neuroradiology
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O.T. Wiebenga, A.M. Klauser, M.M. Schoonheim, G.J.A. Nagtegaal, M.D. Steenwijk, J.A. van Rossum, C.H. Polman, F. Barkhof, P.J.W. Pouwels, J.J.G. Geurts
Enhanced Axonal Metabolism during Early Natalizumab Treatment in Relapsing-Remitting Multiple Sclerosis
American Journal of Neuroradiology Jun 2015, 36 (6) 1116-1123; DOI: 10.3174/ajnr.A4252

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Enhanced Axonal Metabolism during Early Natalizumab Treatment in Relapsing-Remitting Multiple Sclerosis
O.T. Wiebenga, A.M. Klauser, M.M. Schoonheim, G.J.A. Nagtegaal, M.D. Steenwijk, J.A. van Rossum, C.H. Polman, F. Barkhof, P.J.W. Pouwels, J.J.G. Geurts
American Journal of Neuroradiology Jun 2015, 36 (6) 1116-1123; DOI: 10.3174/ajnr.A4252
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