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

doi:10.3174/ajnr.A4252

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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 controls^{^a}

	Natalizumab (n = 25)	IFNb/GA (n = 18)	Healthy Controls (n = 12)	P Value
Age (yr)	36.0 ± 8.9	38.2 ± 5.0	37.6 ± 8.7	.619
Sex (male/female)	9:16	9:9	3:9	.368
EDSS^{^b,^c}	3.0 (1.5–6.5)	2.5 (1.0–6.5)		.589
Duration since onset (yr)	7.9 ± 6.1	8.8 ± 5.3		.550
Prior IFNb/GA duration at baseline (yr)	2.6 ± 3.0	4.4 ± 3.9		.121
Brain volumes
NGMV (L)	0.75 ± 0.04	0.73 ± 0.05	0.77 ± 0.04	.063
NWMV (L)	0.70 ± 0.03	0.69 ± 0.03	0.72 ± 0.04	.061
NBV (L)	1.45 ± 0.05	1.42 ± 0.08	1.49 ± 0.07	.020^{^d}
T2 lesion volume (mL)^{^e}	6.1 (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 GM^{^a}

	Natalizumab (n = 25)			IFNb/GA (n = 18)			Controls (n = 12)
	NAWM	LWM	GM	NAWM	LWM	GM	WM	GM
tCr
Frontal	4.86 ± 0.71	4.35^{^c} ± 0.58	8.70 ± 1.89	4.93 ± 0.92	4.95 ± 0.90	8.70 ± 1.41	4.93 ± 0.64	8.48 ± 1.31
Semiovale	4.67 ± 0.63	4.30^{^c} ± 0.81		4.83 ± 0.75	4.41^{^b} ± 0.77		4.72 ± 0.60
Parietal	4.52 ± 0.62	4.42 ± 0.52	7.78 ± 0.88	4.72 ± 0.69	4.57 ± 0.93	8.24 ± 1.02	4.58 ± 0.45	7.48 ± 0.99
tNAA
Frontal	7.17 ± 1.20	5.89^{^c} ± 0.81	11.1 ± 1.74	7.06 ± 1.16	6.75 ± 1.54	10.93 ± 1.61	7.62 ± 0.96	11.66 ± 1.37
Semiovale	7.96 ± 0.87	6.70^{^c} ± 1.51		8.25 ± 1.56	7.05^{^c} ± 1.17		8.51 ± 0.94
Parietal	7.43^{^d} ± 1.05	6.55^{^c} ± 0.74	10.51 ± 1.08	7.59 ± 0.98	7.08 ± 1.24	11.52 ± 1.46	8.22 ± 0.81	10.89 ± 1.30
Cho
Frontal	1.50 ± 0.20	1.51 ± 0.25	2.16 ± 0.49	1.59 ± 0.28	1.64 ± 0.29	2.11 ± 0.45	1.62 ± 0.25	2.08 ± 0.39
Semiovale	1.44 ± 0.19	1.42 ± 0.28		1.53 ± 0.21	1.49 ± 0.28		1.49 ± 0.16
Parietal	1.13 ± 0.24	1.36 ± 0.19	1.31 ± 0.22	1.34 ± 0.23	1.39 ± 0.27	1.36 ± 0.24	1.37 ± 0.17	1.13 ± 0.20
mIns
Frontal	4.82^{^e} ± 1.18	5.29 ± 1.01	7.49 ± 1.57	4.44 ± 0.92	5.45^{^c} ± 1.51	7.30 ± 1.11	3.90 ± 0.65	7.00 ± 1.16
Semiovale	4.47^{^e} ± 1.18	4.76 ± 0.91		4.27 ± 0.69	4.71 ± 1.01		3.56 ± 0.44
Parietal	4.79^{^e} ± 0.64	5.59^{^b} ± 1.07	6.47 ± 0.91	4.98 ± 0.93	5.32 ± 1.42	6.47 ± 0.83	4.01 ± 0.62	5.85 ± 0.52
Glu
Frontal	6.34 ± 1.46	5.36^{^b} ± 1.13	12.96 ± 2.98	5.86 ± 1.18	6.03 ± 1.48	12.71 ± 2.57	6.25 ± 0.96	14.01 ± 2.40
Semiovale	5.38 ± 1.08	4.73^{^b} ± 1.16		5.50 ± 0.91	5.11 ± 0.96		5.49 ± 0.72
Parietal	5.17 ± 1.34	4.22^{^b} ± 0.94	12.99 ± 3.87	5.37 ± 1.57	4.80 ± 0.68	12.68 ± 1.44	5.31 ± 0.67	11.81 ± 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).