Immunological and short-term brain volume changes in relapsing forms of multiple sclerosis treated with interferon beta-1a subcutaneously three times weekly: an open-label two-arm trial.

BACKGROUND: Brain volume atrophy is observed in relapsing-remitting multiple sclerosis (RRMS). METHODS: Brain volume changes were evaluated in 23 patients with RRMS treated with interferon ß-1a 44 µg given subcutaneously (SC) three times a week (tiw) and 15 healthy controls. Percentages of whole brain and tissue-specific volume change were measured from baseline (0 months) to 3 months, from 3 to 6 months, and from baseline to 6 months using SIENAX Multi Time Point (SX-MTP) algorithms. Immunological status of patients was also determined and correlations between subsets of T cells and changes in brain volume were assessed. RESULTS: Interferon ß-1a 44 µg SC tiw in 23 patients with RRMS resulted in significant reductions in whole brain and gray matter tissue volume early in the treatment course (baseline to 3 months; mean change; -0.95%; P = 0.030, -1.52%; P = 0.004, respectively), suggesting a short-term treatment-induced pseudoatrophy effect. From baseline to 6 months, there were significant correlations observed between decreased T- cell expression of IL-17 F and decreased whole brain and brain tissue-specific volume. CONCLUSIONS: These findings are consistent with the interpretation of the pseudoatrophy effect as resolution of inflammation following treatment initiation with interferon ß-1a 44 µg SC tiw, rather than disease-related tissue loss. TRIAL REGISTRATION: ClinicalTrials.gov; NCT01085318.

Effect of switching from glatiramer acetate 20 mg/daily to glatiramer acetate 40 mg three times a week on gray and white matter pathology in subjects with relapsing multiple sclerosis: A longitudinal DTI study.

BACKGROUND: Glatiramer acetate (GA) 40 mg × 3/weekly was approved for the treatment of relapsing-remitting multiple sclerosis (RRMS). While the beneficial effect of GA 20 mg/daily in MS patients on non-conventional MRI measures has been demonstrated, the effect of GA 40 mg × 3/weekly at the microstructural tissue level has yet to be explored. OBJECTIVE: To investigate the effect of switching from GA 20 mg/daily to GA 40 mg × 3/weekly on the evolution of microstructural changes in the thalamus and normal appearing white matter (NAWM), using diffusion tensor imaging (DTI). METHODS: In this observational, longitudinal, cross-over, 34-month MRI study, we recruited 150 RRMS patients that underwent MRI 12-18 months before switching (pre-index), during the switch (index) and 12-18 months after switching (post-index) from GA 20 mg/daily to GA 40 mg × 3/weekly. Regional DTI metrics and tract-based spatial statistics (TBSS) analyses were performed. Mean diffusivity (MD), axial diffusivity (AD), radial diffusivity (RD) and fractional anisotropy (FA) were measured in thalamus and NAWM. RESULTS: Regional DTI measures, measures of whole brain, white and gray matter, and thalamus volumes, as well as lesion volume, showed no significant changes. However, the voxel-wise TBSS analysis showed increased FA both in the NAWM and thalamus, as well as increased MD and AD in NAWM, and decreased RD in NAWM (p < .05). Areas of increased FA and MD as well as decreased RD in the NAWM, and increased AD both in the NAWM and thalamus were detected between index to post-index (p < .05). CONCLUSIONS: This study confirms a comparable effect of GA 40 mg × 3/weekly to GA 20 mg/daily on DTI measures over 34 months.

Immune cell BDNF secretion is associated with white matter volume in multiple sclerosis.

PURPOSE: To investigate the relationship between immune cell secretion of brain-derived neurotrophic factor (BDNF) with clinical and MRI variables in multiple sclerosis (MS) patients. BACKGROUND: BDNF exerts beneficial effects on neuronal growth and repair and is secreted by both neurons and immune cells. Consequently, it may mediate the crosstalk between the immune system and CNS in autoimmune diseases such as MS. METHODS: Fifty-two relapsing MS patients (41 females, age: 48.8+/-6.6 years, disease duration: 12.7+/-8.4 years) were enrolled. Clinical and MRI measurements (including, T1-, T2- and contrast-enhancing (CE) lesion volumes (LVs); normalized measures of whole brain, white matter (WM) and gray matter (GM) volumes; diffusion weighted imaging measure of mean whole brain (WB) parenchyma diffusivity and magnetization transfer ratio (MTR) measures were obtained. RESULTS: Immune cell BDNF secretion after anti-CD3 plus anti-CD28 stimulation was positively associated with increased CE-LV (p=0.026). The MTR of CE-LV and normal-appearing (NA) WM (NAWM) were negatively associated with immune cell BDNF secretion after anti-CD3 plus anti-CD28 stimulation. Immune cell BDNF secretion after anti-CD3 plus anti-CD28 was positively associated with higher WM volume (p=0.027). Immune cell BDNF secretion after anti-CD3 plus anti-CD28 stimulation was decreased with increasing disease duration (p=0.031). The BDNF secretion was independent of the BDNF Val66Met (dBSNP ID: rs6265) SNP genotype. CONCLUSIONS: Immune cell BDNF secretion is associated with the sites of higher inflammatory activity as evidenced by CE lesions and may represent an important factor associated with the WM volume of patients with MS.

A sensitive, noise-resistant method for identifying focal demyelination and remyelination in patients with multiple sclerosis via voxel-wise changes in magnetization transfer ratio.

Magnetization transfer imaging (MTI) provides a reliable and histopathologically validated means for identifying important tissue changes in multiple sclerosis (MS), including demyelination and remyelination. However, most approaches to date have been based on a priori regions of interest (ROIs) and have been relatively insensitive to small focal changes or competing processes. More recent techniques have sought to address this through a voxel-wise approach, but have been limited in their detection capabilities by the amount of noise in standard MTR images. To address this issue while remaining sensitive to local changes, we propose the use of the recently introduced threshold-free cluster enhancement (TFCE) technique in combination with a Monte Carlo estimation approach. TFCE is first applied to enhance individual voxels based on their level of local cluster support, and then Monte Carlo estimation is performed to allow meaningful statistical interpretation of the resulting TFCE values. We validated this technique in three complementary ways: healthy control scan-rescan analysis, analysis of a "gold standard" simulated dataset, and analysis of a group of MS patients and healthy volunteers with 1-year longitudinal MRI scans. Scan-rescan analysis demonstrated a very low false-positive rate (1.44 mL increasing and 1.48 mL decreasing at the optimal detection threshold). Simulated dataset analysis yielded an area under receiver-operating characteristic curve of 0.942 (compared to 0.801 for a more conventional voxel-wise thresholding analysis). Finally, analysis of the real subject population showed highly significant differences (p<0.001) in volume of decreasing MTR between patients and controls. The proposed method provides a valuable means for quantifying MS-related tissue changes, particularly demyelination and remyelination, in vivo and without the use of highly complex or experimental MRI acquisition techniques. It improves on the sensitivity of other approaches, and may increase the statistical power of studies investigating the effects of therapy on MRI outcomes in MS.

Preservation of gray matter volume in multiple sclerosis patients with the Met allele of the rs6265 (Val66Met) SNP of brain-derived neurotrophic factor.

To investigate the association of the rs6265 (Val66Met) single nucleotide polymorphism (SNP) of brain-derived neurotrophic factor (BDNF) with brain morphometry and functional status as measured by quantitative magnetic resonance imaging (MRI) and neurocognitive testing in multiple sclerosis (MS) patients. BDNF is released by neurons and by immune cells in MS brain. The rs6265 SNP variation of BDNF causes substitution of valine (Val) for methionine (Met) and interferes with activity-dependent BDNF secretion. A total of 209 treated MS patients (161 females; 48 males) underwent clinical brain MRI and were genotyped for the BDNF rs6265 Val66Met SNP. A subset of 108 patients had neurocognitive testing for processing speed, memory and executive function. The MRI measurements included T2 and T1-lesion volume (LV); normalized brain volume measures of whole brain (WB) volume, white and gray matter volume (NWMV and NGMV) and the diffusion-weighted imaging measure of WB mean parenchyma diffusivity (MPD). The Met66 allele status was positively associated with NGMV (P = 0.015, standardized beta = 0.15) and negatively associated with T2-LV (P = 0.041, standardized beta = -0.14). There were no significant associations between Met66 allele status and T1-LV, NWMV or MPD. On the Paced Serial Addition Test (PASAT), a trend (P = 0.057) favoring the Met66 allele group was observed. There were no significant associations between Met66 allele status and other neurocognitive measures. The BDNF Met66 allele is associated with lower damage as evidenced by measurement of NGMV and T2-LV in MS patients.