Abnormal White Matter Volume Conversion Linked to MS Disease Progression

April 16, 2020

In those with secondary progressive MS, evaluating diffusely abnormal white matter may provide a useful measure for therapies aiming to protect at-risk tissue, which may be able to slow progression.

Mahsa Dadar, PhD, MSc

New study data published in the Multiple Sclerosis Journal suggest that in patients with secondary progressive multiple sclerosis (MS), the transformation of diffusely abnormal white matter (DAWM) into focal white matter lesions (FWML) is associated with disease progression.

All told, DAWM-to-FWML volume was higher in those who showed disease progression (2.75&thinsp;cm3), as measured by Expanded Disability Status Scale (EDSS) score, compared to those who did not (1.70 cm3; P&thinsp;<&thinsp;0.0001). As disease duration increased, FMWL volume increased in parallel fashion while DAWM volume decreased (P <.001).

The investigators, including Mahsa Dadar, PhD, MSc, postdoctoral researcher, McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, and colleagues, assessed 589 patients with secondary progressive MS in an attempt to determine the role of DAWM in clinical progression. All analyses included treatment (natalizumab) as a fixed effect, showing no effect on the MRI variables that were investigated.

“FWML volume was significantly associated with grey matter brain atrophy, 9-Hole Peg Test, Symbol Digit Modalities Test, specific EDSS functional systems, and progression in this group of SPMS participants,” Dadar and colleagues wrote. “DAWM transformed into FWML over time, and this transformation was significantly associated with clinical progression. DAWM voxels that transformed had greater normalized T1w intensity decrease over time, that is, relatively greater tissue damage. Therefore, evaluation of DAWM in progressive MS may provide a useful measure for therapies that aim to protect this at-risk tissue, which would have the potential to slow progression.”

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At baseline, the mean age of participants was 49.24 ±7.36 years, with a mean overall disease duration of 17.63 ±7.32 years (6.38 ±3.53 years with secondary progressive disease). The median FWML volume in the dataset was 10.21 cm3 (range, 0.03—13.61), while DAWM volume was 21.59 cm3 (range, 0.87—95.19)—significantly higher than the FWML volume (P <.0001).

Dadar et al. observed that both FWML (t = —4.23; P <.0001) and DAWM (t = —6.55; P <.0001) volumes were significantly and negatively linked with age at disease onset, with older individuals having lower volumes. As previously mentioned, FMWL and DAWM volume increased (t = 3.18; P = .001) and decreased (t = −4.99; P <.0001), respectively, as disease duration increased.

Additionally, the ratio of FWML-DAWM volume per participant increased in parallel fashion, significantly, with disease duration (t = 10.78; P <.0001). The EDSS scores were positively associated with FWML volumes (P&thinsp;=&thinsp;.002), but not with DAWM.

Confirmed Disability Progression (CDP) for the 12- and 24-week marks showed a significant and positive association with increases in FWML volume (P <.0001 for both time points), while DAWM volumes were not significantly associated with progression. The DAWM-to-FWML volumes were significantly associated with progression as well at both 12 (P = .0001) and 24 weeks (P <.0001). At 12 weeks, those with CDP had significantly higher median DAWM-to-FWML volume (2.61 cm3) compared to those without (1.75 cm3; P <.0001), representative of 14% of the total DAWM volume at screening for those with CDP compared to 10% in those without 12-week CDP.

Similarly, the median DAWM-to-FWML volume was notably higher in those with 24-week CDP (2.70 cm3) compared to those without (1.76 cm3; P <.0001). According to the investigators, this represented 14% of the total DAWM volume at screening compared to 10% in those who did not have 24-week CDP.

“Our study is not without limitations. There were no quantitative MRI sequences such as MTR images or diffusion available, to assess the nature of the changes in a given area in a more quantitative manner,” Dadar and colleague acknowledged. “We have used T1w-normalized intensity values as a proxy of lesion severity and demyelination since previous studies have shown significant associations between MTR and T1w-normalized intensity values.”

“Future studies using quantitative MRI sequences are required to further establish such associations. Finally, another limitation is the lack of scans during the relapsing-remitting course of the disease,” they added.

REFERENCE

Dadar M, Narayanan S, Arnold DL, Collins DL, Maranzano J. Conversion of diffusely abnormal white matter to focal lesions is linked to progression in secondary progressive multiple sclerosis. Mult Scler J. Published online March 23, 2020. Accessed April 15, 2020. doi: 10.1177/1352458520912172