MS Progression More Closely Linked to Atrophy of Gray Matter Than White Matter
Gray matter atrophy seen on MRI showed better association with MS progression than did white matter atrophy at 5 and 10 years, although atrophy occurred in whole brain, cortex, and putamen
Gray matter (GM) atrophy seen on MRI showed better association with multiple sclerosis (MS) disease progression than did white matter (WM) atrophy at 5 and 10 years, according to findings of a 10-year follow-up study published online first in the Journal of Neurology, Neurosurgery and Psychiatry (Jacobsen et al., 2014). The investigators also found significant associations between disease progression and atrophy in the whole brain, the cortex, and the putamen.
“The search for reliable MRI markers to predict disease progression in MS has been ongoing for more than two decades,” wrote Cecilie Jacobsen of the Department of Neurology at Stavanger University Hospital in Norway and colleagues. “Standard MRI can be used to measure longitudinal changes in global, tissue-specific and regional brain volumes. GM atrophy has been found to correlate with disability progression in some studies, while others did not confirm this.”
The study goals were to find MRI biomarkers associated with long-term progression of disability in persons with MS and to determine their rate of development of global, tissue-specific, and regional atrophy over the long term.
At their first visit and after 5 and 10 years of follow-up, 81 persons with MS underwent clinical neurological evaluation and brain MRI acquired on 1.5-T scanners for calculation of T1-lesion and T2-lesion volumes (LVs).
By calculating percentage volume changes between different time points, the investigators determined changes in global and tissue-specific atrophy over time. They also calculated regional tissue volumes for subcortical deep GM structures. Increase in Expanded Disability Status Scale of ≥1.0 from baseline to 5-year and 10-year follow-up determined disability progression.
Compared to persons with MS and no disability progression, those with progression of disability over 5 years had significantly increased loss of whole brain (−3.8% vs. −2.0%, p < 0.001), cortex (−3.4% vs. −1.8%, p = 0.009), and putamen (−10.6% vs. −3.8%, p = 0.003), but not of white matter. Over 10 years, persons with progression had greater decrease in whole-brain volume (−5.5% vs. −3.7%, p = 0.015). Persons with and without disability progression did not differ significantly in changes in LV measures.
After adjusting for age, sex, scanner type, disease course, baseline volumes of T1- and T2-lesions and of specific brain structures, and months on DMT, the only MRI measures independently associated with disability status at 5 years were rates of whole-brain and of cortical atrophy.
“This long-term study shows that whole brain, cortical and putamen atrophy occurs throughout the 10-year follow-up of this MS cohort and is more pronounced in the group that showed disability progression at 5, but not at 10 years of follow-up,” the study authors wrote. “Overall, GM atrophy showed better association with disease progression than WM atrophy over 5-year and 10-year follow-up.”
Although MS has long been considered to be a disease of the cerebral WM and spinal cord, volumetric brain tissue analysis has shown that GM pathology is at least as important as WM pathology. In this study, cortical and putamen volume loss were significantly associated with disability progression after 5 years, but WM volume was not, suggesting that GM pathology may be playing a crucial role in MS-related disability progression.
Study limitations include use of two different MRI scanners, assessment of disability progression at discrete 5- and 10-year time points, and relatively small sample size with considerable dropout (31 patients, 38.3%) from baseline to 10-year follow-up.
“The search for biomarkers that can predict the course of MS is an ongoing pursuit,” the study authors concluded. “MRI is one of the available tools to monitor disease activity, but is well known not to correlate very well with clinical outcomes. Assessment of GM pathology may add to the understanding of the disease progression in MS, and overcome the clinical–MRI paradox.”
Key open questions
- How can MRI biomarkers be used to predict course and development of disability in persons with MS?
- How can MRI biomarkers be used clinically and in research trials to monitor treatment response in persons with MS?
Disclosures and sources of funding
Some of the study authors reported various financial disclosures with BNAC, Allergan, Almirall, Bayer Schering, Biogen Idec, Genzyme, Merck Serono, Novartis, Sanofi-Aventis, Teva, Lundbeck Pharma, GSK, Bayer, EMD Serono, Claret, Sanofi-Genzyme, and EMD. Dr. Minagar reported having no financial disclosures.