MRI Findings Support Gradient of Spinal Cord Demyelination in Multiple Sclerosis
Key findings
- Massachusetts General Hospital researchers used 7T MRI to characterize lesions in the spinal cord and brain of 20 patients with early relapsing-remitting multiple sclerosis (RRMS), 15 with secondary progressive MS (SPMS) and 11 healthy controls
- Spinal cord lesions typically manifested near subpial cerebrospinal fluid (CSF) interfaces in RRMS patients, suggesting CSF plays an important role in lesion development in early MS
- In patients with SPMS, lesions were predominantly near the central canal along the inner portion of the spinal cord, providing additional support for the "outside-in" pathogenic theory of MS
- As in previous research, white matter brain lesions originated near the CSF in the ventricular system
- Both spinal cord and brain lesions contributed to neurological disability
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The "outside-in" pathogenic theory of multiple sclerosis (MS) holds that inflammatory factors in cerebrospinal fluid (CSF) penetrate the brain surface, causing focal lesions and provoking a gradient of diffuse demyelination. Brain regions commonly affected include periventricular white matter and subpial cortical layers.
Now, Caterina Mainero, MD, PhD, director of multiple sclerosis research at the Martinos Center for Biomedical Imaging at Massachusetts General Hospital, and colleagues have become the first to identify in vivo a specific spatial pattern of lesion development in the spinal cord of MS patients in which meningeal inflammation may play a role. In Brain, they report that spinal cord lesions preferentially occur in close proximity to CSF, supporting the outside-in theory.
Study Methods
The researchers prospectively enrolled 35 adults with MS:
- 20 with early-stage relapsing–remitting MS (RRMS, diagnosed <5 years previously)
- 15 with secondary progressive MS (SPMS)
Eleven age- and gender-matched volunteers served as control subjects. All participants underwent ultra–high-field 7T MRI of the brain and spinal cord.
Spinal Cord and Brain Pathology
Cervical spinal cord lesions were detected in 14 RRMS patients (70%) and all SPMS patients. MS patients had evidence of spinal cord atrophy—compared with controls, they had a significantly lower average cross-sectional area in both gray and white matter. They also had significantly thinner cortices.
Lesion Proximity to CSF
In the spinal cord—In patients with RRMS, lesions were predominantly in the outer subpial portion of the cervical cord, suggesting CSF plays an important role in lesion development in the early stage of the disease. In patients with SPMS, lesions were predominantly near the central canal along the inner portion of the spinal cord.
In the brain, there was a strong gradient of white matter lesions near the ventricular system, and this pattern was particularly evident in SPMS.
Clinical Correlations
- Results on the Expanded Disability Status Scale were most influenced by cortical thickness
- The 9-Hole Peg Test of fine motor disability was primarily associated with lesions bordering the ventricular system and central canal in the brain and spinal cord white matter
- Walking difficulty, assessed on the Timed 25-Foot Walk, was most associated with atrophy in the gray matter of the spinal cord and brain that borders the meninges
Future Directions
The acquisition time for cervical 7T MRI in this study was approximately four to six minutes. Thus, it's a feasible way to obtain useful information about an individual's MS status. Combining neuroimaging with analysis of CSF-borne cellular biomarkers should also yield a better understanding of the pathophysiological processes that drive chronic inflammation in MS.
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