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Original Investigation |

Association of Deep Gray Matter Damage With Cortical and Spinal Cord Degeneration in Primary Progressive Multiple Sclerosis

Serena Ruggieri, MD1,2; Maria Petracca, MD1,3; Aaron Miller, MD4; Stephen Krieger, MD4; Rezwan Ghassemi, PhD1; Yadira Bencosme, CCRC4; Claire Riley, MD5; Jonathan Howard, MD6; Fred Lublin, MD4; Matilde Inglese, MD, PhD7,8,9,10
[+] Author Affiliations
1Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, New York
2Department of Neurology and Psychiatry, Sapienza University of Rome, Rome, Italy
3Department of Neurosciences, Reproductive Sciences, and Odontostomatology, University of Naples Federico II, Naples, Italy
4Corinne Goldsmith Dickinson Center for Multiple Sclerosis, Icahn School of Medicine at Mount Sinai, New York, New York
5The Neurological Institute of New York, Department of Neurology, Columbia University Medical Center, New York, New York
6Department of Neurology, Langone Medical Center, New York University, New York, New York
7Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, New York
8Department of Radiology, Icahn School of Medicine at Mount Sinai, New York, New York
9Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York
10Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy
JAMA Neurol. 2015;72(12):1466-1474. doi:10.1001/jamaneurol.2015.1897.
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Importance  The investigation of cortical gray matter (GM), deep GM nuclei, and spinal cord damage in patients with primary progressive multiple sclerosis (PP-MS) provides insights into the neurodegenerative process responsible for clinical progression of MS.

Objective  To investigate the association of magnetic resonance imaging measures of cortical, deep GM, and spinal cord damage and their effect on clinical disability.

Design, Setting, and Participants  Cross-sectional analysis of 26 patients with PP-MS (mean age, 50.9 years; range, 31-65 years; including 14 women) and 20 healthy control participants (mean age, 51.1 years; range, 34-63 years; including 11 women) enrolled at a single US institution. Clinical disability was measured with the Expanded Disability Status Scale, 9-Hole Peg Test, and 25-Foot Walking Test. We collected data from January 1, 2012, through December 31, 2013. Data analysis was performed from January 21 to April 10, 2015.

Main Outcomes and Measures  Cortical lesion burden, brain and deep GM volumes, spinal cord area and volume, and scores on the Expanded Disability Status Scale (score range, 0 to 10; higher scores indicate greater disability), 9-Hole Peg Test (measured in seconds; longer performance time indicates greater disability), and 25-Foot Walking Test (test covers 7.5 m; measured in seconds; longer performance time indicates greater disability).

Results  The 26 patients with PP-MS showed significantly smaller mean (SD) brain and spinal cord volumes than the 20 control group patients (normalized brain volume, 1377.81 [65.48] vs 1434.06 [53.67] cm3 [P = .003]; normalized white matter volume, 650.61 [46.38] vs 676.75 [37.02] cm3 [P = .045]; normalized gray matter volume, 727.20 [40.74] vs 757.31 [38.95] cm3 [P = .02]; normalized neocortical volume, 567.88 [85.55] vs 645.00 [42.84] cm3 [P = .001]; normalized spinal cord volume for C2-C5, 72.71 [7.89] vs 82.70 [7.83] mm3 [P < .001]; and normalized spinal cord volume for C2-C3, 64.86 [7.78] vs 72.26 [7.79] mm3 [P =.002]). The amount of damage in deep GM structures, especially with respect to the thalamus, was correlated with the number and volume of cortical lesions (mean [SD] thalamus volume, 8.89 [1.10] cm3; cortical lesion number, 12.6 [11.7]; cortical lesion volume, 0.65 [0.58] cm3; r = −0.52; P < .01). Thalamic atrophy also showed an association with cortical lesion count in the frontal cortex (mean [SD] thalamus volume, 8.89 [1.1] cm3; cortical lesion count in the frontal lobe, 5.0 [5.7]; r = −0.60; P < .01). No association was identified between magnetic resonance imaging measures of the brain and spinal cord damage.

Conclusions and Relevance  In this study, the neurodegenerative process occurring in PP-MS appeared to spread across connected structures in the brain while proceeding independently in the spinal cord. These results support the relevance of anatomical connectivity for the propagation of MS damage in the PP phenotype.

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Figure 1.
Magnetic Resonance Imaging Postprocessing Measurement of Spine Volume (SV) and Cervical Cord Cross-Sectional Area (CSA)

The 3-dimensional T1-weighted images are from a patient with primary progressive multiple sclerosis. To segment the spine between C2 and C5, a marker was placed to correspond to the most superior slice in which the odontoid process of the epistropheus was still visible (A). Using the inferior border of C5 as a reference, another marker was placed at this level and then, moving back from C5, a marker was located every 10 slices until the first marker at C2 was reached (B). The final output with the outlined cord is shown (C and D).

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Figure 2.
Partial Regression Plots Between Thalamic Volume and Frontal Lobe Cortical Lesions

The graph shows correlations between thalamic volume and the number and volume of cortical lesions in the frontal lobe controlled for thalamic lesion volume (LV). Thalamic volume constitutes the dependent variable; number and volume of cortical lesions, adjusted for thalamic LV, the independent variables. Axes represent residuals. Linear fit (middle line) and 95% individual CIs (upper and lower lines) are shown.

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