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

Abstract

IMPORTANCEThe 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 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] cm 3 [P = .003]; normalized white matter volume, 650.61 [46.38] vs 676.75 [37.02] cm 3 [P = .045]; normalized gray matter volume, 727.20 [40.74] vs 757.31 [38.95] cm 3 [P = .02]; normalized neocortical volume, 567.88 [85.55] vs 645.00 [42.84] cm 3 [P = .001]; normalized spinal cord volume for C2-C5, 72.71 [7.89] vs 82.70 [7.83] mm 3 [P < .001]; and normalized spinal cord volume for C2-C3, 64.86 [7.78] vs 72.26 [7.79] mm 3 [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] cm 3 ; cortical lesion number , 12.6 [11.7]; cortical lesion volume, 0.65 [0.58] cm 3 ; 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] cm 3 ; 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. Royal Infirmary, Leicester, England, helped with the spinal cord post processing. None of the contributors received compensation for their roles. Accurate, robust, and automated longitudinal and cross-sectional brain change analysis.

Sample size requirements for one-year treatment effects using deep gray matter volume from 3T MRI in progressive forms of multiple sclerosis

“…Our findings are in line with the well-established concept that the DGM are an early and common site of atrophy in patients with MS [17][18][19][20][21][22][35][36][37][38], which progresses longitudinally [20,21,36,37,[39][40][41]. The magnitude of decreased DGM volumes we demonstrated in our study during the observation period is inline with these previous studies.…”

“…First, the caudate and other DGM nuclei are highly metabolically active structures [42] owing to their reciprocal connectivity and core processing role involving nearly all regions of the brain and, in turn, sub-serving a wide range of functions (e.g., cognition, sensation, motor control, visual function, behavior) [43][44][45]. Thus, given the diffuse and widespread damage, including axonal loss, of WM both in lesions and areas free of overt lesions (normal-appearing WM) in patients with MS [46], the DGM are vulnerable to diaschisis and Wallerian degeneration from damage in the brain and spinal cord [22,47]. Second, emerging histologic and ultra-high field MRI studies have shown a propensity for the disease process, particularly in PMS, to directly affect the DGM by the presence of lesions [48].…”

“…GM and white matter (WM) pathology are not necessarily closely coupled [15]. Furthermore, previous studies have shown that the deep gray matter (DGM, i.e., basal ganglia and thalamus) is disproportionately affected as compared to the cortical GM [17] and whole brain [18,19] and such involvement is highly clinically relevant [19][20][21][22]. Regarding the methodology available to assess brain volume loss from MRI CONTACT Rohit Bakshi rbakshi@post.harvard.edu scans, recent data indicate advantages of 3T vs. 1.5T MRI for accuracy and validity [23], which parallels its advantages in assessing lesions [24][25][26].…”

Thalamic Iron Differentiates Primary-Progressive and Relapsing-Remitting Multiple Sclerosis

“…4 No significant association between conventional MR imaging metrics and EDSS has been detected in PPMS, which is consistent with findings in previous studies. 43,49 In RRMS, there was a correlation between EDSS and conventional MR imaging parameters, which reflects WM lesions and brain atrophy. The correlation of EDSS with T1LL was stronger than with T2LL.…”

Clinical Efficacy of Plasma-Exchange in Patients with Progressive forms of Multiple Sclerosis and NMO-Spectrum Disease

“…It appears, therefore, that as the disease evolves into the progressive stage, the inflammation becomes compartmentalized and predominantly mediated by B cells. Such "slow" in situ inflammation can be detected even in the cortex and the deep grey matter and seems to correlate with the progression of disability [33,[35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50].…”