Person:

Bakshi, Rohit

The objective of this study was to test a new version of the Magnetic Resonance Disease Severity Scale (MRDSS2), incorporating cerebral gray matter (GM) and spinal cord involvement from 3 T MRI, in modeling the relationship between MRI and physical disability or cognitive status in multiple sclerosis (MS). Fifty-five MS patients and 30 normal controls underwent high-resolution 3 T MRI. The patients had an Expanded Disability Status Scale score of 1.6±1.7 (mean±SD). The cerebral normalized GM fraction (GMF), the T2 lesion volume (T2LV), and the ratio of T1 hypointense LV to T2LV (T1/T2) were derived from brain images. Upper cervical spinal cord area (UCCA) was obtained from spinal cord images. A within-subject d-score (difference of MS from normal control) for each MRI component was calculated, equally weighted, and summed to form MRDSS2. With regard to the relationship between physical disability and MRDSS2 or its individual components, MRI–Expanded Disability Status Scale correlations were significant for MRDSS2 (r=0.33, P=0.013) and UCCA (r=−0.33, P=0.015), but not for GMF (P=0.198), T2LV (P=0.707), and T1/T2 (P=0.240). The inclusion of UCCA appeared to drive this MRI–disability relationship in MRDSS2. With regard to cognition, MRDSS2 showed a larger effect size (P=0.035) than its individual components [GMF (P=0.081), T2LV (P=0. 179), T1/T2 (P=0.043), and UCCA (P=0.818)] in comparing cognitively impaired with cognitively preserved patients (defined by the Minimal Assessment of Cognitive Function in MS). Both cerebral lesions (T1/T2) and atrophy (GMF) appeared to drive this relationship. We describe a new version of the MRDSS, which has been expanded to include cerebral GM and spinal cord involvement. MRDSS2 has concurrent validity with clinical status.

Background: The reliable and efficient measurement of spinal cord atrophy is of growing interest in monitoring disease progression in multiple sclerosis (MS). Methods: We compared T1- and T2-weighted MRI for measuring cervical spinal cord volume in 31 patients with MS and 18 age-matched controls (NC) from T1-weighted gradient recalled echo and T2-weighted fast spin-echo 1.5 T axial acquisitions. The two sequences were matched on slice thickness, signal averages and voxel size. An active surface software tool determined the normalized mean cervical cord cross-sectional area. Results: T1-derived cord areas were higher than T2 areas in the whole cohort (estimated mean difference = 7.03 mm2 (8.89 %); 95 % Confidence Interval (CI): 5.91, 8.14; p < 0.0001) and in both groups separately. There were trends for lower spinal cord areas in MS vs. NC with both sequences. For the T1 cord area, the mean difference was 3.7 mm2 (4.55 %) (95 % CI: −1.36, 8.78; p = 0.15). For the T2 cord area, the difference was larger [mean difference 4.9 mm2 (6.52 %) (95 % CI: −0.83, 10.67); p = 0.091]. The T1 and T2 cord areas showed similar weak to moderate correlations with measures of clinical status and T2 spinal cord lesion volume in the MS group. Superficial spinal cord T2 lesions had no apparent confounding effect on the outlining tool. The mean intra-rater and inter-rater coefficients of variation ranged from 0.27 to 0.91 % for T1- and 0.66 to 0.99 % for T2-derived cord areas. Conclusion: T2-weighted images may prove efficient for measuring cervical spinal cord atrophy in MS, with the added advantage of lesion detectability.

Objective: To test a new version of the Magnetic Resonance Disease Severity Scale (v.3 = MRDSS3) for multiple sclerosis (MS), incorporating cortical gray matter lesions (CLs) from 3T magnetic resonance imaging (MRI). Background: MRDSS1 was a cerebral MRI-defined composite scale of MS disease severity combining T2 lesion volume (T2LV), the ratio of T1 to T2LV (T1/T2), and whole brain atrophy [brain parenchymal fraction (BPF)]. MRDSS2 expanded the scale to include cerebral gray matter fraction (GMF) and upper cervical spinal cord area (UCCA). We tested the contribution of CLs to the scale (MRDSS3) in modeling the MRI relationship to clinical status. Methods: We studied 51 patients [3 clinically isolated syndrome, 43 relapsing-remitting, 5 progressive forms, age (mean ± SD) 40.7 ± 9.1 years, Expanded Disability Status Scale (EDSS) score 1.6 ± 1.7] and 20 normal controls by high-resolution cerebrospinal MRI. CLs required visibility on both fluid-attenuated inversion-recovery (FLAIR) and modified driven equilibrium Fourier transform sequences. The MACFIMS battery defined cognitively impaired (n = 18) vs. preserved (n = 33) MS subgroups. Results: EDSS significantly correlated with only BPF, UCCA, MRDSS2, and MRDSS3 (all p < 0.05). After adjusting for depressive symptoms, the cognitively impaired group had higher severity of MRI metrics than the cognitively preserved group in regard to only BPF, GMF, T1/T2, MRDSS1, and MRDSS2 (all p < 0.05). CL number was not significantly related to EDSS score or cognition status. Conclusion: CLs from 3T MRI did not appear to improve the validity of the MRDSS. Further studies employing advanced sequences or higher field strengths may show more utility for the incorporation of CLs into composite scales.

Magnetic resonance imaging (MRI) of the brain provides important outcome measures in the longitudinal evaluation of disease activity and progression in MS subjects. Two common measures derived from brain MRI scans are the brain parenchymal fraction (BPF) and T2 hyperintense lesion volume (T2LV), and these measures are routinely assessed longitudinally in clinical trials and observational studies. When measuring each outcome longitudinally, observed changes may be potentially confounded by variability in MRI acquisition parameters between scans. In order to accurately model longitudinal change, the acquisition parameters should thus be considered in statistical models. In this paper, several models for including protocol as well as individual MRI acquisition parameters in linear mixed models were compared using a large dataset of 3453 longitudinal MRI scans from 1341 subjects enrolled in the CLIMB study, and model fit indices were compared across the models. The model that best explained the variance in BPF data was a random intercept and random slope with protocol specific residual variance along with the following fixed-effects: baseline age, baseline disease duration, protocol and study time. The model that best explained the variance in T2LV was a random intercept and random slope along with the following fixed-effects: baseline age, baseline disease duration, protocol and study time. In light of these findings, future studies pertaining to BPF and T2LV outcomes should carefully account for the protocol factors within longitudinal models to ensure that the disease trajectory of MS subjects can be assessed more accurately.

Grey matter (GM) damage is a clinically relevant feature of multiple sclerosis (MS) that has been previously assessed with diffusion tensor imaging (DTI). Fractional anisotropy (FA) of the basal ganglia and thalamus might be increased in MS patients, and correlates with disability scores. Despite the established role of the striatum and thalamus in motor control, mood and cognition, the impact of DTI changes within these structures on motor and neuropsychological performance has not yet been specifically addressed in MS. We investigated DTI metrics of deep GM nuclei and their potential association with mobility and neuropsychological function. DTI metrics from 3T MRI were assessed in the caudate, putamen, and thalamus of 30 MS patients and 10 controls. Sixteen of the patients underwent neuropsychological testing. FA of the caudate and putamen was higher in MS patients compared to controls. Caudate FA correlated with Expanded Disability Status Scale score, Ambulation Index, and severity of depressive symptomatology. Putamen and thalamus FA correlated with deficits in memory tests. In contrast, cerebral white matter (WM) lesion burden showed no significant correlation with any of the disability, mobility and psychometric parameters. Our findings support evidence of FA changes in the basal ganglia in MS patients, as well as deep GM involvement in disabling features of MS, including mobility and cognitive impairment. Deep GM FA appears to be a more sensitive correlate of disability than WM lesion burden.

Assess the sensitivity of the Magnetic Resonance Disease Severity Scale (MRDSS), based on cerebral lesions and atrophy, for treatment monitoring of glatiramer acetate (GA) in relapsing-remitting multiple sclerosis (MS). This retrospective non-randomized pilot study included patients who started daily GA [n = 23, age (median, range) 41 (26.2, 53.1) years, Expanded Disability Status Scale (EDSS) score 1.0 (0, 3.5)], or received no disease-modifying therapy (noDMT) [n = 21, age 44.8 (28.2, 55.4), EDSS 0 (0, 2.5)] for 2 years. MRDSS was the sum of z-scores (normalized to a reference sample) of T2 hyperintense lesion volume (T2LV), the ratio of T1 hypointense LV to T2LV (T1/T2), and brain parenchymal fraction (BPF) multiplied by negative 1. The two groups were compared by Wilcoxon rank sum tests; within group change was assessed by Wilcoxon signed rank tests. Glatiramer acetate subjects had less progression than noDMT on T1/T2 [(median z-score change (range), 0 (−1.07, 1.20) vs. 0.41 (−0.30, 2.51), p = 0.003)] and MRDSS [0.01 (−1.33, 1.28) vs. 0.46 (−1.57, 2.46), p = 0.01]; however, not on BPF [0.12 (−0.18, 0.58) vs. 0.10 (−1.47,0.50), p = 0.59] and T2LV [−0.03 (−0.90, 0.57) vs. 0.01 (−1.69, 0.34), p = 0.40]. While GA subjects worsened only on BPF [0.12 (−0.18, 0.58), p = 0.001], noDMT worsened on BPF [0.10 (−1.47, 0.50), p = 0.002], T1/T2 [0.41 (−0.30, 2.51), p = 0.0002], and MRDSS [0.46 (−1.57, 2.46), p = 0.0006]. These preliminary findings show the potential of two new cerebral MRI metrics to track MS therapeutic response. The T1/T2, an index of the destructive potential of lesions, may provide particular sensitivity to treatment effects.

Multiple sclerosis (MS) commonly affects occupational function. We investigated the link between brain MRI and employment status. Patients with MS (n = 100) completed a Work Productivity and Activity Impairment (WPAI) (general health version) survey measuring employment status, absenteeism, presenteeism, and overall work and daily activity impairment. Patients “working for pay” were considered employed; “temporarily not working but looking for work,” “not working or looking for work due to age,” and “not working or looking for work due to disability” were considered not employed. Brain MRI T1 hypointense (T1LV) and T2 hyperintense (T2LV) lesion volumes were quantified. To assess lesional destructive capability, we calculated each subject’s ratio of T1LV to T2LV (T1/T2). Normalized brain parenchymal volume (BPV) assessed brain atrophy. The mean (SD) age was 45.5 (9.7) years; disease duration was 12.1 (8.1) years; 75 % were women, 76 % were relapsing-remitting, and 76 % were employed. T1LV, T1/T2, Expanded Disability Status Scale (EDSS) scores, and activity impairment were lower and BPV was higher in the employed vs. not employed group (Wilcoxon tests, p < 0.05). Age, disease duration, MS clinical subtype, and T2LV did not differ between groups (p > 0.05). In multivariable logistic regression modeling, adjusting for age, sex, and disease duration, higher T1LV predicted a lower chance of employment (p < 0.05). Pearson correlations showed that EDSS was associated with activity impairment (p < 0.05). Disease duration, age, and MRI measures were not correlated with activity impairment or other WPAI outcomes (p > 0.05). We report a link between brain atrophy and lesions, particularly lesions with destructive potential, to MS employment status.

ABSTRACT BACKGROUND Spinal cord atrophy occurs early in the multiple sclerosis (MS) disease course, is closely related to physical disability, and is a putative neuroprotective therapeutic outcome measure. OBJECTIVE This pilot study explored glatiramer acetate (GA)’s effect on spinal cord volume in patients with relapsing‐remitting MS (RRMS). METHODS Fifteen patients receiving daily subcutaneous GA were prospectively followed. At baseline, age was 43.6 ± 7.4 years, Expanded Disability Status Scale (EDSS) score was 1.4 ± 1.5, timed 25‐foot walk (T25FW) was 4.7 ± 1.1 seconds, and time on GA was 2.1 ± 3.1 years. Healthy controls (n = 10) with similar age and sex to the patients were also enrolled. The spinal cord was imaged at baseline and one year later with 3T magnetic resonance imaging. An active surface method measured the C1–C7 spinal cord volume from which we calculated the normalized area. RESULTS The spinal cord area showed no significant change in the MS group over one year (P = .19). Furthermore, the change in the spinal cord area did not differ significantly between the MS and control groups over one year (P = .26). In the MS group, the EDSS score (P = .44) and T25FW (P = .92) did not change significantly on‐study. CONCLUSION In this pilot study of RRMS, GA therapy was not associated with any ongoing spinal cord atrophy or any difference in the one‐year rate of spinal cord area change versus healthy controls. These results paralleled the lack of clinical worsening and may reflect a treatment effect of GA. Further studies are needed to confirm these preliminary findings.

Purpose We tested the validity of a freely available segmentation pipeline to measure compartmental brain volumes from 3T MRI in patients with multiple sclerosis (MS). Our primary focus was methodological to explore the effect of segmentation corrections on the clinical relevance of the output metrics. Methods: Three-dimensional T1-weighted images were acquired to compare 61 MS patients to 30 age- and gender-matched normal controls (NC). We also tested the within patient MRI relationship to disability (eg, expanded disability status scale [EDSS] score) and cognition. Statistical parametric mapping v. 8 (SPM8)-derived gray matter (GMF), white matter (WMF), and total brain parenchyma fractions (BPF) were derived before and after correcting errors from T1 hypointense MS lesions and/or ineffective deep GM contouring. Results: MS patients had lower GMF and BPF as compared to NC (P<.05). Cognitively impaired patients had lower BPF than cognitively preserved patients (P<.05). BPF was related to EDSS; BPF and GMF were related to disease duration (all P<.05). Errors caused bias in GMFs and WMFs but had no discernable influence on BPFs or any MRI-clinical associations. Conclusions: We report the validity of a segmentation pipeline for the detection of MS-related brain atrophy with 3T MRI. Longitudinal studies are warranted to extend these results.

MRI at 3 T has increased sensitivity in detecting overt multiple sclerosis (MS) brain lesions; a growing body of data suggests clinically relevant damage occurs in the normal-appearing white matter (NAWM). We tested a novel pulse sequence to determine whether 3 T MRI spin–spin relaxometry detected damage in NAWM of MS patients (n = 13) vs. age-matched normal controls [(NL) (n = 11)]. Baseline characteristics of the MS group were: age (mean ± SD) 42.5 ± 5.4 (range 33–51 years), disease duration 9.0 ± 6.4 (range 1–22 years), Expanded Disability Status Scale score 2.5 ± 1.7 (range 1–6.5). Brain MRI measures, obtained at 3 T, included global and regional NAWM transverse relaxation rate [R2 (= 1/T2)], derived from 3D fast spin-echo T2 prepared images, and global white matter volume fraction derived from SPGR images. The regional NAWM areas investigated were the frontal lobe, parietal lobe, and the genu and splenium of the corpus callosum. Mean NAWM R2 was lower (indicating T2 prolongation) in MS than NL in the whole brain (p = 0.00047), frontal NAWM (p = 0.00015), parietal NAWM (p = 0.0069) and callosal genu (p = 0.0019). Similarly, R2 histogram peak position was lower in NAWM in MS than NL in the whole brain (p = 0.019). However, the normalized WM volume fractions were similar in both MS and NL (p > 0.1). This pilot study suggests that a novel 3D fast spin-echo pulse sequence at 3 T, used to derive R2 relaxation maps, can detect tissue damage in the global and regional cerebral NAWM of MS patients that is missed by conventional lesion and atrophy measures. Such findings may represent demyelination, inflammation, glial proliferation and axonal loss.