Person:

Weiner, Howard

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.

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.

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.

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.

Objective: Several factors influence the clinical course of autoimmune inflammatory diseases such as MS and inflammatory bowel disease. Only recently, the complex interaction between the gut microbiome, dietary factors, and metabolism has started to be appreciated with regard to its potential to modulate acute and chronic inflammation. One of the molecular sensors that mediates the effects of these environmental signals on the immune response is the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor with key functions in immune cells. Methods: In this study, we analyzed the levels of AHR agonists in serum samples from patients with MS and healthy controls in a case-control study. Results: We detected a global decrease of circulating AHR agonists in relapsing-remitting MS patients as compared to controls. However, during acute CNS inflammation in clinically isolated syndrome or active MS, we measured increased AHR agonistic activity. Moreover, AHR ligand levels in patients with benign MS with relatively mild clinical impairment despite longstanding disease were unaltered as compared to healthy controls. Conclusions: Collectively, these data suggest that AHR agonists in serum are dynamically modulated during the course of MS. These findings may guide the development of biomarkers to monitor disease activity as well as the design of novel therapeutic interventions for MS.

Background/Purpose: To assess correlation between brain lesions and clinical status with 1.5T and 3T magnetic resonance imaging (MRI). Methods: Brain MRI fluid-attenuated inversion-recovery (FLAIR) sequences were performed in 32 multiple sclerosis (MS) patients. Expanded Disability Status Scale (EDSS) score (mean ± standard deviation) was 2 ± 2.0 (range 0-8), disease duration 9.3 ± 8.0 (range .8-29) years. Results: FLAIR lesion volume (FLLV) at 3T was higher than at 1.5T (P= .01). Correlation between 1.5T FLLV and EDSS score was poor, while 3T FLLV correlated moderately and significantly (rs= .39, P= .03). When controlling for age and depression, correlations between FLLV and cognitive measures were significant at 1.5T for the Judgment of Line Orientation test (JLO) (rs=−.44, P= .05), the Symbol Digit Modalities Test (SDMT) (rs=−.49, P= .02), and the California Verbal Learning Test Delayed Free Recall (CVLT DR) (rs=−.44, P= .04). Correlations at 3T were also significant for these tests, but of greater magnitude: JLO (rs=−.70, P= .0005), SDMT (rs=−.73, P= .0001), CVLT DR (rs=−.061, P= .003). Additional significant correlations obtained only at 3T included the 2 second-paced auditory serial addition test (rs=−.55, P= .01), the Brief Visuospatial Memory Test-Delayed Free Recall (rs=−.56, P= .007), and the California Verbal Learning Test Total Recall (rs=−.42, P= .05). Conclusion: MRI at 3T may boost sensitivity and improve validity in MS brain lesion assessment.

Background: While disease categories (i.e. clinical phenotypes) of multiple sclerosis (MS) are established, there remains MRI heterogeneity among patients within those definitions. MRI-defined lesions and atrophy show only moderate inter-correlations, suggesting that they represent partly different processes in MS. We assessed the ability of MRI-based categorization of cerebral lesions and atrophy in individual patients to identify distinct phenotypes. Methods: We studied 175 patients with MS [age (mean ± SD) 42.7 ± 9.1 years, 124 (71%) women, Expanded Disability Status (EDSS) score 2.5 ± 2.3, n = 18 (10%) clinically isolated demyelinating syndrome (CIS), n = 115 (66%) relapsing-remitting (RR), and n = 42 (24%) secondary progressive (SP)]. Brain MRI measures included T2 hyperintense lesion volume (T2LV) and brain parenchymal fraction (to assess whole brain atrophy). Medians were used to create bins for each parameter, with patients assigned a low or high severity score. Results: Four MRI phenotype categories emerged: Type I = low T2LV/mild atrophy [n = 67 (38%); CIS = 14, RR = 47, SP = 6]; Type II = high T2LV/mild atrophy [n = 21 (12%); RR = 19, SP = 2]; Type III = low T2LV/high atrophy [n = 21 (12%); CIS = 4, RR = 16, SP = 1]; and Type IV = high T2LV/high atrophy [n = 66 (38%); RR = 33, SP = 33]. Type IV was the most disabled and was the only group showing a correlation between T2LV vs. BPF and MRI vs. EDSS score (all p < 0.05). Conclusions: We described MRI-categorization based on the relationship between lesions and atrophy in individual patients to identify four phenotypes in MS. Most patients have congruent extremes related to the degree of lesions and atrophy. However, many have a dissociation. Longitudinal studies will help define the stability of these patterns and their role in risk stratification.

Background and Purpose: VBM has been widely used to study GM atrophy in MS. MS lesions lead to segmentation and registration errors that may affect the reliability of VBM results. Improved segmentation and registration have been demonstrated by WM LI before segmentation. DARTEL appears to improve registration versus the USM. Our aim was to compare the performance of VBM-DARTEL versus VBM-USM and the effect of LI in the regional analysis of GM atrophy in MS. Materials and Methods: 3T T1 MR imaging scans were acquired from 26 patients with RRMS and 28 age-matched NC. LI replaced WM lesions with normal-appearing WM intensities before image segmentation. VBM analysis was performed in SPM8 by using DARTEL and USM with and without LI, allowing the comparison of 4 VBM methods (DARTEL + LI, DARTEL − LI, USM + LI, and USM − LI). Accuracy of VBM was assessed by using NMI, CC, and a simulation analysis. Results: Overall, DARTEL + LI yielded the most accurate GM maps among the 4 methods (highest NMI and CC, P < .001). DARTEL + LI showed significant GM loss in the bilateral thalami and caudate nuclei in patients with RRMS versus NC. The other 3 methods overestimated the number of regions of GM loss in RRMS versus NC. LI improved the accuracy of both VBM methods. Simulated data suggested the accuracy of the results provided from patient MR imaging analysis. Conclusions: We introduce a pipeline that shows promise in limiting segmentation and registration errors in VBM analysis in MS.

ABSTRACT BACKGROUND AND PURPOSE Two common approaches for measuring disease severity in multiple sclerosis (MS) are the clinical exam and brain magnetic resonance imaging (MRI) scan. Although most patients show similar disease severity on both measures, some patients have clinical/MRI dissociation. METHODS Subjects from a comprehensive care MS center who had a concurrent brain MRI, spinal cord MRI, clinical examination, and patient reported outcomes were classified into three groups based on the Expanded Disability Status Scale (EDSS) and cerebral T2 hyperintense lesion volume (T2LV). The first group was the low lesion load/high disability group (LL/HD) with T2LV < 2 ml and EDSS ≥ 3. The second group was the high lesion load/low disability group (HL/LD) with T2LV > 6 ml and EDSS ≤ 1.5. All remaining subjects were classified as not dissociated. The three groups were compared using regression techniques for unadjusted analyses and to adjust for age, disease duration, and gender. RESULTS Twenty‐two subjects were classified as LL/HD (4.1%; 95% CI: 2.6%, 6.2%), and 50 subjects were classified as HL/LD (9.4%; 95% CI: 7.0%, 12.2%). Subjects in the LL/HD group were more likely to have a progressive form of MS and had significantly lower physical quality of life in adjusted and unadjusted analysis. Subjects in HL/LD had significantly more gadolinium‐enhancing lesions, and subjects in the LL/HD group had significantly more cervical spinal cord lesions. CONCLUSIONS Our results indicate that dissociation may occur between physical disability and cerebral lesion volume in either direction in patients with MS. Type of MS, brain atrophy, and spinal cord lesions may help to bridge this dissociation.

Objective: To determine whether peripheral immune responses as measured by serum antigen arrays are linked to cerebral MRI measures of disease severity in multiple sclerosis (MS).

Methods: In this cross-sectional study, serum samples were obtained from patients with relapsing-remitting MS (n = 21) and assayed using antigen arrays that contained 420 antigens including CNS-related autoantigens, lipids, and heat shock proteins. Normalized compartment-specific global brain volumes were obtained from 3-tesla MRI as surrogates of atrophy, including gray matter fraction (GMF), white matter fraction (WMF), and total brain parenchymal fraction (BPF). Total brain T2 hyperintense lesion volume (T2LV) was quantified from fluid-attenuated inversion recovery images.

Results: We found serum antibody patterns uniquely correlated with BPF, GMF, WMF, and T2LV. Furthermore, we identified immune signatures linked to MRI markers of neurodegeneration (BPF, GMF, WMF) that differentiated those linked to T2LV. Each MRI measure was correlated with a specific set of antibodies. Strikingly, immunoglobulin G (IgG) antibodies to lipids were linked to brain MRI measures. Based on the association between IgG antibody reactivity and each unique MRI measure, we developed a lipid index. This comprised the reactivity directed against all of the lipids associated with each specific MRI measure. We validated these findings in an additional independent set of patients with MS (n = 14) and detected a similar trend for the correlations between BPF, GMF, and T2LV vs their respective lipid indexes.

Conclusions: We propose serum antibody repertoires that are associated with MRI measures of cerebral MS involvement. Such antibodies may serve as biomarkers for monitoring disease pathology and progression.