CLA-supplemented diet accelerates experimental colorectal cancer by inducing TGF-ß-producing macrophages and T cells.

Conjugated linoleic acid (CLA) has been shown to activate the nuclear receptor PPAR-γ and modulate metabolic and immune functions. Despite the worldwide use of CLA dietary supplementation, strong scientific evidence for its proposed beneficial actions are missing. We found that CLA-supplemented diet reduced mucosal damage and inflammatory infiltrate in the dextran sodium sulfate (DSS)-induced colitis model. Conditional deletion of PPAR-γ in macrophages from mice supplemented with CLA diet resulted in loss of this protective effect of CLA, suggesting a PPAR-γ-dependent mechanism mediated by macrophages. However, CLA supplementation significantly worsened colorectal tumor formation induced by azoxymethane and DSS by inducing macrophage and T-cell-producing TGF-ß via PPAR-γ activation. Accordingly, either macrophage-specific deletion of PPAR-γ or in vivo neutralization of latency-associated peptide (LAP, a membrane-bound TGF-ß)-expressing cells abrogated the protumorigenic effect of CLA. Thus, the anti-inflammatory properties of CLA are associated with prevention of colitis but also with development of colorectal cancer.

Predictors of hematological abnormalities in multiple sclerosis patients treated with fingolimod and dimethyl fumarate and impact of treatment switch on lymphocyte and leukocyte count.

BACKGROUND: There is limited data regarding the predictors of hematological abnormalities in multiple sclerosis (MS) patients treated with dimethyl fumarate (DMF) or fingolimod (FNG), and the impact of treatment switch on lymphocyte and leukocyte count METHODS: We identified 405 patients on DMF and 300 patients on FNG (treatment duration: at least 12 month) within a large prospective study of MS patients conducted at the Partners MS Center, Brigham and Women's Hospital (CLIMB study) between Jan 2011 to Feb 2016. Patients had complete blood counts with differentials at baseline and every 6 months while on treatment. Most participants had a clinical visit with complete neurologic examinations every 6 months and brain MRI scan every 12 months. T cell subset profile was available for subgroup of patients (n = 116). RESULTS: In the FNG group, the risk of developing lymphopenia grade 4 (< 200) was higher in female patients (p = 0.0117) and those who were previously treated with natalizumab (p = 0.0116), while the risk of lymphopenia grade 3b+4 (< 350) was higher in female patients (p = 0.0009). DMF treated patients with lower baseline lymphocyte count had a higher chance of developing lymphopenia grade 2 (< 800) (p < 0.0001) or 2+3 (< 500) (p < 0.0001). We examined the effect of treatment switch between DMF and FNG. No significant recovery in lymphocyte and leukocyte count was observed after treatment switches. Reduced dosing of FNG in patients with lymphopenia led to increase in lymphocyte count but also increased disease activity in 25% of patients. CONCLUSION: Female sex and prior exposure to natalizumab increased the probability of lymphopenia on FNG, while low absolute lymphocyte count was associated with increased risk of lymphopenia on DMF. Parallel switch did not lead to recovery from hematological abnormalities. Long-term studies with larger number of patients are required to confirm our findings and to establish guidelines for prediction and management of hematological abnormalities.

Brain MRI of nasal MOG therapeutic effect in relapsing-progressive EAE.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) considered to be a T cell-mediated autoimmune disease. Mucosally administered antigens induce regulatory T cells that secrete anti-inflammatory cytokines at the anatomic site where the mucosally administered Ag is located. We have previously reported in a mouse model of stroke that nasal treatment with MOG35-55 peptide reduces ischemic infarct size and improves behavior, by inducing IL-10-secreting T cells. We have also demonstrated that an experimental autoimmune encephalomyelitis (EAE) model in non-obese diabetic (NOD) mice leads to a relapsing progressive disease and that brain lesions can be visualized noninvasively by magnetic resonance imaging (MRI). Here, we investigated whether nasal treatment with 25µg of MOG35-55 after the first attack affects clinical progression and MRI outcome in the NOD model. We found that nasal MOG35-55 treatment administered three times after the first attack and then weekly reduced both the peak clinical disease score and clinical score during remission. Pathology revealed less infiltration of cells and reduction in white-matter damage as measured by Luxol blue staining in treated animals. This model is unique in that there are lesions in the corpus callosum, external capsule, fimbria, internal capsule and thalamus, which is analogous to what is observed in MS. MRI of individual animals using fractional anisotropy (FA) and T1-gadolinum (T1-Gd) imaging was able to identify lesions in all of these anatomic areas, and we found lower levels of brain pathology by MRI in treated mice with both methods. Our results indicate a beneficial effect of nasal MOG on relapsing-progressive EAE and demonstrate that non-invasive MRI imaging may be used to monitor treatment of ongoing disease in this model for testing new therapies for MS.

The impact of lesion in-painting and registration methods on voxel-based morphometry in detecting regional cerebral gray matter atrophy in multiple sclerosis.

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.

Antigen microarrays identify CNS-produced autoantibodies in RRMS.

OBJECTIVE: Multiple sclerosis (MS) is characterized by the local production of antibodies in the CNS and the presence of oligoclonal bands in the CSF. Antigen arrays allow the study of antibody reactivity against a large number of antigens using small volumes of fluid with greater sensitivity than ELISA. We investigated whether there were unique autoantibodies in the CSF of patients with MS as measured by antigen arrays and whether these antibodies differed from those in serum. METHODS: We used antigen arrays to analyze the reactivity of antibodies in matched serum and CSF samples of 20 patients with untreated relapsing-remitting MS (RRMS), 26 methylprednisolone-treated patients with RRMS, and 20 control patients with other noninflammatory neurologic conditions (ONDs) against 334 different antigens including heat shock proteins, lipids, and myelin antigens. RESULTS: We found different antibody signatures in matched CSF and serum samples The targets of these antibodies included epitopes of the myelin antigens CNP, MBP, MOBP, MOG, and PLP (59%), HSP60 and HSP70 (38%), and the 68-kD neurofilament (3%). The antibody response in patients with MS was heterogeneous; CSF antibodies in individual patients reacted with different autoantigens. These autoantibodies were locally synthesized in the CNS and were of the immunoglobulin G class. Finally, we found that treatment with steroids decreased autoantibody reactivity, epitope spreading, and intrathecal autoantibody synthesis. CONCLUSIONS: These studies provide a new avenue to investigate the local antibody response in the CNS, which may serve as a biomarker to monitor both disease progression and response to therapy in MS.

Demographic and clinical characteristics of malignant multiple sclerosis.

OBJECTIVE: Multiple sclerosis (MS) that causes patients to require assistance for ambulation (Expanded Disability Status Scale [EDSS] ≥6) within 5 years from symptom onset is generally termed malignant. Malignant status can be transient (TM) or sustained until year 5 (SM). We studied the incidence, predictors, and demographic and clinical characteristics of malignant MS. METHODS: Patients with symptom onset in 2002-2005 and 5-year follow-up were selected from the Partners Multiple Sclerosis Center database. Patients with TM were further grouped into TM and SM. The mechanism of reaching EDSS 6 (relapse- vs progression-related) was determined. RESULTS: A total of 487 patients were included (17 TM, 42 SM). The incidence proportion of ever malignant (EM=SM+TM) was estimated as 12.11% and SM as 8.62%. Patients with older age at onset, male gender, and positive smoking history were more likely to become SM. Compared to nonmalignant patients, the proportion of progressive-onset MS in the SM group was significantly higher, but not different in TM. Within relapsing-onset patients, most of TM, and a smaller proportion of the SM group had a relapse-related as opposed to progression-related mechanism. The final model predictors for EM vs nonmalignant were older age at onset, motor symptoms at onset, and progressive disease onset. Within the malignant patients, predictors of TM vs SM were younger age and brainstem symptoms at onset. CONCLUSIONS: Over 10% of patients with MS experience a malignant course as defined above. Some demographic and clinical factors are found to predict a malignant outcome. MS in patients who reach a high EDSS based on disease progression is more likely to remain malignant.

HLA (A-B-C and -DRB1) alleles and brain MRI changes in multiple sclerosis: a longitudinal study.

Several major histocompatibility complex (MHC) alleles have been postulated to influence the susceptibility to multiple sclerosis (MS), as well as its clinical/radiological course. In this longitudinal observation, we further explored the impact of human leukocyte antigen (HLA) class I/II alleles on MS outcomes, and we tested the hypothesis that HLA DRB1*1501 might uncover different strata of MS subjects harboring distinct MHC allele associations with magnetic resonance imaging (MRI) measures. Five hundred eighteen MS patients with two-digit HLA typing and at least one brain MRI were recruited for the study. T2-weighted hyperintense lesion volume (T2LV) and brain parenchymal fraction (BPF) were acquired at each time point. The association between allele count and MRI values was determined using linear regression modeling controlling for age, disease duration and gender. Analyses were also stratified by the presence/absence of HLA DRB1*1501. HLA DRB1*04 was associated with higher T2LV (P=0.006); after stratification, its significance remained only in the presence of HLA DRB1*1501 (P=0.012). The negative effect of HLA DRB1*14 on T2LV was exerted in DRB1*1501-negative group (P=0.012). Longitudinal analysis showed that HLA DRB1*10 was significantly protective on T2LV accrual in the presence of HLA DRB1*1501 (P=0.002). Although the majority of our results did not withstand multiple comparison correction, the differential impact of several HLA alleles in the presence/absence of HLA DRB1*1501 suggests that they may interact in determining the different phenotypic expressions of MS.

Seasonal prevalence of MS disease activity.

OBJECTIVE: This observational cohort study investigated the seasonal prevalence of multiple sclerosis (MS) disease activity (likelihood and intensity), as reflected by new lesions from serial T2-weighted MRI, a sensitive marker of subclinical disease activity. METHODS: Disease activity was assessed from the appearance of new T2 lesions on 939 separate brain MRI examinations in 44 untreated patients with MS. Likelihood functions for MS disease activity were derived, accounting for the temporal uncertainty of new lesion occurrence, individual levels of disease activity, and uneven examination intervals. Both likelihood and intensity of disease activity were compared with the time of year (season) and regional climate data (temperature, solar radiation, precipitation) and among relapsing and progressive disease phenotypes. Contrast-enhancing lesions and attack counts were also compared for seasonal effects. RESULTS: Unlike contrast enhancement or attacks, new T2 activity revealed a likelihood 2-3 times higher in March-August than during the rest of the year, and correlated strongly with regional climate data, in particular solar radiation. In addition to the likelihood or prevalence, disease intensity was also elevated during the summer season. The elevated risk season appears to lessen for progressive MS and occur about 2 months earlier. CONCLUSION: This study documents evidence of a strong seasonal pattern in subclinical MS activity based on noncontrast brain MRI. The observed seasonality in MS disease activity has implications for trial design and therapy assessment. The observed activity pattern is suggestive of a modulating role of seasonally changing environmental factors or season-dependent metabolic activity.

HLA B*44: protective effects in MS susceptibility and MRI outcome measures.

OBJECTIVE: In addition to the main multiple sclerosis (MS) major histocompatibility complex (MHC) risk allele (HLA DRB1*1501), investigations of the MHC have implicated several class I MHC loci (HLA A, HLA B, and HLA C) as potential independent MS susceptibility loci. Here, we evaluate the role of 3 putative protective alleles in MS: HLA A*02, HLA B*44, and HLA C*05. METHODS: Subjects include a clinic-based patient sample with a diagnosis of either MS or a clinically isolated syndrome (n = 532), compared to subjects in a bone marrow donor registry (n = 776). All subjects have 2-digit HLA data. Logistic regression was used to determine the independence of each allele's effect. We used linear regression and an additive model to test for correlation between an allele and MRI and clinical measures of disease course. RESULTS: After accounting for the effect of HLA DRB1*1501, both HLA A*02 and HLA B*44 are validated as susceptibility alleles (p(A*02) 0.00039 and p(B*44) 0.00092) and remain significantly associated with MS susceptibility in the presence of the other allele. Although A*02 is not associated with MS outcome measures, HLA B*44 demonstrates association with a better radiologic outcome both in terms of brain parenchymal fraction and T2 hyperintense lesion volume (p = 0.03 for each outcome). CONCLUSION: The MHC class I alleles HLA A*02 and HLA B*44 independently reduce susceptibility to MS, but only HLA B*44 appears to influence disease course, preserving brain volume and reducing the burden of T2 hyperintense lesions in subjects with MS.

Regional white matter atrophy--based classification of multiple sclerosis in cross-sectional and longitudinal data.

BACKGROUND AND PURPOSE: The different clinical subtypes of multiple sclerosis (MS) may reflect underlying differences in affected neuroanatomic regions. Our aim was to analyze the effectiveness of jointly using the inferior subolivary medulla oblongata volume (MOV) and the cross-sectional area of the corpus callosum in distinguishing patients with relapsing-remitting multiple sclerosis (RRMS), secondary-progressive multiple sclerosis (SPMS), and primary-progressive multiple sclerosis (PPMS). MATERIALS AND METHODS: We analyzed a cross-sectional dataset of 64 patients (30 RRMS, 14 SPMS, 20 PPMS) and a separate longitudinal dataset of 25 patients (114 MR imaging examinations). Twelve patients in the longitudinal dataset had converted from RRMS to SPMS. For all images, the MOV and corpus callosum were delineated manually and the corpus callosum was parcellated into 5 segments. Patients from the cross-sectional dataset were classified as RRMS, SPMS, or PPMS by using a decision tree algorithm with the following input features: brain parenchymal fraction, age, disease duration, MOV, total corpus callosum area and areas of 5 segments of the corpus callosum. To test the robustness of the classification technique, we applied the results derived from the cross-sectional analysis to the longitudinal dataset. RESULTS: MOV and central corpus callosum segment area were the 2 features retained by the decision tree. Patients with MOV >0.94 cm(3) were classified as having RRMS. Patients with progressive MS were further subclassified as having SPMS if the central corpus callosum segment area was <55.12 mm(2), and as having PPMS otherwise. In the cross-sectional dataset, 51/64 (80%) patients were correctly classified. For the longitudinal dataset, 88/114 (77%) patient time points were correctly classified as RRMS or SPMS. CONCLUSIONS: Classification techniques revealed differences in affected neuroanatomic regions in subtypes of multiple sclerosis. The combination of central corpus callosum segment area and MOV provides good discrimination among patients with RRMS, SPMS, and PPMS.

Natalizumab treatment is associated with peripheral sequestration of proinflammatory T cells.

BACKGROUND: Natalizumab is an antibody directed against integrin alpha4 that reduces disease activity in patients with multiple sclerosis (MS) by blocking migration of T and B cells into the CNS. The goal of this study was to characterize the effects of natalizumab treatment on cytokine production and expression of activation markers, costimulatory molecules, and trafficking determinants on CD4+ and CD8+ T cells. METHODS: In a longitudinal study, we investigated the expression of surface makers and cytokine expression on peripheral blood lymphocytes from 28 patients with MS who started natalizumab treatment and were followed for 1 year. A mixed effects model was used to compare pretreatment to on-treatment measurements. RESULTS: The frequency of CD4+ T cells producing interferon-gamma, tumor necrosis factor, and interleukin (IL)-17 upon anti-CD3 stimulation increased 6 months after initiation of natalizumab treatment and remained elevated throughout the follow-up. The frequency of CD4+ T cells expressing CD25, HLA-DR, and CCR6 ex vivo was increased at one or more time points during treatment. Among CD8+ T cells, the frequency of cells producing IL-2 and IL-17 after stimulation was increased during natalizumab treatment, as was the frequency of CD8+ T cells expressing CD58 and CCR5 ex vivo. The increase in the frequency of activated cells could not be replicated by in vitro exposure to natalizumab. CONCLUSION: Natalizumab treatment increases the percentage of activated leukocytes producing proinflammatory cytokines in blood, presumably due to sequestration of activated cells in the peripheral circulation.

Incidence and factors associated with treatment failure in the CLIMB multiple sclerosis cohort study.

OBJECTIVE: To determine the rate of treatment failure in patients outside of a controlled treatment trial and to ascertain the factors physicians used to make this decision. METHODS: One hundred and thirty four patients with the diagnosis of relapsing-remitting (RR) multiple sclerosis (MS) or clinically isolated symptom (CIS) enrolled in the CLIMB study (Comprehensive Longitudinal Investigation of Multiple Sclerosis at the Brigham and Women's Hospital) were treated with either interferon beta or glatiramer acetate as their initial treatment for MS. RESULTS: The probability of failing initial treatment within 3 years was 30%. Clinical activity, defined as relapses and/or progression in disability, determined treatment failure in 35.7% (n=10) of nonresponders. New T2 hyperintense or gadolinium-enhancing lesions on MRI was used to define treatment failure in 28.6% (n=8) and new MRI lesions were used in combination with clinical activity in 35.7% (n=10). Treatment failures had a higher T2 hyperintense lesion volume (p=0.015) and number of gadolinium-enhancing lesions (p=0.0001) on the enrollment MRI than responders. CONCLUSIONS: These observations demonstrate that treating physicians use both clinical and MRI parameters to define a response to treatment and initiation of a treatment change and that baseline MRI identified those with increased risk of treatment failure.

Suppression of murine SLE by oral anti-CD3: inducible CD4+CD25-LAP+ regulatory T cells control the expansion of IL-17+ follicular helper T cells.

Lupus is an antibody-mediated autoimmune disease. The production of pathogenic, class switched and affinity maturated autoantibodies in lupus is dependent on T cell help. A potential mechanism of disease pathogenesis is a lack of control of pathogenic T helper cells by regulatory T cells in lupus. It has been repeatedly shown that the naturally occurring CD4+CD25+ regulatory T cells in lupus prone mice and patients with SLE are defective both in frequency and function. Thus, the generation of inducible regulatory T cells that can control T cell help for autoantibody production is a potential avenue for the treatment of SLE. We have found that oral administration of anti-CD3 monoclonal antibody attenuated lupus development and arrested on-going disease in lupus prone SNF1 mice. Oral anti-CD3 induces a CD4+CD25-LAP+ regulatory T cell that secrets high levels of TGF-beta and suppresses in vitro in TFG-beta-dependent fashion. Animals treated with oral anti-CD3 had less glomerulonephritis and diminished levels of anti-dsDNA autoantibodies. Oral anti-CD3 led to a downregulation of IL-17+CD4+ICOS-CXCR5+ follicular helper T cells, CD138+ plasma cells and CD73+ mature memory B cells. Our results show that oral anti-CD3 induces CD4+CD25-LAP+ regulatory T cells that suppress lupus in mice and is associated with downregulation of T cell help for autoantibody production.

Daclizumab in treatment of multiple sclerosis patients.

BACKGROUND: Daclizumab is a humanized monoclonal antibody (mAb) that blocks the interleukin-2 receptor alpha subunit (IL-2R-alpha chain; CD25) expressed on activated T cells leading to the inhibition of T-cell expansion, thus strongly reduces brain inflammation in patients with multiple sclerosis (MS). Another mechanism is significant expansion of CD56 (bright) natural killer (NK) cells that in turn inhibit T-cell survival. OBJECTIVE: At the Partners MS center, we have been using Daclizumab in an open-label fashion in patients who fail first line therapy or non-standard immunosuppressive treatment. Our aim was to assess its safety and tolerability in our patient population.

CTLA4Ig treatment in patients with multiple sclerosis: an open-label, phase 1 clinical trial.

BACKGROUND: The modulation of costimulatory pathways represents an original therapeutic approach to regulate T cell-mediated autoimmune diseases by preventing or reducing autoantigen-driven T-cell activation in humans. Autoreactive CD4(+) T cells play a critical role in initiating the immune response leading to the chronic inflammation and demyelination characteristic of multiple sclerosis (MS). METHODS: We used IV infusions of CTLA4Ig to block the CD28/B7 T-cell costimulatory pathway in a phase 1 dose-escalation study in MS. Sixteen patients with relapsing-remitting MS received a single CTLA4Ig infusion and were monitored for up to 3 months after treatment. In an extension study, four additional subjects received four doses of CTLA4Ig. RESULTS: CTLA4Ig was well tolerated in patients with MS, and most adverse events were rated as mild. Immunologic assessment of the patients showed a reduction in myelin basic protein (MBP) proliferation within 2 months of infusion and decreased interferon-gamma production by MBP-specific lines. CONCLUSIONS: Inhibiting costimulatory molecule interactions by using CTLA4Ig seems safe in multiple sclerosis (MS), and the immunologic effects suggest that it may be a promising approach to regulate the inflammatory process associated with MS.

Epilepsy surgery in tuberous sclerosis complex: early predictive elements and outcome.

AIM: The aim of the study was to evaluate the surgical treatment of epilepsy and detection of possible early surgery predictive elements in patients with tuberous sclerosis complex (TSC). MATERIALS AND METHODS: Forty-two TSC patients with epilepsy were selected and divided into two main groups: definite and fruste forms. Definite forms were divided into different groups: patients with pharmacologically controlled epilepsy, patients with pharmacoresistant epilepsy excluded from surgery after an extensive presurgical assessment, and patients with a pharmacoresistant epilepsy who underwent surgery. We compared the definite TSC groups to identify elements that predict surgical candidacy. Second, we compared all operated patients to assess surgical outcome. CONCLUSION: We found several factors that could predict a surgical intervention even if identification of patients with refractory epilepsy who can benefit from surgery is an evolving process. Also, several positive factors for good surgical outcome were identified. Patients with the fruste form had excellent surgical outcome.

Medulla oblongata volume: a biomarker of spinal cord damage and disability in multiple sclerosis.

BACKGROUND AND PURPOSE: While brain MR imaging is routinely performed, the MR imaging assessment of spinal cord pathology in multiple sclerosis (MS) is less frequent in clinical practice. The purpose of this study was to determine whether measurements of medulla oblongata volume (MOV) on routine brain MR imaging could serve as a biomarker of spinal cord damage and disability in MS. MATERIALS AND METHODS: We identified 45 patients with MS with both head and cervical spinal cord MR imaging and 29 age-matched and sex-matched healthy control subjects with head MR imaging. Disability was assessed by the expanded disability status scale (EDSS) and ambulation index (AI). MOV and upper cervical cord volume (UCCV) were manually segmented; semiautomated segmentation was used for brain parenchymal fraction (BPF). These measures were compared between groups, and linear regression models were built to predict disability. RESULTS: In the patients, MOV correlated significantly with UCCV (r = 0.67), BPF (r = 0.45), disease duration (r = -0.64), age (r = -0.47), EDSS score (r = -0.49) and AI (r = -0.52). Volume loss of the medulla oblongata was -0.008 cm(3)/year of age in patients with MS, but no significant linear relationship with age was found for healthy control subjects. The patients had a smaller MOV (mean +/- SD, 1.02 +/- 0.17 cm(3)) than healthy control subjects (1.15 +/- 0.15 cm(3)), though BPF was unable to distinguish between these 2 groups. MOV was smaller in patients with progressive MS (secondary- progressive MS, 0.88 +/- 0.19 cm(3) and primary-progressive MS, 0.95 +/- 0.30 cm(3)) than in patients with relapsing-remitting MS (1.08 +/- 0.15 cm(3)). A model including both MOV and BPF better predicted AI than BPF alone (P = .04). Good reproducibility in MOV measurements was demonstrated for intrarater (intraclass correlation coefficient, 0.97), interrater (0.79), and scan rescan data (0.81). CONCLUSION: MOV is associated with disability in MS and can serve as a biomarker of spinal cord damage.

MR imaging intensity modeling of damage and repair in multiple sclerosis: relationship of short-term lesion recovery to progression and disability.

BACKGROUND AND PURPOSE: Formation of lesions in multiple sclerosis (MS) shows pronounced short-term fluctuation of MR imaging hyperintensity and size, a qualitatively known but poorly characterized phenomenon. With the use of time-series modeling of MR imaging intensity, our study relates the short-term dynamics of new T2 lesion formation to those of contrast enhancement and markers of long-term progression of disease. MATERIALS AND METHODS: We analyzed 915 examinations from weekly to monthly MR imaging in 40 patients with MS using a time-series model, emulating 2 opposing processes of T2 prolongation and shortening, respectively. Patterns of activity, duration, and residual hyperintensity within new T2 lesions were measured and evaluated for relationships to disability, atrophy, and clinical phenotype in long-term follow-up. RESULTS: Significant T2 activity was observed for 8 to 10 weeks beyond contrast enhancement, which suggests that T2 MR imaging is sensitive to noninflammatory processes such as degeneration and repair. Larger lesions showed longer subacute phases but disproportionally more recovery. Patients with smaller average peak lesion size showed trends toward greater disability and proportional residual damage. Higher rates of disability or atrophy were associated with subjects whose lesions showed greater residual hyperintensity. CONCLUSION: Smaller lesions appeared disproportionally more damaging than larger lesions, with lesions in progressive MS smaller and of shorter activity than in relapsing-remitting MS. Associations of lesion dynamics with rates of atrophy and disability and clinical subtype suggest that changes in lesion dynamics may represent a shift from inflammatory toward degenerative disease activity and greater proximity to a progressive stage, possibly allowing staging of the progression of MS earlier, before atrophy or disability develops.

Cognitive dysfunction in patients with clinically isolated syndromes or newly diagnosed multiple sclerosis.

Cognitive dysfunction is common in patients with multiple sclerosis (MS), and has been associated with MRI measures of lesion burden and atrophy. Little is known about the prevalence of cognitive impairment in patients with early MS. The associations between cognitive impairment and MRI measures of disease severity early in the disease course are also unclear. This study used a brief battery of cognitive tests to determine the prevalence and pattern of cognitive impairment in patients with clinically isolated syndromes or newly diagnosed MS. The associations between cognitive impairment and MRI measures of disease severity early in the disease course were also examined. Ninety-two patients with clinically isolated syndromes or the diagnosis of MS within the last 3 years participating in the CLIMB study underwent a neurologic examination, neuropsychological evaluation and MRI at 1.5 T. Forty-nine percent of patients were impaired on one or more cognitive measures. There were no significant correlations between cognitive scores and MRI measures of disease severity including total T2 lesion volume, normal appearing white matter volume, grey matter volume, and brain parenchymal fraction. These findings suggest that cognitive impairment may predate the appearance of gross structural abnormalities on MRI and serve as an early marker of disease activity in MS.

Predicting short-term disability in multiple sclerosis.

OBJECTIVE: To develop covariate specific short-term disability curves to demonstrate the probability of progressing by Expanded Disability Status Scale (EDSS) at semiannual visits. METHODS: Semiannual EDSS scores were prospectively collected in 218 relapsing-remitting (RR) and clinically isolated syndrome (CIS) patients as part of the Comprehensive Longitudinal Investigation of Multiple Sclerosis at the Brigham and Women's Hospital (CLIMB) study. Baseline brain parenchymal fraction (BPF) and T2 lesion volume were available on 205 patients. A partial proportional odds model determined the influence of covariates on the change in EDSS score at subsequent visits. A discrete second order Markov transitional model was fit and generated a probability matrix for each subject; the 6-month probabilities of EDSS change were graphically represented. RESULTS: The univariate analysis demonstrated the lowest baseline BPF quartile (OR 1.99; p = 0.0203) and the highest T2 lesion volume quartile (OR 2.19; p = 0.0130) were associated with progression in EDSS. Covariate specific disability curves demonstrated the effect of BPF and T2 lesion volume on short-term progression. In subjects with a 6-month EDSS of 2, the probability of a sustained progression of an EDSS of 3 within 3 years was 0.277 for a subject with low BPF and a high T2 lesion volume vs 0.055 for a subject with high BPF and a low T2 lesion volume. CONCLUSIONS: Markov transitional models allow for the comparison of covariate specific short-term disability changes among groups of patients with multiple sclerosis.