Secondary Progressive Patients Research Articles

Matrix metalloproteinases and their tissue inhibitors as markers of disease subtype and response to interferon-beta therapy in relapsing and secondary-progressive multiple sclerosis patients.

Matrix metalloproteinases (MMPs) have recently been implicated in the pathogenesis of multiple sclerosis. Their suggested role includes the disruption of the blood-brain barrier, immune cell transmigration into the central nervous system, and myelin degradation. The present study characterized the mRNA level of a wide spectrum of MMPs and tissue inhibitors of metalloproteinases (TIMPs) expressed by peripheral blood leukocytes from relapsing-remitting (n = 16) and secondary-progressive (n = 12) multiple sclerosis patients. The expression of the same MMPs and TIMPs was evaluated also in a prospective 12-month follow-up of 6 patients randomly chosen from each of the 2 groups during interferon beta-1a treatment. Reverse transcription-polymerase chain reaction assessment demonstrated elevated levels of MT1-MMP and MMP-7 mRNA levels in both groups of patients, and no significant differences in MMP-9 levels, compared with healthy controls. Divergent expression of MMP-2 between relapsing-remitting and secondary-progressive patients compared with controls was observed. Interferon-beta treatment was associated with significant suppression of MMP-9 and MMP-7 mRNA in relapsing-remitting patients, though no significant changes were observed in the secondary-progressive group. These results contribute to the understanding of the IFN-beta-mediated immunomodulatory and therapeutic effects in multiple sclerosis patients and also support evidence for distinct immune mechanism(s) underlying relapsing-remitting versus secondary-progressive multiple sclerosis. The study also suggests that MMPs may be considered as potential biomarkers for response to treatment as well as targets for immunotherapy in multiple sclerosis.

Regional brain atrophy is associated with physical disability in multiple sclerosis: semiquantitative magnetic resonance imaging and relationship to clinical findings.

Brain atrophy may occur early in the course of multiple sclerosis (MS) and may be associated with disability. Brain magnetic resonance imaging (MRI) of 114 MS patients (group A) were analyzed for regional atrophy (vs age-/gender-matched controls) and T1 and T2 lesions using 4-point rating systems. Thirty-five separate patients (group B) were analyzed for cortical atrophy (ordinal scale), third ventricular width, and total T2 hyperintense lesion volume (computer assisted). In group A, regression modeling indicated that inferior frontal atrophy (P = .0003) and T2 lesions in the pons (P = .02) predicted physical disability (Expanded Disability Status Scale [EDSS] score). Secondary progressive (SP) versus relapsing patients were predicted by inferior parietal (P = .002), superior parietal (P = .006), temporal (P = .008), inferior frontal (P = .01), superior frontal (P = .01), cerebellum (P = .01), occipital (P = .01), and midbrain (P = .02) atrophy. SP patients were also predicted by total atrophy (P = .01) and third ventricular enlargement (P = .03) but not T1 or T2 lesions. In group B, the regression model predicting EDSS score included only superior frontal atrophy (r = 0.515, P = .002). Mean kappa coefficients of ordinal ratings were 0.9 (intraobserver) and 0.8 (interobserver). Ordinal ratings correlated well with quantitative assessments. The authors conclude that brain atrophy is closely associated with physical disability and clinical course in MS patients and can be appreciated using a semiquantitative MRI regional rating system.

Information Processing Efficiency in Patients with Multiple Sclerosis

Reduced information processing efficiency, consequent to impaired neural transmission, has been proposed as underlying various cognitive problems in patients with Multiple Sclerosis (MS). This study employed two measures developed from experimental psychology that control for the potential confound of perceptual-motor abnormalities (Salthouse, Babcock, & Shaw, 1991; Sternberg, 1966, 1969) to assess the speed of information processing and working memory capacity in patients with mild to moderate MS. Although patients had significantly more cognitive complaints than neurologically intact matched controls, their performance on standard tests of immediate memory span did not differ from control participants and their word list learning was within normal limits. On the experimental measures, both relapsing-remitting and secondary-progressive patients exhibited significantly slowed information processing speed relative to controls. However, only the secondary-progressive patients had an additional decrement in working memory capacity. Depression, fatigue, or neurologic disability did not account for performance differences on these measures. While speed of information processing may be slowed early in the disease process, deficits in working memory capacity may appear only as there is progression of MS. It is these latter deficits, however, that may underlie the impairment of new learning that patients with MS demonstrate.

Fatigue in multiple sclerosis: relationship to depression, disability, and disease pattern.

In order to investigate the associations between fatigue and depression, disability, and disease subtype, 207 individuals with clinically definite Multiple Sclerosis (MS) were administered the Fatigue Severity Scale and the Zung Self-rating Depression Scale during a regular clinic appointment. Their current level of disability was established using the Expanded Disability Status Scale. Fatigue and depression were highly correlated (r=0.58), even when the depression measure was corrected for items overlapping with fatigue and other symptoms or consequences of MS (r=0.44). Fatigue and disability were also correlated (r=0.33). Multiple regression revealed that both depressed mood and disability were significant predictors of fatigue, together accounting for approximately 23% of the variance in patients' self-reported fatigue. The combined groups of primary progressive (n=45) and secondary progressive patients (n=25) appeared to have higher fatigue scores than relapsing-remitting patients (n=137). However, an analysis of covariance revealed that this apparent difference was in fact attributable almost exclusively to differences in disability among the three subtypes of MS. Other reports of differences in fatigue between subtypes of MS should be re-examined in light of this finding.

Evaluation of the clinical utility of cerebrospinal fluid (CSF) indices of inflammatory markers in multiple sclerosis.

Accumulating evidence indicates significant heterogeneity in MS and soluble (s) adhesion molecules are postulated as markers of disease activity. We sought to evaluate intrathecal production of these and other molecules across the clinical spectrum of MS. CSF indices of IgG, sICAM-1, sVCAM-1, sE-selectin and sCD30 were calculated in 17 primary progressive (PPMS) patients, 15 secondary progressive patients (SPMS), 28 relapsing-remitting patients in relapse (RRMSR) and 14 RRMS patients in remission (RRMSNR) using commercially available ELISA kits. Patients had not received any immunomodulating therapy within the previous 6 months. MS patients were compared with 44 patients with non-inflammatory neurological diseases (NINDs). The most sensitive CSF index at a 90% level of specificity was for IgG which had 93% sensitivity in RRMSR and 92% sensitivity in RRMSNR. Corresponding sensitivity in PPMS and SPMS was 71% and 73% respectively. None of the other indices had sensitivity >50% apart from sVCAM-1 (64% in RRMSR and 52% RRMSNR) and sCD30 (53% in PPMS). Unsurprisingly the strongest association in MS was with the intrathecal production of IgG. Similar results in PPMS and SPMS may reflect comparable rates of progression in these 2 groups. Of the other molecules only intrathecal sVCAM-1 production is significantly associated with MS and only in relapsing-remitting disease.

MS functional composite: relation to disease phenotype and disability strata.

The MS Functional Composite (MSFC), a recently developed outcome measure for clinical trials, was applied to 240 patients with MS to explore its utility in different subgroups of MS and for comparison with the Expanded Disability Status Scale (EDSS). Three clinical dimensions were examined: arm/hand function, leg function/ambulation, and cognition. Predictions of relative scores on the MSFC and its components in three major MS phenotypes (relapsing-remitting, primary progressive, and secondary progressive) and three strata of disability were developed and tested. Also, correlations with EDSS were calculated and the effect of an external reference population was assessed. Mean MSFC score was positive in the relapsing-remitting (0.4) and mildly disabled (0.4) groups and negative in the secondary progressive (-0.3), primary progressive (-0.4), and moderately (-0.07) and severely disabled (-1.0) groups. The correlation between EDSS and MSFC was strong (-0.68). EDSS correlated strongly with ambulation in secondary and primary progressive patients and severely disabled patients, moderately with arm/hand function for all analyzed groups, and not at all with cognition. Comparison with an external reference population showed changes in MSFC- and Z-scores, but did not result in altered differences between the subgroups. Our prospective study in subgroups of MS confirmed and extended the construct validity of the MSFC. The MSFC also showed good concurrent validity with the EDSS, and includes information about cognition.

The natural history of multiple sclerosis: a geographically based study. 7. Progressive-relapsing and relapsing-progressive multiple sclerosis: a re-evaluation.

Classifications of multiple sclerosis subtypes have been largely based on clinical phenomenology. Nevertheless, definitions of relapse, remission and progression have been imprecise. Recently an international consensus group, as part of a reclassification of disease subtypes, recommended dropping the term 'relapsing-progressive' (RP) and retaining the term 'progressive-relapsing' (PR) multiple sclerosis. The term 'RP' multiple sclerosis had been applied when the early course combined both relapses and progression and was believed to identify some patients with a worse than average outcome. The PR group consisted of patients with primary progressive disease who later in their course developed relapses. Since the terminology has been largely arbitrary, we have evaluated the validity of the terms 'RP' and 'PR' multiple sclerosis in the context of long-term outcome within a large population-based cohort of progressive multiple sclerosis patients seen at the London Multiple Sclerosis Clinic (Canada) between 1972 and 1984. Mean follow-up of the entire cohort was 25 years. Designation of RP multiple sclerosis did identify a more rapidly progressive subgroup. To realign these natural history data with consensus recommendations, these patients were reassigned to secondary progressive (SP) or to primary progressive (PP) multiple sclerosis, with progression defined as at least 1 year of progressive deterioration. PP multiple sclerosis patients with relapses after a year were designated as having PR multiple sclerosis. Relapses in primary progressive multiple sclerosis occurred in 27.8% of patients at some point even two to three decades after onset. In general these relapses were mild and remitting, but served to blur the distinction between progressive and relapsing-remitting disease. The long-term outcomes of time to Kurtzke disability scores (DSS) of 3, 6, 8 and 10 were compared among the progressive subtypes. Times to these disability end-points and to death were not different between PR and PP multiple sclerosis. Survival curves for progressive patients have been amended to incorporate the reassignment of PR multiple sclerosis patients into the PP group and the RP multiple sclerosis patients into the PP and SP subgroups. The time to reach DDS 3, 6, 8 and 10 for a population-based cohort of primary and secondary progressive patients resulting from the elimination of the categories of RP multiple sclerosis and PR multiple sclerosis has been established. These results provide justification for retaining only PP and SP multiple sclerosis as the subgroups of progressive disease.

Localized proton magnetic resonance spectroscopy in relapsing remitting versus secondary progressive multiple sclerosis.

To determine the efficacy of MRS in discriminating between relapsing remitting (RR) and secondary progressive (SP) MS. MRS at long and short echo times was carried out in 104 patients with MS stratified for clinical course (RR or SP), and the results were compared with those of 15 control subjects. Normal-appearing white matter (NAWM) was studied in 55 patients, and a high-T2-signal area on MRI in 49 others. At long echo times, there was a highly significant decrease in the ratios N-acetyl-aspartate/creatine (NAA/Cr) and NAA/ choline (Cho) in high-T2-signal areas and in the NAWM in patients with an SP course compared with control subjects and patients with an RR course. There was a significant negative correlation between these ratios and clinical disability measured by Expanded Disability Status Scale score, which was independent of disease duration. Discriminant values between patients with RR and SP courses were found in the NAWM (NAA/Cr = 1.75 and NAA/Cho = 1.5), but not in high-T2-signal areas. At short echo times, there was a significant increase in the ratio myoinositol/Cr in high-signal areas of patients with an SP course compared with control subjects, and the presence of abnormal resonances in the lesions and NAWM for free amino acids and lipids (in 30% and 8%, respectively) and GLX complex (glutamine, glutamate, gamma-aminobutyric acid; 16% and 20%, respectively). Studying normal-appearing white matter on MRI with MRS allows discrimination between relapsing remitting and secondary progressive patients. In the NAWM of patients with MS and an SP course, severe axonal loss/dysfunction is negatively correlated to clinical disability and independent of the duration of the disease.

Statistical power of MRI monitored trials in multiple sclerosis: new data and comparison with previous results

OBJECTIVESTo evaluate the durations of the follow up and the reference population sizes needed to achieve optimal and stable statistical powers for two period cross over and parallel group design...

Three dimensional MRI estimates of brain and spinal cord atrophy in multiple sclerosis

OBJECTIVEThe association between brain atrophy and permanent functional deficits in multiple sclerosis and the temporal relation between atrophy and the clinical disease course have seldom been investigated. This study aims...

Spinal cord atrophy and disability in MS: a longitudinal study.

To assess whether it is possible to measure changes in cord cross-sectional area during a 1-year period in patients with MS reliably. Involvement of the spinal cord in MS is extremely common and an important element in the development of disability. Although little relation has been shown between the cord lesion load and disability, a strong correlation between spinal cord atrophy and the expanded disability status scale (EDSS) has been demonstrated in cross-sectional studies. A highly reproducible semiautomated technique that measures the cross-sectional area of the cord at the C2 level was applied to 13 healthy control subjects and 28 patients serially. This study confirms that patients have significantly smaller cords than control subjects at baseline (control subjects: mean 80.95 mm2, patients: mean 71.25 mm2, p = 0.01) and demonstrates that patients have a significant loss in cord cross-sectional area during 12 months, which was not seen in control subjects (p < 0.001). This reduction in cord size was most marked in the primary progressive patients who had a mean cord cross-sectional area loss of 3.52 mm2 (5.2%) and least in the secondary progressive (-0.26 mm2, 0.7%) and benign patients (-0.41 mm2, 0.8%). The baseline cord cross-sectional area correlated strongly with the EDSS (r = -0.52, p = 0.005) and with disease duration (r = -0.75, p < 0.001); however, there was no significant difference in cord area (p = 0.69) or change in cord area (p = 0.51) between those patients with a definite increase in EDSS and those without. This study demonstrates, for the first time, that it is possible to measure changes in cord cross-sectional area over time. The serial measurement of spinal cord atrophy may thus make an important contribution to the evaluation of therapeutic efficacy, especially in primary progressive disease.

Brain and spinal cord abnormalities in multiple sclerosis. Correlation between MRI parameters, clinical subtypes and symptoms.

We investigated various magnetic resonance MRI parameters for both brain and spinal cord to see if any improved the clinicoradiological correlation in multiple sclerosis. Ninety-one multiple sclerosis patients (28 relapsing-remitting, 32 secondary progressive and 31 primary progressive) were imaged using conventional T1, proton density- and T2-weighted MRI of the brain and spinal cord. Focal brain and spinal cord lesion load was scored, as were diffuse signal abnormalities, brain ventricular volume and spinal cord cross-sectional area. Clinical measures included the expanded disability status scale (EDSS), the functional systems score and a dedicated urology complaint questionnaire. Secondary progressive patients differed from relapsing-remitting and primary progressive patients by a larger number of hypointense T1 lesions in the brain, ventricular enlargement and spinal cord atrophy. Primary progressive patients more often had diffuse abnormalities in the brain and/or spinal cord than did relapsing-remitting and secondary progressive patients. In the entire study population, EDSS correlated with both brain and spinal cord MRI parameters, which were independent. The urological complaint score correlated only with spinal cord MRI parameters. In relapsing-remitting and secondary progressive multiple sclerosis, the correlation between MRI and clinical parameters was better than in the entire population. In this subgroup EDSS variance could be explained best by T1 brain lesion load, ventricle volume and spinal cord cross-sectional area. In the primary progressive subgroup the clinicoradiological correlation was weak for brain parameters but was present between spinal cord symptoms and spinal cord MRI parameters. In conclusion, the different brain and spinal cord MRI parameters currently available revealed considerable heterogeneity between clinical subtypes of multiple sclerosis. In relapsing-remitting and secondary progressive multiple sclerosis both brain and spinal cord MRI may provide a tool for monitoring patients, while in primary progressive multiple sclerosis the clinicoradiological correlation is weak for brain imaging.

Psychological functioning in primary progressive versus secondary progressive multiple sclerosis.

Psychological functioning in two types of multiple sclerosis (MS) patients is assessed: primary progressive (PP) and secondary progressive (SP) patients. On the basis of differences in clinical course and underlying pathology we hypothesized that primary progressive patients and secondary progressive patients might have different psychological functioning. Seventy patients treated in an MS centre were examined cross-sectionally. Forty had an SP course of MS and 30 a PP course. The 33 male and 37 female patients had a mean age of 48.4 years (SD 11.2) and mean age of onset of MS of 30.7 years (SD 11.1). Patients completed questionnaires measuring among others the following aspects of psychological functioning: depression (BDI, SCL-90), anxiety (STAI, SCL-90), agoraphobia (SCL-90), somatic complaints (SCL-90), hostility (SCL-90) and attitude towards handicap (GHAS). Patients with a PP-MS scored significantly better on 5 out of 14 subscales than patients with SP-MS (p < .05). On the basis of our operationalizations of psychological functioning, the findings support the conclusion that on average 18 years after diagnosis of MS, amongst patients attending an MS unit, primary progressive patients were found to have better psychological functioning.

Cerebrospinal fluid analysis differentiates between relapsing-remitting and secondary progressive multiple sclerosis

OBJECTIVESTo find whether CSF analysis may differentiate between relapsing-remitting and secondary progressive multiple sclerosis.METHODSIn 17 patients with relapsing-remitting and 16 patients with secondary progressive multiple sclerosis, all without current or...

Daily urinary neopterin excretion as an immunological marker of disease activity in multiple sclerosis.

The aim of this study was to assess neopterin, a marker of interferon gamma (IFN-gamma) induced macrophage activity, as a possible surrogate marker of inflammation in patients with multiple sclerosis. Urinary neopterin to creatinine ratios (UNCRs) were measured daily in 10 primary progressive (PP). 10 relapsing remitting (RR) and 11 secondary progressive (SP) patients with multiple sclerosis, and 14 normal control (NC) subjects, for periods of up to 12 weeks. After excluding measurements related to infection, the median of the individuals' average UNCRs was significantly higher in patients than in controls (P < 0.001 for all patients and P < 0.01 for each of the three groups of patients); the median UNCRs (and interquartile ranges) were 187 (135-231), 187 (165-277), 218 (164-517) and 134 (97-152) mumol/mol for PP, RR, SP patients and controls, respectively. Similarly, patients had a greater median proportion of days with a UNCR above normal (P < 0.001 for all patients and P < 0.01 for each group); the median percentage (and interquartile ranges) were 16 (6-62), 28 (21-36), 49 (14-86) and 0 (0-6)% for PP, RR, SP patients and controls, respectively. They also had a greater number of peaks in their serial UNCR measurements than controls (P < 0.001 for all patients and P < 0.01 for each group); the means +/- SD peaks/subject/month were: 2.1 +/- 1.8; 3.0 +/- 1.7; 3.3 +/- 2.3 and 0.2 +/- 0.6 for PP, RR, SP patients and controls, respectively. Nine relapses occurred in nine patients during the study, and all were associated with increased neopterin excretion, which tended to be greater than that on days not associated with a relapse. Three of the nine relapses were preceded by an upper respiratory tract infection. In eight out of 13 patients who had infections during the study, increased neopterin excretion was noted for periods of up to 6 weeks post-infection, significantly longer than that which occurred after infections in controls. This confirms infection as a potent inducer of symptomatic and asymptomatic disease activity in mutiple sclerosis, and provides further support of a pivotal role for IFN-gamma in te pathogenesis of mutiple sclerosis. Urinary neopterin excretion is increased in patients with both progressive and relapsing mutiple sclerosis, and therefore has potential as a surrogate marker of the inflammatory component of mutiple sclerosis disease activity.

Accumulation of hypointense lesions ("black holes") on T1 spin-echo MRI correlates with disease progression in multiple sclerosis.

MRI findings are increasingly used as outcome measures in therapeutic trials in MS. The discrepancy between the extent of the lesions on conventional T2 images and the clinical condition of the patient is one of the problems encountered in such studies. This clinical-radiological paradox prevents the use of MRI data as surrogate markers of disability in MS. A recent pilot study suggested a relationship between hypointense lesions on T1 MRI and disability. To assess in more detail the correlation of changes in hypointense lesion load on T1-weighted spin-echo MR images ("black holes") with changes in disability in MS, we studied 46 patients with clinically definite MS at baseline and after a median follow-up of 40 months. There was a significant correlation between baseline disability and hypointense lesion load (Spearman rank correlation coefficient [SRCC] = 0.46, p = 0.001). In secondary progressive patients, the rate of accumulation of these "black holes" was significantly related to progression rate (SRCC = 0.81, p < 0.0001). We speculate that the appearance of hypointense lesions is the MRI equivalent of a failure of remission. Overall, T1 lesion load measurements correlated better with clinical assessments than T2 lesion load measurements. Quantification of hypointense lesion load on T1-weighted spin-echo MRI helps to resolve the clinical-radiological paradox between disability and MRI and has the potential to be a surrogate marker of disability in MS.

Correlation of magnetization transfer ratio with clinical disability in multiple sclerosis.

We performed spin echo magnetic resonance imaging with and without application of an off-resonance saturation pulse in 43 patients with multiple sclerosis (MS), 10 age-matched controls, and 4 elderly asymptomatic patients with the radiological diagnosis of small-vessel disease. Magnetization transfer (MT) ratio images were obtained from these. All MS subgroups (primary progressive, secondary progressive, benign, early relapsing-remitting) showed significantly lower average lesion MT ratios than small-vessel disease patients. Secondary progressive MS patients showed significantly lower lesion MT ratios than those with benign disease, and there was an inverse correlation of disability with average lesion MT ratio. The degree of reduction of MT ratios is an indicator of the extent of tissue destruction. Thus, reduced MT ratios in MS may provide an indication of the degree of demyelination and axonal loss, both of which are likely to cause functional deficits in MS. We conclude that MT measurement is (1) a robust quantitative method that may increase the pathological specificity of magnetic resonance imaging, (2) has the potential to differentiate demyelination in MS from less destructive pathological changes, and (3) may be useful in monitoring modifications in tissue structure brought about by treatment.