Heterogeneity of Multiple Sclerosis White Matter Lesions Detected With T2*-Weighted Imaging at 7.0 Tesla.

BACKGROUND AND PURPOSE: Postmortem studies in multiple sclerosis (MS) indicate that in some white matter lesions (WM-Ls), iron is detectable with T2*-weighted (T2*-w), and its reciprocal R2* relaxation rate, magnetic resonance imaging (MRI) at 7.0 Tesla (7T). This iron appears as a hyperintense rim in R2* images surrounding a hypointense core. We describe how this observation relates to clinical/radiological characteristics of patients, in vivo. METHODS: We imaged 16 MS patients using 3T and 7T scanners. WM-Ls were identified on T1-w / T2-w 3T-MRIs. Thereafter, WM-Ls with a rim of elevated R2* at 7T were counted and compared to their appearance on conventional MRIs. RESULTS: We counted 36 WM-Ls presenting a rim of elevated R2* in 10 patients. Twenty-three (64%) lesions coincided with focal WM-Ls on T2-w MRIs; 13 (36%) coincided with only portions of larger lesions on T2-w images; and 20 (56%) corresponded to a hypointense chronic black hole. WM-Ls presenting a rim of elevated R2* were seen in both relapsing-remitting patients with low disability and in those with long-standing secondary progressive MS. CONCLUSIONS: WM-Ls with a contour of high R2* are present at different MS stages, potentially representing differences in the contribution of iron in MS disease evolution.

Diffuse and focal corticospinal tract disease and its impact on patient disability in multiple sclerosis.

BACKGROUND AND PURPOSE: We investigated the impact of focal and diffuse corticospinal tracts damage on sensory-motor disability in multiple sclerosis (MS) patients. METHODS: Twenty-five MS patients underwent 3.0 Tesla (3T) magnetic resonance imaging with diffusion tensor imaging (DTI). The Expanded Disability Status Scale (EDSS) and the Timed 25-Foot Walk test (T25FW) quantified patient physical disability. Fractional anisotropy (FA) and mean diffusivity (MD) of the corticospinal tracts, whole brain and corticospinal tracts lesion volume were also computed. Spearman rank correlation analyses measured the associations between DTI-derived metrics and other measures of disease. Partial correlation analyses between DTI and disability measures were performed and corrected for lesion volumes as appropriate. RESULTS: Significant associations were seen between FA of the corticospinal tracts and EDSS (r = -.500, P = .0011), motor-EDSS (r = -.519, P = .008), and T25WF (r = -.637, P = .001) scores and MD of the corticospinal tracts and motor-EDSS (r = .469, P = .018) and T25WF (r = .428, P = .033) scores. When correcting for lesion volumes, only the association between FA of the corticospinal tracts and EDSS (r ≤ -.516, p ≤ .01) or motor-EDSS score (r ≤ -.516, p ≤ .01) persisted. CONCLUSIONS: DTI at 3T shows that the impact of diffuse corticospinal tracts disease on sensory-motor disability is greatly mediated by focal lesions in MS.

Cognitive impairment and its relation to imaging measures in multiple sclerosis: a study using a computerized battery.

BACKGROUND AND PURPOSE: Cognitive impairment (CI) is an important component of multiple sclerosis (MS) disability. A complex biological interplay between white matter (WM) and gray matter (GM) disease likely sustains CI. This study aims to address this issue by exploring the association between the extent of normal WM and GM disease and CI. METHODS: Cognitive function of 24 MS patients and 24 healthy volunteers (HVs) was studied using the Automated Neuropsychological Assessment Metrics (ANAM) battery. WM focal lesions and normal appearing WM (NAWM) volume in patients, cortical thickness (CTh) and deep GM structure volumes in both patients and HVs were measured by high field strength (3.0-Tesla; 3T) imaging. RESULTS: An analysis of covariance showed that patients performed worse than HVs on Code Substitution Delayed Memory (P = .04) and Procedural Reaction Time (P = .05) indicative of reduced performance in memory, cognitive flexibility, and processing speed. A summary score (Index of Cognitive Efficiency) indicating global test battery performance was also lower for the patient group (P = .04). Significant associations, as determined by the Spearman rank correlation tests, were noted between each of these 3 cognitive scores and measures of NAWM volume [CDD-TP1(r = .609; P = .0035), PRO-TP1 (r = .456; P = .029) and ICE (r = .489; P = .0129)], CTh (r = .5; P ≤ .05) and volume of subcortical normal appearing GM (NAGM) structures (r = .4; P≤ .04), but not WM lesions. CONCLUSIONS: Both NAWM and NAGM volumes are related to CI in MS. The results highlight once again the urgent need to develop pharmacological strategies protecting patients from widespread neurodegeneration as possible preventive strategies of CI development.

Quality and quantity of diffuse and focal white matter disease and cognitive disability of patients with multiple sclerosis.

BACKGROUND AND PURPOSE: Using high-field magnetic resonance imaging (MRI), we investigated the relationships between white matter (WM) lesion volume (LV), normal-appearing WM (NAWM) normalized volume, WM-lesion and NAWM magnetization transfer ratios (MTRs), brain parenchyma fraction (BPF), and cognitive impairment (CI) in multiple sclerosis (MS). METHODS: Twenty-four patients and 24 healthy volunteers (age, sex, and years of education-matched) underwent a 3.0 Tesla (3T) scan and evaluation of depression, fatigue, and CI using the Minimal Assessment of Cognitive Function in MS (MACFIMS) battery. RESULTS: In this clinically relatively well-preserved cohort of patients (median score on the Expanded Disability Status Scale=1.5), CI was detected on Symbol Digit Modalities Test (SDMT), California Verbal Learning Test-II (CVLT-II), and Controlled Oral Word Association Test. MT data were available in 19 pairs on whom correlation analyses were performed. Associations were seen between SDMT and normalized NAWM volume (P=.034, r=.502), CVLT-II long delay and normalized NAWM volume (P=.012, r=.563), WM-LV (P=.024, r=.514), and BPF (P=.002, r=.666). CONCLUSIONS: The use of 3T MRI in a sample of clinically stable MS patients shows the importance of WM disease in hampering processing speed and word retrieval.

Relationship of cortical atrophy to fatigue in patients with multiple sclerosis.

BACKGROUND: Fatigue is a common and disabling symptom of multiple sclerosis (MS). Previous studies reported that damage of the corticostriatothalamocortical circuit is critical in its occurrence. OBJECTIVE: To investigate the relationship between fatigue in MS and regional cortical and subcortical gray matter atrophy. DESIGN: Case-control study. SETTING: National Institutes of Health. PARTICIPANTS: Twenty-four patients with MS and 24 matched healthy volunteers who underwent 3.0-T magnetic resonance imaging and evaluations of fatigue (Modified Fatigue Impact Scale) and depression (Center for Epidemiologic Studies Depression Scale). MAIN OUTCOME MEASURES: Relationship between thalamic and basal ganglia volume, cortical thickness of frontal and parietal lobes, and, in patients, T2 lesion volume and normal-appearing white matter volume and the extent of fatigue. RESULTS: Patients were more fatigued than healthy volunteers (P = .04), while controlling for the effect of depression. Modified Fatigue Impact Scale score correlated with cortical thickness of the parietal lobe (r = -0.50, P = .01), explaining 25% of its variance. The posterior parietal cortex was the only parietal area significantly associated with the Modified Fatigue Impact Scale scores. CONCLUSIONS: Cortical atrophy of the parietal lobe had the strongest relationship with fatigue. Given the implications of the posterior parietal cortex in motor planning and integration of information from different sources, our preliminary results suggest that dysfunctions in higher-order aspects of motor control may have a role in determining fatigue in MS.

Clinical and imaging metrics for monitoring disease progression in patients with multiple sclerosis.

Multiple sclerosis (MS) is an autoimmune disease of the CNS leading to clinical disability in 250,000-350,000 young adults in the USA and Europe. The disease affects both white matter (WM) and gray matter (GM) tissues of the brain and spinal cord. While WM disease is easily quantified using currently available magnetic resonance imaging (MRI) techniques, identification and quantification of GM disease present a daily challenge. Nonconventional brain and spinal cord MRI techniques, including magnetization transfer, MRI spectroscopy and diffusion tensor imaging, have improved our understanding of MS pathology in the deep GM. The sensitivity of high-resolution MRI obtained at a high magnetic field will improve the detection of spinal cord and brain cortical GM disease. The appropriate use of the above-mentioned techniques has the potential to more accurately explain the level of disability in MS patients.

Effects of interferon beta-1b on black holes in multiple sclerosis over a 6-year period with monthly evaluations.

BACKGROUND: Chronic, hypointense black holes (BHs) are recognized as a sign of permanent damage in patients with multiple sclerosis. Although the effects of interferon beta-1b in reducing the formation of new BHs are established, it is not clear whether the drug may reduce BH duration after these lesions are formed. OBJECTIVE: To analyze the effects of interferon beta-1b in reducing the duration of T1 BHs in patients with multiple sclerosis. DESIGN: Patients were clinically assessed and imaged monthly over a 36-month natural history phase and 36-month therapy phase. Numbers of contrast-enhanced lesions and newly formed BHs were counted on each scan. Each BH was counted until it was no longer seen. SETTING: Outpatient service of the Neuroimmunology Branch at the National Institutes of Health, Bethesda, Md. PATIENTS: Six patients with relapsing-remitting multiple sclerosis were included. One patient did not form any BHs during the therapy phase. Analyses were performed on the remaining 5 individuals. INTERVENTIONS: Interferon beta-1b at the dosage of 8 million international units every other day. MAIN OUTCOME MEASURES: Number and duration (in months) of newly formed BHs. RESULTS: Rate of BH accumulation decreased with treatment (P = .01), but Kaplan-Meier models revealed that the duration of BHs did not shorten (chi2(1) = 2.47, P = .12). CONCLUSIONS: Interferon beta-1b reduces the frequency of new BH formation but does not appear to decrease their duration in time. Analyses with larger patient cohorts are needed to confirm these preliminary findings.

HLA-DRB5*0101 and -DRB1*1501 expression in the multiple sclerosis-associated HLA-DR15 haplotype.

The HLA region, and particularly the DR15 haplotype (containing the two DRB* genes DRB1*1501 and DRB5*0101 and the tightly linked DQ alleles DQA*0102 and DQB1*0602, which together form the DQw6 molecule) in Caucasians, shows the strongest genetic association with multiple sclerosis (MS). In the DR15 haplotype, two beta-chains HLA-DRB1*1501 and -DRB5*0101 are co-expressed resulting in two different surface HLA-DR alphabeta heterodimers, DR2b and DR2a. Most previous studies focused on DRB1*1501, however, both DR2a and DR2b may contribute to MS pathogenesis via antigen presentation to myelin-specific T lymphocytes. We therefore analyzed the expression of the two DR15 genes in various antigen presenting cells (APCs), central nervous system and thymic tissues. Transcript levels were higher for DRB5*0101 in all cell types and tissues. Both HLA-DR heterodimers were expressed at significant levels on the cell surface, where they showed a differential expression pattern in different APCs. They were similarly regulated after stimulation with interferon-gamma and interleukin-4. Finally, immunohistochemistry experiments indicated that both molecules were expressed in thymic tissue. Our results encourage future research to investigate the potential functional relevance of both genes for the pathogenesis of MS.

Evolution of T1 black holes in patients with multiple sclerosis imaged monthly for 4 years.

T1 black holes (BHs) on MRIs may represent either areas of oedema or axonal loss in patients with multiple sclerosis. BHs begin as contrast enhancing lesions (CELs) and evolve differently from patient to patient, and within the same patient over time. We analysed BHs formation over a 4-year period. Forty-eight monthly MRIs of nine non-treated multiple sclerosis patients were evaluated for numbers of CELs and BHs. A BH was defined as a hypointense lesion on a T1 pre-contrast image that coincided with a region of high signal intensity on the T2-weighted images. A BH was considered as acute (ABH) when it occurred coincidently with the presence of enhancement and as persisting (PBH) when present after the cessation of enhancement. The present study aimed to analyse: (i) the incidence of CELs and new PBHs, and the accumulation of PBHs; (ii) the relationship between the quantity of the CELs in a given month and the likelihood of accumulating PBHs in the subsequent month; and (iii) the relationship between the duration of CELs and PBHs. Pitman's correlation test evaluated the effect of time on either the increase of CELs and new PBHs or the accumulation of PBHs, while a multiple logistic regression analysis evaluated the relationship between progression of time and CELs, and the increase of PBHs in a multivariate model. The relationship between the enhancing lesions duration and the PBHs duration, or the time to revert back to an isointense lesion was analysed using Kaplan-Meier survival models. PBHs accumulated (P < 0.001) in all patients, but the formation of new PBHs increased in four patients (P < or = 0.007) in conjunction with an increase in either the quantity of CELs (P < 0.001, for two patients) or the proportion of CELs turning into PBHs (P < or = 0.02, for two patients). Logistic regression analysis showed that neither progression of time nor the number of CELs in a given month were able to predict the probability of increasing the number of PBHs in the subsequent month in any patient. Out of 397 ABHs, 55.7% evolved to a PBH. The duration of PBHs correlated with the duration of enhancement. PBHs preceded by CELs observable on a single MRI persisted for a shorter time (P < 0.002) than those preceded by CELs visible on > or =2 monthly MRIs. The formation of a new PBH was found to be related to CELs activity; however, duration of PBHs is most likely a consequence of the duration of the enhancement.

Increased detection of serum HHV-6 DNA sequences during multiple sclerosis (MS) exacerbations and correlation with parameters of MS disease progression.

In recent years, human herpesvirus 6 (HHV-6) has been investigated as a possible causative agent for MS. To determine if the detection of HHV-6 DNA in the serum of MS patients correlates with clinical parameters of MS disease progression, a total of 215 serum samples was obtained from 59 MS patients followed prospectively for a 5-month period. These samples were analyzed for the presence of HHV-6 DNA by nested PCR and compared in parallel to MS disease activity. HHV-6 DNA was amplified in 22% (4/18) of samples obtained during a period of clinical exacerbation. Significantly fewer (P = 0.008) sera, 5.6% (11/197), obtained from MS patients during clinical remission tested positive for the presence of HHV-6 DNA. This work demonstrates that the detection of serum HHV-6 DNA is significantly correlated with clinical exacerbations in MS. Moreover, the findings presented in this study have confirmed previous reports supporting an association between MS and HHV-6 and suggest a role for this human herpesvirus in the pathogenesis of MS.