Objective: To determine whether glatiramer acetate (GA) slows accumulation of disability in primary progressive multiple sclerosis. Methods: A total of 943 patients with primary progressive multiple sclerosis were randomized to GA or placebo (PBO) in this 3-year, double-blind trial. The primary end point was an intention-to-treat analysis of time to 1-(entry expanded disability status scale, 3.0 -5.0) or 0.5-point expanded disability status scale change (entry expanded disability status scale, 5.5-6.5) sustained for 3 months. The trial was stopped after an interim analysis by an independent data safety monitoring board indicated no discernible treatment effect on the primary outcome. Intention-to-treat analyses of disability and magnetic resonance imaging end points were performed. Results: There was a nonsignificant delay in time to sustained accumulated disability in GA-versus PBO-treated patients (hazard ratio, 0.87 [95% confidence interval, 0.71-1.07]; p ϭ 0.1753), with significant decreases in enhancing lesions in year 1 and smaller increases in T2 lesion volumes in years 2 and 3 versus PBO. Post hoc analysis showed that survival curves for GA-treated male patients diverged early from PBO-treated male subjects (hazard ratio, 0.71 [95% confidence interval, 0.53-0.95]; p ϭ 0.0193). Interpretation:The trial failed to demonstrate a treatment effect of GA on primary progressive multiple sclerosis. Both the unanticipated low event rate and premature discontinuation of study medication decreased the power to detect a treatment effect. Post hoc analysis suggests GA may have slowed clinical progression in male patients who showed more rapid progression when untreated.

Brain imaging studies find evidence of prefrontal cortical dysfunction in cocaine-dependent subjects. Similarly, cocaine-dependent subjects have problems with behaviors related to executive function and impulsivity. Since prefrontal cortical axonal tracts cross between hemispheres in the corpus callosum, it is possible that white matter integrity in the corpus callosum could also be diminished in cocainedependent subjects. The purpose of this study was to compare corpus callosum white matter integrity as measured by the fractional anisotropy (FA) on diffusion tensor imaging (DTI) between 18 cocaine-dependent subjects and 18 healthy controls. The Barratt Impulsiveness Scale (BIS-11) and a continuous performance test: the Immediate and Delayed Memory Task (IMT/DMT) were also collected. Results of the DTI showed significantly reduced FA in the genu and rostral body of the anterior corpus callosum in cocainedependent subjects compared to controls. Cocaine-dependent subjects also had significantly higher BIS-11 scores, greater impulsive (commission) errors, and reduced ability to discriminate target from catch stimuli (discriminability) on the IMT/DMT. Within cocaine dependent subjects there was a significant negative correlation between FA in the anterior corpus callosum and behavioral laboratory measured impulsivity, and there was a positive correlation between FA and discriminability. The finding that reduced integrity of anterior corpus callosum white matter in cocaine users is related to impaired impulse control and reduced ability to discriminate between target and catch stimuli is consistent with prior theories regarding frontal cortical involvement in impaired inhibitory control in cocainedependent subjects.

Serial magnetic resonance (MR) studies that included proton MR spectroscopic imaging (MRSI), contrast-enhanced MR imaging (MRI), and lesion volumetric studies were performed on 25 multiple sclerosis (MS) patients with mild to modest clinical deficits. Each patient was scanned at varying intervals for up to 2 years, resulting in a total of 124 usable MR sessions. In these longitudinal studies, metabolic changes were observed on MRSI for some subjects before the appearance of lesions on MRI scanning. Regional changes in metabolite levels were observed to be dynamic and reversible in some patients. Transient changes in N-acetylaspartate (NAA) levels were sometimes found in acute plaques and indicate that a reduced NAA level does not necessarily imply axonal loss. An inverse correlation between the average NAA within the spectroscopic volume and the total lesion volume in the whole brain was observed. This negative correlation implies that NAA can serve as an objective marker of the disease burden. Strong lipid peaks in the absence of gadolinium enhancement and MRI-defined lesions were observed in 4 patients. This observation suggests that demyelination can occur independent of perivenous inflammatory changes and supports the presence of more than one pathophysiological process leading to demyelination in MS.

Brain water may increase in hepatic encephalopathy (HE). Diffusion tensor imaging was performed in patients with cirrhosis with or without HE to quantify the changes in brain water diffusivity and to correlate it with neuropsychological (NP) tests. Thirty-nine patients with cirrhosis, with minimal (MHE) or overt HE, were studied and compared to 18 controls. Mean diffusivity (MD) and fractional anisotropy (FA) were calculated in corpus callosum, internal capsule, deep gray matter nuclei, periventricular frontal, and occipital white matter regions in both cerebral hemispheres. The MD and FA values from different regions in different groups were compared using analysis of variance and Spearman's rank correlation test. In 10 patients with MHE, repeat studies were performed after 3 weeks of lactulose therapy to look for any change in MD, FA, and NP scores.

BACKGROUND AND PURPOSE:Accurate detection and classification of purely intracortical lesions in multiple sclerosis (MS) are important in understanding their role in disease progression and impact on the clinical manifestations of the disease. However, detection of these lesions with conventional MR imaging remains a challenge. Although double inversion recovery (DIR) has been shown to improve the sensitivity of the detection of cortical lesions, this sequence has low signal-to-noise ratio (SNR), poor delineation of lesion borders, and is prone to image artifacts. We demonstrate that intracortical lesions can be identified and classified with greater confidence by the combination of DIR with phase-sensitive inversion recovery (PSIR) images.

Objective A double-blind, randomized, controlled study to determine if combined use of interferon beta-1a (IFN) 30ug IM weekly and glatiramer acetate (GA) 20mg daily is more efficacious than either agent alone in relapsing-remitting multiple sclerosis (RRMS). Methods 1008 participants were randomized and followed until the last participant enrolled completed 3 yrs. The primary endpoint was reduction in annualized relapse rate utilizing a strict definition of relapse. Secondary outcomes included time to confirmed disability, Multiple Sclerosis Functional Composite (MSFC) score and MRI metrics. Results Combination IFN + GA was not superior to the better of the single agents (GA) in risk of relapse. Both the combination therapy and GA were significantly better than IFN in reducing the risk of relapse. The Combination was not better than either agent alone in lessening confirmed EDSS progression or change in MSFC over 36 months. The combination was superior to either agent alone in reducing new lesion activity and accumulation of total lesion volumes. In a post hoc analysis, combination therapy resulted in a higher proportion of participants attaining disease activity free status (DAFS) compared to either single arm; driven by the MRI results. Interpretation Combining the two most commonly prescribed therapies for MS did not produce a significant clinical benefit over three years. An effect was seen on some MRI metrics. In a test of comparative efficacy, GA was superior to IFN in reducing the risk of exacerbation. The extension phase for CombiRx will address if the observed differences in MRI and DAFS findings predict later clinical differences.

Diffusion tensor MRI (DT-MRIKey words: magnetic resonance imaging; diffusion tensor encoding; fractional anisotropy; relative anisotropy; mean diffusivity; icosahedral encoding; Monte Carlo simulations Diffusion tensor MRI (DT-MRI) has become an increasingly important modality for understanding the organization of normal brain structures (1-4) and the evolution of neurological and psychiatric disorders (1,5-8). Currently, there are different methods for acquiring, processing, and modeling the measured DT-MRI data (1,9 -14). However, there are many technical and scientific challenges limiting the interpretation, validation, and assignment of the true contributors to the DT-MRI signal in complex biological systems (1,(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17). In general, the DT-MRI derived and rotationally invariant maps, such as (D), RA, and FA (6,18,19), are computed offline because of the intense computational nature of the analysis. The availability of online DW procedures to compute these measures would extend the utility of DT-MRI to clinical applications for acute diseases, where immediate feedback to the attending clinicians is important.It was recently shown that useful information can be gained by applying spatially independent component analysis (offline and computationally intensive) and higher-moment statistics to the diffusion data (12). Additional studies (20) have suggested that anisotropy measures can be used to investigate the complex fiber structures within a voxel without certain model assumptions about the signal sources. The relationship between DW-based invariants and those obtained from the single tensor model (when it is an operationally acceptable working model) has not been formally explored. The influence of bias introduced by the encoding scheme and the SNR has also not been addressed.There is considerable evidence that icosahedral encoding sets are the least biased and the most rotationally invariant sets (9,21-26) suitable for acquiring DW data. This work shows that by employing the uniformly distributed principal icosahedron sampling scheme, a diffusion anisotropy measurement analogous to FA can be directly obtained from the DW data. The effects of SNR, encoding scheme, and diffusion sensitization on the accuracy of the method are also investigated using Monte Carlo simulations and normal brain DT-MRI measurements. THEORYBefore the algorithm and the requirements to obtain the rotationally invariant (D), RA, and FA maps directly from the DW data are presented, the basic mathematical underpinnings of the DT-MRI tensor estimation and encoding theory, using matrix algebra, are briefly summarized (1, 24 -27). Self-DT Encoding TheorySince the DT is symmetric, a minimum of six noncollinear encoding directions are needed to obtain the six independent elements of the DT, D, represented as a 3 ϫ 3 matrix [1]The unique tensor elements can be represented by the column vector (24):

The presence of large number of false lesion classification on segmented brain MR images is a major problem in the accurate determination of lesion volumes in multiple sclerosis (MS) brains. In order to minimize the false lesion classifications, a strategy that combines parametric and nonparametric techniques is developed and implemented. This approach uses the information from the proton density (PD)-and T2-weighted and fluid attenuation inversion recovery (FLAIR) images. This strategy involves CSF and lesion classification using the Parzen window classifier. Image processing, morphological operations and ratio maps of PD and T2 weighted images are used for minimizing false positives. Contextual information is exploited for minimizing the false negative lesion classifications using hidden Markov random field -expectation maximization (HMRF-EM) algorithm. Lesions are delineated using fuzzy connectivity. The performance of this algorithm is quantitatively evaluated on 23 MS patients. Similarity index, percentages of over, under and correctestimations of lesions are computed by spatially comparing the results of present procedure with expert manual segmentation. The automated processing scheme detected 80% of the manually segmented lesions in the case of low-lesion load and 93% of the lesions in those cases with high lesion load.