Charles R. G. Guttmann

Predictive value of gadolinium-enhanced magnetic resonance imaging for relapse rate and changes in disability or impairment in multiple sclerosis: a meta-analysis

BACKGROUND Reliable prognostic factors are lacking for multiple sclerosis (MS). Gadolinium enhancement in magnetic resonance imaging (MRI) of the brain detects with high sensitivity disturbance of the blood-brain barrier, an early event in the development of inflammatory lesions in MS. To investigate the prognostic value of gadolinium-enhanced MRI, we did a meta-analysis of longitudinal MRI studies. METHODS From the members of MAGNIMS (European Magnetic Resonance Network in Multiple Sclerosis) and additional centres in the USA, we collected data from five natural-course studies and four placebo groups of clinical trials completed between 1992 and 1995. We included a total of 307 patients, 237 with relapsing disease course and 70 with secondary progressive disease course. We investigated by regression analysis the relation between initial count of gadolinium-enhancing lesions and subsequent worsening of disability or impairment as measured by the expanded disability status scale (EDSS) and relapse rate. FINDINGS The relapse rate in the first year was predicted with moderate ability by the mean number of gadolinium-enhancing lesions in monthly scans during the first 6 months (relative risk per five lesions 1.13, p=0.023). The predictive value of the number of gadolinium-enhancing lesions in one baseline scan was less strong. The best predictor for relapse rate was the variation (SD) of lesion counts in the first six monthly scans which allowed an estimate of relapse in the first year (relative risk 1.2, p=0.020) and in the second year (risk ratio=1.59, p=0.010). Neither the initial scan nor monthly scans over six months were predictive of change in the EDSS in the subsequent 12 months or 24 months. The mean of gadolinium-enhancing-lesion counts in the first six monthly scans was weakly predictive of EDSS change after 1 year (odds ratio=1.34, p=0.082) and 2 years (odds ratio=1.65, p=0.049). INTERPRETATION Although disturbance of the blood-brain barrier as shown by gadolinium enhancement in MRI is a predictor of the occurrence of relapses, it is not a strong predictor of the development of cumulative impairment or disability. This discrepancy supports the idea that variant pathogenetic mechanisms are operative in the occurrence of relapses and in the development of long-term disability in MS.

White matter changes with normal aging

We evaluated brain tissue compartments in 72 healthy volunteers between the ages of 18 and 81 years with quantitative MRI. The intracranial fraction of white matter was significantly lower in the age categories above 59 years. The CSF fraction increased significantly with age, consistent with previous reports. The intracranial percentage of gray matter decreased somewhat with age, but there was no significant difference between the youngest subjects and the subjects above 59. A covariance adjustment for the volume of hyperintensities did not alter the foregoing results. The intracranial percentage of white matter volume was strongly correlated with the percentage volume of CSF. The finding of a highly significant decrease with age in white matter, in the absence of a substantial decrease in gray matter, is consistent with recent neuropathologic reports in humans and nonhuman primates.

Multi-component apparent diffusion coefficients in human brain†

The signal decay with increasing b‐factor at fixed echo time from brain tissue in vivo has been measured using a line scan Stejskal–Tanner spin echo diffusion approach in eight healthy adult volunteers. The use of a 175 ms echo time and maximum gradient strengths of 10 mT/m allowed 64 b‐factors to be sampled, ranging from 5 to 6000 s/mm2, a maximum some three times larger than that typically used for diffusion imaging. The signal decay with b‐factor over this extended range showed a decidedly non‐exponential behavior well‐suited to biexponential modeling. Statistical analyses of the fitted biexponential parameters from over 125 brain voxels (15 × 15 × 1 mm3 volume) per volunteer yielded a mean volume fraction of 0.74 which decayed with a typical apparent diffusion coefficient around 1.4 µm2/ms. The remaining fraction had an apparent diffusion coefficient of approximately 0.25 µm2/ms. Simple models which might explain the non‐exponential behavior, such as intra‐ and extracellular water compartmentation with slow exchange, appear inadequate for a complete description. For typical diffusion imaging with b‐factors below 2000 s/mm2, the standard model of monoexponential signal decay with b‐factor, apparent diffusion coefficient values around 0.7 µm2/ms, and a sensitivity to diffusion gradient direction may appear appropriate. Over a more extended but readily accessible b‐factor range, however, the complexity of brain signal decay with b‐factor increases, offering a greater parametrization of the water diffusion process for tissue characterization. Copyright

Thalamic atrophy and cognition in multiple sclerosis

Objectives: Recent studies have indicated that brain atrophy is more closely associated with cognitive impairment in multiple sclerosis (MS) than are conventional MRI lesion measures. Enlargement of the third ventricle shows a particularly strong correlation with cognitive impairment, suggesting clinical relevance of damage to surrounding structures, such as the thalamus. Previous imaging and pathology studies have demonstrated thalamic involvement in MS. In this study, we tested the hypothesis that thalamic volume is lower in MS than in normal subjects, and that thalamic atrophy in MS correlates with cognitive function. Methods: We studied 79 patients with MS and 16 normal subjects. A subgroup of 31 MS subjects underwent cognitive testing. The thalamus was segmented in whole from three-dimensional MRI scans. We also determined whole brain atrophy (brain parenchymal fraction), third ventricular width, and whole brain T2-weighted (fluid-attenuated inversion recovery) hyperintense, T1 hypointense, and gadolinium-enhanced lesion volumes. Results: Normalized thalamic volume was 16.8% lower in the MS group (p < 0.0001) vs controls. Cognitive performance in all domains was moderately to strongly related to thalamic volume in the MS group (r = 0.506 to 0.724, p < 0.005), and thalamic volume entered and remained in all regression models predicting cognitive performance. Thalamic volume showed a weak relationship to physical disability score (r = −0.316, p = 0.005). Conclusion: These findings suggest that thalamic atrophy is a clinically relevant biomarker of the neurodegenerative disease process in multiple sclerosis.

MRI in multiple sclerosis: current status and future prospects

Many promising MRI approaches for research or clinical management of multiple sclerosis (MS) have recently emerged, or are under development or refinement. Advanced MRI methods need to be assessed to determine whether they allow earlier diagnosis or better identification of phenotypes. Improved post-processing should allow more efficient and complete extraction of information from images. Magnetic resonance spectroscopy should improve in sensitivity and specificity with higher field strengths and should enable the detection of a wider array of metabolites. Diffusion imaging is moving closer to the goal of defining structural connectivity and, thereby, determining the functional significance of lesions at specific locations. Cell-specific imaging now seems feasible with new magnetic resonance contrast agents. The imaging of myelin water fraction brings the hope of providing a specific measure of myelin content. Ultra-high-field MRI increases sensitivity, but also presents new technical challenges. Here, we review these recent developments in MRI for MS, and also look forward to refinements in spinal-cord imaging, optic-nerve imaging, perfusion MRI, and functional MRI. Advances in MRI should improve our ability to diagnose, monitor, and understand the pathophysiology of MS.

Automatic identification of gray matter structures from MRI to improve the segmentation of white matter lesions

The segmentation of MRI scans of patients with white matter lesions (WML) is difficult because the MRI characteristics of WML are similar to those of gray matter. Intensity-based statistical classification techniques misclassify some WML as gray matter and some gray matter as WML. We developed a fast elastic matching algorithm that warps a reference data set containing information about the location of the gray matter into the approximate shape of the patients brain. The region of white matter was segmented after segmenting the cortex and deep gray matter structures. The cortex was identified by using a three-dimensional, region-growing algorithm that was constrained by anatomical, intensity gradient, and tissue class parameters. White matter and WML were then segmented without interference from gray matter by using a two-class minimum-distance classifier. Analysis of double-echo spin-echo MRI scans of 16 patients with clinically determined multiple sclerosis (MS) was carried out. The segmentation of the cortex and deep gray matter structures provided anatomical context. This was found to improve the segmentation of MS lesions by allowing correct classification of the white matter region despite the overlapping tissue class distributions of gray matter and MS lesion.

MRI contrast uptake in new lesions in relapsing-remitting MS followed at weekly intervals

Background: One of the diagnostic imaging hallmarks of MS is the uptake of IV administered contrast material in new lesions in the brain, signaling blood–brain barrier breakdown and active inflammation. Many clinical drug trials are designed based on the assumption that lesion enhancement on MRI remains visible on average for 1 month. For practical reasons, few serial MRI studies of patients with MS have been performed at intervals shorter than 4 weeks. Methods: The authors performed a year-long longitudinal study in 26 patients with relapsing-remitting MS (RRMS), which comprised an initial phase of MRI follow-up at weekly intervals for 8 weeks, followed by imaging every other week for another 16 weeks, and monthly thereafter. They present a quantitative analysis (using a supervised interactive thresholding procedure) of new enhancing lesions appearing during the first 6 weeks in this cohort and evaluated from the time of first detection until enhancement was no longer seen. Results: The average duration of Gd-DTPA enhancement in individual new lesions was 3.07 weeks (median, 2 weeks). Significant correlations were demonstrated between the duration of contrast enhancement or initial growth rates and lesion volumes. Different lesions in the same patient appeared to develop largely independent of each other and demonstrated a large range in the duration of enhancement during the acute phase of their evolution. Conclusions: The average duration of blood–brain barrier impairment in RRMS is shorter than earlier estimates. Early lesion growth parameters may predict final lesion size. Within-patient heterogeneity of lesion evolution suggests that individual lesions develop independently.

White matter abnormalities in mobility-impaired older persons

Objective: To investigate the relationship between white matter abnormalities and impairment of gait and balance in older persons. Methods: Quantitative MRI was used to evaluate the brain tissue compartments of 28 older individuals separated into normal and impaired groups on the basis of mobility performance testing using the Short Physical Performance Battery. In addition, individuals were tested on six indices of gait and balance. For imaging data, segmentation of intracranial volume into four tissue classes was performed using template-driven segmentation, in which signal-intensity–based statistical tissue classification is refined using a digital brain atlas as anatomic template. Results: Both decreased white matter volume, which was age-related, and increased white matter signal abnormalities, which were not age-related, were observed in the mobility-impaired group compared with the control subjects. The average volume of white matter signal abnormalities for impaired individuals was nearly double that of control subjects. Conclusions: This cross-sectional study suggests that decreased white matter volume is age-related, whereas increased white matter signal abnormalities are most likely to occur as a result of disease. Both of these changes are independently associated with impaired mobility in older persons and therefore likely to be additive factors of motor disability.

Cognitive profile and brain morphological changes in obstructive sleep apnea

Obstructive sleep apnea (OSA) is accompanied by neurocognitive impairment, likely mediated by injury to various brain regions. We evaluated brain morphological changes in patients with OSA and their relationship to neuropsychological and oximetric data. Sixteen patients affected by moderate-severe OSA (age: 55.8±6.7 years, 13 males) and fourteen control subjects (age: 57.6±5.1 years, 9 males) underwent 3.0 Tesla brain magnetic resonance imaging (MRI) and neuropsychological testing evaluating short- and long-term memory, executive functions, language, attention, praxia and non-verbal learning. Volumetric segmentation of cortical and subcortical structures and voxel-based morphometry (VBM) were performed. Patients and controls differed significantly in Rey Auditory-Verbal Learning test (immediate and delayed recall), Stroop test and Digit span backward scores. Volumes of cortical gray matter (GM), right hippocampus, right and left caudate were smaller in patients compared to controls, with also brain parenchymal fraction (a normalized measure of cerebral atrophy) approaching statistical significance. Differences remained significant after controlling for comorbidities (hypertension, diabetes, smoking, hypercholesterolemia). VBM analysis showed regions of decreased GM volume in right and left hippocampus and within more lateral temporal areas in patients with OSA. Our findings indicate that the significant cognitive impairment seen in patients with moderate-severe OSA is associated with brain tissue damage in regions involved in several cognitive tasks. We conclude that OSA can increase brain susceptibility to the effects of aging and other clinical and pathological occurrences.

Smoking and Disease Progression in Multiple Sclerosis

BACKGROUND Although cigarette smokers are at increased risk of developing multiple sclerosis (MS), the effect of smoking on the progression of MS remains uncertain. OBJECTIVE To establish the relationship between cigarette smoking and progression of MS using clinical and magnetic resonance imaging outcomes DESIGN Cross-sectional survey and longitudinal follow-up for a mean of 3.29 years, ending January 15, 2008. SETTING Partners MS Center (Boston, Massachusetts), a referral center for patients with MS. PATIENTS Study participants included 1465 patients with clinically definite MS (25.1% men), with mean (range) age at baseline of 42.0 (16-75) years and disease duration of 9.4 (0-50.4) years. Seven hundred eighty patients (53.2%) were never-smokers, 428 (29.2%) were ex-smokers, and 257 (17.5%) were current smokers. MAIN OUTCOME MEASURES Smoking groups were compared for baseline clinical and magnetic resonance imaging characteristics as well as progression and sustained progression on the Expanded Disability Status Scale at 2 and 5 years and time to disease conversion to secondary progressive MS. In addition, the rate of on-study change in the brain parenchymal fraction and T2 hyperintense lesion volume were compared. RESULTS Current smokers had significantly worse disease at baseline than never-smokers in terms of Expanded Disability Status Scale score (adjusted P < .001), Multiple Sclerosis Severity Score (adjusted P < .001), and brain parenchymal fraction (adjusted P = .004). In addition, current smokers were significantly more likely to have primary progressive MS (adjusted odds ratio, 2.41; 95% confidence interval, 1.09-5.34). At longitudinal analyses, MS in smokers progressed from relapsing-remitting to secondary progressive disease faster than in never-smokers (hazard ratio for current smokers vs never-smokers, 2.50; 95% confidence interval, 1.42-4.41). In addition, in smokers, the T2-weighted lesion volume increased faster (P = .02), and brain parenchymal fraction decreased faster (P = .02). CONCLUSION Our data suggest that cigarette smoke has an adverse influence on the progression of MS and accelerates conversion from a relapsing-remitting to a progressive course.