What Have We Learned from Perfusion MRI in Multiple Sclerosis?

Using MR imaging, perfusion can be assessed either by dynamic susceptibility contrast MR imaging or arterial spin-labeling. Alterations of cerebral perfusion have repeatedly been described in multiple sclerosis compared with healthy controls. Acute lesions exhibit relative hyperperfusion in comparison with normal-appearing white matter, a finding mostly attributed to inflammation in this stage of lesion development. In contrast, normal-appearing white and gray matter of patients with MS has been mostly found to be hypoperfused compared with controls, and correlations with cognitive impairment as well as fatigue in multiple sclerosis have been described. Mitochondrial failure, axonal degeneration, and vascular dysfunction have been hypothesized to underlie the perfusion MR imaging findings. Clinically, perfusion MR imaging could allow earlier detection of the acute focal inflammatory changes underlying relapses and new lesions, and could constitute a marker for cognitive dysfunction in MS. Nevertheless, the clinical relevance and pathogenesis of the brain perfusion changes in MS remain to be clarified.

Multiple measures of corticospinal excitability are associated with clinical features of multiple sclerosis.

In individuals with multiple sclerosis (MS), transcranial magnetic stimulation (TMS) may be employed to assess the integrity of corticospinal system and provides a potential surrogate biomarker of disability. The purpose of this study was to provide a comprehensive examination of the relationship between multiple measures corticospinal excitability and clinical disability in MS (expanded disability status scale (EDSS)). Bilateral corticospinal excitability was assessed using motor evoked potential (MEP) input-output (IO) curves, cortical silent period (CSP), short-interval intracortical inhibition (SICI), intracortical facilitation (ICF) and transcallosal inhibition (TCI) in 26 individuals with MS and 11 healthy controls. Measures of corticospinal excitability were compared between individuals with MS and controls. We evaluated the relationship(s) between age and clinical demographics such as age at MS onset (AO), disease duration (DD) and clinical disability (EDSS) with measures of corticospinal excitability. Corticospinal excitability thresholds were higher, MEP latency and CSP onset delayed and MEP durations prolonged in individuals with MS compared to controls. Age, DD and EDSS correlated with corticospinal excitability thresholds. Also, TCI duration and the linear slope of the MEP amplitude IO curve correlated with EDSS. Hierarchical regression modeling demonstrated that combining multiple TMS-based measures of corticospinal excitability accounted for unique variance in clinical disability (EDSS) beyond that of clinical demographics (AO, DD). Our results indicate that multiple TMS-based measures of corticospinal and interhemispheric excitability provide insights into the potential neural mechanisms associated with clinical disability in MS. These findings may aid in the clinical evaluation, disease monitoring and prediction of disability in MS.

Progressive multiple sclerosis exhibits decreasing glutamate and glutamine over two years.

BACKGROUND: Few biomarkers of progressive multiple sclerosis (MS) are sensitive to change within the two-year time frame of a clinical trial. OBJECTIVE: To identify biomarkers of MS disease progression with magnetic resonance spectroscopy (MRS) in secondary progressive MS (SPMS). METHODS: Forty-seven SPMS subjects were scanned at baseline and annually for two years. Concentrations of N-acetylaspartate, total creatine, total choline, myo-inositol, glutamate, glutamine, and the sum glutamate+glutamine were measured in a single white matter voxel. RESULTS: Glutamate and glutamine were the only metabolites to show an effect with time: with annual declines of (95% confidence interval): glutamate -4.2% (-6.2% to -2.2%, p < 10(-4)), glutamine -7.3% (-11.8% to -2.9%, p = 0.003), and glutamate+glutamine -5.2% (-7.6% to -2.8%, p < 10(-4)). Metabolite rates of change were more apparent than changes in clinical scores or brain atrophy measures. CONCLUSIONS: The high rates of change of both glutamate and glutamine over two years suggest they are promising new biomarkers of MS disease progression.

Dehydration affects spinal cord cross-sectional area measurement on MRI in healthy subjects.

STUDY DESIGN: This was a prospective cohort observational study. OBJECTIVE: To determine the effect of dehydration and rehydration on spinal cord cross-sectional area (CSA) measurement on magnetic resonance imaging (MRI). SETTING: MRI Research Centre, University of British Columbia, Canada. METHODS: Ten healthy subjects (aged 21-32 years) were scanned on a 3T MRI scanner at four time points: (1) baseline, (2) rescan after 1 h, (3) the next day after fasting for a minimum of 14 h and (4) after rehydration with 1.5 l of water over the course of 1 h. Two independent, established semi-automatic CSA measurement techniques (one based on two-dimensional (2D) edge detection, the other on three-dimensional (3D) surface fitting) were applied to a 3D T1-weighted scan of each subject at each time point, with the operator blinded to scan order. The percentage change in CSA from baseline to each subsequent time point was calculated. One-tailed paired t-tests were used to assess the significance of the changes from baseline. RESULTS: A decrease in CSA following dehydration was detected by both measurement methods, with a mean change of -0.654% (s.d.=0.778, P<0.05) and -0.650% (s.d.=1.071, P<0.05) for the first and second methods, respectively. CONCLUSION: Dehydration can confound CSA measurements on MRI. The magnitude of the effect is significant relative to short-term pathological changes that have been observed in diseases such as multiple sclerosis.

Application and a proposed modification of the 2010 McDonald criteria for the diagnosis of multiple sclerosis in a Canadian cohort of patients with clinically isolated syndromes.

BACKGROUND: The 2005 and 2010 McDonald criteria utilize magnetic resonance imaging (MRI) to provide evidence of disease dissemination in space (DIS) and time (DIT) for the diagnosis of multiple sclerosis (MS) in patients who have clinically isolated syndromes (CIS). METHODS: Data from 109 CIS patients not satisfying the 2005 criteria at entry into a randomized controlled minocycline trial were analyzed to determine the proportion who would have been diagnosed with MS at screening based on 2010 criteria. The impact of including symptomatic, as well as asymptomatic, MRI lesions to confirm DIT was also explored. RESULTS: Thirty percent (33/109) of patients, retrospectively, met the 2010 criteria for a diagnosis of MS at baseline. When both symptomatic and asymptomatic lesions were used to confirm DIT, three additional patients met the 2010 criteria. There was a significant 10.1% increase in the proportion of patients who met the 2010 DIS criteria, compared with the 2005 DIS criteria; however, two patients satisfied the 2005 DIS but not 2010 DIS criteria. CONCLUSION: Using 2010 McDonald criteria, 30% of the CIS patients could be diagnosed with MS using a single MRI scan. Inclusion of symptomatic lesions in the DIT criteria further increases this proportion to 33%.

Two-year study of cervical cord volume and myelin water in primary progressive multiple sclerosis.

BACKGROUND: Spinal cord involvement in multiple sclerosis (MS) is common and an important element in disability. Previous studies demonstrated smaller cervical cord area at the C2 level in MS compared to controls, and a decrease in cord area over 12 months, most marked in primary progressive MS (PPMS). A subset of subjects participating in a multicentre, double-blind, placebo-controlled clinical trial evaluating the efficacy of glatiramer acetate in PPMS (PROMiSe trial) were followed for 2 years. METHODS: 24 PPMS subjects, randomized to placebo (n = 9) and glatiramer acetate (n = 15), and 24 matched controls were studied. Cervical cord volume (CCV) at C2-3 was determined using a 3D inversion recovery (IR)-prepared spoiled-gradient echo sequence. Myelin water fraction (MWF) at C2-3 was obtained using a 32-echo IR-prepared relaxation sequence. Scans were repeated at baseline, years 1 and 2. RESULTS: Baseline CCV was significantly smaller for PPMS than controls [median (interquartile range) 951 (829-1043) vs. 1072 (1040-1129) mm(3), p = 0.0004] and MWF trended to be lower in PPMS cord [median (interquartile range) 0.225 (0.187-0.267) vs. 0.253 (0.235-0.266), p = 0.12]. Baseline CCV correlated with baseline Expanded Disability Status Scale, disease duration, brain white and grey matter volume. In PPMS, CCV was significantly decreased at year 1 (-0.83%, p = 0.04) and year 2 (-1.65%, p = 0.02). Baseline MWF correlated with baseline CCV and brain white and grey matter volume. MWF was significantly decreased from baseline for PPMS at year 2 (-10.5%, p = 0.01). Treatment effect was not detected on change in CCV nor MWF. CONCLUSIONS: Metrics at the level of the cord, including volume and MWF at C2-3, were lower in PPMS than controls and changed over 2 years only in PPMS.

MR relaxation in multiple sclerosis.

This article provides an overview of relaxation times and their application to normal brain and brain and cord affected by multiple sclerosis. The goal is to provide readers with an intuitive understanding of what influences relaxation times, how relaxation times can be accurately measured, and how they provide specific information about the pathology of MS. The article summarizes significant results from relaxation time studies in the normal human brain and cord and from people who have multiple sclerosis. It also reports on studies that have compared relaxation time results with results from other MR techniques.

Dirty-appearing white matter in multiple sclerosis: preliminary observations of myelin phospholipid and axonal loss.

"Dirty-appearing white matter" (DAWM) in multiple sclerosis (MS) is defined as a region(s) with ill-defined borders of intermediate signal intensity between that of normal-appearing white matter (NAWM) and that of plaque on T(2)-weighted and proton density imaging. To delineate the histopathology of DAWM, four formalin-fixed cerebral hemisphere slices of three MS patients with DAWM were scanned with T(2)- weighted and proton density sequences. The myelin water fraction (MWF) was obtained by expressing the short T(2) component as a fraction of the total T(2) distribution. Hemispheric sections were then stained with Luxol fast blue (LFB) for myelin phospholipids, for myelin basic protein (MBP) and 2',3'-cyclic nucleotide 3'-phosphohydrolase (CNP) for myelin; Bielschowsky silver impregnation for axons; and for glial fibrillary acidic protein (GFAP) for astrocytes. Compared to NAWM, DAWM showed reduction in MWF, corresponding to a reduction of LFB staining. DAWM also showed reduced Bielschowsky staining. Quantitatively, the change in MWF in DAWM most consistently correlated with the change in LFB staining. The findings of this preliminary study suggest that DAWM is characterized by loss of myelin phospholipids, detected by the short T(2) component, and axonal reduction.

Multi-parametric MR assessment of T(1) black holes in multiple sclerosis : evidence that myelin loss is not greater in hypointense versus isointense T(1) lesions.

BACKGROUND: Chronic T(1) hypointense lesions in multiple sclerosis (MS) are areas of severe tissue destruction. The purpose of this study was to compare total water content (WC),myelin water content (MWC), magnetization transfer ratio (MTR), T(1) relaxation time (T(1)), mean T(2) relaxation time (GMT(2)) between stable MS lesions that are hypointense and isointense on T(1)-weighted images. METHODS: Six MS patients were scanned five times over one year. WC, MWC, MTR, T(1) and GMT(2) were calculated for 15 isointense and 15 hypointense chronically stable T(1) lesions, as well as contralateral normal appearing white matter (NAWM). RESULTS: All MR measurements from both iso- and hypointense stable lesion types were significantly different from NAWM. WC, T(1) and GMT(2) were significantly higher and MTR significantly lower in hypointense T(1) lesions compared to isointense lesions. MWC was not significantly different between iso- and hypointense lesions. CONCLUSIONS: This work suggests that myelin loss occurs equally in both the chronic isointense and hypointense lesions but hypointense lesions are distinguished by increased extracellular water.

Myelin water imaging in multiple sclerosis: quantitative correlations with histopathology.

Various magnetic resonance (MR) techniques are used to study the pathological evolution of demyelinating diseases, such as multiple sclerosis (MS). However, few studies have validated MR derived measurements with histopathology. Here, we determine the correlation of myelin water imaging, an MR measure of myelin content, with quantitative histopathologic measures of myelin density. The multi-component T2 distribution of water was determined from 25 formalin-fixed MS brain samples using a multi-echo T2 relaxation MR experiment. The myelin water fraction (MWF), defined as T2 signal below 30 milliseconds divided by the total signal, was determined for various regions of interest and compared to Luxol fast blue (myelin stain) mean optical density (OD) for each sample. MWF had a strong correlation with myelin stain [mean (range) R2 = 0.67 (0.45-0.92)], validating MWF as a measure of myelin density. This quantitative technique has many practical applications for the in vivo monitoring of demyelination and remyelination in a variety of disorders of myelin.