Brain volume and fatigue in patients with postpoliomyelitis syndrome.

BACKGROUND: Acute paralytic poliomyelitis is associated with encephalitis. Early brain inflammation may produce permanent neuronal injury with brain atrophy, which may result in symptoms such as fatigue. Brain volume has not been assessed in postpoliomyelitis syndrome (PPS). OBJECTIVE: To determine whether brain volume is decreased compared with that in normal controls, and whether brain volume is associated with fatigue in patients with PPS. DESIGN: A cross-sectional study. SETTING: Tertiary university-affiliated hospital postpolio and multiple sclerosis (MS) clinics. PARTICIPANTS: Forty-nine ambulatory patients with PPS, 28 normal controls, and 53 ambulatory patients with MS. METHODS: We studied the brains of all study subjects with magnetic resonance imaging by using a 1.5 T Siemens Sonata machine. The subjects completed the Fatigue Severity Scale. Multivariable linear regression models were computed to evaluate the contribution of PPS and MS compared with controls to explain brain volume. MAIN OUTCOME MEASUREMENTS: Normalized brain volume (NBV) was assessed with the automated program Structured Image Evaluation, using Normalization, of Atrophy method from the acquired magnetic resonance images. This method may miss brainstem atrophy. RESULTS: Technically adequate NBV measurements were available for 42 patients with PPS, 27 controls, and 49 patients with MS. The mean (standard deviation) age was 60.9 ± 7.6 years for patients with PPS, 47.0 ± 14.6 years for controls, and 46.2 ± 9.4 years for patients with MS. In a multivariable model adjusted for age and gender, NBV was not significantly different in patients with PPS compared with that in controls (P = .28). As expected, when using a similar model for patients with MS, NBV was significantly decreased compared with that in controls (P = .006). There was no significant association between NBV and fatigue in subjects with PPS (Spearman ρ = 0.23; P = .19). CONCLUSIONS: No significant whole-brain atrophy was found, and no association of brain volume with fatigue in PPS. Brain atrophy was confirmed in MS. It is possible that brainstem atrophy was not recognized by this study.

Automatic detection of gadolinium-enhancing multiple sclerosis lesions in brain MRI using conditional random fields.

Gadolinium-enhancing lesions in brain magnetic resonance imaging of multiple sclerosis (MS) patients are of great interest since they are markers of disease activity. Identification of gadolinium-enhancing lesions is particularly challenging because the vast majority of enhancing voxels are associated with normal structures, particularly blood vessels. Furthermore, these lesions are typically small and in close proximity to vessels. In this paper, we present an automatic, probabilistic framework for segmentation of gadolinium-enhancing lesions in MS using conditional random fields. Our approach, through the integration of different components, encodes different information such as correspondence between the intensities and tissue labels, patterns in the labels, or patterns in the intensities. The proposed algorithm is evaluated on 80 multimodal clinical datasets acquired from relapsing-remitting MS patients in the context of multicenter clinical trials. The experimental results exhibit a sensitivity of 98% with a low false positive lesion count. The performance of the proposed algorithm is also compared to a logistic regression classifier, a support vector machine and a Markov random field approach. The results demonstrate superior performance of the proposed algorithm at successfully detecting all of the gadolinium-enhancing lesions while maintaining a low false positive lesion count.

Bayesian classification of multiple sclerosis lesions in longitudinal MRI using subtraction images.

Accurate and precise identification of multiple sclerosis (MS) lesions in longitudinal MRI is important for monitoring disease progression and for assessing treatment effects. We present a probabilistic framework to automatically detect new, enlarging and resolving lesions in longitudinal scans of MS patients based on multimodal subtraction magnetic resonance (MR) images. Our Bayesian framework overcomes registration artifact by explicitly modeling the variability in the difference images, the tissue transitions, and the neighbourhood classes in the form of likelihoods, and by embedding a classification of a reference scan as a prior. Our method was evaluated on (a) a scan-rescan data set consisting of 3 MS patients and (b) a multicenter clinical data set consisting of 212 scans from 89 RRMS (relapsing-remitting MS) patients. The proposed method is shown to identify MS lesions in longitudinal MRI with a high degree of precision while remaining sensitive to lesion activity.

Detection of Gad-enhancing lesions in multiple sclerosis using conditional random fields.

Identification of Gad-enhancing lesions is of great interest in Multiple Sclerosis (MS) disease since they are associated with disease activity. Current techniques for detecting Gad-enhancing lesions use a contrast agent (Gadolinium) which is administered intravenously to highlight Gad-enhancing lesions. However, the contrast agent not only highlights these lesions, but also causes other tissues (e.g., blood vessels) or noise in the Magnetic Resonance Image (MRI) to appear hyperintense. Discrimination of enhanced lesions from other enhanced structures is particularly challenging as these lesions are typically small and can be found in close proximity to vessels. We present a new approach to address the segmentation of Gad-enhancing MS lesions using Conditional Random Fields (CRF). CRF performs the classification by simultaneously incorporating the spatial dependencies of data and labels. The performance of the CRF classifier on 20 clinical data sets shows promising results in successfully capturing all Gad-enhancing lesions. Furthermore, the quantitative results of the CRF classifier indicate a reduction in the False Positive (FP) rate by an average factor of 5.8 when comparing to Linear Discriminant Analysis (LDA) and 1.6 comparing to a Markov Random Field (MRF) classifier.

Evaluation of automated techniques for the quantification of grey matter atrophy in patients with multiple sclerosis.

Several methods exist and are frequently used to quantify grey matter (GM) atrophy in multiple sclerosis (MS). Fundamental to all available techniques is the accurate segmentation of GM in the brain, a difficult task confounded even further by the pathology present in the brains of MS patients. In this paper, we examine the segmentations of six different automated techniques and compare them to a manually defined reference standard. Results demonstrate that, although the algorithms perform similarly to manual segmentations of cortical GM, severe shortcomings are present in the segmentation of deep GM structures. This deficiency is particularly relevant given the current interest in the role of GM in MS and the numerous reports of atrophy in deep GM structures.

Gradient distortions in MRI: characterizing and correcting for their effects on SIENA-generated measures of brain volume change.

Precise and accurate quantification of whole-brain atrophy based on magnetic resonance imaging (MRI) data is an important goal in understanding the natural progression of neurodegenerative disorders such as Alzheimer's disease and multiple sclerosis. We found that inconsistent MRI positioning of subjects is common in typically acquired clinical trial data - particularly along the magnet's long (i.e., Z) axis. We also found that, if not corrected for, the gradient distortion effects associated with such Z-shifts can significantly decrease the accuracy and precision of MRI-derived measures of whole-brain atrophy - negative effects that increase in magnitude with (i) increases in the Z-distance between the brains to be compared and (ii) increases in the Z-distance from magnet isocenter of the center of the pair of brains to be compared. These gradient distortion effects can be reduced by accurate subject positioning, and they can also be corrected post hoc with the use of appropriately-generated gradient-distortion correction fields. We used a novel DUPLO-based phantom to develop a spherical-harmonics-based gradient distortion field that was used to (i) correct for observed Z-shift-associated gradient distortion effects on SIENA-generated measures of brain atrophy and (ii) simulate the gradient distortion effects that might be expected with a greater range of Z-shifts than those that we were able to acquire. Our results suggest that consistent alignment to magnet isocenter and/or correcting for the observed effects of gradient distortion should lead to more accurate and precise estimates of brain-related changes and, as a result, to increased statistical power in studies aimed at understanding the natural progression and the effective treatment of neurodegenerative disorders.

Measuring demyelination and remyelination in acute multiple sclerosis lesion voxels.

OBJECTIVE: To validate the use of the magnetization transfer ratio (MTR) as a practical imaging marker of demyelination and remyelination in acute multiple sclerosis lesions. DESIGN: Case study. SETTING: University hospital multiple sclerosis clinic. Patients Six patients with relapsing-remitting multiple sclerosis and acute gadolinium-enhancing lesions were studied serially using a quantitative magnetization transfer examination. MAIN OUTCOME MEASURES: Changes in the water content and macromolecular content, a marker of myelin content that, unlike MTR, is not affected by changes in water content (edema) associated with acute inflammation, and changes in MTR of lesions. RESULTS: Both the macromolecular content and MTR were lower than normal in acute lesions and recovered over several months. The decrease in macromolecular content relative to contralateral normal-appearing white matter was greater than the decrease in MTR (0.46 vs 0.75 at the time of gadolinium enhancement), likely because edema in the acute lesion increased the T1 relaxation time of water and attenuated the decrease in MTR. Nevertheless, there was still a strong correlation between changes in the relative MTR and macromolecular content (R(2) = 0.70; P < .001). CONCLUSION: Our data support the use of MTR as a practical marker of demyelination and remyelination, even in acute lesions where decreases in MTR are attenuated because of the effects of edema.

Lesion distribution in children with clinically isolated syndromes.

We evaluated the incidence, volume, and spatial distribution of T2-weighted magnetic resonance imaging lesions in 58 children with clinically isolated syndromes at risk for multiple sclerosis compared with 58 adults with relapsing-remitting multiple sclerosis. Pediatric patients with clinically isolated syndromes who had brain lesions had supratentorial lesion volumes similar to adult multiple sclerosis patients, but greater infratentorial lesion volumes (p < 0.009), particularly in the pons of male patients. The predilection for infratentorial lesions the pediatric patients with clinically isolated syndromes may reflect immunological differences or differences in myelin, possibly related to the caudorostral temporal gradient in myelin maturation.

Axonal injury in the cerebral normal-appearing white matter of patients with multiple sclerosis is related to concurrent demyelination in lesions but not to concurrent demyelination in normal-appearing white matter.

We assessed axonal injury and demyelination in the cerebral normal-appearing white matter (NAWM) of MS patients in a pilot study using proton magnetic resonance spectroscopic imaging and quantitative magnetization transfer (MT) imaging. Resonance intensities of N-acetylaspartate (NAA) relative to creatine (Cr) were measured in a large central brain volume. NAA/Cr in NAWM was estimated by regression of the NAA/Cr in each voxel against white matter fraction and extrapolation to a white matter fraction of 1. The fractional size of the semi-solid pool (F) was obtained from the binary spin bath model of MT by computing the model parameters from multiple MT-weighted and relaxometry acquisitions. F in NAWM was significantly smaller in the patients [0.109 (0.009)] relative to controls [0.123 (0.007), P = 0.011], but did not differ between RR [0.1085] and SP [0.1087] patients [P > 0.99]. NAA/Cr and F in the NAWM were not correlated (r = 0.16, P > 0.7), mainly due to a lack of variation in F among patients. This may indicate a floor to the extent of myelin pathology that can occur in NAWM before a lesion appears, or that axonal damage is not strictly related to demyelination. The correlation between NAWM NAA/Cr and T2w lesion volume was not significant (P > 0.1). However, dividing the lesion volumes by the mean F in T2w lesions resulted in a quantity that correlated well with NAWM NAA/Cr (r = -0.78, P = 0.038), possibly reflecting the association of Wallerian degeneration in the NAWM with axonal transection associated with demyelination within lesions.

The role of edema and demyelination in chronic T1 black holes: a quantitative magnetization transfer study.

PURPOSE: To use quantitative magnetization transfer imaging (qMTI) in an investigation of T1-weighted hypointensity observed in clinical magnetic resonance imaging (MRI) scans of multiple sclerosis (MS) patients, which has previously been proposed as a more specific indicator of tissue damage than the more commonly detected T2 hyperintensity. MATERIALS AND METHODS: A cross-sectional study of 10 MS patients was performed using qMTI. A total of 60 MTI measurements were collected in each patient at a resolution of 2 x 2 x 7 mm, over a range of saturation pulses. The observed T1 and T2 were also measured. qMT model parameters were estimated using a voxel-by-voxel fit. RESULTS: A total of 65 T2-hyperintense lesions were identified; 53 were also T1 hypointense. In these black holes, the qMTI-derived semisolid pool fraction F correlated negatively with T(1,obs) (r2 = 0.76; P < 0.0001). The water pool absolute size (PDf) showed a weaker correlation with T(1,obs) (positive, r2 = 0.53; P < 0.0001). The magnetization transfer ratio (MTR) showed a similarly strong correlation with F and a weaker correlation with PDf (r2 = 0.18; P < 0.04). CONCLUSION: T1 increases in chronic black holes strongly correlated with the decline in semisolid pool size, and somewhat less to the confounding effect of edema. MTR was less sensitive than T(1,obs) to liquid pool changes associated with edema.

The relationship between diffuse axonal damage and fatigue in multiple sclerosis.

BACKGROUND: Fatigue is a common and distressing symptom for patients with multiple sclerosis (MS). There is growing evidence that fatigue in MS has a central nervous system component. We hypothesized that diffuse cerebral axonal damage could be associated with fatigue and used proton magnetic resonance spectroscopy to noninvasively measure axonal damage or loss in the brains of patients with MS. OBJECTIVE: To assess the strength of the relationship between central brain N-acetylaspartate and fatigue. DESIGN: Data from 73 patients who had undergone proton magnetic resonance spectroscopy imaging and completed the Fatigue Severity Scale questionnaire were analyzed. RESULTS: The N-acetylaspartate-creatine ratio (NAA/Cr) was significantly lower in the high-fatigue group than the low-fatigue group (mean +/- SD, 2.69 +/- 0.29 and 2.99 +/- 0.33, respectively. P =.003). Independent of the Kurtzke Expanded Disability Status Scale, T2 lesion volume, age, and disease duration, NAA/Cr was significantly lower in the high-fatigue group as compared with the low-fatigue group. There was a statistically significant linear correlation between the Fatigue Severity Scale scores and NAA/Cr (Spearman rank rho = -0.361, P =.02). CONCLUSIONS: The results of this study, combined with those of others, suggest that widespread axonal dysfunction is associated with fatigue in MS. Increased recruitment of cortical areas and pathways in response to brain injury may be responsible for the patient's sense that the effort required to perform actions is disproportionately high.

Diffuse axonal and tissue injury in patients with multiple sclerosis with low cerebral lesion load and no disability.

BACKGROUND: Although in situ pathological studies and in vivo magnetic resonance (MR) investigations have shown that axonal injury can be significant in the early stages of multiple sclerosis (MS), diffuse axonal injury is generally considered a secondary event. Cerebral axonal damage can be specifically assessed in vivo by measuring levels of brain N-acetylaspartate (NAA, a specific index of axonal integrity detected by MR spectroscopy). Other new MR measurements such as magnetization transfer ratio (MTr) or computed estimation of brain volume can provide less specific indexes of tissue damage. OBJECTIVE: To determine whether diffuse axonal and tissue injury is present in patients with definite MS who do not show clinically significant disability. METHODS: We measured brain NAA levels (normalized to creatine [Cr]), MTr values, and cerebral volumes in patients with definite MS who had low T2-weighted MR imaging lesion volumes and no clinical disability, and also in age-matched healthy control subjects. RESULTS: Values of central brain NAA/Cr and MTr in normal-appearing white matter were significantly lower in the MS patients than in controls (P<.001). In contrast, total brain volumes were not significantly different between these groups. Similar results were found for MS patients with early disease (duration, <3 years) and with a particularly low cerebral T2-weighted MR imaging lesion load (< or = 2 cm(3)). CONCLUSIONS: Cerebral NAA/Cr and MTr values are diffusely decreased in MS patients with early disease, low demyelinating lesion load, and no significant disability. This suggests that axonal and/or tissue injury begins very early in the course of MS and might be at least partially independent of cerebral demyelination.

Magnetization transfer can predict clinical evolution in patients with multiple sclerosis.

The clinical course of multiple sclerosis (MS) is highly variable ranging from benign to aggressive, and is difficult to predict. Since magnetization transfer (MT) imaging can detect focal abnormalities in normal-appearing white matter (NAWM) before the appearance of lesions on conventional MRI, we hypothesized that changes in MT might be able to predict the clinical evolution of MS. We assessed MR data from MS patients who were subsequently followed clinically for 5 years. We computed the mean MT ratio (MTr) in gray matter, in lesions identified on T2-weighted MRI, and in NAWM, as well as in a thick central brain slice for each patient. Patients were divided into stable and worsening groups according to their change in Expanded Disability Status Scale (EDSS) scores over 5 years. We calculated the sensitivity, specificity, predictive value, and odds ratio of the baseline MTr measures in order to assess their prognostic utility. We found significant differences in baseline MTr values in NAWM (p = 0.005) and brain slice (p = 0.03) between clinically stable and worsening MS patients. When these MTr values were compared with changes in EDSS over 5 years, a strong correlation was found between the EDSS changes and MTr values in both NAWM (SRCC = -0.76, p < 0.001) and in the brain slice (SRCC = 0.59, p = 0.01). Baseline NAWM MTr correctly predicted clinical evolution in 15/18 patients (1 false positive and 2 false negatives), yielding a positive predictive value of 77.78 %, a negative predictive value of 88.89 %, and an odds ratio of 28. The relationship between 5-year changes in EDSS and MTr values in T2 weighted MRI lesions was weaker (SRCC = -0.43, p = 0.07). Our data support the notion that the quantification of MTr in the NAWM can predict the clinical evolution of MS. Lower MTr values predict poorer long-term clinical outcome. Abnormalities of MTr values in the NAWM are more relevant to the development of future patient disability than those in the T2-weighted MRI lesions.