Change In Lesion Volume Research Articles

Automatic Quantification of Changes in Bone in Serial MR Images of Joints

Recent innovations in drug therapies have made it highly desirable to obtain sensitive biomarkers of disease progression that can be used to quantify the performance of candidate disease modifying drugs. In order to measure potential image-based biomarkers of disease progression in an experimental model of rheumatoid arthritis (RA), we present two different methods to automatically quantify changes in a bone in in-vivo serial magnetic resonance (MR) images from the model. Both methods are based on rigid and nonrigid image registration to perform the analysis. The first method uses segmentation propagation to delineate a bone from the serial MR images giving a global measure of temporal changes in bone volume. The second method uses rigid body registration to determine intensity change within a bone, and then maps these into a reference coordinate system using nonrigid registration. This gives a local measure of temporal changes in bone lesion volume. We detected significant temporal changes in local bone lesion volume in five out of eight identified candidate bone lesion regions, and significant difference in local bone lesion volume between male and female subjects in three out of eight candidate bone lesion regions. But the global bone volume was found to be fluctuating over time. Finally, we compare our findings with histology of the subjects and the manual segmentation of bone lesions.

Longitudinal magnetic resonance imaging of spinal cord injury in mouse: changes in signal patterns associated with the inflammatory response

Contusion-type spinal cord injury (SCI) in mice was followed longitudinally using in vivo magnetic resonance (MR) imaging along with neurobehavioral tests performed on postinjury Days 1, 7, 14 and 28. Magnetic resonance images were acquired from seven injured wild-type mice using a 9.4-T scanner and presented in sagittal and axial views to reflect the current state of the injured cord neuropathology on each day. The data were analyzed individually to gain more insights on the neuroinflammatory response unique to the mouse, to characterize the spatiotemporal evolution of the lesion and to quantify the changes in lesion volume and length with time. The MR intensity patterns on Day 1 showed acute injuries as focal in one group of three mice and as diffuse in the remaining group of four mice. The focal injuries appeared as a region of hypointensity with well-defined boundaries. These injuries first enlarged on Day 7, but then shrunk slightly by Days 14 and 28. In contrast, the diffuse injuries were initially obscure on Day 1, mainly because of loss of contrast between gray and white matters. On Day 7, lesions expanded asymptotically in both rostral and caudal directions with respect to the epicenter, and maintained its size on Days 14 and 28. Previous studies based on postmortem histological analysis have reported lesions behaving more like in the focal group. However, this new injury with diffuse characteristics may have important implications for SCI research carried out with mice. Unique experiments on genetically engineered mice with altered neuroinflammatory response should help clarify the origin of these differences in the lesion formation.

Significance of T2 lesions in multiple sclerosis: A 13-year longitudinal study

To evaluate the relation between T2 lesions and disease severity in relapsing-remitting multiple sclerosis (MS). This article describes a 13-year longitudinal study in 30 patients. Patients were 36.3 +/- 6.0 years old, had MS for 6.1 +/- 5.8 years, Expanded Disability Status Scale was 2.2 +/- 0.8, and brain parenchymal fraction (BPF) was 0.825 +/- 0.015 at study entry. At last visit, Expanded Disability Status Scale was 4.4 +/- 1.95, Multiple Sclerosis Functional Composite was -0.34 +/- 1.7, and BPF was 0.774 +/- 0.037. Baseline T2 lesion volume correlated with the BPF of the last visit (r = -0.66; p < 0.0001), magnetization transfer ratio (MTR) in normal-appearing brain tissue (r = -0.52; p = 0.004), and lesion MTR (r = -0.76; p < 0.0001). Change in T2 lesion volume in the first 2 years correlated with BPF of the last visit (r = -0.40; p = 0.03), normal-appearing brain tissue MTR (r = -0.44; p = 0.015), lesion MTR (r = -0.46; p = 0.018), Multiple Sclerosis Functional Composite scores (r = -0.50; p = 0.005), and Paced Auditory Serial Addition Task scores (r = -0.52; p = 0.003). Age was a significant covariate for clinical but not magnetic resonance imaging outcomes. T2 lesions in relapsing-remitting MS correlate strongly with brain tissue loss and brain tissue integrity 13 years later, and with clinical disease severity, though age significantly impacts the clinical correlation. The results provide direct evidence for the disability threshold hypothesis in MS and support monitoring T2 lesions in relapsing-remitting MS.

White matter and subcortical gray matter lesion volume changes and late-life depression outcome: a 4-year magnetic resonance imaging study

Cross-sectional studies have shown that late-onset depression is associated with larger deep white matter lesions (WMLs) and subcortical gray matter lesions (GMLs). In a longitudinal analysis, we examined changes in deep WMLs and subcortical GMLs in older depressed and nondepressed subjects over a 4-year period. Brain magnetic resonance imaging (MRI) scans were obtained on 164 depressed and 126 healthy subjects aged 60 years or older at baseline, and 2 and 4 years after recruitment. WMLs and GMLs were measured using a semiautomated technique. We used repeated-measures analysis of covariance to determine cross-sectional lesion volume differences, whether lesion volume changes differed between patients and controls, and the effect of lesion volume changes on outcome in late-life depression. Mean volumes of lesions for the depressive group were 6.51, 8.18 and 7.75 cm2 for WMLs and 0.23, 0.30 and 0.34 cm2 for GMLs at baseline, 2-year and 4-year follow-up, respectively. Mean volumes of lesions for the control group were 4.83, 6.22 and 6.45 cm2 for WMLs and 0.17, 0.25 and 0.23 cm2 for GMLs at baseline, 2-year and 4-year follow-up, respectively. Cross-sectional between-group mean lesion volumes were significantly different for each measure. However, the pattern of WML and GML volume changes over time was not significantly different between groups. Treatment outcome was associated with changes in total and white matter lesion volume over time. Lesion volume progression is associated with aging and the pathological condition of late-life depression. The mechanisms that produce these progressive lesion changes remain unclear. Treatments aimed at arresting lesion progression may play a role in the management of late-life depression.

The Evolution of Cerebral Ischemia in a Rat Model of Complete Unilateral Carotid Artery Occlusion With Severe Hypotension as Detected By Diffusion-, T2-, and Postcontrast T1-Weighted Magnetic Resonance Images

Severe internal carotid artery stenosis or occlusion is considered to be one of the important causes of stroke. The authors created a complete unilateral carotid artery occlusion model in 15 Sprague-Dawley rats, induced severe hypotension for at least 36 minutes by exsanguination with the target mean arterial pressure being equal or less than 35 mmHg, and investigated the temporal and spatial evolution of cerebral ischemia by diffusion-, T2-, and postcontrast T1-weighted magnetic resonance images. Cerebral ischemia was detected in most regions of the right middle cerebral artery territory during exsanguination. There was no significant relationship between ischemic lesion volume detected on apparent diffusion coefficient (ADC) map (ADC lesion volume) and infarction volume found on histopathology. However, there was a linear relationship between the change in ADC lesion volume at blood reinfusion (after reinfusion minus before reinfusion) and the enlargement of the lesion volume during the postreinfusion period (Y = 0.4X + 161.7, P = 0.0066) and a significant logarithmic correlation between the volume of vasogenic edema found on postcontrast T1-weighted image at 1 hour of the postreinfusion period and the enlargement of the lesion volume during the postreinfusion period (Y = 62.1 x logX - 115.4, P = 0.022). In conclusion, although it may be difficult to predict the outcome of cerebral ischemia (infarction volume) from the lesion volume during exsanguination, the evolution of cerebral ischemia may be partly predicted by lesion volume changes seen on the ADC maps at the time of the blood reinfusion or by the severity of blood-brain barrier disruption at the early stage of the postreinfusion period.

Experimental stroke: ischaemic lesion volume and oedema formation differ among rat strains (a comparison between Wistar and Sprague–Dawley rats using MRI)

Investigating focal cerebral ischaemia requires animal models that are relevant to human stroke. This study was designed to evaluate the influence of early reperfusion and choice of rat strains on infarct volume and oedema formation. Thirty-six Wistar and Sprague-Dawley rats were subjected to temporary middle cerebral artery occlusion (MCAO) for 90 min (groups I and II) or to permanent MCAO (groups III and IV) using the suture technique. Ischaemic lesion volume and oedema formation were quantified 24 h after MCAO using 7T-magnetic resonance imaging (MRI). Impact of rat strains: Reperfusion led to significant larger ischaemic lesion volumes in Wistar rats as compared to Sprague-Dawley rats (P<0.0005). Oedema formation was similar in both rat strains. Permanent MCAO led to significantly larger ischaemic lesion volumes in Sprague-Dawley rats (P<0.05). Oedema formation, however, was significantly more accentuated in Wistar rats (P<0.005). Impact of reperfusion: Reperfusion did not cause any changes in ischaemic lesion volume in Wistar rats. Oedema formation, however, was significantly reduced (P<0.0005). In Sprague-Dawley rats, reperfusion caused a significant reduction of ischaemic lesion volume (P<0.00005), but did not modify oedema formation. These findings emphasize the critical importance of rat strain differences in experimental stroke research.

Suppression of Ongoing Disease in a Nonhuman Primate Model of Multiple Sclerosis by a Human-Anti-Human IL-12p40 Antibody

IL-12p40 is a shared subunit of two cytokines with overlapping activities in the induction of autoreactive Th1 cells and therefore a potential target of therapy in Th1-mediated diseases. We have examined whether ongoing disease in a nonhuman primate model of multiple sclerosis (MS) can be suppressed with a new human IgG1kappa Ab against human IL-12p40. Lesions developing in the brain white matter were visualized and characterized with standard magnetic resonance imaging techniques. To reflect the treatment of MS patients, treatment with the Ab was initiated after active brain white matter lesions were detected in T2-weighted images. In placebo-treated control monkeys we observed the expected progressive increase in the total T2 lesion volume and markedly increased T2 relaxation times, a magnetic resonance imaging marker of inflammation. In contrast, in monkeys treated with anti-IL-12p40 Ab, changes in the total T2 lesion volume and T2 relaxation times were significantly suppressed. Moreover, the time interval to serious neurological deficit was delayed from 31 +/- 10 to 64 +/- 20 days (odds ratio, 0.312). These results, in a disease model with high similarity to MS, are important for ongoing and planned trials of therapies that target IL-12 and/or IL-23.

White matter lesion progression, brain atrophy, and cognitive decline: The Austrian stroke prevention study

White matter lesions progress over time, but the clinical consequences are widely unknown. Three-hundred twenty-nine elderly community-dwelling volunteers underwent serial magnetic resonance imaging scanning and cognitive testing at baseline and at 3- and 6-year follow-up. We measured the changes in white matter lesion and brain parenchymal volumes. After 6 years, the median increase in white matter lesion load was 0.2 cm3 (interquartile range [IQR], 0.0-0.80 cm3) with a maximum of 31.4 cm3. The median loss of brain volume was 2.3% (IQR, 1.13-3.58%). Increasing white matter lesion volume was correlated with loss of brain volume (p < 0.0001) and performance decline in tests of memory (p = 0.022), conceptualization (p = 0.046), and visuopractical skills (p = 0.005). Associations between changes in white matter lesion load and cognitive functioning were no longer significant when adding change in brain volume to the models, suggesting that cognitive decline related directly to loss of brain substance with progression of lesion burden.

1187 Changes in lesion volume and apparent diffusion coefficient value are associated with clinical progression of pure lacunar Infarcts

1187 Changes in lesion volume and apparent diffusion coefficient value are associated with clinical progression of pure lacunar Infarcts

White matter lesion progression: a surrogate endpoint for trials in cerebral small-vessel disease.

There is neuropathologic evidence that confluent MRI white matter lesions in the elderly reflect ischemic brain damage due to microangiopathy. The authors hypothesize that measuring changes in the progression of white matter lesions as shown by MRI may provide a surrogate marker in clinical trials on cerebral small-vessel disease in which the currently used primary outcomes are cognitive impairment and dementia. This hypothesis is based on evidence that confluent white matter lesions progress rapidly as shown in a recent follow-up study in community-dwelling subjects. The mean increase in lesion volume was 5.2 cm(3) after 3 years. Based on these data in a clinical trial, 195 subjects with confluent lesions would be required per treatment arm to demonstrate a 20% reduction in the rate of disease progression over a 3-year period. Like any other MRI metric, the change in white matter lesion volume cannot be considered preferable to clinical outcomes unless it has been demonstrated that it matters to the patient in terms of function.

Morphometry of hepatic neoplasms and altered foci in the mummichog, Fundulus heteroclitus.

The goal of this study was to intensively sample a small number of livers from a population of mummichog exposed to PAH-contaminated sediments and evaluate them for lesion pathology, distribution, shape, and volume, and the number of histological sections needed to adequately describe the extent of various lesions. Volumetric data for each lesion type from each step section was derived from digitized section images. The total number of hepatic alterations ranged from 10-125 per fish. Alterations included: eosinophilic, basophilic, and clear cell foci; hepatocellular carcinomas; hemangiopericytomas; and cholangiomas. Lesion volumes ranged from 0.00012-64 mm3 and represented 0.21%-67% of total liver volume. There was a tendency for the lesions to be more dorsal-ventrally compressed than spherical or ropelike when observed from longitudinal sections. Periodic subsampling of the data indicated that. on average, 6 evenly spaced, longitudinal histological sections were required to accurately estimate lesion volume and extent in our model population. These data provide a formulation for histological sampling techniques and methodological support for piscine and other cancer study models that observe lesion volume changes over time. Further, this study fosters the development of early quantitative endpoints. rather than using a large number of animals and waiting for tumor progression or death to occur.

Multispectral analysis of bone lesions in the hands of patients with rheumatoid arthritis

Quantitative measures of rheumatoid arthritis (RA) disease progression can provide valuable tools for evaluation of new treatments during clinical trials. In this study, a novel multispectral (MS) MRI analysis method is presented to quantify changes in bone lesion volume (DeltaBLV) in the hands of RA patients. Image registration and MS analysis were employed to identify MS tissue class transitions between two serial MRI exams. DeltaBLV was determined from MS class transitions between two time points. The following three classifiers were investigated: (a) multivariate Gaussian (MVG), (b) k-nearest neighbor (k-NN), and (c) K-means (KM). Unlike supervised classifiers (MVG, k-NN), KM, an unsupervised classifier, does not require labeled training data, resulting in potentially greater clinical utility. All MS estimates of DeltaBLV were linearly correlated (r(p)) with manual estimates. KM and k-NN estimates also exhibited a significant rank-order correlation (r(s)) with manual estimates. For KM, r(p) = 0.94 p < 0.0001, r(s) = 0.76 p = 0.002; for k-NN, r(p) = 0.86 p = 0.0001, r(s) = 0.69 p = 0.009; and for MVG, r(p) = 0.84 p = 0.0003, r(s) = 0.49 p = 0.09. Temporal classification rates were as follows: for KM, 90.1%; for MVG, 89.5%; and for k-NN, 86.7%. KM matched the performance of k-NN, offering strong potential for use in multicenter clinical trials. This study demonstrates that MS tissue class transitions provide a quantitative measure of DeltaBLV.

Use of multispectral magnetic resonance imaging analysis to quantify erosive changes in the hands of patients with rheumatoid arthritis: short-term and long-term longitudinal studies.

Magnetic resonance imaging (MRI) has been shown to be more sensitive than radiography for detecting bone erosions in rheumatoid arthritis (RA). Semiquantitative scoring based on visual image assessment has been introduced. However, there is considerable interest in true quantitative measures, particularly in the context of clinical trials designed to show differences between treatment groups. This study was undertaken to investigate the use of a new quantitative approach, multispectral (MS) image analysis, for assessing erosive change. T1-weighted spin-echo (SE) and fat-suppressed gradient-echo (GE) sequences of metacarpophalangeal joints of the dominant hand were acquired at various time points throughout a 2-year period. MS analysis was applied to all images, resulting in segmentation into a generalized bone and a soft tissue class. Voxel changes from one to the other class identified apparent bone lesion volume change (Delta BLV). MR images were also visually scored for erosions (E score). All analyses were performed separately, on a per-joint basis, for short-term and long-term data sets. Analysis of variance with adjustment for individual effect revealed similar results in the short-term and the long-term studies, using either GE or SE images for visual assessment. Patients with an increase in E score on visual assessment had a significantly higher Delta BLV than those without. Temporal MS analysis of MRIs can be used to detect and quantify erosive changes in RA. This semiautomated method may be useful for demonstrating differences between treatment groups in clinical trials.

Early development of multiple sclerosis is associated with progressive grey matter atrophy in patients presenting with clinically isolated syndromes.

While brain atrophy occurs early in the clinical course of multiple sclerosis, exactly how early, which tissues are affected and the rate at which early atrophy occurs are unclear. Regional brain atrophy was investigated in 58 patients recruited within 3 months of onset of a clinically isolated syndrome (CIS) suggestive of multiple sclerosis, who were followed-up for 3 years. At 3 years, 31 subjects had developed multiple sclerosis as defined by the McDonald criteria, while 27 had not (13 had MRI-visible brain lesions and 14 did not). In those who developed multiple sclerosis, the mean decrease in grey matter fractional volume (GMF, as a fraction of total intracranial volume) was -0.017 (-3.3%) and was significantly larger than in the combined lesion-positive and lesion-negative CIS subjects [-0.005 (-1.1%), P = 0.001]. No decrease in white matter fractional volumes (WMF) was seen. Change in GMF correlated only modestly with the change in T2 lesion volume from baseline to year 3 (r = -0.428, P = 0.004). These results suggest that progressive grey matter, but not white matter, atrophy is seen in the earliest clinically observable stages of relapse onset multiple sclerosis, and this is only moderately related to lesion accumulation. Longer-term follow-up is required to determine whether early grey matter atrophy is associated with subsequent disability or cognitive impairment.

Clinical and MRI outcome after autologous hematopoietic stem cell transplantation in MS.

The authors report the outcome of 14 patients with severe multiple sclerosis treated with autologous hematopoietic stem cell transplantation (AHSCT) after a median follow-up period of 3 years. The 3-year actuarial probability of progression-free survival was 85.7% and that of disease activity-free survival was 46.4%. On MRI, no T1-enhanced lesions were detected after AHSCT. The mean change in T2 lesion volume from baseline to the third year was -20.2% and that of the corpus callosum area was -12.7%; 50% of this reduction was seen during the first year.

Serial MRI in multiple sclerosis: a prospective pilot study of lesion load, whole brain volume and thalamic atrophy.

Using serial magnetic resonance imaging (MRI), we investigated the relationship between diffuse cerebral atrophy, T1 and T2 lesion volumes, mean thalamic volumes and clinical progression in patients with established multiple sclerosis (MS). Eleven patients were included in this prospective serial study. Cerebral volumes, T1 hypointense lesion volumes, and T2 hyperintense lesion volumes at baseline and at up to 3 years follow-up were assessed on MRI brain scans. As a putative measure of cerebral atrophy mean thalamic volumes were also obtained. The outcome measures were the MRI parameters and disability on Kurtzke's expanded disability status scale (EDSS). Of the 11 patients 6 worsened clinically as measured by an increase of 0.5 or more on the EDSS. Cerebral atrophy occurred in 91% of patients and was independent of changes in lesion volumes and was not associated with disease progression as determined by the EDSS.

Serial MR Imaging of Volumes of Hyperintense White Matter Lesions in Elderly Patients: Correlation with Vascular Risk Factors

The purpose of the study was to examine change in volume of hyperintense white matter lesions in a cohort of community-dwelling elderly subjects without neuropsychiatric disease. SUBJECTS AND METHODS. One hundred seventeen volunteers underwent brain MR imaging on a 1.5-T scanner. Demographic data and the presence of specific medical illnesses were recorded at the time of the initial scanning. Hyperintense white matter lesion volume was measured using a supervised semiautomated technique that seeded lesions and then created a segmented lesion image. Subjects underwent repeated MR imaging at a mean of 25 months. Mean change in lesion volume and mean percentage of change were determined between the two time points. Logistic regression models were used to examine the differential effects of age, sex, race, and self-reported medical morbidity. Mean baseline volume of cerebral hyperintense lesions was 4.91 cc, and at 2-year follow-up, it was 6.42 cm(2) (p < 0.0001), for a mean increase of 26.7%. Comparable results were seen in separate analyses of hemispheric hyperintense lesion volumes. Neither sex, race, nor baseline hyperintense lesion volume was significantly associated with an interval increase in lesion volume. Age (p = 0.0117) and presence of diabetes (p = 0.0215) were associated with greater change. Elderly subjects exhibited approximately a 27% increase in hyperintense lesion volume over a 2-year period, a finding influenced by both age and medical comorbidity rates. Because hyperintense lesions can be associated with several neuropsychiatric conditions, further research is needed to determine if interventions designed to slow hyperintense lesion disease progression may improve neuropsychiatric outcomes.

Choline is increased in pre-lesional normal appearing white matter in multiple sclerosis.

Our aim was to determine if the resonance intensity of choline-containing compounds (Cho) measured using proton magnetic resonance spectroscopy (MRS) was increased in pre-lesional normal appearing white matter (NAWM) in patients with multiple sclerosis (MS) relative to NAWM that remained stable in subsequent scans. The Cho peak in MR spectra is associated with membrane phospholipids and increases in acute MS plaques, possibly even before the appearance of MRI-visible MS lesions. Three combined proton MRI and MRS imaging examinations of the corpus callosum and adjacent periventricular white matter were performed on 12 MS patients at intervals of 6 months. Proton density (PD) images were visually matched across 3 time points and the lesion volume in each voxel of the volume of interest was determined. The voxels were subdivided into four groups based on the presence or absence of lesion at baseline and change or no change in lesion volume on the subsequent scan. We found a significantly higher baseline Cho/Creatine (Cr) ratio in NAWM voxels that displayed MRI visible lesions 6 months later than NAWM voxels that remained unchanged (1.57 +/- 0.30 and 1.37 +/- 0.33, respectively, p < 0.001). The 12-month interval data revealed similar pre-lesional elevated Cho/Cr, (1.51 +/- 0.29 versus 1.39 +/- 0.32, p = 0.009). Voxels that contained lesion at baseline and increased in lesion volume at 6 months also showed a significantly higher Cho/Cr ratio than those whose lesion volume did not change (1.60 +/- 0.32 and 1.49 +/- 0.36, respectively, p = 0.043). The results of this study are consistent with focal pre-lesional myelin membrane pathology in the NAWM at least 12 months before lesions become visible on conventional MRI. This could reflect altered myelin chemistry or the presence of inflammation as seen in experimental allergic encephalomyelitis.

Major Ongoing Stroke Trials

Major Ongoing Stroke Trials

Major Ongoing Stroke Trials

Major Ongoing Stroke Trials