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Jacqueline Tien-Hsiang Chen,
Kathryn Easley,
Colleen Schneider, Kunio Nakamura,
Grahame J Kidd,
Ansi Chang,
Susan M Staugaitis,
Robert J Fox,
Elizabeth Fisher,
Douglas L Arnold,
Bruce D Trapp
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ABSTRACT: OBJECTIVE: Presently there is no clinically feasible imaging modality that can effectively detect cortical demyelination in patients with multiple sclerosis (MS). The objective of this study is to determine if clinically feasible magnetization transfer ratio (MTR) imaging is sensitive to cortical demyelination in MS. METHODS: MRI were acquired in situ on 7 recently deceased patients with MS using clinically feasible sequences at 3 T, including relatively high-resolution T1-weighted and proton density-weighted images with/without a magnetization transfer pulse for calculation of MTR. The brains were rapidly removed and placed in fixative. Multiple cortical regions from each brain were immunostained for myelin proteolipid protein and classified as mostly myelinated (MM(ctx)), mostly demyelinated (MD(ctx)), or intermediately demyelinated (ID(ctx)). MRIs were registered with the cortical sections so that the cortex corresponding to each cortical section could be identified, along with adjacent subcortical white matter (WM). Mean cortical MTR normalized to mean WM MTR was calculated for each cortical region. Linear mixed-effects models were used to test if mean normalized cortical MTR was significantly lower in demyelinated cortex. RESULTS: We found that mean normalized cortical MTR was significantly lower in cortical tissue with any demyelination (ID(ctx) or MD(ctx)) compared to MM(ctx) (demyelinated cortex: least-squares mean [LSM] = 0.797, SE = 0.007; MM(ctx): LSM = 0.837, SE = 0.006; p = 0.01, n = 89). CONCLUSIONS: This result demonstrates that clinically feasible MTR imaging is sensitive to cortical demyelination and suggests that MTR will be a useful tool to help detect MS cortical lesions in living patients with MS.
Neurology 12/2012; · 8.31 Impact Factor
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ABSTRACT: Measurement of changes in brain cortical thickness is useful for the assessment of regional gray matter atrophy in neurodegenerative conditions. A new longitudinal method, called CLADA (cortical longitudinal atrophy detection algorithm), has been developed for the measurement of changes in cortical thickness in magnetic resonance images (MRI) acquired over time. CLADA creates a subject-specific cortical model which is longitudinally deformed to match images from individual time points. The algorithm was designed to work reliably for lower resolution images, such as the MRIs with 1×1×5 mm(3) voxels previously acquired for many clinical trials in multiple sclerosis (MS). CLADA was evaluated to determine reproducibility, accuracy, and sensitivity. Scan-rescan variability was 0.45% for images with 1mm(3) isotropic voxels and 0.77% for images with 1×1×5 mm(3) voxels. The mean absolute accuracy error was 0.43 mm, as determined by comparison of CLADA measurements to cortical thickness measured directly in post-mortem tissue. CLADA's sensitivity for correctly detecting at least 0.1mm change was 86% in a simulation study. A comparison to FreeSurfer showed good agreement (Pearson correlation=0.73 for global mean thickness). CLADA was also applied to MRIs acquired over 18 months in secondary progressive MS patients who were imaged at two different resolutions. Cortical thinning was detected in this group in both the lower and higher resolution images. CLADA detected a higher rate of cortical thinning in MS patients compared to healthy controls over 2 years. These results show that CLADA can be used for reliable measurement of cortical atrophy in longitudinal studies, even in lower resolution images.
NeuroImage 01/2011; 54(1):278-89. · 5.89 Impact Factor
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ABSTRACT: Gray matter (GM) pathology is an important component of the multiple sclerosis (MS) disease process. Accelerated gray matter atrophy has been observed in MS patients, but its relationship to neurological disability is not defined. This study was done to determine the relationship between whole brain, GM, and white matter (WM) atrophy and MS disability progression.
Patients with MS and Clinically Isolated Syndromes (CIS), and age- and gender-matched healthy controls were entered into an observational protocol. Baseline brain parenchymal fraction (BPF), GM fraction, and WM fraction, and change over 4 years were correlated with sustained disability progression over the entire study duration. Disability progression was measured using the Multiple Sclerosis Functional Composite (MSFC) and the Expanded Disability Status Scale (EDSS).
Seventy MS and CIS patients and 17 HCs were studied for an average of 6.6 years (range, 3.6-7.8 years). At the final visit, 7 patients were classified as CIS, 36 as relapsing-remitting MS (RRMS), and 27 as secondary progressive MS (SPMS). Baseline whole brain, GM, and WM atrophy predicted EDSS >6.0 at the last study visit. Twenty-one (33%) patients worsened using the EDSS to define disability progression; 29 (46%) worsened using MSFC to define disability progression. Patients with MSFC progression had significantly higher GM atrophy rates compared with patients who were stable on MSFC. White matter atrophy was similar in patients with and without disability progression. Atrophy rates were not different in patients with or without disability progression defined using EDSS.
Whole brain, GM, and WM atrophy predicted MS disability progression observed over the next 6.6 years. Gray matter atrophy rates over 4 years correlated with disability progression measured with the MSFC, but not EDSS. This indicates that MSFC defined disability progression is more closely linked to brain atrophy than EDSS defined disability progression, and provides important new insight into the poor correlation between MRI and clinical disability in MS. The findings confirm the clinical relevance of gray matter atrophy in MS.
Journal of the neurological sciences 12/2008; 282(1-2):106-11. · 2.32 Impact Factor
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ABSTRACT: Multiple sclerosis (MS) affects both white matter and gray matter (GM). Measurement of GM volumes is a particularly useful method to estimate the total extent of GM tissue damage because it can be done with conventional magnetic resonance images (MRI). Many algorithms exist for segmentation of GM, but none were specifically designed to handle issues associated with MS, such as atrophy and the effects that MS lesions may have on the classification of GM. A new GM segmentation algorithm has been developed specifically for calculation of GM volumes in MS patients. The new algorithm uses a combination of intensity, anatomical, and morphological probability maps. Several validation tests were performed to evaluate the algorithm in terms of accuracy, reproducibility, and sensitivity to MS lesions. The accuracy tests resulted in error rates of 1.2% and 3.1% for comparisons to BrainWeb and manual tracings, respectively. Similarity indices indicated excellent agreement with the BrainWeb segmentation (0.858-0.975, for various levels of noise and rf inhomogeneity). The scan-rescan reproducibility test resulted in a mean coefficient of variation of 1.1% for GM fraction. Tests of the effects of varying the size of MS lesions revealed a moderate and consistent dependence of GM volumes on T2 lesion volume, which suggests that GM volumes should be corrected for T2 lesion volumes using a simple scale factor in order to eliminate this technical artifact. The new segmentation algorithm can be used for improved measurement of GM volumes in MS patients, and is particularly applicable to retrospective datasets.
NeuroImage 11/2008; 44(3):769-76. · 5.89 Impact Factor
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ABSTRACT: To determine gray matter (GM) atrophy rates in multiple sclerosis (MS) patients at all stages of disease, and to identify predictors and clinical correlates of GM atrophy.
MS patients and healthy control subjects were observed over 4 years with standardized magnetic resonance imaging (MRI) and neurological examinations. Whole-brain, GM, and white matter atrophy rates were calculated. Subjects were categorized by disease status and disability progression to determine the clinical significance of atrophy. MRI predictors of atrophy were determined through multiple regression.
Subjects included 17 healthy control subjects, 7 patients with clinically isolated syndromes, 36 patients with relapsing-remitting MS (RRMS), and 27 patients with secondary progressive MS (SPMS). Expressed as fold increase from control subjects, GM atrophy rate increased with disease stage, from 3.4-fold normal in clinically isolated syndromes patients converting to RRMS to 14-fold normal in SPMS. In contrast, white matter atrophy rates were constant across all MS disease stages at approximately 3-fold normal. GM atrophy correlated with disability. MRI measures of focal and diffuse tissue damage accounted for 62% of the variance in GM atrophy in RRMS, but there were no significant predictors of GM atrophy in SPMS.
Gray matter tissue damage dominates the pathological process as MS progresses, and underlies neurological disabillity. Imaging correlates of gray matter atrophy indicate that mechanisms differ in RRMS and SPMS. These findings demonstrate the clinical relevance of gray matter atrophy in MS, and underscore the need to understand its causes.
Annals of Neurology 09/2008; 64(3):255-65. · 11.09 Impact Factor
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ABSTRACT: T2-weighted magnetic resonance imaging is a sensitive tool for monitoring progression of multiple sclerosis, but it does not provide information on the severity of the underlying tissue damage. Measurement of T1 hypointensities and magnetization transfer ratio (MTR) can potentially distinguish lesions with more severe tissue damage. The objective of this study was to use image-guided pathology to determine histological differences between lesions that are abnormal only on T2-weighted images versus lesions that are abnormal on T2-weighted, T1-weighted, and MTR images.
A total of 110 regions were selected from postmortem magnetic resonance images of 10 multiple sclerosis patients. Regions were classified into three magnetic resonance imaging-defined categories: normal-appearing white matter; abnormal on T2-weighted image only (T2-only); and abnormal on T2-weighted, T1-weighted, and MTR images (T2T1MTR). Myelin status, lesion activity, astrocytosis, serum protein distribution, axonal area, and axonal loss were evaluated histopathologically.
Comparisons between groups showed that T2T1MTR regions were more likely to be demyelinated (83% compared with 55% of T2-only regions) and more likely to be chronic inactive lesions (68% compared with 0% of demyelinated T2-only regions). There was no difference between T2-only and T2T1MTR regions in axonal area, but there was a significant difference in axonal count, indicating that axons in the T2T1MTR regions were enlarged relative to those in T2-only regions.
Axonal swelling and axonal loss were major pathological features that distinguish T2T1MTR regions from T2-only regions.
Annals of Neurology 09/2007; 62(3):219-28. · 11.09 Impact Factor
