Publications

2007
BI Glanz, CM Holland, SA Gauthier, EL Amunwa, Z Liptak, MK Houtchens, RA Sperling, SJ Khoury, CRG Guttmann, and HL Weiner. 2007. “Cognitive dysfunction in patients with clinically isolated syndromes or newly diagnosed multiple sclerosis.” Mult Scler, 13, 8, Pp. 1004-10.Abstract
Cognitive dysfunction is common in patients with multiple sclerosis (MS), and has been associated with MRI measures of lesion burden and atrophy. Little is known about the prevalence of cognitive impairment in patients with early MS. The associations between cognitive impairment and MRI measures of disease severity early in the disease course are also unclear. This study used a brief battery of cognitive tests to determine the prevalence and pattern of cognitive impairment in patients with clinically isolated syndromes or newly diagnosed MS. The associations between cognitive impairment and MRI measures of disease severity early in the disease course were also examined. Ninety-two patients with clinically isolated syndromes or the diagnosis of MS within the last 3 years participating in the CLIMB study underwent a neurologic examination, neuropsychological evaluation and MRI at 1.5 T. Forty-nine percent of patients were impaired on one or more cognitive measures. There were no significant correlations between cognitive scores and MRI measures of disease severity including total T2 lesion volume, normal appearing white matter volume, grey matter volume, and brain parenchymal fraction. These findings suggest that cognitive impairment may predate the appearance of gross structural abnormalities on MRI and serve as an early marker of disease activity in MS.
Micha Mandel, Susan A Gauthier, Charles RG Guttmann, Howard L Weiner, and Rebecca A Betensky. 2007. “Estimating Time to Event From Longitudinal Categorical Data: An Analysis of Multiple Sclerosis Progression.” J Am Stat Assoc, 102, 480, Pp. 1254-1266.Abstract
The expanded disability status scale (EDSS) is an ordinal score that measures progression in multiple sclerosis (MS). Progression is defined as reaching EDSS of a certain level (absolute progression) or increasing of one point of EDSS (relative progression). Survival methods for time to progression are not adequate for such data since they do not exploit the EDSS level at the end of follow-up. Instead, we suggest a Markov transitional model applicable for repeated categorical or ordinal data. This approach enables derivation of covariate-specific survival curves, obtained after estimation of the regression coefficients and manipulations of the resulting transition matrix. Large sample theory and resampling methods are employed to derive pointwise confidence intervals, which perform well in simulation. Methods for generating survival curves for time to EDSS of a certain level, time to increase of EDSS of at least one point, and time to two consecutive visits with EDSS greater than three are described explicitly. The regression models described are easily implemented using standard software packages. Survival curves are obtained from the regression results using packages that support simple matrix calculation. We present and demonstrate our method on data collected at the Partners MS center in Boston, MA. We apply our approach to progression defined by time to two consecutive visits with EDSS greater than three, and calculate crude (without covariates) and covariate-specific curves.
Istvan Csapo, Christopher M Holland, and Charles RG Guttmann. 2007. “Image registration framework for large-scale longitudinal MRI data sets: strategy and validation.” Magn Reson Imaging, 25, 6, Pp. 889-93.Abstract
Advanced magnetic resonance imaging (MRI) studies often require the transformation of large numbers of images into a common space. Calculating transformations that relate each image to every other and applying them to the images on demand are theoretically possible; however, these can be computationally prohibitive. Therefore, relating each image to only one other image, then linking those transforms together to relate any two images in the database, may be an efficient alternative. Evaluated were the feasibility and validity of image registration to bring intraindividual MR images into mutual correspondence for longitudinal analysis through the concatenation of precomputed transforms. A longitudinal data set of 10 multiple sclerosis patients with nine serial dual-echo spin-echo, 1.5-T MRI scans was used. Intrasubject registrations were performed stepwise between consecutive images and direct from each time point to the baseline. Consecutive transforms were concatenated and evaluated against direct registrations by comparing the resulting transformed images (using Pearson correlation coefficient). Confounding variables such as time between scans, brain atrophy, and change in lesion load were evaluated. We found the images resampled with the direct and the concatenated transforms to be highly correlated, and there was no significant difference between methods. Differences in brain parenchymal fraction (a measure of brain atrophy) showed significant inverse correlation with the correspondence of the resampled images. Results indicate that concatenating multiple transforms that link two images together produces near-identical results to that of direct registration; thus, this method is both useful and valid.
Mark A Horsfield, Rohit Bakshi, Marco Rovaris, Mara A Rocca, Venkata SR Dandamudi, Paola Valsasina, Elda Judica, Fulvio Lucchini, Charles RG Guttmann, Maria Pia Sormani, and Massimo Filippi. 2007. “Incorporating domain knowledge into the fuzzy connectedness framework: application to brain lesion volume estimation in multiple sclerosis.” IEEE Trans Med Imaging, 26, 12, Pp. 1670-80.Abstract
A method for incorporating prior knowledge into the fuzzy connectedness image segmentation framework is presented. This prior knowledge is in the form of probabilistic feature distribution and feature size maps, in a standard anatomical space, and "intensity hints" selected by the user that allow for a skewed distribution of the feature intensity characteristics. The fuzzy affinity between pixels is modified to encapsulate this domain knowledge. The method was tested by using it to segment brain lesions in patients with multiple sclerosis, and the results compared to an established method for lesion outlining based on edge detection and contour following. With the fuzzy connections (FC) method, the user is required to identify each lesion with a mouse click, to provide a set of seed pixels. The algorithm then grows the features from the seeds to define the lesions as a set of objects with fuzzy connectedness above a preset threshold. The FC method gave improved interobserver reproducibility of lesion volumes, and the set of pixels determined to be lesion was more consistent compared to the contouring method. The operator interaction time required to evaluate one subject was reduced from an average of 111 min with contouring to 16 min with the FC method.
DS Meier, HL Weiner, and CRG Guttmann. 2007. “MR imaging intensity modeling of damage and repair in multiple sclerosis: relationship of short-term lesion recovery to progression and disability.” AJNR Am J Neuroradiol, 28, 10, Pp. 1956-63.Abstract
BACKGROUND AND PURPOSE: Formation of lesions in multiple sclerosis (MS) shows pronounced short-term fluctuation of MR imaging hyperintensity and size, a qualitatively known but poorly characterized phenomenon. With the use of time-series modeling of MR imaging intensity, our study relates the short-term dynamics of new T2 lesion formation to those of contrast enhancement and markers of long-term progression of disease. MATERIALS AND METHODS: We analyzed 915 examinations from weekly to monthly MR imaging in 40 patients with MS using a time-series model, emulating 2 opposing processes of T2 prolongation and shortening, respectively. Patterns of activity, duration, and residual hyperintensity within new T2 lesions were measured and evaluated for relationships to disability, atrophy, and clinical phenotype in long-term follow-up. RESULTS: Significant T2 activity was observed for 8 to 10 weeks beyond contrast enhancement, which suggests that T2 MR imaging is sensitive to noninflammatory processes such as degeneration and repair. Larger lesions showed longer subacute phases but disproportionally more recovery. Patients with smaller average peak lesion size showed trends toward greater disability and proportional residual damage. Higher rates of disability or atrophy were associated with subjects whose lesions showed greater residual hyperintensity. CONCLUSION: Smaller lesions appeared disproportionally more damaging than larger lesions, with lesions in progressive MS smaller and of shorter activity than in relapsing-remitting MS. Associations of lesion dynamics with rates of atrophy and disability and clinical subtype suggest that changes in lesion dynamics may represent a shift from inflammatory toward degenerative disease activity and greater proximity to a progressive stage, possibly allowing staging of the progression of MS earlier, before atrophy or disability develops.
Julien Milles, Yue Min Zhu, Gérard Gimenez, Charles RG Guttmann, and Isabelle E Magnin. 2007. “MRI intensity nonuniformity correction using simultaneously spatial and gray-level histogram information.” Comput Med Imaging Graph, 31, 2, Pp. 81-90.Abstract
A novel approach for correcting intensity nonuniformity in magnetic resonance imaging (MRI) is presented. This approach is based on the simultaneous use of spatial and gray-level histogram information. Spatial information about intensity nonuniformity is obtained using cubic B-spline smoothing. Gray-level histogram information of the image corrupted by intensity nonuniformity is exploited from a frequential point of view. The proposed correction method is illustrated using both physical phantom and human brain images. The results are consistent with theoretical prediction, and demonstrate a new way of dealing with intensity nonuniformity problems. They are all the more significant as the ground truth on intensity nonuniformity is unknown in clinical images.
SA Gauthier, M Mandel, CRG Guttmann, BI Glanz, SJ Khoury, RA Betensky, and HL Weiner. 2007. “Predicting short-term disability in multiple sclerosis.” Neurology, 68, 24, Pp. 2059-65.Abstract
OBJECTIVE: To develop covariate specific short-term disability curves to demonstrate the probability of progressing by Expanded Disability Status Scale (EDSS) at semiannual visits. METHODS: Semiannual EDSS scores were prospectively collected in 218 relapsing-remitting (RR) and clinically isolated syndrome (CIS) patients as part of the Comprehensive Longitudinal Investigation of Multiple Sclerosis at the Brigham and Women's Hospital (CLIMB) study. Baseline brain parenchymal fraction (BPF) and T2 lesion volume were available on 205 patients. A partial proportional odds model determined the influence of covariates on the change in EDSS score at subsequent visits. A discrete second order Markov transitional model was fit and generated a probability matrix for each subject; the 6-month probabilities of EDSS change were graphically represented. RESULTS: The univariate analysis demonstrated the lowest baseline BPF quartile (OR 1.99; p = 0.0203) and the highest T2 lesion volume quartile (OR 2.19; p = 0.0130) were associated with progression in EDSS. Covariate specific disability curves demonstrated the effect of BPF and T2 lesion volume on short-term progression. In subjects with a 6-month EDSS of 2, the probability of a sustained progression of an EDSS of 3 within 3 years was 0.277 for a subject with low BPF and a high T2 lesion volume vs 0.055 for a subject with high BPF and a low T2 lesion volume. CONCLUSIONS: Markov transitional models allow for the comparison of covariate specific short-term disability changes among groups of patients with multiple sclerosis.
MK Houtchens, RHB Benedict, R Killiany, J Sharma, Z Jaisani, B Singh, B Weinstock-Guttman, CRG Guttmann, and R Bakshi. 2007. “Thalamic atrophy and cognition in multiple sclerosis.” Neurology, 69, 12, Pp. 1213-23.Abstract
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.
Dominik S Meier, Howard L Weiner, and Charles RG Guttmann. 2007. “Time-series modeling of multiple sclerosis disease activity: a promising window on disease progression and repair potential?” Neurotherapeutics, 4, 3, Pp. 485-98.Abstract
This article discusses and reviews advanced forms of serial morphometry in the context of a disease progression model in multiple sclerosis (MS). This model of disease activity distinguishes between overall disease activity and the proportion thereof that becomes permanent damage. This translates into a progression model that features a repair potential, which, when exhausted, marks the conversion or progression from relapsing to progressive disease. The level of repair capacity at a given time determines the rate of progression. Both clinical and MRI variables appear to be in support of such a model. We examine possible MRI markers for this repair capacity, particularly the short-term behavior of new MRI lesions, quantified by methods of time-series analysis--that is, capturing lesion dynamics in the form of MRI intensity change directly, rather than shape or volume change. Lower rates of individual lesion recovery may represent lower repair and greater proximity to a progressive stage. Individuals with low transient lesion turnover appear to undergo more rapid progression and atrophy. Because disease-modifying therapies aim to alter the pathophysiological chain of inflammation, demyelination, and axonal loss, a therapeutic effect may therefore be more readily apparent as a change in lesion dynamics and recovery rate and level, rather than a change in total lesion burden or enhancing lesion number.
2006
Ying Wu, Simon K Warfield, Leng I Tan, William M Wells, Dominik S Meier, Ronald A van Schijndel, Frederik Barkhof, and Charles RG Guttmann. 2006. “Automated segmentation of multiple sclerosis lesion subtypes with multichannel MRI.” Neuroimage, 32, 3, Pp. 1205-15.Abstract
PURPOSE: To automatically segment multiple sclerosis (MS) lesions into three subtypes (i.e., enhancing lesions, T1 "black holes", T2 hyperintense lesions). MATERIALS AND METHODS: Proton density-, T2- and contrast-enhanced T1-weighted brain images of 12 MR scans were pre-processed through intracranial cavity (IC) extraction, inhomogeneity correction and intensity normalization. Intensity-based statistical k-nearest neighbor (k-NN) classification was combined with template-driven segmentation and partial volume artifact correction (TDS+) for segmentation of MS lesions subtypes and brain tissue compartments. Operator-supervised tissue sampling and parameter calibration were performed on 2 randomly selected scans and were applied automatically to the remaining 10 scans. Results from this three-channel TDS+ (3ch-TDS+) were compared to those from a previously validated two-channel TDS+ (2ch-TDS+) method. The results of both the 3ch-TDS+ and 2ch-TDS+ were also compared to manual segmentation performed by experts. RESULTS: Intra-class correlation coefficients (ICC) of 3ch-TDS+ for all three subtypes of lesions were higher (ICC between 0.95 and 0.96) than that of 2ch-TDS+ for T2 lesions (ICC = 0.82). The 3ch-TDS+ also identified the three lesion subtypes with high specificity (98.7-99.9%) and accuracy (98.5-99.9%). Sensitivity of 3ch-TDS+ for T2 lesions was 16% higher than with 2ch-TDS+. Enhancing lesions were segmented with the best sensitivity (81.9%). "Black holes" were segmented with the least sensitivity (62.3%). CONCLUSION: 3ch-TDS+ is a promising method for automated segmentation of MS lesion subtypes.
Charles RG Guttmann, Dominik S Meier, and Christopher M Holland. 2006. “Can MRI reveal phenotypes of multiple sclerosis?” Magn Reson Imaging, 24, 4, Pp. 475-81.Abstract
The multicontrast capability of magnetic resonance imaging (MRI) is discussed in its role in the search for phenotypes of multiple sclerosis (MS). Aspects of MRI specificity, putative markers for pathogenetic components of disease and issues of spatial and temporal distribution are discussed. While particular reference is made to MS, the concepts apply to common pathological features of many neurologic diseases and to neurodegenerative disease in general. The assessment and dissociation of disease activity and disease severity, as well as the combination of varied metrics for the purposes of inferential and predictive disease modeling, are explored with respect to biomarkers and clinical outcomes. By virtue of its noninvasive nature and multicontrast capabilities depicting multiple facets of MS pathology, MRI lends itself to the systematic search of pathogenetically distinct subtypes of MS in large populations of patients. In conjunction with clinical, immunological, serological and genetic information, clusters of MS patients with distinct clinical prognosis and diverse response profiles to available and future treatments may be identified.
Charles RG Guttmann, Dominik S Meier, and Christopher M Holland. 2006. “Can MRI reveal phenotypes of multiple sclerosis?” Magn Reson Imaging, 24, 4, Pp. 475-81.Abstract
The multicontrast capability of magnetic resonance imaging (MRI) is discussed in its role in the search for phenotypes of multiple sclerosis (MS). Aspects of MRI specificity, putative markers for pathogenetic components of disease and issues of spatial and temporal distribution are discussed. While particular reference is made to MS, the concepts apply to common pathological features of many neurologic diseases and to neurodegenerative disease in general. The assessment and dissociation of disease activity and disease severity, as well as the combination of varied metrics for the purposes of inferential and predictive disease modeling, are explored with respect to biomarkers and clinical outcomes. By virtue of its noninvasive nature and multicontrast capabilities depicting multiple facets of MS pathology, MRI lends itself to the systematic search of pathogenetically distinct subtypes of MS in large populations of patients. In conjunction with clinical, immunological, serological and genetic information, clusters of MS patients with distinct clinical prognosis and diverse response profiles to available and future treatments may be identified.
Julien Milles, Yue Min Zhu, Nan-kuei Chen, Lawrence P Panych, Gérard Gimenez, and Charles RG Guttmann. 2006. “Computation of transmitted and received B1 fields in magnetic resonance imaging.” IEEE Trans Biomed Eng, 53, 5, Pp. 885-95.Abstract
Computation of B1 fields is a key issue for determination and correction of intensity nonuniformity in magnetic resonance images. This paper presents a new method for computing transmitted and received B1 fields. Our method combines a modified MRI acquisition protocol and an estimation technique based on the Levenberg-Marquardt algorithm and spatial filtering. It enables accurate estimation of transmitted and received B1 fields for both homogeneous and heterogeneous objects. The method is validated using numerical simulations and experimental data from phantom and human scans. The experimental results are in agreement with theoretical expectations.
Petra JW Pouwels, Joost PA Kuijer, John P Mugler, Charles RG Guttmann, and Frederik Barkhof. 2006. “Human gray matter: feasibility of single-slab 3D double inversion-recovery high-spatial-resolution MR imaging.” Radiology, 241, 3, Pp. 873-9.Abstract
The purpose of this study was to develop and prospectively evaluate the feasibility of a single-slab three-dimensional (3D) double inversion-recovery, or DIR, sequence for magnetic resonance imaging at 1.5 T. The study was approved by the local ethics committee, and informed consent was obtained from six healthy control subjects (one woman, five men; age range, 26-47 years) and two patients with multiple sclerosis (one woman, aged 39; one man, aged 56). Gray matter (GM)-only images were obtained by selectively suppressing cerebrospinal fluid (CSF) and white matter (WM) signals. Whole-brain high-spatial-resolution 3D images (1.2 x 1.2 x 1.3 mm) were acquired within 10 minutes. Cortical and deep GM structures were clearly delineated from WM and CSF, and there were regional differences in GM signal intensity. No flow artifacts from blood or CSF were observed. These GM images with high spatial resolution are suitable to identify cortical pathologic conditions and can potentially be used for segmentation purposes to determine cortical thickness or volume.
Petra JW Pouwels, Joost PA Kuijer, John P Mugler, Charles RG Guttmann, and Frederik Barkhof. 2006. “Human gray matter: feasibility of single-slab 3D double inversion-recovery high-spatial-resolution MR imaging.” Radiology, 241, 3, Pp. 873-9.Abstract
The purpose of this study was to develop and prospectively evaluate the feasibility of a single-slab three-dimensional (3D) double inversion-recovery, or DIR, sequence for magnetic resonance imaging at 1.5 T. The study was approved by the local ethics committee, and informed consent was obtained from six healthy control subjects (one woman, five men; age range, 26-47 years) and two patients with multiple sclerosis (one woman, aged 39; one man, aged 56). Gray matter (GM)-only images were obtained by selectively suppressing cerebrospinal fluid (CSF) and white matter (WM) signals. Whole-brain high-spatial-resolution 3D images (1.2 x 1.2 x 1.3 mm) were acquired within 10 minutes. Cortical and deep GM structures were clearly delineated from WM and CSF, and there were regional differences in GM signal intensity. No flow artifacts from blood or CSF were observed. These GM images with high spatial resolution are suitable to identify cortical pathologic conditions and can potentially be used for segmentation purposes to determine cortical thickness or volume.
Dominik S Meier and Charles RG Guttmann. 2006. “MRI time series modeling of MS lesion development.” Neuroimage, 32, 2, Pp. 531-7.Abstract
A mathematical model was applied to new lesion formation in multiple sclerosis, as apparent on frequent T2-weighted MRI. The pathophysiologically motivated two-process model comprises two opposing nonlinear self-limiting processes, intended to represent degenerative and reparatory processes, respectively, investigating T2 activity from a dynamic/temporal rather than a spatial/static perspective. Parametric maps were obtained from the model to characterize the MRI dynamics of lesion development, answering the questions of how long new T2 lesion activity persists, how much residual damage/hyperintensity remains and how the T2 dynamics compare to those of contrast-enhancing MRI indicating active inflammation. 997 MRI examinations were analyzed, acquired weekly to monthly from 45 patients over a 1-year period. The model was applied to all pixels within 332 new lesions, capturing the time profiles with excellent fidelity (r = 0.89 +/- 0.03 average correlation between model and image data). From this modeling perspective, the observed dynamics in new T2 lesions are in agreement with two opposing processes of longitudinal intensity change, such as inflammation and degeneration versus resorbtion and repair. On average, about one third of a new lesion consisted of transient signal change with little or no residual hyperintensity and activity of 10 weeks or less. Global lesion burden as MRI surrogate of disease activity may therefore be confounded by large amounts of transient hyperintensity. T2 activity also persisted significantly beyond the period of contrast enhancement, thereby defining MRI sensitivity toward a subacute phase of lesion development beyond blood-brain barrier patency. Concentric patterns of dynamic properties within a lesion were observed, consistent with concentric histological appearance of resulting MS plaques.
David-Axel Laplaud, Laureline Berthelot, Patrick Miqueu, Kasia Bourcier, Julien Moynard, Yannick Oudinet, Marina Guillet, Catherine Ruiz, Neal Oden, Sophie Brouard, Charles RG Guttmann, Howard L Weiner, Samia J Khoury, and Jean-Paul Soulillou. 2006. “Serial blood T cell repertoire alterations in multiple sclerosis patients; correlation with clinical and MRI parameters.” J Neuroimmunol, 177, 1-2, Pp. 151-60.Abstract
A significant skewing of the peripheral T cell repertoire has been shown in relapsing-remitting multiple sclerosis (MS). Most of the studies already performed in this field are cross-sectional and therefore, little is known of the T cell repertoire evolution over time in MS and the correlation of T cell repertoire variation with clinical and MRI parameters. This study was performed on serially harvested frozen PBMC from nine untreated MS patients (27 samples) and 14 healthy individuals. The blood T cell repertoire of each patient was analysed at the complementarity determining region 3 (CDR3) level and compared with a monthly MRI scan performed over a six month period with assessment of T2 lesion load and gadolinium enhancing lesions. A highly significant blood T cell repertoire skewing was observed in MS patients as compared with healthy controls (p<0.01). In addition, the number of altered Vbeta families correlated significantly with both the T2 lesion volume and the number of gadolinium enhancing lesions as assessed by MRI (Spearman correlation tests, r=0.51 and r=0.44, p<0.01 and p<0.05 respectively). Furthermore, the variation of the number of altered Vbeta families over time also correlated with the appearance of new gadolinium enhancing lesions (r=0.36, p=0.05). These findings which need confirmation on larger serial cohorts, suggest an association between the magnitude of TCRBV CDR3 length distribution alterations in the peripheral blood of MS patients and the disease process.
2005
Leslie Wolfson, Xingchang Wei, Charles B Hall, Victoria Panzer, Dorothy Wakefield, Randall R Benson, Julia A Schmidt, Simon K Warfield, and Charles RG Guttmann. 2005. “Accrual of MRI white matter abnormalities in elderly with normal and impaired mobility.” J Neurol Sci, 232, 1-2, Pp. 23-7.Abstract
White matter signal abnormality (WMSA) is often present in the MRIs of older persons with mobility impairment. We examined the relationship between impaired mobility and the progressive accrual of WMSA. Mobility was assessed with the Short Physical Performance Battery (SPPB) and quantitative measures of gait and balance. Fourteen subjects had baseline and follow-up MRI scans performed 20 months apart. WMSA was detected and quantified using automated computer algorithms. In the control subjects, WMSA volume increased by 0.02+/-0.05% ICCV (percent intracranial cavity volume)/year while the WMSA of mobility impaired subjects increased five-times faster (0.10+/-0.10 ICCV/year, p=0.03). WMSA volume was related to some of the mobility measures and was sensitive to change which was not true of the other MRI variables. The study demonstrates the sensitivity of longitudinal automated volumetric analysis of WMSA to differentiate differences in the accrual rate of WMSA in groups selected on the basis of mobility. Based on these results, we propose that a subset of subjects with mobility impairment have accelerated, disease related WMSA accrual, thus explaining the rapid progression of mobility impairment in some older persons without apparent cause. This study demonstrates that quantitative MRI and performance measures can provide valuable insight into the rate of progression and pathophysiologic abnormalities underlying mobility impairment.
Seung-Schik Yoo, Heather M O'Leary, Chandlee C Dickey, Xingchang Wei, Charles RG Guttmann, HyunWook Park, and Lawrence P Panych. 2005. “Functional asymmetry in human primary auditory cortex: identified from longitudinal fMRI study.” Neurosci Lett, 383, 1-2, Pp. 1-6.Abstract
The leftward hemispheric dominance in language processing may be associated with fundamental functional asymmetry in the primary auditory cortex (PAC). Based on repeated functional MRI (fMRI) measurements, we investigated the presence of functional asymmetry in the human PAC using binaural presentation of linguistic sounds (two-syllable nouns) and simple tonal stimulation. Eight right-handed volunteers underwent nine fMRI sessions, approximately eight weeks apart, spanning the duration of more than a year. The PAC from each hemisphere was manually segmented and the volume of activation, detected within the segmented region-of-interest, was measured across the subjects and sessions to generate functional laterality indices. Although variations existed in activation volume between sessions and subjects, we found predominant and consistent leftward functional asymmetry in PAC during both linguistic and non-linguistic sound stimulations.
DN Bourdette, E Edmonds, C Smith, JD Bowen, CRG Guttmann, ZP Nagy, J Simon, R Whitham, J Lovera, V Yadav, M Mass, L Spencer, N Culbertson, RM Bartholomew, G Theofan, J Milano, H Offner, and AA Vandenbark. 2005. “A highly immunogenic trivalent T cell receptor peptide vaccine for multiple sclerosis.” Mult Scler, 11, 5, Pp. 552-61.Abstract
BACKGROUND: T cell receptor (TCR) peptide vaccination is a novel approach to treating multiple sclerosis (MS). The low immunogenicity of previous vaccines has hindered the development of TCR peptide vaccination for MS. OBJECTIVE: To compare the immunogenicity of intramuscular injections of TCR BV5S2, BV6S5 and BV13S1 CDR2 peptides in incomplete Freunds adjuvant (IFA) with intradermal injections of the same peptides without IFA. METHODS: MS subjects were randomized to receive TCR peptides/IFA, TCR peptides/saline or IFA alone. Subjects were on study for 24 weeks. RESULTS: The TCR peptides/IFA vaccine induced vigorous T cell responses in 100% of subjects completing the 24-week study (9/9) compared with only 20% (2/10) of those receiving the TCR peptides/saline vaccine (P =0.001). IFA alone induced a weak response in only one of five subjects. Aside from injection site reactions, there were no significant adverse events attributable to the treatment. CONCLUSIONS: The trivalent TCR peptide in IFA vaccine represents a significant improvement in immunogenicity over previous TCR peptide vaccines and warrants investigation of its ability to treat MS.

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