Automated Determination of Brain Parenchymal Fraction in Multiple Sclerosis

Background: Tissue damage in both multiple sclerosis (MS) lesions and normal-appearing white matter (NAWM) are important contributors to disability and progression. Specific aspects of MS pathology can be measured using advanced imaging. Alemtuzumab is a humanised monoclonal antibody targeting CD52 developed for MS treatment. Objective: To investigate changes over 2 years of advanced magnetic resonance (MR) metrics in lesions and NAWM of MS patients treated with alemtuzumab. Methods: A total of 42 relapsing–remitting alemtuzumab-treated MS subjects were scanned for 2 years at 3 T. T1 relaxation, T2 relaxation, diffusion tensor, MR spectroscopy and volumetric sequences were performed. Mean T1 and myelin water fraction (MWF) were determined for stable lesions, new lesions and NAWM. Fractional anisotropy was calculated for the corpus callosum (CC) and N-acetylaspartate (NAA) concentration was determined from a large NAWM voxel. Brain parenchymal fraction (BPF), cortical thickness and CC area were also calculated. Results: No change in any MR measurement was found in lesions or NAWM over 24 months. BPF, cortical thickness and CC area all showed decreases in the first year followed by stability in the second year. Conclusion: Advanced MR biomarkers of myelin (MWF) and neuron/axons (NAA) show no change in NAWM over 24 months in alemtuzumab-treated MS participants.

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Has your patient's multiple sclerosis lesion burden or brain atrophy actually changed?

Multiple Sclerosis Journal ◽

10.1191/1352458504ms1061oa ◽

2004 ◽

Vol 10 (4) ◽

pp. 402-406 ◽

Cited By ~ 16

Author(s):

Xingchang Wei ◽

Charles RG Guttmann ◽

Simon K Warfield ◽

Michael Eliasziw ◽

J Ross Mitchell

Keyword(s):

Multiple Sclerosis ◽

Measurement Error ◽

Brain Tissue ◽

Brain Atrophy ◽

Multiple Sclerosis Lesion ◽

Lesion Volume ◽

Measurement Variability ◽

Brain Parenchymal Fraction ◽

Significant Change ◽

Brain Parenchymal

Changes in mean magnetic resonance imaging (MRI)-derived measurements between patient groups are often used to determine outcomes in therapeutic trials and other longitudinal studies of multiple sclerosis (MS). However, in day-to-day clinical practice the changes withinindividual patients may also be of interest. In this paper, we estimated the measurement error of an automated brain tissue quantification algorithm and determined the thresholds for statistically significant change of MRI-derived T2 lesion volume and brain atrophy in individual patients. Twenty patients with MS were scanned twice within 30 min. Brain tissue volumes were measured using the computer algorithm. Brain atrophy was estimated by calculation of brain parenchymal fraction. The threshold of change between repeated scans that represented statistically significant change beyond measurement error with 95% certainty was 0.65 mL for T2 lesion burden and 0.0056 for brain parenchymal fraction. Changes in lesion burden and brain atrophy below these thresholds can be safely (with 95% certainty) explained by measurement variability alone. These values provide clinical neurologists with a useful reference to interpret MRI-derived measures in individual patients.

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Frontal parenchymal atrophy measures in multiple sclerosis

Multiple Sclerosis Journal ◽

10.1191/1352458504ms1093oa ◽

2004 ◽

Vol 10 (5) ◽

pp. 562-568 ◽

Cited By ~ 27

Author(s):

Laura Locatelli ◽

Robert Zivadinov ◽

Attilio Grop ◽

Marino Zorzon

Keyword(s):

Multiple Sclerosis ◽

Cognitive Functions ◽

Brain Atrophy ◽

Neuropsychological Functioning ◽

Intraclass Correlation ◽

Quantitative Mri ◽

Cross Sectional ◽

Regional Brain ◽

Brain Parenchymal Fraction ◽

Brain Parenchymal

The aim of this study was to establish whether, in a cross-sectional study, the normalized measures of whole and regional brain atrophy correlate better with tests assessing the cognitive function than the absolute brain atrophy measures. The neuropsychological performances and disability have been assessed in 39 patients with relapsing-remitting multiple sclerosis (MS). T1- and T2-lesion load (LL) of total brain and frontal lobes (FLs) were measured using a reproducible semiautomated technique. The whole brain volume and the regional brain parenchymal volume (RBPV) of FLs were obtained using a computerized interactive program, which incorporates semiautomated and automated segmentation processes. Normalized measures of brain atrophy, i.e., brain parenchymal fraction (BPF) and regional brain parenchymal fraction (RBPF) of FLs, were calculated. The scan-rescan, inter- and intrarater coefficient of variation (COV) and intraclass correlation coefficient (ICC) have been estimated. The RBPF of FLs showed an acceptable level of reproducibility which ranged from 1.7% for intrarater variability to 3.2% for scan-rescan variability. The mean ICC was 0.88 (CI 0.82-0.93). The RBPF of FLs demonstrated stronger magnitudes of correlation with neuropsychological functioning, disability and quantitative MRI lesion measures than RBPV. These differences were statistically significant: P=0.001 for Stroop Color Word Interference test, P=0.001 for Paced Auditory Serial Addition Test, P=0.04 for Standard Raven Progressive Matrices, P=0.049 for Expanded Disability Status Scale, P=0.01 for T2-LL of FLs and P< 0.001 for T1-LL of FLs. BPF demonstrated significant correlations with tests assessing cognitive functions, whereas BPAV did not. The correlation analysis results were supported by the results of multiple regression analysis which showed that only the normalized brain atrophy measures were associated with tests exploring the cognitive functions. These data suggest that RBPF is a reproducible and sensitive method for measuring frontal parenchymal atrophy. The normalized measures of whole and regional brain parenchymal atrophy should be preferred to absolute measures in future studies that correlate neuropsychological performances and brain atrophy measures in patients with MS.

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A new evaluation of the brain parenchymal fraction: Application in multiple sclerosis longitudinal studies

2008 5th IEEE International Symposium on Biomedical Imaging: From Nano to Macro ◽

10.1109/isbi.2008.4540933 ◽

2008 ◽

Cited By ~ 1

Author(s):

J.C. Souplet ◽

C. Lebrun ◽

N. Ayache ◽

G. Malandain

Keyword(s):

Multiple Sclerosis ◽

Longitudinal Studies ◽

Brain Parenchymal Fraction ◽

Brain Parenchymal ◽

The Brain

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Disease modeling in multiple sclerosis: Assessment and quantification of sources of variability in brain parenchymal fraction measurements

NeuroImage ◽

10.1016/j.neuroimage.2010.03.075 ◽

2010 ◽

Vol 52 (4) ◽

pp. 1367-1373 ◽

Cited By ~ 21

Author(s):

Mehul P. Sampat ◽

Brian C. Healy ◽

Dominik S. Meier ◽

Elisa Dell'Oglio ◽

Maria Liguori ◽

...

Keyword(s):

Multiple Sclerosis ◽

Disease Modeling ◽

Brain Parenchymal Fraction ◽

Brain Parenchymal

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Smartphone-Based Symbol-Digit Modalities Test Reliably Measures Cognitive Function in Multiple Sclerosis Patients

10.1101/2020.03.09.20033316 ◽

2020 ◽

Author(s):

Linh Pham ◽

Thomas Harris ◽

Mihael Varosanec ◽

Peter Kosa ◽

Bibiana Bielekova

Keyword(s):

Multiple Sclerosis ◽

Cognitive Processing ◽

Processing Speed ◽

Test Performance ◽

Relevant Information ◽

Imaging Features ◽

Speed Test ◽

Brain Parenchymal Fraction ◽

Brain Parenchymal ◽

Multiple Sclerosis Patients

AbstractLimited time for patient encounters prevents reliable evaluation of all neurological functions in routine clinical practice. Quantifying neurological disability in a patient-autonomous manner via smartphones may remedy this problem, if such tests provide reliable, disease-relevant information.We developed a smartphone version of the cognitive processing speed test, the Symbol-Digit Modalities Test (SDMT), and assessed its clinical utility. The traditional SDMT uses identical symbol-number codes, allowing memorization after repeated trials. In the phone app, the symbol-number codes are randomly generated.In 154 multiple sclerosis (MS) patients and 39 healthy volunteers (HV), traditional and smartphone SDMT have good agreement (Lin’s coefficient of concordance [CCC] = 0.84) and comparable test-retest variance. In subjects with available volumetric MRI and digitalized neurological examinations (112 MS, 12 HV), the SDMT scores were highly associated with T2 lesion load and brain parenchymal fraction, when controlled for relevant clinical characteristics. The smartphone SDMT association with clinical/imaging features was stronger (R2 = 0.75, p < 0.0001) than traditional SDMT (R2 = 0.65, p < 0.0001). In the longitudinal subcohort, improvements from testing repetition (learning effects), were identifiable using non-linear regression in 14/16 subjects and, on average, peaked after 8 trials. Averaging several post-learning SDMT results significantly lowers the threshold for detecting true decline in test performance.In conclusion, smartphone, self-administered SDMT is a reliable substitute of the traditional SDMT for measuring processing speed in MS patients. Granular measurements at home increase sensitivity to detect true performance decline in comparison to sporadic assessments in the clinic.

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Periventricular magnetisation transfer ratio abnormalities in multiple sclerosis improve after alemtuzumab

Multiple Sclerosis Journal ◽

10.1177/1352458519852093 ◽

2019 ◽

Vol 26 (9) ◽

pp. 1093-1101

Author(s):

J William L Brown ◽

Ferran Prados Carrasco ◽

Arman Eshaghi ◽

Carole H Sudre ◽

Tom Button ◽

...

Keyword(s):

Multiple Sclerosis ◽

White Matter ◽

White Matter Lesions ◽

Magnetisation Transfer ◽

Magnetisation Transfer Ratio ◽

Brain Volumes ◽

Transfer Ratio ◽

Lesion Number ◽

Brain Parenchymal Fraction ◽

Brain Parenchymal

Background: In multiple sclerosis (MS), disease effects on magnetisation transfer ratio (MTR) increase towards the ventricles. This periventricular gradient is evident shortly after first symptoms and is independent of white matter lesions. Objective: To explore if alemtuzumab, a peripherally acting disease-modifying treatment, modifies the gradient’s evolution, and whether baseline gradients predict on-treatment relapses. Methods: Thirty-four people with relapsing-remitting MS underwent annual magnetic resonance imaging (MRI) scanning (19 receiving alemtuzumab (four scans each), 15 untreated (three scans each)). The normal-appearing white matter was segmented into concentric bands. Gradients were measured over the three bands nearest the ventricles. Mixed-effects models adjusted for age, gender, relapse rate, lesion number and brain parenchymal fraction compared the groups’ baseline gradients and evolution. Results: Untreated, the mean MTR gradient increased (+0.030 pu/band/year) but decreased following alemtuzumab (−0.045 pu/band/year, p = 0.037). Within the alemtuzumab group, there were no significant differences in baseline lesion number ( p = 0.568) nor brain parenchymal fraction ( p = 0.187) between those who relapsed within 4 years ( n = 4) and those who did not ( n = 15). However, the baseline gradient was significantly different ( p = 0.020). Conclusion: Untreated, abnormal periventricular gradients worsen with time, but appear reversible with peripheral immunotherapy. Baseline gradients – but not lesion loads or brain volumes – may predict on-treatment relapses. Larger confirmatory studies are required.

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A novel classification of fatigue in multiple sclerosis based on longitudinal assessments

Multiple Sclerosis Journal ◽

10.1177/1352458519898112 ◽

2020 ◽

Vol 26 (6) ◽

pp. 725-734

Author(s):

Miklos Palotai ◽

Michele Cavallari ◽

Brian C Healy ◽

Charles RG Guttmann

Keyword(s):

Multiple Sclerosis ◽

Statistical Power ◽

Temporal Dynamics ◽

Lesion Volume ◽

Brain Parenchymal Fraction ◽

Magnetic Resonance Imaging Mri ◽

Brain Parenchymal ◽

Time Point

Background: Magnetic resonance imaging (MRI) studies of multiple sclerosis–related fatigue had limited reproducibility. Temporal fatigue fluctuations have not been considered. Objective: To investigate whether a novel group allocation that reflects temporal dynamics of fatigue improves our ability to detect fatigue-associated structural brain abnormalities. Methods: Patient stratification based on biennial fatigue assessments: sustained fatigue (SF, n = 29, fatigued at the latest ⩾2 assessments), one time-point fatigue (1F, n = 15, fatigued at the latest, but non-fatigued at the penultimate assessment), reversible fatigue (RF, n = 31, non-fatigued at the latest assessment, but reported fatigue previously), and never fatigued (NF, n = 54). Brain parenchymal fraction (BPF) and T2 lesion volume (T2LV) were compared between these groups and were derived using a conventional, single time-point fatigued versus non-fatigued stratification. Results: The SF versus NF stratification yielded improved power. SF ( p = 0.005) and RF ( p = 0.043) showed significantly higher T2LV than NF. T2LV showed no significant differences in SF versus 1F, SF versus RF, or 1F versus RF. Fatigued versus non-fatigued patients showed significantly higher T2LV ( p = 0.030). We found no significant differences in BPF between the groups. Conclusion: Taking into account temporal fatigue dynamics increases the statistical power with respect to T2LV and may improve characterization of brain pathological correlates of MS-related fatigue.

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Relationship between brain atrophy and disability: an 8-year follow-up study of multiple sclerosis patients

Multiple Sclerosis Journal ◽

10.1177/135245850000600602 ◽

2000 ◽

Vol 6 (6) ◽

pp. 373-377 ◽

Cited By ~ 107

Author(s):

E Fisher ◽

R A Rudick ◽

G Cutter ◽

M Baier ◽

D Miller ◽

...

Keyword(s):

Multiple Sclerosis ◽

Disease Progression ◽

Brain Atrophy ◽

Phase Iii ◽

Phase Iii Trial ◽

Follow Up Study ◽

Relapsing Remitting ◽

Brain Parenchymal Fraction ◽

Brain Parenchymal

Brain atrophy measurement can provide an estimate of the amount of tissue destruction due to the pathologic processes in multiple sclerosis. The potential usefulness of atrophy as a marker of disease progression depends upon the concurrent and predictive relationships between atrophy and disability. A follow-up study was performed to measure atrophy and disability scores in patients from the Multiple Sclerosis Collaborative Research Group's phase III trial of IFNb-1a (Avonex) in relapsing-remitting multiple sclerosis. New data were obtained on 160 out of 172 eligible patients from the original trial were enrolled in the follow-up study approximately 8 years after randomization. The follow-up visit consisted of several tests and questionnaires including a clinical exam to determine Expanded Disability Status Score (EDSS) and Multiple Sclerosis Functional Composite (MSFC), and a magnetic resonance imaging exam to calculate the brain parenchymal fraction. Brain parenchymal fraction was correlated with both EDSS and MSFC at each of the four time points for which data were available (baseline 1, 2 and 8 years). Furthermore, the change in BPF was correlated with the changes in disability scores from the end of the phase III trial to the follow-up exam. These data suggest that brain atrophy may be a useful and clinically relevant marker of disease progression in relapsing-remitting MS.

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