Publications by authors named "David K B Li"

82 Publications

A data-driven T relaxation analysis approach for myelin water imaging: Spectrum analysis for multiple exponentials via experimental condition oriented simulation (SAME-ECOS).

Magn Reson Med 2021 Sep 7. Epub 2021 Sep 7.

Physics & Astronomy, University of British Columbia, Vancouver, British Columbia, Canada.

Purpose: The decomposition of multi-exponential decay data into a T spectrum poses substantial challenges for conventional fitting algorithms, including non-negative least squares (NNLS). Based on a combination of the resolution limit constraint and machine learning neural network algorithm, a data-driven and highly tailorable analysis method named spectrum analysis for multiple exponentials via experimental condition oriented simulation (SAME-ECOS) was proposed.

Theory And Methods: The theory of SAME-ECOS was derived. Then, a paradigm was presented to demonstrate the SAME-ECOS workflow, consisting of a series of calculation, simulation, and model training operations. The performance of the trained SAME-ECOS model was evaluated using simulations and six in vivo brain datasets. The code is available at https://github.com/hanwencat/SAME-ECOS.

Results: Using NNLS as the baseline, SAME-ECOS achieved over 15% higher overall cosine similarity scores in producing the T spectrum, and more than 10% lower mean absolute error in calculating the myelin water fraction (MWF), as well as demonstrated better robustness to noise in the simulation tests. Applying to in vivo data, MWF from SAME-ECOS and NNLS was highly correlated among all study participants. However, a distinct separation of the myelin water peak and the intra/extra-cellular water peak was only observed in the mean T spectra determined using SAME-ECOS. In terms of data processing speed, SAME-ECOS is approximately 30 times faster than NNLS, achieving a whole-brain analysis in 3 min.

Conclusion: Compared with NNLS, the SAME-ECOS method yields much more reliable T spectra in a dramatically shorter time, increasing the feasibility of multi-component T decay analysis in clinical settings.
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http://dx.doi.org/10.1002/mrm.29000DOI Listing
September 2021

Water content changes in new multiple sclerosis lesions have a minimal effect on the determination of myelin water fraction values.

J Neuroimaging 2021 Jul 26. Epub 2021 Jul 26.

Department of Radiology, University of British Columbia, Vancouver, British Columbia, Canada.

Background And Purpose: Myelin water fraction (MWF) is a histopathologically validated in vivo myelin marker. As MWF is the proportion of water with a short T relative to the total water, increases in water from edema and inflammation may confound MWF determination in multiple sclerosis (MS) lesions. Total water content (TWC) measurement enables calculation of absolute myelin water content (MWC) and can be used to distinguish edema/inflammation from demyelination. We assessed what influence changes in total water might have on MWF by calculating MWC values in new MS lesions.

Methods: 3T 32-echo T relaxation data were collected monthly for 6 months from six relapsing-remitting MS participants. TWC was determined and multiplied with MWF images to calculate corrected MWC images. The effect of this water content correction was examined in 20 new lesions by comparing mean MWF and MWC over time.

Results: On average, at lesion first appearance, lesion TWC increased by 6.4% (p = .003; range: -1% to +21%), MWF decreased by 24% (p = .006; range: -70% to +12%), and MWC decreased by 20% (p = .026; range: -68% to +21%), relative to prelesion values. Average TWC in lesions then gradually decreased, whereas MWF and MWC remained low. The shape of the MWF and MWC lesion evolution curves was nearly identical, differing only by an offset.

Conclusion: MWF mirrors MWC and is able to monitor myelin in new lesions. Even after taking into account water content increases, MWC still decreased at lesion first appearance attributed to demyelination.
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http://dx.doi.org/10.1111/jon.12908DOI Listing
July 2021

2021 MAGNIMS-CMSC-NAIMS consensus recommendations on the use of MRI in patients with multiple sclerosis.

Lancet Neurol 2021 08 14;20(8):653-670. Epub 2021 Jun 14.

Section of Neuroradiology, Department of Radiology, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain. Electronic address:

The 2015 Magnetic Resonance Imaging in Multiple Sclerosis and 2016 Consortium of Multiple Sclerosis Centres guidelines on the use of MRI in diagnosis and monitoring of multiple sclerosis made an important step towards appropriate use of MRI in routine clinical practice. Since their promulgation, there have been substantial relevant advances in knowledge, including the 2017 revisions of the McDonald diagnostic criteria, renewed safety concerns regarding intravenous gadolinium-based contrast agents, and the value of spinal cord MRI for diagnostic, prognostic, and monitoring purposes. These developments suggest a changing role of MRI for the management of patients with multiple sclerosis. This 2021 revision of the previous guidelines on MRI use for patients with multiple sclerosis merges recommendations from the Magnetic Resonance Imaging in Multiple Sclerosis study group, Consortium of Multiple Sclerosis Centres, and North American Imaging in Multiple Sclerosis Cooperative, and translates research findings into clinical practice to improve the use of MRI for diagnosis, prognosis, and monitoring of individuals with multiple sclerosis. We recommend changes in MRI acquisition protocols, such as emphasising the value of three dimensional-fluid-attenuated inversion recovery as the core brain pulse sequence to improve diagnostic accuracy and ability to identify new lesions to monitor treatment effectiveness, and we provide recommendations for the judicious use of gadolinium-based contrast agents for specific clinical purposes. Additionally, we extend the recommendations to the use of MRI in patients with multiple sclerosis in childhood, during pregnancy, and in the post-partum period. Finally, we discuss promising MRI approaches that might deserve introduction into clinical practice in the near future.
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http://dx.doi.org/10.1016/S1474-4422(21)00095-8DOI Listing
August 2021

Nonlesional diffusely abnormal appearing white matter in clinically isolated syndrome: Prevalence, association with clinical and MRI features, and risk for conversion to multiple sclerosis.

J Neuroimaging 2021 Sep 15;31(5):981-994. Epub 2021 Jun 15.

Department of Radiology, University of British Columbia, Vancouver, British Columbia, Canada.

Background And Purpose: While diffusely abnormal white matter (DAWM) is a nonlesional MRI abnormality identified in ∼25% of patients with multiple sclerosis (MS), it has yet to be investigated in patients at an earlier disease stage, namely clinically isolated syndrome (CIS). The goals of this study were to (1) determine the prevalence of DAWM in patients with a CIS suggestive of MS, (2) evaluate the association between DAWM and demographic, clinical, and MRI features, and (3) evaluate the prognostic significance of DAWM on conversion from CIS to MS.

Methods: One hundred and forty-two CIS participants were categorized into DAWM and non-DAWM groups at baseline and followed for up to 24 months or until MS diagnosis. The primary outcome was conversion to MS (2005 McDonald criteria) within 6 months.

Results: DAWM was present in 27.5% of participants, and was positively associated with brainstem symptom onset, receiving corticosteroids, dissemination in space, and T lesion volume. DAWM was associated with an increased risk of conversion to MS over 6 months after adjustment for age and disability (hazard ratio [HR] = 2.24, p = 0.004). This association remained at a trend-level after adjustment for high-risk imaging features (HR = 1.68, p = 0.10).

Conclusions: DAWM is present in a similar proportion of patients with CIS and clinically definite MS, and it is associated with increased risk of conversion to MS over 6 months.
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http://dx.doi.org/10.1111/jon.12900DOI Listing
September 2021

Deep grey matter injury in multiple sclerosis: a NAIMS consensus statement.

Brain 2021 08;144(7):1974-1984

Department of Neurology, University of Southern California Keck School of Medicine, Los Angeles, CA 90033, USA.

Although multiple sclerosis has traditionally been considered a white matter disease, extensive research documents the presence and importance of grey matter injury including cortical and deep regions. The deep grey matter exhibits a broad range of pathology and is uniquely suited to study the mechanisms and clinical relevance of tissue injury in multiple sclerosis using magnetic resonance techniques. Deep grey matter injury has been associated with clinical and cognitive disability. Recently, MRI characterization of deep grey matter properties, such as thalamic volume, have been tested as potential clinical trial end points associated with neurodegenerative aspects of multiple sclerosis. Given this emerging area of interest and its potential clinical trial relevance, the North American Imaging in Multiple Sclerosis (NAIMS) Cooperative held a workshop and reached consensus on imaging topics related to deep grey matter. Herein, we review current knowledge regarding deep grey matter injury in multiple sclerosis from an imaging perspective, including insights from histopathology, image acquisition and post-processing for deep grey matter. We discuss the clinical relevance of deep grey matter injury and specific regions of interest within the deep grey matter. We highlight unanswered questions and propose future directions, with the aim of focusing research priorities towards better methods, analysis, and interpretation of results.
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http://dx.doi.org/10.1093/brain/awab132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8370433PMC
August 2021

Outcomes and Risk Factors Associated With SARS-CoV-2 Infection in a North American Registry of Patients With Multiple Sclerosis.

JAMA Neurol 2021 06;78(6):699-708

Washington University School of Medicine in St Louis, St Louis, Missouri.

Importance: Emergence of SARS-CoV-2 causing COVID-19 prompted the need to gather information on clinical outcomes and risk factors associated with morbidity and mortality in patients with multiple sclerosis (MS) and concomitant SARS-CoV-2 infections.

Objective: To examine outcomes and risk factors associated with COVID-19 clinical severity in a large, diverse cohort of North American patients with MS.

Design, Setting, And Participants: This analysis used deidentified, cross-sectional data on patients with MS and SARS-CoV-2 infection reported by health care professionals in North American academic and community practices between April 1, 2020, and December 12, 2020, in the COVID-19 Infections in MS Registry. Health care professionals were asked to report patients after a minimum of 7 days from initial symptom onset and after sufficient time had passed to observe the COVID-19 disease course through resolution of acute illness or death. Data collection began April 1, 2020, and is ongoing.

Exposures: Laboratory-positive SARS-CoV-2 infection or highly suspected COVID-19.

Main Outcomes And Measures: Clinical outcome with 4 levels of increasing severity: not hospitalized, hospitalization only, admission to the intensive care unit and/or required ventilator support, and death.

Results: Of 1626 patients, most had laboratory-positive SARS-CoV-2 infection (1345 [82.7%]), were female (1202 [74.0%]), and had relapsing-remitting MS (1255 [80.4%]). A total of 996 patients (61.5%) were non-Hispanic White, 337 (20.8%) were Black, and 190 (11.7%) were Hispanic/Latinx. The mean (SD) age was 47.7 (13.2) years, and 797 (49.5%) had 1 or more comorbidity. The overall mortality rate was 3.3% (95% CI, 2.5%-4.3%). Ambulatory disability and older age were each independently associated with increased odds of all clinical severity levels compared with those not hospitalized after adjusting for other risk factors (nonambulatory: hospitalization only, odds ratio [OR], 2.8 [95% CI, 1.6-4.8]; intensive care unit/required ventilator support, OR, 3.5 [95% CI, 1.6-7.8]; death, OR, 25.4 [95% CI, 9.3-69.1]; age [every 10 years]: hospitalization only, OR, 1.3 [95% CI, 1.1-1.6]; intensive care unit/required ventilator support, OR, 1.3 [95% CI, 0.99-1.7]; death, OR, 1.8 [95% CI, 1.2-2.6]).

Conclusions And Relevance: In this registry-based cross-sectional study, increased disability was independently associated with worse clinical severity including death from COVID-19. Other risk factors for worse outcomes included older age, Black race, cardiovascular comorbidities, and recent treatment with corticosteroids. Knowledge of these risk factors may improve the treatment of patients with MS and COVID-19 by helping clinicians identify patients requiring more intense monitoring or COVID-19 treatment.
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http://dx.doi.org/10.1001/jamaneurol.2021.0688DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7980147PMC
June 2021

Multimodal peripheral fluid biomarker analysis in clinically isolated syndrome and early multiple sclerosis.

Mult Scler Relat Disord 2021 May 3;50:102809. Epub 2021 Feb 3.

Departments of Clinical Neurosciences, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.

Background: Increasing evidence suggests that various inflammatory, immunological and metabolic pathways are altered in the clinically isolated syndrome (CIS) of multiple sclerosis (MS). Moreover, recent diagnostic criteria have made possible the very early diagnosis of MS. We evaluated multiple fluid biomarkers in people with early MS and CIS.

Methods: We measured blood levels of cytokines, matrix metalloproteinases (MMPs), serum metabolomics and immune cell immunophenotyping in participants in the Trial of Minocycline in a Clinically Isolated Syndrome of Multiple Sclerosis.

Results: When compared with healthy controls, people with early MS/CIS had higher levels of eotaxin, MCP-3, IL-1 receptor antagonist, IL-1β, IL-9 and IP-10, as well as MMPs 1, 8 and 9. In metabolomics analysis, the alanine, aspartate and glutamate metabolism and the synthesis and degradation of ketone bodies pathways were altered compared to healthy controls. There were no differences in lymphocyte subpopulation numbers. Out of all these biomarkers, only MMP-1 was able to differentiate between early MS and CIS, and was found to correlate with lesion volume and gadolinium enhancing lesions on MRI.

Conclusion: The immunological and metabolic profile of CIS and early MS is remarkably similar, supporting that these are a continuum of a common underlying pathophysiological process.
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http://dx.doi.org/10.1016/j.msard.2021.102809DOI Listing
May 2021

Comparison of multi echo T relaxation and steady state approaches for myelin imaging in the central nervous system.

Sci Rep 2021 01 14;11(1):1369. Epub 2021 Jan 14.

Physics and Astronomy, University of British Columbia, Vancouver, BC, Canada.

The traditional approach for measuring myelin-associated water with quantitative magnetic resonance imaging (MRI) uses multi-echo T relaxation data to calculate the myelin water fraction (MWF). A fundamentally different approach, abbreviated "mcDESPOT", uses a more efficient steady-state acquisition to generate an equivalent metric (f). Although previous studies have demonstrated inherent instability and bias in the complex mcDESPOT analysis procedure, f has often been used as a surrogate for MWF. We produced and compared multivariate atlases of MWF and f in healthy human brain and cervical spinal cord (available online) and compared their ability to detect multiple sclerosis pathology. A significant bias was found in all regions (p < 10), albeit reversed for spinal cord (f-MWF =  - 3.4%) compared to brain (+ 6.2%). MWF and f followed an approximately linear relationship for regions with MWF <  ~ 10%. For MWF >  ~ 10%, the relationship broke down and f no longer increased in tandem with MWF. For multiple sclerosis patients, MWF and f Z score maps showed overlapping areas of low Z score and similar trends between patients and brain regions, although those of f generally had greater spatial extent and magnitude of severity. These results will guide future choice of myelin-sensitive quantitative MRI and improve interpretation of studies using either myelin imaging approach.
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http://dx.doi.org/10.1038/s41598-020-80585-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7809349PMC
January 2021

An atlas for human brain myelin content throughout the adult life span.

Sci Rep 2021 01 11;11(1):269. Epub 2021 Jan 11.

Physics and Astronomy, University of British Columbia, Vancouver, BC, Canada.

Myelin water imaging is a quantitative neuroimaging technique that provides the myelin water fraction (MWF), a metric highly specific to myelin content, and the intra-/extra-cellular T (IET2), which is related to water and iron content. We coupled high-resolution data from 100 adults with gold-standard methodology to create an optimized anatomical brain template and accompanying MWF and IET2 atlases. We then used the MWF atlas to characterize how myelin content relates to demographic factors. In most brain regions, myelin content followed a quadratic pattern of increase during the third decade of life, plateau at a maximum around the fifth decade, then decrease during later decades. The ranking of mean myelin content between brain regions remained consistent across age groups. These openly available normative atlases can facilitate evaluation of myelin imaging results on an individual basis and elucidate the distribution of myelin content between brain regions and in the context of aging.
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http://dx.doi.org/10.1038/s41598-020-79540-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7801525PMC
January 2021

An International Standardized Magnetic Resonance Imaging Protocol for Diagnosis and Follow-up of Patients with Multiple Sclerosis: Advocacy, Dissemination, and Implementation Strategies.

Int J MS Care 2020 Sep-Oct;22(5):226-232. Epub 2020 Oct 27.

Standardized magnetic resonance imaging (MRI) protocols are important for the diagnosis and monitoring of patients with multiple sclerosis (MS). The Consortium of Multiple Sclerosis Centers (CMSC) convened an international panel of MRI experts to review and update the current guidelines. The objective was to update the standardized MRI protocol and clinical guidelines for diagnosis and follow-up of MS and develop strategies for advocacy, dissemination, and implementation. Conference attendees included neurologists, radiologists, technologists, and imaging scientists with expertise in MS. Representatives from the CMSC, Magnetic Resonance Imaging in MS (MAGNIMS), North American Imaging in Multiple Sclerosis Cooperative, US Department of Veteran Affairs, National Multiple Sclerosis Society, Multiple Sclerosis Association of America, MRI manufacturers, and commercial image analysis companies were present. Before the meeting, CMSC members were surveyed about standardized MRI protocols, gadolinium use, need for diffusion-weighted imaging, and the central vein sign. The panel worked to make the CMSC and MAGNIMS MRI protocols similar so that the updated guidelines could ultimately be accepted by international consensus. Advocacy efforts will promote the importance of standardized MS MRI protocols. Dissemination will include publications, meeting abstracts, educational programming, webinars, "meet the expert" teleconferences, and examination cards. Implementation will require comprehensive and coordinated efforts to make the protocol easy to access and use. The ultimate vision, and goal, is for the guidelines to be universally useful, usable, and used as the standard of care for patients with MS.
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http://dx.doi.org/10.7224/1537-2073.2020-094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7643842PMC
October 2020

Associations Between Findings From Myelin Water Imaging and Cognitive Performance Among Individuals With Multiple Sclerosis.

JAMA Netw Open 2020 09 1;3(9):e2014220. Epub 2020 Sep 1.

Department of Medicine (Neurology), The University of British Columbia, Vancouver, British Columbia, Canada.

Importance: Cognitive impairment is a debilitating symptom of multiple sclerosis (MS) that affects up to 70% of patients. An improved understanding of the underlying pathology of MS-related cognitive impairment would provide considerable benefit to patients and clinicians.

Objective: To determine whether there is an association between myelin damage in tissue that appears completely normal on standard clinical imaging, but can be detected by myelin water imaging (MWI), with cognitive performance in MS.

Design, Setting, And Participants: In this cross-sectional study, participants with MS and controls underwent cognitive testing and magnetic resonance imaging (MRI) from August 23, 2017, to February 20, 2019. Participants were recruited through the University of British Columbia Hospital MS clinic and via online recruitment advertisements on local health authority websites. Cognitive testing was performed in the MS clinic, and MRI was performed at the adjacent academic research neuroimaging center. Seventy-three participants with clinically definite MS fulfilling the 2017 revised McDonald criteria for diagnosis and 22 age-, sex-, and education-matched healthy volunteers without neurological disease were included in the study. Data analysis was performed from March to November 2019.

Exposures: MWI was performed at 3 T with a 48-echo, 3-dimensional, gradient and spin-echo (GRASE) sequence. Cognitive testing was performed with assessments drawn from cognitive batteries validated for use in MS.

Main Outcomes And Measures: The association between myelin water measures, a measurement of the T2 relaxation signal from water in the myelin bilayers providing a specific marker for myelin, and cognitive test scores was assessed using Pearson correlation. Three white matter regions of interest-the cingulum, superior longitudinal fasciculus (SLF), and corpus callosum-were selected a priori according to their known involvement in MS-related cognitive impairment.

Results: For the 95 total participants, the mean (SD) age was 49.33 (11.44) years. The mean (SD) age was 50.2 (10.7) years for the 73 participants with MS and 46.4 (13.5) for the 22 controls. Forty-eight participants with MS (66%) and 14 controls (64%) were women. The mean (SD) years of education were 14.7 (2.2) for patients and 15.8 (2.5) years for controls. In MS, significant associations were observed between myelin water measures and scores on the Symbol Digit Modalities Test (SLF, r = -0.490; 95% CI, -0.697 to -0.284; P < .001; corpus callosum, r = -0.471; 95% CI, -0.680 to -0.262; P < .001; and cingulum, r = -0.419; 95% CI, -0.634 to -0.205; P < .001), Selective Reminding Test (SLF, r = -0.444; 95% CI, -0.660 to -0.217; P < .001; corpus callosum, r = -0.411; 95% CI, -0.630 to -0.181; P = .001; and cingulum, r = -0.361; 95% CI, -0.602 to -0.130; P = .003), and Controlled Oral Word Association Test (SLF, r = -0.317; 95% CI, -0.549 to -0.078; P = .01; and cingulum, r = -0.335; 95% CI, -0.658 to -0.113; P = .006). No significant associations were found in controls.

Conclusions And Relevance: This study used MWI to demonstrate that otherwise normal-appearing brain tissue is diffusely damaged in MS, and the findings suggest that myelin water measures are associated with cognitive performance. MWI offers an in vivo biomarker feasible for use in clinical trials investigating cognition, providing a means for monitoring changes in myelination and its association with symptom worsening or improvement.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.14220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7525360PMC
September 2020

Brain Myelin Water Fraction and Diffusion Tensor Imaging Atlases for 9-10 Year-Old Children.

J Neuroimaging 2020 03 16;30(2):150-160. Epub 2020 Feb 16.

Department of Physics and Astronomy, University of British Columbia, Vancouver, BC, Canada.

Background And Purpose: Myelin water imaging (MWI) and diffusion tensor imaging (DTI) provide information about myelin and axon-related brain microstructure, which can be useful for investigating normal brain development and many childhood brain disorders. While pediatric DTI atlases exist, there are no pediatric MWI atlases available for the 9-10 years old age group. As myelination and structural development occurs throughout childhood and adolescence, studies of pediatric brain pathologies must use age-specific MWI and DTI healthy control data. We created atlases of myelin water fraction (MWF) and DTI metrics for healthy children aged 9-10 years for use as normative data in pediatric neuroimaging studies.

Methods: 3D-T , DTI, and MWI scans were acquired from 20 healthy children (mean age: 9.6 years, range: 9.2-10.3 years, 4 females). ANTs and FSL registration were used to create quantitative MWF and DTI atlases. Region of interest (ROI) analysis in nine white matter regions was used to compare pediatric MWF with adult MWF values from a recent study and to investigate the correlation between pediatric MWF and DTI metrics.

Results: Adults had significantly higher MWF than the pediatric cohort in seven of the nine white matter ROIs, but not in the genu of the corpus callosum or the cingulum. In the pediatric data, MWF correlated significantly with mean diffusivity, but not with axial diffusivity, radial diffusivity, or fractional anisotropy.

Conclusions: Normative MWF and DTI metrics from a group of 9-10 year old healthy children provide a resource for comparison to pathologies. The age-specific atlases are ready for use in pediatric neuroimaging research and can be accessed: https://sourceforge.net/projects/pediatric-mri-myelin-diffusion/.
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http://dx.doi.org/10.1111/jon.12689DOI Listing
March 2020

Myelin water imaging data analysis in less than one minute.

Neuroimage 2020 04 21;210:116551. Epub 2020 Jan 21.

Physics & Astronomy, University of British Columbia, Canada; International Collaboration on Repair Discoveries (ICORD), University of British Columbia, Canada; Radiology, University of British Columbia, Canada; Pathology & Laboratory Medicine, University of British Columbia, Canada. Electronic address:

Purpose: Based on a deep learning neural network (NN) algorithm, a super fast and easy to implement data analysis method was proposed for myelin water imaging (MWI) to calculate the myelin water fraction (MWF).

Methods: A NN was constructed and trained on MWI data acquired by a 32-echo 3D gradient and spin echo (GRASE) sequence. Ground truth labels were created by regularized non-negative least squares (NNLS) with stimulated echo corrections. Voxel-wise GRASE data from 5 brains (4 healthy, 1 multiple sclerosis (MS)) were used for NN training. The trained NN was tested on 2 healthy brains, 1 MS brain with segmented lesions, 1 healthy spinal cord, and 1 healthy brain acquired from a different scanner.

Results: Production of whole brain MWF maps in approximately 33 ​s can be achieved by a trained NN without graphics card acceleration. For all testing regions, no visual differences between NN and NNLS MWF maps were observed, and no obvious regional biases were found. Quantitatively, all voxels exhibited excellent agreement between NN and NNLS (all R>0.98, p ​< ​0.001, mean absolute error <0.01).

Conclusion: The time for accurate MWF calculation can be dramatically reduced to less than 1 ​min by the proposed NN, addressing one of the barriers facing future clinical feasibility of MWI.
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http://dx.doi.org/10.1016/j.neuroimage.2020.116551DOI Listing
April 2020

Onset of clinical and MRI efficacy of ocrelizumab in relapsing multiple sclerosis.

Neurology 2019 11 4;93(19):e1778-e1786. Epub 2019 Sep 4.

From the Department of Radiology and Nuclear Medicine (F.B.), VU University Medical Centre, Amsterdam, the Netherlands; UCL Institutes of Healthcare Engineering and Neurology (F.B.), London, UK; Neurologic Clinic and Policlinic, Departments of Medicine, Clinical Research, Biomedicine and Biomedical Engineering (L.K.), University Hospital Basel, University of Basel, Switzerland; Department of Neurology (J.S.W.), McGovern Medical School, UTHealth, Houston, TX; Department of Radiology (D.K.B.L.), University of British Columbia, Vancouver, Canada; Department of Neurology and Center for Neuroinflammation and Experimental Therapeutics (A.B.-O.), University of Pennsylvania, Philadelphia; Department of Neurology, Medical Faculty (H.-P.H.), Heinrich-Heine University Düsseldorf, Germany; F. Hoffmann-La Roche Ltd. (S.B., A.S., J.N., H.K.), Basel, Switzerland; Genentech, Inc. (J.H., L.J.), South San Francisco; and Department of Neurology (S.L.H.), University of California, San Francisco. During completion of the work related to this article, S. Belachew was an employee of F. Hoffmann-La Roche Ltd.; his current affiliation is Biogen, Cambridge, MA.

Objective: To assess the onset of ocrelizumab efficacy on brain MRI measures of disease activity in the phase II study in relapsing-remitting multiple sclerosis (RRMS), and relapse rate in the pooled phase III studies in relapsing multiple sclerosis (RMS).

Methods: Brain MRI activity was determined in the phase II trial at monthly intervals in patients with RRMS receiving placebo, ocrelizumab (600 mg), or intramuscular interferon (IFN) β-1a (30 μg). Annualized relapse rate (ARR; over various epochs) and time to first relapse were analyzed in the pooled population of the phase III OPERA (A Study of Ocrelizumab in Comparison With Interferon Beta-1a [Rebif] in Participants With Relapsing Multiple Sclerosis) I and OPERA II trials in patients with RMS receiving ocrelizumab (600 mg) or subcutaneous IFN-β-1a (44 μg).

Results: In patients with RRMS, ocrelizumab reduced the number of new T1 gadolinium-enhancing lesions by week 4 vs placebo ( = 0.042) and by week 8 vs intramuscular IFN-β-1a ( < 0.001). Ocrelizumab also reduced the number of new or enlarging T2 lesions appearing between weeks 4 and 8 vs both placebo and IFN-β-1a (both < 0.001). In patients with RMS, ocrelizumab significantly reduced ARR ( = 0.005) and the probability of time to first protocol-defined relapse ( = 0.014) vs subcutaneous IFN-β-1a within the first 8 weeks.

Conclusion: Epoch analysis of MRI-measured lesion activity in the phase II study and relapse rate in the phase III studies consistently revealed a rapid suppression of acute MRI and clinical disease activity following treatment initiation with ocrelizumab in patients with RRMS and RMS, respectively.

Classification Of Evidence: This study provides Class II evidence that for patients with RRMS and RMS, ocrelizumab suppressed MRI activity within 4 weeks and clinical disease activity within 8 weeks.
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http://dx.doi.org/10.1212/WNL.0000000000008189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6946481PMC
November 2019

Data fusion detects consistent relations between non-lesional white matter myelin, executive function, and clinical characteristics in multiple sclerosis.

Neuroimage Clin 2019 2;24:101926. Epub 2019 Jul 2.

Faculty of Medicine, Division of Neurology, The University of British Columbia, Canada. Electronic address:

We examined the influence of dysfunctional, non-lesional white matter on cognitive performance in multiple sclerosis (MS). Forty-six MS subjects were assessed using MRI-based myelin water imaging (MWI), and average myelin water fraction (MWF) values across 20 white matter regions of interest (ROIs) were determined. A data-fusion method, multiset canonical correlation analysis (MCCA), was used to investigate the multivariate, deterministic joint relations between MWF, executive function, and demographic and clinical characteristics. MCCA revealed one significant component (p = 0.009) which consisted of three linked profiles, with a pairwise correlation between the MWF and cognitive profiles of r = 0.37, a correlation between MWF and demographics profiles of r = 0.31, and between cognitive and demographics profiles r = 0.64. White matter ROIs representing long-range intra-hemispheric tracts and ROIs connecting the two hemispheres were positively related through their individual profiles to overall cognitive performance, education and female gender, while age, EDSS, and disease duration were related negatively. Surprisingly, lesions within the ROIs had a negligible effect on overall relations between imaging, cognitive, and demographic variables. These findings indicate that there is a strong association between a pattern of MWF values and cognitive performance in MS, which is modulated by age, education, and disease severity. Moreover, this consistent relation involves multiple white matter regions and is separate from the influence of lesions.
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http://dx.doi.org/10.1016/j.nicl.2019.101926DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6704047PMC
September 2020

Myelin Water Fraction and Intra/Extracellular Water Geometric Mean T Normative Atlases for the Cervical Spinal Cord from 3T MRI.

J Neuroimaging 2020 01 13;30(1):50-57. Epub 2019 Aug 13.

Department of Physics & Astronomy, University of British Columbia, Vancouver, Canada.

Background And Purpose: Acquiring and interpreting quantitative myelin-specific MRI data at an individual level is challenging because of technical difficulties and natural myelin variation in the population. To overcome these challenges, we used multiecho T myelin water imaging (MWI) to create T metric healthy population atlases that depict the mean and variation of myelin water fraction (MWF), and intra- and extracellular water mobility as described by geometric mean T (IEGMT ).

Methods: Cervical cord MWI was performed at 3T on 20 healthy individuals (10M/10F, mean age: 36 years) and 3 relapsing remitting multiple sclerosis (RRMS) participants (1M/2F, age: 39/42/37 years). Anatomical data were collected for the purpose of image segmentation and registration. Atlases were created by coregistering and averaging T metrics from all controls. Voxel-wise z-score maps from 3 RRMS participants were produced to demonstrate the preliminary utility of the MWF and IEGMT atlases.

Results: The average MWF atlas provides a representation of myelin in the spinal cord consistent with well-known spinal cord anatomical characteristics. The IEGMT atlas also depicted structural variations in the spinal cord. Z-score analysis illustrated distinct abnormalities in MWF and IEGMT in the 3 RRMS cases.

Conclusions: Our findings highlight the potential for using a quantitative T relaxation metric atlas to visualize and detect pathology in spinal cord. Our MWF and IEGMT atlases (URL: https://sourceforge.net/projects/mwi-spinal-cord-atlases/) can serve as normative references in the cervical spinal cord for other studies.
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http://dx.doi.org/10.1111/jon.12659DOI Listing
January 2020

Myelin Water Atlas: A Template for Myelin Distribution in the Brain.

J Neuroimaging 2019 11 25;29(6):699-706. Epub 2019 Jul 25.

Department of Physics and Astronomy, University of British Columbia, Vancouver, British Columbia, Canada.

Background And Purpose: Myelin water imaging (MWI) is a magnetic resonance imaging technique that quantifies myelin in-vivo. Although MWI has been extensively applied to study myelin-related diseases in groups, clinical use in individual patients is challenging mainly due to population heterogeneity. The purpose of this study was twofold: (1) create a normative brain myelin water atlas depicting the population mean and regional variability of myelin content; and (2) apply the myelin atlas to assess the degree of demyelination in individuals with multiple sclerosis (MS).

Methods: 3T MWI was performed on 50 healthy adults (25 M/25 F, mean age 25 years [range 17-42 years]). The myelin water atlas was created by averaging coregistered myelin water fraction (MWF) maps from all healthy individuals. To illustrate the preliminary utility of the atlas, white matter (WM) regional MWF variations were evaluated and voxel-wise z-score maps (z < -1.96) from the MWI of three MS participants were produced to assess individually the degree of demyelination.

Results: The myelin water atlas demonstrated significant MWF variation across control WM. No significant MWF differences were found between male and female healthy participants. MS z-score maps revealed diffuse regions of demyelination in the two participants with Expanded Disability Status Scale (EDSS) = 2.0 but not in the participant with EDSS = 0.

Conclusions: The myelin water atlas can be used as a reference (URL: https://sourceforge.net/projects/myelin-water-atlas/) to demonstrate areas of demyelination in individual MS participants. Future studies will expand the atlas age range, account for education, and other variables that may affect myelination.
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http://dx.doi.org/10.1111/jon.12657DOI Listing
November 2019

Rapid myelin water imaging for the assessment of cervical spinal cord myelin damage.

Neuroimage Clin 2019 17;23:101896. Epub 2019 Jun 17.

Physics and Astronomy, University of British Columbia, 6224 Agricultural Road, Vancouver, BC V6T 1Z1, Canada; Radiology, University of British Columbia, 2775 Laurel Street, Vancouver, BC V5Z 1M9, Canada; International Collaboration on Repair Discoveries, University of British Columbia, 818 West 10th Avenue, Vancouver, BC V5Z 1M9, Canada; Medicine (Neurology), University of British Columbia, 2211 Wesbrook Mall, Vancouver, BC, V6T 2B5, Canada.

Background: Rapid myelin water imaging (MWI) using a combined gradient and spin echo (GRASE) sequence can produce myelin specific metrics for the human brain. Spinal cord MWI could be similarly useful, but technical challenges have hindered routine application. GRASE rapid MWI was recently successfully implemented for imaging of healthy cervical spinal cord and may complement other advanced imaging methods, such as diffusion tensor imaging (DTI) and quantitative T (qT).

Objective: To demonstrate the feasibility of cervical cord GRASE rapid MWI in multiple sclerosis (MS), primary lateral sclerosis (PLS) and neuromyelitis optica spectrum disorder (NMO), with comparison to DTI and qT metrics.

Methods: GRASE MWI, DTI and qT data were acquired in 2 PLS, 1 relapsing-remitting MS (RRMS), 1 primary-progressive MS (PPMS) and 2 NMO subjects, as well as 6 age (±3 yrs) and sex matched healthy controls (HC). Internal cord structure guided template registrations, used for region of interest (ROI) analysis. Z score maps were calculated for the difference between disease subject and mean HC metric values.

Results: PLS subjects had low myelin water fraction (MWF) in the lateral funiculi compared to HC. RRMS subject MWF was heterogeneous within the cord. The PPMS subject showed no trends in ROI results but had a region of low MWF Z score corresponding to a focal lesion. The NMO subject with a longitudinally extensive transverse myelitis lesion had low values for whole cord mean MWF of 12.8% compared to 24.3% (standard deviation 2.2%) for HC. The NMO subject without lesions also had low MWF compared to HC. DTI and qT metrics showed similar trends, corroborating the MWF results and providing complementary information.

Conclusion: GRASE is sufficiently sensitive to detect decreased myelin within MS spinal cord plaques, NMO lesions, and PLS diffuse spinal cord injury. Decreased MWF in PLS is consistent with demyelination secondary to motor neuron degeneration. GRASE MWI is a feasible method for rapid assessment of myelin content in the cervical spinal cord and provides complementary information to that of DTI and qT measures.
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http://dx.doi.org/10.1016/j.nicl.2019.101896DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6611998PMC
June 2020

Intra- and inter-site reproducibility of human brain single-voxel proton MRS at 3 T.

NMR Biomed 2019 06 19;32(6):e4083. Epub 2019 Mar 19.

Physics & Astronomy, University of British Columbia, Vancouver, British Columbia, Canada.

Introduction: Clinical trials that involve participants from multiple sites necessitate standardized and reliable quantitative MRI outcomes to detect significant group differences over time. Metabolite concentrations measured by proton MRS ( H-MRS) provide valuable information about in vivo metabolism of the central nervous system, but can vary based on the acquisition and quantitation methods used by different MR sites. Therefore, we investigated the intra- and inter-site reproducibility of metabolite concentrations measured by H-MRS on MRI scanners from a single manufacturer across six sites.

Methods: Five healthy controls were scanned twice within 24 h at six participating 3 T MR sites with large single-voxel PRESS (TE/TR/NSA = 36 ms/4000 ms/56) and anatomical images for voxel positioning and correction of partial volume relaxation. Absolute metabolite concentrations were calculated relative to the T and T relaxation corrected signal from water. Intra- and inter-site reproducibility was assessed using Bland-Altman plots and intra- and inter-site coefficient of variation (CoV) as well as intra- and inter-site intra-class correlation coefficient.

Results: The median intra-site CoVs for the five major metabolite concentrations ([NAA], [tCr], [Glu], [tCho] and [Ins]) were between 2.5 and 5.3%. Inter-site CoVs were also low, with the median CoVs for all metabolites between 3.7 and 6.4%. Metabolite concentrations were robust to small inconsistencies in voxel placement and site was not the driving factor in the variance of the measurement of any metabolite concentration. Between-subject differences accounted for the majority of the concentration variability for creatine, choline and myo-inositol (42-65% of the variance).

Conclusion: A large single-voxel H-MRS acquisition from a single manufacturer's MRI scanner is highly reproducible and reliable for multi-site clinical trials.
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http://dx.doi.org/10.1002/nbm.4083DOI Listing
June 2019

Longitudinal advanced MRI case report of white matter radiation necrosis.

Ann Clin Transl Neurol 2019 02 10;6(2):379-385. Epub 2018 Dec 10.

Department of Medicine Division of Neurology University of British Columbia Vancouver British Columbia Canada.

Radiation necrosis mostly occurs in and near the radiation field. We used magnetic resonance imaging to study radiation-induced necrosis of atypical onset, severity, and extent following stereotactic radiosurgery for a symptomatic arteriovenous malformation. Susceptibility-sensitive imaging, T-relaxation, myelin water imaging, and magnetic resonance spectroscopy were acquired three times up to 52 months postradiosurgery. Increasing water content outside the radiation field, contralateral neuronal loss, and gliosis were detected over time. Our findings suggest that radiation-induced vasculopathic changes spread more diffusely than previously described. An autoimmune response to brain antigens could underlie white matter changes outside the initial radiation field.
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http://dx.doi.org/10.1002/acn3.704DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6389755PMC
February 2019

Imaging outcome measures of neuroprotection and repair in MS: A consensus statement from NAIMS.

Neurology 2019 03 20;92(11):519-533. Epub 2019 Feb 20.

From the Division of Neurology (J.O.), St. Michael's Hospital, University of Toronto, Canada; Department of Neurology (J.O., P.A.C., B.D., D.S.R.), Johns Hopkins University, Baltimore, MD; Mellen Center for Multiple Sclerosis (D.O.), Cleveland Clinic, OH; Department of Neurology (C.A., D.P.), University of Southern California, Los Angeles; Department of Neurology (E.C.K.), Massachusetts General Hospital, Harvard Medical School, Boston; Translational Neuroradiology Unit (M.A., G.N., P.S., D.S.R.), National Institute of Neurological Disorders and Stroke, Bethesda, MD; Brain Imaging Centre (D.L.A., S.N.), Montreal Neurological Institute, McGill University, Canada; Departments of Neurology (R.B.) and Radiology (R.B.), Brigham and Women's Hospital, Harvard Medical School, Boston; Department of Biostatistics (C.C.), Johns Hopkins School of Public Health, Baltimore, MD; Department of Neurology (L.F.), University of Texas Health Science Center at Houston; Department of Neurology (S.G., Y.W.), Weill Cornell Medical College, Cornell University, Ithaca, NY; Department of Neurology (R.H.), University of California at San Francisco; Department of Neurology (M.I., A.T.), Mount Sinai Hospital, New York, NY; Division of Neurology, Department of Medicine (S.K., D.K.B.L.), Department of Radiology (S.K., D.K.B.L., A.R.), Department of Physics and Astronomy (S.K., A.R., A.T., Y.Y.), MS/MRI Research Group (S.K., D.K.B.L., A.T., Y.Y.), MRI Research Centre (S.K., D.K.B.L., A.R.), and Department of Pediatrics (A.R.), University of British Columbia, Vancouver, Canada; A. A. Martinos Center for Biomedical Imaging (C.M.), Department of Radiology, Massachusetts General Hospital, Boston; Centre for Functional and Metabolic Mapping (R.S.M.), Robarts Research Institute, Western University, London, CA; Department of Neurology (F.N.), University of Minnesota, Minneapolis; Advanced Imaging Research Center (W.R., D.S., I.T.), Oregon Health & Science University, Portland; Department of Biostatistics, Epidemiology, and Informatics (R.T.S.), University of Pennsylvania Perelman School of Medicine, Philadelphia; Division of Neuroradiology and Neurophysics (T.Y.), University College London Institute of Neurology, UK; Department of Radiology (Y.Z.) and Department of Clinical Neurosciences and Hotchkiss Brain Institute (Y.Z.), University of Calgary, Canada; and Department of Neurology (N.L.S.), Cedars-Sinai Medical Center, Los Angeles, CA.

Objective: To summarize current and emerging imaging techniques that can be used to assess neuroprotection and repair in multiple sclerosis (MS), and to provide a consensus opinion on the potential utility of each technique in clinical trial settings.

Methods: Clinicians and scientists with expertise in the use of MRI in MS convened in Toronto, Canada, in November 2016 at a North American Imaging in Multiple Sclerosis (NAIMS) Cooperative workshop meeting. The discussion was compiled into a manuscript and circulated to all NAIMS members in attendance. Edits and feedback were incorporated until all authors were in agreement.

Results: A wide spectrum of imaging techniques and analysis methods in the context of specific study designs were discussed, with a focus on the utility and limitations of applying each technique to assess neuroprotection and repair. Techniques were discussed under specific themes, and included conventional imaging, magnetization transfer ratio, diffusion tensor imaging, susceptibility-weighted imaging, imaging cortical lesions, magnetic resonance spectroscopy, PET, advanced diffusion imaging, sodium imaging, multimodal techniques, imaging of special regions, statistical considerations, and study design.

Conclusions: Imaging biomarkers of neuroprotection and repair are an unmet need in MS. There are a number of promising techniques with different strengths and limitations, and selection of a specific technique will depend on a number of factors, notably the question the trial seeks to answer. Ongoing collaborative efforts will enable further refinement and improved methods to image the effect of novel therapeutic agents that exert benefit in MS predominately through neuroprotective and reparative mechanisms.
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http://dx.doi.org/10.1212/WNL.0000000000007099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6511106PMC
March 2019

Quantitative neuroimaging measures of myelin in the healthy brain and in multiple sclerosis.

Hum Brain Mapp 2019 05 15;40(7):2104-2116. Epub 2019 Jan 15.

Department of Radiology, University of British Columbia, Vancouver, British Columbia, Canada.

Quantitative magnetic resonance imaging (MRI) techniques have been developed as imaging biomarkers, aiming to improve the specificity of MRI to underlying pathology compared to conventional weighted MRI. For assessing the integrity of white matter (WM), myelin, in particular, several techniques have been proposed and investigated individually. However, comparisons between these methods are lacking. In this study, we compared four established myelin-sensitive MRI techniques in 56 patients with relapsing-remitting multiple sclerosis (MS) and 38 healthy controls. We used T2-relaxation with combined GRadient And Spin Echoes (GRASE) to measure myelin water fraction (MWF-G), multi-component driven equilibrium single pulse observation of T and T (mcDESPOT) to measure MWF-D, magnetization-transfer imaging to measure magnetization-transfer ratio (MTR), and T relaxation to measure quantitative T (qT ). Using voxelwise Spearman correlations, we tested the correspondence of methods throughout the brain. All four methods showed associations that varied across tissue types; the highest correlations were found between MWF-D and qT (median ρ across tissue classes 0.8) and MWF-G and MWF-D (median ρ = 0.59). In eight WM tracts, all measures showed differences (p < 0.05) between MS normal-appearing WM and healthy control WM, with qT1 showing the highest number of different regions (8), followed by MWF-D and MTR (6), and MWF-G (n = 4). Comparing the methods in terms of their statistical sensitivity to MS lesions in WM, MWF-D demonstrated the best accuracy (p < 0.05, after multiple comparison correction). To aid future power analysis, we provide the average and standard deviation volumes of the four techniques, estimated from the healthy control sample.
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http://dx.doi.org/10.1002/hbm.24510DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6590140PMC
May 2019

Inter-Vendor Reproducibility of Myelin Water Imaging Using a 3D Gradient and Spin Echo Sequence.

Front Neurosci 2018 21;12:854. Epub 2018 Nov 21.

Department of Medicine, The University of British Columbia, Vancouver, BC, Canada.

Myelin water imaging can be achieved using multicomponent T relaxation analysis to quantify measurement of myelin content, termed the myelin water fraction (MWF). Therefore, myelin water imaging can be a valuable tool to better understand the underlying white matter pathology in demyelinating diseases, such as multiple sclerosis. To apply myelin water imaging in multisite studies and clinical applications, it must be acquired in a clinically feasible scan time (less than 15 min) and be reproducible across sites and scanner vendors. Here, we assessed the reproducibility of MWF measurements in regional and global white matter in 10 healthy human brains across two sites with two different 3 T magnetic resonance imaging scanner vendors (Philips and Siemens), using a 32-echo gradient and spin echo (GRASE) sequence. A strong correlation was found between the MWF measurements in the global white matter (Pearson's = 0.91; < 0.001) for all participants across the two sites. The mean intersite MWF coefficient of variation across participants was 2.77% in the global white matter and ranged from 4.47% (splenium of the corpus callosum) to 17.89% (genu of the corpus callosum) in white matter regions of interest. Bland-Altman analysis showed a good agreement in MWF measurements between the two sites with small bias of 0.002. Overall, MWF estimates were in good agreement across the two sites and scanner vendors. Our findings support the use of quantitative multi-echo T relaxation metrics, such as the MWF, in multicenter studies and clinical trials to gain deeper understanding about the pathological processes resulting from the underlying disease progression in neurodegenerative diseases.
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http://dx.doi.org/10.3389/fnins.2018.00854DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6258882PMC
November 2018

Increased mean R2* in the deep gray matter of multiple sclerosis patients: Have we been measuring atrophy?

J Magn Reson Imaging 2019 07 4;50(1):201-208. Epub 2018 Dec 4.

UBC MRI Research Centre, University of British Columbia, Vancouver, Canada.

Background: Magnetic resonance relaxometry studies in multiple sclerosis (MS) have suggested that iron accumulates within deep gray matter (DGM) structures early in the disease course. However, the commonly utilized mean R2* and magnetic susceptibility measures reflect regional iron concentration but not a structure's total iron content. Thus, tissue atrophy could impact mean R2* and magnetic susceptibility estimates.

Purpose: To demonstrate that both average iron concentration and total iron content need to be reported in order to distinguish between atrophy-related and definite magnetic susceptibility changes.

Study Type: Observational.

Population: The study was performed on 30 healthy controls (HCs) and 39 people with definite MS.

Field Strength/sequence: 3T Philips Achieva using an 8-channel SENSE head coil. R2* data were acquired using a multiecho gradient echo sequence and diffusion tensor imaging data were acquired using an echo-planar sequence.

Assessment: Total iron content in DGM structures was assessed by calculating the sum of all R2* values within a region (denoted as ) and compared to the mean R2* as a measure of iron concentration.

Statistical Test: Significant group differences were investigated in a linear regression model. All DGM structures were assessed individually and the significance threshold was adjusted using the Bonferroni-Holm correction for multiple comparisons.

Results: There was an increased mean DGM R2* in MS patients compared to HCs (significant in the pallidus, P = 0.0051). In contrast, in patients was found to be lower in the thalamus and the caudate (P = 0.0011) compared to HCs, and similar between the two cohorts in the other DGM regions.

Data Conclusion: An increase in mean R2* may not necessarily reflect increased iron accumulation. We propose as an additional metric to account for the effects of tissue atrophy when assessing tissue content changes, such as iron deposition or loss.

Level Of Evidence: 1 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2019;50:201-208.
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http://dx.doi.org/10.1002/jmri.26561DOI Listing
July 2019

Diffusely Abnormal White Matter, T Burden of Disease, and Brain Volume in Relapsing-Remitting Multiple Sclerosis.

J Neuroimaging 2019 01 30;29(1):151-159. Epub 2018 Oct 30.

Department of Radiology, University of British Columbia, Vancouver, British Columbia, Canada.

Background And Purpose: Multiple sclerosis (MS) diffusely abnormal white matter (DAWM) is a mildly hyperintense magnetic resonance imaging abnormality distinct from typical lesions. Our goal was to investigate the prevalence and natural history of DAWM in a large cohort (n = 348) of relapsing-remitting MS (RRMS) patients.

Methods: The presence of DAWM and relationship to changes in T burden of disease (BOD), brain volume (brain fractional ratio, BFR), and disability (Expanded Disability Status Scale, EDSS) were investigated at baseline and year 7-8 (long-term follow-up, LTF).

Results: DAWM was present in 25.3% (88 of 348) of patients at baseline. At LTF, DAWM was unchanged in 69.3% (61 of 88), decreased in 28.4% (25 of 88), and increased in 2.3% (2 of 88) of patients. Baseline BOD and change in BOD did not significantly differ between patients with and without DAWM. DAWM was associated with greater reduction in BFR at LTF (P = .038). DAWM and DAWM change did not predict EDSS or EDSS progression.

Conclusions: DAWM is present in a quarter of RRMS patients, and rarely increases or develops de novo. DAWM predicts brain atrophy but does not predict physical disability. Because of its posterior periventricular location, further investigation is warranted to evaluate its relationship to other measures of disability, including visual spatial processing and cognitive function.
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http://dx.doi.org/10.1111/jon.12574DOI Listing
January 2019

Correlating new directional measures of myelin and axonal integrity in T2-weighted MRI with quantitative histology in multiple sclerosis.

J Neurosci Methods 2019 01 19;311:369-376. Epub 2018 Sep 19.

Department of Radiology, University of Calgary, Alberta, Canada; Department of Clinical Neurosciences, University of Calgary, Alberta, Canada; Hotchkiss Brain Institute, University of Calgary, Alberta, Canada. Electronic address:

Background: Imaging measurement of structure alignment has shown increasing importance in determining tissue properties. It is not known if a similar ability for characterizing neuropathology exists.

New Methods: This study aimed to validate a new alignment-assessing method for measuring myelin and axonal properties using quantitative histological metrics. The new method involved analysis of the Fourier transform (FT) power spectrum in standard magnetic resonance imaging (MRI). T-weighted MRI were collected from 10 post-mortem multiple sclerosis (MS) brain samples. Three tissue types were examined: lesions, diffusely abnormal white matter, and normal appearing white matter. MRI analysis included computing the FT power spectrum; extracting alignment histograms; and calculating dominant orientation and alignment complexity (angular entropy). Post MRI, the brain samples were processed for myelin and axonal staining, and the stained images were used to derive quantitative orientation measures using structure tensor analysis for MRI comparison.

Results: There were significant differences in orientation metrics between tissue types in both MRI and histology, and MRI measurements correlated strongly with histological indices. Moreover, the joint effect of myelin and axonal entropy explained over 95% of the variance of MRI angular entropy.

Comparison With Existing Method: There is no established method for characterizing myelin and axonal pathology using standard MRI. Advanced MRI methods have the potential to do this but are still in research development and are not yet routinely acquired in clinical practice.

Conclusions: Alignment measurement using clinical MRI scans may become a valuable new method for characterizing myelin and axonal properties in MS patients.
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http://dx.doi.org/10.1016/j.jneumeth.2018.09.020DOI Listing
January 2019

Education, and the balance between dynamic and stationary functional connectivity jointly support executive functions in relapsing-remitting multiple sclerosis.

Hum Brain Mapp 2018 12 21;39(12):5039-5049. Epub 2018 Sep 21.

Graduate Program in Neuroscience, University of British Columbia, Vancouver, British Columbia, Canada.

Graphical network characteristics and nonstationary functional connectivity features, both derived from resting-state functional magnetic resonance imaging (rsfMRI) data, have been associated with cognitive performance in healthy subjects. How these features jointly relate to cognition in diseased states has not been investigated. In this study, 46 relapsing-remitting multiple sclerosis subjects underwent rsfMRI scans and a focused cognitive battery. With a sliding window approach, we examined six dynamic network features that indicated how connectivity changed over time as well as six measures derived from graph theory to reflect static network characteristics. Multiset canonical correlation analysis (MCCA) was then carried out to investigate the relations between dynamic network features, stationary network characteristics, cognitive testing, demographic, disease severity, and mood. Multiple sclerosis (MS) subjects demonstrated weaker connectivity strength, decreased network density, reduced global changes, but increased changes in interhemispheric connectivity compared to controls. The MCCA model determined that executive functions and processing speed ability measured by Wechsler Adult Intelligence Scale IV (WAIS-IV) Working Memory Index, WAIS-IV Processing Speed Index, and the Verbal Fluency Test were positively correlated with education, dynamic connectivity, and static connectivity strength; while poor task switching was correlated with disease severity, psychiatric comorbidities such as depression, anxiety, and fatigue, and static network density. Taken together, our results suggest that better executive functioning in MS requires maintenance of a continued coordination between stationary and dynamic functional connectivity as well as the support of education, and dynamic functional connectivity may provide an additional cognitive biomarker of disease severity in the MS population.
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http://dx.doi.org/10.1002/hbm.24343DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6866468PMC
December 2018

Multicenter Measurements of T Relaxation and Diffusion Tensor Imaging: Intra and Intersite Reproducibility.

J Neuroimaging 2019 01 19;29(1):42-51. Epub 2018 Sep 19.

Department of Radiology, University of British Columbia, UBC MRI Research Centre, Vancouver, British Columbia, Canada.

Background And Purpose: Quantitative T and diffusion tensor imaging (DTI) may provide information about pathological changes underlying disability and progression in diseases like multiple sclerosis (MS). Imaging the corpus callosum (CC), a primary site of damage in MS with a critical role in interhemispheric connectivity, may be useful for assessing overall brain health, prognosis, and therapy efficacy. We assessed the feasibility of multisite clinical trials using advanced MRI by examining the intra and intersite reproducibility of T and DTI measurements in the CC and segmented white matter (WM).

Methods: Five healthy volunteers were scanned twice within 24 hours at six 3T sites. Coefficients of variation (COVs) and intraclass correlation coefficients (ICCs) for CC and WM T , fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (D ), and radial diffusivity (D ) assessed intrasite and intersite reliability.

Results: CC and WM T showed excellent intrasite reproducibility with low COVs (mean = .90% and .89%, respectively) and good ICCs (CC = .78, WM = .90). T also demonstrated intersite reliability (low COVs: CC = 2.4%, WM = 1.8%; moderate ICCs: CC = .43, WM = .69). DTI had low intrasite COVs (CC: FA = 1.3%, MD = 1.5%, D = 1.4%, D = 2.2%; WM: FA = .9%, MD = .9%, D = .7%, D = 1.2%) and high intrasite ICCs (CC: FA = .95, MD = .97, D = .94, D = .97; CC: FA = .9, MD = .66, D = .88, D = .63), indicating excellent intrasite reproducibility. DTI also showed excellent intersite reliability with low COVs (CC: FA = 2.1%, MD = 4.1%, D = 3.4%, D = 5.3%, WM: FA = 1.3%, MD = 1.9%, D = 1.8%, D = 2.1%,) and good ICCs (CC: FA = .90, MD = .84, D = .72, D = .90; WM: FA = .83, MD = .34, D = .62, D = .41).

Conclusions: T and DTI measures are reproducible using equivalent MRI scanners and sequence protocols. Using a similar MR system, it is feasible to carry out multicenter studies using T and DTI to evaluate changes within the CC and WM.
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http://dx.doi.org/10.1111/jon.12559DOI Listing
January 2019

Effect of interferon beta-1a subcutaneously three times weekly on clinical and radiological measures and no evidence of disease activity status in patients with relapsing-remitting multiple sclerosis at year 1.

BMC Neurol 2018 Sep 14;18(1):143. Epub 2018 Sep 14.

Mount Sinai Hospital, 5 East 98th Street, 1st Floor, New York, NY, 10029, USA.

Background: In the PRISMS study, interferon beta-1a subcutaneously (IFN β-1a SC) reduced clinical and radiological disease burden at 2 years in patients with relapsing-remitting multiple sclerosis. The study aimed to characterize efficacy of IFN β-1a SC 44 μg and 22 μg three times weekly (tiw) at Year 1.

Methods: Exploratory endpoints included annualized relapse rate (ARR), 3-month confirmed disability progression (1-point Expanded Disability Status Scale increase if baseline was < 6.0 [0.5-point if baseline was ≥6.0]), active T2 lesions, and no evidence of disease activity (NEDA; defined as no relapses [subanalyzed by relapse severity], 3-month confirmed progression, or active T2 lesions). Effect of IFN β-1a SC in prespecified patient subgroups was also assessed.

Results: Patients were randomized to IFN β-1a 22 μg (n = 189), 44 μg (n = 184), or placebo (n = 187). At 1 year, IFN β-1a SC tiw reduced ARR (p < 0.001), risk of disability progression (p ≤ 0.029), and mean number of active T2 lesions per patients per scan (p < 0.001) versus placebo. Clinical and radiological benefits were seen as early as Month 2 and 3. Outcomes in subgroups were consistent with those in the overall population. More patients treated with IFN β-1a SC tiw achieved NEDA status, versus placebo, regardless of relapse severity (p ≤ 0.006).

Conclusion: Clinical, radiological, and NEDA outcomes at Year 1 were consistent with Year 2 results. Treatment efficacy was consistent in pre-specified patient subgroups.
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http://dx.doi.org/10.1186/s12883-018-1145-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6137887PMC
September 2018

Pathological Insights From Quantitative Susceptibility Mapping and Diffusion Tensor Imaging in Ice Hockey Players Pre and Post-concussion.

Front Neurol 2018 6;9:575. Epub 2018 Aug 6.

Division of Neurology, Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada.

Myelin sensitive MRI techniques, such as diffusion tensor imaging and myelin water imaging, have previously been used to reveal changes in myelin after sports-related concussions. What is not clear from these studies, however, is how myelin is affected: whether it becomes degraded and possibly removed, or whether the myelin sheath loosens and becomes "decompacted". Previously, our team revealed myelin specific changes in ice hockey players 2 weeks post-concussion using myelin water imaging. In that study, 45 subjects underwent a pre-season baseline scan, 11 of which sustained a concussion during play and received follow-up scans: eight were scanned within 3 days, 10 were scanned at 14 days, and nine were scanned at 60 days. In the current retrospective analysis, we used quantitative susceptibility mapping, along with the diffusion tensor imaging measures axial diffusivity and radial diffusivity, to investigate this myelin disruption. If sports-related concussive hits lead to myelin fragmentation in regions of lowered MWF, this should result in a measurable increase in magnetic susceptibility, due to the anisotropic myelin fragmenting into isotropic myelin debris, and the diamagnetic myelin tissue being removed, while no such changes should be expected if the myelin sheath simply loosens and becomes decompacted. An increase in radial diffusivity would likewise reveal myelin fragmentation, as myelin sheaths block water diffusion out of the axon, with little to no changes expected for myelin sheath loosening. Statistical analysis of the same voxels-of-interest that were found to have reduced myelin water fraction 2 weeks post-concussion, revealed no statistically significant changes in magnetic susceptibility, axial diffusivity, or radial diffusivity at any time-point post-concussion. This suggests that myelin water fraction changes are likely due to a loosening of the myelin sheath structure, as opposed to fragmentation and removal of myelin debris.
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http://dx.doi.org/10.3389/fneur.2018.00575DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6091605PMC
August 2018
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