Publications by authors named "Cornelia Laule"

71 Publications

Elevated levels of serum CD5 antigen-like protein distinguish secondary progressive multiple sclerosis from other disease subtypes.

Mult Scler Relat Disord 2021 Sep 20;56:103269. Epub 2021 Sep 20.

Department of Pathology & Laboratory Medicine, Faculty of Medicine, University of British Columbia, Vancouver, Canada; International Collaboration on Repair Discoveries (ICORD), Faculty of Medicine, University of British Columbia, Vancouver, Canada. Electronic address:

CD5 antigen-like (CD5L) protein is a macrophage-secreted protein with roles in immunomodulation and lipid homeostasis. We compared serum CD5L levels in healthy controls to individuals diagnosed with clinically isolated syndrome, relapsing remitting (RR), secondary progressive (SP), and primary progressive (PP) multiple sclerosis (MS). CD5L was increased in SPMS relative to controls, RRMS, and PPMS. SPMS CD5L was associated with longer disease duration independent of age, sex, or disease severity. The positive relationship between CD5L and disease duration in SPMS suggests a chronic peripheral inflammatory profile compared to other subtypes, particularly PPMS, warranting investigation of functional roles for CD5L in MS.
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http://dx.doi.org/10.1016/j.msard.2021.103269DOI Listing
September 2021

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

Generic acquisition protocol for quantitative MRI of the spinal cord.

Nat Protoc 2021 Oct 16;16(10):4611-4632. Epub 2021 Aug 16.

MR Clinical Science, Philips Healthcare, Markham, Ontario, Canada.

Quantitative spinal cord (SC) magnetic resonance imaging (MRI) presents many challenges, including a lack of standardized imaging protocols. Here we present a prospectively harmonized quantitative MRI protocol, which we refer to as the spine generic protocol, for users of 3T MRI systems from the three main manufacturers: GE, Philips and Siemens. The protocol provides guidance for assessing SC macrostructural and microstructural integrity: T1-weighted and T2-weighted imaging for SC cross-sectional area computation, multi-echo gradient echo for gray matter cross-sectional area, and magnetization transfer and diffusion weighted imaging for assessing white matter microstructure. In a companion paper from the same authors, the spine generic protocol was used to acquire data across 42 centers in 260 healthy subjects. The key details of the spine generic protocol are also available in an open-access document that can be found at https://github.com/spine-generic/protocols . The protocol will serve as a starting point for researchers and clinicians implementing new SC imaging initiatives so that, in the future, inclusion of the SC in neuroimaging protocols will be more common. The protocol could be implemented by any trained MR technician or by a researcher/clinician familiar with MRI acquisition.
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http://dx.doi.org/10.1038/s41596-021-00588-0DOI Listing
October 2021

Open-access quantitative MRI data of the spinal cord and reproducibility across participants, sites and manufacturers.

Sci Data 2021 08 16;8(1):219. Epub 2021 Aug 16.

MR Clinical Science, Philips Healthcare, Markham, ON, Canada.

In a companion paper by Cohen-Adad et al. we introduce the spine generic quantitative MRI protocol that provides valuable metrics for assessing spinal cord macrostructural and microstructural integrity. This protocol was used to acquire a single subject dataset across 19 centers and a multi-subject dataset across 42 centers (for a total of 260 participants), spanning the three main MRI manufacturers: GE, Philips and Siemens. Both datasets are publicly available via git-annex. Data were analysed using the Spinal Cord Toolbox to produce normative values as well as inter/intra-site and inter/intra-manufacturer statistics. Reproducibility for the spine generic protocol was high across sites and manufacturers, with an average inter-site coefficient of variation of less than 5% for all the metrics. Full documentation and results can be found at https://spine-generic.rtfd.io/ . The datasets and analysis pipeline will help pave the way towards accessible and reproducible quantitative MRI in the spinal cord.
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http://dx.doi.org/10.1038/s41597-021-00941-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8368310PMC
August 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

Characterization of multiple sclerosis neuroinflammation and neurodegeneration with relaxation and diffusion basis spectrum imaging.

Mult Scler 2021 Jun 16:13524585211023345. Epub 2021 Jun 16.

Department of Radiology, The University of British Columbia, Vancouver, BC, Canada/International Collaboration on Repair Discoveries (ICORD), The University of British Columbia, Vancouver, BC, Canada/Department of Physics & Astronomy, The University of British Columbia, Vancouver, BC, Canada/Department of Pathology and Laboratory Medicine, The University of British Columbia, Vancouver, BC, Canada.

Background: Advanced magnetic resonance imaging (MRI) methods can provide more specific information about various microstructural tissue changes in multiple sclerosis (MS) brain. Quantitative measurement of T and T relaxation, and diffusion basis spectrum imaging (DBSI) yield metrics related to the pathology of neuroinflammation and neurodegeneration that occurs across the spectrum of MS.

Objective: To use relaxation and DBSI MRI metrics to describe measures of neuroinflammation, myelin and axons in different MS subtypes.

Methods: 103 participants (20 clinically isolated syndrome (CIS), 33 relapsing-remitting MS (RRMS), 30 secondary progressive MS and 20 primary progressive MS) underwent quantitative T, T, DBSI and conventional 3T MRI. Whole brain, normal-appearing white matter, lesion and corpus callosum MRI metrics were compared across MS subtypes.

Results: A gradation of MRI metric values was seen from CIS to RRMS to progressive MS. RRMS demonstrated large oedema-related differences, while progressive MS had the most extensive abnormalities in myelin and axonal measures.

Conclusion: Relaxation and DBSI-derived MRI measures show differences between MS subtypes related to the severity and composition of underlying tissue damage. RRMS showed oedema, demyelination and axonal loss compared with CIS. Progressive MS had even more evidence of increased oedema, demyelination and axonal loss compared with CIS and RRMS.
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http://dx.doi.org/10.1177/13524585211023345DOI Listing
June 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 09 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

Temperature dependence and histological correlation of inhomogeneous magnetization transfer and myelin water imaging in ex vivo brain.

Neuroimage 2021 08 20;236:118046. Epub 2021 Apr 20.

University of British Columbia MRI Research Centre, 2221 Wesbrook Mall, M10 Purdy Pavilion, Vancouver, BC V6T 2B5, Canada; Radiology, University of British Columbia, 2775 Laurel Street, 11th Floor, Vancouver, BC V5Z 1M9, Canada; ICORD (International Collaboration on Repair Discoveries), 818 W. 10th Ave., Vancouver, BC V5Z 1M9, Canada. Electronic address:

Purpose: The promise of inhomogeneous magnetization transfer (ihMT) as a new myelin imaging method was studied in ex vivo human brain tissue and in relation to myelin water fraction (MWF). The temperature dependence of both methods was characterized, as well as their correspondence with a histological measure of myelin content. Unfiltered and filtered ihMT protocols were studied by adjusting the saturation scheme to preserve or attenuate signal from tissue with short dipolar relaxation time T.

Methods: ihMT ratio (ihMTR) and MWF maps were acquired at 7 T from formalin-fixed human brain samples at 22.5 °C, 30 °C and 37 °C. The impact of temperature on unfiltered ihMTR, filtered ihMTR and MWF was investigated and compared to myelin basic protein staining.

Results: Unfiltered ihMTR exhibited no temperature dependence, whereas filtered ihMTR increased with increasing temperature. MWF decreased at higher temperature, with an increasing prevalence of areas where the myelin water signal was unreliably determined, likely related to a reduction in T peak separability at higher temperatures ex vivo. MWF and ihMTR showed similar per-sample correlation with myelin staining at room temperature. At 37 C, filtered ihMTR was more strongly correlated with myelin staining and had increased dynamic range compared to unfiltered ihMTR.

Conclusions: Given the temperature dependence of filtered ihMT, increased dynamic range, and strong myelin specificity that persists at higher temperatures, we recommend carefully controlled temperatures close to 37 °C for filtered ihMT acquisitions. Unfiltered ihMT may also be useful, due to its independence from temperature, higher amplitude values, and sensitivity to short T components. Ex vivo myelin water imaging should be performed at room temperature, to avoid fitting issues found at higher temperatures.
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http://dx.doi.org/10.1016/j.neuroimage.2021.118046DOI Listing
August 2021

Cervical cord myelin abnormality is associated with clinical disability in multiple sclerosis.

Mult Scler 2021 Mar 22:13524585211001780. Epub 2021 Mar 22.

Division of Neurology, Department of Medicine, The University of British Columbia, Vancouver, BC, Canada; Department of Radiology, The University of British Columbia, Vancouver, BC, Canada/Department of Physics and Astronomy, The University of British Columbia, Vancouver, BC, Canada; International Collaboration on Repair and Discoveries, Vancouver, BC, Canada.

Background: Myelin water imaging (MWI) was recently optimized to provide quantitative in vivo measurement of spinal cord myelin, which is critically involved in multiple sclerosis (MS) disability.

Objective: To assess cervical cord myelin measurements in relapsing-remitting multiple sclerosis (RRMS) and progressive multiple sclerosis (ProgMS) participants and evaluate the correlation between myelin measures and clinical disability.

Methods: We used MWI data from 35 RRMS, 30 ProgMS, and 28 healthy control (HC) participants collected at cord level C2/C3 on a 3 T magnetic resonance imaging (MRI) scanner. Myelin heterogeneity index (MHI), a measurement of myelin variability, was calculated for whole cervical cord, global white matter, dorsal column, lateral and ventral funiculi. Correlations were assessed between MHI and Expanded Disability Status Scale (EDSS), 9-Hole Peg Test (9HPT), timed 25-foot walk, and disease duration.

Results: In various regions of the cervical cord, ProgMS MHI was higher compared to HC (between 9.5% and 31%,  ⩽ 0.04) and RRMS (between 13% and 26%,  ⩽ 0.02), and ProgMS MHI was associated with EDSS ( = 0.42-0.52) and 9HPT ( = 0.45-0.52).

Conclusion: Myelin abnormalities within clinically eloquent areas are related to clinical disability. MWI metrics have a potential role for monitoring subclinical disease progression and adjudicating treatment efficacy for new therapies targeting ProgMS.
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http://dx.doi.org/10.1177/13524585211001780DOI Listing
March 2021

Exploring the Contribution of Myelin Content in Normal Appearing White Matter to Cognitive Outcomes in Cerebral Small Vessel Disease.

J Alzheimers Dis 2021 ;80(1):91-101

Department of Physical Therapy, University of British Columbia (UBC), Vancouver, Canada.

Background: Myelin damage is a salient feature in cerebral small vessel disease (cSVD). Of note, myelin damage extends into the normal appearing white matter (NAWM). Currently, the specific role of myelin content in cognition is poorly understood.

Objective: The objective of this exploratory study was to investigate the association between NAWM myelin and cognitive function in older adults with cSVD.

Methods: This exploratory study included 55 participants with cSVD. NAWM myelin was measured using myelin water imaging and was quantified as myelin water fraction (MWF). Assessment of cognitive function included processing speed (Trail Making Test Part A), set shifting (Trail Making Test Part B minus A), working memory (Verbal Digit Span Backwards Test), and inhibition (Stroop Test). Multiple linear regression analyses assessed the contribution of NAWM MWF on cognitive outcomes controlling for age, education, and total white matter hyperintensity volume. The overall alpha was set at ≤0.05.

Results: After accounting for age, education, and total white matter hyperintensity volume, lower NAWM MWF was significantly associated with slower processing speed (β  = -0.29, p = 0.037) and poorer working memory (β= 0.30, p = 0.048). NAWM MWF was not significantly associated with set shifting or inhibitory control (p > 0.132).

Conclusion: Myelin loss in NAWM may play a role in the evolution of impaired processing speed and working memory in people with cSVD. Future studies, with a longitudinal design and larger sample sizes, are needed to fully elucidate the role of myelin as a potential biomarker for cognitive function.
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http://dx.doi.org/10.3233/JAD-201134DOI Listing
September 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

Myelin Water Imaging Demonstrates Lower Brain Myelination in Children and Adolescents With Poor Reading Ability.

Front Hum Neurosci 2020 16;14:568395. Epub 2020 Oct 16.

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

Magnetic resonance imaging (MRI) provides a means to non-invasively investigate the neurological links with dyslexia, a learning disability that affects one's ability to read. Most previous brain MRI studies of dyslexia and reading skill have used structural or diffusion imaging to reveal regional brain abnormalities. However, volumetric and diffusion MRI lack specificity in their interpretation at the microstructural level. Myelin is a critical neural component for brain function and plasticity, and as such, deficits in myelin may impact reading ability. MRI can estimate myelin using myelin water fraction (MWF) imaging, which is based on evaluation of the proportion of short T2 myelin-associated water from multi-exponential T2 relaxation analysis, but has not yet been applied to the study of reading or dyslexia. In this study, MWF MRI, intelligence, and reading assessments were acquired in 20 participants aged 10-18 years with a wide range of reading ability to investigate the relationship between reading ability and myelination. Group comparisons showed markedly lower MWF by 16-69% in poor readers relative to good readers in the left and right thalamus, as well as the left posterior limb of the internal capsule, left/right anterior limb of the internal capsule, left/right centrum semiovale, and splenium of the corpus callosum. MWF over the entire group also correlated positively with three different reading scores in the bilateral thalamus as well as white matter, including the splenium of the corpus callosum, left posterior limb of the internal capsule, left anterior limb of the internal capsule, and left centrum semiovale. MWF imaging from T2 relaxation suggests that myelination, particularly in the bilateral thalamus, splenium, and left hemisphere white matter, plays a role in reading abilities. Myelin water imaging thus provides a potentially valuable imaging tool for the study of dyslexia and its remediation.
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http://dx.doi.org/10.3389/fnhum.2020.568395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7596275PMC
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

Learning-Challenged Youth Show an Abnormal Relationship Between Fronto-Parietal Myelination and Mathematical Ability.

J Neuroimaging 2020 09 13;30(5):648-657. Epub 2020 Jun 13.

Department of Educational & Counselling Psychology, and Special Education, University of British Columbia, Vancouver, British Columbia, Canada.

Background And Purpose: Differences in the microstructure of fronto-parietal white matter tracts have been associated with mathematical achievement. However, much of the supporting evidence relies on nonspecific diffusion-weighted magnetic resonance imaging, making it difficult to isolate the role of myelin in math ability.

Methods: We used myelin water imaging to measure brain myelin. We related myelin water fraction (MWF) to Woodcock-Johnson III (WJ-III) basic math scores using region of interest (ROI) and tract-based spatial statistics (TBSS) analyses, in 14 typically developing and 36 learning challenged youth aged 9-17 years.

Results: The ROI analysis found a positive relationship between fronto-parietal MWF and math in typically developing youth, but not in learning challenged youth. The relationship between fronto-parietal MWF and math observed in typically developing youth was fully mediated by age. No group differences in fronto-parietal MWF were found between typically developing and learning challenged youth. TBSS also found no group differences in MWF values. TBSS indicated math-MWF relationships extend beyond fronto-parietal tracts to descending and ascending projection tracts in typically developing youth. TBSS identified math-MWF relationships in the cerebral peduncles of learning challenged youth.

Conclusions: Our results suggest that in typically developing youth, brain myelination contributes to individual differences in basic math achievement. In contrast, youth with learning challenges appear to have less capacity to leverage myelin to improve math achievement.
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http://dx.doi.org/10.1111/jon.12741DOI Listing
September 2020

Imaging Mechanisms of Disease Progression in Multiple Sclerosis: Beyond Brain Atrophy.

J Neuroimaging 2020 05;30(3):251-266

Neuroimaging Unit, Neuroimmunology Division, Department of Neurology, Vanderbilt University Medical Center, Nashville, TN.

Clinicians involved with different aspects of the care of persons with multiple sclerosis (MS) and scientists with expertise on clinical and imaging techniques convened in Dallas, TX, USA on February 27, 2019 at a North American Imaging in Multiple Sclerosis Cooperative workshop meeting. The aim of the workshop was to discuss cardinal pathobiological mechanisms implicated in the progression of MS and novel imaging techniques, beyond brain atrophy, to unravel these pathologies. Indeed, although brain volume assessment demonstrates changes linked to disease progression, identifying the biological mechanisms leading up to that volume loss are key for understanding disease mechanisms. To this end, the workshop focused on the application of advanced magnetic resonance imaging (MRI) and positron emission tomography (PET) imaging techniques to assess and measure disease progression in both the brain and the spinal cord. Clinical translation of quantitative MRI was recognized as of vital importance, although the need to maintain a relatively short acquisition time mandated by most radiology departments remains the major obstacle toward this effort. Regarding PET, the panel agreed upon its utility to identify ongoing pathological processes. However, due to costs, required expertise, and the use of ionizing radiation, PET was not considered to be a viable option for ongoing care of persons with MS. Collaborative efforts fostering robust study designs and imaging technique standardization across scanners and centers are needed to unravel disease mechanisms leading to progression and discovering medications halting neurodegeneration and/or promoting repair.
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http://dx.doi.org/10.1111/jon.12700DOI Listing
May 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

Myelin Damage in Normal Appearing White Matter Contributes to Impaired Cognitive Processing Speed in Multiple Sclerosis.

J Neuroimaging 2020 03 24;30(2):205-211. Epub 2019 Nov 24.

Department of Medicine (Neurology), Radiology, Physics & Astronomy, University of British Columbia, Vancouver, British Columbia, Canada.

Background And Purpose: Cognitive impairment is a core symptom in multiple sclerosis (MS). Damage to normal appearing white matter (NAWM) is likely involved. We sought to determine if greater myelin heterogeneity in NAWM is associated with decreased cognitive performance in MS.

Methods: A total of 27 participants with MS and 13 controls matched for age, sex, and education underwent myelin water imaging (MWI) from which the myelin water fraction (MWF) was calculated. Corpus callosum, superior longitudinal fasciculus, and cingulum were chosen as regions of interest (ROIs) a priori based on their involvement in MS-related cognitive impairment. Cognitive performance was assessed using the Symbol Digit Modalities Test (SDMT). Pearson ́s product moment correlations were performed to assess relationships between cognitive performance and myelin heterogeneity (variance of MWF within an ROI).

Results: In MS, myelin heterogeneity in all three ROIs was significantly associated with performance on the SDMT. These correlations ranged from moderate (r = -.561) to moderately strong (r = -.654) and were highly significant (P values ranged from .001 to .0002). Conversely, myelin heterogeneity was not associated with SDMT performance in controls in any ROI (P > .108).

Conclusion: Increased myelin heterogeneity in NAWM is associated with decreased cognitive processing speed performance in MS.
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http://dx.doi.org/10.1111/jon.12679DOI Listing
March 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

Brain MRI features and scoring of leukodystrophy in adult-onset Krabbe disease.

Neurology 2019 08 23;93(7):e647-e652. Epub 2019 Jul 23.

From the Department of Neurology, Reference Center for Lysosomal Diseases, UF Neuro-Genetics and Metabolism (L.C., R.D., Y.N.), and Department of Neuroradiology (B.L.-Y., N.P., D.L.), Pitié-Salpêtrière Hospital, Paris; Service de Biochimie et Biologie Moléculaire Grand Est (R.F., M.P.), Unité Médicale Pathologies Métaboliques, Erythrocytaires et Dépistage Périnatal, Centre de Biologie et de Pathologie Est, Hospices Civils de Lyon, Bron; UMR 5305 CNRS/UCBL (R.F.), Lyon, France; Department of Medicine, Surgery and Neurosciences (A.F., S.S.), Unit of Neurology and Neurometabolic Diseases, Medical School, University of Siena; Neuroradiology Unit (A.C.), Azienda Ospedaliera Universitaria Senese, Siena, Italy; Department of Neurology (M.C.M., J.D.), Coimbra Hospital and University Centre, Portugal; Department of Neurology (S.H.K.), College of Medicine, Hanyang University, Seoul, Korea; Division of Neurology (H.A.), Hyogo Prefectural Amagasaki General Medical Center, Hyogo, Japan; Department of Neurology (B.A.), La Timone Hospital; Aix-Marseille University (B.A.), CNRS, CRMBM UMR, Marseille; Department of Neurology (X.A.), Montpellier University Hospital, France; Department of Neurology (Y.D.), Xuan Wu Hospital, Capital Medical University, Beijing, China; Department of Neurology (R.H.), Royal Brisbane Hospital, Brisbane, Australia; Laboratory of Neurogenetics of Motion and Department of Neuroradiology (R.L.P.), Montréal Neurological Institute and Hospital, McGill University, Montréal; Department of Radiology (C.L.), Department of Pathology and Laboratory Medicine (C.L.), International Collaboration on Repair Discoveries (ICORD) (C.L.), Department of Physics and Astronomy (C.L.), and Division of Endocrinology, Department of Medicine (S.M.S.), University of British Columbia, Vancouver, Canada; Department of Neurology (K.N.), Division of Clinical Medicine, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan; Department of Radiology (R.R.), Uppsala University, Sweden; Department of Neurology and Hertie-Institute for Clinical Brain Research (L.S.), Eberhard-Karls-University; German Center of Neurodegenerative Diseases (DZNE) (L.S.), Tübingen, Germany; Department of Neurology (F.V.), Caen-Normandie University Hospital, Caen; Inserm U1077 (F.V.), EPHE, Caen-Normandie University, Caen, France; and Department of Neurology and Stroke (K.J.), Medical University of Lodz, Poland.

Objective: To perform a systematic analysis and scoring of brain MRI white matter hyperintensities (WMH) in adult-onset Krabbe disease.

Methods: We retrospectively collected basic clinical data and the first available brain MRI from patients with confirmed Krabbe disease with first clinical manifestations beyond 10 years of age. Data were obtained from our reference center for lysosomal diseases (n = 6) and from contacted authors of published articles describing patients with adult-onset Krabbe disease (n = 15). T2-weighted fluid-attenuated inversion recovery images of each patient were analyzed and scored using a radiologic score of WMH in a single center.

Results: The corticospinal tract was always affected by WMH (100% of patients), however, with some distinctions along the tract: the precentral gyrus (100%), corona radiata (95%), and posterior internal capsule (81%) were highly abnormal, whereas the mesencephalon (57%), pons (52%), and medulla oblongata (5%) were less affected. WMH were also frequently present in the posterior lateral periventricular white matter (95%), optic radiations (86%), postcentral gyrus (71%), medial lemniscus (62%), and corpus callosum, especially in the isthmus (71%), whereas the genu was always normal. A few patients did not have the classical MRI pattern but extensive hyperintensities (n = 3), or patchy distribution of hyperintensities mimicking an acquired etiology (n = 2), or very subtle hyperintensities of the corticospinal tract (n = 1).

Conclusions: We specified the main locations of WMH, which were observed in the earliest stages of the disease and were also present in patients with atypical MRI pattern, highlighting the importance of radiologic features to guide the diagnosis.
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http://dx.doi.org/10.1212/WNL.0000000000007943DOI Listing
August 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

Longer Repetition Time Proton MR Spectroscopy Shows Increasing Hippocampal and Parahippocampal Metabolite Concentrations with Aging.

J Neuroimaging 2019 09 4;29(5):592-597. Epub 2019 Jul 4.

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

Background And Purpose: Previous magnetic resonance spectroscopy (MRS) studies have concluded that hippocampal and parahippocampal metabolite concentrations remain stable during healthy adult aging. However, these studies used short repetition times (TR ≤ 2 seconds), which lead to incomplete longitudinal magnetization recovery, and thus, heavily T -weighted measurements. It is important to accurately characterize brain metabolites changes with age to enable appropriate interpretations of MRS findings in the context of neurodegenerative diseases. Our goal was to assess hippocampal brain metabolite concentrations in a large cohort of diversely aged healthy volunteers using a longer TR of 4 seconds.

Methods: Left hippocampal MR spectra were collected from 38 healthy volunteers at 3T. Absolute metabolite concentrations were determined for total N-acetyl-aspartate (tNAA), total creatine (tCr), total choline (tCho), glutamate and glutamine (Glx), and myoinositol (mI). Individual partial correlations between each metabolite with age were assessed using demographic information and voxel compartmentation as confounders.

Results: Hippocampal tNAA, tCr, tCho, and mI all increased with age (NAA: R = .17, P = .041; tCr: R = .45, P = .0002; tCho: R = .37, P = .001; mI: R = .44, P = .0003). There were no relationships between age and signal to noise ratio, linewidth, or scan date, indicating the correlations were not confounded by spectral quality. Furthermore, we did not observe a trend with age in the voxel tissue compartmentations.

Conclusions: We observed increases in hippocampal/parahippocampal metabolite concentrations with age, a finding that is in contrast to previous literature. Our findings illustrate the importance of using a sufficiently long TR in MRS to avoid T -relaxation effects influencing the measurement of absolute metabolite concentrations.
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http://dx.doi.org/10.1111/jon.12648DOI Listing
September 2019

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

Coexistence of Multiple Sclerosis and Alzheimer's disease: A review.

Mult Scler Relat Disord 2019 Jan 27;27:232-238. Epub 2018 Oct 27.

Djavad Mowafaghian Centre for Brain Health, Vancouver, BC, Canada; Department of Medicine (Neurology), University of British Columbia, Vancouver, BC, Canada. Electronic address:

Background: People with multiple sclerosis (MS) are living longer than ever and will likely face the same age-related diseases as other seniors; however, there is strikingly little information on the coexistence of MS with many common diseases of aging. In particular, little appears to be known about the coexistence of MS with Alzheimer's disease (AD), the most common form of dementia.

Methods: In this review, we explore what is known about the coexistence of MS and AD, including a focused literature search to identify any reports of individuals with both MS and AD (PubMed, to May 2017). We also discuss the wider epidemiology, diagnosis, and pathophysiology of MS and AD.

Results: In total, we found 24 individuals with pathological features of both MS and AD described as case series or reports (published between 1976-2014), but no epidemiological or population-based studies, aside from one conference proceeding (2011). Comorbid MS and AD was reported in a broad range of MS disease courses including relapsing-remitting, primary progressive, secondary progressive and so-called 'benign.' Despite the clear diagnostic challenges involved, these individual case reports provide evidence that AD and MS can coexist in the same person.

Conclusion: In summary, we highlight a major knowledge gap in our understanding of two potentially common neurological conditions. With the ageing population, and an estimated 2.3 million people living with MS and 46 million with AD or other dementias worldwide, it will become increasingly important to recognize and understand how to manage individuals with these complex comorbid conditions.
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http://dx.doi.org/10.1016/j.msard.2018.10.109DOI Listing
January 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

Myelin water imaging to detect demyelination and remyelination and its validation in pathology.

Brain Pathol 2018 09;28(5):750-764

Pathology & Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.

Damage to myelin is a key feature of multiple sclerosis (MS) pathology. Magnetic resonance imaging (MRI) has revolutionized our ability to detect and monitor MS pathology in vivo. Proton density, T and T can provide qualitative contrast weightings that yield superb in vivo visualization of central nervous system tissue and have proved invaluable as diagnostic and patient management tools in MS. However, standard clinical MR methods are not specific to the types of tissue damage they visualize, and they cannot detect subtle abnormalities in tissue that appears otherwise normal on conventional MRIs. Myelin water imaging is an MR method that provides in vivo measurement of myelin. Histological validation work in both human brain and spinal cord tissue demonstrates a strong correlation between myelin water and staining for myelin, validating myelin water as a marker for myelin. Myelin water varies throughout the brain and spinal cord in healthy controls, and shows good intra- and inter-site reproducibility. MS plaques show variably decreased myelin water fraction, with older lesions demonstrating the greatest myelin loss. Longitudinal study of myelin water can provide insights into the dynamics of demyelination and remyelination in plaques. Normal appearing brain and spinal cord tissues show reduced myelin water, an abnormality which becomes progressively more evident over a timescale of years. Diffusely abnormal white matter, which is evident in 20%-25% of MS patients, also shows reduced myelin water both in vivo and postmortem, and appears to originate from a primary lipid abnormality with relative preservation of myelin proteins. Active research is ongoing in the quest to refine our ability to image myelin and its perturbations in MS and other disorders of the myelin sheath.
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http://dx.doi.org/10.1111/bpa.12645DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8028667PMC
September 2018
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