Parallel Session Sat, Sep 12, 2020
Moderators
  • B. Stankoff
  • J. Oh
Session Type
Parallel Session
Date
Sat, Sep 12, 2020
Time (ET)
09:15 - 10:45
Invited Presentations Invited Abstracts

PS11.01 - Quantitative Susceptibility Mapping (QSM): Clinical Applications for MS

Speakers
  • S. Gauthier
Authors
  • S. Gauthier
Presentation Number
PS11.01
Presentation Topic
Invited Presentations
Lecture Time
09:15 - 09:30

Abstract

Abstract

Background

The tissue field generated by a magnetic susceptibility source, such as iron, and experienced by the surrounding water protons is linearly related to the MR signal phase, which can be measured with high precision in MRI. Quantitative susceptibility mapping (QSM) provides an effective means to directly map the distribution of susceptibility sources by solving the field-to-source inversion problem. The clinical utility of QSM has been primarily applied to the brain and has shown utility across a vast range of neurodegenerative diseases.

Objectives

This presentation will provide the participants an opportunity to gain insight into the clinical potential of QSM, as it relates to the study of multiple sclerosis (MS).

Methods

QSM provides extensive insight into the early MS lesion, opening a new venue to investigate MS lesion inflammatory activity after blood brain barrier (BBB) closure. Chronic CNS inflammation in the MS lesion is maintained with pro-inflammatory microglia and macrophages (m/M), which have been demonstrated to be present at the rim of chronic active MS lesions and at the site of ongoing demyelination. The majority of the m/M found at the rim of chronic active multiple sclerosis lesions contain iron, and conversely iron-enriched microglia and macrophages are not found at the rim of remyelinated or shadow plaques. MRI with a gradient echo (GRE) sequence is sensitive to iron and has been utilized by many investigators to detect an iron rim in chronic active multiple sclerosis lesions. QSM provides quantification and localization of the magnetic sources, thus yielding benefits over other methods to identify and assess the paramagnetic rim present within this subset of chronic lesions.

Results

Utilizing PK11195-PET, it has been demonstrated that lesions with a rim of hyperintensity on QSM (rim+) have a significantly higher level of inflammation as compared on lesions lacking this rim. QSM rim+ lesions were also found to have more tissue injury, as measured by myelin water imaging. Building on this work, as well as histopathological validation studies, larger clinical studies are being are designed to establish the role of QSM rim+ lesions as a prognostic biomarker for disease activity and identify patients at risk for future disability. Similarly, the quantitative aspect of QSM provides the potential tool to assess treatment effect for drugs that may cross the BBB and target the innate immune response. Lastly, additional clinical applications of QSM for MS will be introduced and future directions will be discussed.

Conclusions

In conclusion, QSM is a validated quantitative imaging tool to explore the impact of chronic lesion pathology on clinical disability and to assess the potential therapeutic benefit of drugs targeting the innate immune response.

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Invited Presentations Invited Abstracts

PS11.02 - PET Imaging of Microglial Activation

Speakers
  • M. Hagens
Authors
  • M. Hagens
Presentation Number
PS11.02
Presentation Topic
Invited Presentations
Lecture Time
09:30 - 09:45

Abstract

Abstract

Current radiological evaluation of multiple sclerosis is mainly based on new T2 lesions and active gadolinium enhancing lesions on magnetic resonance imaging (MRI), which only partly identify the pathophysiological processes in MS. Positron Emission Tomography (PET) is an imaging technique that can visualise distinct molecular processes in vivo, and as such provides a unique insight into the pathophysiology of MS. PET imaging of neuroinflammation in MS has focussed on the various receptors upregulated on different microglia phenotypes, as the dynamic and complex process of microglia activation is the hallmark of neuroinflammation in MS. To date, the most important PET marker for neuroinflammation is the 18kDa-translocator protein (TSPO), upregulated on the mitochondria of microglia. Although in general results have been positive and the second generation TSPO tracers have improved the signal-to-noise ratio and increased the bioavailability in the brain, there are still several limitations: the rs6971 polymorphism determining genetic binding affinity, binding sites that are not specific to microglia and the inability to differentiate between the different microglial phenotypes. Therefore, new PET targets for neuroinflammation have been developed. Currently two tracers have successfully been evaluated in MS patients: the adenosine A2A-receptor tracer [11C]TMSX and the purinergic P2X7-receptor tracer [11C]SMW139. Besides the challenges of tracer development, progress in the field of PET research in MS has been hindered by a lack of consensus on suitable analysis methods. Kinetic modelling using arterial input functions provides a method for accurate quantification of specific tracer binding, but arterial sampling limits widespread applicability of PET. Reference tissue methods have been proposed as an alternative, but the diffuse neuroinflammation in MS and the disruption of the blood-brain barrier violate the assumptions underlying such models. Addressing both the tracer development challenges and the modelling challenges specific to MS, will help progress PET imaging from the field of research to a clinical relevant biomarker of neuroinflammation in MS.

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Neuroprotection, Regeneration and/or Remyelination Oral Presentation

PS11.03 - Lesion-specific perfusion levels affect myelin loss and repair in multiple sclerosis: a positron emission tomography study

Speakers
  • A. Colombi
Authors
  • A. Colombi
  • V. Ricigliano
  • E. Morena
  • A. Yazdan Panah
  • M. Tonietto
  • B. Bodini
  • B. Stankoff
Presentation Number
PS11.03
Presentation Topic
Neuroprotection, Regeneration and/or Remyelination
Lecture Time
09:45 - 09:57

Abstract

Background

Following demyelination, remyelination may take place in multiple sclerosis (MS) lesions, but this process is heterogeneous and often fails. Brain perfusion was shown to impact remyelination in rodents, but this relationship has never been assessed in patients with MS. Positron emission tomography (PET) with 11C-PiB allows to simultaneously map demyelination and remyelination in vivo, and to generate quantitative maps of brain perfusion.

Objectives

To analyse the relationship between baseline perfusion and subsequent myelin content changes in white matter (WM) lesions.

Methods

11C-PIB PET and 3T MRI were acquired in 15 patients with relapsing-remitting MS at baseline and after 2-4 months. Nine hundred and four lesions were identified at baseline on T2-weighted scans with the exclusion of gadolinium-enhancing lesions to avoid artefacts in perfusion quantification. Logan reference graphical analysis and simplified reference tissue model were used to generate voxelwise maps of distribution volume ratio (DVR) and relative delivery (R1) from 11C-PiB images, respectively. Perfusion at baseline, as measured by R1, and the percentage of demyelinating and remyelinating voxels over the follow-up, derived from DVR maps, were calculated for each lesion.

Mixed-effect models were employed to evaluate the association between perfusion at baseline and the percentage of demyelinating and remyelinating voxels over the follow-up in WM lesions. A logistic regression was employed to determine the impact of perfusion on the probability of lesions to successfully repair, I.e. to remyelinate at least 50% of their demyelinated voxels at baseline and to undergo demyelination over the follow-up in less than 25% of voxels classified as normally myelinated at study entry.

Results

WM lesions showed lower perfusion compared to normal-appearing WM (0.43±0.08 vs 0.49±0.03, p<0.001), although single-lesion R1 values were remarkably heterogeneous (range: [0.08-2.5]). At the single lesion level, a higher perfusion at baseline was associated with a more extensive remyelination (β=0.32, p<0.001) and a reduced demyelination (β=-0.28, p<0.001) over the follow-up. Lesion-specific perfusion at baseline was an independent predictor of successful myelin repair over the follow-up (OR=8.4, p<0.001).

Conclusions

The level of perfusion of single MS lesions is critical for myelin repair and may be one key factor underlying the heterogeneous levels of remyelination across patients with MS.

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Imaging Oral Presentation

PS11.04 - Quantitative susceptibility mapping classifies white matter lesions with different myelin and axonal content and quantifies diffuse pathology in MS

Speakers
  • R. Rahmanzadeh
Authors
  • R. Rahmanzadeh
  • P. Lu
  • M. Barakovic
  • M. Weigel
  • T. Nguyen
  • P. Spincemaille
  • S. Schiavi
  • A. Daducci
  • F. La Rosa
  • D. Reich
  • P. Sati
  • M. Bach Cuadra
  • E. Radue
  • J. Kuhle
  • L. Kappos
  • Y. Wang
  • C. Granziera
Presentation Number
PS11.04
Presentation Topic
Imaging
Lecture Time
09:57 - 10:09

Abstract

Background

Quantitative susceptibility mapping (QSM) identifies iron accumulation and myelin loss in smoldering white matter lesions (WMLs). Yet, QSM may be also used to provide a broader understanding of focal and diffuse MS pathology.

Objectives

To study QSM features across WMLs, to assess myelin and axonal loss in WMLs with different QSM features and to quantify QSM pathology in normal-appearing white and cortical grey matter (NAWM, NAGM).

Methods

Ninety-one MS patients (62 RRMS, 29 PMS) and 72 healthy controls (HC) underwent QSM, myelin water imaging (MWI) and multishell diffusion at 3T MRI. In WMLs, cortical lesions (CLs), NAWM and NAGM, we extracted mean QSM, myelin water fraction (MWF) and neurite density index (NDI). WMLs were classified into 5 groups according to their appearance on 3D-EPI QSM: (i) isointense; (ii) with hyperintense rim, Rim+ (iii); with hypointense rim relative to the lesion core, hypo Rim; (iv) hyperintense; (v) hypointense. Mann-Whitney and Kruskal-Wallis test with Dunn’s correction for multiple comparison were used to compare (a) lesion types and (b) specific lesions vs all other WMLs. Voxel-wise comparisons of NAWM QSM were performed using Threshold-Free Cluster Enhancement (TFCE) clustering. Cortical analysis of QSM NAGM and GM-HC was performed using FreeSurfer and compared using a General Linear model (GLM).

Results

Of 1136 WMLs in QSM maps, we detected: (i) 314 (27.6%), (ii) 183 (16.1%), (iii) 16 (1.41%), (iv) 577 (50.8%) and (v) 46 (4.05%) WML. All WML exhibited lower NDI than NAWM and WM-HC (P<0.0001). Isointense lesions exhibited higher NDI (P=0.0115) and MWF (P<0.0001) than other WMLs. Rim + and hyperintense lesions exhibited lower MWF than NAWM and WM-HC (P<0.0001). Rim + lesions showed lower MWF and NDI than other WML types (P<0.001). Hypo Rim+ lesions and hypointense lesions exhibited higher MWF than other WMLs (P=0.0006, P<0.05). Hyperintense lesions exhibited lower MWF than other WMLs types (P<0.01) except Rim+ lesions. TFCE and vertex-wise cortical surface analysis showed areas throughout the NA tissue, where QSM is either lower or higher compared to healthy tissue in HC and in PMS compared to RMS (P<0.01).

Conclusions

QSM is sensitive to diffuse and focal pathology with various myelin and axonal characteristics. We hypothesize that isointense WMLs show high repair activity, hypointense WMLs are remyelinated lesions and hyperintense WMLs are chronic inactive lesions. MRI-histopathology work is ongoing to confirm these findings.

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Imaging Oral Presentation

PS11.05 - Inclusion of small ovoid lesions in central vein sign assessment improves sensitivity for multiple sclerosis

Speakers
  • O. Al-Louzi
Authors
  • L. Daboul
  • E. Beck
  • S. Roy
  • J. Ohayon
  • D. Pham
  • A. Solomon
  • I. Cortese
  • P. Sati
  • D. Reich
Presentation Number
PS11.05
Presentation Topic
Imaging
Lecture Time
10:09 - 10:21

Abstract

Background

The ‘central vein sign’ (CVS) is increasingly recognized as a valuable biomarker with high specificity and sensitivity for multiple sclerosis (MS) MRI lesions. Current consensus North American Imaging in Multiple Sclerosis (NAIMS) guidelines recommend excluding lesions <3mm in diameter in any plane for CVS assessment. However, different lesion-size exclusion cut-offs for CVS have not been systematically evaluated.

Objectives

To evaluate the impact of different lesion size cut-offs and exclusion methodologies on CVS analysis and select3* criteria for MS diagnosis.

Methods

MS patients and non-MS controls were recruited as part of the National Institute of Neurological Disorders and Stroke MS natural history study and underwent 3T MRI on either Siemens Skyra or Philips Achieva scanners. MS lesions were segmented using a deep learning-based method and manually corrected by a single rater. Individual lesions were extracted as clusters of connected voxels, and their principal axes lengths (calculated as the lengths of the major axes of an ellipsoid with the same normalized second central moments) were used to measure lesion size in 3 dimensions. Ground truth CVS assessment was conducted by two raters on all lesions regardless of size. Two paradigms of lesion exclusion were compared: (1) excluding lesions if any dimension was less than threshold (ExcAny), or (2) if all dimensions were less than threshold (ExcAll).

Results

A total of 3920 lesions from 71 subjects (8 healthy controls, 36 RRMS, 12 SPMS, 14 PPMS, 1 CIS) were included in the analysis. CVS+ lesions were more likely to be ovoid and less spherical compared to their CVS- counterparts, as measured by the fractional anisotropy of lesion dimensions (mean difference 0.02, p=0.001). Of the 1679 CVS+ lesions in the cohort, 82% met the ExcAny criteria to be excluded at a 3mm cut-off, which was reduced to 29% when ExcAll criteria were used (McNemar test, p < 0.001). At the subject-level, an increase in the sensitivity of select3* CVS criteria for MS diagnosis was noted at 3mm using the less strict ExcAll (95%) compared to the more conservative ExcAny criteria (61%), without impacting specificity (100% for both methods). There was a reduction in specificity for both ExcAny and ExcAll criteria when size cut-offs less than or equal to 2mm were used (88% for both).

Conclusions

Compared to the current NAIMS guidelines, ExcAll criteria for CVS lesion analysis allow the inclusion of a larger proportion of CVS+ lesions and improve the sensitivity of select3* criteria for MS diagnosis. These findings improve the applicability of the CVS as a diagnostic marker for MS in clinical practice and provide evidence for future modifications of CVS lesion exclusion guidelines.

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