Author Of 1 Presentation
PS11.02 - PET Imaging of Microglial Activation
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.
Presenter Of 1 Presentation
PS11.02 - PET Imaging of Microglial Activation
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.
Invited Speaker Of 1 Presentation
PS11.02 - PET Imaging of Microglial Activation
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.
Author Of 2 Presentations
P0247 - Comparison of the 2017 and 2010 revisions of the McDonald criteria in patients with cis suggestive of MS: a multicentre MAGNIMS study (ID 1121)
- P. Preziosa
- A. Meani
- A. Rovira
- S. Mesaros
- O. Ciccarelli
- J. Frederiksen
- C. Enzinger
- F. Barkhof
- C. Gasperini
- E. Fainardi
- W. Brownlee
- J. Drulovic
- X. Montalban
- S. Cramer
- M. Kalil
- M. Hagens
- S. Ruggieri
- G. Dalla Costa
- V. Martinelli
- K. Miszkiel
- M. Tintore
- G. Comi
- I. Dekker
- B. Uitdehaag
- J. Ivanović
- M. Amato
- M. Rocca
Abstract
Background
In 2017, a revision of the 2010 McDonald criteria for multiple sclerosis (MS) diagnosis in clinically isolated syndrome (CIS) patients has been proposed. However, its validation in a large multicenter cohort of CIS patients is still needed.
Objectives
To compare the performance of 2017 and 2010 revisions of the McDonald criteria with respect to MS development in a large multicentric cohort of CIS suggestive of MS.
Methods
Brain and spinal cord magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) examination obtained ≤5 months from CIS onset and a follow-up brain MRI acquired ≤15 months from CIS onset were assessed in 626 CIS patients from 9 European MS centres. The occurrence of a second clinical attack (clinically definite [CD] MS) was recorded. Performances of the 2017 and 2010 revisions of McDonald criteria for dissemination in space (DIS), time (DIT) and DIS plus DIT, also including OCB assessment, were evaluated with a time-dependent receiver operating characteristic curve analysis. Median time to MS diagnosis for the different sets of criteria was estimated through Kaplan-Meier curves.
Results
At the last evaluation (median=61.9 months [IQR=39.1-102.5]), 319 (51%) of 626 patients had CDMS. At 36 months, for DIS, the 2017 MRI criteria had higher sensitivity (0.84 [95% CI=0.79-0.88] vs 0.77 [0.72-0.82]), lower specificity (0.33 [0.28-0.39] vs 0.40 [0.35-0.46]), and similar area under the curve values (AUC, 0.59 [0.55-0.62] for both). The 2017 DIS plus DIT MRI criteria had higher sensitivity (0.68 [0.63-0.74] vs 0.62 [0.56-0.68]), lower specificity (0.55 [0.49-0.61] vs 0.62 [0.56-0.68]), and similar AUC values (0.62 [0.58-0.66] for both). CSF-specific OCB assessment as part of the 2017 criteria revision, increased the sensitivity (0.81 [0.75-0.85]), decreased specificity (0.40 [0.34-0.46]) and preserved AUC values (0.60 [0.56-0.64]). Median time to MS diagnosis was earlier with the 2017 revision compared to the 2010 or CDMS criteria, especially with OCB assessment (2017 revision with OCBs=3.6 months [3.1-4.0], 2017 revision without OCB=11.6 months [7.8-13.5], 2010 revision=13.9 months [12.4-15.3], CDMS=56.3 months [43.8-76.0]).
Conclusions
The 2017 revision of the McDonald criteria showed overall similar accuracy to the 2010 McDonald criteria in predicting CDMS development. The suggested modifications are expected to simplify the clinical use of MRI criteria without reducing accuracy and allow an earlier diagnosis of MS.
P0579 - FLAIR-only joint volumetric analysis of brain lesions and atrophy in clinically isolated syndrome (CIS) suggestive of MS (ID 395)
Abstract
Background
MRI assessment in MS focuses on the presence of typical white matter (WM) lesions. Neurodegeneration characterised by brain atrophy is recognised in the research field as an important prognostic factor. It is not routinely reported clinically, in part due to difficulty in achieving reproducible measurements. Automated MRI quantification of WM lesions and brain volume could provide important clinical monitoring data. In general, lesion quantification relies on both T1 and FLAIR input images, while tissue volumetry relies on T1. However, T1-weighted scans are not routinely included in the clinical MS protocol, limiting the utility of automated quantification.
Objectives
We address this important translational challenge by assessing the performance of FLAIR-only lesion and brain segmentation, against a conventional approach requiring multi-contrast acquisition. We explore whether FLAIR-only grey matter (GM) segmentation yields more variability in performance compared with two-channel segmentation; whether this is related to field strength; and whether the results meet a level of clinical acceptability demonstrated by the ability to reproduce established biological associations.
Methods
We used a multicentre dataset of subjects with a CIS suggestive of MS scanned at 1.5T and 3T in the same week. WM lesions were manually segmented by two raters, ‘manual 1’ guided by consensus reading of CIS-specific lesions and ‘manual 2’ by any WM hyperintensity. An existing brain segmentation method was adapted for FLAIR-only input. Automated segmentation of WM hyperintensity and brain volumes were performed with conventional (T1/T1+FLAIR) and FLAIR-only methods.
Results
WM lesion volumes were comparable at 3T between ‘manual 2’, T1+FLAIR and FLAIR-only methods. For cortical GM volume, linear regression measures between conventional and FLAIR-only segmentation were high (1.5T: α=1.029, R2=0.997, standard error (SE)= 0.007; 3T: α=1.019, R2=0.998, SE=0.006). Age-associated change in cortical GM volume was a significant covariate in both T1 (p=0.001) and FLAIR-only (p=0.005) methods, confirming the expected relationship between age and GM volume for FLAIR-only segmentations.
Conclusions
FLAIR-only automated frameworks for segmentation of WM lesions and brain volumes were consistent with results obtained through conventional methods and had the ability to demonstrate biological effects in our study population. This could facilitate the integration of automated WM lesion volume and brain atrophy analysis as clinical tools in radiological MS reporting.