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In vivo analyses of the correlates of cortical and white matter pathology in patients with multiple sclerosis by quantitative 7 Tesla and 3 Tesla MRI and molecular imaging.
Get PDFThis thesis is divided in two sections. The first reports the results from a project regarding the application of ultra-high-field quantitative MRI for the study of cortical grey matter pathology in patients with early multiple sclerosis (MS). Applying a Combined Myelin Estimation method, obtained by 7 Tesla magnetic resonance imaging, we aimed at characterizing cortical microstructural abnormalities related to myelin content in cortical lesions and normal-appearing cortex, to assess their evolution at 1-year follow-up and to relate cortical myelin changes to clinical and radiological disease burden.
Data obtained from 25 patients with early MS and 19 healthy volunteers showed overall abnormally low myelin content in cortical lesions and several areas of normal-appearing cortex. Myelin content along the cortex correlated with neurological impairment. Individual cortical lesion analysis revealed heterogenous patterns, ranging from extensive to partial demyelination, or even measurements comparable to the healthy group. At 1-year follow-up, cortical myelin was overall decreased in cortical lesions and scattered areas in the normal-appearing cortex. Diffusion metrics obtained in the same regions did not show the presence of cortical neural loss accompanying early demyelination.
The second section reports results from a study in which we combined 11C-PBR28 positron-emission tomography, marking activated microglia, with the more recently validated synthetic magnetic resonance imaging for myelin content assessment, aiming at researching the presence of correlates of pathology in the white matter of patients with multiple sclerosis at different disease stages, and assessing the interplay between neuroinflammation and demyelination. We found abnormal increase of microglia activation in MS patients compared to healthy volunteers in several areas across the white matter, correlating with clinical and radiological disease burden. An individual analysis of white matter lesions showed the presence of active lesions in the early phases of the disease, evolving in inactive or peripherally active lesions in the late disease phases, the latter correlating with clinical disability. Myelin content in the normal-appearing white matter of MS patients correlated with neurological impairment and lesion load. Higher microglia activation in the white matter lesions was related to lower myelin content in the non-lesioned white matter
Interferon beta failure predicted by EMA criteria or isolated MRI activity in multiple sclerosis.
No full textObjective :The objective of this paper is to investigate four-year outcomes of interferon beta (IFNB)-treated patients with multiple sclerosis (MS) according to their clinical or magnetic resonance imaging (MRI) activity status at first year of treatment.
METHODS:
A total of 370 patients with MS duration ≤5 years before IFNB start were followed-up for four years. The optimal threshold for one-year MRI activity that more accurately predicted subsequent relapses or disability worsening was identified. The risk of relapses and disability worsening after the first year was then estimated by propensity score (PS)-adjusted analyses in patients fulfilling European Medicines Agency (EMA) criteria for second-line escalation and in those with isolated MRI activity.
RESULTS:
A total of 192 (51.9%) patients relapsed, and 66 (17.8%) worsened in disability from year 1 to 4 of follow-up. The more accurate threshold for one-year MRI activity was the occurrence of ≥1 enhancing or ≥2 new T2-lesions. An increased risk of relapses and disability worsening was found in either patients fulfilling EMA criteria (hazard ratio (HR) = 3.69, and HR = 6.02) and in those experiencing isolated MRI activity (HR = 3.15, and HR = 5.31) at first year of treatment, when compared with stable patients (all p values <0.001).
CONCLUSION:
The four-year outcomes of patients with isolated MRI activity did not differ from those fulfilling EMA criteria at first year of IFNB treatment
Predictors of freedom from disease activity in natalizumab treated-patients with multiple sclerosis
No full text
Evidence of diffuse cerebellar neuroinflammation in multiple sclerosis by 11 C-PBR28 MR-PET
No full textBackground: Activated microglia, which can be detected in vivo by 11 C-PBR28 positron emission tomography (PET), represent a main component of MS pathology in the brain. Their role in the cerebellum is still unexplored, although cerebellar involvement in MS is frequent and accounts for disability progression. Objectives: We aimed at characterizing cerebellar neuroinflammation in MS patients compared to healthy subjects by combining 11 C-PBR28 MRI-Positron Emission Tomography (MR-PET) with 7 Tesla (T) MRI and assessing its relationship with brain neuroinflammation and clinical outcome measures. Methods: Twenty-eight MS patients and 16 healthy controls underwent 11 C-PBR28 MR-PET to measure microglia activation in normal appearing cerebellum and lesions segmented from 7 T scans. Patients were evaluated using the Expanded Disability Status Scale and Symbol Digit Modalities Test. 11 C-PBR28 binding was assessed in regions of interest using 60–90 minutes standardized uptake values normalized by a pseudo-reference region in the brain normal appearing white matter. Multilinear regression was used to compare tracer uptake in MS and healthy controls and assess correlations with clinical scores. Results: In all cerebellar regions examined, MS patients showed abnormally increased tracer uptake, which correlated with cognitive and neurological disability. Conclusion: Neuroinflammation is widespread in the cerebellum of patients with MS and related to neurological disability and cognitive impairment
In vivo characterization of cerebellar microglia activation in multiple sclerosis by combined 11C-PBR28 MR-PET and 7 Tesla MRI.
No full textIntroduction
Cerebellar involvement occurs early in multiple sclerosis (MS), and is associated with neurological impairment and disease progression. Neuropathological cerebellar examinations in MS reported heterogeneous processes including demyelination, neurodegeneration and microglia activation. The role of microglia in the pathogenesis of cerebellar pathology is unknown. Activated microglia upregulate expression of the 18kDa translocator protein (TSPO), which can be imaged in vivo using the 11C-PBR28 radioligand.
Objectives
We investigated, using integrated 3 Tesla (3T) magnetic resonance-positron emission tomography (MR-PET) imaging with 11C-PBR28, TSPO expression in lesional and non lesional white and grey matter (WM, GM) in the cerebellum of a heterogeneous MS cohort, and its association with cerebellar lesions, atrophy and clinical parameters. Cerebellar lesions were characterized using ultra high resolution 7 Tesla (7T) MRI.
Methods
Twenty-seven patients with MS (13 relapsing-remitting, RRMS, 14 secondary progressive, SPMS) and 18 healthy controls (HC) matched for age and
PBR28 affinity, were included in the study. All subjects underwent 90-min 11C-PBR28 MR-PET. Anatomical 3T images of the cerebellum for regions of interest segmentation were also acquired. A manual segmentation was performed to extract whole cerebellum (WHC) masks on Freesurfer (Figure 1A). In
patients, normal appearing WHC (NAWHC) was obtained by subtracting the lesion masks to the WHC mask using FSL. Cerebellar WM and GM were segmented using Volbrain (Figure 1B), and volumes were normalized by total intracranial volume in Freesurfer. In patients, cerebellar lesions were segmented on 7 T T1-weighted images (0.6x0.6x1.5 mm3) obtained on a separate session by using Slicer v 4.2 (Figure 2). Quantification of 11C-PBR28 uptake in the WHC, NAWHC, GM, WM and cerebellar lesions (CL) was performed using 60-90 minutes standardized uptake values normalized by a pseudoreference region in the normal appearing basal ganglia. Tracer uptake was extracted in cerebellar lesions that have been grouped according to localization in cortical (CCL), leukocortical (LCL), deep grey matter (DGML), and purely WM lesions (WML). All patients underwent neurological and cognitive assessment by Expanded Disability Status Scale (EDSS) and Symbol Digit Modality Test (SDMT). Linear regression models were used to compare cerebellar 11C-PBR28 uptake in MS patients versus controls, and to assess their relationship with EDSS. Age and binding affinity were included as covariates of no interest. Spearman correlation coefficient was used to assess the association between clinical parameters (EDSS, SDMT) and uptake values. Matched-pair T-test was performed to search for differences in lesion uptake between different regions of interest.
Results
Mean age for patients was 48±10, EDSS ranged from 1.5 to 7.5 (median 3.5, mean 4.0). Mean age for HC was 49±12. Cerebellar lesions were found in 13 out of 14 SPMS and in 10 out of 13 RRMS. In RRMS, most of the lesions are localized in the WM; in progressive patients, a majority of leucocortical lesions has been detected. No significant differences in the uptake were found in lesions affecting different regions in the cerebellum, when considering all patients as one group, and after separating SPMS and RRMS patients. Compared to controls, MS subjects showed significantly higher PBR28 uptake in all examined regions: WHC (p=0.04), NAWHC (p=0.05), GM (p=0.04), WM (p=0.03). Within patients, the mean uptake was higher in lesions then in the rest of the parenchyma (1.45 versus 1.39) though not significantly.
There was a significative difference between global lesion uptake and the uptake in the cerebellum of HC (p=0.02, Figure 3D). No differences in uptake were found in SPMS versus RRMS. Tracer uptake in the WM correlated positively with EDSS (p=0.03), and negatively with SDMT z-scores (p<0.01). When corrected for age and tracer binding affinity, this significance became a trend for EDSS (p=0.07) but was maintained for SDMT (p=0.04), being the age a determinant for motor and cognitive performance reduction. There was no correlation between cerebellar volume, cerebellar lesion load and tracer uptake in any of the regions examined.
Discussion
Our data provide in vivo evidence for the presence of diffuse microglia activation in the cerebellum in MS. Interestingly, the highest increase in microglia activation was detected in lesions that were mainly concentrated in WM in RRMS, while they extensively involved the cortical cerebellar GM in SPMS. Abnormal microglia activation in the WM was related to worse neurological disability and cognitive performance in the whole MS cohort.
Conclusions
MR-PET is a valid tool to estimate cerebellar neuroinflammation in patients with MS. Future studies will assess its longitudinal evolution in relation to structural pathology and clinical outcome
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
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