Marco Castellaro

Heterogeneity of Cortical Lesions in Multiple Sclerosis: An MRI Perfusion Study

In this study, dynamic susceptibility contrast-magnetic resonance imaging (DSC-MRI) was used to quantify the cerebral blood flow (CBF), the cerebral blood volume (CBV), and the mean transit time (MTT) and to analyze the changes in cerebral perfusion associated with the cortical lesions in 44 patients with relapsing-remitting multiple sclerosis. The cortical lesions showed a statistically significant reduction in CBF and CBV compared with the normal-appearing gray matter, whereas there were no significant changes in the MTT. The reduced perfusion suggests a reduction of metabolism because of the loss of cortical neurons. A small population of outliers showing an increased CBF and/or CBV has also been detected. The presence of hyperperfused outliers may imply that perfusion could evolve during inflammation. These findings show that perfusion is altered in cortical lesions and that DSC-MRI can be a useful tool to investigate more deeply the evolution of cortical lesions in multiple sclerosis.

Regional distribution and evolution of gray matter damage in different populations of multiple sclerosis patients

Background Both gray-matter (GM) atrophy and lesions occur from the earliest stages of Multiple Sclerosis (MS) and are one of the major determinants of long-term clinical outcomes. Nevertheless, the relationship between focal and diffuse GM damage has not been clarified yet. Here we investigate the regional distribution and temporal evolution of cortical thinning and how it is influenced by the local appearance of new GM lesions at different stages of the disease in different populations of MS patients. Methods We studied twenty MS patients with clinically isolated syndrome (CIS), 27 with early relapsing-remitting MS (RRMS, disease duration <5 years), 29 with late RRMS (disease duration ≥ 5 years) and 20 with secondary-progressive MS (SPMS). The distribution and evolution of regional cortical thickness and GM lesions were assessed during 5-year follow-up. Results The results showed that new lesions appeared more frequently in hippocampus and parahippocampal gyri (9.1%), insula (8.9%), cingulate cortex (8.3%), superior frontal gyrus (8.1%), and cerebellum (6.5%). The aforementioned regions showed the greatest reduction in thickness/volume, although (several) differences were observed across subgroups. The correlation between the appearance of new cortical lesions and cortical thinning was stronger in CIS (r2 = 50.0, p<0.001) and in early RRMS (r2 = 52.3, p<0.001), compared to late RRMS (r2 = 25.5, p<0.001) and SPMS (r2 = 6.3, p = 0.133). Conclusions We conclude that GM atrophy and lesions appear to be different signatures of cortical disease in MS having in common overlapping spatio-temporal distribution patterns. However, the correlation between focal and diffuse damage is only moderate and more evident in the early phase of the disease.

Epilepsy in multiple sclerosis: The role of temporal lobe damage

Background: Although temporal lobe pathology may explain some of the symptoms of multiple sclerosis (MS), its role in the pathogenesis of seizures has not been clarified yet. Objectives: To investigate the role of temporal lobe damage in MS patients suffering from epilepsy, by the application of advanced multimodal 3T magnetic resonance imaging (MRI) analysis. Methods: A total of 23 relapsing remitting MS patients who had epileptic seizures (RRMS/E) and 23 disease duration matched RRMS patients without any history of seizures were enrolled. Each patient underwent advanced 3T MRI protocol specifically conceived to evaluate grey matter (GM) damage. This includes grey matter lesions (GMLs) identification, evaluation of regional cortical thickness and indices derived from the Neurite Orientation Dispersion and Density Imaging model. Results: Regional analysis revealed that in RRMS/E, the regions most affected by GMLs were the hippocampus (14.2%), the lateral temporal lobe (13.5%), the cingulate (10.0%) and the insula (8.4%). Cortical thinning and alteration of diffusion metrics were observed in several regions of temporal lobe, in insular cortex and in cingulate gyrus of RRMS/E compared to RRMS (p< 0.05 for all comparisons). Conclusions: Compared to RRMS, RRMS/E showed more severe damage of temporal lobe, which exceeds what would be expected on the basis of the global GM damage observed.

Cortical Gray Matter MR Imaging in Multiple Sclerosis

Several neuropathologic and imaging studies have consistently confirmed that multiple sclerosis affects both white (WM) and gray matter (GM) and that GM damage plays a key role in disability progression. However, differently from WM damage, the less inflammatory cell infiltration, the absence of significant blood-brain barrier damage, the low myelin density in upper cortical layers, as well as technical constraints, make the GM damage almost undetectable by means of conventional MR imaging.

A Variational Bayesian inference method for parametric imaging of PET data

Abstract In dynamic Positron Emission Tomography (PET) studies, compartmental models provide the richest information on the tracer kinetics of the tissue. Inverting such models at the voxel level is however quite challenging due to the low signal‐to‐noise ratio of the time activity curves. In this study, we propose the use of a Variational Bayesian (VB) approach to efficiently solve this issue and thus obtain robust quantitative parametric maps. VB was adapted to the non‐uniform noise distribution of PET data. Moreover, we propose a novel hierarchical scheme to define the model parameter priors directly from the images in case such information are not available from the literature, as often happens with new PET tracers. VB was initially tested on synthetic data generated using compartmental models of increasing complexity, providing accurate (%bias<2%±2%, root mean square error<15%±5%) parameter estimates. When applied to real data on a paradigmatic set of PET tracers (L‐[1‐11C]leucine, [11C]WAY100635 and [18F]FDG), VB was able to generate reliable parametric maps even in presence of high noise in the data (unreliable estimates<11%±5%). Graphical abstract Figure. No Caption available. HighlightsVariational Bayesian (VB) approach is applied for the first time to PET data.VB was adapted to the specific non‐uniform noise distribution of PET data.Various PET tracers described by different compartmental models were tested.VB provided robust and accurate model estimates with low percentage of unreliable estimates.

Inflammatory intrathecal profiles and cortical damage in multiple sclerosis

Gray matter (GM) damage and meningeal inflammation have been associated with early disease onset and a more aggressive disease course in multiple sclerosis (MS), but can these changes be identified in the patient early in the disease course?

A case of epilepsy in multiple sclerosis: Three-dimensional double inversion recovery sequences revealed cortical dysplasia

In epileptic patients with multiple sclerosis (MS), cortical lesions have been suggested to cause seizures. In brain magnetic resonance imaging (MRI), double inversion recovery (DIR) sequences are generally used to evaluate MS cortical disease burden. We present the case of a woman, diagnosed with MS, suffering from drug-resistant partial seizures initially attributed to MS. The patient underwent many MRI exams, but only by means of high-resolution three-dimensional DIR sequences was a focal cortical dysplasia discovered. The MRI findings and FDG-PET/CT supported the diagnosis. This case recommends the use of DIR sequences both in patients with suspect epileptogenic lesions not detected with routine MRI protocols and in epileptic patient with MS, before ascribing seizures to MS.

Heterogeneity of cortical lesion susceptibility mapping in multiple sclerosis

The authors characterized the susceptibility mapping of cortical lesions in patients with MS (n=36) and compared it with neuropathologic observations (n=16). Neuropathologic analysis revealed the presence of an intense band of microglia activation close to the pial membrane in subpial cortical lesions or to the WM border of leukocortical cortical lesions. The quantitative susceptibility mapping analysis revealed 131 cortical lesions classified as hyperintense; 33, as isointense; and 84, as hypointense. They conclude that cortical lesion susceptibility maps are highly heterogeneous, even at individual levels and that the quantitative susceptibility mapping hyperintensity edge found in proximity to the pial surface might be due to the subpial gradient of microglial activation. BACKGROUND AND PURPOSE: Quantitative susceptibility mapping has been used to characterize iron and myelin content in the deep gray matter of patients with multiple sclerosis. Our aim was to characterize the susceptibility mapping of cortical lesions in patients with MS and compare it with neuropathologic observations. MATERIALS AND METHODS: The pattern of microglial activation was studied in postmortem brain tissues from 16 patients with secondary-progressive MS and 5 age-matched controls. Thirty-six patients with MS underwent 3T MR imaging, including 3D double inversion recovery and 3D-echo-planar SWI. RESULTS: Neuropathologic analysis revealed the presence of an intense band of microglia activation close to the pial membrane in subpial cortical lesions or to the WM border of leukocortical cortical lesions. The quantitative susceptibility mapping analysis revealed 131 cortical lesions classified as hyperintense; 33, as isointense; and 84, as hypointense. Quantitative susceptibility mapping hyperintensity edge found in the proximity of the pial surface or at the white matter/gray matter interface in some of the quantitative susceptibility mapping–hyperintense cortical lesions accurately mirrors the microglia activation observed in the neuropathology analysis. CONCLUSIONS: Cortical lesion susceptibility maps are highly heterogeneous, even at individual levels. Quantitative susceptibility mapping hyperintensity edge found in proximity to the pial surface might be due to the subpial gradient of microglial activation.

Detection of a slow-flow component in contrast-enhanced ultrasound of the synovia for the differential diagnosis of arthritis

Contrast Enhanced Ultrasound (CEUS) is a sensitive imaging technique to assess tissue vascularity, that can be useful in the quantification of different perfusion patterns. This can particularly important in the early detection and differentiation of different types of arthritis. A Gamma-variate can accurately quantify synovial perfusion and it is flexible enough to describe many heterogeneous patterns. However, in some cases the heterogeneity of the kinetics can be such that even the Gamma model does not properly describe the curve, especially in presence of recirculation or of an additional slowflow component. In this work we apply to CEUS data both the Gamma-variate and the single compartment recirculation model (SCR) which takes explicitly into account an additional component of slow flow. The models are solved within a Bayesian framework. We also employed the perfusion estimates obtained with SCR to train a support vector machine classifier to distinguish different types of arthritis. When dividing the patients into two groups (rheumatoid arthritis and polyarticular RA-like psoriatic arthritis vs. other arthritis types), the slow component amplitude was significantly different across groups: mean values of a1 and its variability were statistically higher in RA and RA-like patients (131% increase in mean, p = 0.035 and 73% increase in standard deviation, p = 0.049 respectively). The SVM classifier achieved a balanced accuracy of 89%, with a sensitivity of 100% and a specificity of 78%.

Dimethyl fumarate: a possible exit strategy from natalizumab treatment in patients with multiple sclerosis at risk for severe adverse events

Introduction Among disease-modifying treatments for multiple sclerosis, natalizumab (NTZ) is highly effective, well tolerated and generally safe. Major concerns regard the risk of developing progressive multifocal leukoencephalopathy (PML), and the occurrence of rebounds or disease activity after its discontinuation. The aim of this study was to explore the efficacy of dimethyl fumarate (DMF) in preventing disease reactivation after NTZ discontinuation. Methods Thirty-nine patients with relapsing remitting multiple sclerosis, at high risk of PML, were switched from NTZ to DMF and underwent neurological and 3T MRI monitoring for 2 years. Clinical and MRI data regarding the 2-year period preceding NTZ treatment, the 2 years of NTZ treatment and the 2 years of DMF were collected. Results During the DMF phase, among the 39 patients, one or more relapses occurred in five patients (12.8%), increased disability progression in 4 (10.3%) and MRI activity in 8 (20.5%). Post-NTZ rebound effect was observed only in one patient. Overall, only two dropouts (one rebound activity and one gastrointestinal side effect) were registered and almost 80% of the patients have still no evidence of disease activity at the end of DMF treatment. The multiple linear regression model revealed that the number of relapses and MRI parameters before DMF treatment were good predictors of disease activity during treatment with DMF. Discussion DMF appeared generally safe and no carryover PML among investigated cases was observed. Although DMF did not eliminate the possibility of disease reactivation, it seems anyway a promising drug for those patients who shall discontinue NTZ. The clinical and radiological activity preceding the DMF treatment might be used as a prognostic marker of therapy response.