Estimation of the density of veins from susceptibility-weighted imaging by using Mamdani fuzzy-type rule-based system. Investigating the neurovascular coupling in migraine.

BACKGROUND AND PURPOSE: An impaired neurovascular coupling has been described as a possible player in neurodegeneration and cognitive decline. Migraine is a recurrent and incapacitating disorder that starts early in life and has shown neurovascular coupling abnormalities. Despite its high prevalence, the physiology and underlying mechanisms are poorly understood. In this context, new biomarkers from magnetic resonance imaging (MRI) are needed to bring new knowledge into the field. The aim of this study was to determine the vein density from Susceptibility-Weighted Imaging (SWI) MRI, in subjects with migraine and healthy controls; and to assess whether it relates to Resting-State functional MRI (RS-fMRI). MATERIALS AND METHODS: The cohort included 30 healthy controls and 70 subjects with migraine (26 episodic, 44 chronic) who underwent a brain 3.0 T MRI. Clinical characteristics were also collected. Maps of density of veins were generated based on a Mamdani Fuzzy-Type Rule-Based System from the SWI MRI. Mean values of vein density were obtained in grey (GM) and white matter (WM) Freesurfer lobar parcellations. The Amplitude of Low-Frequency Fluctuations (ALFF) image was calculated for the RS-fMRI, and the mean values over the parcellated GM lobes were estimated. Differences between groups were assessed through and analysis of variance (age, sex, education and anxiety as covariates; p < 0.05), followed by post-hoc comparisons. Associations were run between clinical and MRI-derived variables. RESULTS: When comparing the density of veins in GM, no differences between groups were found, neither associations with clinical variables. The density of veins was significantly higher in the WM of the occipital lobe for subjects with chronic migraine compared to controls (30%, p < 0.05). WM vein density in either frontal, temporal or cingulate regions was associated with clinical variables such as headache days, disability scores, and cognitive impairment (r between 0.25 and 0.41; p < 0.05). Mean values of ALFF did not differ significantly between controls and subjects with migraine. Strong significant associations between vein density and ALFF measures were obtained in most GM lobes for healthy subjects (r between 0.50 and 0.67; p < 0.05), instead, vein density in WM was significantly associated with ALFF for subjects with migraine (r between 0.32 and 0.58; p < 0.05). CONCLUSIONS: Results point towards an increase in vein density in subjects with migraine, when compared to healthy controls. In addition, the association between GM vein density and ALFF found in healthy subjects was lost in migraine. Taken together, these results support the idea of abnormalities in the neurovascular coupling in migraine. Quantitative SWI MRI indicators in migraine might be an interesting target that may contribute to its comprehension.

Validation of a New Semiautomated Segmentation Pipeline Based on the Spinal Cord Toolbox DeepSeg Algorithm to Estimate the Cervical Canal Area.

BACKGROUND AND PURPOSE: As in the brain reserve concept, a larger cervical canal area may also protect against disability. In this context, a semiautomated pipeline has been developed to obtain quantitative estimations of the cervical canal area. The aim of the study was to validate the pipeline, to evaluate the consistency of the cervical canal area measurements during a 1-year period, and to compare cervical canal area estimations obtained from brain and cervical MRI acquisitions. MATERIALS AND METHODS: Eight healthy controls and 18 patients with MS underwent baseline and follow-up 3T brain and cervical spine sagittal 3D MPRAGE. The cervical canal area was measured in all acquisitions, and estimations obtained with the proposed pipeline were compared with manual segmentations performed by 1 evaluator using the Dice similarity coefficient. The cervical canal area estimations obtained on baseline and follow-up T1WI were compared; brain and cervical cord acquisitions were also compared using the individual and average intraclass correlation coefficients. RESULTS: The agreement between the manual cervical canal area masks and the masks provided by the proposed pipeline was excellent, with a mean Dice similarity coefficient mean of 0.90 (range, 0.73-0.97). The cervical canal area estimations obtained from baseline and follow-up scans showed a good level of concordance (intraclass correlation coefficient = 0.76; 95% CI, 0.44-0.88); estimations obtained from brain and cervical MRIs also had good agreement (intraclass correlation coefficient = 0.77; 95% CI, 0.45-0.90). CONCLUSIONS: The proposed pipeline is a reliable tool to estimate the cervical canal area. The cervical canal area is a stable measure across time; moreover, when cervical sequences are not available, the cervical canal area could be estimated using brain T1WI.

Assessing the Equivalence of Brain-Derived Measures from Two 3D T1-Weighted Acquisitions: One Covering the Brain and One Covering the Brain and Spinal Cord.

BACKGROUND AND PURPOSE: In MS, it is common to acquire brain and spinal cord MR imaging sequences separately to assess the extent of the disease. The goal of this study was to see how replacing the traditional brain T1-weighted images (brain-T1) with an acquisition that included both the brain and the cervical spinal cord (cns-T1) affected brain- and spinal cord-derived measures. MATERIALS AND METHODS: Thirty-six healthy controls (HC) and 42 patients with MS were included. Of those, 18 HC and 35 patients with MS had baseline and follow-up at 1 year acquired on a 3T magnet. Two 3D T1-weighted images (brain-T1 and cns-T1) were acquired at each time point. Regional cortical thickness and volumes were determined with FastSurfer, and the percentage brain volume change per year was obtained with SIENA. The spinal cord area was estimated with the Spinal Cord Toolbox. Intraclass correlation coefficients (ICC) were calculated to check for consistency of measures obtained from brain-T1 and cns-T1. RESULTS: Cortical thickness measures showed an ICC >0.75 in 94% of regions in healthy controls and 80% in patients with MS. Estimated regional volumes had an ICC >0.88, and the percentage brain volume change had an ICC >0.79 for both groups. The spinal cord area measures had an ICC of 0.68 in healthy controls and 0.92 in patients with MS. CONCLUSIONS: Brain measurements obtained from 3D cns-T1 are highly equivalent to those obtained from a brain-T1, suggesting that it could be feasible to replace the brain-T1 with cns-T1.

T1w/FLAIR ratio standardization as a myelin marker in MS patients.

INTRODUCTION: Calculation of a T1w/T2w ratio was introduced as a proxy for myelin integrity in the brain of multiple sclerosis (MS) patients. Since nowadays 3D FLAIR is commonly used for lesion detection instead of T2w images, we introduce a T1w/FLAIR ratio as an alternative for the T1w/T2w ratio. OBJECTIVES: Bias and intensity variation are widely present between different scanners, between subjects and within subjects over time in T1w, T2w and FLAIR images. We present a standardized method for calculating a histogram calibrated T1w/FLAIR ratio to reduce bias and intensity variation in MR sequences from different scanners and at different time-points. MATERIAL AND METHODS: 207 Relapsing Remitting MS patients were scanned on 4 different 3 T scanners with a protocol including 3D T1w, 2D T2w and 3D FLAIR images. After bias correction, T1w/FLAIR ratio maps and T1w/T2w ratio maps were calculated in 4 different ways: without calibration, with linear histogram calibration as described by Ganzetti et al. (2014), and by using 2 methods of non-linear histogram calibration. The first nonlinear calibration uses a template of extra-cerebral tissue and cerebrospinal fluid (CSF) brought from Montreal Neurological Institute (MNI) space to subject space; for the second nonlinear method we used an extra-cerebral tissue and CSF template of our own subjects. Additionally, we segmented several brain structures such as Normal Appearing White Matter (NAWM), Normal Appearing Grey Matter (NAGM), corpus callosum, thalami and MS lesions using Freesurfer and Samseg. RESULTS: The coefficient of variation of T1w/FLAIR ratio in NAWM for the no calibrated, linear, and 2 nonlinear calibration methods were respectively 24, 19.1, 9.5, 13.8. The nonlinear methods of calibration showed the best results for calculating the T1w/FLAIR ratio with a smaller dispersion of the data and a smaller overlap of T1w/FLAIR ratio in the different segmented brain structures. T1w/T2w and T1w/FLAIR ratios showed a wider range of values compared to MTR values. CONCLUSIONS: Calibration of T1w/T2w and T1w/FLAIR ratio maps is imperative to account for the sources of variation described above. The nonlinear calibration methods showed the best reduction of between-subject and within-subject variability. The T1w/T2w and T1w/FLAIR ratio seem to be more sensitive to smaller changes in tissue integrity than MTR. Future work is needed to determine the exact substrate of T1w/FLAIR ratio and to obtain correlations with clinical outcome.

Neuritis óptica: etiopatogenia, diagnóstico, pronóstico y manejo / Optic neuritis: aetiopathogenesis, diagnosis, prognosis and management

La neuritis óptica (NO) tiene como principales causas la esclerosis múltiple (EM), las enfermedades dentro del espectro de la neuromielitis óptica (NMOSD) y la enfermedad asociada a anticuerpos contra la proteína de la mielina del oligodendrocito, también conocida como MOGAD. Cuando todo el cribado es negativo, podemos hablar de NO idiopática, aunque este diagnóstico deberá ser provisional. La NO se puede diagnosticar clínicamente y no se requieren de forma rutinaria pruebas paraclínicas para confirmarla. Sin embargo, pruebas como la resonancia magnética (RM), los potenciales evocados visuales (PEV) y la tomografía de coherencia óptica (OCT) pueden dar soporte al diagnóstico si la presentación clínica es atípica. El uso de nuevas secuencias de RM, la OCT, los PEV multifocales y la determinación de neurofilamentos han posibilitado el uso de la NO como modelo de remielinización y neuroprotección, propiciando la realización de ensayos clínicos de fase II. Algunos de estos fármacos, como el opicinumab, la clemastina, la fenitoína o la simvastatina, han obtenido resultados positivos; no obstante, su efecto clínico está por definir. Se acepta que los corticoides no mejoran el pronóstico a largo plazo de la NO, aunque algunos estudios retrospectivos sugieren que existe una ventana terapéutica desde el inicio de los síntomas. La plasmaféresis también ha demostrado eficacia en pacientes con NO. En esta revisión abordaremos aspectos básicos del manejo de la NO, en el contexto fundamental de la EM, la NMOSD y la MOGAD, haciendo hincapié en las novedades etiopatogénicas, diagnósticas, pronósticas y terapéuticas.(AU)

The main causes of optic neuritis (ON) are multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein antibody disease, also known as MOGAD. When all screening is negative, we can speak of idiopathic ON, although this diagnosis should be provisional. ON can be diagnosed clinically and paraclinical tests are not routinely required to confirm it. However, tests such as magnetic resonance imaging (MRI), visual evoked potentials (VEP) and optical coherence tomography (OCT) can lend support to the diagnosis if the clinical presentation is atypical. The use of new MRI sequences, OCT, multifocal VEPs and the determination of neurofilaments has allowed ON to be used as a model for remyelination and neuroprotection, leading to phase II clinical trials. Some of these drugs, such as opicinumab, clemastine, phenytoin or simvastatin, have shown positive results; however, their clinical effect remains to be defined. It is accepted that corticosteroids do not improve the long-term prognosis of ON, although some retrospective studies suggest that there is a therapeutic window from the onset of symptoms. Plasmapheresis has also been shown to be effective in patients with ON. In this review we will address basic aspects of the management of ON, in the fundamental context of MS, NMOSD and MOGAD, with emphasis on etiopathogenic, diagnostic, prognostic and therapeutic developments.(AU)

[Optic neuritis: aetiopathogenesis, diagnosis, prognosis and management]. / Neuritis óptica: etiopatogenia, diagnóstico, pronóstico y manejo.

The main causes of optic neuritis (ON) are multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein antibody disease, also known as MOGAD. When all screening is negative, we can speak of idiopathic ON, although this diagnosis should be provisional. ON can be diagnosed clinically and paraclinical tests are not routinely required to confirm it. However, tests such as magnetic resonance imaging (MRI), visual evoked potentials (VEP) and optical coherence tomography (OCT) can lend support to the diagnosis if the clinical presentation is atypical. The use of new MRI sequences, OCT, multifocal VEPs and the determination of neurofilaments has allowed ON to be used as a model for remyelination and neuroprotection, leading to phase II clinical trials. Some of these drugs, such as opicinumab, clemastine, phenytoin or simvastatin, have shown positive results; however, their clinical effect remains to be defined. It is accepted that corticosteroids do not improve the long-term prognosis of ON, although some retrospective studies suggest that there is a therapeutic window from the onset of symptoms. Plasmapheresis has also been shown to be effective in patients with ON. In this review we will address basic aspects of the management of ON, in the fundamental context of MS, NMOSD and MOGAD, with emphasis on etiopathogenic, diagnostic, prognostic and therapeutic developments.

TITLE: Neuritis óptica: etiopatogenia, diagnóstico, pronóstico y manejo.La neuritis óptica (NO) tiene como principales causas la esclerosis múltiple (EM), las enfermedades dentro del espectro de la neuromielitis óptica (NMOSD) y la enfermedad asociada a anticuerpos contra la proteína de la mielina del oligodendrocito, también conocida como MOGAD. Cuando todo el cribado es negativo, podemos hablar de NO idiopática, aunque este diagnóstico deberá ser provisional. La NO se puede diagnosticar clínicamente y no se requieren de forma rutinaria pruebas paraclínicas para confirmarla. Sin embargo, pruebas como la resonancia magnética (RM), los potenciales evocados visuales (PEV) y la tomografía de coherencia óptica (OCT) pueden dar soporte al diagnóstico si la presentación clínica es atípica. El uso de nuevas secuencias de RM, la OCT, los PEV multifocales y la determinación de neurofilamentos han posibilitado el uso de la NO como modelo de remielinización y neuroprotección, propiciando la realización de ensayos clínicos de fase II. Algunos de estos fármacos, como el opicinumab, la clemastina, la fenitoína o la simvastatina, han obtenido resultados positivos; no obstante, su efecto clínico está por definir. Se acepta que los corticoides no mejoran el pronóstico a largo plazo de la NO, aunque algunos estudios retrospectivos sugieren que existe una ventana terapéutica desde el inicio de los síntomas. La plasmaféresis también ha demostrado eficacia en pacientes con NO. En esta revisión abordaremos aspectos básicos del manejo de la NO, en el contexto fundamental de la EM, la NMOSD y la MOGAD, haciendo hincapié en las novedades etiopatogénicas, diagnósticas, pronósticas y terapéuticas.

Optical coherence tomography measures correlate with brain and spinal cord atrophy and multiple sclerosis disease-related disability.

BACKGROUND AND PURPOSE: Both optical coherence tomography (OCT) and magnetic resonance imaging (MRI) volumetric measures have been postulated as potential biomarkers of multiple sclerosis (MS)-related disability. The aim of the study was to investigate the association between OCT and brain volume and spinal cord area (SCA) parameters in patients with relapsing MS and to assess their independent associations with disability. METHODS: This was a cross-sectional analysis of 90 patients with MS who underwent OCT and MRI examination. Values of peripapillary retinal nerve fibre layer (pRNFL), ganglion cell/inner plexiform layer (GCIPL) and inner nuclear layer of eyes without previous optic neuritis were obtained. SCA and brain parenchymal fraction (BPF), grey and white matter fractions were obtained. Multivariable regression analyses were conducted with disability as dependent variable. RESULTS: Lower pRNFL thickness and lower GCIPL volume as well as lower BPF, grey matter fraction and SCA were associated with a longer disease duration and a higher Expanded Disability Status Scale score. Lower pRNFL thickness and GCIPL volumes were associated with lower BPF and SCA. In the multivariable logistic regression analyses, pRNFL thickness and GCIPL volume outperformed MRI in predicting disability. CONCLUSIONS: The OCT measures correlate with brain and spinal cord atrophy and appear more closely associated with disability than MRI volumetric measures.

Value of 3T Susceptibility-Weighted Imaging in the Diagnosis of Multiple Sclerosis.

BACKGROUND AND PURPOSE: Previous studies have suggested that the central vein sign and iron rims are specific features of MS lesions. Using 3T SWI, we aimed to compare the frequency of lesions with central veins and iron rims in patients with clinically isolated syndrome and MS-mimicking disorders and test their diagnostic value in predicting conversion from clinically isolated syndrome to MS. MATERIALS AND METHODS: For each patient, we calculated the number of brain lesions with central veins and iron rims. We then identified a simple rule involving an absolute number of lesions with central veins and iron rims to predict conversion from clinically isolated syndrome to MS. Additionally, we tested the diagnostic performance of central veins and iron rims when combined with evidence of dissemination in space. RESULTS: We included 112 patients with clinically isolated syndrome and 35 patients with MS-mimicking conditions. At follow-up, 94 patients with clinically isolated syndrome developed MS according to the 2017 McDonald criteria. Patients with clinically isolated syndrome had a median of 2 central veins (range, 0-19), while the non-MS group had a median of 1 central vein (range, 0-6). Fifty-six percent of patients who developed MS had ≥1 iron rim, and none of the patients without MS had iron rims. The sensitivity and specificity of finding ≥3 central veins and/or ≥1 iron rim were 70% and 86%, respectively. In combination with evidence of dissemination in space, the 2 imaging markers had higher specificity than dissemination in space and positive findings of oligoclonal bands currently used to support the diagnosis of MS. CONCLUSIONS: A single 3T SWI scan offers valuable diagnostic information, which has the potential to prevent MS misdiagnosis.

Ratio of T1-Weighted to T2-Weighted Signal Intensity as a Measure of Tissue Integrity: Comparison with Magnetization Transfer Ratio in Patients with Multiple Sclerosis.

The study aim was to compare the ratio of T1WI to T2WI signal intensity (T1/T2) with magnetization transfer ratio, a marker of myelin integrity, in patients with multiple sclerosis. A moderate correlation (r = 0.50, P = .034) was found between the magnetization transfer ratio and T1/T2 in normal-appearing gray matter, and a strong correlation for normal-appearing white matter (r = 0.63, P = .005) and lesions (r = 0.70, P = .001). Results suggest that besides myelin integrity, other factors may be playing a role in T1/T2 measures.

Brain networks associated with cognitive and hedonic responses to a meal.

BACKGROUND: We recently reported interrelated digestive, cognitive, and hedonic responses to a meal. The aim of this study was to identify brain networks related to the hedonic response to eating. METHODS: Thirty-eight healthy subjects (20-38 age range) were evaluated after a 5-hour fast and after ingestion of a test meal (juice and warm ham and cheese sandwich, 300 mL, 425 kcal). Perceptual and affective responses (satiety, abdominal fullness, digestive well-being, and positive mood), and resting scans of the brain using functional MRI (3T Trio, Siemens, Germany) were evaluated immediately before and after the test meal. A high-order group independent component analysis was performed to investigate ingestion-related changes in the intrinsic connectivity of brain networks, with a focus on thalamic and insular networks. KEY RESULTS: Ingestion induced satiation (3.3±0.4 score increase; P<.001) and abdominal fullness (2.4±0.3 score increase; P<.001). These sensations included an affective dimension involving digestive well-being (2.8±0.3 score increase; P<.001) and positive mood (1.8±0.2 score increase; P<.001). In general, thalamo-cortical connectivity increased with meal ingestion while insular-cortical connectivity mainly decreased. Furthermore, larger meal-induced changes (increase/decrease) in specific thalamic connections were associated with smaller changes in satiety/fullness. In contrast, a larger meal-induced decrease in insular-anterior cingulate cortex connectivity was associated with increased satiety, fullness, and digestive well-being. CONCLUSIONS AND INFERENCES: Perceptual and emotional responses to food intake are related to brain connectivity in defined functional networks. Brain imaging may provide objective biomarkers of subjective effects of meal ingestion.

Measurement of Cortical Thickness and Volume of Subcortical Structures in Multiple Sclerosis: Agreement between 2D Spin-Echo and 3D MPRAGE T1-Weighted Images.

BACKGROUND AND PURPOSE: Gray matter pathology is known to occur in multiple sclerosis and is related to disease outcomes. FreeSurfer and the FMRIB Integrated Registration and Segmentation Tool (FIRST) have been developed for measuring cortical and subcortical gray matter in 3D-gradient-echo T1-weighted images. Unfortunately, most historical MS cohorts do not have 3D-gradient-echo, but 2D-spin-echo images instead. We aimed to evaluate whether cortical thickness and the volume of subcortical structures measured with FreeSurfer and FIRST could be reliably measured in 2D-spin-echo images and to investigate the strength and direction of clinicoradiologic correlations. MATERIALS AND METHODS: Thirty-eight patients with MS and 2D-spin-echo and 3D-gradient-echo T1-weighted images obtained at the same time were analyzed by using FreeSurfer and FIRST. The intraclass correlation coefficient between the estimates was obtained. Correlation coefficients were used to investigate clinicoradiologic associations. RESULTS: Subcortical volumes obtained with both FreeSurfer and FIRST showed good agreement between 2D-spin-echo and 3D-gradient-echo images, with 68.8%-76.2% of the structures having either a substantial or almost perfect agreement. Nevertheless, with FIRST with 2D-spin-echo, 18% of patients had mis-segmentation. Cortical thickness had the lowest intraclass correlation coefficient values, with only 1 structure (1.4%) having substantial agreement. Disease duration and the Expanded Disability Status Scale showed a moderate correlation with most of the subcortical structures measured with 3D-gradient-echo images, but some correlations lost significance with 2D-spin-echo images, especially with FIRST. CONCLUSIONS: Cortical thickness estimates with FreeSurfer on 2D-spin-echo images are inaccurate. Subcortical volume estimates obtained with FreeSurfer and FIRST on 2D-spin-echo images seem to be reliable, with acceptable clinicoradiologic correlations for FreeSurfer.

Comparison between gadolinium-enhanced 2D T1-weighted gradient-echo and spin-echo sequences in the detection of active multiple sclerosis lesions on 3.0T MRI.

OBJECTIVES: To compare the sensitivity of enhancing multiple sclerosis (MS) lesions in gadolinium-enhanced 2D T1-weighted gradient-echo (GRE) and spin-echo (SE) sequences, and to assess the influence of visual conspicuity and laterality on detection of these lesions. METHODS: One hundred MS patients underwent 3.0T brain MRI including gadolinium-enhanced 2D T1-weighted GRE and SE sequences. The two sets of contrast-enhanced scans were evaluated in random fashion by three experienced readers. Lesion conspicuity was assessed by the image contrast ratio (CR) and contrast-to-noise ratio (CNR). The intracranial region was divided into four quadrants and the impact of lesion location on detection was assessed in each slice. RESULTS: Six hundred and seven gadolinium-enhancing MS lesions were identified. GRE images were more sensitive for lesion detection (0.828) than SE images (0.767). Lesions showed a higher CR in SE than in GRE images, whereas the CNR was higher in GRE than SE. Most misclassifications occurred in the right posterior quadrant. CONCLUSIONS: The gadolinium-enhanced 2D T1-weighted GRE sequence at 3.0T MRI enables detection of enhancing MS lesions with higher sensitivity and better lesion conspicuity than 2D T1-weighted SE. Hence, we propose the use of gadolinium-enhanced GRE sequences rather than SE sequences for routine scanning of MS patients at 3.0T. KEY POINTS: • 2D SE and GRE sequences are useful for detecting active MS lesions. • Which of these sequences is more sensitive at high field remains uncertain. • GRE sequence showed better sensitivity for detecting active MS lesions than SE. • We propose GRE sequence for detecting active MS lesions at 3.0T.

Improved Automatic Detection of New T2 Lesions in Multiple Sclerosis Using Deformation Fields.

BACKGROUND AND PURPOSE: Detection of disease activity, defined as new/enlarging T2 lesions on brain MR imaging, has been proposed as a biomarker in MS. However, detection of new/enlarging T2 lesions can be hindered by several factors that can be overcome with image subtraction. The purpose of this study was to improve automated detection of new T2 lesions and reduce user interaction to eliminate inter- and intraobserver variability. MATERIALS AND METHODS: Multiparametric brain MR imaging was performed at 2 time points in 36 patients with new T2 lesions. Images were registered by using an affine transformation and the Demons algorithm to obtain a deformation field. After affine registration, images were subtracted and a threshold was applied to obtain a lesion mask, which was then refined by using the deformation field, intensity, and local information. This pipeline was compared with only applying a threshold, and with a state-of-the-art approach relying only on image intensities. To assess improvements, we compared the results of the different pipelines with the expert visual detection. RESULTS: The multichannel pipeline based on the deformation field obtained a detection Dice similarity coefficient close to 0.70, with a false-positive detection of 17.8% and a true-positive detection of 70.9%. A statistically significant correlation (r = 0.81, P value = 2.2688e-09) was found between visual detection and automated detection by using our approach. CONCLUSIONS: The deformation field-based approach proposed in this study for detecting new/enlarging T2 lesions resulted in significantly fewer false-positives while maintaining most true-positives and showed a good correlation with visual detection annotations. This approach could reduce user interaction and inter- and intraobserver variability.

Lesion filling effect in regional brain volume estimations: a study in multiple sclerosis patients with low lesion load.

INTRODUCTION: Regional brain volume estimation in multiple sclerosis (MS) patients is prone to error due to white matter lesions being erroneously segmented as grey matter. The Lesion Segmentation Toolbox (LST) is an automatic tool that estimates a lesion mask based on 3D T2-FLAIR images and then uses this mask to fill the structural MRI image. The goal of this study was (1) to test the LST for estimating white matter lesion volume in a cohort of MS patients using 2D T2-FLAIR images, and (2) to evaluate the performance of the optimized LST on image segmentation and the impact on the calculated grey matter fraction (GMF). METHODS: The study included 110 patients with a clinically isolated syndrome and 42 with a relapsing-remitting MS scanned on a 3.0-T MRI system. In a subset of consecutively selected patients, the lesion mask was semi-manually delineated over T2-FLAIR images. After establishing the optimized LST parameters, the corresponding regional fractions were calculated for the original, filled, and masked images. RESULTS: A high agreement (intraclass correlation coefficient (ICC) = 0.955) was found between the (optimized) LST and the semi-manual lesion volume estimations. The GMF was significantly smaller when lesions were masked (mean difference -0.603, p < 0.001) or when the LST filling technique was used (mean difference -0.598, p < 0.001), compared to the GMF obtained from the original image. CONCLUSION: LST lesion volume calculation seems reliable. GMFs are significantly reduced when a method to correct the contribution of MS lesions is used, and it may have an impact in assessing GMF differences between clinical cohorts.

Juxtacortical Lesions and Cortical Thinning in Multiple Sclerosis.

BACKGROUND AND PURPOSE: The role of juxtacortical lesions in brain volume loss in multiple sclerosis has not been fully clarified. The aim of this study was to explore the role of juxtacortical lesions on cortical atrophy and to investigate whether the presence of juxtacortical lesions is related to local cortical thinning in the early stages of MS. MATERIALS AND METHODS: A total of 131 patients with clinically isolated syndrome or with relapsing-remitting MS were scanned on a 3T system. Patients with clinically isolated syndrome were classified into 3 groups based on the presence and topography of brain lesions: no lesions (n = 24), only non-juxtacortical lesions (n = 33), and juxtacortical lesions and non-juxtacortical lesions (n = 34). Patients with relapsing-remitting MS were classified into 2 groups: only non-juxtacortical lesions (n = 10) and with non-juxtacortical lesions and juxtacortical lesions (n = 30). A juxtacortical lesion probability map was generated, and cortical thickness was measured by using FreeSurfer. RESULTS: Juxtacortical lesion volume in relapsing-remitting MS was double that of patients with clinically isolated syndrome. The insula showed the highest density of juxtacortical lesions, followed by the temporal, parietal, frontal, and occipital lobes. Patients with relapsing-remitting MS with juxtacortical lesions showed significantly thinner cortices overall and in the parietal and temporal lobes compared with those with clinically isolated syndrome with normal brain MR imaging. The volume of subcortical structures (thalamus, pallidum, putamen, and accumbens) was significantly decreased in relapsing-remitting MS with juxtacortical lesions compared with clinically isolated syndrome with normal brain MR imaging. The spatial distribution of juxtacortical lesions was not found to overlap with areas of cortical thinning. CONCLUSIONS: Cortical thinning and subcortical gray matter volume loss in patients with a clinically isolated syndrome or relapsing-remitting MS was related to the presence of juxtacortical lesions, though the cortical areas with the most marked thinning did not correspond to those with the largest number of juxtacortical lesions.

Apoptotic markers in cultured fibroblasts correlate with brain metabolites and regional brain volume in antipsychotic-naive first-episode schizophrenia and healthy controls.

Cultured fibroblasts from first-episode schizophrenia patients (FES) have shown increased susceptibility to apoptosis, which may be related to glutamate dysfunction and progressive neuroanatomical changes. Here we determine whether apoptotic markers obtained from cultured fibroblasts in FES and controls correlate with changes in brain glutamate and N-acetylaspartate (NAA) and regional brain volumes. Eleven antipsychotic-naive FES and seven age- and gender-matched controls underwent 3-Tesla magnetic resonance imaging scanning. Glutamate plus glutamine (Glx) and NAA levels were measured in the anterior cingulate (AC) and the left thalamus (LT). Hallmarks of apoptotic susceptibility (caspase-3-baseline activity, phosphatidylserine externalization and chromatin condensation) were measured in fibroblast cultures obtained from skin biopsies after inducing apoptosis with staurosporine (STS) at doses of 0.25 and 0.5 µM. Apoptotic biomarkers were correlated to brain metabolites and regional brain volume. FES and controls showed a negative correlation in the AC between Glx levels and percentages of cells with condensed chromatin (CC) after both apoptosis inductions (STS 0.5 µM: r = -0.90; P = 0.001; STS 0.25 µM: r = -0.73; P = 0.003), and between NAA and cells with CC (STS 0.5 µM induction r = -0.76; P = 0.002; STS 0.25 µM r = -0.62; P = 0.01). In addition, we found a negative correlation between percentages of cells with CC and regional brain volume in the right supratemporal cortex and post-central region (STS 0.25 and 0.5 µM; P < 0.05 family-wise error corrected (FWEc)). We reveal for the first time that peripheral markers of apoptotic susceptibility may correlate with brain metabolites, Glx and NAA, and regional brain volume in FES and controls, which is consistent with the neuroprogressive theories around the onset of the schizophrenia illness.

Pixel-by-Pixel Comparison of Volume Transfer Constant and Estimates of Cerebral Blood Volume from Dynamic Contrast-Enhanced and Dynamic Susceptibility Contrast-Enhanced MR Imaging in High-Grade Gliomas.

BACKGROUND AND PURPOSE: Estimates of blood volume and volume transfer constant are parameters commonly used to characterize hemodynamic properties of brain lesions. The purposes of this study were to compare values of volume transfer constant and estimates of blood volume in high-grade gliomas on a pixel-by-pixel basis to comprehend whether they provide different information and to compare estimates of blood volume obtained by dynamic contrast-enhanced MR imaging and dynamic susceptibility contrast-enhanced MR imaging. MATERIALS AND METHODS: Thirty-two patients with biopsy-proved grade IV gliomas underwent dynamic contrast-enhanced MR imaging and dynamic susceptibility contrast-enhanced MR imaging, and parametric maps of volume transfer constant, plasma volume, and CBV maps were calculated. The Spearman rank correlation coefficients among matching values of CBV, volume transfer constant, and plasma volume were calculated on a pixel-by-pixel basis. Comparison of median values of normalized CBV and plasma volume was performed. RESULTS: Weak-but-significant correlation (P < .001) was noted for all comparisons. Spearman rank correlation coefficients were as follows: volume transfer constant versus CBV, ρ = 0.113; volume transfer constant versus plasma volume, ρ = 0.256; CBV versus plasma volume, ρ = 0.382. We found a statistically significant difference (P < .001) for the estimates of blood volume obtained by using dynamic contrast-enhanced MR imaging (mean normalized plasma volume, 13.89 ± 11.25) and dynamic susceptibility contrast-enhanced MR imaging (mean normalized CBV, 4.37 ± 4.04). CONCLUSIONS: The finding of a very weak correlation between estimates of microvascular density and volume transfer constant suggests that they provide different information. Estimates of blood volume obtained by using dynamic contrast-enhanced MR imaging are significantly higher than those obtained by dynamic susceptibility contrast-enhanced MR imaging in human gliomas, most likely due to the effect of contrast leakage.

Brain atrophy in natalizumab-treated patients: A 3-year follow-up.

BACKGROUND: A pseudoatrophy effect has been held responsible for the lack of net impact of natalizumab on brain volume outcomes in 2-year trials, but no data are available beyond 24 months. OBJECTIVE: We aimed to investigate brain volume dynamics in natalizumab-treated patients in up to 3 years after therapy initiation with clinical correlations. METHODS: Patients on natalizumab for at least 3 years were clinically assessed 3-monthly. Magnetic resonance imaging scans were performed at baseline and yearly. Brain volume changes were obtained with SIENA. Multivariate models were used to investigate the association between baseline inflammation and changes in brain volume and disability. RESULTS: Sixty-two patients with multiple sclerosis were analysed. Mean age and disease duration were 34.7 (SD: 8.3) and 10.4 (SD: 6.6) years. Presence of gadolinium enhancement at baseline was not associated with Expanded Disability Status Scale changes (p=0.468), but was associated with larger brain volume decreases (p=0.005) in the first (p=0.024) and second year (p=0.019) but not in the third year (p=0.863). Brain volume changes at 12 and 36 months were marginally associated with disability status at month 12 (p=0.094) and 36 (p=0.084), respectively. CONCLUSIONS: Baseline inflammation affects brain volume measures up to 24 months after natalizumab initiation. A marginal association of brain volume changes with disability is present.

Positron emission tomography with 11C-flumazenil in the rat shows preservation of binding sites during the acute phase after 2 h-transient focal ischemia.

BACKGROUND AND PURPOSE: Positron emission tomography (PET) studies in humans have used (11)C-flumazenil (FMZ) to assess neuronal viability after stroke. Here we aimed to study whether (11)C-FMZ binding was sensitive to neuronal damage in the acute phase following ischemia/reperfusion in the rat brain. EXPERIMENTAL PROCEDURES: Transient (2 h followed by reperfusion) and permanent intraluminal middle cerebral artery occlusion was carried out. (11)C-FMZ binding was studied by PET up to 24 h after the onset of ischemia. Tissue infarction was evaluated post-mortem at 24 h. Immunohistochemistry against a neuronal nuclei specific protein (NeuN) was performed to assess neuronal injury. RESULTS: No decrease in (11)C-FMZ binding was detected in the ipsilateral cortex up to 24 h post-ischemia in the model of transient occlusion despite the fact that rats developed cortical and striatal infarction, and neuronal injury was clearly apparent at this time. In contrast, (11)C-FMZ binding was significantly depressed in the ipsilateral cortex at 24 h following permanent ischemia. CONCLUSIONS: This finding evidences that (11)C-FMZ binding is not sensitive to neuronal damage on the acute phase of ischemia/reperfusion in the rat brain.

Consensus recommendations for MS cortical lesion scoring using double inversion recovery MRI.

BACKGROUND: Different double inversion recovery (DIR) sequences are currently used in multiple sclerosis (MS) research centers to visualize cortical lesions, making it difficult to compare published data. This study aimed to formulate consensus recommendations for scoring cortical lesions in patients with MS, using DIR images acquired in 6 European centers according to local protocols. METHODS: Consensus recommendations were formulated and tested in a multinational meeting. RESULTS: Cortical lesions were defined as focal abnormalities on DIR, hyperintense compared to adjacent normal-appearing gray matter, and were not scored unless ≥ 3 pixels in size, based on at least 1.0 mm(2) in-plane resolution. Besides these 2 obligatory criteria, additional, supportive recommendations concerned a priori artifact definition on DIR, use of additional MRI contrasts to verify suspected lesions, and a constant level of displayed image contrast. Robustness of the recommendations was tested in a small dataset of available, heterogeneous DIR images, provided by the different participating centers. An overall moderate agreement was reached when using the proposed recommendations: more than half of the readers agreed on slightly more than half (54%) of the cortical lesions scored, whereas complete agreement was reached in 19.4% of the lesions (usually larger, mixed white matter/gray matter lesions). CONCLUSIONS: Although not designed as a formal interobserver study, the current study suggests that comparing available literature data on cortical lesions may be problematic, and increased consistency in acquisition protocols may improve scoring agreement. Sensitivity and specificity of the proposed recommendations should now be studied in a more formal, prospective, multicenter setting using similar DIR protocols.