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The Italian Neuroimaging Network Initiative (INNI) supports the creation of a repository, where MRI, clinical, and neuropsychological data from multiple sclerosis (MS) patients and healthy controls are collected from Italian Research Centers with internationally recognized expertise in MRI applied to MS. However, multicenter MRI data integration needs standardization and quality control (QC). This study aimed to implement quantitative measures for characterizing the standardization and quality of MRI collected within INNI. MRI scans of 423 MS patients, including 3D T1- and T2-weighted, were obtained from INNI repository (from Centers A, B, C, and D). QC measures were implemented to characterize: (1) head positioning relative to the magnet isocenter; (2) intensity inhomogeneity; (3) relative image contrast between brain tissues; and (4) image artefacts. Centers A and D showed the most accurate subject positioning within the MR scanner (median z-offsets = − 2.6 ± 1.7cm and − 1.1 ± 2cm). A low, but significantly different, intensity inhomogeneity on 3D T1-weighted MRI was found between all centers (p < 0.05), except for Centers A and C that showed comparable image bias fields. Center D showed the highest relative contrast between gray and normal appearing white matter (NAWM) on 3D T1-weighed MRI (0.63 ± 0.04), while Center B showed the highest relative contrast between NAWM and MS lesions on FLAIR (0.21 ± 0.06). Image artefacts were mainly due to brain movement (60%) and ghosting (35%). The implemented QC procedure ensured systematic data quality assessment within INNI, thus making available a huge amount of high-quality MRI to better investigate pathophysiological substrates and validate novel MRI biomarkers in MS.

The author(s) disclosed receipt of the following financial support for the research, authorship and/or publication of this article: This research has been supported by a programme grant (14-358e) from the Dutch MS Research Foundation (Voorschoten, The Netherlands). The study in London was supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre. Background: Compared to 1.5 T, 3 T magnetic resonance imaging (MRI) increases signal-to-noise ratio leading to improved image quality. However, its clinical relevance in clinically isolated syndrome suggestive of multiple sclerosis remains uncertain. Objectives: The purpose of this study was to investigate how 3 T MRI affects the agreement between raters on lesion detection and diagnosis. Methods: We selected 30 patients and 10 healthy controls from our ongoing prospective multicentre cohort. All subjects received baseline 1.5 and 3 T brain and spinal cord MRI. Patients also received follow-up brain MRI at 3-6 months. Four experienced neuroradiologists and four less-experienced raters scored the number of lesions per anatomical region and determined dissemination in space and time (McDonald 2010). Results: In controls, the mean number of lesions per rater was 0.16 at 1.5 T and 0.38 at 3 T (p = 0.005). For patients, this was 4.18 and 4.40, respectively (p = 0.657). Inter-rater agreement on involvement per anatomical region and dissemination in space and time was moderate to good for both field strengths. 3 T slightly improved agreement between experienced raters, but slightly decreased agreement between less-experienced raters. Conclusion: Overall, the interobserver agreement was moderate to good. 3 T appears to improve the reading for experienced readers, underlining the benefit of additional training.

Background To investigate serum concentrations of high-sensitive C-reactive protein (CRP) and alpha(1)-acid glycoprotein (AGP) in patients with T1DM, at diagnosis and after 12 months of intensive insulin therapy (T12). Methods CRP and AGP were measured in 44 recent onset T1DM patients (26M/18F, mean age 14.9 ± 9.1 years), and 44 age- and sex-matched controls, using a highly sensitive immunonephelometric assay. Results There were no significant differences in the concentrations of high-sensitive C-reactive protein (hs-CRP) and AGP between patients and controls. hs-CRP levels significantly increased in patients at T12 compared to the levels at diagnosis [0.69 (0.14–15.5) versus 0.43 (0.14–7.47) mg/L, p < 0.05; for males: 0.77 (0.14–15.5) versus 0.35 (0.14–7.47) mg/L, p < 0.05; for females the increase was not significant]. AGP levels were not different at T12 compared to diagnosis. No significant correlations were found between hs-CRP and body mass index (BMI), C-peptide, glycosylated haemoglobin, or insulin dose. A strong correlation was found between hs-CRP values at diagnosis and those at T12 (ρ = 0.73, p < 0.001); indeed, patients with hs-CRP levels above the 50th percentile at diagnosis showed significantly increased hs-CRP values at T12 compared to patients with baseline hs-CRP levels under the 50th percentile [1.61 (0.18–15.5) versus 0.16 (0.14–1.92) mg/L, p < 0.0001)], and to controls [0.55 (0.14–6.50), p = 0.001]. Conclusions This is the first report showing that, despite good metabolic control, 1 year of overt T1DM is sufficient to increase hs-CRP levels, especially in males. hs-CRP levels at diagnosis is a predictor for the values observed at 12 months, suggesting the possibility to select a subgroup of patients requiring strict follow-up for cardiovascular complications. Copyright © 2006 John Wiley & Sons, Ltd.

The present study was planned to investigate the relationship between the plasma lipid profile and disease activity in patients with a first clinical episode suggestive of multiple sclerosis (MS).Eighteen consecutive out-patients underwent a monthly brain magnetic resonance imaging (MRI), blood sample and neurological assessment over 6 months. Blood samples were used to evaluate total cholesterol and triglyceride levels as well as their lipoprotein fractions. Plasma total apolipoprotein E concentration was also determined.We found a significant correlation between the mean number of enhancing lesions and the mean plasma level of both total and low density lipoprotein cholesterol. The total plasma cholesterol level increased on average by 4.4 mg/dl for each enhancing lesion.Our preliminary data suggest a potential role of plasma cholesterol level as a biological marker of disease activity after a first demyelinating event. Further studies need, however, to be designed to determine whether the plasma cholesterol level is of practical use in monitoring the disease course.

We used positron emission tomography to study the effects of unilateral vascular thalamic lesions on cortical oxygen or glucose utilisation in 10 patients. There was a significant ipsilateral cortex hypometabolism in 9 of the 10 patients, affecting diffusely the whole cortical mantle. The only patient spared was free of neuropsychological deficit at time of PET study. In 4 patients, the magnitude of ipsilateral cortical hypometabolism was significantly less at follow-up PET study, together with improved neuropsychological function. When plotted altogether, the 14 studies showed a significant tendency for the hypometabolism to improve with time elapsed since clinical onset. On the whole, these data suggest that the ipsilateral cortical hypometabolism reflects an essentially functional alteration an not only a degenerating process. This most likely indicates a cortical deafferentation due to loss of non-specific thalamo-cortical connections, i.e. a phenomenon akin to "diaschisis". However, a causal relationship between cortical hypometabolism and neuropsychological deficit cannot be firmly established from the present data.

We describe the case of a young man who, despite the presence of a tumour in the left sensorimotor cortex, exhibited no motor deficit. Integrated MRI/SPECT-CBF study during motor activation was aimed at determining which cerebral areas were involved in movement execution in this patient and their relationship with the tumour. CBF changes during motor activation were located in two motor areas: anteriorly and medially to the tumour in the left frontal lobe (+29%) and in the right medial frontal cortex (+43%). Integrated MRI/SPECT images provided both an anatomical and functional definition of the motor areas in a patient with a rolandic tumour and could prove useful in determining preoperatively an appropriate surgical strategy.

BACKGROUND AND PURPOSE: The use of MR angiography and contrast-enhanced T1-weighted MR imaging in cases of acute cerebral ischemia may be helpful in the evaluation of middle cerebral artery (MCA) occlusion and leptomeningeal collaterals, respectively. The aim of our work was to investigate the relationship between MCA occlusion, T1-weighted vascular contrast enhancement, hemodynamic alterations, and tissue damage in cases of acute ischemic stroke. METHODS: We studied the MCA territory in 15 patients with acute ischemic stroke within 8 hr of symptom onset. The first MR imaging study (

International audience; OBJECTIVE: Involvement of the central nervous system (CNS) in patients with hepatitis C virus (HCV) mixed cryoglobulinemia (MC) is rare. The mechanism by which brain lesions are produced is unclear. We investigated these phenomena by clinical evaluation (neuropsychological tests) and cerebral magnetic resonance imaging (MRI) studies in patients with HCV-MC vasculitis. METHODS: This prospective study included 40 patients with MC vasculitis and chronic active HCV infection (HCV RNA+), 11 HCV controls without MC, and 36 healthy controls, matched for sex and age. A battery of 10 standardized neuropsychological tests was administered by one experienced neuropsychiatrist. All patients underwent cerebral MRI investigation. RESULTS: Twenty-four of the 27 (89%) evaluated patients with HCV-MC had a deficiency in one or more of the 10 cognitive domains examined. The most commonly involved domains were those of attention (70%), executive functions (44%), visual construction (37%), and visual spatial functions (33%). The number of impaired cognitive functions was significantly higher in patients with MC vasculitis than in HCV controls (2.18 +/- 1.84 vs 0.87 +/- 3.1; p < 0.05). MRI analysis showed that HCV-MC patients had a higher mean number of total (7.03 +/- 9.9 vs 0.90 +/- 1.81 and 2.03 +/- 3.1; p < 0.05) and periventricular (2.4 +/- 3.0 vs 0.38 +/- 0.5 and 0.8 +/- 1.4; p < 0.05) white matter high intensity signals than HCV controls and healthy controls, respectively. CONCLUSION: The high frequency of impaired cognitive function and the extent of MRI brain abnormalities in patients with HCV-associated mixed cryoglobulinemia vasculitis strongly suggest specific inflammatory involvement of the CNS.

Many patients with multiple sclerosis (MS) experience information processing speed (IPS) deficits, and the Symbol Digit Modalities Test (SDMT) has been recommended as a valid screening test. Magnetic resonance imaging (MRI) has markedly improved the understanding of the mechanisms associated with cognitive deficits in MS. However, which structural MRI markers are the most closely related to cognitive performance is still unclear. We used the multicenter 3T-MRI data set of the Italian Neuroimaging Network Initiative to extract multimodal data (i.e., demographic, clinical, neuropsychological, and structural MRIs) of 540 MS patients. We aimed to assess, through machine learning techniques, the contribution of brain MRI structural volumes in the prediction of IPS deficits when combined with demographic and clinical features. We trained and tested the eXtreme Gradient Boosting (XGBoost) model following a rigorous validation scheme to obtain reliable generalization performance. We carried out a classification and a regression task based on SDMT scores feeding each model with different combinations of features. For the classification task, the model trained with thalamus, cortical gray matter, hippocampus, and lesions volumes achieved an area under the receiver operating characteristic curve of 0.74. For the regression task, the model trained with cortical gray matter and thalamus volumes, EDSS, nucleus accumbens, lesions, and putamen volumes, and age reached a mean absolute error of 0.95. In conclusion, our results confirmed that damage to cortical gray matter and relevant deep and archaic gray matter structures, such as the thalamus and hippocampus, is among the most relevant predictors of cognitive performance in MS.

BACKGROUND AND PURPOSE: Conventional MR imaging explains only a fraction of the clinical outcome variance in multiple sclerosis. We aimed to evaluate machine learning models for disability prediction on the basis of radiomic, volumetric, and connectivity features derived from routine brain MR images. MATERIALS AND METHODS: In this retrospective cross-sectional study, 3T brain MR imaging studies of patients with multiple sclerosis, including 3D T1-weighted and T2-weighted FLAIR sequences, were selected from 2 institutions. T1-weighted images were processed to obtain volume, connectivity score (inferred from the T2 lesion location), and texture features for an atlas-based set of GM regions. The site 1 cohort was randomly split into training (n = 400) and test (n = 100) sets, while the site 2 cohort (n = 104) constituted the external test set. After feature selection of clinicodemographic and MR imaging–derived variables, different machine learning algorithms predicting disability as measured with the Expanded Disability Status Scale were trained and cross-validated on the training cohort and evaluated on the test sets. The effect of different algorithms on model performance was tested using the 1-way repeated-measures ANOVA. RESULTS: The selection procedure identified the 9 most informative variables, including age and secondary-progressive course and a subset of radiomic features extracted from the prefrontal cortex, subcortical GM, and cerebellum. The machine learning models predicted disability with high accuracy (r approaching 0.80) and excellent intra- and intersite generalizability (r ≥ 0.73). The machine learning algorithm had no relevant effect on the performance. CONCLUSIONS: The multidimensional analysis of brain MR images, including radiomic features and clinicodemographic data, is highly informative of the clinical status of patients with multiple sclerosis, representing a promising approach to bridge the gap between conventional imaging and disability.

Objective The process of diagnosing many neurodegenerative diseases, such as Parkinson's and progressive supranuclear palsy, involves the study of brain magnetic resonance imaging (MRI) scans in order to identify and locate morphological markers that can highlight the health status of the subject. A fundamental step in the pre-processing and analysis of MRI scans is the identification of the mid-sagittal plane, which corresponds to the mid-brain and allows a coordinate reference system for the whole MRI scan set. Approach To improve the identification of the mid-sagittal plane we have developed an algorithm in Matlab® based on the k-means clustering function. The results have been compared with the evaluation of four experts who manually identified the mid-sagittal plane and whose performances have been combined with a cognitive decisional algorithm in order to define a gold standard. Main results The comparison provided a mean percentage error of 1.84%. To further refine the automatic procedure we trained a machine learning system using the results from the proposed algorithm and the gold standard. We tested this machine learning system and obtained results comparable to medical raters with a mean absolute error of 1.86 slices. Significance The system is promising and could be directly incorporated into broader diagnostic support systems.

Magnetic resonance imaging (MRI) is an important paraclinical tool to diagnose and monitor multiple sclerosis (MS). Conventional MRI measures lack of pathological specificity and are weakly correlated with MS clinical manifestations. Advanced MRI techniques are improving the understanding of the mechanisms underlying tissue injury, repair, and functional adaptation in MS; however, they require careful standardization. The definition of standardized methods for the collection and analysis of advanced MRI techniques is central not only to improve the understanding of disease pathophysiology and evolution, but also to generate research hypotheses, monitor treatment, increase cost-effectiveness and power of clinical trials. We promoted the Italian Neuroimaging Network Initiative (INNI), involving centers and investigators with an International recognized expertise, with the major goal to determine and validate novel MRI biomarkers to be utilized as predictors and/or outcomes in future MS studies. The INNI initiative supported the creation of a centralized repository, where advanced structural and functional MRI scans available at the participating sites, with the related clinical and neuropsychological data, are collected. These data will be used to perform research studies to identify clinical, neuropsychological and imaging biomarkers characteristics of the entire spectrum of MS. INNI will be instrumental to help to define standardized MRI and clinical protocols towards an increasing uptake of personalized interventions for people with MS at a national and international level. Upon approval of the INNI Steering Committee, the data collected in the online database will be shared with any research center detailing specific research proposals on disease pathophysiology or treatment effects.

In this paper we derive a reaction-diffusion-chemotaxis model for the dynamics of multiple sclerosis. We focus on the early inflammatory phase of the disease characterized by activated local microglia, with the recruitment of a systemically activated immune response, and by oligodendrocyte apoptosis. The model consists of three equations describing the evolution of macrophages, cytokine and apoptotic oligodendrocytes. The main driving mechanism is the chemotactic motion of macrophages in response to a chemical gradient provided by the cytokines. Our model generalizes the system proposed by Calvez and Khonsari (Math Comput Model 47(7–8):726–742, 2008) and Khonsari and Calvez (PLos ONE 2(1):e150, 2007) to describe Balo’s sclerosis, a rare and aggressive form of multiple sclerosis. We use a combination of analytical and numerical approaches to show the formation of different demyelinating patterns. In particular, a Turing instability analysis demonstrates the existence of a threshold value for the chemotactic coefficient above which stationary structures develop. In the case of subcritical transition to the patterned state, the numerical investigations performed on a 1-dimensional domain show the existence, far from the bifurcation, of complex spatio-temporal dynamics coexisting with the Turing pattern. On a 2-dimensional domain the proposed model supports the emergence of different demyelination patterns: localized areas of apoptotic oligodendrocytes, which closely fit existing MRI findings on the active MS lesion during acute relapses; concentric rings, typical of Balo’s sclerosis; small clusters of activated microglia in absence of oligodendrocytes apoptosis, observed in the pathology of preactive lesions.

Regional cerebral and cerebellar blood flows were studied by N, N, N'-trimethyl- N'-(2-hydroxy-3-methyl-5-[123I]iodobenzyl)-1,3-propanediamine 2 HC1 (1-123 HIPDM) and single-photon emission computerized tomography (SPECT) in a patient with an ischemic lesion of the pons. An asymmetry of perfusion of the cerebellar hemispheres, normal on transmission computerized tomography scan, was demonstrated by SPECT studies in the early acute phase and confirmed 15 days after. This finding may be related to the interruption of the corticopontocerebellar pathways.

The remote effects of small unilateral cerebrovascular lesions confined to subcortical structures were evaluated by single photon emission computerized tomography (SPECT) and a CBF tracer, I-123 HIPDM. A CBF study was performed in 34 patients presenting with subcortical stroke either in the acute or in the chronic stages. Twenty-one of the 34 patients showed areas of cortical hypoperfusion ipsilateral to the subcortical lesion. In 14 patients, asymmetry of perfusion was also observed at the cerebellar level, perfusion being significantly reduced in the cerebellar hemisphere contralateral to the lesion. There was no correlation between the degree and extension of these remote effects and the type of stroke (ischemic or hemorrhagic), the patency of cerebral arteries, or the size and site of the lesion by transmissive computerized tomography (TCT). Subcortical hematomas showed a correlation between occurrence of remote effects and time interval from the onset of stroke, occurring more frequently in the acute phase. A correlation was observed between cortical and cerebellar remote effects and the severity of clinical presentation. The causes of remote effects are still unclear and have been extensively debated. Our data indicate that there is a relationship of remote effect to the neurological status. It is possible to show, by noninvasive, low-cost methods, remote CBF effects after stroke that may contribute to the assessment of brain functional impairment.

BACKGROUND AND PURPOSE: Psychiatric symptoms occur in approximately 30% of patients with MS. Such symptoms include OCD, which may interfere heavily with the patient9s daily life. We hypothesized that the widespread involvement of both GM and WM, which characterizes MS, may be responsible for the occurrence of OCD when specific brain structures are affected. The aim of this study was to evaluate the relationship between GM and WM tissue damage and OCD in patients with MS. MATERIALS AND METHODS: We evaluated 16 patients with relapsing-remitting MS who had been diagnosed with OCD on the basis of the Diagnostic and Statistical Manual of Mental Disorders (4th edition) and 15 age- and sex-matched patients with relapsing-remitting MS with no psychiatric disorders as a CG. The MR study (1.5T) included 3D T1-weighted fast-field echo sequences, DTI (32 directions), and conventional MRI. Images were processed using SPM5, FSL, and Jim 5.0 software to evaluate VBM, TBSS, and global and regional LV, respectively. RESULTS: The VBM analysis revealed a set of clusters of reduced GM volume in the OCD group, compared with the CG, located in the right inferior and middle temporal gyri and in the inferior frontal gyrus. TBSS did not detect any differences in the FA values between the 2 groups; global and regional LV values also did not differ significantly between the 2 groups. CONCLUSIONS: Our study suggests that OCD in MS may be caused by damage in the right frontotemporal cortex.

MRI is highly sensitive in detecting focal white matter lesions in multiple sclerosis (MS). For this reason, it has been formally included in the diagnostic workup of patients with clinically isolated syndromes suggestive of MS, through the definition of ad hoc sets of criteria to show disease dissemination in space and time. MRI is used in virtually all clinical trials of the disease as a surrogate measure of treatment response. Several guidelines have been published to help characterizing the imaging features on conventional MR sequences of "typical" MS lesions and work has also been performed to identify "red flags" which should alert the clinicians to exclude possible alternative conditions. Despite this, the application of the available guidelines and criteria in daily life clinical practice is still limited and varies among and within countries (including Italy) due to regulatory issues and heterogeneity of MRI facilities. It is crucial for neurologists and neuroradiologists to become familiar with these criteria to improve the quality of their diagnostic assessment. In patients with established MS, the main problem is to define standard procedures for monitoring the course of the disease and treatment response. This review aims at providing daily life guidelines to clinicians for a correct application of MRI in the workup of patients suspected of having MS as well as in the monitoring of disease evolution in those with established MS. It also offers clues for the standardization of MRI studies and relative reporting to be applied at a national level.

Amnestic mild cognitive impairment (a-MCI) is associated with the highest annual incidence of conversion to Alzheimer's disease (AD) (10-15%). a-MCI patients may have only a memory deficit (single domain: sd-a-MCI) or additional dysfunctions affecting other cognitive domains (multiple domain: md-a-MCI). Using functional magnetic resonance imaging (fMRI), we investigated brain activation in 16 sd-a-MCI patients and 14 controls during four different tasks assessing language, memory, attention and empathy functions. We found greater activation in sd-a-MCI compared with controls in the left inferior temporal gyrus (language), the right superior temporal gyrus (memory) and the right dorsal precentral gyrus (attention). Moreover, patients' activation correlated significantly with neuropsychological scores obtained at tests exploring the corresponding function. These findings indicate that fMRI is sensitive to detect early changes occurring in AD pathology and that individuals with sd-a-MCI show increased activation in multiple task-related brain regions. We suggest that these functional changes relate to the development of early compensatory mechanisms that reduce cognitive deficits associated with the progressive accumulation of brain damage.

Crossed cerebellar diaschisis (CCD) was investigated in a series of 59 patients (34 completed strokes and 25 reversible ischemic attacks, RIAs) using single photon emission computerized tomography (SPECT) with 123I-HIPDM as a cerebral blood flow (CBF) indicator. CCD was present in 17 (50%) of the patients with completed stroke and in 6 (24%) of the patients with RIAs. CCD was significantly correlated to the clinical severity (p less than 0.001) and to the extension of the supratentorial lesion (p less than 0.05). However, CCD was also recorded in 3 out of 16 patients with normal neurological examination and CT scan, suggesting that a 'functional' hemispheric disturbance may be sufficient to produce a remote effect on the contralateral cerebellar hemisphere. Time elapsed between the clinical onset and SPECT study was not critical, since CCD was recorded in the acute as well as in chronic studies. Follow-up SPECT studies showed that CCD disappeared in 5 out of 18 patients after a successful extra-intracranial bypass, while a spontaneous recovery was observed in only one of 16 nonsurgical patients.