Laura Bonzano

Magnetic resonance imaging as a potential surrogate for relapses in multiple sclerosis: A meta-analytic approach†

The aim of this work was to evaluate whether the treatment effects on magnetic resonance imaging (MRI) markers at the trial level were able to predict the treatment effects on relapse rate in relapsing‐remitting multiple sclerosis.

Callosal Contributions to Simultaneous Bimanual Finger Movements

Corpus callosum (CC) is involved in the performance of bimanual motor tasks. We asked whether its functional role could be investigated by combining a motor behavioral study on bimanual movements in multiple sclerosis (MS) patients with a quantitative magnetic resonance diffusion tensor imaging (DTI) analysis of CC, which is shown to be damaged in this disease. MS patients and normal subjects were asked to perform sequences of bimanual finger opposition movements at different metronome rates; then we explored the structural integrity of CC by means of DTI. Significant differences in motor performance, mainly referred to timing accuracy, were observed between MS patients and control subjects. Bimanual motor coordination was impaired in MS patients as shown by the larger values of the interhand interval observed at all the tested metronome rates with respect to controls. Furthermore, DTI revealed a significant reduction of fractional anisotropy (FA), indicative of microstructural tissue damage, in the CC of MS patients. By correlating the mean FA values with the different motor behavior parameters, we found that the degree of damage in the anterior callosal portions mainly influences the bimanual coordination and, in particular, the movement phase preceding the finger touch. Finally, the described approach, which correlates quantitative measures of tissue damage obtained by advanced magnetic resonance imaging tools with appropriate behavioral measurements, may help the exploration of different aspects of motor performance impairment attributable to the disease.

Surrogate endpoints for EDSS worsening in multiple sclerosis. A meta-analytic approach.

Objective: To evaluate whether the effects on potential surrogate endpoints, such as MRI markers and relapses, observed in trials of experimental treatments are able to predict the effects of these treatments on disability progression as defined in relapsing-remitting multiple sclerosis (RRMS) trials. Methods: We used a pooled analysis of all the published randomized controlled clinical trials in RRMS reporting data on Expanded Disability Status Scale (EDSS) worsening and relapses or MRI lesions or both. We extracted data on relapses, MRI lesions, and the proportion of progressing patients. A regression analysis weighted on trial size and duration was performed to study the relationship between the treatment effect observed in each trial on relapses and MRI lesions and the observed treatment effect on EDSS worsening. Results: A set of 19 randomized double-blind controlled trials in RRMS were identified, for a total of 44 arms, 25 contrasts, and 10,009 patients. A significant correlation was found between the effect of treatments on relapses and the effect of treatments on EDSS worsening: the adjusted R2 value of the weighted regression was 0.71. The correlation between the treatment effect on MRI lesions and EDSS worsening was slightly weaker (R2 = 0.57) but significant. Conclusions: These findings support the use of commonly used surrogate markers of EDSS worsening as endpoints in multiple sclerosis clinical trials. Further research is warranted to validate surrogate endpoints at the individual level rather than at the trial level, to draw important conclusions in the management of the individual patient.

Detection of motor cortex thinning and corticospinal tract involvement by quantitative MRI in amyotrophic lateral sclerosis

We prospectively investigated pathological modifications in the corticospinal tract (CST), by diffusion tensor imaging (DTI) in 14 patients with sporadic amyotrophic lateral sclerosis (ALS) and 12 healthy volunteers. We used a validated automated method to accurately measure the in vivo thickness of the cerebral cortex. We found a reduction of precentral cortical ribbon thickness in ALS patients with respect to control subjects. DTI metrics demonstrated disorganization of the CST, as characterized by decreased fractional anisotropy (FA) and increased Apparent Diffusion Coefficient in ALS patients with respect to control subjects. Decreased mean FA values along the CST significantly correlated with clinical measures of pyramidal and bulbar impairment. Quantitative analysis of MR data shows that thinning of the motor cortex coexists with CST damage in ALS patients.

Multiple Sclerosis: Hyperintense Dentate Nucleus on Unenhanced T1-weighted MR Images Is Associated with the Secondary Progressive Subtype

PURPOSE To describe the occurrence of abnormal hyperintensity in the dentate nucleus on T1-weighted magnetic resonance (MR) images in patients with multiple sclerosis (MS) as a neuroradiologic sign of gray matter involvement. Presence of the finding was evaluated for association with disability, clinical MS subtype, total lesion volume on T1- and T2-weighted MR images (lesion load), and brain atrophy. MATERIALS AND METHODS Written informed consent was waived by the Ethics Committee because of the retrospective nature of this single-center Institutional Review Board-approved study. MR examinations of 185 patients with MS were reviewed, and 119 patients were included for analysis. Two neuroimagers, who were blinded to clinical data, assessed the presence of a hyperintense dentate nucleus on T1-weighted MR images. The presence of this radiologic alteration was then evaluated in relation to MS subtype, clinical disability, T1 and T2 lesion load, and whole-brain atrophy measurements. Fisher exact, chi(2), and Mann-Whitney U tests were used to evaluate differences in clinical and imaging features between patients with and those without a T1 hyperintense dentate nucleus. RESULTS Twenty-three (19.3%) of the 119 patients had a hyperintense dentate nucleus on unenhanced T1-weighted MR images. This finding was related to the secondary progressive subtype of the disease, a higher score on the Expanded Disability Status Scale, a higher brain lesion load, and tissue loss. None of the patients with primary progressive MS had a hypterintense dentate nucleus. CONCLUSION Hyperintensity of the dentate nucleus may be present on unenhanced T1-weighted MR images of patients with MS and is associated with the secondary progressive disease subtype and with increased clinical disability, lesion load, and brain atrophy.

Cortical cultures coupled to micro-electrode arrays: a novel approach to perform in vitro excitotoxicity testing.

In vitro neuronal cultures exhibit spontaneous electrophysiological activity that can be modulated by chemical stimulation and can be monitored over time by using Micro-Electrode Arrays (MEAs), devices composed by a glass substrate and metal electrodes. Dissociated networks respond to transmitters, their blockers and many other pharmacological substances, including neurotoxic compounds. In this paper we present results related to the effects, both acute (i.e. 1 hour after the treatment) and chronic (3 days after the treatment), of increasing glutamatergic transmission induced by the application of rising concentrations of glutamate and its agonists (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid - AMPA, N-methyl-D-aspartate - NMDA and AMPA together with cyclothiazide - CTZ). Increase of available glutamate was obtained in two ways: 1) by direct application of exogenous glutamate and 2) by inhibiting the clearance of the endogenously released glutamate through DL-threo-β-benzyloxyaspartate (TBOA). Our findings show that fine modulations (i.e. low concentrations of drug) of the excitatory synaptic transmission are reflected in the electrophysiological activation of the network, while intervention leading to excessive direct stimulation of glutamatergic pathways (i.e. medium and high concentrations of drug) results in the abolishment of the electrophysiological activity and eventually cell death. The results obtained by means of the MEA recordings have been compared to the analysis of cell viability to confirm the excitotoxic effect of the applied drug. In conclusion, our study demonstrates that MEA-coupled cortical networks are very sensitive to pharmacological manipulation of the excitatory ionotropic glutamatergic transmission and might provide sensitive endpoints to detect acute and chronic neurotoxic effects of chemicals and drugs for predictive toxicity testing.

Frontal networks play a role in fatigue perception in multiple sclerosis.

Fatigue, an overwhelming lack of physical or mental energy, is a common complaint in patients affected by multiple sclerosis (MS). Although different mechanisms have been proposed to explain MS-related fatigue, injury of distinct anatomical networks seems to be relevant in fatigue etiology. Particularly, theories point to fronto-striatal network pathological changes as a possible neural basis of fatigue. To investigate the role of fronto-striatal white matter structural alterations in fatigue perception we prospectively recruited 40 relapsing remitting patients with MS and 15 healthy controls. In patients with MS, fatigue was assessed using a validated measure, the Modified Fatigue Impact Scale (MFIS; Kos et al., 2005). Brain MRI scans were acquired for each subject enrolled with diffusion tensor imaging. Diffusion tensor data were correlated with MFIS scores using voxel-wise analysis of fractional anisotropy maps and fiber tractography algorithms. A significant cluster of voxels correlating with fatigue scores located in the deep left frontal white matter was identified. Fiber tractography revealed the cluster to be included in a complex fronto-frontal, fronto-striatal, fronto-occipital, and fronto-limbic network. Structural properties of the traced white matter fiber bundles correlated with fatigue perception and patients with clinically relevant fatigue were found to present reduced white matter integrity in the aforementioned tracts compared to those with lower levels of fatigue. Our observations show a significant involvement of different frontal networks in the pathophysiology of fatigue, thus accounting for the multifaceted nature of this disabling symptom.

Structural connectivity influences brain activation during PVSAT in Multiple Sclerosis

To assess the influence of white matter pathology on cortical reorganization, we probed the fronto-parietal attention network in Multiple Sclerosis (MS) patients by combining the Paced Visual Serial Addition Test (PVSAT) with fMRI-guided fiber tractography (FT). During the PVSAT, the control subjects activated the left inferior parietal lobule, superior temporal gyrus, precuneus, precentral gyrus, and medial and middle frontal gyri; while the precuneus and the inferior parietal lobule gyrus bilaterally, the left precentral and angular gyri and the right superior parietal lobule were activated in the MS group. At fMRI-guided FT, the superior longitudinal fasciculus (SLF) was the main white matter tract connecting areas active during the PVSAT. We then identified two subgroups of MS patients according to the SLF mean Fractional Anisotropy, used as indicator of integrity. The activations of the MS patients with a less damaged tract were in the left hemisphere, similarly to controls; while the patients with a more damaged SLF showed bilateral cortical activations. The MS subgroups, however, did not differ in PVSAT performance. This approach could be useful to investigate the relationship between brain structural and functional plastic changes and to identify different MRI endophenotypes related to the same level of cognitive impairment.

The long-term effect of AHSCT on MRI measures of MS evolution: A five-year follow-up study

Using MRI, we measured disease activity and brain atrophy in nine multiple sclerosis patients treated with autologous hematopoietic stem cell transplantation (AHSCT) for a mean follow up of 63 months. We show that AHSCT is associated to a longlasting suppression of inflammation and to a marked decrease of the rate of brain atrophy after the second year following treatment. Multiple Sclerosis 2007; 13 : 1068—1070. http://msj.sagepub.com

Diagnostic accuracy of diffusion tensor imaging in amyotrophic lateral sclerosis: A systematic review and individual patient data meta-analysis

RATIONALE AND OBJECTIVES There have been a large number of case-control studies using diffusion tensor imaging (DTI) in amyotrophic lateral sclerosis (ALS). The objective of this study was to perform an individual patient data (IPD) meta-analysis for the estimation of the diagnostic accuracy measures of DTI in the diagnosis of ALS using corticospinal tract data. MATERIALS AND METHODS MEDLINE, EMBASE, CINAHL, and Cochrane databases (1966-April 2011) were searched. Studies were included if they used DTI region of interest or tractography techniques to compare mean cerebral corticospinal tract fractional anisotropy values between ALS subjects and healthy controls. Corresponding authors from the identified articles were contacted to collect individual patient data. IPD meta-analysis and meta-regression were performed using Stata. Meta-regression covariate analysis included age, gender, disease duration, and Revised Amyotrophic Lateral Sclerosis Functional Rating Scale scores. RESULTS Of 30 identified studies, 11 corresponding authors provided IPD and 221 ALS patients and 187 healthy control subjects were available for study. Pooled area under the receiver operating characteristic curve (AUC) was 0.75 (95% CI: 0.66-0.83), pooled sensitivity was 0.68 (95% CI: 0.62-0.75), and pooled specificity was 0.73 (95% CI: 0.66-0.80). Meta-regression showed no significant differences in pooled AUC for each of the covariates. There was moderate to high heterogeneity of pooled AUC estimates. Study quality was generally high. Data from 19 of the 30 eligible studies were not ascertained, raising possibility of selection bias. CONCLUSION Using corticospinal tract individual patient data, the diagnostic accuracy of DTI appears to lack sufficient discrimination in isolation. Additional research efforts and a multimodal approach that also includes ALS mimics will be required to make neuroimaging a critical component in the workup of ALS.