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SUMMARY: In this study, we used a multiparametric MR imaging approach to assess a patient with Hirayama disease (HD). We found that cervical cord damage extends beyond cord T2-visible lesions. We also showed an altered pattern of cortical activations during movements of clinically unaffected limbs. Whereas this study suggests a more widespread cord involvement in HD than seen on routine MR imaging, its cause remains unclear (vascular damage versus a primary lower motor neuron disease).

OBJECTIVE: Recent findings support greater efficacy of early vs. delayed interferon beta (IFNbeta) treatment in patients with a first clinical event suggestive of multiple sclerosis (MS). We aimed to evaluate the effectiveness of early IFNbeta treatment in definite relapsing-remitting MS (RRMS) and to assess the optimal time to initiate IFNbeta treatment with regard to the greatest benefits on disability progression. METHODS: A cohort of 2,570 IFNbeta-treated RRMS patients was prospectively followed for up to 7 years in 15 Italian MS Centers. A Cox proportional hazards regression model adjusted for propensity score (PS) quintiles was used to assess differences between groups of patients with early vs. delayed IFNbeta treatment on risk of reaching a 1-point progression in the Expanded Disability Status Scale (EDSS) score, and the EDSS 4.0 and 6.0 milestones. A set of PS-adjusted Cox hazards regression models were calculated according to different times of treatment initiation (within 1 year up to within 5 years from disease onset). A sensitivity analysis was performed to assess the robustness of findings. RESULTS: The lowest hazard ratios (HRs) for the three PS quintiles-adjusted models were obtained by a cutoff of treatment initiation within 1 year from disease onset. Early treatment significantly reduced the risk of reaching a 1-point progression in EDSS score (HR = 0.63; 95% CI = 0.48-0.85; p < 0.002), and the EDSS 4.0 milestone (HR = 0.56; 95% CI = 0.36-0.90; p = 0.015). Sensitivity analysis showed the bound of significance for unmeasured confounders. INTERPRETATION: Greater benefits on disability progression may be obtained by an early IFNbeta treatment in RRMS.

To define the extent of overall brain damage in patients with clinically isolated syndromes (CIS) suggestive of multiple sclerosis (MS) and to identify non-conventional magnetic resonance (MR) metrics predictive of evolution to definite MS. Brain conventional and magnetization transfer (MT) MRI scans were obtained from 208 CIS patients and 55 matched healthy controls, recruited in four centres. Patients were assessed clinically at the time of MRI acquisition and after a median period of 3.1 years from disease onset. The following measures were derived: T2, T1 and gadolinium (Gd)- enhancing lesion volumes (LV), normalized brain volume (NBV), MTR histogram-derived quantities of the normal-appearing white matter (NAWM) and grey matter (GM). During the follow-up, 43 % of the patients converted to definite MS. At baseline, a significant inter-centre heterogeneity was detected for T2 LV (p = 0.003), T1 LV (p = 0.006), NBV (p < 0.001) and MTR histogram-derived metrics (p < 0.001). Pooled average MTR values differed between CIS patients and controls for NAWM (p = 0.003) and GM (p = 0.01). Gdactivity and positivity of International Panel (IP) criteria for disease dissemination in space (DIS), but not NAWM and GM MTR and NBV, were associated with evolution to definite MS. The final multivariable model retained only MRI IP criteria for DIS (p = 0.05; HR = 1.66, 95 % CI = 1.00–2.77) as an independent predictor of evolution to definite MS. Although irreversible tissue injury is present from the earliest clinical stages of MS, macroscopic focal lesions but not "diffuse" brain damage measured by MTR are associated to an increased risk of subsequent development of definite MS in CIS patients.

Metaglidasen is a fibrate-like drug reported as a selective modulator of peroxisome proliferator-activated receptor γ (PPARγ), able to lower plasma glucose levels in the absence of the side effects typically observed with thiazolidinedione antidiabetic agents in current use. Herein we report an improved synthesis of metaglidasen's metabolically active form halofenic acid (R)-2 and that of its enantiomer (S)-2. The activity of the two stereoisomers was carefully examined on PPARα and PPARγ subtypes. As expected, both showed partial agonist activity toward PPARγ; the investigation of PPARα activity, however, led to unexpected results. In particular, (S)-2 was found to act as a partial agonist, whereas (R)-2 behaved as an antagonist. X-ray crystallographic studies with PPARγ were carried out to gain more insight on the molecular-level interactions and to propose a binding mode. Given the adverse effects provoked by fibrate drugs on skeletal muscle function, we also investigated the capacity of (R)-2 and (S)-2 to block conductance of the skeletal muscle membrane chloride channel. The results showed a more beneficial profile for (R)-2, the activity of which on skeletal muscle function, however, should not be overlooked in the ongoing clinical trials studying its long-term effects.

The preparation of a new series of 2-aryloxy-3-phenyl-propanoic acids, resulting from the introduction of a linker into the diphenyl system of the previously reported PPAR alpha/gamma dual agonist 1, allowed the identification of new ligands with improved potency on PPAR alpha and unchanged activity on PPAR gamma. For the most interesting stereoisomers S-2 and S-4, X-ray studies in PPAR gamma and docking experiments in PPAR alpha provided a molecular explanation for their different behavior as full and partial agonists of PPAR alpha and PPAR gamma, respectively. Due to the adverse effects provoked by hypolipidemic drugs on skeletal muscle function, we also investigated the blocking activity of S-2 and S-4 on skeletal muscle membrane chloride channel conductance and found that these ligands have a pharmacological profile more beneficial compared to fibrates currently used in therapy.

Using diffusion tensor (DT) tractography, we quantified optic radiation (OR) structural changes in seven migraine patients with (MA) and eight without visual aura (MoA) and their relation to clinical manifestations and T2-visible burden. The corticospinal tract and the corpus callosum were studied as ‘control’ white matter (WM). No difference was found for any of the WM fibre bundles metrics between controls and MoA patients. MA patients had reduced average fractional anisotropy (FA) of both OR compared with controls and reduced average FA of the right OR compared with MoA patients. They also showed higher right OR mean diffusivity than controls. OR metrics were not correlated with clinical and magnetic resonance imaging (MRI) metrics. DT tractography reveals OR changes in MA patients that might represent a phenotypic biomarker of the disease given the lack of correlation with clinical and structural MRI metrics.

Objective: The mirror neuron system (MNS) is an observation-execution matching system activated, in humans, during action observation, motor learning, and imitation of action. We used functional MRI (fMRI) to investigate the properties of the MNS in patients with multiple sclerosis (MS). Methods: Using a 3 tesla scanner, we acquired fMRI in 16 right-handed patients with relapsing-remitting MS and 14 controls. Two motor tasks were studied. The first consisted of repetitive flexion-extension of the last four fingers of the right hand (simple task) alternated to epochs of rest; the second (MNS task) consisted of observation of a movie showing the hand of another subject while performing the same task. Results: During the simple task, compared to controls, patients with MS had more significant activations of the contralateral primary sensorimotor cortex and supplementary motor area. During the MNS task, both groups showed the activation of several visual areas, the infraparietal sulcus, and the inferior frontal gyrus (IFG), bilaterally. The IFG and the visual areas were significantly more active in patients than controls. The between-group interaction analysis showed that in patients with MS, part of the regions of the MNS were more active also during the simple task. Conclusions: This study suggests increased activation of the mirror neuron system in patients with multiple sclerosis (MS) with a normal level of function and widespread CNS damage. The potentialities of this system in facilitating clinical recovery in patients with MS and other neurologic conditions should be investigated.

Behavioral studies have provided important insights into the mechanisms governing interlimb coordination. In this study, we combined kinematic and functional magnetic resonance imaging (fMRI) analysis to investigate the brain cortical and subcortical areas involved in interlimb coordination and the influence of direction of movement and of body segment position on the activity of those areas. Fifteen right‐handed healthy subjects were studied while performing cyclic in‐phase and antiphase hand and foot movements with the dominant, right limbs, with the upper limb positioned either prone or supine, and in front or behind with respect to the trunk. When contrasting antiphase to in‐phase movements, fMRI analysis demonstrated an increased recruitment of a widespread sensorimotor network (including regions in the frontal and parietal lobes, bilaterally, the cingulated motor area, the thalami, the visual cortex, and the cerebellum) considered to function in motor, sensory, and multimodal integration processing. When contrasting the anterior to the posterior position of the upper limb with respect to the trunk, we found different recruitment patterns in the frontal and parietal regions as well as the preferential recruitment of the basal ganglia, the insula, and the cerebellum during the first condition and of regions located in the temporal lobes during the second one. Different brain areas are engaged at a different extent during interlimb coordination. In addition to the relative difficulty of the movement, the different cognitive and sensorial loads needed to control and perform the motor act might be responsible for these findings. Hum Brain Mapp, 2007. © 2006 Wiley‐Liss, Inc.

Background: Understanding long-term disability in multiple sclerosis (MS) is a key goal of research; it is relevant to how we monitor and treat the disease. Objectives: The Magnetic Imaging in MS (MAGNIMS) collaborative group sought to determine the relationship of brain lesion load, and brain and spinal cord atrophy, with physical disability in patients with long-established MS. Methods: Patients had a magnetic resonance imaging (MRI) scan of their brain and spinal cord, from which we determined brain grey (GMF) and white matter (WMF) fractional volumes, upper cervical spinal cord cross-sectional area (UCCA) and brain T2-lesion volume (T2LV). We assessed patient disability using the Expanded Disability Status Scale (EDSS). We analysed associations between EDSS and MRI measures, using two regression models (dividing cohort by EDSS into two and four sub-groups). Results: In the binary model, UCCA (p < 0.01) and T2LV (p = 0.02) were independently associated with the requirement of a walking aid. In the four-category model UCCA (p < 0.01), T2LV (p = 0.02) and GMF (p = 0.04) were independently associated with disability. Conclusions: Long-term physical disability was independently linked with atrophy of the spinal cord and brain T2 lesion load, and less consistently, with brain grey matter atrophy. Combinations of spinal cord and brain MRI measures may be required to capture clinically-relevant information in people with MS of long disease duration.

The aim of this study is to investigate the expression of P2X7R, IL-1beta and the ATP activity modulating ecto-apyrase CD39 on peripheral blood monocytes of MS patients and to observe the possible effects of Glatiramer Acetate (GA) on such expression. Twelve RR treatment-free MS patients were selected and peripheral blood monocytes were obtained. The expression of P2X7R, IL-1beta and CD39 on monocytes was investigated by qrt-PCR. The in vitro effects of GA on the expression of monocytes stimulated with BzATP (a potent P2X7R agonist)-were evaluated. Ten healthy donors (HDs) were similarly studied. Finally, 5 MS patients were given GA therapy and the monocytes obtained before treatment, after 3 and 12 months of GA treatment were similarly investigated. No differences were found in P2X7R, IL-1beta and CD39 expression between patients and controls. In MS Bz-ATP stimulated monocytes, GA pre-conditioning clearly downregulated P2X7R (p=0.003) but IL-1beta expression also showed a decreasing trend (p=0.07). Conversely, CD39 showed an increasing trend (p=0.07). Similar evidence was found in HDs. GA in vivo treatment induced a reduction in the expression that was clear for P2X7R and CD39 (p0.05) but only not significant for IL-1beta after 12 months of treatment. Monocytes from both MS and control subjects express P2X7R, IL-1beta and CD39, and GA seems to interfere with such expression.

In this prospective study, we estimated the prevalence of restless legs syndrome (RLS) in multiple sclerosis (MS) patients, and compared the extent of brain and cervical cord damage between patients with and without RLS using conventional and diffusion tensor magnetic resonance imaging (MRI). Eighty-two consecutive MS patients were evaluated. Each patient underwent a medical history interview, a neurological examination and brain/cervical cord MRI. Global and regional dual-echo lesion load (LL), number of cervical cord lesions, mean diffusivity (MD) and fractional anisotropy (FA) histograms metrics of the normal-appearing tissues of the brain and cervical cord were assessed. Thirty subjects had RLS; they showed a higher Expanded Disability Status Scale score than patients without. No difference between the two groups was found in whole brain, cerebellar and brainstem T2-LLs; MD and FA histograms derived metrics of the normal appearing brain tissues; basal ganglia MD; number of cervical cord lesions and cord MD histograms derived metrics. Cervical cord average FA was significantly reduced in MS patients with RLS compared to those without. RLS symptoms are very common in MS. This form of RLS should be considered as symptomatic. Higher disability and cervical cord damage represent a significant risk factor for RLS in MS patients. Multiple Sclerosis 2008; 14: 86—93. http://msj.sagepub.com

The aims of this study were to improve, using a 3.0 Tesla (T) scanner and diffusion tensor (DT) magnetic resonance imaging (MRI) with sensitivity encoding, our understanding of: 1) the possible pathological substrates of normal-appearing white matter (NAWM) and grey matter (GM) damage in multiple sclerosis (MS) and 2) the factors associated to WM and GM atrophy in this condition. Conventional and DT MRI of the brain were acquired from 32 relapsing-remitting (RR) MS patients and 16 controls. Lesion load, WM (WMV), overall GM (GMV), and neocortical GM (NCV) volumes were measured. NAWM mean diffusivity (MD) and fractional anisotropy (FA), and GM MD were calculated. GMV and NCV were lower (por = 0.001) in MS patients than controls, whereas WMV did not differ significantly. MS patients had higher NAWM and GM average MD and lower NAWM average FA (por = 0.001) than controls. Moderate correlations were found between intrinsic lesion and tissue damage with both GM volumetric and diffusivity changes (-0.41or = ror = 0.42, por = 0.04). DT MRI and volumetry measurements at 3.0 T confirm the presence of NAWM and GM abnormalities in RRMS patients. Although histopathology was not available, axonal and neuronal damage and consequent reactive glial proliferation are the most likely substrates of the changes observed.

Background and objective: Diffusion tensor (DT) magnetic resonance imaging (MRI) has the potential to disclose subtle abnormalities in the brain of migraine patients. This ability may be increased by the use of high field magnets. A DT MRI on a 3.0 tesla scanner was used to measure the extent of tissue damage of the brain normal appearing white (NAWM) and grey matter in migraine patients with T2 visible abnormalities. Methods: Dual echo, T1 weighted and DT MRI with diffusion gradients applied in 32 non-collinear directions were acquired from 16 patients with migraine and 15 sex and age matched controls. Lesion load on T2 weighted images was measured using a local thresholding segmentation technique, and brain atrophy assessed on T1 weighted images using SIENAx. Mean diffusivity and fractional anisotropy histograms of the NAWM and mean diffusivity histograms of the grey matter were also derived. Results: Brain atrophy did not differ between controls and patients. Compared with healthy subjects, migraine patients had significantly reduced mean diffusivity histogram peak height of the grey matter (p = 0.04). No diffusion changes were detected in patients’ NAWM. In migraine patients, no correlation was found between T2 weighted lesion load and brain DT histogram derived metrics, whereas age was significantly correlated with grey matter mean diffusivity histogram peak height (p = 0.05, r = −0.52). Conclusions: DT MRI at high field strength discloses subtle grey matter damage in migraine patients, which might be associated with cognitive changes in these patients.

Contrary to what happens in adult-onset multiple sclerosis (MS), in a previous preliminary magnetic resonance imaging (MRI) study we showed only subtle normal-appearing brain tissue changes in patients with earlyonset MS. Our objective was to evaluate the presence and extent of tissue damage in the brain normalappearing white matter (NAWM) and gray matter (GM) from a larger population of patients with earlyonset MS.Using diffusion tensor (DT) and magnetization transfer (MT) MRI, we obtained DT and MT ratio (MTR) maps of the NAWM and GM from 23 patients with early-onset MS and 16 sex- and age-matched healthy volunteers.Compared with healthy volunteers, patients with early-onset MS had significantly increased average MD (p = 0.02) and FA peak height (p = 0.007) and decreased average FA (p0.0001) of the NAWM. Brain dual-echo lesion load was significantly correlated with average FA (r = -0.48, p = 0.02) and with FA peak height (r = 0.45, p = 0.03) of the NAWM. No MTR and diffusion changes were detected in the GM.This study confirms the paucity of the 'occult' brain tissue damage in patients with earlyonset MS. It also suggests that in these patients GM is spared by the disease process and that NAWM changes are likely to be secondary to Wallerian degeneration of fibers passing through macroscopic lesions.

Background and Purpose— In migraine patients, functional imaging studies have shown changes in several brain gray matter (GM) regions. However, 1.5-T MRI has failed to detect any structural abnormality of these regions. We used a 3-T MRI scanner and voxel-based morphometry (VBM) to assess whether GM density abnormalities can be seen in patients with migraine with T2-visible abnormalities and to grade their extent. Methods— In 16 migraine patients with T2-visible abnormalities and 15 matched controls, we acquired a T2-weighted and a high-resolution T1-weighted sequence. Lesion loads were measured on T2-weighted images. An optimized version of VBM analysis was used to assess regional differences in GM densities on T1-weighted scans of patients versus controls. Statistical parametric maps were thresholded at P Results— Compared with controls, migraine patients had areas of reduced GM density, mainly located in the frontal and temporal lobes. Conversely, patients showed increased periacqueductal GM (PAG) density. Compared with patients without aura, migraine patients with aura had increased density of the PAG and of the dorsolateral pons. In migraine patients, reduced GM density was strongly related to age, disease duration, and T2-visible lesion load ( r ranging from −0.84 to −0.73). Conclusions— Structural GM abnormalities can be detected in migraine patients with brain T2-visible lesions using VBM and a high-field MRI scanner. Such GM changes comprise areas with reduced and increased density and are likely related to the pathological substrates associated with this disease.

Background: In patients with migraine, functional changes have been described in the red nucleus (RN), substantia nigra (SN) and periaqueductal gray matter (PAG). Purpose: To evaluate whether and at which frequency these structures are involved by MRI-detectable structural abnormalities in migraineurs and to investigate the pathogenic role of these abnormalities by assessing their frequency and extent in patients with multiple sclerosis (MS) and migraine. Methods: On brain dual-echo scans obtained from 58 migraineurs (40 without and 18 with aura), 37 MS patients with migraine without aura and 42 MS patients without migraine, the presence of hyperintense lesions involving the brainstem structures was recorded. A test of heterogeneity between groups was used to compare the presence of lesions among patient groups. Results: Lesions of RN, SN and PAG were found in all patient groups, with frequency from 57.5% to 86.5%. Significant between-group differences for all these regions were found. No difference was found between migraine patients with and without aura. Compared with MS patients without migraine, MS patients with migraine had more significant involvement of the SN (p = 0.02) and RN (p < 0.0001). Compared with migraine patients, MS patients with migraine had more significant involvement of the SN and PAG (p ranging from 0.009 to 0.02). Conclusions: T2-visible lesions in the brainstem are frequent in patients with migraine, but do not seem to be associated with the presence of aura. Demyelinating lesions in the RN, SN and PAG might be among the factors responsible for the presence of migraine in patients with MS