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Biomedical subjects

M Filippi

Publications and source records attributed to M Filippi.

At least 73 records · Page 4Linked to original sources
PubMed2003

MRI metrics as surrogate endpoints for EDSS progression in SPMS patients treated with IFN beta-1b.

BACKGROUND: Although metrics derived from conventional MRI (cMRI) are widely used as outcome measures in clinical trials of MS, no formal study has been performed to validate cMRI metrics as surrogate endpoints for disability progression in MS. METHODS: A validation procedure was applied to the clinical and MRI data collected in the context of the European randomized, double-blind, placebo-controlled trial of interferon beta-1b (IFNbeta-1b) in patients with secondary progressive MS. The Prentice operational criteria were used to assess surrogacy for the number of active lesions seen on the first year T2-weighted MRI scans and the percentage T2 lesion volume change between the baseline and the first year MRI scans. The primary clinical outcome was disability at study exit (3 years), adjusted for the baseline disability. RESULTS: The number of active T2 lesions and the T2 lesion volume percentage change over the first year of the study accounted for 57% of the treatment effect on disability progression over the entire study duration. On the contrary, the same cMRI metrics accounted for 79% of the treatment effect on the relapse rate. CONCLUSIONS: This study shows that the beneficial effect of IFNbeta-1b on disability accumulation in patients with secondary progressive MS is, to a large extent, independent of the changes detected using cMRI. As a consequence, cMRI metrics should not be used as a stand-alone measure of outcome in phase III trials of IFNbeta in secondary progressive MS.

Biomarkers↗
PubMed2003

Evidence of early cortical atrophy in MS: relevance to white matter changes and disability.

OBJECTIVE: To assess cortical gray matter (GM) changes in MS and establish their relevance to clinical disability and to inflammatory changes of white matter (WM) in patients with the relapsing-remitting (RR) and primary progressive (PP) forms of the disease. METHODS: Conventional MRI examinations were obtained in patients with definite MS who had either the RR or the PP form of the disease. An automated analysis tool was used with conventional T1-weighted MR images to obtain total and cortical brain volumes normalized for head size. Total brain lesion load was estimated on conventional proton density and T2-weighted MR images. The relationship between volumetric MR measures and scores of clinical disability was assessed. RESULTS: Normalized cortical volumes (NCV) were lower for both RR and PP MS patients than for normal control subjects (p < 0.001) but were similar between the two patient groups (p > 0.5). NCV decreases in both patients groups were detected even in those patients with short disease duration (<5 years; p < 0.001 in RR MS and p < 0.05 in PP MS) and minimal brain lesion volume (<5 mL; p < 0.0001 in RR MS and p < 0.005 in PP MS). Measures of NCV in individual patients were negatively correlated with T2-weighted lesion volume (r = -0.47, p < 0.001) and disease duration (r = -0.25, p < 0.05) only in the patients with RR MS. NCV correlated with Expanded Disability Status Scale scores across all of the patients, but the strength of the correlation was stronger (p < 0.05) for PP (r = -0.64, p < 0.0001) than for RR (r = -0.27, p = 0.04) MS patients. CONCLUSIONS: These data confirm substantial neocortical volume loss in MS patients and suggest that neocortical GM pathology may occur early in the course of the disease in both RR and PP MS patients and contribute significantly to neurologic impairment. Although a proportion of this neocortical pathology may be secondary to WM inflammation, the extent of the changes suggests that, especially in patients with PP MS, an independent neurodegenerative process also is active.

Adolescent↗
PubMed2003

The effect of interferon beta-1b on quantities derived from MT MRI in secondary progressive MS.

BACKGROUND: Magnetization transfer (MT) MRI can provide in vivo markers reflecting the severity of irreversible, MS-related brain damage occurring within and outside T2-visible lesions. OBJECTIVE: To assess the effect of interferon (IFN) beta-1b treatment on the accumulation of brain damage in patients with secondary progressive (SP) MS, measured using MT MRI. METHODS: Eighty-two patients with SPMS from five centers participating in a European, multicenter, double-blind, placebo-controlled trial of IFNbeta-1b in SPMS underwent brain T2-weighted and MT MRI at baseline. Evaluable follow-up data were available for 75 patients at 12 months, 54 at 24 months, and 47 at 36 months. MT MRI scans were postprocessed and analyzed to obtain histograms of MT ratio (MTR) values from the whole brain. A region of interest-based analysis of MTR values from the normal-appearing white matter (NAWM) was also performed. RESULTS: In both the treatment arms, there was a decrease of average brain MTR values from baseline to month 24 (mean change -4.9%) and month 36 (mean change -4.3%). These changes were significant for the placebo group at both timepoints and for the IFNbeta-1b group at month 24 only, with no significant treatment effect. A decrease of NAWM MTR was also observed, with no significant difference between the two treatment arms. CONCLUSION: In this cohort of patients with secondary progressive MS, interferon beta-1b did not show an overall effect on the worsening of magnetization transfer MRI measures, when compared with placebo. The data show that change in magnetization transfer ratio is a promising tool for monitoring disease evolution in secondary progressive MS and that the information obtained from magnetization transfer MRI complements that obtained from MRI measures of lesion load and inflammation.

Adult↗
PubMed2003

Magnetic resonance studies of abnormalities in the normal appearing white matter and grey matter in multiple sclerosis.

Magnetic resonance (MR) techniques are of value in following the pathological process of multiple sclerosis in vivo. They are widely applied to monitor the disease natural history and its modification by treatment. However, serial studies of lesion measures have yielded generally disappointing correlations with the development of clinical disability. A potential explanation for this is the presence of abnormalities, beyond the visible lesions, in the normal appearing white matter (NAWM) and grey matter (NAGM). Quantitative structural MR techniques, including measures of magnetisation transfer, diffusion, relaxation times and spectroscopic metabolite concentrations, reveal that there are abnormalities in NAWM and NAGM. These are present from clinical onset and become more pronounced with clinical progression, increasing disability and increasing lesion load. Furthermore, functional MRI (fMRI) studies of motor and visual paradigms has identified a range of responses suggesting that cortical plasticity exists; such modified responses are seen in the earliest stages of disease and in the absence of visible lesions, but are more pronounced with disease progression and increasing lesion load and abnormality in the NAWM. Limited reproducibility and sensitivity to change can pose methodological limitations for MR studies of NAWM and NAGM, especially when follow up intervals are relatively short. Whilst existing quantitative MR measures from normal appearing tissues provide valuable information to understand the natural history and monitor treatment effects in MS, none of them fully or even predominantly accounts for the patient's functional state nor can be relied on as a definitive surrogate measure of treatment effect. Better resolution of the abnormalities is needed especially in grey matter where pathological foci are known to be abundant. Studies correlating structural MR and fMRI parameters with measures of function in well defined anatomical pathways should further elucidate the pathogenic role of abnormality in the normal appearing tissues. In future, new imaging modalities are needed that provide a more specific measure of histopathological and cellular aspects of the disease process in vivo.

Brain↗
PubMed2003

MRI aspects of the "inflammatory phase" of multiple sclerosis.

In early relapsing-remitting (RR) multiple sclerosis (MS), conventional magnetic resonance imaging (MRI) has proved to be a valuable tool to assess disease activity over time. However, conventional MRI can only provide gross estimates of irreversible tissue damage within and outside such lesions. Other MR-based techniques, including magnetization transfer MRI, diffusion-weighted MRI, proton MR spectroscopy and functional MRI, have the potential to provide additional pieces of information about the nature and the extent of MS tissue damage since the early "inflammatory phase" of the disease. The application of these MR techniques to the study of early RRMS is likely to improve our understanding of the pathophysiology of MS and our ability to assess the efficacy of experimental treatments.

Brain↗
PubMed2003

Evidence for widespread axonal damage at the earliest clinical stage of multiple sclerosis.

Although axonal pathology is recognized as one of the major pathological features of multiple sclerosis, it is less clear how early in its course it occurs and how it correlates with MRI-visible lesion loads. To assess this early axonal pathology, we quantified the concentration of whole-brain N-acetylaspartate (WBNAA) in a group of patients at the earliest clinical stage of the disease and compared the results with those from healthy controls. Conventional brain MRI and WBNAA using unlocalized proton magnetic resonance spectroscopy were obtained from 31 patients at presentation with clinically isolated syndromes suggestive of multiple sclerosis and paraclinical evidence of dissemination in space, and from 16 matched controls. An additional conventional MRI scan was obtained in all patients 4-6 months later to detect dissemination of lesions in time. The mean WBNAA concentration was significantly lower in patients compared with the controls (P < 0.0001). It was not significantly different between patients with and without enhancing lesions at the baseline MRI or between patients with and without lesion dissemination in time. No correlation was found between WBNAA concentrations and lesion volumes. Widespread axonal pathology, largely independent of MRI-visible inflammation and too extensive to be completely reversible, occurs in patients even at the earliest clinical stage of multiple sclerosis. This finding lessens the validity of the current concept that the axonal pathology of multiple sclerosis is the end-stage result of repeated inflammatory events, and argues strongly in favour of early neuroprotective intervention.

Adult↗
PubMed2003

Beta endorphin concentrations in PBMC of patients with different clinical phenotypes of multiple sclerosis.

The possible link between the opioid peptide beta endorphin and the heterogeneity of the clinical course of multiple sclerosis (MS) was investigated. Peripheral blood mononuclear cells (PBMC) concentrations of beta endorphin were measured in 50 patients in different phases of MS. Thirty nine patients also underwent post-contrast magnetic resonance imaging of the brain. Among MS forms, the highest beta endorphin concentrations were found in PBMC from patients with relapsing remitting MS and the lowest in patients with the progressive forms. Average beta endorphin concentrations were lower, although not significantly, in patients with than in those without magnetic resonance imaging enhanced lesions. These data suggest that beta endorphin may have a role in the downregulation of the inflammatory process.

Adult↗
PubMed2003

A diffusion tensor magnetic resonance imaging study of brain tissue from patients with migraine.

OBJECTIVE: To measure in vivo, using diffusion tensor magnetic resonance imaging (DT-MRI) the extent of pathological damage of normal appearing brain tissue (NABT) from patients with migraine. METHODS: Dual echo and DT-MRI scans of the brain were acquired from 34 patients with migraine and 17 sex and age matched healthy volunteers. Mean diffusivity (MD) and fractional anisotropy (FA) histograms of the NABT were obtained from all subjects and the histograms' peak heights and average NABT MD and FA measured. When present, average MD and FA values of T2 visible lesions were also measured. RESULTS: In comparison with healthy volunteers, patients with migraine had lower MD histogram peak height (p=0.02) of the NABT. No differences were found in FA histogram derived metrics between migraine patients and healthy subjects. No difference was found for any MD and FA histogram derived metrics between migraine patients with and without brain MRI lesions, and between patients with and without aura. CONCLUSIONS: This study shows that, although brain damage may extend beyond T2 weighted abnormalities in patients with migraine, the severity of these "occult" changes is mild compared with that found in other diseases associated with white matter abnormality.

Adolescent↗
PubMed2003

An MRI study of Chlamydia pneumoniae infection in Italian multiple sclerosis patients.

We amplified sequences of the Chlamydia pneumoniae (CP) major-outer membrane protein in the cerebrospinal fluid (CSF) from 23 of 107 (21.5%) relapsing-remitting or secondary progressive multiple sclerosis (MS) patients and two of 77 (2.6%) patients with other neurological diseases (OND) (P = 0.00022). CP+ patients showed magnetic resonance imaging (MRI) evidence of more active disease (P = 0.02) compared to CP- MS patients and tended to have an anticipation of age at disease onset (32.3 +/- 12 versus 28.5 +/- 10 years; P = ns) causing a longer disease duration (7.5 +/- 5 versus 4.4 +/- 4 years; P = 0.016) at the time of clinical evaluation. These findings, although indirectly, suggest that CP infection of the central nervous system (CNS) might affect disease course in a subgroup of MS patients.

Adolescent↗
PubMed2002

Effect of glatiramer acetate on MS lesions enhancing at different gadolinium doses.

This baseline-vs-treatment study of 20 patients with relapsing-remitting MS investigated whether glatiramer acetate (GA) has a graduated effect on MS inflammatory activity, which was measured using monthly, standard, and triple dose gadolinium (Gd)-enhanced MRI. GA significantly reduced the mean numbers of enhancing lesions/patient/month on both standard dose and triple dose scans, without interactions with the Gd dose. GA is effective in reducing MS activity, independent of the severity of the MRI-detectable inflammatory process.

Adolescent↗
PubMed2002

Copaxone's effect on MRI-monitored disease in relapsing MS is reproducible and sustained.

All but 6% of the subjects with relapsing remitting MS who were randomly assigned to receive glatiramer acetate or placebo for the 9-month controlled phase of the European/Canadian MRI trial entered an open-label extension with quarterly clinical and MRI evaluations for another 9 months. There was a 54% reduction in the mean number of enhanced lesions for those converted from placebo to glatiramer acetate and an additional 24.6% reduction for those always on glatiramer acetate. Over the entire study the accumulated T2 disease burden was 34.2% less for those always on glatiramer acetate.

Cross-Over Studies↗
PubMed2002

Longitudinal evaluation of leukoaraiosis with whole brain ADC histograms.

FLAIR and diffusion-weighted MRI were obtained twice (mean interval 20 +/- 4 months) in 10 patients with leukoaraiosis. At follow-up, visual extension of leukoaraiosis was unchanged, whereas the median of whole brain apparent diffusion coefficient (WB-ADC) histogram was increased (p= 0.008) and brain volume index (BVI) was decreased (p = 0.006). WB-ADC histogram and BVI are sensitive to leukoaraiosis and might be considered for monitoring progression of the disease.

Aged↗
PubMed2002

Evidence for widespread movement-associated functional MRI changes in patients with PPMS.

BACKGROUND: Previous work has suggested that functional reorganization of cortical motor areas might have a role in limiting the motor deficits in patients with MS. OBJECTIVE: To test whether movement-associated cortical changes in MS might extend beyond the "classic" motor areas and involve sites for multimodal integration. METHODS: fMRI was used to assess patterns of brain activations associated with 3 different motor tasks in 30 right-handed patients with primary progressive MS (PPMS) and variable degrees of motor impairment, which were compared with those from 15 right-handed, sex- and age-matched control subjects. RESULTS: Compared with control subjects, patients with MS showed increased activation of brain regions within both traditional motor planning and execution regions (including the supplementary motor area and the cingulate motor area), the insula (a region implicated in sensory processing), and several multimodal cortical regions in the temporal, parietal, and occipital lobes. In patients, the extent of the fMRI activations was strongly correlated with MR lesion burden (r ranging from 0.70 to 0.86, p < 0.001). CONCLUSIONS: This study shows that movement-associated cortical activation in patients with PPMS is widely distributed and also involves multimodal "nonmotor" cortical networks. It also suggests that adaptive cortical reorganization might be one of the mechanisms limiting the clinical impact of MS in the progressive phases of the disease.

Adult↗
PubMed2002

Cerebral grey matter pathology and fatigue in patients with multiple sclerosis: a preliminary study.

In patients with multiple sclerosis (MS), we investigated whether the extent of cerebral grey matter (GM) pathology is associated with the presence and severity of fatigue. We quantified cerebral GM pathology in 28 MS patients (14 with fatigue and 14 without fatigue) using magnetization transfer (MT) and diffusion tensor (DT) magnetic resonance imaging (MRI). The average MT ratio and mean diffusivity from cerebral GM did not differ between fatigued and non-fatigued patients. Fatigued and non-fatigued patients also did not differ in terms of GM pathology of the cerebral cortex of the frontal lobe and basal ganglia. No correlations were found between the fatigue severity scale scores and any of the MT- and DT-MRI quantities. These preliminary results suggest that structural GM pathology is not a major contributing factor to the development of fatigue in patients with MS.

Adult↗
PubMed2002

Role of magnetic resonance imaging in the diagnosis and monitoring of multiple sclerosis: consensus report of the White Matter Study Group.

On June 24-26, 2001, the first meeting of the White Matter Study Group (WMSG) of the International Society for Magnetic Resonance in Medicine (ISMRM) was held in Bordeaux, France. This paper is the report of the consensus reached among the delegates of the meeting on how to use magnetic resonance imaging (MRI) to make an early diagnosis of multiple sclerosis (MS), to measure MS activity accurately and reliably, and to monitor the effect of treatment on disease evolution.

Brain↗
PubMed2002

Functional magnetic resonance imaging correlates of fatigue in multiple sclerosis.

Although fatigue is a common and troublesome symptom of multiple sclerosis (MS), its pathogenesis is poorly understood. In this study, we used functional magnetic resonance imaging (fMRI) to test whether a different pattern of movement-associated cortical and subcortical activations might contribute to the development of fatigue in patients with MS. We obtained fMRI during the execution of a simple motor task with completely normally functioning hands from 15 MS patients with fatigue (F), 14 MS patients without fatigue (NF), and 15 sex- and age-matched healthy volunteers. F and NF MS patients were also matched for major clinical and MRI variables. FMRI data were analyzed using statistical parametric mapping. In all patients, severity of fatigue was rated using the Fatigue Severity Scale (FSS). Compared to healthy subjects, MS patients showed more significant activations of the contralateral primary somatomotor cortex, the contralateral ascending limb of the Sylvian fissure, the contralateral intraparietal sulcus (IPS), the contralateral supplementary motor area, and the ipsilateral and contralateral cingulate motor area (CMA). Compared to F MS patients, NF patients showed more significant activations of the ipsilateral cerebellar hemisphere, the ipsilateral rolandic operculum, the ipsilateral precuneus, the contralateral thalamus, and the contralateral middle frontal gyrus. In contrast, F MS patients had a more significant activation of the contralateral CMA. Significant inverse correlations were found between FSS scores and relative activations of the contralateral IPS (r = -0.63), ipsilateral rolandic operculum (r = -0.61), and thalamus (r = -0.62). This study provides additional evidence that fatigue in MS is related to impaired interactions between functionally related cortical and subcortical areas. It also suggests that fMRI might be a valuable tool to monitor the efficacy of treatment aimed at reducing MS-related fatigue.

Adult↗