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Biomedical subjects

M Filippi

Publications and source records attributed to M Filippi.

At least 19 recordsLinked to original sources
PubMed1999

Comparison of MS clinical phenotypes using conventional and magnetization transfer MRI.

OBJECTIVE: To identify differences in pathology between the principal clinical phenotypes of MS using conventional and magnetization transfer (MT) MRI. METHODS: T1-weighted and T2-weighted images as well as MT scans were obtained from 20 controls, 21 patients presenting with clinically isolated syndromes suggestive of MS, and 93 MS patients with relapsing-remitting, secondary progressive, benign, or primary progressive course. Metrics considered: hypointense T1 and T2 lesion volumes, average lesion MT ratio, average brain MT ratio, peak height and position from MT histograms. RESULTS: MS patients had lower MT metrics than controls. Patients with clinically isolated syndromes had MT measures similar to controls, whereas primary progressive MS patients had lower histogram peak height with normal peak position. Relapsing-remitting MS patients had lower MT measures, higher T2 lesion load and ratio of hypointense T1 to T2 lesion volumes than patients with clinically isolated syndromes, and lower MT ratio and peak height than benign MS patients. Benign MS patients were similar to controls and patients with clinically isolated syndromes. Secondary progressive MS patients had the lowest MT measures and highest lesion loads. CONCLUSIONS: Pathology in patients with clinically isolated syndromes is confined to modest tissue damage in the lesions seen on T2-weighted scans. Severe damage is important for the later development of disability. However, microscopic damage in normal-appearing white matter may be a major contributor to disability in primary progressive MS.

Adult↗
PubMed1999

Characteristic MR lesion pattern and correlation of T1 and T2 lesion volume with neurologic and neuropsychological findings in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).

BACKGROUND AND PURPOSE: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an arteriopathy related to a genetic defect of the notch 3 gene on chromosome 19. The purpose of this study was to evaluate lesion distribution and volume using MR imaging and to correlate the lesion volume with the neurologic and neuropsychological findings. METHODS: Twenty members of two families (14 with CADASIL as determined by linkage analysis, six healthy) were studied with MR imaging. Two observers evaluated the MR findings semiquantitatively and quantitatively. MR results were then correlated with neurologic and neuropsychological findings. RESULTS: A typical pattern of lesion distribution in patients with CADASIL was found: the frontal lobe was the site with the highest lesion load, followed by the temporal lobe and the insula. The total lesion volume on T1-weighted MR images correlated significantly with the degree of disability and the degree of impairment in neuropsychological functions (including attention, memory, and conceptual and visuospatial functions). CONCLUSION: In CADASIL patients, a common pattern of cerebral lesion distribution is found. The total T1 lesion volume is an important parameter to correlate with disability, as it may prove to be helpful in predicting the natural history of the disease.

Adult↗
PubMed1999

Interscanner variation in brain MR lesion load measurements in multiple sclerosis using conventional spin-echo, rapid relaxation-enhanced, and fast-FLAIR sequences.

BACKGROUND AND PURPOSE: Different MR pulse sequences have been proposed for measuring multiple sclerosis (MS)-related abnormalities. The reproducibility of measured brain MS lesion volumes was compared for MR images performed using different scanners and different pulse sequences. METHODS: Nine patients with relapsing-remitting MS were each imaged on two scanners and, on each occasion, dual-echo conventional spin-echo, dual-echo rapid-acquisition relaxation-enhanced (RARE), and fast fluid-attenuated inversion recovery (fast-FLAIR) images were obtained. The lesion volume present on each image was evaluated three times by a single observer in random order, using a local thresholding technique. RESULTS: The mean lesion volumes present on fast-FLAIR images were significantly higher than those measured on dual-echo conventional spin-echo and RARE images. The mean intraobserver coefficients of variation for the different sequences and scanners ranged from 3.0% to 4.2% (no statistically significant difference). For each of the sequences, the use of different scanners introduced a variability that was higher than the intraobserver variability: the interscanner coefficient of variation was 7.4% for conventional spin-echo, 9.5% for RARE, and 18.5% for fast-FLAIR images. CONCLUSION: Our study confirms that the use of different scanners significantly influences lesion loads measured from MR images of patients with MS and establishes that newer sequences are more susceptible to measurement variability. It also indicates that, if newer sequences are to be used in clinical trials, careful standardization is needed.

Adult↗
PubMed1998

Follow-up of interhemispheric differences of motor evoked potentials from the 'affected' and 'unaffected' hemispheres in human stroke.

We analysed motor-evoked potentials (MEPs) from the hand muscles during focal transcranial magnetic stimulation (TCS) in both the affected (AH) and the unaffected (UH) hemispheres of 17 monohemispheric stroke patients followed-up in subacute stage. Recording sessions were performed at 2 (T1 session) and 4 (T2 session) months from acute stroke. Clinical and functional scores were evaluated. An age-sex matched group of 20 healthy subjects have been referenced. In T1, relaxed MEPs from AH were smaller than UH (p<0.001) and normals (p<0.001). In T2, an increase of AH relaxed-MEPs amplitude was observed, combined with an improvement of clinical and functional scores (p<0.001). On the other hand, the amplitude of contracted MEPs from the AH in T1 was larger than in the normal group. This parameter decreased toward normal limits in T2, provided that the amplitude of the MEPs from the AH improved, while it further increased when TCS of the AH continued to fail in eliciting MEPs. This phenomenon was statistically combined with clinical improvement of disability and neurological scores. Recovery of the excitability AH threshold with progressive 'balancing' of the UH hyperresponsiveness represents a good prognostic parameter for clinical outcome of hand motor function.

Adult↗
PubMed1998

Magnetization transfer ratios of multiple sclerosis lesions with variable durations of enhancement.

We evaluated whether new multiple sclerosis (MS) lesions with variable durations of enhancement have different magnetization transfer ratios (MTR) at the time of their appearance. We scanned ten patients with relapsing-remitting MS every four weeks on four occasions. During each of the monthly sessions, we obtained dual echo, MT and T1-weighted scans. Five minutes after gadolinium-DTPA (Gd) injection, another T1-weighted scan was obtained. We measured the MTR of new enhancing lesions on co-registered quantitative MTR images. During the three-month follow up, 54 new enhancing lesions were seen with a mean MTR value of 33.6% (SD=7.8%). The mean MTR values were 35.3% (SD=7.0%) for lesions enhancing on only one scan and 29.3% (SD=8.6%) for those enhancing on at least two consecutive scans (P=0.01). These results suggest that enhancing lesions in MS have heterogeneous pathological substrates, which may be associated with different durations of the enhancing phase.

Adult↗
PubMed1998

A longitudinal brain MRI study comparing the sensitivities of the conventional and a newer approach for detecting active lesions in multiple sclerosis.

Monthly dual-echo spin-echo (SE) and enhanced magnetic resonance imaging (MRI) after the injection of a standard dose (SD) of gadolinium (Gd) is the conventional approach to monitor short-term disease activity in multiple sclerosis (MS). In this study, the sensitivity of this approach in detecting active lesions in MS was compared with that of monthly fast fluid attenuated inversion recovery (FLAIR) scans associated with enhanced MRI after the injection of a triple dose (TD) of Gd. Thirteen patients with relapsing-remitting MS entered the study. Monthly MRI scans were obtained on four occasions in two separate sessions (interval between 12 and 24 h). In one session, dual-echo conventional SE and SD Tl-weighted scans were obtained; in the other, fast-FLAIR and TD Tl-weighted scans. The order of the two sessions was randomized. Three observers counted the number of active lesions detected by each of the two approaches. One hundred and four active lesions were detected by the conventional approach and 199 by the newer approach (average increase per patient = 75%, range = 0-325%). The mean number of active lesions per month per patient was 2.0 for the conventional approach and 3.8 for the new approach (P = 0.004). Scans with active lesions were 34/52 (65%) with the conventional approach and 37/52 (71%) with the new approach. Our data indicate that the combined use of monthly fast-FLAIR and TD enhanced Tl-weighted scans increases the number of active lesions detected on serial MRI scans from patients with MS.

Adult↗
PubMed1998

Quantitative volumetric analysis of brain magnetic resonance imaging from patients with multiple sclerosis.

We compared the volumes of the brain as a whole and of different cerebral structures from patients with multiple sclerosis (MS) and normal subjects. In the patients, we also correlated brain volumes with T2 and T1 lesion loads and disability. A magnetization-prepared rapid acquisition gradient echo (MP RAGE) sequence with subsequent reconstruction of axial 1-mm thick slices and a dual-echo sequence were obtained in 15 patients with relapsing-remitting or secondary progressive MS and 15 sex-, age-, height- and weight-matched normal subjects. The brains and the different cerebral structures studied (cerebral hemispheres, cerebellum and brainstem) were segmented manually by a single observer on the 1-mm MP RAGE scans. The hyperintense lesion volumes seen on dual-echo scans and the hypointense lesion volumes seen on the 1-mm MP RAGE scans were measured using a semi-automated segmentation technique based on local thresholding. Compared to the normal volunteers, patients had significantly lower cerebral (P = 0.008), hemispheric (P = 0.01) and brainstem (P = 0.03) volumes. Cerebral atrophy was detected in seven (47%) MS patients. Patients with brainstem signs had significantly lower mean brainstem volume than the others (P = 0.04). No significant correlations were found between the cerebral volumes and the EDSS scores, the hyperintense lesion volumes and the hypointense lesion volumes. We conclude that cerebral atrophy is a relatively frequent finding in MS, but its relationship with physical disability is modest.

Adult↗
PubMed1998

Triple dose of gadolinium-DTPA increases the sensitivity of spinal cord MRI in detecting enhancing lesions in multiple sclerosis.

We compared the sensitivity of single and triple dose Gd-DTPA magnetic resonance imaging (MRI) in detecting enhancing lesions in the spinal cord of 13 patients with multiple sclerosis (MS). We detected two enhancing lesions in two of 13 (15%) patients when the single dose of Gd-DTPA was used and 12 lesions in five of 13 (38%) patients when the triple dose of Gd-DTPA was used. These results suggest that: (1) the use of triple dose increases the sensitivity of spinal cord MRI when studying relapsing-remitting or secondary progressive MS patients, (2) triple dose Gd-DTPA enhanced of the spinal cord MRI might be useful in monitoring disease activity in patients with MS.

Adult↗
PubMed1998

A one year study of new lesions in multiple sclerosis using monthly gadolinium enhanced MRI: correlations with changes of T2 and magnetization transfer lesion loads.

In this study, 14 patients with either relapsing-remitting or secondary progressive multiple sclerosis (MS) were scanned monthly using gadolinium enhanced magnetic resonance imaging (MRI). At the start of the study and at 1 year follow up, T2-weighted and magnetization transfer (MT) scans were also performed. The correlation between the frequency and extent of enhancement and changes of lesion load over a 1 year period on T2-weighted and MT images were assessed. For all patients, and for the relapsing-remitting patients only, the number and volume of enhancing lesions per month showed no significant correlation with the change between baseline and 1 year follow up of lesion volumes on T2 and MT images. However, strong correlations were found between the number and volume of gadolinium enhancing lesions with changes of T2 (r = 0.93, P = 0.02) and MT (r = 0.82, P = 0.04) lesion loads in patients with secondary progressive MS. Strong correlations were also found between the lesion loads on T2-weighted scans and on MT images both at baseline and at 1 year follow up (r = 0.83, P = 0.003). In addition, the changes in lesion load over 1 year, detected using the two techniques, were moderately correlated (r = 0.51, P = 0.05). This study provides further evidence that the pathological processes in MS are at different stages in relapsing-remitting and secondary progressive MS. It also suggests that the effectiveness of recovery mechanisms within lesions might be one of the major factors responsible for such a difference.

Adult↗
PubMed1998

Correlations between monthly enhanced MRI lesion rate and changes in T2 lesion volume in multiple sclerosis.

Magnetic resonance imaging (MRI) provides a powerful tool for assessing disease activity in multiple sclerosis (MS), and its role as a surrogate marker for monitoring treatment efficacy is now becoming established. The most commonly used MRI parameters in treatment trials are (1) monthly gadolinium-enhanced MRI, with the number of active lesions serving as the outcome measure, and (2) annual lesion load quantification, in which change in MS lesion volume provides the MRI endpoint. We evaluated clinical/MRI correlations and the relationship between these two markers of disease activity in 73 patients with clinically definite MS. Quantification of T2 lesion load was performed at study entry and exit, with a median study duration of 11 months (range, 9 to 14 months). Monthly postgadolinium T1-weighted images were acquired between these time points. Lesion load at study entry was significantly correlated with the baseline Expanded Disability Status Scale (EDSS) score, but no significant longitudinal correlation was demonstrated. The number of enhancing lesions on the entry scan was predictive of subsequent relapse rate over the study duration and also correlated with the subsequent enhancing lesion activity over the study period. A significant correlation was found between change in lesion load and disease activity on the monthly scans. Our results suggest that annual lesion load quantification provides an efficient measure of ongoing disease activity, and this supports its application as a surrogate marker of disease evolution in phase III treatment trials.

Adolescent↗
PubMed1998

Proinflammatory cytokines regulate antigen-independent T-cell activation by two separate calcium-signaling pathways in multiple sclerosis patients.

Central nervous system (CNS) lesions typical of multiple sclerosis (MS) are characterized by demyelinating inflammatory infiltrates that contain few CNS antigen-specific autoreactive T cells and a multitude of pathogenic non-antigen-specific mononuclear cells. Here, we report that in patients with MS the combined action of interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNFalpha), interleukin (IL)-2, and IL-6 leads to the activation of most peripheral T cells (mainly CD4 memory) by promoting a persistent intracellular calcium increase via two independent signaling pathways. The activation of these pathways, one activated by IFNgamma and the other by the combination TNFalpha/IL-2/IL-6, is independent from myelin antigens and precedes by 2 weeks phases of disease activity (eg, clinical relapses and/or appearance of gadolinium-enhancing lesions on brain magnetic resonance imaging scans during 1 year of follow-up). Our results indicate that an appropriate combination of the four cytokines, three with a proinflammatory profile and one necessary for T-cell growth and differentiation, can activate in an antigen-independent fashion most peripheral T cells from MS patients. This mechanism is likely to contribute to the recruitment of nonspecific lymphocytes into the cellular activation processes leading to CNS demyelination and may represent a major target for immune intervention in MS.

Antigens↗
PubMed1998

Guidelines for using quantitative measures of brain magnetic resonance imaging abnormalities in monitoring the treatment of multiple sclerosis.

The change of brain lesion load, measured on T2-weighted magnetic resonance imaging (MRI) using computer-assisted techniques, is a widely used secondary endpoint for phase III clinical trials in multiple sclerosis (MS). Collection, transfer, and analysis of the electronic data across multiple centers have all proved challenging and give rise to potential errors. However, many new acquisition schemes and postprocessing techniques have been developed; these may reduce scan times and result in better lesion conspicuity or lessen the human interaction needed for data analysis. This review considers many aspects of the use of MRI in clinical trials for MS and provides international consensus guidelines, derived from a task force of the European Magnetic Resonance Networks in Multiple Sclerosis (MAGNIMS) together with a group of North American experts. The main points considered are the organization of correctly powered trials and selection of participating sites; the appropriate choice of pulse sequences and image acquisition protocol given the current state of technology; quality assurance for data acquisition and analysis; accuracy and reproducibility of lesion load assessments; and the potential for the application of quantitative methods to other MRI-derived measures of disease burden.

Brain↗
PubMed1998

Magnetization transfer changes in the normal appearing white matter precede the appearance of enhancing lesions in patients with multiple sclerosis.

Serial monthly magnetization transfer (MT) imaging was performed to evaluate whether a change of the normal appearing white matter (NAWM), which precedes the appearance of enhancing lesions, is seen in patients with multiple sclerosis (MS). Every 4 weeks for 3 months, 10 patients with relapsing-remitting MS were scanned with a T1-weighted sequence, 20 minutes after injection with 0.3 mmol/kg gadolinium-DTPA (Gd-DTPA). During each of the monthly sessions, MT and dual echo scans were also performed before Gd-DTPA injection. On coregistered images, the MT ratio (MTR) was measured in NAWM subsequently involved by enhancing lesions, in NAWM areas on the same slices but outside any present or future MR abnormality, and in enhancing lesions at the time of their appearance. Forty-eight new enhancing lesions with no corresponding abnormalities on previous scans were identified. Their average MTR was 33.1% (+/-8.4%). Three, 2, and 1 month before enhancement appearance, the mean MTR in NAWM, measured from areas corresponding to future enhancing lesions, was significantly lower than the mean MTR in NAWM outside enhancing areas; the MTR decreased steadily as the time when the enhanced lesion approached. These results suggest that changes in the NAWM of patients with MS occur before lesions become evident on conventional MRI scans.

Adult↗
PubMed1998

The effect of repositioning on brain MRI lesion load assessment in multiple sclerosis: reliability of subjective quality criteria.

The aim of this study was to assess the variability of lesion load measurements for repeated brain magnetic resonance imaging (MRI) scans judged to have either poor or good repositioning quality on the basis of subjective criteria used for clinical trials in multiple sclerosis (MS). Scan-rescan variability was also compared with the intra-observer variability assessed from three repeated volume measurements of the same scan. Nine patients with MS were studied; each of them underwent the scan-rescan procedure on the same day. Five scans were considered to have poor and four scans to have good repositioning. Between these two groups there were no differences in either the mean lesion loads or the measurement variance. For the whole group of patients, the intra-observer variability of repeated measurements gave a significantly lower coefficient of variation (COV = 4.9%) than the variability owing to repositioning (COV = 8.9%, P < 0.01, F test). Our results confirm that the effect of repositioning on brain MRI lesion load assessment is stronger than that owing to the intra-observer variability for repeated measurements and indicate that the simple visual judgment about the scan repositioning quality seems unable to predict the scan-rescan reproducibility.

Adult↗
PubMed1998

How does brain MRI lesion volume change on serial scans in patients with multiple sclerosis?

Although lesion load changes on conventional T2-weighted brain magnetic resonance imaging (MRI) scans from patients with multiple sclerosis (MS) are used to monitor the effect of treatment, there is no clear definition of how lesion load changes over years according to the lesion load present at a baseline evaluation. In the present study, we evaluated the relationship between lesion load changes over time and lesion load at a baseline evaluation in a group of untreated patients with MS. We scanned nineteen patients on two separate occasions with a mean interval 16.4 months between the two examinations. In each scanning session, a scan with forty contiguous 3-mm-thick axial slices was acquired. We assessed MRI lesion loads using a semi-automated local thresholding technique. Both a linear (p < 0.0001) and a quadratic component (p = 0.0008) of the baseline volume were significant in describing the follow-up volume. The equation to model this finding was as follows: Vf = beta0 Vb + beta1 (Vb)2, where Vf is the lesion volume at follow-up, Vb is the lesion volume at baseline, beta0 = 0.834 (SE = 0.098), and beta1 = 0.014 (SE = 0.003) (mL)(-1). Our data indicate that lesion volume changes detectable on serial brain MRI studies from patients with MS are dependent on the extent of lesion burden present on the baseline MRI scans. This finding has to be considered when planning phase III trials.

Adult↗
PubMed1998

Brain MRI lesion volume measurement reproducibility is not dependent on the disease burden in patients with multiple sclerosis.

We evaluated the potential effect of the lesion burden on the reproducibility of repeated lesion volume (LV) measurements from brain magnetic resonance imaging (MRI) scans of patients with multiple sclerosis (MS). Dual-echo, conventional spin echo brain MRI scans were obtained from 107 patients with MS. On proton density-weighted images, LV was assessed three times by the same raters, using a semi-automated, local thresholding technique for lesion segmentation. Mean LV (MLV) was 16.1 mL (range = 0.7-57.3 mL). The mean intra-observer coefficient of variation (COV) for the three measurement replicates was 2.6% (range = 0.2-7.2%). The intra-observer measurement variance (Var) increased with MLV and the fitted model was Var = 0.00187 MLV1.84. This indicates that LV measurements can be considered as measures whose variances are proportional to the square of their mean values, i.e., these measures have constant COV. Using a semi-automated, local thresholding segmentation technique, the reproducibility of LV measurements from brain MRI scans of patients with MS is not significantly influenced by varying lesion burdens.

Analysis of Variance↗
PubMed1998

A multi-centre longitudinal study comparing the sensitivity of monthly MRI after standard and triple dose gadolinium-DTPA for monitoring disease activity in multiple sclerosis. Implications for phase II clinical trials.

In this study we assessed the safety, efficacy and cost-effectiveness of the use of triple dose gadolinium-DTPA (Gd) in serial monthly brain MRI of patients with multiple sclerosis, such as could be selected for clinical trials. The number of enhancing lesions, the number of new enhancing lesions and the number of active scans were used to evaluate the sensitivity of the contrast-enhanced MRI to disease activity. The dose of Gd, and the effect of introducing a delay between the contrast injection and the scan were both appraised. Every 4 weeks for 3 months, and in two separate sessions, scans were obtained from 40 patients with relapsing-remitting or secondary progressive multiple sclerosis, 5 min (early) and 20 min (delayed) after a standard dose (0.1 mmol/kg) or triple dose (0.3 mmol/kg) Gd injection. There were 435 enhancing lesions (242 of which were new) on the early standard dose scans, 479 (263 new) on the delayed standard dose, 772 (365 new) on the early triple dose and 827 (404 new) on the delayed triple dose. There were 109 scans revealing active disease on the early standard dose scans, 112 on the delayed standard dose, 119 on the early triple dose and 120 on the delayed triple dose. Statistical simulations indicated that the sample sizes needed for both cross-over and parallel-group trials with similar powers are lower if serial monthly triple dose MRI is used. No side-effects were reported and no significant changes in blood test parameters were found throughout the study. This study shows that the serial use of triple dose Gd is safe, and that it increases the sensitivity of serial monthly enhanced MRI in detecting multiple sclerosis activity significantly. Its use should enable preliminary trials of experimental therapies for multiple sclerosis to be conducted in small patient populations, over a short period of time.

Adult↗