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Massimo Filippi

Publications and source records attributed to Massimo Filippi.

At least 73 records · Page 4Linked to original sources
PubMed2004

Imaging primary progressive multiple sclerosis: the contribution of structural, metabolic, and functional MRI techniques.

Patients with primary progressive multiple sclerosis (PPMS) typically experience a progressive disease course from onset, leading to the accumulation of severe neurological disability. This is in contrast with the observation that the burden and activity of lesions on conventional magnetic resonance imaging (MRI) scans of the brain are much lower in patients with PPMS than in those with other less disabling forms of the disease. Studies with structural and functional MRI techniques are providing relevant contributions to the understanding of the mechanisms underlying the accumulation of irreversible neurological deficits in patients with PPMS. The results of these studies underpin that the main factors possibly explaining the clinical/MRI discrepancy observed in patients with PPMS include the presence of a diffuse tissue damage that is beyond the resolution of conventional imaging, the extent of cervical cord damage, and the impairment of the adaptive capacity of the cortex to limit the functional consequences of subcortical pathology.

Central Nervous System↗
PubMed2004

The use of magnetic resonance imaging in multiple sclerosis: lessons learned from clinical trials.

Magnetic resonance imaging (MRI) is an important paraclinical tool for the diagnosis of multiple sclerosis (MS) and for monitoring its disease course. The efficacy of most of the available MS disease-modifying treatments has been tested in clinical trials where MRI-derived quantities served as primary or secondary outcome measures. However, conventional MRI measures (i.e., the number and volume of contrast-enhancing, the volumes of T2-hyperintense and T1-hypointense lesions and the assessment of brain volume changes) are limited in terms of pathological specificity and, as a consequence, are modestly correlated with clinical measures of disease activity and have a modest prognostic value as predictors of MS evolution. In the present review, we discuss the main factors potentially responsible for the so-called 'clinical MRI paradox' and how modern quantitative MR-based techniques might contribute to, at least partially, overcome it. The lessons learned from MS trials suggest that future applications of MRI to assess MS evolution should rely upon the use of composite measures thought to reflect the various components of the disease, as well as on study protocols specifically designed on the individual trial characteristics.

Clinical Trials as Topic↗
PubMed2004

A new method for analyzing histograms of brain magnetization transfer ratios: comparison with existing techniques.

BACKGROUND AND PURPOSE: Previously reported quantitative parameters for the magnetization transfer ratio (MTR) do not give identical results, which can limit their ability to differentiate normal from diseased tissue and render them vulnerable to variations among MR systems. Our purpose was to systematically study different MTR metrics; propose a new MTR histogram parameter, AMTR(2/3); and compare AMTR(2/3) with existing parameters in a study of multiple sclerosis (MS). METHODS: Seven conventional MTR parameters were proposed: global and mean MTR; peak height and position of the histogram; and percentiles MTR25, MTR50, and MTR75. Additionally, we investigated a parameter, AMTR(2/3), to indicate the normalized pixel count (area under the histogram curve) inside the band size of two-thirds MTR histogram peak height. All parameters were measured in 10 patients with relapsing-remitting MS (group A), 10 healthy control subjects from the same imaging center as that of patients (group B), and four healthy control subjects from an outside institution (group C). Comparison of findings was performed between groups A and B to assess the discriminating ability of MTR parameters and groups B and C to evaluate intersystem variations. RESULTS: All MTR parameters differed between groups A and B, but the difference was significant for only global MTR, mean MTR, MTR25, and AMTR(2/3). With the exception of AMTR(2/3), all parameters differed significantly between the two control groups. CONCLUSION: AMTR(2/3) is less sensitive to MR imaging system variations than are other MTR parameters and was most effective in differentiating patients with MS from healthy control subjects. This finding supports the use of AMTR(2/3) in multicenter MT MR imaging studies of MS.

Adult↗
PubMed2003

Conventional and magnetization transfer MRI predictors of clinical multiple sclerosis evolution: a medium-term follow-up study.

The correlation between conventional MRI lesion load accumulation and multiple sclerosis clinical evolution is only modest. The assessment of brain parenchymal volume and of its changes over time may provide adjunctive MRI markers reflecting the more disabling aspects of multiple sclerosis pathology. Magnetization transfer (MT) MRI is sensitive to 'occult' multiple sclerosis-related brain damage and might also contribute to overcome the clinical/MRI paradox. In this study, we assessed the value of conventional and MT MRI-derived metrics in predicting the medium-term clinical evolution of patients with different multiple sclerosis phenotypes. We studied 73 patients, with relapsing-remitting multiple sclerosis (n = 34), secondary progressive multiple sclerosis (n = 19) and clinically isolated syndromes suggestive of multiple sclerosis (n = 20), and 16 healthy subjects. Brain dual-echo, T1-weighted (only in patients) and MT MRI scans were obtained at baseline and after 12 months. T2-hyperintense and T1-hypointense lesion volumes, normalized brain volume and average lesion MT ratio (MTR) were measured. MTR histograms from the whole brain tissue were also obtained. Clinical multiple sclerosis evolution and neurological disability were re-assessed in all patients after a median follow-up of 4.5 years. A multivariate analysis was performed to establish which clinical and MRI-derived variables were significant predictors of neurological deterioration at the end of the study period. At the end of follow-up, 34 patients showed significant neurological deterioration. The final multivariable model included average brain MTR percentage change after one year [P = 0.02, odds ratio (OR) = 0.86] and baseline T2-hyperintense lesion volume (P = 0.04, OR=1.04) as independent predictors of medium-term disability accumulation (r2 = 0.23). In this cohort of patients, abnormal values of average brain MTR changes showed a relatively high specificity (76.9%) and positive predictive value (59.1%) for Expanded Disability Status Scale score deterioration in individual cases. In patients with multiple sclerosis, a comprehensive estimation of the short-term changes of both conventional and MT MRI-detectable lesion burden might provide useful prognostic information for the medium-term clinical disease evolution.

Adult↗
PubMed2003

Age-related changes in conventional, magnetization transfer, and diffusion-tensor MR imaging findings: study with whole-brain tissue histogram analysis.

PURPOSE: To investigate the influence of aging on conventional magnetic resonance (MR) imaging-, magnetization transfer MR imaging-, and diffusion-tensor MR imaging-derived measurements. MATERIALS AND METHODS: Dual-echo T1-weighted magnetization transfer and diffusion-tensor MR images of the brain were obtained in 89 healthy subjects. Normalized brain parenchymal volume (NBV) was measured by using a fully automated technique. Magnetization transfer ratio (MTR), apparent diffusion coefficient (ADC), and fractional anisotropy (FA) histograms were created for the whole brain (MTR values) or for a large representative portion of it (ADC and FA values). Bivariate correlations were assessed by using the Spearman rank correlation coefficient. A stepwise selection procedure was used to identify the combination of variables that were most influenced by subject age in a multivariate regression model. RESULTS: Significant correlations were found between subject age and the following variables: number of hyperintense areas in the brain at T2-weighted MR imaging (r = 0.63, P <.001), NBV (r = -0.79, P <.001), mean ADC (r = 0.34, P =.001), ADC peak height (r = -0.34, P =.001), and FA peak height (r = -0.57, P <.001). NBV correlated significantly with number of hyperintense areas (P <.001), MTR peak height (P <.001), mean ADC (P =.001), ADC peak height (P =.001), and FA peak height (P <.001). The final multivariable regression model included NBV and number of hyperintense areas at T2-weighted MR imaging as independent predictors of subject age. CONCLUSION: In addition to the extent of T2-weighted MR imaging hyperintense areas and the measurement of NBV, diffusion-tensor MR imaging provides additional in vivo information about microstructural age-related brain tissue changes.

Adult↗
PubMed2003

MRI-clinical correlations in the primary progressive course of MS: new insights into the disease pathophysiology from the application of magnetization transfer, diffusion tensor, and functional MRI.

Despite patients with primary progressive multiple sclerosis (PPMS) experience a progressive disease course from onset, the burden and activity of lesions on conventional magnetic resonance imaging (MRI) scans of the brain are lower than in all other main clinical phenotypes of MS. This review outlines the major contributions given by magnetization transfer MRI, diffusion tensor MRI and functional MRI to the understanding of the pathophysiology of PPMS and provides evidence that, at least, three factors might explain this clinical/MRI discrepancy: (a) the presence of a diffuse tissue damage at a microscopic level; (b) a prevalent involvement of the cervical cord, and (c) an impairment of the adaptive capacity of the cortex to limit the functional consequences of subcortical structural damage.

Brain↗
PubMed2003

Evidence for cortical functional changes in patients with migraine and white matter abnormalities on conventional and diffusion tensor magnetic resonance imaging.

BACKGROUND: In this study, we used functional MRI (fMRI) to investigate the pattern of cortical activations after a simple motor task in patients with migraine and white matter (WM) abnormalities on conventional MRI scans of the brain. We also investigated whether the extent of brain activations was correlated with WM structural pathology measured using diffusion tensor (DT) MRI. METHODS: From 15 right-handed patients with migraine and 15 sex- and age-matched, right-handed healthy volunteers, we obtained the following: (1) fMRI (repetitive flexion-extension of the last 4 fingers of the right hand), (2) dual-echo turbo spin echo scans, and (3) pulsed-gradient spin-echo echo-planar sequence to calculate DT-MRI maps. fMRI analysis was performed using SPM99 and cluster detection. We measured the volume, the average mean diffusivity (), and the average fractional anisotropy of all lesions seen on the dual-echo scans. histograms of the normal-appearing WM were also produced. RESULTS: Compared with healthy volunteers, migraine patients had a larger relative activation of the contralateral primary sensorimotor cortex (P=0.01) and a rostral displacement of the supplementary motor area (P=0.03). The shapes of the curves reflecting the time course for fMRI signal intensity changes were similar between migraine patients and controls for all of the cortical areas we studied. Compared with healthy subjects, migraine patients had significantly lower histogram peak height of the normal-appearing WM histogram (P=0.02), which was found to be correlated with the extent of displacement of the supplementary motor area (r=-0.80, P<0.001). CONCLUSIONS: This study suggests that functional cortical changes occur in patients with migraine and brain MRI abnormalities and that they might be secondary to the extent of subcortical structural damage.

Adolescent↗
PubMed2003

A diffusion tensor MRI study of basal ganglia from patients with ADEM.

Using diffusion tensor (DT) MRI and histogram analysis, we measured mean diffusivity ((-)D) of basal ganglia grey matter (GM) from eight patients with acute disseminated encephalomyelitis (ADEM), 10 patients with multiple sclerosis (MS), and 10 healthy controls. Patients with ADEM had higher average (-)D (p=0.02) and lower (-)D histogram peak height (p=0.008) of the basal ganglia GM than patients with MS. Microscopic tissue damage occurs in the basal ganglia of ADEM patients, but not in MS patients with a similar burden of MRI-visible brain lesions.

Adult↗
PubMed2003

Evidence of subtle gray-matter pathologic changes in healthy elderly individuals with nonspecific white-matter hyperintensities.

OBJECTIVE: To investigate whether additional "occult" tissue changes can be detected in the normal-appearing white matter and gray matter of otherwise normal elderly individuals with nonspecific white-matter hyperintensities on conventional magnetic resonance images of the brain. METHODS: Conventional and magnetization transfer magnetic resonance images were obtained from 12 otherwise normal elderly subjects with white-matter hyperintensities and 11 age- and sex-matched normal individuals. After automatic tissue segmentation, image coregistration, and masking of T2-visible lesions, we obtained magnetization transfer ratio histograms of the normal-appearing white matter and gray matter. For each histogram, the average magnetization transfer ratio, the peak height, and the peak position were measured. We also calculated the percentages of gray-matter and white-matter volumes normalized over the total volume of the intracranial content and the total normalized brain volumes. RESULTS: Average magnetization transfer ratio (P =.03) and mean peak position (P =.01) of the gray-matter histograms from elderly individuals with white-matter hyperintensities were significantly lower than the corresponding quantities from those without white-matter hyperintensities. The normalized percentages of gray and white matter and normalized brain volume did not differ between the 2 groups. The average gray-matter magnetization transfer ratio was correlated with the average lesion magnetization transfer ratio (r = 0.68; P<.01). CONCLUSIONS: This study shows that brain abnormalities in otherwise normal elderly subjects with nonspecific white-matter hyperintensities extend beyond the macroscopic white-matter lesions visualized on conventional magnetic resonance images.

Aged↗
PubMed2003

Validation of diagnostic magnetic resonance imaging criteria for multiple sclerosis and response to interferon beta1a.

In the recently proposed diagnostic criteria for multiple sclerosis (MS) by McDonald, the modified magnetic resonance imaging (MRI) Barkhof criteria have been incorporated. We examined the validity of this implementation in the Early Treatment of MS study, a randomized, double-blind, placebo-controlled study of 22 microg interferon beta1a given subcutaneously once weekly in 309 patients with a first episode consistent with demyelinating disease (and abnormal MRI). Conversion to clinically definite MS (CDMS) within 2 years of follow-up, as evidenced by a new clinical episode, occurred in 41% of patients (independent of treatment) with gadolinium enhancement or nine or more T2 lesions versus 11% of those without either finding (p = 0.017); similarly, proportions converting were 44% versus 31% for infratentorial lesions (p = 0.026), 40% versus 35% for juxtacortical lesions (p = 0.413), and 41% versus 17% for three or more periventricular lesions (p = 0.034). The rate of conversion to CDMS based on the number of modified Barkhof criteria was 22% for two or fewer positive criteria, increasing to 47% with four positive criteria. For a cutoff of three positive criteria, the hazard ratio for time to CDMS was 2.3 (95% confidence interval, 1.17-4.55; p = 0.016). Treatment effect seemed more evident as the number of positive criteria increased, and the number of patients needed to avoid one patient converting to CDMS decreased from 50 in patients with one or two positive criteria to 5.6 in patients with four positive criteria. However, the study was not powered to detect statistically significant treatment by variable interaction, and this remains an important issue for further study.

Adjuvants, Immunologic↗
PubMed2003

Guidelines for using quantitative magnetization transfer magnetic resonance imaging for monitoring treatment of multiple sclerosis.

Quantitative evaluation of brain magnetic resonance imaging (MRI) scans is now an accepted part of the trial of new putative treatments for multiple sclerosis (MS). However, conventional MRI is not pathologically specific, and it does not reveal the details of the pathological processes that underlie the progression of the disease. Magnetization transfer (MT) imaging is a relatively new quantitative technique that appears to offer some pathological specificity, and can be used to monitor the changes over time in both individual lesions and the central nervous system as a whole. This paper considers the case for incorporating MT imaging into new clinical trials, so that the utility of MT for monitoring the modification of MS progression by treatment can be assessed. Specific guidelines for implementing MT imaging as part of a large multicenter clinical trial are given, and practical considerations when planning such a trial are detailed. It is anticipated that MT imaging will be incorporated into many new trials in the near future.

Brain↗
PubMed2003

Occult tissue damage in patients with primary progressive multiple sclerosis is independent of T2-visible lesions--a diffusion tensor MR study.

Although quantitative magnetic resonance (MR) studies have shown that primary progressive multiple sclerosis (PPMS) patients have subtle and diffuse changes of the normal-appearing brain tissue (NABT), the nature of these changes is still poorly understood. The aim of this study was to improve our understanding of the NABT damage in PPMS patients by comparing diffusion tensor magnetic resonance (DT MR) quantities of a large portion of the brain from these patients with those from healthy subjects with and without T2-visible lesions. Dual-echo and DT MR images of the brain were obtained from 20 patients with PPMS, 20 age- and gender-matched healthy volunteers with normal conventional MR scans of the brain, and 20 age-, gender- and T2 lesion volume-matched healthy subjects. Mean diffusivity (MD) and fractional anisotropy (FA) histograms of the NABT were derived from all the individuals. Average lesion MD and FA were calculated in PPMS patients and healthy controls with T2-visible lesions. MD and FA histogram-derived metrics of the NABT from PPMS patients differed significantly from the corresponding quantities from healthy volunteers with no brain T2-visible lesions and from those from healthy volunteers with overt brain MR abnormalities (p values ranging from < 0.0001 to 0.01). Average lesion MD was also significantly higher in PPMS patients than in healthy volunteers with T2-visible lesions (p = 0.03). In PPMS patients, no significant correlation was found between any of the DT MR quantities of NABT damage and a) the T2 lesion volume, b) the average lesion MD, and c) the normalized brain volume. This study shows that in PPMS patients there is a significant microscopic damage of the NABT which is independent of the extent of T2-visible abnormalities. This suggests that Wallerian degeneration of fibers passing through macroscopic abnormalities is not a major factor contributing to diffuse NABT pathology of these patients.

Adult↗
PubMed2003

Demyelination and cortical reorganization: functional MRI data from a case of subacute combined degeneration.

Although it is accepted that functional changes of the cortex can occur in patients with white matter diseases of the brain and might have an adaptive role in limiting the clinical consequences of subcortical injury, the pathological substrates able to elicit such cortical changes are still unknown. This multiparametric magnetic resonance study of a patient with an early diagnosis of subacute combined degeneration suggests that demyelination alone does not necessarily induce adaptive functional changes of the cerebral cortex.

Cerebral Cortex↗
PubMed2003

Evidence for axonal pathology and adaptive cortical reorganization in patients at presentation with clinically isolated syndromes suggestive of multiple sclerosis.

Previous work has suggested that functional reorganization of cortical areas might have a role in limiting the clinical impact of axonal pathology in patients with established multiple sclerosis (MS). Since there is evidence for irreversible tissue damage even in patients with early MS, we assessed, using functional MRI (fMRI) and a general search method, the brain pattern of movement-associated cortical activations in patients at presentation with clinically isolated syndromes (CIS) suggestive of MS. To elucidate the role of cortical reorganization in these patients, we also investigated the extent to which the fMRI changes correlated with the extent of overall axonal injury of the brain. From 16 right-handed patients at presentation with CIS and 15 right-handed, age- and sex-matched healthy volunteers, we obtained: (1). fMRI (repetitive flexion-extension of the last four fingers of the right hand), (2). conventional MRI scans, and (3). a new, unlocalized proton MR spectroscopy ((1)HMRS) sequence to measure the concentration of N-acetylaspartate of the whole brain (WBNAA). Compared to controls, patients with CIS had more significant activations of the contralateral primary somatomotor cortex (SMC), secondary somatosensory cortex, and inferior frontal gyrus. They also had significant decreased WBNAA concentration. Relative activation of the contralateral primary SMC was strongly correlated with WBNAA levels (r = -0.78, P < 0.001). This study shows that axonal pathology and functional cortical changes over a rather distributed sensorimotor network occur in patients at presentation with CIS suggestive of MS and that these two aspects of the disease are strictly correlated. This suggests that the increased functional recruitment of the cortex in these patients might have an adaptive role in limiting the clinical impact of irreversible tissue damage.

Adaptation, Physiological↗
PubMed2003

Functional cortical changes in patients with multiple sclerosis and nonspecific findings on conventional magnetic resonance imaging scans of the brain.

Recent functional magnetic resonance imaging (fMRI) work has suggested that cortical reorganisation might have an adaptive role in limiting the clinical impact of multiple sclerosis (MS) structural damage. In this study, we investigated whether, in patients with MS, the presence and extent of structural damage of the normal-appearing brain tissue are associated with the extent of the movement-associated pattern of cortical activations. Using fMRI and a general search method, we assessed the patterns of brain activations associated with simple motor tasks in 12 right-handed patients with clinically definite MS and nonspecific T2-weighted abnormalities on conventional MRI scans of the brain and compared them with those from 12 sex- and age-matched right- handed healthy controls. Also investigated were the extent to which the fMRI changes correlated with normal-appearing white matter and grey matter (GM) pathology, measured using diffusion tensor MRI. When performing the simple motor task with the dominant hand, MS patients had more significant activations of the ipsilateral supplementary motor area (SMA), the ipsilateral superior frontal sulcus, the contralateral superior temporal gyrus, and the thalamus than controls. On the contrary, healthy subjects showed more significant activations of the medial part of the contralateral parieto-occipital fissure and the ipsilateral primary sensorimotor cortex (SMC) than patients with MS. In patients with MS, the relative activation of the ipsilateral SMA was correlated with the peak height (r = -0.88, P < 0.001) and position (r = 0.87, P < 0.001) of the GM mean diffusivity histogram. This study shows that cortical reorganisation occurs over a rather distributed sensorimotor network even in patients with MS and nonspecific abnormalities on conventional brain MRI scans. This suggests that, in patients with MS, an increased recruitment of movement-associated cortical network can be elicited by the presence of normal-appearing tissue pathology, which is independent of macroscopic T2-weighted abnormalities.

Adult↗
PubMed2003

A functional magnetic resonance imaging study of patients with secondary progressive multiple sclerosis.

Although several functional magnetic resonance imaging (fMRI) studies have shown adaptive cortical changes in patients with early multiple sclerosis (MS), the presence of brain plasticity and its role in limiting the functional consequences of brain tissue damage in patients with secondary progressive (SP) MS have not been fully investigated yet. In this study, we assessed the movement-associated brain pattern of cortical activations in patients with SPMS and investigated whether the extent of cortical brain activations is correlated with the extent of brain structural changes. From 13 right-handed SPMS patients and 15 sex- and age-matched healthy volunteers, we obtained: (a) brain dual-echo scans; (b) brain mean diffusivity and fractional anisotropy maps of the normal-appearing white (NAWM) and gray matter (NAGM); (c) fMRI during the performance of simple motor tasks [flexion-extension of the last four fingers of the right hand (task 1) and flexion-extension of the right foot (task 2)]. Compared to healthy volunteers, during task 1 performance, SPMS patients showed more significant activations of the ipsilateral inferior frontal gyrus, middle frontal gyrus, bilaterally, and contralateral intraparietal sulcus. During task 2 performance, SPMS patients had more significant activations of the contralateral primary sensorimotor cortex and thalamus and of the ipsilateral upper bank of sylvian fessure. For both tasks, strong correlations (r values ranging from -0.83 to 0.88) were found between relative activations of cortical areas of the motor network and the severity of structural changes of the NAWM and NAGM. This study demonstrates that cortical plasticity does occur in patients with SPMS and that it might have a role in limiting the clinical impact of MS-related damage. It also suggests that, in these patients, functional abilities are sustained by increased recruitment of highly specialized cortical areas.

Adult↗
PubMed2003

The use of quantitative magnetic-resonance-based techniques to monitor the evolution of multiple sclerosis.

Conventional MRI can improve accuracy in the diagnosis of multiple sclerosis (MS) and monitor the efficacy of experimental treatments. However, conventional MRI provides only gross estimates of the extent and nature of tissue damage associated with this disease. Other quantitative magnetic-resonance-based techniques have the potential to overcome the limitations of conventional MRI and, as a consequence, to improve our understanding of the natural history of MS. Magnetisation-transfer, diffusion-weighted, and functional MRI--as well as proton magnetic-resonance spectroscopy--are helping us to elucidate the mechanisms that underlie injury, repair, and functional adaptation in patients with MS. These techniques are substantially changing our understanding of how MS causes irreversible disability and should be used more extensively in clinical trials and in studies of disease progression.

Brain Mapping↗