Paola Tortorella

Istituto di Cura e Cura a Carattere Scientifico Basilicata, Rionero in Vulture, Basilicate, Italy

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Publications (18)62.38 Total impact

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    ABSTRACT: Primary progressive multiple sclerosis (PPMS) and amyotrophic lateral sclerosis (ALS) seem to share some clinical and pathological features. MRI studies revealed the presence of grey matter (GM) atrophy in both diseases, but no comparative data are available. The objective was to compare the regional patterns of GM tissue loss in PPMS and ALS with voxel-based morphometry (VBM). Eighteen PPMS patients, 20 ALS patients, and 31 healthy controls (HC) were studied with a 1.5 Tesla scanner. VBM was performed to assess volumetric GM differences with age and sex as covariates. Threshold-free cluster enhancement analysis was used to obtain significant clusters. Group comparisons were tested with family-wise error correction for multiple comparisons (p < 0.05) except for HC versus MND which was tested at a level of p < 0.001 uncorrected and a cluster threshold of 20 contiguous voxels. Compared to HC, ALS patients showed GM tissue reduction in selected frontal and temporal areas, while PPMS patients showed a widespread bilateral GM volume decrease, involving both deep and cortical regions. Compared to ALS, PPMS patients showed tissue volume reductions in both deep and cortical GM areas. This preliminary study confirms that PPMS is characterized by a more diffuse cortical and subcortical GM atrophy than ALS and that, in the latter condition, brain damage is present outside the motor system. These results suggest that PPMS and ALS may share pathological features leading to GM tissue loss.
    09/2014;
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    ABSTRACT: T-cell immunoglobulin and mucin domain 3 (Tim-3) ligates galectin-9 (Gal-9); this process, resulting in the inhibition of Th1 responses and in the apoptosis of antigen-specific cells, is hampered by binding of the molecular adaptor human leukocyte antigen B (HLA-B)-associated transcript 3 (Bat3) to the intracellular tail of Tim-3. Apoptosis of myelin basic protein (MBP)-specific T lymphocytes correlates with reduced rates of disease progression in multiple sclerosis (MS). We extensively analyzed the Tim-3/Gal-9/Bat3 pathway in 87 patients with a diagnosis of stable relapsing-remitting MS (RRMS), primary progressive MS (PPMS), or benign MS (BEMS), as well as in 40 healthy control (HC) subjects. Results showed that MBP-specific CD4(+)Tim-3(+), CD4(+)/Gal-9(+), and CD4(+)/Tim-3(+)/AV(+) (apoptotic) T lymphocytes were augmented in the BEMS group, whereas CD4(+)/Bat3(+) and CD8(+)/Bat3(+) T lymphocytes were increased and CD4(+)/Tim-3(+)/AV(+) T cells were reduced in the PPMS group (>2 fold and P<0.05 in all cases). Blocking the Tim-3/Gal-9 interaction with specific mAb reduced T-lymphocyte apoptosis and augmented production of IFNγ and IL-17 in the BEMS, RRMS, and HC groups, but not in the PPMS group. The Tim-3/Gal-9 interaction favors apoptosis of MBP-specific T lymphocytes in BEMS; this process is reduced in PPMS by the up-regulation of Bat3. Therapeutic interventions aimed at silencing Bat3 could be beneficial in MS.-Saresella, M, Piancone, F., Marventano, I., La Rosa, F., Tortorella, P., Caputo, D., Rovaris, M., Clerici, M. A role for the TIM-3/GAL-9/BAT3 pathway in determining the clinical phenotype of multiple sclerosis.
    FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 08/2014;
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    ABSTRACT: Despite advances in the application of nonconventional MRI techniques in furthering the understanding of multiple sclerosis pathogenic mechanisms, there are still many unanswered questions, such as the relationship between gray and white matter damage. We applied a combination of advanced surface-based reconstruction and diffusion tensor imaging techniques to address this issue. We found significant relationships between white matter tract integrity indices and corresponding cortical structures. Our results suggest a direct link between damage in white and gray matter and contribute to the notion of gray matter loss relating to clinical disability.
    SPIE Medical Imaging; 03/2014
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    ABSTRACT: Multiple sclerosis (MS) is characterized by a wide interpatient clinical variability and available biomarkers of disease severity still have suboptimal reliability. We aimed to assess immunological and MRI-derived measures of brain tissue damage in patients with different motor impairment degrees, for in vivo investigating the pathogenesis of MS-related disability. Twenty-two benign (B), 26 secondary progressive (SP), and 11 early, nondisabled relapsing-remitting (RR) MS patients and 37 healthy controls (HC) underwent conventional and diffusion tensor brain MRI and, as regards MS patients, immunophenotypic and functional analysis of stimulated peripheral blood mononuclear cells (PBMC). Corticospinal tract (CST) fractional anisotropy and grey matter volume were lower and CST diffusivity was higher in SPMS compared to RRMS and BMS patients. CD14+IL6+ and CD4+IL25+ cell percentages were higher in BMS than in SPMS patients. A multivariable model having EDSS as the dependent variable retained the following independent predictors: grey matter volume, CD14+IL6+ and CD4+IL25+ cell percentages. In patients without motor impairment after long-lasting MS, the grey matter and CST damage degree seem to remain as low as in the earlier disease stages and an immunological pattern suggestive of balanced pro- and anti-inflammatory activity is observed. MRI-derived and immunological measures might be used as complementary biomarkers of MS severity.
    BioMed research international. 01/2014; 2014:875768.
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    ABSTRACT: TLR-dependent signal transduction pathways were analyzed in patients with a diagnosis of either relapsing-remitting (RRMS), secondary progressive (PMS) or benign (BMS) MS and healthy controls (HC). Prototypical TLR molecules expressed either on the cell surface (TLR4) or intracellularly (TLR3) were stimulated with specific antigens (LPS and poly I:C, respectively). Expression of factors involved in TLR signaling cascades, production of downstream immune mediators and TLR expression were evaluated. Results showed that, whereas LPS-stimulation of TLR4 had a marginal effect on cell activation, poly I:C-stimulated TLR3 expression on immune cells was significantly increased in PMS and BMS compared to HC. This was associated with a higher responsiveness to poly I:C that resulted in the activation of the TLR3-mediated pathway and the production of inflammatory cytokines in PMS and, in contrast, in the up-regulation of a peculiar mosaic of inflammation-dampening genes in BMS. Results herein might explain different MS disease phenotypes.
    Clinical Immunology 11/2013; 150(1):109-120. · 3.77 Impact Factor
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    ABSTRACT: 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. 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. 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). 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. 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.
    Multiple Sclerosis 06/2013; · 4.47 Impact Factor
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    ABSTRACT: MS (multiple sclerosis) and ALS (amyotrophic lateral sclerosis) differ in important respects, but common pathogenic features seem to be shared in these two diseases. To shed light on such features, immunophenotypic and functional analysis were performed in peripheral monocytes and T lymphocytes of ALS and primary progressive (PP) MS patients and healthy controls (HC). Results showed that TH1-, TH17-, and IL-6-driven inflammation characterize both diseases; this is unsuccessfully hampered by TH2 activation and, possibly, BDNF secretion. Results herein clarify the pathogenic similarities between ALS and PP-MS and could be helpful for the design of novel diagnostic and therapeutic approaches to ALS.
    Clinical Immunology 04/2013; 148(1):79-88. · 3.77 Impact Factor
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    ABSTRACT: 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.
    Cephalalgia 10/2008; 28(10):1061-8. · 3.49 Impact Factor
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    ABSTRACT: 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.
    Journal of Neurology 05/2008; 255(5):683-91. · 3.58 Impact Factor
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    ABSTRACT: 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). 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. 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. 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.
    Neurology 02/2008; 70(4):255-62. · 8.30 Impact Factor
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    ABSTRACT: 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 T(2)-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 02/2008; 14(1):86-93. · 4.47 Impact Factor
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    ABSTRACT: 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.
    Human Brain Mapping 04/2007; 28(3):218-27. · 6.88 Impact Factor
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    ABSTRACT: 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 (p < or = 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 (p < or = 0.001) than controls. Moderate correlations were found between intrinsic lesion and tissue damage with both GM volumetric and diffusivity changes (-0.41 < or = r < or = 0.42, p < or = 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.
    Journal of Neurology 04/2007; 254(4):513-8. · 3.58 Impact Factor
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    ABSTRACT: 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 (p <0.0001) 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.
    Journal of Neurology 08/2006; 253(7):903-7. · 3.58 Impact Factor
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    ABSTRACT: 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. 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<0.001, uncorrected for multiple comparisons. 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). 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.
    Stroke 07/2006; 37(7):1765-70. · 6.16 Impact Factor
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    ABSTRACT: 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. 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. 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). DT MRI at high field strength discloses subtle grey matter damage in migraine patients, which might be associated with cognitive changes in these patients.
    Journal of Neurology Neurosurgery & Psychiatry 06/2006; 77(5):686-9. · 4.92 Impact Factor
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    ABSTRACT: In patients with migraine, functional changes have been described in the red nucleus (RN), substantia nigra (SN) and periaqueductal gray matter (PAG). 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. 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. 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). 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.
    Journal of the Neurological Sciences 06/2006; 244(1-2):137-41. · 2.24 Impact Factor
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    ABSTRACT: 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).
    American Journal of Neuroradiology 27(10):2115-7. · 3.17 Impact Factor