Publications by authors named "Elisabetta Pagani"

127 Publications

Prevalence and determinants of serum antibodies to SARS-CoV-2 in the general population of the Gardena valley.

Epidemiol Infect 2021 08 3;149:e194. Epub 2021 Aug 3.

Service for Innovation, Research and Teaching, Hospital of Bolzano (SABES-ASDAA), Bolzano-Bozen, Italy.

Estimating the spread of SARS-CoV-2 infection in communities is critical. We surveyed 2244 stratified random sample community members of the Gardena valley, a winter touristic area, amidst the first expansion phase of the COVID-19 pandemic in Europe. We measured agreement between Diasorin and Abbott serum bioassay outputs and the Abbott optimal discriminant threshold of serum neutralisation titres with recursive receiver operating characteristic curve. We analytically adjusted serum antibody tests for unbiased seroprevalence estimate and analysed the determinants of infection with non-response weighted multiple logistic regression. SARS-CoV-2 seroprevalence was 26.9% (95% CI 25.2-28.6) by June 2020. The bioassays had a modest agreement with each other. At a lower threshold than the manufacturer's recommended level, the Abbott assay reflected greater discrimination of serum neutralisation capacity. Seropositivity was associated with place and economic activity, not with sex or age. Symptoms like fever and weakness were age-dependent. SARS-CoV-2 mitigation strategies should account for context in high prevalence areas.
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http://dx.doi.org/10.1017/S0950268821001886DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8387688PMC
August 2021

Association of Age at Onset With Gray Matter Volume and White Matter Microstructural Abnormalities in People With Multiple Sclerosis.

Neurology 2021 Oct 4. Epub 2021 Oct 4.

Neuroimaging Research Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy

Objective: To investigate whether age at onset influences brain gray matter volume (GMV) and white matter (WM) microstructural abnormalities in adult multiple sclerosis (MS) patients, given its influence on clinical phenotype and disease course.

Method: In this hypothesis-driven cross-sectional study, we enrolled 67 pediatric-onset MS (POMS) patients and 143 sex- and disease duration (DD)-matched randomly-selected adult-onset MS (AOMS) patients, together with 208 healthy controls. All subjects underwent neurological evaluation and 3T MRI acquisition. MRI variables were standardized based on healthy controls, to remove effects of age and sex. Associations with DD in POMS and AOMS patients were studied with linear models. Time to reach clinical and MRI milestones was assessed with product-limit approach.

Results: At DD=1 year, GMV and WM fractional anisotropy (FA) were abnormal in AOMS but not in POMS patients. Significant interaction of age at onset (POMS AOMS) into the association with DD was found for GMV and WM FA. The crossing point of regression lines in POMS and AOMS patients was at 20 years of DD for GMV and 14 for WM FA. For POMS and AOMS patients, median DD was 29 and 19 years to reach Expanded Disability Status Scale=3 (p<0.001), 31 and 26 years to reach abnormal Paced Auditory Serial Addition Task-3 (p=0.01), 24 and 18 years to reach abnormal GMV (p=0.04), and 19 and 17 years to reach abnormal WM FA (p=0.36).

Conclusions: Younger patients are initially resilient to MS-related damage. Then, compensatory mechanisms start failing with loss of WM integrity, followed by GM atrophy and finally disability.
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http://dx.doi.org/10.1212/WNL.0000000000012869DOI Listing
October 2021

Functional and structural MRI correlates of executive functions in multiple sclerosis.

Mult Scler 2021 Aug 13:13524585211033184. Epub 2021 Aug 13.

Neuroimaging Research Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy/Neurology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy/Neurorehabilitation Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy/Neurophysiology Service, IRCCS San Raffaele Scientific Institute, Milan, Italy/Vita-Salute San Raffaele University, Milan, Italy.

Background: Executive dysfunctions, including difficulties in attention, working memory, planning, and inhibition affect 15%-28% of multiple sclerosis (MS) patients.

Objectives: To investigate structural and functional magnetic resonance imaging (MRI) abnormalities underlying executive function (EF) in MS patients.

Methods: A total 116 MS patients and 65 controls underwent resting-state (RS) and diffusion-weighted sequences and neuropsychological examination, including Wisconsin Card Sorting Test (WCST) to test EF. Brain RS cognitive networks and fractional anisotropy (FA) from a priori selected white matter tracts were derived. Associations of WCST scores with RS functional connectivity (FC) and FA abnormalities were investigated.

Results: In MS patients, predictors of working memory/updating were: lower corpus callosum (CC) FA, lower left working-memory network (WMN), right WMN RS FC for worse performance; lower executive control network (ECN), higher default-mode network (DMN), and salience network (SN) RS FC for better performance ( = 0.35). Predictors of attention were lower CC genu FA, lower left WMN, and DMN RS FC for worse performance; higher left WMN and ECN RS FC for better performance ( = 0.24). Predictors of worse shifting/inhibition were lower CC genu and superior cerebellar peduncle (SCP) FA, lower left WMN RS FC for worse performance; and higher ECN RS FC for better performance ( = 0.24).

Conclusions: CC and SCP microstructural damage and RS FC abnormalities in cognitive networks underlie EF frailty in MS.
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http://dx.doi.org/10.1177/13524585211033184DOI Listing
August 2021

Unraveling the substrates of cognitive impairment in multiple sclerosis: A multiparametric structural and functional magnetic resonance imaging study.

Eur J Neurol 2021 11 29;28(11):3749-3759. Epub 2021 Jul 29.

Neuroimaging Research Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy.

Background: Cognitive impairment frequently affects multiple sclerosis (MS) patients. However, its neuroanatomical correlates still need to be fully explored. We investigated the contribution of structural and functional magnetic resonance imaging (MRI) abnormalities in explaining cognitive impairment in MS.

Methods: Brain dual-echo, diffusion tensor, 3D T1-weighted and resting-state (RS) MRI sequences were acquired from 276 MS patients and 102 healthy controls. Using random forest analysis, the contribution of regional white matter (WM) lesions, WM fractional anisotropy (FA) abnormalities, gray matter (GM) atrophy and RS functional connectivity (FC) alterations to cognitive impairment in MS patients was investigated.

Results: Eighty-four MS patients (30.4%) were cognitively impaired. The best MRI predictors of cognitive impairment (relative importance [%]) (out-of-bag area under the curve [AUC] = 0.795) were (a) WM lesions in the right superior longitudinal fasciculus (100%), left anterior thalamic radiation (93.4%), left posterior corona radiata (78.5%), left medial lemniscus (74.2%), left inferior longitudinal fasciculus (70.4%), left optic radiation (68.7%), right middle cerebellar peduncle (60.6%) and right optic radiation (53.5%); (b) decreased FA in the splenium of the corpus callosum (64.3%), left optic radiation (61.0%), body of the corpus callosum (51.9%) and fornix (50.9%); and (c) atrophy of the left precuneus (91.4%), right cerebellum crus I (84.4%), right caudate nucleus (78.6%), left thalamus (76.2%) and left supplementary motor area (59.8%). The relevance of these MRI measures in explaining cognitive impairment was confirmed in a cross-validation analysis (AUC =0.765).

Conclusion: Structural damage in strategic WM and GM regions explains cognitive impairment in MS patients more than RS FC abnormalities.
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http://dx.doi.org/10.1111/ene.15023DOI Listing
November 2021

Network Damage Predicts Clinical Worsening in Multiple Sclerosis: A 6.4-Year Study.

Neurol Neuroimmunol Neuroinflamm 2021 07 21;8(4). Epub 2021 May 21.

From the Neuroimaging Research Unit (M.A.R.), Division of Neuroscience; and Neurology Unit, IRCCS San Raffaele Scientific Institute; Vita-Salute San Raffaele University (M.A.R., M.F.); Neuroimaging Research Unit (P.V., A.M., E.P., Claudio Cordani, Chiara Cervellin), Division of Neuroscience, IRCCS San Raffaele Scientific Institute; and Neuroimaging Research Unit (M.F.), Division of Neuroscience, Neurology Unit, Neurorehabilitation Unit, and Neurophysiology Service, IRCCS San Raffaele Scientific Institute, Milan, Italy.

Objective: In multiple sclerosis (MS), clinical impairment is likely due to both structural damage and abnormal brain function. We assessed the added value of integrating structural and functional network MRI measures to predict 6.4-year MS clinical disability deterioration.

Methods: Baseline 3D T1-weighted and resting-state functional MRI scans were obtained from 233 patients with MS and 77 healthy controls. Patients underwent a neurologic evaluation at baseline and at 6.4-year median follow-up (interquartile range = 5.06-7.51 years). At follow-up, patients were classified as clinically stable/worsened according to disability changes. In relapsing-remitting (RR) MS, secondary progressive (SP) MS conversion was evaluated. Global brain volumetry was obtained. Furthermore, independent component analysis identified the main functional connectivity (FC) and gray matter (GM) network patterns.

Results: At follow-up, 105/233 (45%) patients were clinically worsened; 26/157 (16%) patients with RRMS evolved to SPMS. The treatment-adjusted random forest model identified normalized GM and brain volumes, decreased FC between default-mode networks, increased FC of the left precentral gyrus in the sensorimotor network (SMN), and GM atrophy in the fronto-parietal network (false discovery rate [FDR]-corrected = range 0.01-0.09) as predictors of clinical worsening (out-of-bag [OOB] accuracy = 0.74). An expected contribution of baseline disability was also present (FDR-p = 0.01). Baseline disability, normalized GM volume, and GM atrophy in the SMN (FDR-p = range 0.01-0.09) were independently associated with SPMS conversion (OOB accuracy = 0.84). At receiver operating characteristic analysis, including network MRI variables improved disability worsening ( = 0.05) and SPMS conversion ( = 0.02) prediction.

Conclusions: Integration of MRI network measures helped determining the relative contributions of global/local GM damage and functional reorganization to clinical deterioration in MS.
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http://dx.doi.org/10.1212/NXI.0000000000001006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8143700PMC
July 2021

Impact of Prior Antibiotic Use in Primary Care on Resistance to Third Generation Cephalosporins: A Case-Control Study.

Antibiotics (Basel) 2021 Apr 16;10(4). Epub 2021 Apr 16.

Department of Medical Sciences and Public Health, Faculty of Medicine and Surgery, University of Cagliari, 09124 Cagliari, Italy.

Research is lacking on the reversibility of antimicrobial resistance (AMR). Thus, we aimed to determine the influence of previous antibiotic use on the development and decay over time of third generation cephalosporin (3GC)-resistance of . Using the database of hospital laboratories of the Autonomous Province of Bolzano/Bozen (Italy), anonymously linked to the database of outpatient pharmaceutical prescriptions and the hospital discharge record database, this matched case-control study was conducted including as cases all those who have had a positive culture from any site for 3GC resistant (3GCREC) during a 2016 hospital stay. Data were analyzed by conditional logistic regression. 244 cases were matched to 1553 controls by the date of the first isolate. Male sex (OR 1.49, 95% CI 1.10-2.01), older age (OR 1.11, 95% CI 1.02-1.21), the number of different antibiotics taken in the previous five years (OR 1.20, 95% CI 1.08-1.33), at least one antibiotic prescription in the previous year (OR 1.92, 95% CI 1.36-2.71), and the diagnosis of diabetes (OR 1.57, 95% CI 1.08-2.30) were independent risk factors for 3GCREC colonization/infection. Patients who last received an antibiotic prescription two years or three to five years before hospitalization showed non-significant differences with controls (OR 0.97, 95% CI 0.68-1.38 and OR 0.85, 95% CI 0.59-1.24), compared to an OR of 1.92 (95% CI 1.36-2.71) in those receiving antibiotics in the year preceding hospitalization. The effect of previous antibiotic use on 3GC-resistance of is highest after greater cumulative exposure to any antibiotic as well as to 3GCs and in the first 12 months after antibiotics are taken and then decreases progressively.
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http://dx.doi.org/10.3390/antibiotics10040451DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8073604PMC
April 2021

Survey of diagnostic and typing capacity for enterovirus infection in Italy and identification of two echovirus 30 outbreaks.

J Clin Virol 2021 04 27;137:104763. Epub 2021 Feb 27.

Department of Infectious Diseases, Istituto Superiore di Sanità, Rome, Italy. Electronic address:

Background: Enterovirus infections can cause a variety of illnesses, ranging from asymptomatic infections to severe illness and death.

Aim: To support polio eradication activities, in February 2019, the WHO Regional Reference Laboratory for polio in Italy, at the National Institute of Public Health (Istituto Superiore di Sanità), promoted an investigation on non-polio enterovirus laboratory capacity, with the support of the Italian Ministry of Health. The aim was to collect data on the assays used routinely for diagnostic purposes and to characterize enterovirus outbreaks strains by sequence analysis of the Viral Protein 1 region.

Methods: A questionnaire was administered to public health laboratories through all Italian Regions for 2018 and subsequently, an electronic form for lab-confirmed enterovirus infection reported from February 2019 to January 2020, including patients clinical characteristics, and laboratory data was distributed through 25 laboratories participating the survey.

Results: Overall, a homogenous laboratory capacity for enterovirus infection diagnosis was found and 21,000 diagnostic tests were retrospectively reported in 2018. Then, in 2019, two outbreaks of Echovirus 30 were identified and confirmed by molecular analyses.

Conclusion: These results underline the need monitor the circulation of non-polio enterovirus to ascertain the real burden of the disease in the country.
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http://dx.doi.org/10.1016/j.jcv.2021.104763DOI Listing
April 2021

Quantitative MRI adds to neuropsychiatric lupus diagnostics.

Rheumatology (Oxford) 2021 07;60(7):3278-3288

Università Vita-Salute San Raffaele.

Objective: Attributing neuropsychiatric manifestations to SLE is often challenging. Brain white matter lesions are frequent in SLE at MRI, but their diagnostic role is unclear. Here, we assessed whether white matter lesions count, volume and distribution measurement can help in the diagnosis of neuropsychiatric systemic lupus erythematosus (NPSLE).

Methods: Brain dual-echo and 3D T1-weighted sequences were acquired from 32 patients with SLE and 32 healthy controls with a 3 T-scanner and employed to derive T2-hyperintense lesion volume (T2LV), number (T2LN) and probability maps (LPM) using a semi-automatic local thresholding segmentation technique. NPSLE was classified as per the ACR nomenclature, the Italian Society for Rheumatology algorithm and by clinical impression. Clinical descriptors including the SLE International Collaborating Clinics/ACR damage index (SDI) were also recorded.

Results: Higher T2LV were observed in SLE vs healthy controls (P < 0.001) and in NPSLE vs other SLE (P =0.006). Patients with NPSLE also had higher T2LN (P =0.003) compared with other SLE. In SLE, T2LPM revealed a high prevalence of lesions in the splenium of the corpus callosum, right superior longitudinal fasciculus and right corona radiata. T2LV and T2LN correlated with SLE duration (rho = 0.606; P <0.001 and rho = 0.483; P =0.005, respectively) and age (rho = 0.478; P =0.006 and rho = 0.362; P = 0.042, respectively). T2LV also correlated with SDI (rho = 0.352; P =0.048). SLE patients with fatigue had lower T2LN (P =0.038) compared with patients without fatigue. Thresholds of T2LV ≥ 0.423 cm3 or of T2LN ≥ 12 were associated with definite NPSLE and improved the classification of patients with possible NPSLE per clinical impression.

Conclusion: Brain white matter lesions (WML) quantitation adds to NPSLE diagnostics.
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http://dx.doi.org/10.1093/rheumatology/keaa779DOI Listing
July 2021

Occurrence and microstructural features of slowly expanding lesions on fingolimod or natalizumab treatment in multiple sclerosis.

Mult Scler 2021 09 13;27(10):1520-1532. Epub 2020 Nov 13.

Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy/Neurology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy/Vita-Salute San Raffaele University, Milan, Italy.

Background: In multiple sclerosis (MS), up to 57% of white matter lesions are chronically active. These slowly expanding lesions (SELs) contribute to disability progression.

Objective: The aim of this study is to compare fingolimod and natalizumab effects on progressive linearly enlarging lesions (i.e. SELs), a putative biomarker of smouldering inflammation.

Methods: Relapsing-remitting MS patients starting fingolimod ( = 24) or natalizumab ( = 28) underwent 3T brain magnetic resonance imaging (MRI) at baseline, months 6, 12 and 24. SELs were identified among baseline-visible lesions showing ⩾ 12.5% of annual increase, calculated by linearly fitting the Jacobian of the nonlinear deformation field between timepoints obtained combining - and -weighted scans. SEL burden, magnetization transfer ratio (MTR) and signal intensity were compared using linear models.

Results: The prevalences of fingolimod (75%) and natalizumab patients (46%) with ⩾ 1 SEL were not significantly different (adjusted- = 0.08). Fingolimod group had higher SEL number and volume (adjusted- ⩽ 0.047, not false discovery rate (FDR) survived). In both groups, SELs versus non-SELs showed lower MTR and signal intensity (adjusted- ⩽ 0.01, FDR-survived). Longitudinally, non-SEL MTR increased in both treatment groups (adjusted- ⩽ 0.005, FDR-survived). signal intensity decreased in SELs with both treatments (adjusted- ⩽ 0.049, FDR-survived in fingolimod group) and increased in natalizumab non-SELs (adjusted- = 0.03, FDR-survived).

Conclusion: The effects of natalizumab and fingolimod on SEL occurrence seem modest, with natalizumab being slightly more effective. Both treatments may promote reparative mechanisms in stable or chronic inactive lesions.
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http://dx.doi.org/10.1177/1352458520969105DOI Listing
September 2021

MRI correlates of clinical disability and hand-motor performance in multiple sclerosis phenotypes.

Mult Scler 2021 07 14;27(8):1205-1221. Epub 2020 Sep 14.

Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy/Neurology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.

Background: Hand-motor impairment affects a large proportion of multiple sclerosis (MS) patients; however, its substrates are still poorly understood.

Objectives: To investigate the association between global disability, hand-motor impairment, and alterations in motor-relevant structural and functional magnetic resonance imaging (MRI) networks in MS patients with different clinical phenotypes.

Methods: One hundred thirty-four healthy controls (HC) and 364 MS patients (250 relapsing-remitting MS (RRMS) and 114 progressive MS (PMS)) underwent Expanded Disability Status Scale (EDSS) rating, nine-hole peg test (9HPT), and electronic finger tapping rate (EFTR). Structural and resting state (RS) functional MRI scans were used to perform a source-based morphometry on gray matter (GM) components, to analyze white matter (WM) tract diffusivity indices and to perform a RS seed-based approach from the primary motor cortex involved in hand movement (hand-motor cortex). Random forest analyses identified the predictors of clinical impairment.

Result: In RRMS, global measures of atrophy and lesions together with measures of structural damage of motor-related regions predicted EDSS (out-of-bag (OOB)- = 0.19, -range = <0.001-0.04), z9HPT (right: OOB- = 0.14; left: OOB- = 0.24, -range = <0.001-0.03). No RS functional connectivity (FC) abnormalities were identified in RRMS models. In PMS, cerebellar and sensorimotor regions atrophy, cerebellar peduncles integrity and increased RS FC between left hand-motor cortex and right inferior frontal gyrus predicted EDSS (OBB- = 0.16, -range = 0.02-0.04).

Conclusion: In RRMS, only measures of structural damage contribute to explain motor impairment, whereas both structural and functional MRI measures predict clinical disability in PMS. A multiparametric MRI approach could be relevant to investigate hand-motor impairment in different MS phenotypes.
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http://dx.doi.org/10.1177/1352458520958356DOI Listing
July 2021

Country Income Is Only One of the Tiles: The Global Journey of Antimicrobial Resistance among Humans, Animals, and Environment.

Antibiotics (Basel) 2020 Aug 1;9(8). Epub 2020 Aug 1.

Infectious Diseases Unit; Bolzano Central Hospital, 39100 Bolzano, Italy.

Antimicrobial resistance (AMR) is one of the most complex global health challenges today: decades of overuse and misuse in human medicine, animal health, agriculture, and dispersion into the environment have produced the dire consequence of infections to become progressively untreatable. Infection control and prevention (IPC) procedures, the reduction of overuse, and the misuse of antimicrobials in human and veterinary medicine are the cornerstones required to prevent the spreading of resistant bacteria. Purified drinking water and strongly improved sanitation even in remote areas would prevent the pollution from inadequate treatment of industrial, residential, and farm waste, as all these situations are expanding the resistome in the environment. The One Health concept addresses the interconnected relationships between human, animal, and environmental health as a whole: several countries and international agencies have now included a One Health Approach within their action plans to address AMR. Improved antimicrobial usage, coupled with regulation and policy, as well as integrated surveillance, infection control and prevention, along with antimicrobial stewardship, sanitation, and animal husbandry should all be integrated parts of any new action plan targeted to tackle AMR on the Earth. Since AMR is found in bacteria from humans, animals, and in the environment, we briefly summarize herein the current concepts of One Health as a global challenge to enable the continued use of antibiotics.
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http://dx.doi.org/10.3390/antibiotics9080473DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7460298PMC
August 2020

Measurement of white matter fiber-bundle cross-section in multiple sclerosis using diffusion-weighted imaging.

Mult Scler 2021 05 14;27(6):818-826. Epub 2020 Jul 14.

Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy; Neurology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.

Background: When investigating white matter (WM) microstructure, the axonal fiber orientation should be considered. Constrained spherical deconvolution (CSD) is a diffusion-weighted imaging (DWI) method that estimates distribution of fibers within each imaging voxel.

Objective: To study fiber-bundle cross-section (FC) as measured by CSD in multiple sclerosis (MS) patients versus healthy controls (HCs).

Methods: DWI and three-dimensional (3D) T-weighted magnetic resonance imaging (MRI) were obtained from 45 MS patients and 45 HCs. We applied fixel-based morphometry analysis to assess differences of FC in MS against HCs and voxel-based analysis of fractional anisotropy (FA).

Results: We found a significant widespread reduction of WM FC in MS compared to HCs. The decrease in FA was less extensive, mainly located in regions with high lesion occurrence such as the periventricular WM and the corpus callosum. Progressive MS patients showed a significant FC reduction in the right anterior cingulum, bilateral cerebellum, and in several mesencephalic and diencephalic regions compared to relapsing-remitting MS patients.

Conclusion: The CSD method can be applied in MS for a fiber-specific study of WM microstructure and quantification of FC. Fixel-based findings offered greater anatomical specificity and biological interpretability by identifying tract-specific differences and allowed substantial abnormalities to be detected.
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http://dx.doi.org/10.1177/1352458520938999DOI Listing
May 2021

Cognitive impairment in benign multiple sclerosis: a multiparametric structural and functional MRI study.

J Neurol 2020 Dec 2;267(12):3508-3517. Epub 2020 Jul 2.

Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy.

Introduction: The substrates of cognitive impairment in benign MS (BMS) still need to be identified. We investigated whether cognitive impairment in BMS patients is associated with specific patterns of brain structural and functional abnormalities.

Methods: Thirty-seven BMS patients (EDSS score ≤ 3.0 and disease duration ≥ 15 years) and 50 healthy controls (HC) were studied. In BMS patients, a cognitive impairment index (CII) was derived. Gray matter (GM) volumes, white matter (WM) fractional anisotropy (FA) and resting-state (RS) functional connectivity (FC) were investigated for whole-brain relevant regions (cortex, lobes, subcortical nuclei, fiber tracts) and functional networks. Univariate and multivariate analyses identified independent predictors of cognitive impairment.

Results: In BMS, median CII was 9 (IQR: 4-16). Compared to HC, BMS patients showed reduced WM FA, GM atrophy and increased RS FC in fronto-temporo-parietal regions. At multivariate analysis, percentage of T2-lesions of the corpus callosum, reduced posterior corona radiata (PCR) FA and caudate nucleus atrophy were independent predictors of worse CII. A multivariate model identified reduced PCR FA (R = 0.39; p = 0.001) as the only predictor of CII.

Conclusions: Cognitive impairment in BMS is associated with structural damage of relevant brain areas. WM damage of parietal regions was the predominant predictor of worse cognitive performance in these patients.
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http://dx.doi.org/10.1007/s00415-020-10025-zDOI Listing
December 2020

Clinical Relevance of Multiparametric MRI Assessment of Cervical Cord Damage in Multiple Sclerosis.

Radiology 2020 09 23;296(3):605-615. Epub 2020 Jun 23.

From the Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience (R.B., E.P., A.M., L.C., P.P., E.D.M., M.F., M.A.R.), Neurology Unit (R.B., L.C., P.P., E.D.M., M.F., M.A.R.), and Neurophysiology Unit (M.F.), IRCCS San Raffaele Scientific Institute, Via Olgettina 60, Milan 20132, Italy; and Vita-Salute San Raffaele University, Milan, Italy (R.B., L.C., E.D.M., M.F.).

Background In multiple sclerosis (MS), knowledge about how spinal cord abnormalities translate into clinical manifestations is incomplete. Comprehensive, multiparametric MRI studies are useful in this perspective, but studies for the spinal cord are lacking. Purpose To identify MRI features of cervical spinal cord damage that could help predict disability and disease course in MS by using a comprehensive, multiparametric MRI approach. Materials and Methods In this retrospective hypothesis-driven analysis of longitudinally acquired data between June 2017 and April 2019, 120 patients with MS (58 with relapsing-remitting MS [RRMS] and 62 with progressive MS [PMS]) and 30 age- and sex-matched healthy control participants underwent 3.0-T MRI of the brain and cervical spinal cord. Cervical spinal cord MRI was performed with three-dimensional (3D) T1-weighted, T2-weighted, and diffusion-weighted imaging; sagittal two-dimensional (2D) short inversion time inversion-recovery imaging; and axial 2D phase-sensitive inversion-recovery imaging at the C2-C3 level. Brain MRI was performed with 3D T1-weighted, fluid-attenuated inversion-recovery and T2-weighted sequences. Associations between MRI variables and disability were explored with age-, sex- and phenotype-adjusted linear models. Results In patients with MS, multivariable analysis identified phenotype, cervical spinal cord gray matter (GM) cross-sectional area (CSA), lateral funiculi fractional anisotropy (FA), and brain GM volume as independent predictors of Expanded Disability Status Scale (EDSS) score ( = 0.86). The independent predictors of EDSS score in RRMS were lateral funiculi FA, normalized brain volume, and cervical spinal cord GM T2 lesion volume ( = 0.51). The independent predictors of EDSS score in PMS were cervical spinal cord GM CSA and brain GM volume ( = 0.44). Logistic regression analysis identified cervical spinal cord GM CSA and T2 lesion volume as independent predictors of phenotype (area under the receiver operating characteristic curve = 0.95). An optimal cervical spinal cord GM CSA cut-off value of 11.1 mm was found to enable accurate differentiation of patients with PMS, having values below the threshold, from those with RRMS (sensitivity = 90% [56 of 62], specificity = 91% [53 of 58]). Conclusion Cervical spinal cord MRI involvement has a central role in explaining disability in multiple sclerosis (MS): Lesion-induced damage in the lateral funiculi and gray matter (GM) in relapsing-remitting MS and GM atrophy in patients with progressive MS are the most relevant variables. Cervical spinal cord GM atrophy is an accurate predictor of progressive phenotype. Cervical spinal cord GM lesions may subsequently cause GM atrophy, which may contribute to evolution to PMS. © RSNA, 2020 See also the editorial by Zivadinov and Bergsland in this issue.
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http://dx.doi.org/10.1148/radiol.2020200430DOI Listing
September 2020

Multicenter Evaluation of the C6 Lyme ELISA Kit for the Diagnosis of Lyme Disease.

Microorganisms 2020 Mar 24;8(3). Epub 2020 Mar 24.

Unit of Microbiology, The Great Romagna Area Hub Laboratory, 47522 Pievesestina di Cesena (FC), Italy.

Lyme disease (LD), caused by infection with , is the most common tick-borne infection in many regions of Eurasia. Antibody detection is the most frequently used laboratory test, favoring a two-step serodiagnostic algorithm; immunoenzymatic detection of antibodies to C6 has been shown to perform similarly to a standard two-step workflow. The aim of this study was the performance evaluation of the C6 Lyme ELISA kit compared to a standard two-step algorithm in three laboratories located in the northeastern region of Italy which cater to areas with different LD epidemiology. A total of 804 samples were tested, of which 695 gave concordant results between C6 testing and routine workflow (564 negative, 131 positive). Wherever available, clinical presentation and additional laboratory tests were analyzed to solve discrepancies. The C6 based method showed a good concordance with the standard two-step algorithm (Cohen's κ = 0.619), however, the distribution of discrepancies seems to point towards a slightly lower specificity of C6 testing, which is supported by literature and could impact on patient management. The C6 ELISA, therefore, is not an ideal stand-alone test; however, if integrated into a two-step algorithm, it might play a part in achieving a sensitive, specific laboratory diagnosis of LD.
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http://dx.doi.org/10.3390/microorganisms8030457DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7143974PMC
March 2020

Two-year regional grey and white matter volume changes with natalizumab and fingolimod.

J Neurol Neurosurg Psychiatry 2020 05 28;91(5):493-502. Epub 2020 Feb 28.

Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy

Objective: To compare the efficacy of fingolimod and natalizumab in preventing regional grey matter (GM) and white matter (WM) atrophy in relapsing-remitting multiple sclerosis (RRMS) over 2 years.

Methods: Patients with RRMS starting fingolimod (n=25) or natalizumab (n=30) underwent clinical examination and 3T MRI scans at baseline (month (M) 0), M6, M12 and M24. Seventeen healthy controls were also scanned at M0 and M24. Tensor-based morphometry and SPM12 were used to assess the longitudinal regional GM/WM volume changes.

Results: At M0, no clinical or GM/WM volume differences were found between treatment groups. At M24, both drugs reduced relapse rate (p<0.001 for both) and stabilised disability. At M6 vs M0, both groups experienced significant atrophy of several areas in the cortex, deep GM nuclei and supratentorial WM. Significant bilateral cerebellar GM and WM atrophy occurred in fingolimod patients only. At M12 vs M6 and M24 vs M12, further supratentorial GM and WM atrophy occurred in both groups. Bilateral GM/WM cerebellar atrophy continued to progress in fingolimod patients only. Compared with natalizumab, fingolimod-treated patients showed a significant cerebellar GM/WM atrophy, mainly at M6 vs M0, but still occurring up to M24. Compared with fingolimod, natalizumab-treated patients had a small number of areas of GM atrophy in temporo-occipital regions at the different time-points.

Conclusions: Natalizumab and fingolimod are associated with heterogeneous temporal and regional patterns of GM and WM atrophy progression. Compared with natalizumab, fingolimod-treated patients experience accelerated GM and WM atrophy in the cerebellum, while both drugs show minimal regional volumetric differences in supratentorial regions.
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http://dx.doi.org/10.1136/jnnp-2019-322439DOI Listing
May 2020

Polysorbate 80 add-on therapy in the treatment of Helicobacter pylori infection: Polysorbate 80 and HP antibiotic resistance.

Clin Nutr ESPEN 2019 12 19;34:101-103. Epub 2019 Aug 19.

Department of Internal Medicine, IRCCS "S. Matteo" Hospital Foundation, University of Pavia, Pavia, Italy.

Polysorbate 80, a sorbitan derivate, is a surfactant used as an emulsifier in some foods in concentrations of up to 0.5%. It was recently shown in vitro that polysorbate 80 decreases the minimum bactericidal concentrations of clarithromycin and metronidazole and may also revert antibiotic resistance. We report the case of an adult man, suffering from symptomatic Helicobacter pylori (HP) infection resistant to two courses of treatment with PPI plus amoxicillin and clarithromycin, and PPI plus clarithromycin and metronidazole. He was treated with a further antibiotic approach consisting of two-week administration of clarithromycin, metronidazole, PPI and polysorbate 80 as an add on therapy. Eradication of infection was confirmed by C-urea breath test two and five months after completion of the treatment course. Complete regression of symptoms was also achieved. To our knowledge, this is the first case of HP infection eradicated with a combination therapy based on polysorbate 80 added to antibiotics.
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http://dx.doi.org/10.1016/j.clnesp.2019.08.005DOI Listing
December 2019

MRI quality control for the Italian Neuroimaging Network Initiative: moving towards big data in multiple sclerosis.

J Neurol 2019 Nov 17;266(11):2848-2858. Epub 2019 Aug 17.

Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Via Olgettina, 60, 20132, Milan, Italy.

The Italian Neuroimaging Network Initiative (INNI) supports the creation of a repository, where MRI, clinical, and neuropsychological data from multiple sclerosis (MS) patients and healthy controls are collected from Italian Research Centers with internationally recognized expertise in MRI applied to MS. However, multicenter MRI data integration needs standardization and quality control (QC). This study aimed to implement quantitative measures for characterizing the standardization and quality of MRI collected within INNI. MRI scans of 423 MS patients, including 3D T- and T-weighted, were obtained from INNI repository (from Centers A, B, C, and D). QC measures were implemented to characterize: (1) head positioning relative to the magnet isocenter; (2) intensity inhomogeneity; (3) relative image contrast between brain tissues; and (4) image artefacts. Centers A and D showed the most accurate subject positioning within the MR scanner (median z-offsets = - 2.6 ± 1.7 cm and - 1.1 ± 2 cm). A low, but significantly different, intensity inhomogeneity on 3D T-weighted MRI was found between all centers (p < 0.05), except for Centers A and C that showed comparable image bias fields. Center D showed the highest relative contrast between gray and normal appearing white matter (NAWM) on 3D T-weighed MRI (0.63 ± 0.04), while Center B showed the highest relative contrast between NAWM and MS lesions on FLAIR (0.21 ± 0.06). Image artefacts were mainly due to brain movement (60%) and ghosting (35%). The implemented QC procedure ensured systematic data quality assessment within INNI, thus making available a huge amount of high-quality MRI to better investigate pathophysiological substrates and validate novel MRI biomarkers in MS.
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http://dx.doi.org/10.1007/s00415-019-09509-4DOI Listing
November 2019

Occurrence of two Norovirus outbreaks in the same cafeteria in one week.

New Microbiol 2019 Jul 15;42(3):156-160. Epub 2019 Jul 15.

Department of Food Safety, Nutrition and Veterinary Public Health, Istituto Superiore di Sanità, Rome, Italy.

In October 2017, two outbreaks of gastroenteritis (GE) occurred among patrons of a cafeteria in Italy in one week. Virological and bacteria investigations on stool samples, environment and food were conducted to identify the infectious agents and the possible source of infection. Forty-five cases occurred in the two outbreaks, including 13 laboratory-confirmed cases of norovirus GI. Nine staff members were interviewed, six were confirmed positive for NoV GI and 3 experienced GE symptoms. Bacteria faecal indicators and other bacteria pathogens were not detected in either environmental swab samples or food. A low level of NoV GII was detected in two environmental swab samples. The same GI.6 strain was identified in cases related to both outbreaks, suggesting a common source of infection. Since the two outbreaks occurred in one week, the NoV contamination could have persisted in the cafeteria. Furthermore, virological investigation revealed confirmed cases among food handlers who had worked at the cafeteria between and during the two outbreaks. Several studies highlighted the importance of excluding symptomatic food handlers to prevent contamination of foods and environment.
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July 2019

Borrelia microti infection in an Italian woman returning from Kyrgyzstan and Tajikistan.

Travel Med Infect Dis 2020 May - Jun;35:101448. Epub 2019 Jul 6.

Department of Infectious Diseases, Istituto Superiore di Sanità, Rome, Italy. Electronic address:

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http://dx.doi.org/10.1016/j.tmaid.2019.07.004DOI Listing
February 2021

Prevalence and pathophysiology of post-prandial migraine in patients with functional dyspepsia.

Cephalalgia 2019 Oct 15;39(12):1560-1568. Epub 2019 Jun 15.

1 Department of Medicine, University of Pavia, Foundation IRCCS "S.Matteo" Hospital, Pavia, Italy.

Background: Migraine is a condition frequently associated with gastrointestinal disorders. Previous reports have shown the relationship between irritable bowel syndrome and migraine, but no data are yet available in patients with functional dyspepsia. We therefore evaluated whether alteration of gastric sensorimotor activity may be related to migraine.

Methods: Sixty patients affected by functional dyspepsia, 38 with postprandial distress syndrome and 22 with epigastric pain syndrome were enrolled in a cohort study. Presence and severity of dyspeptic symptoms, migraine presence and severity, gastric sensitivity thresholds during fasting and postprandial period, gastric accommodation and gastric emptying time were evaluated.

Results: In epigastric pain syndrome, 12/22 (54%) patients suffered from migraine and this condition was never correlated with meal ingestion. In postprandial distress syndrome patients, 29/38 (76%) suffered from migraine, in 26/29 (89%) its onset was considered as meal-related, and migraine severity was significantly correlated with postprandial modification of the gastric discomfort threshold (r = -0.73;  < 0.001). In patients with postprandial distress syndrome, in the subgroup with moderate to severe migraine, the severity of fullness and early satiation was significantly higher than in patients with mild or absent migraine. In patients with moderate to severe migraine, gastric accommodation, sensitivity thresholds and gastric emptying time were similar to patients with mild or no migraine.

Conclusions: In patients with functional dyspepsia and postprandial symptoms, migraine is a very frequent comorbidity. On clinical grounds, it is associated with an increased severity of fullness and early satiation and, on pathophysiological grounds, it seems correlated with postprandial hypersensitivity.
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http://dx.doi.org/10.1177/0333102419857596DOI Listing
October 2019

Cocirculation of Hajj and non-Hajj strains among serogroup W meningococci in Italy, 2000 to 2016.

Euro Surveill 2019 Jan;24(4)

Department of Infectious Diseases, Istituto Superiore di Sanità, Rome, Italy.

In Italy, B and C are the predominant serogroups among meningococci causing invasive diseases. Nevertheless, in the period from 2013 to 2016, an increase in serogroup W (MenW) was observed. This study intends to define the main characteristics of 63 MenW isolates responsible of invasive meningococcal disease (IMD) in Italy from 2000 to 2016. We performed whole genome sequencing on bacterial isolates or single gene sequencing on culture-negative samples to evaluate molecular heterogeneity. Our main finding was the cocirculation of the Hajj and the South American sublineages belonging to MenW/clonal complex (cc)11, which gradually surpassed the MenW/cc22 in Italy. All MenW/cc11 isolates were fully susceptible to cefotaxime, ceftriaxone, ciprofloxacin, penicillin G and rifampicin. We identified the full-length NadA protein variant 2/3, present in all the MenW/cc11. We also identified the fHbp variant 1, which we found exclusively in the MenW/cc11/Hajj sublineage. Concern about the epidemic potential of MenW/cc11 has increased worldwide since the year 2000. Continued surveillance, supported by genomic characterisation, allows high-resolution tracking of pathogen dissemination and the detection of epidemic-associated strains.
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http://dx.doi.org/10.2807/1560-7917.ES.2019.24.4.1800183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6352001PMC
January 2019

Imaging correlates of hand motor performance in multiple sclerosis: A multiparametric structural and functional MRI study.

Mult Scler 2020 02 18;26(2):233-244. Epub 2019 Jan 18.

Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy/ Department of Neurology, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy.

Background: Hand motor impairment has considerable effects on daily-life activities of patients with multiple sclerosis (pwMS). Understanding its anatomo-functional substrates is relevant to provide more specific therapeutic interventions.

Objectives: To investigate the association between hand motor performance and anatomo-functional magnetic resonance imaging (MRI) abnormalities in pwMS.

Methods: A total of 134 healthy controls (HC) and 366 pwMS underwent the Nine-Hole-Peg-Test (9HPT), structural and resting state (RS) functional MRI. Multivariate analyses identified the independent predictors of hand motor performance.

Results: PwMS versus HC showed widespread gray matter atrophy, microstructural white matter abnormalities, and decreased RS functional connectivity in motor and cognitive networks. Predictors of worse right-9HPT ( = 0.52) were decreased right superior cerebellar peduncle and right lemniscus fractional anisotropy (FA) ( ⩽ 0.02), left angular gyrus atrophy ( < 0.003), decreased RS connectivity in left superior frontal gyrus, and left posterior cerebellum ( < 0.001). Worse left 9HPT ( = 0.56) was predicted by decreased right corticospinal FA ( = 0.003), atrophy of left anterior cingulum and left cerebellum ( ⩽ 0.02), decreased RS connectivity of left lingual gyrus and right posterior cerebellum in cerebellar and executive networks ( ⩽ 0.02).

Conclusion: Structural and functional abnormalities of regions involved in motor functions contribute to explain motor disability in pwMS. The integration of clinical and advanced MRI measures contributes to improve our understanding of multiple sclerosis clinical manifestations.
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http://dx.doi.org/10.1177/1352458518822145DOI Listing
February 2020

Brain and cord imaging features in neuromyelitis optica spectrum disorders.

Ann Neurol 2019 03 28;85(3):371-384. Epub 2019 Jan 28.

Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy.

Objectives: To validate imaging features able to discriminate neuromyelitis optica spectrum disorders from multiple sclerosis with conventional magnetic resonance imaging (MRI).

Methods: In this cross-sectional study, brain and spinal cord scans were evaluated from 116 neuromyelitis optica spectrum disorder patients (98 seropositive and 18 seronegative) in chronic disease phase and 65 age-, sex-, and disease duration-matched multiple sclerosis patients. To identify independent predictors of neuromyelitis optica diagnosis, after assessing the prevalence of typical/atypical findings, the original cohort was 2:1 randomized in a training sample (where a multivariate logistic regression analysis was run) and a validation sample (where the performance of the selected variables was tested and validated).

Results: Typical brain lesions occurred in 50.9% of neuromyelitis optica patients (18.1% brainstem periventricular/periaqueductal, 32.7% periependymal along lateral ventricles, 3.4% large hemispheric, 6.0% diencephalic, 4.3% corticospinal tract), 72.2% had spinal cord lesions (46.3% long transverse myelitis, 36.1% short transverse myelitis), 37.1% satisfied 2010 McDonald criteria, and none had cortical lesions. Fulfillment of at least 2 of 5 of absence of juxtacortical/cortical lesions, absence of periventricular lesions, absence of Dawson fingers, presence of long transverse myelitis, and presence of periependymal lesions along lateral ventricles discriminated neuromyelitis optica patients in both training (sensitivity = 0.92, 95% confidence interval [CI] = 0.84-0.97; specificity = 0.91, 95% CI = 0.78-0.97) and validation samples (sensitivity = 0.82, 95% CI = 0.66-0.92; specificity = 0.91, 95% CI = 0.71-0.99). MRI findings and criteria performance were similar irrespective of serostatus.

Interpretation: Although up to 50% of neuromyelitis optica patients have no typical lesions and a relatively high percentage of them satisfy multiple sclerosis criteria, several easily applicable imaging features can help to distinguish neuromyelitis optica from multiple sclerosis. ANN NEUROL 2019;85:371-384.
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http://dx.doi.org/10.1002/ana.25411DOI Listing
March 2019

Structural connectivity in multiple sclerosis and modeling of disconnection.

Mult Scler 2020 02 9;26(2):220-232. Epub 2019 Jan 9.

Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy/Department of Neurology, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy.

Background: Multiple sclerosis (MS) is characterized by focal white matter damage, and when the brain is modeled as a network, lesions can be treated as disconnection events.

Objective: To evaluate whether modeling disconnection caused by lesions helps explain motor and cognitive impairment in MS.

Methods: Pathways connecting 116 cortical regions were reconstructed with magnetic resonance imaging (MRI) tractography from diffusion tensors averaged across healthy controls (HCs); maps of pathways were applied to 227 relapse-onset MS patients and 50 HCs to derive structural connectivity. Then, the likelihood of individual connections passing through lesions was used to model disconnection. Patients were grouped according to clinical phenotype (113 relapsing-remitting multiple sclerosis (RRMS), 69 secondary progressive multiple sclerosis (SPMS), 45 benign MS), and then network metrics were compared between groups (analysis of variance (ANOVA)) and correlated with motor and cognitive scores (linear regression).

Results: Global metrics differentiated RRMS from SPMS and benign MS patients, but not benign from SPMS patients. Nodal connectivity strength replicated global results. After disconnection, few nodes were significantly different between benign MS and RRMS patients. Correlations revealed nodes pertinent to motor and cognitive dysfunctions; these became slightly stronger after disconnection.

Conclusion: Connectivity did not change greatly after modeled disconnection, suggesting that the brain network is robust against damage caused by MS lesions.
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http://dx.doi.org/10.1177/1352458518820759DOI Listing
February 2020

Functional and structural plasticity following action observation training in multiple sclerosis.

Mult Scler 2019 10 7;25(11):1472-1487. Epub 2018 Aug 7.

Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy/Department of Neurology, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy.

Background: Hand motor deficits contribute to multiple sclerosis (MS)-related disability. Action observation training (AOT) is promising to improve upper limb function in neurologic patients.

Objectives: In this preliminary study, we investigated AOT effects on dominant-hand motor performance in MS patients with upper limb motor impairment and performed an explorative analysis of their anatomical and functional magnetic resonance imaging (MRI) substrates.

Methods: In total, 46 healthy controls (HC) and 41 MS patients with dominant-hand motor impairment were randomized to AOT (HC-AOT = 23; MS-AOT = 20; watching daily-life action videos and execution) or control-training (HC-Control = 23; MS-Control = 21; watching landscapes videos and execution). Behavioral, structural, and functional (at rest and during object manipulation) MRI scans were acquired before and after a 2-week training.

Results: After training, MS groups improved in right upper limb functions, mainly in AOT group ( from 0.02 to 0.0001). All groups showed regional increased and decreased gray matter volume, with specific AOT effects in fronto-temporal areas in MS-AOT ( < 0.001), without white matter (WM) integrity modifications. Increased and reduced recruitments of the action observation matching system and its connections in MS-AOT were found ( < 0.001). Motor improvements were correlated with volumetric and functional MRI modifications ( from -0.78 to 0.77,  < 0.001).

Conclusion: The 10-day AOT promotes clinical improvements in MS patients through structural and functional modifications of the action observation matching system.
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http://dx.doi.org/10.1177/1352458518792771DOI Listing
October 2019

Dynamic volumetric changes of hippocampal subfields in clinically isolated syndrome patients: A 2-year MRI study.

Mult Scler 2019 08 24;25(9):1232-1242. Epub 2018 Jul 24.

Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy/Department of Neurology, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy.

Background: Different subregional patterns of hippocampal involvement have been observed in diverse multiple sclerosis (MS) phenotypes.

Objective: To evaluate the occurrence of regional hippocampal variations in clinically isolated syndrome (CIS) patients, their relationships with focal white matter (WM) lesions, and their prognostic implications.

Methods: Brain dual-echo and three-dimensional (3D) T1-weighted scans were acquired from 14 healthy controls and 36 CIS patients within 2 months from clinical onset and after 3, 12, and 24 months. Radial distance distribution was assessed using 3D parametric surface mesh models. A cognitive screening was also performed.

Results: Patients showed clusters of reduced radial distance in the Cornu Ammonis 1 from month 3, progressively extending to the subiculum, negatively correlated with ipsilateral T2 and T1 lesion volume. Increased radial distance appeared in the right dentate gyrus after 3 ( < 0.05), 12, and 24 ( < 0.001) months, and in the left one after 3 and 24 months ( < 0.001), positively correlated with lesional measures. Hippocampal volume variations were more pronounced in patients converting to MS after 24 months and did not correlate with cognitive performance.

Conclusion: Regional hippocampal changes occur in CIS, are more pronounced in patients converting to MS, and are modulated by focal WM lesions.
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http://dx.doi.org/10.1177/1352458518787347DOI Listing
August 2019

Gray matter volume modifications in migraine: A cross-sectional and longitudinal study.

Neurology 2018 07 20;91(3):e280-e292. Epub 2018 Jun 20.

From the Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience (R.M., M.A.R., E.P., M.F.) and Departments of Neurology (R.M., M.A.R., B.C., M.F.) and Neuroradiology (A.F.), San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy; and NIHR-Wellcome Trust King's Clinical Research Facility (P.J.G.), King's College London, UK.

Objective: To explore cross-sectional and longitudinal gray matter (GM) volume changes in patients with migraine and their association with patients' clinical characteristics and disease activity.

Methods: Brain T2-weighted and 3-dimensional T1-weighted scans were acquired from 73 episodic migraineurs and 46 age- and sex-matched nonmigraine controls at baseline. Twenty-four migraineurs and 25 controls agreed to be reexamined after a mean follow-up of 4 years. Using a general linear model and SPM12, a whole-brain analysis was performed to assess GM volume modifications.

Results: At baseline, compared to controls, patients with migraine showed lower cerebellar GM volume and higher volume of regions of the frontotemporal lobes. At follow-up, migraineurs were significantly older than controls. Over the follow-up, migraineurs developed an increased volume of frontotemporoparietal regions, which was more prominent in patients with a higher baseline disease activity: long disease duration and high attack frequency. Migraineurs also developed decreased GM volume of visual areas, which was related to higher pain severity. Patients with an increased attack frequency at follow-up experienced both increased and decreased volume of nociceptive regions. In migraineurs, reduced GM volume of extrastriate visual areas during the follow-up was significantly correlated to baseline disease activity: shorter disease duration and lower attack frequency.

Conclusion: In this cohort, the migraine brain changes dynamically over time, and different pathophysiologic mechanisms can occur in response to patients' disease severity. The interaction between predisposing brain traits and experience-dependent responses might vary across different nociceptive and visual areas, thus leading to distinct patterns of longitudinal GM volume changes.
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http://dx.doi.org/10.1212/WNL.0000000000005819DOI Listing
July 2018

Measurement of Whole-Brain and Gray Matter Atrophy in Multiple Sclerosis: Assessment with MR Imaging.

Radiology 2018 08 1;288(2):554-564. Epub 2018 May 1.

From the Neuroimaging Research Unit (L.S., M.A.R., E.P., M.F.) and Department of Neurology, Institute of Experimental Neurology, Division of Neuroscience (M.A.R., M.F.), San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Via Olgettina 60, 20132 Milan, Italy; Department of Research and Development, Icometrix, Leuven, Belgium (W.V.H., D. Sima, D. Smeets); Xinapse Systems, Colchester, England (M.A.H.); Department of Medicine, Surgery and Neuroscience, University of Siena, Siena, Italy (N.D.S.); Section of Neuroradiology, Department of Radiology, Hospital Universitari Vall d'Hebron, Barcelona, Spain (A.R.); Unit of Clinical Neuroimmunology, CEM-Cat, Hospital Universitari Vall d'Hebron, Barcelona, Spain (J.S.G.); and Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, England (J.P.).

Purpose To compare available methods for whole-brain and gray matter (GM) atrophy estimation in multiple sclerosis (MS) in terms of repeatability (same magnetic resonance [MR] imaging unit) and reproducibility (different system/field strength) for their potential clinical applications. Materials and Methods The softwares ANTs-v1.9, CIVET-v2.1, FSL-SIENAX/SIENA-5.0.1, Icometrix-MSmetrix-1.7, and SPM-v12 were compared. This retrospective study, performed between March 2015 and March 2017, collected data from (a) eight simulated MR images and longitudinal data (2 weeks) from 10 healthy control subjects to assess the cross-sectional and longitudinal accuracy of atrophy measures, (b) test-retest MR images in 29 patients with MS acquired within the same day at different imaging unit field strengths/manufacturers to evaluate precision, and (c) longitudinal data (1 year) in 24 patients with MS for the agreement between methods. Tissue segmentation, image registration, and white matter (WM) lesion filling were also evaluated. Multiple paired t tests were used for comparisons. Results High values of accuracy (0.87-0.97) for whole-brain and GM volumes were found, with the lowest values for MSmetrix. ANTs showed the lowest mean error (0.02%) for whole-brain atrophy in healthy control subjects, with a coefficient of variation of 0.5%. SPM showed the smallest mean error (0.07%) and coefficient of variation (0.08%) for GM atrophy. Globally, good repeatability (P > .05) but poor reproducibility (P < .05) were found for all methods. WM lesion filling technique mainly affected ANTs, MSmetrix, and SPM results (P < .05). Conclusion From this comparison, it would be possible to select a software for atrophy measurement, depending on the requirements of the application (research center, clinical trial) and its goal (accuracy and repeatability or reproducibility). An improved reproducibility is required for clinical application. RSNA, 2018 Online supplemental material is available for this article.
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http://dx.doi.org/10.1148/radiol.2018172468DOI Listing
August 2018

Hippocampal-related memory network in multiple sclerosis: A structural connectivity analysis.

Mult Scler 2019 05 23;25(6):801-810. Epub 2018 Apr 23.

Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy/Department of Neurology, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy.

Background: We used graph theoretical analysis to quantify structural connectivity of the hippocampal-related episodic memory network and its association with memory performance in multiple sclerosis (MS) patients.

Methods: Brain diffusion and T1-weighted sequences were obtained from 71 MS patients and 50 healthy controls (HCs). A total of 30 gray matter regions (selected a priori) were used as seeds to perform probabilistic tractography and create connectivity matrices. Global, nodal, and edge graph theoretical properties were calculated. In patients, verbal and visuospatial memory was assessed.

Results: MS patients showed decreased network strength, assortativity, transitivity, global efficiency, and increased average path length. Several nodes had decreased strength and communicability in patients, whereas insula and left temporo-occipital cortex increased communicability. Patients had widespread decreased streamline count (SC) and communicability of edges, although a few ones increased their connectivity. Worse memory performance was associated with reduced network efficiency, decreased right hippocampus strength, and reduced SC and communicability of edges related to medial temporal lobe, thalamus, insula, and occipital cortex.

Conclusion: Impaired structural connectivity occurs in the hippocampal-related memory network, decreasing the efficiency of information transmission. Network connectivity measures correlate with episodic memory, supporting the relevance of structural integrity in preserving memory processes in MS.
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http://dx.doi.org/10.1177/1352458518771838DOI Listing
May 2019
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