Publications by authors named "Vittorio Martinelli"

161 Publications

PCA-LBD in Gaucher disease type 1: a case description.

Neurol Sci 2021 Oct 7. Epub 2021 Oct 7.

Neurology Unit, IRCCS San Raffaele Scientific Institute, Via Olgettina, 60, 20132, Milan, Italy.

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http://dx.doi.org/10.1007/s10072-021-05648-7DOI Listing
October 2021

Genomic and functional evaluation of TNFSF14 in multiple sclerosis susceptibility.

J Genet Genomics 2021 06 25;48(6):497-507. Epub 2021 May 25.

Department of Health Sciences, Center on Autoimmune and Allergic Diseases (CAAD), UPO, University of Eastern Piedmont, A. Avogadro, Novara 28100, Italy. Electronic address:

Among multiple sclerosis (MS) susceptibility genes, the strongest non-human leukocyte antigen (HLA) signal in the Italian population maps to the TNFSF14 gene encoding LIGHT, a glycoprotein involved in dendritic cell (DC) maturation. Through fine-mapping in a large Italian dataset (4,198 patients with MS and 3,903 controls), we show that the TNFSF14 intronic SNP rs1077667 is the primarily MS-associated variant in the region. Expression quantitative trait locus (eQTL) analysis indicates that the MS risk allele is significantly associated with reduced TNFSF14 messenger RNA levels in blood cells, which is consistent with the allelic imbalance in RNA-Seq reads (P < 0.0001). The MS risk allele is associated with reduced levels of TNFSF14 gene expression (P < 0.01) in blood cells from 84 Italian patients with MS and 80 healthy controls (HCs). Interestingly, patients with MS are lower expressors of TNFSF14 compared to HC (P < 0.007). Individuals homozygous for the MS risk allele display an increased percentage of LIGHT-positive peripheral blood myeloid DCs (CD11c, P = 0.035) in 37 HCs, as well as in in vitro monocyte-derived DCs from 22 HCs (P = 0.04). Our findings suggest that the intronic variant rs1077667 alters the expression of TNFSF14 in immune cells, which may play a role in MS pathogenesis.
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http://dx.doi.org/10.1016/j.jgg.2021.03.017DOI Listing
June 2021

Spinal Fluid Myeloid Microvesicles Predict Disease Course in Multiple Sclerosis.

Ann Neurol 2021 Aug 20;90(2):253-265. Epub 2021 Jul 20.

Clinical Neuroimmunology Unit, Division of Neuroscience, Institute of Experimental Neurology, San Raffaele Scientific Institute, Milan, Italy.

Objective: In vivo measures of myeloid activity are promising biomarkers in multiple sclerosis. We previously demonstrated that cerebrospinal fluid (CSF) myeloid microvesicles are markers of microglial/macrophage activity and neuroinflammation in multiple sclerosis. Here, we aimed at investigating the diagnostic and prognostic value of myeloid microvesicles in a clinical setting.

Methods: Six hundred one patients discharged with a diagnosis of neuroinflammatory, neurodegenerative, or no neurological disease were enrolled. Myeloid microvesicles were measured with flow cytometry as isolectin B4-positive events in fresh CSF. Clinical, demographical, and magnetic resonance imaging (MRI) data were collected at diagnosis (all patients) and during follow-up (n = 176).

Results: CSF myeloid microvesicles were elevated in neuroinflammatory patients compared to the neurodegenerative and control groups. In multiple sclerosis, microvesicles were higher in patients with MRI disease activity and their concentration increased along with the number of enhancing lesions (p < 0.0001, Jonckheere-Terpstra test). CSF myeloid microvesicles were also higher in patients with higher disease activity in the month and year preceding diagnosis. Microvesicles excellently discriminated between the relapsing-remitting and control groups (receiver operator characteristic curve, area under the curve = 0.939, p < 0.0001) and between radiologically isolated syndrome and unspecific brain lesions (0.942, p < 0.0001). Furthermore, microvesicles were independent predictors of prognosis for both the relapsing-remitting and progressive groups. Microvesicles independently predicted future disease activity in relapsing-remitting patients (hazard ratio [HR] = 1.967, 95% confidence interval [CI] = 1.147-3.372), correcting for prognostic factors of standard clinical use. In the progressive group, microvesicles were independent predictors of disability accrual (HR = 10.767, 95% CI = 1.335-86.812).

Interpretation: Our results confirm that CSF myeloid microvesicles are a clinically meaningful biomarker of neuroinflammation and microglial/macrophage activity in vivo. These findings may support a possible use in clinical practice during diagnostic workup and prognostic assessment. ANN NEUROL 2021;90:253-265.
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http://dx.doi.org/10.1002/ana.26154DOI Listing
August 2021

Dysregulated copper transport in multiple sclerosis may cause demyelination via astrocytes.

Proc Natl Acad Sci U S A 2021 Jul;118(27)

Division of Neuroscience, Institute of Experimental Neurology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute, 20132, Milan, Italy;

Demyelination is a key pathogenic feature of multiple sclerosis (MS). Here, we evaluated the astrocyte contribution to myelin loss and focused on the neurotrophin receptor TrkB, whose up-regulation on the astrocyte finely demarcated chronic demyelinated areas in MS and was paralleled by neurotrophin loss. Mice lacking astrocyte TrkB were resistant to demyelination induced by autoimmune or toxic insults, demonstrating that TrkB signaling in astrocytes fostered oligodendrocyte damage. In vitro and ex vivo approaches highlighted that astrocyte TrkB supported scar formation and glia proliferation even in the absence of neurotrophin binding, indicating TrkB transactivation in response to inflammatory or toxic mediators. Notably, our neuropathological studies demonstrated copper dysregulation in MS and model lesions and TrkB-dependent expression of copper transporter (CTR1) on glia cells during neuroinflammation. In vitro experiments evidenced that TrkB was critical for the generation of glial intracellular calcium flux and CTR1 up-regulation induced by stimuli distinct from neurotrophins. These events led to copper uptake and release by the astrocyte, and in turn resulted in oligodendrocyte loss. Collectively, these data demonstrate a pathogenic demyelination mechanism via the astrocyte release of copper and open up the possibility of restoring copper homeostasis in the white matter as a therapeutic target in MS.
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http://dx.doi.org/10.1073/pnas.2025804118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8271600PMC
July 2021

Pregnancy in multiple sclerosis women with relapses in the year before conception increases the risk of long-term disability worsening.

Mult Scler 2021 Jun 16:13524585211023365. Epub 2021 Jun 16.

Division Neurological Rehabilitation, Department of NEUROFARBA, University of Florence, Florence, Italy/IRCCS Fondazione Don Carlo Gnocchi, Florence, Italy.

Background: The influence of pregnancy on long-term disability in multiple sclerosis (MS) is still controversial.

Objective: To assess the risk of long-term disability worsening after pregnancy in MS women as compared with a propensity-score (PS) matched group of MS women without pregnancy.

Methods: In the setting of the Italian Pregnancy Dataset, MS patients with (pregnancy group (PG)) and without pregnancy (control group (CG)) were recruited. Time to disability worsening on the Expanded Disability Status Scale (EDSS) was assessed through a multivariable Cox regression model.

Results: The PS-matching retained 230 PG and 102 CG patients. After a follow-up of 6.5 +/- 3.1 years, disability worsening occurred in 87 (26.2%) women. In the multivariable analysis, disability worsening was associated with pregnancy in women with relapses in the year before conception (adjusted hazard ratio (aHR) = 1.74; 95% confidence interval (CI) 1.06-2.84; = 0.027), higher EDSS (aHR = 1.39; 95% CI 1.12-1.74; = 0.003), younger age (aHR = 0.95; 95% CI 0.91-0.99; = 0.022) and shorter DMD exposure over the follow-up ( < 0.008).

Conclusion: Pregnancy in MS women with relapses in the year before conception increases the risk of long-term disability worsening. Our findings underscore the importance of counselling in MS women facing a pregnancy that should be planned after a period of clinical stability, favouring treatment optimization in patients with recent disease activity.
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http://dx.doi.org/10.1177/13524585211023365DOI Listing
June 2021

Cortico-subcortical functional connectivity modifications in fatigued multiple sclerosis patients treated with fampridine and amantadine.

Eur J Neurol 2021 07 26;28(7):2249-2258. Epub 2021 Apr 26.

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

Background And Purpose: Fatigue in multiple sclerosis (MS) is common and disabling; medication efficacy is still not fully proven. The aim of this study was to investigate 4-week modifications of fatigue severity in 45 relapsing-remitting MS patients after different symptomatic treatments, and changes in concomitant resting state (RS) functional connectivity (FC).

Methods: Patients were randomly, blindly assigned to treatment with fampridine (n = 15), amantadine (n = 15) or placebo (n = 15), and underwent clinical assessment and 3-Tesla RS functional magnetic resonance imaging at baseline (t0) and after 4 weeks (w4) of treatment. Fifteen healthy controls (HCs) were also studied. Changes in modified fatigue impact scale (MFIS) score and network RS FC were assessed.

Results: In MS, abnormalities of network RS FC at t0 did not differ between treatment groups and correlated with fatigue severity. At w4, global scores and subscores on the MFIS decreased in all groups, with no time-by-treatment interaction. At w4, all patient groups had changes in RS FC in several networks, with significant time-by-treatment interactions in basal ganglia, sensorimotor and default-mode networks in fampridine-treated patients versus the other groups, and in frontoparietal network in amantadine-treated patients. In the fampridine group, RS FC changes correlated with concurrently decreased MFIS score (r range = -0.75 to 0.74, p range = 0.003-0.05).

Conclusions: Fatigue improved in all MS groups, independently of treatment. Concomitant RS FC modifications were located in sensorimotor, inferior frontal and subcortical regions for fampridine- and amantadine-treated patients, and in associative sensory cortices for placebo-treated patients.
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http://dx.doi.org/10.1111/ene.14867DOI Listing
July 2021

Subclinical anterior optic pathway involvement in early multiple sclerosis and clinically isolated syndromes.

Brain 2021 04;144(3):848-862

Experimental Neurophysiology Unit, Institute of Experimental Neurology (INSPE), San Raffaele Scientific Institute, Milan, Italy.

Optical coherence tomography (OCT) is gaining increasing relevance in the assessment of patients with multiple sclerosis. Converging evidence point to the view that neuro-retinal changes, in eyes without acute optic neuritis, reflect inflammatory and neurodegenerative processes taking place throughout the CNS. The present study aims at exploring the usefulness of OCT as a marker of inflammation and disease burden in the earliest phases of the disease. Thus, a cohort of 150 consecutive patients underwent clinical, neurophysiological and brain MRI assessment as well as lumbar puncture as part of their diagnostic workup for a neurological episode suggestive of inflammatory CNS disorder; among those 32 patients had another previous misdiagnosed episode. For the present study, patients also received a visual pathway assessment (OCT, visual evoked potentials, visual acuity), measurement of CSF inflammatory markers (17 cytokines-chemokines, extracellular vesicles of myeloid origin), and dosage of plasma neurofilaments. Subclinical optic nerve involvement is frequently found in clinically isolated syndromes by visual evoked potentials (19.2%). OCT reveals ganglion cell layer asymmetries in 6.8% of patients; retinal fibre layer asymmetries, despite being more frequent (17.8%), display poor specificity. The presence of subclinical involvement is associated with a greater disease burden. Second, ganglion cell layer thinning reflects the severity of disease involvement even beyond the anterior optic pathway. In fact, the ganglion cell layer in eyes without evidence of subclinical optic involvement is correlated with Expanded Disability Status Scale, low contrast visual acuity, disease duration, brain lesion load, presence of gadolinium enhancing lesions, abnormalities along motor and somatosensory evoked potentials, and frequency of CSF-specific oligoclonal bands. Third, the inner nuclear layer thickens in a post-acute (1.1-3.7 months) phase after a relapse, and this phenomenon is counteracted by steroid treatment. Likewise, a longitudinal analysis on 65 patients shows that this swelling is transient and returns to normal values after 1 year follow-up. Notwithstanding, the clinical, MRI, serological and CSF markers of disease activity considered in the study are strictly associated with one another, but none of them are associated with the inner nuclear layer. Our findings challenge the current hypothesis that the inner nuclear layer is an acute phase marker of inflammatory activity. The present study suggests that instrumental evidence of subclinical optic nerve involvement is associated with a greater disease burden in clinically isolated syndrome. Neuro-retinal changes are present since the earliest phases of the disease and yield important information regarding the neurodegenerative and inflammatory processes occurring in the CNS.
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http://dx.doi.org/10.1093/brain/awaa458DOI Listing
April 2021

MYD88 L265P mutation and interleukin-10 detection in cerebrospinal fluid are highly specific discriminating markers in patients with primary central nervous system lymphoma: results from a prospective study.

Br J Haematol 2021 05 23;193(3):497-505. Epub 2021 Feb 23.

Pathology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.

Reliable biomarkers are needed to avoid diagnostic delay and its devastating effects in patients with primary central nervous system (CNS) lymphoma (PCNSL). We analysed the discriminating sensitivity and specificity of myeloid differentiation primary response (88) (MYD88) L265P mutation (mut-MYD88) and interleukin-10 (IL-10) in cerebrospinal fluid (CSF) of both patients with newly diagnosed (n = 36) and relapsed (n = 27) PCNSL and 162 controls (118 CNS disorders and 44 extra-CNS lymphomas). The concordance of MYD88 mutational status between tumour tissue and CSF sample and the source of ILs in PCNSL tissues were also investigated. Mut-MYD88 was assessed by TaqMan-based polymerase chain reaction. IL-6 and IL-10 messenger RNA (mRNA) was assessed on PCNSL biopsies using RNAscope technology. IL levels in CSF were assessed by enzyme-linked immunosorbent assay. Mut-MYD88 was detected in 15/17 (88%) PCNSL biopsies, with an 82% concordance in paired tissue-CSF samples. IL-10 mRNA was detected in lymphomatous B cells in most PCNSL; expression of IL-6 transcripts was negligible. In CSF samples, mut-MYD88 and high IL-10 levels were detected, respectively, in 72% and 88% of patients with newly diagnosed PCNSL and in 1% of controls; conversely, IL-6 showed a low discriminating sensitivity and specificity. Combined analysis of MYD88 and IL-10 exhibits a sensitivity and specificity to distinguish PCNSL of 94% and 98% respectively. Similar figures were recorded in patients with relapsed PCNSL. In conclusion, high detection rates of mut-MYD88 and IL-10 in CSF reflect, respectively, the MYD88 mutational status and synthesis of this IL in PCNSL tissue. These biomarkers exhibit a very high sensitivity and specificity in detecting PCNSL both at initial diagnosis and relapse. Implications of these findings in patients with lesions unsuitable for biopsy deserve to be investigated.
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http://dx.doi.org/10.1111/bjh.17357DOI Listing
May 2021

Early Predictors of 9-Year Disability in Pediatric Multiple Sclerosis.

Ann Neurol 2021 05 27;89(5):1011-1022. Epub 2021 Feb 27.

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

Objective: The purpose of this study was to assess early predictors of 9-year disability in pediatric patients with multiple sclerosis.

Methods: Clinical and magnetic resonance imaging (MRI) assessments of 123 pediatric patients with multiple sclerosis were obtained at disease onset and after 1 and 2 years. A 9-year clinical follow-up was also performed. Cox proportional hazard and multivariable regression models were used to assess independent predictors of time to first relapse and 9-year outcomes.

Results: Time to first relapse was predicted by optic nerve lesions (hazard ratio [HR] = 2.10, p = 0.02) and high-efficacy treatment exposure (HR = 0.31, p = 0.005). Predictors of annualized relapse rate were: at baseline, presence of cerebellar (β = -0.15, p < 0.001), cervical cord lesions (β = 0.16, p = 0.003), and high-efficacy treatment exposure (β = -0.14, p = 0.01); considering also 1-year variables, number of relapses (β = 0.14, p = 0.002), and the previous baseline predictors; considering 2-year variables, time to first relapse (2-year: β = -0.12, p = 0.01) entered, whereas high-efficacy treatment exposure exited the model. Predictors of 9-year disability worsening were: at baseline, presence of optic nerve lesions (odds ratio [OR] = 6.45, p = 0.01); considering 1-year and 2-year variables, Expanded Disability Status Scale (EDSS) changes (1-year: OR = 26.05, p < 0.001; 2-year: OR = 16.38, p = 0.02), and ≥ 2 new T2-lesions in 2 years (2-year: OR = 4.91, p = 0.02). Predictors of higher 9-year EDSS score were: at baseline, EDSS score (β = 0.58, p < 0.001), presence of brainstem lesions (β = 0.31, p = 0.04), and number of cervical cord lesions (β = 0.22, p = 0.05); considering 1-year and 2-year variables, EDSS changes (1-year: β = 0.79, p < 0.001; 2-year: β = 0.55, p < 0.001), and ≥ 2 new T2-lesions (1-year: β = 0.28, p = 0.03; 2-year: β = 0.35, p = 0.01).

Interpretation: A complete baseline MRI assessment and an accurate clinical and MRI monitoring during the first 2 years of disease contribute to predict 9-year prognosis in pediatric patients with multiple sclerosis. ANN NEUROL 2021;89:1011-1022.
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http://dx.doi.org/10.1002/ana.26052DOI Listing
May 2021

CSF extracellular vesicles and risk of disease activity after a first demyelinating event.

Mult Scler 2021 09 19;27(10):1606-1610. Epub 2021 Jan 19.

Clinical Neuroimmunology Unit, Institute of Experimental Neurology, Division of Neuroscience, IRCCS San Raffaele Hospital, Milan, Italy.

Background: Extracellular vesicles (EVs), a recently described mechanism of cell communication, are released from activated microglial cells and macrophages and are a candidate biomarker in diseases characterized by chronic inflammatory process such as multiple sclerosis (MS).

Methods: We explored cerebrospinal fluid extracellular vesicle (CSF EV) of myeloid origin (MEVs), cytokine and chemokine levels in patients with clinically isolated syndrome (CIS).

Results: We found that CSF MEVs were significantly higher in CIS patients than in controls and were inversely correlated to CSF CCL2 levels. MEVs level were significantly associated with an shorter time to evidence of disease activity (hazard ratio: 1.01, 95% confidence interval: 1.00-1.02,  < 0.01) independently from other known prognostic markers.

Conclusion: After a first demyelinating event, CSF EVs may improve risk stratification of these patients and allow more targeted intervention strategies.
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http://dx.doi.org/10.1177/1352458520987542DOI Listing
September 2021

Neutrophil-to-lymphocyte ratio: a marker of neuro-inflammation in multiple sclerosis?

J Neurol 2021 Feb 3;268(2):717-723. Epub 2021 Jan 3.

Neurology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.

Background: The significance of neutrophil-to-lymphocyte ratio (NLR) has been explored in different diseases. Few studies addressed its role in patients with multiple sclerosis (MS), with promising results regarding its association with disease activity or disability.

Objectives: We aimed at confirming the role of NLR as a marker of neuro-inflammation in a cohort of newly diagnosed MS and clinically isolated syndrome (CIS) patients. Furthermore, we compared the validity of NLR with established markers of neuro-inflammation, such as serum neurofilament light chain (Nfl), CSF microvesicles (CSF-MVs) and CSF IgG indices.

Methods: We retrospectively selected, from a prospectively collected cohort of newly diagnosed MS/CIS patients hospitalized for diagnostic work-up, 121 patients who underwent CSF examination, brain MRI and blood cell count within the time of hospitalization and did not receive steroid treatment before sample collection. Patients were grouped according to presence of gadolinium enhancement at brain MRI.

Results: No association was found between NLR and disease activity, nor with other clinical measures. Nfl, CSF-MVs, Link and Tourtellotte indices were significantly higher in patients with brain MRI activity.

Conclusions: Our negative results do not support the use of NLR as a marker of disease activity and disability in patients with MS.
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http://dx.doi.org/10.1007/s00415-020-10322-7DOI Listing
February 2021

Inferring Multiple Sclerosis Stages from the Blood Transcriptome via Machine Learning.

Cell Rep Med 2020 Jul 21;1(4):100053. Epub 2020 Jul 21.

Institute of Experimental Neurology and Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy.

Peripheral blood mononuclear cells (PBMCs) bear specific dysregulations in genes and pathways at distinct stages of multiple sclerosis (MS) that may help with classifying MS and non-MS subjects, specifying the early stage of disease, or discriminating among MS courses. Here we describe an unbiased machine learning workflow to build MS stage-specific classifiers based on PBMC transcriptomics profiles from more than 300 individuals, including healthy subjects and patients with clinically isolated syndromes, relapsing-remitting MS, primary or secondary progressive MS, or other neurological disorders. The pipeline, designed to optimize and compare the performance of distinct machine learning algorithms in the training cohort, generates predictive models not influenced by demographic features, such as age and gender, and displays high accuracy in the independent validation cohort. Proper application of machine learning to transcriptional profiles of circulating blood cells may allow identification of disease state and stage in MS.
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http://dx.doi.org/10.1016/j.xcrm.2020.100053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7659538PMC
July 2020

Early evidence of disease activity during fingolimod predicts medium-term inefficacy in relapsing-remitting multiple sclerosis.

Mult Scler 2021 08 25;27(9):1374-1383. Epub 2020 Sep 25.

Neurology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy/Neurorehabilitation Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy/Laboratory of Human Genetics of Neurological Disorders, Institute of Experimental Neurology, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy.

Background: Fingolimod (FTY) is an effective second-line drug for relapsing-remitting multiple sclerosis, with ~50% patients showing no evidence of disease activity (NEDA) after 2 years. Nonetheless, the early identification of non-responders is extremely important, to promptly address them to more aggressive drugs.

Objectives: This cohort study evaluates FTY medium-term effectiveness, searching for early markers of treatment failure.

Patients And Methods: Three hundred eighty patients starting FTY were enrolled and classified according to NEDA and time to first relapse criteria at 4-year follow-up. Logistic and Cox regression analyses were applied to identify early predictors of non-response.

Results: At 4 years, 65.6% of patients were free from relapses and 35.4% had NEDA. Female gender was associated with a higher risk of non-response. Moreover, evidence of clinical and/or magnetic resonance imaging (MRI) activity during the first year of treatment was highly predictive of disease activity in the follow-up: the positive predictive value for non-response was 0.74 for the presence of ⩾1 relapse, 0.73 for the presence of ⩾1 active MRI lesion, and 0.83 for the presence of both clinical and MRI activity.

Conclusions: FTY effectiveness persists at medium-term follow-up; a close monitoring during the first year of treatment is warranted to early identify non-responders requiring treatment optimization.
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http://dx.doi.org/10.1177/1352458520961690DOI Listing
August 2021

Paramagnetic Rim Lesions are Specific to Multiple Sclerosis: An International Multicenter 3T MRI Study.

Ann Neurol 2020 11 9;88(5):1034-1042. Epub 2020 Sep 9.

Department of Neurology, Johns Hopkins University, Baltimore, MD.

In multiple sclerosis (MS), a subset of chronic active white matter lesions are identifiable on magnetic resonance imaging by their paramagnetic rims, and increasing evidence supports their association with severity of clinical disease. We studied their potential role in differential diagnosis, screening an international multicenter clinical research-based sample of 438 individuals affected by different neurological conditions (MS, other inflammatory, infectious, and non-inflammatory conditions). Paramagnetic rim lesions, rare in other neurological conditions (52% of MS vs 7% of non-MS cases), yielded high specificity (93%) in differentiating MS from non-MS. Future prospective multicenter studies should validate their role as a diagnostic biomarker. ANN NEUROL 2020;88:1034-1042.
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http://dx.doi.org/10.1002/ana.25877DOI Listing
November 2020

Risk attitude and personality in people with multiple sclerosis facing the choice of different disease-modifying therapy scenarios.

J Neurol Sci 2020 Oct 28;417:117064. Epub 2020 Jul 28.

Department of Neurology, San Raffaele Hospital Scientific Institute, Milan, Italy. Electronic address:

Background: As available disease-modifying therapies (DMTs) increase, evaluating benefit/risk presents greater difficulties, requiring people with MS (PwMS) to play crucial roles in choosing treatment. Although individual attitude toward risk may predict this evaluation, its relation to personality is little studied in MS literature.

Objective: To prospectively assess risk attitudes and personality traits of PwMS choosing a DMT.

Methods: In three Italian MS centers (2012-2015), 420 PwMS completed an ad hoc questionnaire on socio-demographic variables, personality, and standard-gamble questions, to evaluate MS- and DMT-related risks through two hypothetical drug scenarios. We assessed the influence of previously collected socio-demographic/clinical characteristics, and personality factors on risk attitude.

Results: Almost half of participants were mainly concerned about progressive multifocal leukoencephalopathy; <25% about relapses. Median acceptable risk of death for both hypothetical drug scenarios was 1:10,000; 19-20% would not take any risk related to DMT. Regression analysis revealed that being male, more educated, and with higher impulsivity/sensation-seeking propensity was significantly associated with a higher risk attitude.

Conclusions: Both socio-demographic and personality factors affect risk attitude of PwMS facing different DMT scenarios. These findings could affect the shared decision-making process in selecting best treatment option for PwMS.
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http://dx.doi.org/10.1016/j.jns.2020.117064DOI Listing
October 2020

Spinal Cord Atrophy in Neuromyelitis Optica Spectrum Disorders Is Spatially Related to Cord Lesions and Disability.

Radiology 2020 10 28;297(1):154-163. Epub 2020 Jul 28.

From the Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience (L.C., P.V., M.F., M.A.R.) and Neurology Unit (L.C., V.M., M.F., M.A.R.), IRCCS San Raffaele Scientific Institute, via Olgettina 60, Milan 20132, Italy; Vita-Salute San Raffaele University, Milan, Italy (L.C., M.F.); and Clinic of Neurology, Faculty of Medicine, University of Belgrade, Belgrade, Serbia (S.M., J.D.).

Background The spinal cord is commonly involved in patients with neuromyelitis optica spectrum disorders (NMOSDs). However, the relationship between inflammation and atrophy remains unclear. Purpose To characterize the spatial distribution of T1-hypointense lesions in the spinal cord at MRI, its association with cord atrophy, and its correlation with disability in participants with NMOSDs. Materials and Methods This prospective study evaluated three-dimensional T1-weighted spinal cord MRI scans in seropositive participants with NMOSDs and in age-matched healthy control participants acquired between February 2010 and July 2018. Binary masks of T1-hypointense lesions and lesion probability maps were produced. Cross-sectional area of the cervical and upper thoracic cord (down to T3 level) was calculated with the active-surface method. Full factorial models were used to assess cord atrophy in participants with NMOSDs. Correlations between cord atrophy and clinical and brain MRI measures were investigated with multiple regression models. Results A total of 52 participants with NMOSDs (mean age ± standard deviation, 44 years ± 15; 45 women) and 28 age-matched healthy control participants (mean age, 44 years ± 13; 16 women) were evaluated. Thirty-eight of 52 (73%) participants with NMOSDs had T1-hypointense cord lesions. No cord lesions were detected in the healthy control participants. Lesion probability maps showed a predominant involvement of the upper cervical (C2-C4) and upper thoracic (T1-T3 level) cord. The greater involvement of C1-C4 survived Bonferroni correction ( value range, .007-.04), with a higher percentage lesion extent in the gray matter ( < .001). Atrophy colocalized with focal cord lesions and correlated with pyramidal subscore ( ranging from -0.53 to -0.40; < .001) and sensitive subscore ( ranging from -0.48 to -0.46; = .001) of the Expanded Disability Status Scale. Participants without cord lesions had no cord atrophy. Conclusion In participants with neuromyelitis optica spectrum disorders, focal areas of spinal cord atrophy at MRI were topographically associated with lesions and correlated to motor and sensory disability. Participants without visible cord lesions had no atrophy. © RSNA, 2020
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http://dx.doi.org/10.1148/radiol.2020192664DOI Listing
October 2020

Refractory anti-NMDAR encephalitis successfully treated with bortezomib and associated movements disorders controlled with tramadol: a case report with literature review.

J Neurol 2020 Aug 13;267(8):2462-2468. Epub 2020 Jun 13.

Neurophysiology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a potentially fatal autoimmune disease, characterized by autoantibody-mediated neurotransmission impairment in multiple brain locations. The course of this condition often comprises altered mental status, autonomic dysfunctions, refractory seizures and hyperkinetic movement disorders. Available disease-modifying therapies include corticosteroids, i.v. immunoglobulins, plasma exchange, rituximab and cyclophosphamide. In a subgroup of patients not responding to B-cell depletion, bortezomib, a proteasome inhibitor, has shown promising evidence of efficacy. The time course of recovery from acute phase may be very slow (weeks/months), and only few data are available in literature about the concurrent management of encephalitis-associated movement disorders. We report a case of severe anti-NMDAR encephalitis in a 29-year-old woman, not responsive to first- and second-line treatments, with persistent involuntary motor manifestations. Starting three months after symptom onset, four cycles of bortezomib have been administered; subsequently we observed a progressive improvement of neurological status. Meanwhile, motor manifestations were controlled after the administration of tramadol, a non-competitive NMDA receptor antagonist.
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http://dx.doi.org/10.1007/s00415-020-09988-wDOI Listing
August 2020

CSF p-tau/Aβ ratio and brain FDG-PET may reliably detect MCI "imminent" converters to AD.

Eur J Nucl Med Mol Imaging 2020 12 15;47(13):3152-3164. Epub 2020 May 15.

Neurology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.

Purpose: To know whether mild cognitive impairment (MCI) patients will develop Alzheimer's disease (AD) dementia in very short time or remain stable is of crucial importance, also considering new experimental drugs usually tested within very short time frames. Here we combined cerebrospinal fluid (CSF) AD biomarkers and a neurodegeneration marker such as brain FDG-PET to define an objective algorithm, suitable not only to reliably detect MCI converters to AD dementia but also to predict timing of conversion.

Methods: We included 77 consecutive MCI patients with neurological/neuropsychological assessment, brain 18F-FDG-PET and CSF analysis available at diagnosis and a neuropsychological/neurological evaluation every 6 months for a medium- to a long-term follow-up (at least 2 and up to 8 years). Binomial logistic regression models and Kaplan-Meier survival analyses were performed to determine the best biomarker (or combination of biomarkers) in detecting MCI converters to AD dementia and then, among the converters, those who converted in short time frames.

Results: Thirty-five out of 77 MCI patients (45%) converted to AD dementia, with an average conversion time since MCI diagnosis of 26.07 months. CSF p-tau/Aβ42 was the most accurate predictor of conversion from MCI to AD dementia (82.9% sensitivity; 90% specificity). CSF p-tau/Aβ42 and FDG-PET-positive MCIs converted to AD dementia significantly earlier than the CSF-positive-only MCIs (median conversion time, 17.1 vs 31.3 months).

Conclusions: CSF p-tau/Aβ42 ratio and brain FDG-PET may predict both occurrence and timing of MCI conversion to full-blown AD dementia. MCI patients with both biomarkers suggestive for AD will likely develop an AD dementia shortly, thus representing the ideal target for any new experimental drug requiring short periods to be tested for.
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http://dx.doi.org/10.1007/s00259-020-04853-4DOI Listing
December 2020

Diagnosing autoimmune encephalitis in a real-world single-centre setting.

J Neurol 2020 Feb 30;267(2):449-460. Epub 2019 Oct 30.

Department of Neurology, San Raffaele Scientific Institute and University Hospital, Via Olgettina 48, 20132, Milan, Italy.

Background: Early recognition and treatment of autoimmune encephalitis (AE) are crucial for patients, but diagnosis is often difficult and time-consuming. For this purpose, a syndrome-based diagnostic approach was published by Graus et al. (Lancet Neurol 15:391-404, 2016), but very little is known in the literature about its application in clinical practice.

Aim: Our aims are to test the feasibility of such approach in a real-world single-centre setting and to analyse the most relevant factors in criteria fulfilment.

Methods: We retrospectively applied these criteria to our cohort of patients discharged from our hospital with diagnosis of autoimmune encephalitis (n = 33, 58% antibody-positive).

Results: All the subjects fulfilled criteria for possible AE (pAE), with EEG and MRI playing a central role in diagnosis, while CSF was useful mainly to rule out other conditions. Three patients respected criteria for probable anti-NMDA-R encephalitis (pNMDA). Definite anti-NMDAR encephalitis was diagnosed in 4 patients with detection of the autoantibody but, surprisingly, none of these subjects had fulfilled criteria for pNMDA. 18 patients were diagnosed with definite limbic AE (15 patients were antibody-positive, three antibody-negative). Need for MRI bilateral involvement in antibody-negative limbic AE limited diagnosis. One patient fulfilled criteria for probable antibody-negative AE, while ten patients remained classified as pAE.

Conclusion: From our retrospective analysis, some suggestions for a better definition of the criteria may emerge. Larger studies on prospective cohorts may be more helpful to explore possible important issues.
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http://dx.doi.org/10.1007/s00415-019-09607-3DOI Listing
February 2020

Changes in cortical motor outputs after a motor relapse of multiple sclerosis.

Mult Scler J Exp Transl Clin 2019 Jul-Sep;5(3):2055217319866480. Epub 2019 Sep 25.

Department of Neurorehabilitation and Department of Clinical Neurophysiology, Hospital San Raffaele, Milan, Italy.

Background: Motor recovery following a multiple sclerosis (MS) relapse depends on mechanisms of tissue repair but also on the capacity of the central nervous system for compensating of permanent damage.

Objectives: We aimed to investigate changes in corticospinal plasticity and interhemispheric connections after a relapse of MS using transcranial magnetic stimulation (TMS).

Methods: Twenty healthy and 13 relapsing-remitting MS subjects with a first motor relapse were included. TMS mapping and ipsilateral silent period (iSP) were performed after relapse and at 6-month follow-up.

Results: Strength and dexterity of the paretic hand were impaired at baseline and improved over time. After relapse, map and map were decreased for the ipsilesional-corticospinal tract (IL-CST) while expanded for the contralesional-CST (CL-CST). At follow-up, map parameters normalized for the CL-CST independently from recovery while the increase of outputs from the IL-CST was associated with straight and dexterity improvement. iSP measurements were impaired in MS irrespective of the phase of the disease. Prolonged iSP at baseline was associated with less dexterity recovery.

Conclusions: After a motor relapse, TMS mapping shows acute changes in corticospinal excitability and rearrangements of motor outputs. iSP is less influenced by the phase of disease but may better predict recovery, possibly reflecting the integrity of interhemispheric motor networks.
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http://dx.doi.org/10.1177/2055217319866480DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6764060PMC
September 2019

Multiple sclerosis associated with pembrolizumab in a patient with non-small cell lung cancer.

J Neurol 2019 12 4;266(12):3163-3166. Epub 2019 Oct 4.

Neurology Unit, IRCCS San Raffaele Scientific Institute, Via Olgettina 60, 20132, Milan, Italy.

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http://dx.doi.org/10.1007/s00415-019-09562-zDOI Listing
December 2019

Loss of Circulating CD8+ CD161 T Cells in Primary Progressive Multiple Sclerosis.

Front Immunol 2019 14;10:1922. Epub 2019 Aug 14.

Division of Neuroscience, Institute of Experimental Neurology, San Raffaele Scientific Institute, Milan, Italy.

Recent evidence suggests that the primary progressive form of multiple sclerosis (PP-MS) may present with specific immunological alterations. In this study we focused our attention on CD161, an NK and T cell marker upregulated in relapsing-remitting MS, and investigated its transcript and protein levels in blood cells from PP-MS and healthy individuals. We demonstrated transcriptional downregulation of CD161 in PP-MS and described concomitant mRNA reduction for RORgt, CCR6, CXCR6, KLRK1/NKG2D and many other markers typical of mucosa associated invariant T (MAIT) cells. Targeted multiparametric flow cytometry on fresh blood cells from an independent cohort of case-control subjects confirmed the selective loss of circulating CD8 CD161 T cells, which consist mainly of MAIT cells, and not of CD8 CD161 T cells in PP-MS. These data demonstrate alterations in a specific circulating immune cell subset in MS patients with progressive onset.
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http://dx.doi.org/10.3389/fimmu.2019.01922DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6702304PMC
October 2020

High-dose steroid therapy for CNS inflammatory diseases increases INR in patients taking oral vitamin K antagonist.

J Neurol 2019 12 21;266(12):3160-3161. Epub 2019 Aug 21.

Neurology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.

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http://dx.doi.org/10.1007/s00415-019-09515-6DOI Listing
December 2019

Subclinical neurodegeneration in multiple sclerosis and neuromyelitis optica spectrum disorder revealed by optical coherence tomography.

Mult Scler 2020 09 8;26(10):1197-1206. Epub 2019 Aug 8.

Department of Neurorehabilitation and Department of Clinical Neurophysiology, Hospital San Raffaele, Milan, Italy/ INSPE, Institute of Experimental Neurology (INSPE), San Raffaele Scientific Institute, Milan, Italy/ University Vita-Salute San Raffaele, Milan, Italy.

Background: Neuroretinal atrophy is associated with whole-brain atrophy and disease activity in multiple sclerosis (MS). Recent findings support that subclinical visual pathway involvement might also occur in neuromyelitis optica spectrum disorders (NMOSDs).

Objective: The objective of this study is to assess retinal thinning in MS and NMOSD and its association with disease activity.

Methods: In total, 27 NMOSD and 54 propensity-score-matched MS patients underwent optical coherence tomography, visual acuity, and visual-evoked potentials at 2.4 years apart, in addition to routine clinical and magnetic resonance imaging (MRI) assessment. We excluded eyes with acute optic neuritis.

Results: In NMOSD, we detected peripapillary retinal nerve fiber layer (pRNFL) thinning in patients with disease activity during follow-up (-0.494 µm/year), but not in stable patients (-0.012 µm/year). Macular ganglion cell-inner plexiform layer (GCIPL) thinning occurred instead in all patients (-0.279 µm/year). Relapsing-remitting multiple sclerosis (RRMS) meeting NEDA-3 criteria had no pRNFL or GCIPL thinning during follow-up. Active-disease RRMS and progressive MS, both active and stable, displayed pRNFL (-0.724, -0.586, -0.556 µm/year, respectively) and GCIPL loss.

Conclusion: In MS, neuroretinal atrophy was associated with disease activity but occurred in progressive MS even when achieving NEDA-3 criteria. In NMOSD, pRNFL thinning was associated with non-ocular relapses due to a spreading of inflammatory activity. GCIPL thinning was found in all patients, supporting a primary retinal pathology targeting AQP4-rich structures.
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http://dx.doi.org/10.1177/1352458519861603DOI Listing
September 2020

The CSF p-tau181/Aβ42 Ratio Offers a Good Accuracy "In Vivo" in the Differential Diagnosis of Alzheimer's Dementia.

Curr Alzheimer Res 2019 ;16(7):587-595

Department of Neurology, INSPE, Vita-Salute University and IRCCS-San Raffaele Hospital, Milan, Italy.

Background: The incoming disease-modifying therapies against Alzheimer's disease (AD) require reliable diagnostic markers to correctly enroll patients all over the world. CSF AD biomarkers, namely amyloid-β 42 (Aβ42), total tau (t-tau), and tau phosphorylated at threonine 181 (p-tau181), showed good diagnostic accuracy in detecting AD pathology, but their real usefulness in daily clinical practice is still a matter of debate. Therefore, further validation in complex clinical settings, that is patients with different types of dementia, is needed to uphold their future worldwide adoption.

Methods: We measured CSF AD biomarkers' concentrations in a sample of 526 patients with a clinical diagnosis of dementia (277 with AD and 249 with Other Type of Dementia, OTD). Brain FDG-PET was also considered in a subsample of 54 patients with a mismatch between the clinical diagnosis and the CSF findings.

Results: A p-tau181/Aβ42 ratio higher than 0.13 showed the best diagnostic performance in differentiating AD from OTD (86% accuracy index, 74% sensitivity, 81% specificity). In cases with a mismatch between clinical diagnosis and CSF findings, brain FDG-PET partially agreed with the p-tau181/Aβ42 ratio, thus determining an increase in CSF accuracy.

Conclusion: The p-tau181/Aβ42 ratio alone might reliably detect AD pathology in heterogeneous samples of patients suffering from different types of dementia. It might constitute a simple, cost-effective and reproducible in vivo proxy of AD suitable to be adopted worldwide not only in daily clinical practice but also in future experimental trials, to avoid the enrolment of misdiagnosed AD patients.
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http://dx.doi.org/10.2174/1567205016666190725150836DOI Listing
September 2020

In vivo structural and functional assessment of optic nerve damage in neuromyelitis optica spectrum disorders and multiple sclerosis.

Sci Rep 2019 07 17;9(1):10371. Epub 2019 Jul 17.

University Vita-Salute San Raffaele, Milan, Italy.

Early detection of neuromyelitis optica spectrum disorders (NMOSD), especially after optic neuritis, a presenting manifestation commonly observed also in multiple sclerosis (MS), is crucial for timely treatment and prognosis. Integrated visual pathway assessment with optical coherence tomography (OCT) and visual evoked potentials (VEP) may help in this task, showing in vivo different pathophysiological backgrounds. We evaluated combined VEP and OCT in a cross-sectional, single-centre study assessing 50 consecutive NMOSD patients, 57 MS patients and 52 healthy controls. After optic neuritis, VEP were more frequently absent in NMOSD compared to MS; most NMOSD eyes with recordable VEP showed prolonged latency, but extreme latency delays were less common than in MS. OCT showed predominantly axonal involvement in NMOSD, with 88% eyes (95% CI: 69-97%) displaying retinal nerve fibre layer thickness <60 µm even after first optic neuritis episode. Accuracy of OCT was further enhanced by combination with VEP into a new Z-score derived OCT-VEP index, measuring prevalence of axonal damage or demyelination. Our results suggest that integrated optic nerve assessment may elucidate differences in optic neuritis pathophysiology; conduction slowing with relatively preserved nerve fibre layer suggests MS, while severe neuroaxonal loss after optic neuritis, often hindering VEP response, characterizes NMOSD.
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http://dx.doi.org/10.1038/s41598-019-46251-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6637174PMC
July 2019
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