Publications by authors named "Giovanni Ristori"

61 Publications

Multiple Sclerosis and SARS-CoV-2: Has the Interplay Started?

Front Immunol 2021 27;12:755333. Epub 2021 Sep 27.

Centre for Experimental Neurological Therapies (CENTERS), Department of Neurosciences, Mental Health and Sensory Organs, Sapienza University of Rome, Rome, Italy.

Current knowledge on Multiple Sclerosis (MS) etiopathogenesis encompasses complex interactions between the host's genetic background and several environmental factors that result in dysimmunity against the central nervous system. An old-aged association exists between MS and viral infections, capable of triggering and sustaining neuroinflammation through direct and indirect mechanisms. The novel Coronavirus, SARS-CoV-2, has a remarkable, and still not fully understood, impact on the immune system: the occurrence and severity of both acute COVID-19 and post-infectious chronic illness (long COVID-19) largely depends on the host's response to the infection, that echoes several aspects of MS pathobiology. Furthermore, other MS-associated viruses, such as the Epstein-Barr Virus (EBV) and Human Endogenous Retroviruses (HERVs), may enhance a mechanistic interplay with the novel Coronavirus, with the potential to interfere in MS natural history. Studies on COVID-19 in people with MS have helped clinicians in adjusting therapeutic strategies during the pandemic; similar efforts are being made for SARS-CoV-2 vaccination campaigns. In this Review, we look over 18 months of SARS-CoV-2 pandemic from the perspective of MS: we dissect neuroinflammatory and demyelinating mechanisms associated with COVID-19, summarize pathophysiological crossroads between MS and SARS-CoV-2 infection, and discuss present evidence on COVID-19 and its vaccination in people with MS.
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http://dx.doi.org/10.3389/fimmu.2021.755333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8503550PMC
October 2021

Intestinal Permeability and Circulating CD161+CCR6+CD8+T Cells in Patients With Relapsing-Remitting Multiple Sclerosis Treated With Dimethylfumarate.

Front Neurol 2021 26;12:683398. Epub 2021 Aug 26.

Department of Neuroscience, Mental Health and Sensory Organs, Sapienza University, Rome, Italy.

The changes of the gut-brain axis have been recently recognized as important components in multiple sclerosis (MS) pathogenesis. To evaluate the effects of DMF on intestinal barrier permeability and mucosal immune responses. We investigated intestinal permeability (IP) and circulating CD161+CCR6+CD8+T cells in 25 patients with MS, who met eligibility criteria for dimethyl-fumarate (DMF) treatment. These data, together with clinical/MRI parameters, were studied at three time-points: baseline (before therapy), after one (T1) and 9 months (T2) of treatment. At baseline 16 patients (64%) showed altered IP, while 14 cases (56%) showed active MRI. During DMF therapy we found the expected decrease of disease activity at MRI compared to T0 (6/25 at T1, = 0.035 and 3/25 at T2, < 0.00), and a reduction in the percentage of CD161+CCR6+CD8+ T cells (16/23 at T2; < 0.001). The effects of DMF on gut barrier alterations was variable, without a clear longitudinal pattern, while we found significant relationships between IP changes and drop of MRI activity ( = 0.04) and circulating CD161+CCr6+CD8+ T cells ( = 0.023). The gut barrier is frequently altered in MS, and the CD161+ CCR6+CD8+ T cell-subset shows dynamics which correlate with disease course and therapy.
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http://dx.doi.org/10.3389/fneur.2021.683398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8426620PMC
August 2021

Cognitive and behavioral associated changes in manifest Huntington disease: A retrospective cross-sectional study.

Brain Behav 2021 07 10;11(7):e02151. Epub 2021 Jun 10.

Huntington and Rare Diseases Unit, Fondazione IRCCS Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Italy.

Introduction: Behavioral and cognitive changes can be observed across all Huntington disease (HD) stages. Our multicenter and retrospective study investigated the association between cognitive and behavioral scale scores in manifest HD, at three different yearly timepoints.

Methods: We analyzed cognitive and behavioral domains by the Unified Huntington's Disease Rating Scale (UHDRS) and by the Problem Behaviors Assessment Short Form (PBA-s), at three different yearly times of life (t0 or baseline, t1 after one year, t2 after two years), in 97 patients with manifest HD (mean age 48.62 ± 13.1), from three ENROLL-HD Centers. In order to test the disease progression, we also examined patients' motor and functional changes by the UHDRS, overtime.

Results: The severity of apathy and of perseveration/obsession was associated with the severity of the cognitive decline (p < .0001), regardless of the yearly timepoint. The score of irritability significantly and positively correlated with perseveration errors in the verbal fluency test at t0 (r = .34; p = .001), while the psychosis significantly and negatively correlated with the information processing speed at t0 (r = -.21; p = .038) and significantly and positively correlated with perseveration errors in the verbal fluency test at t1 (r = .35; p < .0001). The disease progression was confirmed by the significant worsening of the UHDRS-Total Motor Score (TMS) and of the UHDRS-Total Functional Capacity (TFC) scale score after two-year follow-up (p < .0001).

Conclusion: Although the progression of abnormal behavioral manifestations cannot be predicted in HD, the severity of apathy and perseveration/obsessions are significantly associated with the severity of the cognitive function impairment, thus contributing, together, to the disease development and to patients' loss of independence, in addition to the neurological manifestations. This cognitive-behavior pattern determines a common underlying deficit depending on a dysexecutive syndrome.
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http://dx.doi.org/10.1002/brb3.2151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8323039PMC
July 2021

MAIT Cells and Microbiota in Multiple Sclerosis and Other Autoimmune Diseases.

Microorganisms 2021 May 24;9(6). Epub 2021 May 24.

Centre for Experimental Neurological Therapies (CENTERS), Department of Neurosciences, Mental Health and Sensory Organs, Sapienza University of Rome, 00189 Rome, Italy.

The functions of mucosal-associated invariant T (MAIT) cells in homeostatic conditions include the interaction with the microbiota and its products, the protection of body barriers, and the mounting of a tissue-repair response to injuries or infections. Dysfunction of MAIT cells and dysbiosis occur in common chronic diseases of inflammatory, metabolic, and tumor nature. This review is aimed at analyzing the changes of MAIT cells, as well as of the microbiota, in multiple sclerosis and other autoimmune disorders. Common features of dysbiosis in these conditions are the reduced richness of microbial species and the unbalance between pro-inflammatory and immune regulatory components of the gut microbiota. The literature concerning MAIT cells in these disorders is rather complex, and sometimes not consistent. In multiple sclerosis and other autoimmune conditions, several studies have been done, or are in progress, to find correlations between intestinal permeability, dysbiosis, MAIT cell responses, and clinical biomarkers in treated and treatment-naïve patients. The final aims are to explain what activates MAIT cells in diseases not primarily infective, which interactions with the microbiota are potentially pathogenic, and their dynamics related to disease course and disease-modifying treatments.
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http://dx.doi.org/10.3390/microorganisms9061132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8225125PMC
May 2021

Circulating hsa-miR-323b-3p in Huntington's Disease: A Pilot Study.

Front Neurol 2021 5;12:657973. Epub 2021 May 5.

Department of Neurosciences, Centre for Experimental Neurological Therapies (CENTERS), Mental Health and Sensory Organs, Sapienza University of Rome, Rome, Italy.

The momentum of gene therapy in Huntington's disease (HD) deserves biomarkers from easily accessible fluid. We planned a study to verify whether plasma miRNome may provide useful peripheral "reporter(s)" for the management of HD patients. We performed an exploratory microarray study of whole non-coding RNA profiles in plasma from nine patients with HD and 13 matched controls [eight healthy subjects (HS) and five psychiatric patients (PP) to minimize possible iatrogenic impact on the profile of non-coding RNAs]. We found an HD-specific signature: downregulation of hsa-miR-98 (fold change, -1.5, = 0.0338 HD vs. HS, and fold change, 1.5, = 0.0045 HD vs. PP) and upregulation of hsa-miR-323b-3p (fold change, 1.5, = 0.0007 HD vs. HS, and fold change, 1.5, = 0.0111 HD vs. PP). To validate this result in an independent cohort, we quantify by digital droplet PCR (ddPCR) the presence of the two microRNA in the plasma of 33 HD patients and 49 matched controls (25 HS and 24 PP patients). We were able to confirm that hsa-miR-323b-3p was upregulated in HD and premanifest HD vs. HS and PP: the median values (first-third quartile) were 4.1 (0.9-10.53) and 5.8 (1.9-10.70) vs. 0.69 (0.3-2.75) and 1.4 (0.78-2.70), respectively, < 0.05. No significant difference was found for hsa-miR-98. To evaluate the biological plausibility of the hsa-miR-323b-3p as a component of the disease pathophysiology, we performed a bioinformatic analysis based on its targetome and the huntingtin (HTT) interactome. We found a statistically significant overconnectivity between the targetome of hsa-miR-323b-3p and the HTT interactome ( = 1.48e-08). Furthermore, there was a significant transcription regulation of the HTT interactome by the miR-323b-3p targetome ( = 0.02). The availability of handy, reproducible, and minimally invasive biomarkers coming from peripheral miRNome may be valuable to characterize the illness progression, to indicate new therapeutic targets, and to monitor the effect of disease-modifying treatments. Our data deserve further studies with larger sample size and longitudinal design.
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http://dx.doi.org/10.3389/fneur.2021.657973DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8131841PMC
May 2021

A Case of Double Standard: Sex Differences in Multiple Sclerosis Risk Factors.

Int J Mol Sci 2021 Apr 2;22(7). Epub 2021 Apr 2.

Centre for Experimental Neurological Therapies (CENTERS), Department of Neurosciences, Mental Health and Sensory Organs, Sapienza University of Rome, 00189 Rome, Italy.

Multiple sclerosis is a complex, multifactorial, dysimmune disease prevalent in women. Its etiopathogenesis is extremely intricate, since each risk factor behaves as a variable that is interconnected with others. In order to understand these interactions, sex must be considered as a determining element, either in a protective or pathological sense, and not as one of many variables. In particular, sex seems to highly influence immune response at chromosomal, epigenetic, and hormonal levels. Environmental and genetic risk factors cannot be considered without sex, since sex-based immunological differences deeply affect disease onset, course, and prognosis. Understanding the mechanisms underlying sex-based differences is necessary in order to develop a more effective and personalized therapeutic approach.
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http://dx.doi.org/10.3390/ijms22073696DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8037645PMC
April 2021

SARS-CoV-2 meta-interactome suggests disease-specific, autoimmune pathophysiologies and therapeutic targets.

F1000Res 2020 17;9:992. Epub 2020 Aug 17.

Department of Neurosciences, Mental Health and Sensory Organs, Sapienza University of Rome, Rome, 00189, Italy.

Severe coronavirus disease 2019 (COVID-19) is associated with multiple comorbidities and is characterized by an auto-aggressive inflammatory state leading to massive collateral damage. To identify preventive and therapeutic strategies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), it is important to ascertain the molecular interactions between virus and host, and how they translate into disease pathophysiology. We matched virus-human protein interactions of human coronaviruses and other respiratory viruses with lists of genes associated with autoimmune diseases and comorbidities associated to worse COVID-19 course. We then selected the genes included in the statistically significant intersection between SARS-CoV-2 network and disease associated gene sets, identifying a meta-interactome. We analyzed the meta-interactome genes expression in samples derived from lungs of infected humans, and their regulation by IFN-β. Finally, we performed a drug repurposing screening to target the network's most critical nodes. We found a significant enrichment of SARS-CoV-2 interactors in immunological pathways and a strong association with autoimmunity and three prognostically relevant conditions (type 2 diabetes, coronary artery diseases, asthma), that present more independent physiopathological subnetworks. We observed a reduced expression of meta-interactome genes in human lungs after SARS-CoV-2 infection, and a regulatory potential of type I interferons. We also underscored multiple repurposable drugs to tailor the therapeutic strategies. Our data underscored a plausible genetic background that may contribute to the distinct observed pathophysiologies of severe COVID-19. Also, these results may help identify the most promising therapeutic targets and treatments for this condition.
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http://dx.doi.org/10.12688/f1000research.25593.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7791351PMC
January 2021

Corrigendum: Perivascular Unit: This Must Be the Place. The Anatomical Crossroad Between the Immune, Vascular and Nervous System.

Front Neuroanat 2020 15;14:51. Epub 2020 Sep 15.

Center for Neurological Imaging, Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States.

[This corrects the article DOI: 10.3389/fnana.2020.00017.].
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http://dx.doi.org/10.3389/fnana.2020.00051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7522475PMC
September 2020

Heterozygous variants underlie a wide spectrum of neurodevelopmental and neurodegenerative disorders.

J Med Genet 2021 07 31;58(7):475-483. Epub 2020 Jul 31.

Unit of Neuromuscular and Neurodegenerative Diseases, Department of Neuroscience and Neurorehabilitation, IRCCS Bambino Gesù Children's Hospital, Roma, Italy.

Background: Dominant and recessive variants in the gene on chromosome 2q37.3 are associated with several phenotypes, although only three syndromes are currently listed in the OMIM classification: hereditary sensory and autonomic neuropathy type 2 and spastic paraplegia type 30, both recessively inherited, and mental retardation type 9 with dominant inheritance.

Methods: In this retrospective multicentre study, we describe the clinical, neuroradiological and genetic features of 19 Caucasian patients (aged 3-65 years) harbouring heterozygous variants, and extensively review the available literature to improve current classification of -related disorders.

Results: Patients were divided into two groups. Group 1 comprised patients with a complex phenotype with prominent pyramidal signs, variably associated in all but one case with additional features (ie, epilepsy, ataxia, peripheral neuropathy, optic nerve atrophy); conversely, patients in group 2 presented an early onset or congenital ataxic phenotype. Fourteen different heterozygous missense variants were detected by next-generation sequencing screening, including three novel variants, most falling within the kinesin motor domain.

Conclusion: The present study further enlarges the clinical and mutational spectrum of -related disorders by describing a large series of patients with dominantly inherited pathogenic variants ranging from pure to complex forms of hereditary spastic paraparesis/paraplegias (HSP) and ataxic phenotypes in a lower proportion of cases. A comprehensive review of the literature indicates that screening should be implemented in HSP regardless of its mode of inheritance or presentations as well as in other complex neurodegenerative or neurodevelopmental disorders showing congenital or early onset ataxia.
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http://dx.doi.org/10.1136/jmedgenet-2020-107007DOI Listing
July 2021

Perivascular Unit: This Must Be the Place. The Anatomical Crossroad Between the Immune, Vascular and Nervous System.

Front Neuroanat 2020 16;14:17. Epub 2020 Apr 16.

Harvard Medical School, Center for Neurological Imaging, Brigham and Women's Hospital, Boston, MA, United States.

Most neurological disorders seemingly have heterogenous pathogenesis, with overlapping contribution of neuronal, immune and vascular mechanisms of brain injury. The perivascular space in the brain represents a crossroad where those mechanisms interact, as well as a key anatomical component of the recently discovered glymphatic pathway, which is considered to play a crucial role in the clearance of brain waste linked to neurodegenerative diseases. The pathological interplay between neuronal, immune and vascular factors can create an environment that promotes self-perpetration of mechanisms of brain injury across different neurological diseases, including those that are primarily thought of as neurodegenerative, neuroinflammatory or cerebrovascular. Changes of the perivascular space can be monitored in humans using magnetic resonance imaging (MRI). In the context of glymphatic clearance, MRI-visible enlarged perivascular spaces (EPVS) are considered to reflect glymphatic stasis secondary to the perivascular accumulation of brain debris, although they may also represent an adaptive mechanism of the glymphatic system to clear them. EPVS are also established correlates of dementia and cerebral small vessel disease (SVD) and are considered to reflect brain inflammatory activity. In this review, we describe the "perivascular unit" as a key anatomical and functional substrate for the interaction between neuronal, immune and vascular mechanisms of brain injury, which are shared across different neurological diseases. We will describe the main anatomical, physiological and pathological features of the perivascular unit, highlight potential substrates for the interplay between different noxae and summarize MRI studies of EPVS in cerebrovascular, neuroinflammatory and neurodegenerative disorders.
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http://dx.doi.org/10.3389/fnana.2020.00017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7177187PMC
April 2020

Reworking GWAS Data to Understand the Role of Nongenetic Factors in MS Etiopathogenesis.

Genes (Basel) 2020 01 14;11(1). Epub 2020 Jan 14.

Centre for Experimental Neurological Therapies (CENTERS), Department of Neurosciences, Mental Health and Sensory Organs, Sapienza University of Rome, 00189 Rome, Italy.

Genome-wide association studies have identified more than 200 multiple sclerosis (MS)-associated loci across the human genome over the last decade, suggesting complexity in the disease etiology. This complexity poses at least two challenges:
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http://dx.doi.org/10.3390/genes11010097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7017269PMC
January 2020

Autoimmune Encephalitis and CSF Anti-GluR3 Antibodies in an MS Patient after Alemtuzumab Treatment.

Brain Sci 2019 Oct 30;9(11). Epub 2019 Oct 30.

Department of Neurosciences, Mental Health and Sensory Organs, Centre for Experimental Neurological Therapies (CENTERS), Faculty of Medicine and Psychology, Sapienza University, 00189 Rome, Italy.

A 45-year-old Italian woman, affected by relapsing-remitting multiple sclerosis (RR-MS) starting from 2011, started treatment with alemtuzumab in July 2016. Nine months after the second infusion, she had an immune thrombocytopenic purpura (ITP) with complete recovery after steroid treatment. Three months after the ITP, the patient presented with transient aphasia, cognitive deficits, and focal epilepsy. Serial brain magnetic resonance imaging showed a pattern compatible with encephalitis. Autoantibodies to glutamate receptor 3 peptide A and B were detected in cerebrospinal fluid and serum, in the absence of any other diagnostic cues. After three courses of intravenous immunoglobulin (0.4 mg/kg/day for 5 days, 1 month apart), followed by boosters (0.4 mg/kg/day) every 4-6 weeks, her neurological status improved and is currently comparable with that preceding the encephalitis. Autoimmune complications of the central nervous system during alemtuzumab therapy are relatively rare: only one previous case of autoimmune encephalitis following alemtuzumab treatment has been reported to date.
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http://dx.doi.org/10.3390/brainsci9110299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6895826PMC
October 2019

The Contribution of Gut Barrier Changes to Multiple Sclerosis Pathophysiology.

Front Immunol 2019 28;10:1916. Epub 2019 Aug 28.

Department of Neurosciences, Mental Health and Sensory Organs, Faculty of Medicine and Psychology, Centre for Experimental Neurological Therapies, Sapienza University, Rome, Italy.

The gut barrier consists of several components, including the mucus layer, made of mucins and anti-bacterial molecule, the epithelial cells, connected by tight junction proteins, and a mixed population of cells involved in the interplay with microbes, such as M cells, elongations of "antigen presenting cells" dwelling the lamina propria, intraepithelial lymphocytes and Paneth cells secreting anti-bacterial peptides. Recently, the influence of intestinal permeability (IP) changes on organs far from gut has been investigated, and IP changes in multiple sclerosis (MS) have been described. A related topic is the microbiota dysfunction that underpins the development of neuroinflammation in animal models and human diseases, including MS. It becomes now of interest to better understand the mechanisms through which IP changes contribute to pathophysiology of neuroinflammation. The following aspects seem of relevance: studies on other biomarkers of IP alterations; the relationship with known risk factors for MS development, such as vitamin D deficiency; the link between blood brain barrier and gut barrier breakdown; the effects of IP increase on microbial translocation and microglial activation; the parallel patterns of IP and neuroimmune changes in MS and neuropsychiatric disorders, that afflict a sizable proportion of patients with MS. We will also discuss the therapeutic implications of IP changes, considering the impact of MS-modifying therapies on gut barrier, as well as potential approaches to enhance or protect IP homeostasis.
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http://dx.doi.org/10.3389/fimmu.2019.01916DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6724505PMC
October 2020

Drug Holiday of Interferon Beta 1b in Multiple Sclerosis: A Pilot, Randomized, Single Blind Study of Non-inferiority.

Front Neurol 2019 16;10:695. Epub 2019 Jul 16.

Neurosciences, Mental Health, and Sensory Organs (NESMOS) Department, Center for Experimental Neurological Therapies, S. Andrea Hospital-site, "Sapienza" University of Rome, Rome, Italy.

To compare a schedule with cyclic withdrawal (CW) of interferon beta (IFN-b) 1b, respect to the full regimen (FR), in relapsing-remitting MS (RR-MS). Participants were randomly assigned to CW or FR schedule and monthly monitored with brain MRI scans for 12 months (three of run-in and 9 of treatment). CW schedule included drug withdrawal for 1 month after two of treatment for a total of three quarters over the 9-month treatment period. The assessing neurologist and the expert neuroradiologists were blind. After the blind phase of the study all participants took their indicated disease modifying therapies in a prospectively planned, open-label extension phase (up to 120 months). Of 60 randomized subjects 56 (29 in FR and 27 in CW group) completed the single-blind phase: the two groups were comparable, except for a non-significant difference in the number of contrast-enhanced lesions (CEL) at the end of run-in. The two-sided 90% CI for the ratio between median number of cumulative CEL was 0.29-1.07, allowing to significantly reject the null hypothesis of a ratio ≥1.2 and to meet the primary end-point of non-inferiority (the threshold and the ratio between median were chosen according to the non-normal distribution of the data). The differences (CW vs. FR) were also non-significant for secondary end points: mean cumulative number of T2-weighted new and enlarging lesions (3.48 ± 5.34 vs. 3.86 ± 6.76); mean number and volume (cm) of black holes (1.24 ± 1.61 vs. 2.71 ± 4.56; 489.11 ± 1488.12 vs. 204.48 ± 396.98); number of patients with at least an active scan (21 vs. 22); mean relapse rate (0.52 ± 0.89 vs. 0.34 ± 0.66), relapse risk ratio adjusted for baseline variables (2.15 [0.64-7.18]), EDSS score (1.0 [1-1.56] vs. 1.5 [1-1.78]), proportion of patients with antibodies anti-IFN (5 [21%] vs. 8 [36%]). Fifty-four patients (27 for each study arm) completed the open-label phase. The annualized RR, EDSS, proportion of patients shifting to progressive disease and hazard ratio of shifting, adjusting for baseline covariates, were comparable between the two study groups. A calendar with CW was non-inferior than FR at the beginning of IFN-b therapy, and may not affect the long-term outcome. www.ClinicalTrials.gov, identifier: NCT00270816.
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http://dx.doi.org/10.3389/fneur.2019.00695DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6646514PMC
July 2019

Genome-Wide Multiple Sclerosis Association Data and Coagulation.

Front Neurol 2019 14;10:95. Epub 2019 Feb 14.

Department of Neuroscience, Mental Health and Sensory Organs, Faculty of Medicine and Psychology, Centre for Experimental Neurological Therapies, S. Andrea Hospital, Sapienza University, Rome, Italy.

The emerging concept of a crosstalk between hemostasis, inflammation, and immune system prompt recent works on coagulation cascade in multiple sclerosis (MS). Studies on MS pathology identified several coagulation factors since the beginning of the disease pathophysiology: fibrin deposition with breakdown of blood brain barrier, and coagulation factors within active plaques may exert pathogenic role, especially through the innate immune system. Studies on circulating coagulation factors showed complex imbalance involving several components of hemostasis cascade (thrombin, factor X, factor XII). To analyze the role of the coagulation process in connection with other pathogenic pathways, we implemented a systematic matching of genome-wide association studies (GWAS) data with an informative and unbiased network of coagulation pathways. Using MetaCore (version 6.35 build 69300, 2018) we analyzed the connectivity (i.e., direct and indirect interactions among two networks) between the network of the coagulation process and the network resulting from feeding into MetaCore the MS GWAS data. The two networks presented a remarkable over-connectivity: 958 connections vs. 561 expected by chance; -score = 17.39; -value < 0.00001. Moreover, genes coding for cluster of differentiation 40 (CD40) and plasminogen activator, urokinase (PLAU) shared both networks, pointed to an integral interplay between coagulation cascade and main pathogenic immune effectors. In fact, CD40 pathways is especially operative in B cells, that are currently a major therapeutic target in MS field. The potential interaction of PLAU with a signal of paramount importance for B cell pathogenicity, such as CD40, suggest new lines of research and pave the way to implement new therapeutic targets.
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http://dx.doi.org/10.3389/fneur.2019.00095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6383413PMC
February 2019

The Economic Burden and Impact on Quality of Life of Herpes Zoster and Postherpetic Neuralgia in Individuals Aged 50 Years or Older in Italy.

Open Forum Infect Dis 2019 Feb 12;6(2):ofz007. Epub 2019 Jan 12.

Value Evidence, GSK, Wavre, Belgium.

Background: To estimate the health care resource utilization, costs, and impact on quality of life (QoL) of herpes zoster (HZ) and postherpetic neuralgia (PHN) in adults aged ≥50 years in Italy.

Methods: This was a prospective, observational, multicenter, community physician-based surveillance study (NCT01772160) in Italy. Health-related QoL data were collected using the EuroQoL-5 Dimension (EQ-5D) and Zoster Brief Pain Inventory (ZBPI) questionnaires. Both questionnaires were assessed at days 0 (HZ rash onset), 15, 30, 60, and 90 for all patients, and monthly thereafter for patients who developed PHN. Resource utilization was recorded for 3 months post-HZ onset and 9 months for PHN patients. Costs from both payer and societal perspectives were estimated and were composed of direct medical costs (general practitioner/specialist visits, procedures, hospitalizations, medications), work loss by patient/caregiver, and transport costs.

Results: A total of 391 patients with HZ were included, of whom 40 developed PHN. The mean ZBPI worst pain score was 5.7 at day 0, reducing to 2.6 at day 30 and 0.7 by day 90. Patients with PHN had a mean worst pain score of 5.7 at day 90. We estimated an overall disutility associated with HZ of 0.134. The mean cost per HZ patient from a payer/societal perspective was €153/€298, respectively, and the mean cost per HZ patients who developed PHN was €176/€426, respectively.

Conclusions: HZ is associated with impaired QoL and substantial health care resource use, highlighting the need for preventive strategies. This could reduce the disease burden for the patient and health care system.

Clinicaltrialsgov Study Registry: NCT01772160.
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http://dx.doi.org/10.1093/ofid/ofz007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6377935PMC
February 2019

Oxidative Status in Multiple Sclerosis and Off-Targets of Antioxidants: The Case of Edaravone.

Curr Med Chem 2020 ;27(13):2095-2105

Centre for Experimental Neurological Therapies (CENTERS), Department of Neurosciences, Mental Health and Sensory Organs, Sapienza University, Rome, Italy.

Background: MS is a chronic inflammatory disease of the CNS leading to demyelination and neurodegeneration, with a complex and still to be clarified aetiology. Several data, coming from patients' samples and from animal models, show that Oxidative Status (OS) plays an important role in MS pathogenesis. Overproduction of reactive oxidative species by macrophages/microglia can bring about cellular injury and ensuing cell death by oxidizing cardinal cellular components. Oxidized molecules are present in active MS lesions and are associated with neurodegeneration.

Methods: We undertook a structured search of bibliographic databases for peer-reviewed research literature focusing on OS in MS. The contents of the selected papers were described in the context of a conceptual framework. A special emphasis was given to the results of our study in the field.

Results: The results of our three recent studies were put in the context and discussed taking into account the literature on the topic. Oxidative damage underpinned an imbalance shared by MS and neurodegenerative diseases such as Alzheimer and Parkinson diseases. In people with clinically isolated syndrome (an early phase of MS) oxidative stress proved to contribute to disease pathophysiology and to provide biomarkers that may help predict disease evolution. A drug screening platform based on multiple assays to test the remyelinating potential of library of approved compounds showed two anti-oxidants, edaravone and 5-methyl-7- methoxyisoflavone, as active drugs. Moreover, an analysis of 'structure activity relationship' showed off-targets sites of these compounds that accounted for their remyelinating activity, irrespective of their antioxidant action.

Conclusion: Overall, edaravone emerges as a candidate to treat complex disease such as MS, where inflammation, oxidative stress and neurodegeneration contribute to disease progression, together or individually, in different phases and disease types. Furthermore, approaches based on drug repositioning seem to maintain the promise of helping discover novel treatment for complex diseases, where molecular targets are largely unknown.
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http://dx.doi.org/10.2174/0929867326666190124122752DOI Listing
July 2020

DNA damage signatures in peripheral blood cells as biomarkers in prodromal huntington disease.

Ann Neurol 2019 02 13;85(2):296-301. Epub 2019 Jan 13.

Department of Biology, University of Naples Federico II, Naples, Italy.

Easily accessible biomarkers in Huntington disease (HD) are actively searched. We investigated telomere length and DNA double-strand breaks (histone variant pγ-H2AX) as predictive disease biomarkers in peripheral blood mononuclear cells (PBMC) from 25 premanifest subjects, 58 HD patients with similar CAG expansion in the huntingtin gene (HTT), and 44 healthy controls (HC). PBMC from the pre-HD and HD groups showed shorter telomeres (p < 0.0001) and a significant increase of pγ-H2AX compared to the controls (p < 0.0001). The levels of pγ-H2AX correlated robustly with the presence of the mutated gene in pre-HD and HD. The availability of a potentially reversible biomarker (pγ-H2AX) in the premanifest stage of HD, negligible in HC, provides a novel tool to monitor premanifest subjects and find patient-specific drugs. Ann Neurol 2018;00:1-6 ANN NEUROL 2019;85:296-301.
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http://dx.doi.org/10.1002/ana.25393DOI Listing
February 2019

Bridging the gap between vaccination with Bacille Calmette-Guérin (BCG) and immunological tolerance: the cases of type 1 diabetes and multiple sclerosis.

Curr Opin Immunol 2018 12 15;55:89-96. Epub 2018 Nov 15.

Center for Experimental Neurological Therapies, Sant'Andrea Hospital, Department of Neurosciences, Mental Health and Sensory Organs, Sapienza University of Rome, S. Andrea Hospital, Via di Grottarossa 1035, 00189 Rome, Italy; IRCCS Istituto Neurologico Mediterraneo (INM) Neuromed, 86077 Pozzilli, IS, Italy. Electronic address:

At the end of past century, when the prevailing view was that treatment of autoimmunity required immune suppression, experimental evidence suggested an approach of immune-stimulation such as with the BCG vaccine in type 1 diabetes (T1D) and multiple sclerosis (MS). Translating these basic studies into clinical trials, we showed the following: BCG harnessed the immune system to 'permanently' lower blood sugar, even in advanced T1D; BCG appeared to delay the disease progression in early MS; the effects were long-lasting (years after vaccination) in both diseases. The recently demonstrated capacity of BCG to boost glycolysis may explain both the improvement of metabolic indexes in T1D, and the more efficient generation of inducible regulatory T cells, which counteract the autoimmune attack and foster repair mechanisms.
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http://dx.doi.org/10.1016/j.coi.2018.09.016DOI Listing
December 2018

Analysis of coding and non-coding transcriptome of peripheral B cells reveals an altered interferon response factor (IRF)-1 pathway in multiple sclerosis patients.

J Neuroimmunol 2018 11 15;324:165-171. Epub 2018 Sep 15.

Center for Experimental Neurological Therapies, Sant'Andrea Hospital, Department of Neurosciences, Mental Health and Sensory Organs (NESMOS), Faculty of Medicine and Psychology, Sapienza University of Rome, Rome, Italy. Electronic address:

Several evidences emphasize B-cell pathogenic roles in multiple sclerosis (MS). We performed transcriptome analyses on peripheral B cells from therapy-free patients and age/sex-matched controls. Down-regulation of two transcripts (interferon response factor 1-IRF1, and C-X-C motif chemokine 10-CXCL10), belonging to the same pathway, was validated by RT-PCR in 26 patients and 21 controls. IRF1 and CXCL10 transcripts share potential seeding sequences for hsa-miR-424, that resulted up-regulated in MS patients. We confirmed this interaction and its functional effect by transfection experiments. Consistent findings indicate down-regulation of IRF1/CXCL10 axis, that may plausibly contribute to a pro-survival status of B cells in MS.
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http://dx.doi.org/10.1016/j.jneuroim.2018.09.005DOI Listing
November 2018

Corrigendum to "Novel homozygous GBA2 mutation in a patient with complicated spastic paraplegia" [Clin. Neurol. Neurosurg. 168 (May) (2018) 60-63].

Clin Neurol Neurosurg 2018 Sep 30;172:190. Epub 2018 Jun 30.

Center for Experimental Neurological Therapies, Sant'Andrea Hospital, Neurosciences, Mental Health, and Sensory Organs (NESMOS), Sapienza University of Rome, Rome, Italy. Electronic address:

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http://dx.doi.org/10.1016/j.clineuro.2018.06.025DOI Listing
September 2018

Steps towards Collective Sustainability in Biomedical Research.

Trends Mol Med 2018 05 24;24(5):429-432. Epub 2018 Mar 24.

Department of Research, Italian Multiple Sclerosis Foundation, Genoa, Italy. Electronic address:

The optimism surrounding multistakeholder research initiatives does not match the clear view of policies that are needed to exploit the potential of these collaborations. Here we propose some action items that stem from the integration between research advancements with the perspectives of patient-advocacy organizations, academia, and industry.
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http://dx.doi.org/10.1016/j.molmed.2018.03.001DOI Listing
May 2018

Novel homozygous GBA2 mutation in a patient with complicated spastic paraplegia.

Clin Neurol Neurosurg 2018 05 3;168:60-63. Epub 2018 Mar 3.

Center for Experimental Neurological Therapies, Sant'Andrea Hospital, Neurosciences, Mental Health, and Sensory Organs (NESMOS), Sapienza University of Rome, Rome, Italy. Electronic address:

Hereditary spastic paraplegias (HSPs) are a heterogeneous group of neurological disorders characterized primarily by a pyramidal syndrome with lower limb spasticity, which can manifest as pure HSP or associated with a number of neurological or non-neurological signs (i.e., complicated HSPs). The clinical variability of HSPs is associated with a wide genetic heterogeneity, with more than eighty causative genes known. Recently, next generation sequencing (NGS) has allowed increasing genetic definition in such a heterogeneous group of disorders. We report on a 56- year-old man affected by sporadic complicated HSP consisting of a pyramidal syndrome, cerebellar ataxia, congenital cataract, pes cavus, axonal sensory-motor peripheral neuropathy and cognitive decline. Brain MRI showed cerebellar atrophy and thin corpus callosum. By NGS we found a novel homozygous biallelic c.452-1G > C mutation in the b-glucosidase 2 gene (GBA2), known to be causative for autosomal recessive hereditary spastic paraplegia type 46 (SPG46). The rarity of this inherited form besides reporting on a novel mutation, expands the genetic and clinical spectrum of SPG46 related HSP.
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http://dx.doi.org/10.1016/j.clineuro.2018.02.042DOI Listing
May 2018

Validating Nonlinear Registration to Improve Subtraction Images for Lesion Detection and Quantification in Multiple Sclerosis.

J Neuroimaging 2018 01 24;28(1):70-78. Epub 2017 Oct 24.

Bioengineering Department, George Mason University, Fairfax, VA.

Background And Purpose: To propose and validate nonlinear registration techniques for generating subtraction images because of their ability to reduce artifacts and improve lesion detection and lesion volume quantification.

Methods: Postcontrast T -weighted spin echo and T -weighted dual echo images were acquired for 20 patients with relapsing-remitting multiple sclerosis (RRMS) on a monthly basis for a year (14 women, average age 33.6 ± 6.9). The T -weighted images from the first scan were used as a baseline for each patient. The images from the last scan were registered to the baseline image. Four different registration algorithms used for evaluation included; linear, halfway linear, nonlinear, and nonlinear halfway. Subtraction images were generated after brain extraction, intensity normalization, and Gaussian blurring. Lesion activity changes along with identified artifacts were scored on all four techniques by two independent observers. Additionally, quantitative analysis of the algorithms was performed by estimating the volume changes of simulated lesions and real lesions. For real lesion volume change analysis, five subjects were selected randomly. Subtraction images were generated between all the 11 time points and the baseline image using linear and nonlinear registration for the five subjects.

Results: Lesion activity detection resulted in similar performance among the four registration techniques. Lesion volume measurements on subtraction images using nonlinear registration were closer to lesion volume on T -weighted images. A statistically significant difference was observed among the four registration techniques while evaluating yin-yang artifacts. Pairwise comparisons showed that nonlinear registration results in the least amount of yin-yang artifacts, which are significantly different.

Conclusions: Nonlinear registration for generation of subtraction images has been demonstrated to be a promising new technique as it shows improvement in lesion activity change detection. This approach decreases the number of artifacts in subtraction images. With improved lesion volume estimates and reduced artifacts, nonlinear registration may lead to discarding less subject data and an improvement in the statistical power of subtraction imaging studies.
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http://dx.doi.org/10.1111/jon.12479DOI Listing
January 2018

Geographic Population Structure in Epstein-Barr Virus Revealed by Comparative Genomics.

Genome Biol Evol 2016 12 14;8(11):3284-3291. Epub 2016 Dec 14.

Department of Biosciences, University of Milan, Milan, Italy

Epstein-Barr virus (EBV) latently infects the majority of the human population and is implicated as a causal or contributory factor in numerous diseases. We sequenced 27 complete EBV genomes from a cohort of Multiple Sclerosis (MS) patients and healthy controls from Italy, although no variants showed a statistically significant association with MS. Taking advantage of the availability of ∼130 EBV genomes with known geographical origins, we reveal a striking geographic distribution of EBV sub-populations with distinct allele frequency distributions. We discuss mechanisms that potentially explain these observations, and their implications for understanding the association of EBV with human disease.
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http://dx.doi.org/10.1093/gbe/evw226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5203774PMC
December 2016

Riluzole in patients with hereditary cerebellar ataxia - Authors' reply.

Lancet Neurol 2016 07;15(8):789

Center for Experimental Neurological Therapies-CENTERS, S Andrea Hospital, II Faculty of Medicine, Sapienza University of Rome, Rome 00189, Italy. Electronic address:

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http://dx.doi.org/10.1016/S1474-4422(16)00117-4DOI Listing
July 2016

Altered intestinal permeability in patients with relapsing-remitting multiple sclerosis: A pilot study.

Mult Scler 2017 Mar 11;23(3):442-446. Epub 2016 Jul 11.

Center for Experimental Neurological Therapies, Sant'Andrea Hospital, Department of Neurosciences, Mental Health and Sensory Organs (NESMOS), Faculty of Medicine and Psychology, Sapienza University of Rome, Rome, Italy.

Background: Alterations of intestinal permeability (IP) may contribute to the pathophysiology of immune-mediated diseases.

Objective: We investigated the possible association between IP changes and multiple sclerosis (MS).

Methods: We studied 22 patients with relapsing-remitting multiple sclerosis (RRMS) and 18 age- and sex-matched healthy donors (HDs), including five twin pairs (one concordant, and four discordant for disease). Measurement of lactulose (L) and mannitol (M; two non-metabolized sugars) levels in urine samples, after an oral load, allowed to quantify gut dysfunction.

Results: The proportion of participants with increased IP was significantly higher in patients than in HDs (16/22 (73%) versus 5/18 (28%); p = 0.001). Accordingly, the L/M urinary ratio showed significantly higher values in patients than in controls ( p = 0.0284). Urinary mannitol concentration was significantly lower in patients than in controls ( p = 0.022), suggesting a deficit of absorption from intestinal lumen. Such changes did not appear related to patients' clinical-radiological features.

Conclusion: The relatively high proportion of IP changes in RR-MS patients seems to confirm our work hypothesis and warrants more work to confirm the result on a larger sample, and to understand the implications for related immunological disturbances and intestinal microbiota alterations. Our finding may also have relevance for oral treatments, recently introduced in clinical practice.
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http://dx.doi.org/10.1177/1352458516652498DOI Listing
March 2017

Spinocerebellar Ataxia Type 3 in Italy: Time to Change Mind.

Neuroepidemiology 2016 19;46(4):268. Epub 2016 Mar 19.

Department of Medico-Surgical Sciences and Biotechnologies, Rome Sapienza University, Rome, Italy.

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http://dx.doi.org/10.1159/000444642DOI Listing
March 2018

Riluzole in patients with hereditary cerebellar ataxia: a randomised, double-blind, placebo-controlled trial.

Lancet Neurol 2015 Oct 25;14(10):985-91. Epub 2015 Aug 25.

Center for Experimental Neurological Therapies, Sant'Andrea Hospital, Neurosciences, Mental Health, and Sensory Organs (NESMOS), Sapienza University of Rome, Rome, Italy. Electronic address:

Background: Our previous study in patients with cerebellar ataxias of different causes showed significant benefit of riluzole after 8 weeks. We aimed to confirm these results in patients with spinocerebellar ataxia or Friedreich's ataxia in a 1-year trial.

Methods: Patients with spinocerebellar ataxia or Friedreich's ataxia (2:1 ratio) from three Italian neurogenetic units were enrolled in this multicentre, double-blind, placebo-controlled trial, and randomly assigned to riluzole (50 mg orally, twice daily) or placebo for 12 months. The randomisation list was computer-generated and a centralised randomisation system was implemented. Participants and assessing neurologists were masked to treatment allocation. The primary endpoint was the proportion of patients with improved Scale for the Assessment and Rating of Ataxia (SARA) score (a drop of at least one point) at 12 months. An intention-to-treat analysis was done. This trial is registered at ClinicalTrials.gov, number NCT01104649.

Findings: Between May 22, 2010, and Feb 25, 2013, 60 patients were enrolled. Two patients in the riluzole group and three in the placebo group withdrew their consent before receiving treatment, so the intention-to-treat analysis was done on 55 patients (19 with spinocerebellar ataxia and nine with Friedreich's ataxia in the riluzole group, and 19 with spinocerebellar ataxia and eight with Friedreich's ataxia in the placebo group). The proportion with decreased SARA score was 14 (50%) of 28 patients in the riluzole group versus three (11%) of 27 in the placebo group (OR 8·00, 95% CI 1·95-32·83; p=0·002). No severe adverse events were recorded. In the riluzole group, two patients had an increase in liver enzymes (less than two times above normal limits). In two participants in the riluzole group and two participants in the placebo group, sporadic mild adverse events were reported.

Interpretation: Our findings lend support to the idea that riluzole could be a treatment for cerebellar ataxia. Longer studies and disease-specific trials are needed to confirm whether these findings can be applied in clinical practice.

Funding: Agenzia Italiana del Farmaco.
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http://dx.doi.org/10.1016/S1474-4422(15)00201-XDOI Listing
October 2015

Association between vaccines and neuroinflammation: time, risks, and benefits.

JAMA Neurol 2015 May;72(5):605

Centre for Experimental Neurological Therapies, S. Andrea Hospital-Site, Department of Neuroscience, Mental Health, and Sensory Organs (NESMOS), Sapienza University, Rome, Italy.

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http://dx.doi.org/10.1001/jamaneurol.2015.71DOI Listing
May 2015
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