Publications by authors named "Maura Pugliatti"

82 Publications

Association of Variants in the SPTLC1 Gene With Juvenile Amyotrophic Lateral Sclerosis.

JAMA Neurol 2021 Oct;78(10):1236-1248

Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.

Importance: Juvenile amyotrophic lateral sclerosis (ALS) is a rare form of ALS characterized by age of symptom onset less than 25 years and a variable presentation.

Objective: To identify the genetic variants associated with juvenile ALS.

Design, Setting, And Participants: In this multicenter family-based genetic study, trio whole-exome sequencing was performed to identify the disease-associated gene in a case series of unrelated patients diagnosed with juvenile ALS and severe growth retardation. The patients and their family members were enrolled at academic hospitals and a government research facility between March 1, 2016, and March 13, 2020, and were observed until October 1, 2020. Whole-exome sequencing was also performed in a series of patients with juvenile ALS. A total of 66 patients with juvenile ALS and 6258 adult patients with ALS participated in the study. Patients were selected for the study based on their diagnosis, and all eligible participants were enrolled in the study. None of the participants had a family history of neurological disorders, suggesting de novo variants as the underlying genetic mechanism.

Main Outcomes And Measures: De novo variants present only in the index case and not in unaffected family members.

Results: Trio whole-exome sequencing was performed in 3 patients diagnosed with juvenile ALS and their parents. An additional 63 patients with juvenile ALS and 6258 adult patients with ALS were subsequently screened for variants in the SPTLC1 gene. De novo variants in SPTLC1 (p.Ala20Ser in 2 patients and p.Ser331Tyr in 1 patient) were identified in 3 unrelated patients diagnosed with juvenile ALS and failure to thrive. A fourth variant (p.Leu39del) was identified in a patient with juvenile ALS where parental DNA was unavailable. Variants in this gene have been previously shown to be associated with autosomal-dominant hereditary sensory autonomic neuropathy, type 1A, by disrupting an essential enzyme complex in the sphingolipid synthesis pathway.

Conclusions And Relevance: These data broaden the phenotype associated with SPTLC1 and suggest that patients presenting with juvenile ALS should be screened for variants in this gene.
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http://dx.doi.org/10.1001/jamaneurol.2021.2598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8406220PMC
October 2021

Averting multiple sclerosis long-term societal and healthcare costs: The Value of Treatment (VoT) project.

Mult Scler Relat Disord 2021 Sep 30;54:103107. Epub 2021 Jun 30.

University of Copenhagen, Copenhagen, Denmark and European Academy of Neurology (EAN), Europe.

Background And Purpose: The recent report on Value-of-Treatment (VoT) project highlights the need for early diagnosis-intervention, integrated, seamless care underpinning timely care pathways and access to best treatments. The VoT-multiple-sclerosis (MS) economic case study analysis aimed to estimate the effectiveness/cost-effectiveness of both early treatment and reducing MS risk factors (e.g. smoking and vitamin D insufficiency).

Methods: A series of decision analytical modellings were developed and applied to estimate the cost-effectiveness of: (1) reducing the conversion from clinically-isolated-syndrome (CIS) to clinically-definite-MS (CDMS); (2) smoking cessation and increase of 25 hydroxyvitamin D (25(OH)D) serum level. Both (1) and (2) considered socioeconomic impact on averted MS disability progression. Costs were reported for societal and healthcare provider perspectives (pending on data across nations; Euros). Effectiveness was expressed as Quality-Adjusted-Life-Years (QALYs) gains. Long term (25, 30, 40,50-years) and short (one-year) timelines were considered for (1) and (2), respectively.

Results: Early treatment was cost-effective for the health care provider and both cost-effective/cost-saving for the society across time-horizons and nations. Smoking cessation and an increase of 25(OH)D in MS patients were both cost-effective/cost-saving across nations.

Conclusions: To the best of our knowledge, our work provides the first economic evidence to base appropriate public health interventions to reduce the MS burden in Europe.
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http://dx.doi.org/10.1016/j.msard.2021.103107DOI Listing
September 2021

European Academy of Neurology and European Federation of Neurorehabilitation Societies guideline on pharmacological support in early motor rehabilitation after acute ischaemic stroke.

Eur J Neurol 2021 09 21;28(9):2831-2845. Epub 2021 Jun 21.

RoNeuro Institute for Neurological Research and Diagnostic, Cluj-Napoca, Romania.

Background And Purpose: Early pharmacological support for post-stroke neurorehabilitation has seen an abundance of mixed results from clinical trials, leaving practitioners at a loss regarding the best options to improve patient outcomes. The objective of this evidence-based guideline is to support clinical decision-making of healthcare professionals involved in the recovery of stroke survivors.

Methods: This guideline was developed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) framework. PubMed, Cochrane Library and Embase were searched (from database inception to June 2018, inclusive) to identify studies on pharmacological interventions for stroke rehabilitation initiated in the first 7 days (inclusive) after stroke, which were delivered together with neurorehabilitation. A sensitivity analysis was conducted on identified interventions to address results from breaking studies (from end of search to February 2020).

Results: Upon manually screening 17,969 unique database entries (of 57,001 original query results), interventions underwent meta-analysis. Cerebrolysin (30 ml/day, intravenous, minimum 10 days) and citalopram (20 mg/day, oral) are recommended for clinical use for early neurorehabilitation after acute ischaemic stroke. The remaining interventions identified by our systematic search are not recommended for clinical use: amphetamine (5, 10 mg/day, oral), citalopram (10 mg/day, oral), dextroamphetamine (10 mg/day, oral), Di-Huang-Yi-Zhi (2 × 18 g/day, oral), fluoxetine (20 mg/day, oral), lithium (2 × 300 mg/day, oral), MLC601(3 × 400 mg/day, oral), phosphodiesterase-5 inhibitor PF-03049423 (6 mg/day, oral). No recommendation 'for' or 'against' is provided for selegiline (5 mg/day, oral). Issues with safety and tolerability were identified for amphetamine, dextroamphetamine, fluoxetine and lithium.

Conclusions: This guideline provides information for clinicians regarding existing pharmacological support in interventions for neurorecovery after acute ischaemic stroke. Updates to this material will potentially elucidate existing conundrums, improve current recommendations, and hopefully expand therapeutic options for stroke survivors.
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http://dx.doi.org/10.1111/ene.14936DOI Listing
September 2021

Antipsychotic drugs counteract autophagy and mitophagy in multiple sclerosis.

Proc Natl Acad Sci U S A 2021 Jun;118(24)

Department of Medical Sciences, Section of Experimental Medicine, Laboratory for Technologies of Advanced Therapies, University of Ferrara, 44121 Ferrara, Italy;

Multiple sclerosis (MS) is a neuroinflammatory and neurodegenerative disease characterized by myelin damage followed by axonal and ultimately neuronal loss. The etiology and physiopathology of MS are still elusive, and no fully effective therapy is yet available. We investigated the role in MS of autophagy (physiologically, a controlled intracellular pathway regulating the degradation of cellular components) and of mitophagy (a specific form of autophagy that removes dysfunctional mitochondria). We found that the levels of autophagy and mitophagy markers are significantly increased in the biofluids of MS patients during the active phase of the disease, indicating activation of these processes. In keeping with this idea, in vitro and in vivo MS models (induced by proinflammatory cytokines, lysolecithin, and cuprizone) are associated with strongly impaired mitochondrial activity, inducing a lactic acid metabolism and prompting an increase in the autophagic flux and in mitophagy. Multiple structurally and mechanistically unrelated inhibitors of autophagy improved myelin production and normalized axonal myelination, and two such inhibitors, the widely used antipsychotic drugs haloperidol and clozapine, also significantly improved cuprizone-induced motor impairment. These data suggest that autophagy has a causal role in MS; its inhibition strongly attenuates behavioral signs in an experimental model of the disease. Therefore, haloperidol and clozapine may represent additional therapeutic tools against MS.
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http://dx.doi.org/10.1073/pnas.2020078118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8214668PMC
June 2021

Sex-Related Differences in Cerebrospinal Fluid Plasma-Derived Proteins of Neurological Patients.

Diagnostics (Basel) 2021 May 16;11(5). Epub 2021 May 16.

Department of Neuroscience and Rehabilitation, University of Ferrara, 44121 Ferrara, Italy.

Background And Aims: Cerebrospinal fluid (CSF) protein content presents a sexual dimorphism in humans. We investigated sex-related differences in CSF IgG levels and in the quantification of intrathecal IgG synthesis (IIS).

Methods: CSF, serum albumin and IgG were measured in 1519 neurological patients and both linear and hyperbolic formulas were used for the quantification of IIS. CSF-restricted oligoclonal IgG bands (OCBs) were used as "gold standard".

Results: The linear IgG Index showed a weak agreement with OCBs in males and females (k = 0.559, k = 0.587, respectively), while the hyperbolic Reiber's formulas had a moderate agreement with OCBs in females (k = 0.635) and a weak agreement in males (k = 0.565). Higher CSF albumin and IgG levels were found in men than in women in the whole population and in subjects without IIS after adjusting for age and for serum concentrations of albumin and IgG, respectively (Quade statistics, < 0.000001). CSF and serum albumin and IgG levels positively correlated to age in both sexes. CSF total protein content did not correlate with CSF leukocyte numbers but was higher in patients with marked pleocytosis.

Conclusions: In neurological patients, men have higher levels of CSF serum-derived proteins, such as albumin and IgG.
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http://dx.doi.org/10.3390/diagnostics11050884DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8156001PMC
May 2021

Exposure to breastfeeding and risk of developing multiple sclerosis.

Int J Epidemiol 2021 05;50(2):644-651

Department of Biomedical and Specialty Surgical Sciences, University of Ferrara, Ferrara, Italy.

Background: Early-life factors are reported to modulate the risk of developing multiple sclerosis (MS) among adults. The association between exposure to breastfeeding and the risk of MS is debated. We aimed to disclose whether past exposure to breastfeeding and its duration are associated with the risk of developing MS.

Methods: We used a cohort design linking prospectively collected information on breastfeeding from the Cohort of Norway community-based surveys on health status (CONOR) with the Norwegian MS Registry and the population-based Medical Birth Registry of Norway that includes information on all births in Norway since 1967. MS clinical onset was collected throughout 2016. A total of 95 891 offspring born between 1922 and 1986 to mothers participating in CONOR were included. We identified 215 offspring within this cohort who developed adult-onset MS. Associations between breastfeeding and MS risk were estimated as hazard ratios using Cox proportional hazard models adjusting for maternal factors including education.

Results: We found no association between having been breastfed for ≥4 months and MS risk, also after adjusting for various maternal factors (hazard ratio = 0.90; 95% confidence interval 0.68-1.19). The estimates did not change for different durations of breastfeeding. The results were similar when adjusting for other perinatal factors.

Conclusion: Our study could not confirm previous findings of an association between breastfeeding and risk of MS. Breastfeeding information was less likely to be biased by knowledge of disease compared with case-control studies.
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http://dx.doi.org/10.1093/ije/dyaa250DOI Listing
May 2021

Antibiotic Use and Risk of Multiple Sclerosis: A Nested Case-Control Study in Emilia-Romagna Region, Italy.

Neuroepidemiology 2021 7;55(3):224-231. Epub 2021 May 7.

Neurology Unit, AUSL della Romagna, Forlì, Italy.

Introduction: Known risk factors for multiple sclerosis (MS) include smoking, a low vitamin D status, obesity, and EBV, while the inflammatory feature of the disease strongly suggests the presence of additional infectious agents. The association between use of antibiotics and MS risk that could shed light on these factors is still undetermined. We aimed to evaluate the association between antibiotics and MS risk, in the Emilia-Romagna region (RER), Italy.

Methods: All adult patients with MS seen at any RER MS center (2015-2017) were eligible. For each of the 877 patients included, clinical information was collected and matched to 5 controls (RER residents) (n = 4,205) based on age, sex, place of residence, and index year. Information on antibiotic prescription was obtained through the linkage with the RER drug prescription database.

Results: Exposure to any antibiotic 3 years prior to the index year was associated with an increased MS risk (OR = 1.52; 95% CI = 1.29-1.79). Similar results were found for different classes. No dose-response effect was found.

Discussion/conclusions: Our results suggest an association between the use of antibiotics and MS risk in RER population. However, further epidemiological studies should be done with information on early life and lifestyle factors.
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http://dx.doi.org/10.1159/000515682DOI Listing
May 2021

Different Roles of Mitochondria in Cell Death and Inflammation: Focusing on Mitochondrial Quality Control in Ischemic Stroke and Reperfusion.

Biomedicines 2021 Feb 9;9(2). Epub 2021 Feb 9.

Laboratory for Technologies of Advanced Therapies, Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy.

Mitochondrial dysfunctions are among the main hallmarks of several brain diseases, including ischemic stroke. An insufficient supply of oxygen and glucose in brain cells, primarily neurons, triggers a cascade of events in which mitochondria are the leading characters. Mitochondrial calcium overload, reactive oxygen species (ROS) overproduction, mitochondrial permeability transition pore (mPTP) opening, and damage-associated molecular pattern (DAMP) release place mitochondria in the center of an intricate series of chance interactions. Depending on the degree to which mitochondria are affected, they promote different pathways, ranging from inflammatory response pathways to cell death pathways. In this review, we will explore the principal mitochondrial molecular mechanisms compromised during ischemic and reperfusion injury, and we will delineate potential neuroprotective strategies targeting mitochondrial dysfunction and mitochondrial homeostasis.
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http://dx.doi.org/10.3390/biomedicines9020169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914955PMC
February 2021

Sexual dimorphism in the cerebrospinal fluid total protein content.

Clin Chem Lab Med 2020 10;58(11):1885-1890

Department of Biomedical and Specialist Surgical Sciences, University of Ferrara, Ferrara, Italy.

Objectives Cerebrospinal fluid (CSF) is a clear, colorless body fluid filling the central nervous system. The determination of the CSF total protein (TP) content represents an important screening test of various pathologies. We aimed to address the effect of sex and age on CSF-TP content and the use of the current upper reference limits (URLs). Methods CSF-TP content was analysed in a selected population of 1,252 patients (648 women and 604 men; age 18-89 years) who underwent lumbar puncture as a part of the diagnostic work-up. Samples presenting (i) more than 5 white blood cells (WBC)/µL, (ii) discolorations and (iii) reduced glucose were not included. Results The CSF-TP content median values were significantly higher in men than in women (46 vs. 37 mg/dL) even after adjusting for age and different hospital inpatients. CSF-TP content positively correlated with age both in men and in women with a constant difference between sexes of 8.5 mg/dL. Applying the most used URLs (mainly 45 and 50 mg/dL, but also 60 mg/dL), men received a laboratory report suggestive of altered CSF-TP content more frequently than women. The use of age- and sex-calibrated CSF-TP URLs reduced, but not eliminated, this sex-gap. Conclusions Using the current URLs, a condition of "elevated CSF-TP content" may be overestimated in men or, conversely, underestimated in women, regardless of the age and of the diagnosis. These results highlighted the need to apply CSF-TP URLs values ​​normalized for both sex and age.
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http://dx.doi.org/10.1515/cclm-2020-0419DOI Listing
October 2020

Validity of death certificates in the identification of cases of amyotrophic lateral sclerosis (ALS) in the Limousin region, France. A population-based study.

Amyotroph Lateral Scler Frontotemporal Degener 2020 05 10;21(3-4):228-234. Epub 2020 Apr 10.

INSERM, University of Limoges, CHU Limoges, UMR 1094, Tropical Neuroepidemiology, Institute of Epidemiology and Tropical Neurology, GEIST, Limoges, France, and.

Mortality data have been used as a proxy for amyotrophic lateral sclerosis (ALS) incidence. However, the accuracy of death certificates (DCs) needs to be validated. This study aims to assess the accuracy of DCs in the identification of ALS cases. This is a retrospective population-based validation study. DC information, provided by the "Centre d'épidémiologie sur les causes médicales de décès", including ICD10 codes for specific cause of death for patients recorded in the French register of ALS cases in the Limousin region (FRALim) and deceased between 2000 and 2011, was assessed. The was used as gold standard. In the study period, DCs were available for 197 patients diagnosed with ALS, of whom 185 (93.9%) were correctly identified with an ICD10 code (G12.2) corresponding to ALS. The overall sensitivity was 93.9% (95% CI 89.6-96.8) and the positive predictive value (PPV) was 64.9 (59.1-70.4), with higher values in the period 2004-2011 (75.0-78.9). Stratification for sex, age, and year at death did not show difference in accuracy, except a lower PPV during the first years of observation. DCs identifying subjects with a diagnosis of ALS in the Limousin region, France showed an overall good sensitivity and moderate PPV. The absence of ALS diagnosis as the main and underlying cause of death on DCs highlights the need to use DC in combination with other administrative data to create algorithms with higher accuracy performances.
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http://dx.doi.org/10.1080/21678421.2020.1746811DOI Listing
May 2020

Increased age and male sex are independently associated with higher frequency of blood-cerebrospinal fluid barrier dysfunction using the albumin quotient.

Fluids Barriers CNS 2020 Feb 5;17(1):14. Epub 2020 Feb 5.

Department of Biomedical and Specialist Surgical Sciences, University of Ferrara, Via Aldo Moro 8, Settore 1C3, 44124, Ferrara, Italy.

Background: The cerebrospinal fluid (CSF)/serum quotient of albumin (QAlb) is the most used biomarker for the evaluation of blood-cerebrospinal fluid barrier (B-CSF-B) permeability. For years QAlb was considered only as an age-related parameter but recently it has also been associated to sex. The aim of the present study was to explore the impact of sex in the determination of B-CSF-B dysfunction.

Methods: The analysis was retrospectively conducted on subjects consecutively admitted to the neurological ward. CSF and serum albumin levels were measured by immunonephelometry and pathological QAlb thresholds were considered: 6.5 under 40 years, 8.0 in the age 40-60 and 9.0 over 60 years.

Results: 1209 subjects were included in the study. 718 females and 491 males (age: 15-88 years): 24.6% of patients had a diagnosis of multiple sclerosis, 23.2% suffered from other inflammatory neurological diseases, 24.6% were affected by non-inflammatory neurological diseases, and for 27.6% of patients the final neurological diagnosis could not be traced. Dysfunctional B-CSF-B was detected more frequently (44 vs. 20.1%, p < 0.0001) and median QAlb value were higher (7.18 vs. 4.87, p < 0.0001) in males than in females in the overall study population and in all disease subgroups. QAlb and age were positively correlated both in female (p < 0.0001) and male (p < 0.0001) patients, however the slopes of the two regression lines were not significantly different (p = 0.7149), while the difference between the elevations was extremely significant (p < 0.0001) with a gap of 2.2 units between the two sexes. Finally, in a multivariable linear regression analysis increased age and male sex were independently associated with higher QAlb in the overall study population (both p < 0.001) and after stratification by age and disease group.

Conclusions: Accordingly, identification and validation of sex-targeted QAlb thresholds should be considered as a novel tool in an effort to achieve more precision in the medical approach.
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http://dx.doi.org/10.1186/s12987-020-0173-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7003357PMC
February 2020

Specific antibodies reacting to JC polyomavirus capsid protein mimotopes in sera from multiple sclerosis and other neurological diseases-affected patients.

J Cell Physiol 2020 07 3;235(7-8):5847-5855. Epub 2020 Feb 3.

Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology, School of Medicine, University of Ferrara, Ferrara, Italy.

Published data support the hypothesis that viruses could be trigger agents of multiple sclerosis onset. This link is based on evidence of early exposure to viral agents in patients affected by this neurologic disease. JC (JC polyomavirus [JCPyV]), BK (BKPyV), and simian virus 40 (SV40) neurotropic polyomavirus footprints have been detected in brain tissue specimens and samples from patients affected by different neurological diseases. In this investigation, serum samples from patients affected by multiple sclerosis and other inflammatory and noninflammatory neurologic diseases, as well as healthy subjects representing the control, were investigated for immunoglobulin G (IgG) antibodies against JCPyV. To this end, an immunologic approach was employed, which consists of employing indirect enzyme-linked immunosorbent assay testing with synthetic peptides mimicking viral capsid protein 1 antigens. A significantly lower prevalence of IgG antibodies against JCPyV VP1 epitopes, with a low titer, was detected in serum samples from patients with multiple sclerosis (MS) and other neurologic diseases than in healthy subjects. Our study indicates that the prevalence of JCPyV antibodies from patients with multiple sclerosis is 50% lower than in healthy subjects, suggesting specific immune impairments. These results indicate that patients affected by neurological diseases, including MS, respond poorly to JCPyV VP1 antigens, suggesting specific immunologic dysfunctions.
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http://dx.doi.org/10.1002/jcp.29533DOI Listing
July 2020

Migration - a route to multiple sclerosis risk globalization?

Nat Rev Neurol 2020 02;16(2):67-68

Department of Biomedical and Specialty Surgical Sciences, University of Ferrara, Ferrara, Italy.

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http://dx.doi.org/10.1038/s41582-019-0308-8DOI Listing
February 2020

Autophagy and mitophagy biomarkers are reduced in sera of patients with Alzheimer's disease and mild cognitive impairment.

Sci Rep 2019 12 27;9(1):20009. Epub 2019 Dec 27.

Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology, Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, Italy.

Dementia is a neurocognitive disorder characterized by a progressive memory loss and impairment in cognitive and functional abilities. Autophagy and mitophagy are two important cellular processes by which the damaged intracellular components are degraded by lysosomes. To investigate the contribution of autophagy and mitophagy in degenerative diseases, we investigated the serum levels of specific autophagic markers (ATG5 protein) and mitophagic markers (Parkin protein) in a population of older patients by enzyme-linked immunosorbent assay. Two hundred elderly (≥65 years) outpatients were included in the study: 40 (20 F and 20 M) with mild-moderate late onset Alzheimer's disease (AD); 40 (20 F and 20 M) affected by vascular dementia (VAD); 40 with mild cognitive impairment (MCI); 40 (20 F and 20 M) with "mixed" dementia (MD); 40 subjects without signs of cognitive impairment were included as sex-matched controls. Our data indicated that, in serum samples, ATG5 and Parkin were both elevated in controls, and that VAD compared with AD, MCI and MD (all p < 0.01). Patients affected by AD, MD, and MCI showed significantly reduced circulating levels of both ATG5 and Parkin compared to healthy controls and VAD individuals, reflecting a significant down-regulation of autophagy and mitophagy pathways in these groups of patients. The measurement of serum levels of ATG5 and Parkin may represent an easily accessible diagnostic tool for the early monitoring of patients with cognitive decline.
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http://dx.doi.org/10.1038/s41598-019-56614-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6934625PMC
December 2019

Increased Levels of Endothelin-1 in Cerebrospinal Fluid Are a Marker of Poor Visual Recovery after Optic Neuritis in Multiple Sclerosis Patients.

Dis Markers 2019 10;2019:9320791. Epub 2019 Sep 10.

Department of Biomedical and Specialty Surgical Sciences, University of Ferrara, Ferrara, Italy.

Background: Multiple sclerosis (MS), a chronic inflammatory and degenerative disease of the central nervous system, typically features immune-mediated focal demyelination and secondary axonal degeneration. Cerebral hypoperfusion of the normal-appearing white matter (NAWM) has been reported in MS patients and may be mediated by elevated levels of endothelin-1 (ET-1), a most potent vasoconstrictive peptide released from reactive astrocytes in MS focal lesions. Optic neuritis (ON) is one of the most frequent manifestations of MS and also shows peripapillary vascular hypoperfusion in combination with disc swelling.

Aims: We aimed to compare serum and cerebrospinal fluid (CSF) levels of ET-1 as a potential prognostic marker of MS-ON in two groups of patients differing for severity of MS-ON clinical presentation.

Materials And Methods: A cross-sectional study to compare serum and CSF levels of ET-1 between patients with clinically aggressive MS-ON (A-MS-ON) and nonaggressive MS-ON (NA-MS-ON) according to conventional ophthalmological criteria, including optical coherence tomography. CSF and serum concentrations of ET-1 were measured using a commercially available ELISA method.

Results: Sixteen patients consecutively referred to the Units of Neurology for visual disturbances attributable to MS were recruited, 11 (69%) patients with A-MS-ON and 5 (31%) with NA-MS-ON. Median CSF ET-1 levels and CSF/serum ET-1 quotient were significantly higher in patients with A-MS-ON (0.30 vs. 0.56 ng/ml) as compared to NA-MS-ON (0.16 vs. 0.16).

Conclusions: Severity and failure in the recovery from ON in MS patients may depend from vascular hypoperfusion of the optic nerve induced by high intrathecally produced ET-1, a potential prognostic marker of ON recovery in MS. The detection of CSF ET-1 levels may allow identifying groups of ON patients potentially benefitting from treatment with ET-1 antagonists (e.g., bosentan).
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http://dx.doi.org/10.1155/2019/9320791DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6754925PMC
February 2020

Correlation between auto/mitophagic processes and magnetic resonance imaging activity in multiple sclerosis patients.

J Neuroinflammation 2019 Jun 27;16(1):131. Epub 2019 Jun 27.

Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology, Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, Italy.

Background: An alteration of autophagy and mitophagy, two highly conserved lysosome-dependent degradation pathways involved in the maintenance of cellular homeostasis, has been associated with multiple sclerosis (MS).

Objective: To search the level of autophagy-related 5 (ATG5) and Parkin proteins, as markers of autophagy and mitophagy respectively, and lactate in a cohort of MS patients.

Methods: Cerebrospinal fluid (CSF) and serum samples from 60 MS patients were analyzed: 30 with magnetic resonance imaging (MRI) evidence of disease activity, gadolinium (Gd)-based contrast agent positive (Gd+), and 30 without MRI evidence of disease activity (Gd-). ATG5, Parkin, and lactate were measured using commercially available products.

Results And Conclusions: Serum levels of ATG5, Parkin, and lactate were more elevated in Gd+ than in Gd- MS patients (p < 0.0001), and CSF concentrations of ATG5 and Parkin were greater in Gd+ than in Gd- MS (p < 0.0001). Our results demonstrated that molecular markers of autophagy and mitophagy are increased in CSF of MS patients during the active phases of the disease and that these catabolic markers, together with lactate, are also remarkably augmented in blood suggesting a role of these processes in MS pathogenesis and the possible use of these molecules as biomarkers of disease activity.
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http://dx.doi.org/10.1186/s12974-019-1526-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6598368PMC
June 2019

Changes in the sex ratio are a good indicator of changes in MS incidence - Commentary.

Authors:
Maura Pugliatti

Mult Scler 2019 10 15;25(12):1570-1571. Epub 2019 May 15.

Department of Biomedical and Surgical Sciences, University of Ferrara, Ferrara, Italy.

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http://dx.doi.org/10.1177/1352458519845114DOI Listing
October 2019

Multiplex Matrix Metalloproteinases Analysis in the Cerebrospinal Fluid Reveals Potential Specific Patterns in Multiple Sclerosis Patients.

Front Neurol 2018 18;9:1080. Epub 2018 Dec 18.

Department of Biomedical and Specialty Surgical Sciences, University of Ferrara, Ferrara, Italy.

Matrix metalloproteinases (MMPs) are pleiotropic enzymes involved in extracellular protein degradation and turnover. MMPs are implicated in the pathogenesis of many neurological diseases, including multiple sclerosis (MS). To search the level of MMPs in the cerebrospinal fluid (CSF) of MS patients and detect possible disease-specific patterns. CSF samples from 32 MS patients and, from 15 control subjects with other inflammatory neurological diseases (OIND) were analyzed. The Bio-Plex Pro Human MMP 9-Plex Panel (Bio-Rad) was used for the quantification of MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-10, MMP-12, and MMP-13. CSF MMP-1 and MMP-12 levels were significantly reduced in MS as compared with OIND. In MS patients' CSF: (i) MMP-1 levels were significantly higher in women vs. men; (ii) MMP-10 concentrations were higher in patients with CSF-restricted IgG oligoclonal bands, and (iii) MMP-7 levels were increased in patients with longer disease duration. In the OIND group MMP-7 and MMP-12 levels significantly and directly correlated with age. Our study contributes to investigating the role of MMPs in MS, with regard to CSF immunological features and disease duration. Sex-specific differences were also detected in MMPs CSF levels.
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http://dx.doi.org/10.3389/fneur.2018.01080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6305439PMC
December 2018

Incidence study of Guillain-Barré syndrome in the province of Ferrara, Northern Italy, between 2003 and 2017. A 40-year follow-up.

Neurol Sci 2019 Mar 7;40(3):603-609. Epub 2019 Jan 7.

Department of Biomedical and Specialty-Surgical Sciences, Section of Neurology, Psychology and Psychiatry, University of Ferrara, Via Aldo Moro 8, 44124, Cona, Ferrara, Italy.

Background: Guillain-Barré syndrome (GBS) is an acute/subacute autoimmune inflammatory polyradiculoneuropathy. Previous epidemiological studies carried out in the province of Ferrara, Italy, from 1981 to 2002 indicated that GBS incidence had tendency of increase in the period considered.

Objectives: We aimed at updating the epidemiology of GBS in the years 2003-2017 and carrying on the work started in the 1980s.

Methods: We conducted an incidence study, by adopting a complete enumeration approach. Cases were identified from administrative, medical records, and database of the Ferrara Hospital and other provincial structures of the study area. Case ascertainment and definition are analogous to those adopted in previous surveys.

Results: In the period 1 January 2003 to 31 December 2017, 73 patients living in the province of Ferrara (mean population 353,142) were found to be new cases of GBS fulfilling the NINCDS criteria. Male/female ratio 1.15. The mean incidence rate was 1.38 per 100,000 (95% CI 1.08-1.74), 1.54 per 100,000 for men and 1.23 per 100,000 for women, a nonsignificant difference. During the period considered, the rates had slow increase or mild decrease, without nonsignificant difference. The highest rates were observed for the age groups 70-79 years for both sexes. A half of patients reported infectious events in the weeks before the onset of symptoms.

Conclusion: In line with many epidemiological data, in the whole period 2003-2017, we observed a trend towards increase or decrease in incidence and periods of relative stability. Similar temporal heterogeneity with the comparison to our previous works was found.
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http://dx.doi.org/10.1007/s10072-018-3688-4DOI Listing
March 2019

Shedding light on the link between early life sun exposure and risk of multiple sclerosis: results from the EnvIMS Study.

Int J Epidemiol 2019 08;48(4):1073-1082

Neuroepidemiology Research Unit, Research Institute of the McGill University Health Centre, Montreal, QC, Canada.

Background: Lower levels of sun exposure in childhood have been suggested to be associated with increased risk of multiple sclerosis (MS). In this paper we extend previous work, using two novel analytical strategies.

Methods: Data collected in the Environmental risk factors In MS (EnvIMS) study, a case-control study with MS cases and population-based controls from Canada, Italy and Norway, were used. Participants reported on sun exposure behaviours for 5-year age intervals from birth; we focused on the first three age intervals (≤15 years). We compared two life course epidemiology conceptual models, the critical period and the accumulation model. We also used latent class analysis to estimate MS risk for different latent sun exposure behaviour groups.

Results: The analyses included 2251 cases and 4028 controls. The accumulation model was found to be the best model, which demonstrated a nearly 50% increased risk of MS comparing lowest reported summer sun exposure with highest [risk ratio (RR) = 1.47 (1.24, 1.74)]. The latent sun exposure behaviour group, characterized by low sun exposure during summer and winter and high sun protection use, had the highest risk of MS; a 76% increased risk as compared with the group with high sun exposure and low sun protection use [RR = 1.76 (1.27, 2.46)].

Conclusions: Our analyses provide novel insights into the link between sun exposure and MS. We demonstrate that more time indoors during childhood and early adolescence is linked with MS risk, and that sun protection behaviours in those who spend most time indoors may play a key role in increasing risk.
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http://dx.doi.org/10.1093/ije/dyy269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6693814PMC
August 2019

Multiple Sclerosis in Italy: A 40-Year Follow-Up of the Prevalence in Ferrara.

Neuroepidemiology 2018 21;51(3-4):158-165. Epub 2018 Aug 21.

Multiple Sclerosis Research Center, Section of Neurological Sciences, Department of Biochemical and Specialty Surgical Sciences, University of Ferrara, Ferrara, Italy.

Background: To assess a longitudinal follow-up of the prevalence of multiple sclerosis (MS) through 4 decades in the province of Ferrara, northern Italy, and reappraise the current rates on December 31, 2016.

Methods: We conducted a community-based intensive prevalence study, by adopting a complete enumeration approach. MS cases were identified from administrative health data and medical records from the Units of Neurology and Motor Rehabilitation, Ferrara University Hospital, from other provincial neurological structures and from archives of the National Pension Institute and National Health Insurance scheme of the study area. Case ascertainment method and case definition are analogous to those adopted in previous surveys in the same area of study.

Results: On December 31, 2016, 685 patients (478 women and 207 men) affected by definite or probable MS (Poser's criteria) were living in the province of Ferrara (population 386,896), yielding a crude prevalence ratio of 194.91 (95% CI 180.4-209.6) per 100,000, 260.8 (95% CI 238.10-285.82) for women and 123.1 (95% CI 106.98-141.21) for men The prevalence ratio was 26.9 per 100,000 in 1978, increased to a value of 46.1 per 100,000 in 1981, 69.4 per 100,000 in 1993, 120.9 per 100,000 in 2004. Female to male ratio was 2.31 (1.2 on December 31, 1978). The mean duration of the disease at prevalence day was 17.5 ± 11.9 years (13.9 ± 10.8 years in 1978). The mean age at prevalence day was 52.04 ± 10.8 years (13.8 ± 10.8 years in 1978).

Conclusion: Our study has confirmed the province of Ferrara is an area at high risk for MS, in line with epidemiological data from the regions of continental and insular Italy. The sharp increase in MS prevalence over time in this population can be imputed in part to a greater exposition to risk factors in genetically susceptible subjects but also to an increased survival and improved ascertainment. So, the results suggest that both methodologic and environmental factors are essential in determining the real distribution of MS. The need to get reliable estimates of MS prevalence must be highlighted as a public health and research priority, essential to support planning and prioritization of care services and to reduce the overall burden of chronic disease.
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http://dx.doi.org/10.1159/000491548DOI Listing
September 2019

A framework for measurement and harmonization of pediatric multiple sclerosis etiologic research studies: The Pediatric MS Tool-Kit.

Mult Scler 2019 07 22;25(8):1170-1177. Epub 2018 Jun 22.

Royal Victoria Hospital, Allan Memorial Institute and Neuroepidemiology Research Unit, Research Institute of the McGill University Health Centre, Montreal, QC, Canada/ Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, QC, Canada/ Department of Medicine, McGill University, Montreal, QC, Canada.

Background: While studying the etiology of multiple sclerosis (MS) in children has several methodological advantages over studying etiology in adults, studies are limited by small sample sizes.

Objective: Using a rigorous methodological process, we developed the Pediatric MS Tool-Kit, a measurement framework that includes a minimal set of core variables to assess etiological risk factors.

Methods: We solicited input from the International Pediatric MS Study Group to select three risk factors: environmental tobacco smoke (ETS) exposure, sun exposure, and vitamin D intake. To develop the Tool-Kit, we used a Delphi study involving a working group of epidemiologists, neurologists, and content experts from North America and Europe.

Results: The Tool-Kit includes six core variables to measure ETS, six to measure sun exposure, and six to measure vitamin D intake. The Tool-Kit can be accessed online ( www.maelstrom-research.org/mica/network/tool-kit ).

Conclusion: The goals of the Tool-Kit are to enhance exposure measurement in newly designed pediatric MS studies and comparability of results across studies, and in the longer term to facilitate harmonization of studies, a methodological approach that can be used to circumvent issues of small sample sizes. We believe the Tool-Kit will prove to be a valuable resource to guide pediatric MS researchers in developing study-specific questionnaire.
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http://dx.doi.org/10.1177/1352458518783345DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6572633PMC
July 2019

Multiple sclerosis in the Republic of San Marino, Italian peninsula: an incidence and prevalence study from a high-risk area.

Neurol Sci 2018 Jul 18;39(7):1231-1236. Epub 2018 Apr 18.

Department of Biomedical and Specialty-Surgical Sciences, Section of Neurology, Psychology and Psychiatry, University of Ferrara, Via Aldo Moro 8, 44124, Ferrara, Italy.

Epidemiological studies on multiple sclerosis (MS) carried out in Southern Europe in the last years have shown a significant increase in the disease frequency. Previous surveys conducted in the Republic of San Marino, Northern Italian peninsula, identified that the population is at high risk for MS, with a prevalence of 51.6 per 100,000 population in 1982 and of 166.7 in 2005 and with a mean annual incidence of 7.9 per 100,000 for the period 1990-2005. The present work is a community-based intensive prevalence and incidence survey, by a complete enumeration approach, to update the prevalence and incidence of MS in the Republic of San Marino. The mean annual incidence for the period 2005-14 was 7.7 (95% CI 4.9-11.4) per 100,000, 3.3 (95% CI 1.1-7.6) for men and 11.9 (95% CI 7.2-18.6) for women. On 31 December 2014, 67 patients (19 men and 48 women), suffering from definite or probable MS and living in the Republic of San Marino, yielded a crude prevalence of 204.3 (95% CI 158.4-259.5) per 100,000, 117.8 (95% CI 70.9-183.7) for men and 288.2 (95% CI 212.4-383.3) for women. Our study has confirmed San Marino is an area at high risk for MS, in line with epidemiological data from continental Italy. The marked increase in MS prevalence over time in this population can be ascribable to increased survival and improved ascertainment, in the presence of a substantially stable, yet high, incidence rate.
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http://dx.doi.org/10.1007/s10072-018-3402-6DOI Listing
July 2018

Autophagy and mitophagy elements are increased in body fluids of multiple sclerosis-affected individuals.

J Neurol Neurosurg Psychiatry 2018 Apr 2;89(4):439-441. Epub 2017 Sep 2.

Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology, Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, Italy.

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http://dx.doi.org/10.1136/jnnp-2017-316234DOI Listing
April 2018

Epidemiological Study of Huntington's Disease in the Province of Ferrara, Italy.

Neuroepidemiology 2017 12;49(1-2):18-23. Epub 2017 Aug 12.

Department of Biomedical and Specialty Surgery, Section of Neurology, University of Ferrara, Ferrara, Italy.

Background: Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by the abnormal expansion of CAG triplet repeat. We aimed to reappraise HD epidemiology in a northern Italian population, in relation to introduction of genetic testing.

Methods: Through ICD-9M code 333.4 and medical fare exemption code RF0080, HD cases were identified from administrative health data and medical records from the Units of Neurology and Genetics, Ferrara University Hospital, and from other provincial neurological structures.

Results: HD mean annual incidence rate in 1990-2009 was 0.3 per 100,000 (95% CI 0.2-0.5). All incident cases were found to have symptoms of the disease's classic form, and neither juvenile nor the rigid Westphal variant was detected. The mean (SD) age at onset was 50.2 (12.7 years; range 32-82 years), 54.9 (14.6) for men and 45.8 (9.4) for women. On prevalence day, December 31, 2014, HD prevalence was 4.2 per 100,000 (95% CI 2.4-7.0), with a male:female ratio of 1:2.

Conclusions: The prevalence and incidence of HD in our population were lower than the prevalence and incidence reported for other European and Italian populations, but higher compared to those of Asia, Africa, and Eastern Europe. Compared to previous studies, HD incidence and prevalence did not change significantly.
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http://dx.doi.org/10.1159/000479697DOI Listing
May 2018

Evaluation of total, ceruloplasmin-associated and type II ferroxidase activities in serum and cerebrospinal fluid of multiple sclerosis patients.

J Neurol Sci 2017 Jun 13;377:133-136. Epub 2017 Apr 13.

Department of Biomedical and Specialist Surgical Sciences, University of Ferrara, 44121 Ferrara, Italy.

Multiple sclerosis (MS) patients have increased brain iron deposition with higher oxidative stress (OxS). These two features can be caused by an inefficient removal of free iron from extracellular compartment. Ferroxidase activity (Feox) exerted by ceruloplasmin (FeoxCp) and by other molecules (FeoxII) appears to have a central role in this process. The aim of this study was to investigate serum and cerebrospinal fluid (CSF) total Feox, FeoxII and FeoxCp activities in MS patients and neurological controls. Serum and CSF Feox activity, FeoxII and FeoxCp activity was measured in 91 relapsing-remitting (RR) MS patients, 79 subjects with other inflammatory neurological disorders (OIND) and 65 with non-inflammatory neurological disorders (NIND), as controls. This study was approved by the Local Committee for Medical Ethics in Research. Serum total Feox activity was lower in MS group than in both NIND and OIND, with only the former control group differing significantly (p<0.001); FeoxII and FeoxCp activities were comparable among the groups. Serum Feox activities were not associated with disease activity as assessed by clinical examination or by Magnetic Resonance Imaging (MRI). Only total Feox activity was detectable in the CSF and was not different in MS compared to either OIND or NIND. In conclusion, a condition of low systemic Feox may increase the susceptibility of MS patients to iron(II) mediated-oxidative damage. This alteration is not reflected in CSF, suggesting that agents endowed with Feox activity might have different impact in iron homeostasis in the central nervous system compared to periphery.
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http://dx.doi.org/10.1016/j.jns.2017.04.021DOI Listing
June 2017

Physical activity is associated with a decreased multiple sclerosis risk: The EnvIMS study.

Mult Scler 2018 02 1;24(2):150-157. Epub 2017 Feb 1.

Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway/The Norwegian Multiple Sclerosis Competence Centre, Department of Neurology, Haukeland University Hospital, Bergen, Norway.

Background: The lifestyle factors smoking and obesity have been associated with the risk of multiple sclerosis (MS). Physical activity (PA) may also be of importance.

Objective: To examine the association between PA and MS risk in Italy, Norway, and Sweden and to evaluate the possible influence by established risk factors.

Methods: In this case-control study, 1904 cases and 3694 controls were asked to report their average weekly amounts of light and vigorous PA during adolescence on a scale ranging from none to more than 3 hours activity. We used logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) and adjusted for potential confounders.

Results: Vigorous PA was inversely associated with MS risk in the pooled analysis ( p-trend < 0.001) with an age- and sex-adjusted OR of 0.74 (95% CI: 0.63-0.87) when comparing the highest and lowest levels. Adjusting for outdoor activity, infectious mononucleosis, body size, and smoking yielded similar results. The association was present in all countries and was not affected by exclusion of patients with early disease onset. Light PA was not associated with the risk of MS.

Conclusion: Our findings suggest that vigorous PA can modify the risk of developing MS independent of established risk factors.
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http://dx.doi.org/10.1177/1352458517694088DOI Listing
February 2018

Negative interaction between smoking and EBV in the risk of multiple sclerosis: The EnvIMS study.

Mult Scler 2017 Jun 23;23(7):1018-1024. Epub 2016 Sep 23.

The Kristian Gerhard Jebsen Centre for MS-Research, Department of Clinical Medicine, University of Bergen, Bergen, Norway/The Norwegian Multiple Sclerosis Registry and Biobank, Department of Neurology, Haukeland University Hospital, Bergen, Norway.

Background: Results from previous studies on a possible interaction between smoking and Epstein-Barr virus (EBV) in the risk of multiple sclerosis (MS) are conflicting.

Objectives: To examine the interaction between smoking and infectious mononucleosis (IM) in the risk of MS.

Methods: Within the case-control study on Environmental Factors In Multiple Sclerosis (EnvIMS), 1904 MS patients and 3694 population-based frequency-matched healthy controls from Norway, Italy, and Sweden reported on prior exposure to smoking and history of IM. We examined the interaction between the two exposures on the additive and multiplicative scale.

Results: Smoking and IM were each found to be associated with an increased MS risk in all three countries, and there was a negative multiplicative interaction between the two exposures in each country separately as well as in the pooled analysis ( p = 0.001). Among those who reported IM, there was no increased risk associated with smoking (odds ratio (OR): 0.95, 95% confidence interval (CI): 0.66-1.37). The direction of the estimated interactions on the additive scale was consistent with a negative interaction in all three countries (relative excess risk due to interaction (RERI): -0.98, 95% CI: -2.05-0.15, p = 0.09).

Conclusion: Our findings indicate competing antagonism, where the two exposures compete to affect the outcome.
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http://dx.doi.org/10.1177/1352458516671028DOI Listing
June 2017

People with MS should consume a low-salt diet - Commentary.

Authors:
Maura Pugliatti

Mult Scler 2016 12 8;22(14):1781-1782. Epub 2016 Sep 8.

Department of Biomedical and Specialty Surgical Sciences, University of Ferrara, Ferrara, Italy

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http://dx.doi.org/10.1177/1352458516669003DOI Listing
December 2016

Environmental and genetic factors in pediatric inflammatory demyelinating diseases.

Neurology 2016 Aug;87(9 Suppl 2):S20-7

From the Pediatric MS Center (E.W.), UCSF Benioff Children's Hospital; Neurology Department (E.W.), UCSF, San Francisco, CA; Murdoch Children's Research Institute (A.-L.P.), Royal Children's Hospital, University of Melbourne, Australia; Department of Biomedical and Specialty Surgical Sciences (M.P.), University of Ferrara, Italy; Neurosciences and Mental Health (H.H.), The Hospital for Sick Children, Toronto, Canada; Department of Neurology (E.M.M.), Johns Hopkins, Baltimore, MD; and MS Center ErasMS, Department of Neurology (R.Q.H.), Erasmus MC, Rotterdam, the Netherlands.

The onset of multiple sclerosis (MS) occurs in childhood in about 5% of all patients with MS. The disease in adults has a complex genetic and environmental inheritability. One of the main risk factors, also confirmed in pediatric MS, is HLA DRB1*1501 In addition to genetic factors, a large part of disease susceptibility in adults is conferred by environmental risk factors such as low vitamin D status, exposure to cigarette smoking, and remote Epstein-Barr virus (EBV) infection. In children, both exposure to cigarette smoking and prior EBV infection have been reported consistently as risk factors for MS. The role of vitamin D remains to be confirmed in this age category. Finally, although very likely critical in disease processes, few gene-environment interactions and epigenetic changes have been reported for adult and pediatric MS susceptibility. Of interest, some of the risk factors for MS have also been associated with disease course modification, such as low 25(OH) vitamin D serum levels in pediatric and adult MS. Age is also a clear disease modifier of clinical, CSF, and MRI phenotype in children with the disease. Finally, although much has yet to be unraveled regarding molecular processes at play in MS, there is a larger gap in our knowledge of genetic and environmental risk factors for pediatric neuromyelitis optica spectrum disorders and acute disseminated encephalomyelitis and only collaborative studies will answer those questions.
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http://dx.doi.org/10.1212/WNL.0000000000003029DOI Listing
August 2016
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