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Despite the commonly observed association of anti-myelin oligodendrocyte glycoprotein (MOG) antibodies with bilateral optic neuritis, their connection to uveitis is largely unexplored. The presented case involves a 41-year-old male with uveitis and bilateral optic neuritis, subsequently diagnosed with myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). This case, characterized by bilateral optic neuritis associated to anti-MOG antibodies and the concurrent onset of unilateral anterior uveitis, provides further evidence concerning the features of intraocular inflammation in MOGAD. The patient's treatment response, including the use of rituximab due to contraindications to oral steroids, emphasizes the importance of personalized management strategies in MOGAD-associated ocular manifestations., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objective: To evaluate mortality for Alzheimer's Disease (AD) in Italy over more than three decades (1980-2015) and discuss the possible role of general and specific contributing factors., Methods: Mortality data were extracted by the Italian National Institute of Statistics: crude mortality rates were computed for sex and age, considering the whole country and its five main geographical sub-areas. Rates were standardized in two ways: directly (annual mortality rates AMRs) and indirectly (standardized mortality rates, SMRs). SMRs were then used to evaluate geographical differences; to study mortality trend, AMRs and joinpoint linear regression analysis were used., Results: Considering the entire period and the whole country, mortality rates were similar for females and males and for geographical regions, with the exception of the older age groups where mortality for AD in females slightly prevailed. In these older patients, a steep increase of mortality was seen starting from the current century. The increase in male mortality mirrored the national trend in North-West and Central Italy, but not in North-East, South, and the Islands, where it did not surge until the mid to late 1990s., Conclusions: the general increase of mortality is in line with international data and it reflects the increasing prevalence of the disease, likely due to increasing longevity, and to improvements in diagnostic accuracy. In addition, the accuracy of death certificate compilation could account for both geographical and temporal differences. Currently available drugs for AD do not seem to have an impact on mortality rates., (© 2024. The Author(s).)

Objective: To evaluate: (1) the distribution of gray matter (GM) atrophy in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder (AQP4+NMOSD), and relapsing-remitting multiple sclerosis (RRMS); and (2) the relationship between GM volumes and white matter lesions in various brain regions within each disease., Methods: A retrospective, multicenter analysis of magnetic resonance imaging data included patients with MOGAD/AQP4+NMOSD/RRMS in non-acute disease stage. Voxel-wise analyses and general linear models were used to evaluate the relevance of regional GM atrophy. For significant results (p < 0.05), volumes of atrophic areas are reported., Results: We studied 135 MOGAD patients, 135 AQP4+NMOSD, 175 RRMS, and 144 healthy controls (HC). Compared with HC, MOGAD showed lower GM volumes in the temporal lobes, deep GM, insula, and cingulate cortex (75.79 cm 3 ); AQP4+NMOSD in the occipital cortex (32.83 cm 3 ); and RRMS diffusely in the GM (260.61 cm 3 ). MOGAD showed more pronounced temporal cortex atrophy than RRMS (6.71 cm 3 ), whereas AQP4+NMOSD displayed greater occipital cortex atrophy than RRMS (19.82 cm 3 ). RRMS demonstrated more pronounced deep GM atrophy in comparison with MOGAD (27.90 cm 3 ) and AQP4+NMOSD (47.04 cm 3 ). In MOGAD, higher periventricular and cortical/juxtacortical lesions were linked to reduced temporal cortex, deep GM, and insula volumes. In RRMS, the diffuse GM atrophy was associated with lesions in all locations. AQP4+NMOSD showed no lesion/GM volume correlation., Interpretation: GM atrophy is more widespread in RRMS compared with the other two conditions. MOGAD primarily affects the temporal cortex, whereas AQP4+NMOSD mainly involves the occipital cortex. In MOGAD and RRMS, lesion-related tract degeneration is associated with atrophy, but this link is absent in AQP4+NMOSD. ANN NEUROL 2024;96:276-288., (© 2024 The Author(s). Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Objective: Multiple sclerosis (MS) is a complex disorder in which environmental and genetic factors interact modifying disease risk and course. This multicentre, case-control study involving 18 Italian MS Centres investigated MS course by ethnicity and native-country economic status in foreign-born patients living in Italy., Methods: We identified 457 MS patients who migrated to Italy and 893 age- and sex-matched native-born Italian patients. In our population, 1225 (93.2%) subjects were White Europeans and White Northern Americans (WENA) and 89 (6.8%) patients were from other ethnical groups (OEG); 1109 (82.1%) patients were born in a high-income (HI) Country and 241 (17.9%) in a low-middle-income (LMI) Country. Medical records and patients interviews were used to collect demographic and disease data., Results: We included 1350 individuals (973 women and 377 men); mean (SD) age was 45.0 (11.7) years. At onset, 25.45% OEG patients vs 12.47% WENA (p = 0.039) had > 3 STIR spine lesions. At recruitment, the same group featured mean (SD) EDSS score of 2.85 (2.23) vs 2.64 (2.28) (p = 0.044) reached in 8.9 (9.0) vs 12.0 (9.0) years (p = 0.018) and underwent 1.10 (4.44) vs. 0.99 (0.40) annual MRI examinations (p = 0.035). At disease onset, patients from LMI countries had higher EDSS score than HI patients (2.40 (1.43) vs 1.99 (1.17); p = 0.032)., Discussion: Our results suggested that both ethnicity and socio-economic status of native country shape MS presentation and course and should be considered for an appropriate management of patients. To the best of our knowledge, this is the first study reporting on the impact of ethnicity in MS at an individual level and beyond an ecological population-perspective., (© 2024. The Author(s).)

Introduction: Over the years, disease registers have been increasingly considered a source of reliable and valuable population studies. However, the validity and reliability of data from registers may be limited by missing data, selection bias or data quality not adequately evaluated or checked. This study reports the analysis of the consistency and completeness of the data in the Italian Multiple Sclerosis and Related Disorders Register., Methods: The Register collects, through a standardized Web-based Application, unique patients. Data are exported bimonthly and evaluated to assess the updating and completeness, and to check the quality and consistency. Eight clinical indicators are evaluated., Results: The Register counts 77,628 patients registered by 126 centres. The number of centres has increased over time, as their capacity to collect patients. The percentages of updated patients (with at least one visit in the last 24 months) have increased from 33% (enrolment period 2000-2015) to 60% (enrolment period 2016-2022). In the cohort of patients registered after 2016, there were ≥ 75% updated patients in 30% of the small centres (33), in 9% of the medium centres (11), and in all the large centres (2). Clinical indicators show significant improvement for the active patients, expanded disability status scale every 6 months or once every 12 months, visits every 6 months, first visit within 1 year and MRI every 12 months., Conclusions: Data from disease registers provide guidance for evidence-based health policies and research, so methods and strategies ensuring their quality and reliability are crucial and have several potential applications., (© 2023. The Author(s).)

Background and Purpose: Although two doses of COVID-19 vaccine elicited a protective humoral response in most persons with multiple sclerosis (pwMS), a significant group of them treated with immunosuppressive disease-modifying therapies (DMTs) showed less efficient responses., Methods: This prospective multicenter observational study evaluates differences in immune response after a third vaccine dose in pwMS., Results: Four hundred seventy-three pwMS were analyzed. Compared to untreated patients, there was a 50-fold decrease (95% confidence interval [CI] = 14.3-100.0, p < 0.001) in serum SARS-CoV-2 antibody levels in those on rituximab, a 20-fold decrease (95% CI = 8.3-50.0, p < 0.001) in those on ocrelizumab, and a 2.3-fold decrease (95% CI = 1.2-4.6, p = 0.015) in those on fingolimod. As compared to the antibody levels after the second vaccine dose, patients on the anti-CD20 drugs rituximab and ocrelizumab showed a 2.3-fold lower gain (95% CI = 1.4-3.8, p = 0.001), whereas those on fingolimod showed a 1.7-fold higher gain (95% CI = 1.1-2.7, p = 0.012), compared to patients treated with other DMTs., Conclusions: All pwMS increased their serum SARS-CoV-2 antibody levels after the third vaccine dose. The mean antibody values of patients treated with ocrelizumab/rituximab remained well below the empirical "protective threshold" for risk of infection identified in the CovaXiMS study (>659 binding antibody units/mL), whereas for patients treated with fingolimod this value was significantly closer to the cutoff., (© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background: Krebs von den Lungen-6 (KL-6) is a high molecular weight (MW) glycoprotein mainly secreted by type II pneumocytes because of lung damage or during regeneration. Neurosarcoidosis (NS), where sarcoid granulomas involve the nervous system, occurs in 5-20% of patients with sarcoidosis. No data is currently available on KL-6 in serum or CSF of NS patients. The present study compared KL-6 concentrations in serum and CSF of NS patients versus others with neurodegenerative (ND) or chronic inflammatory demyelinating (DM) diseases., Materials and Methods: Nine NS patients (mean age 46.2 years, range 16-61 years, M/F 5/4), nine patients with a chronic neurodegenerative disease (mean age 53.1 years, range 37-65 years, M/F 5/4) and nine patients with a chronic demyelinating disease (mean age 46.3 years, range 18-65 years, M/F 5/4) were retrospectively enrolled., Results: Measurable CSF concentrations of KL-6 were detected in 7/9 NS patients but in no ND or DM patients. No significant differences in CSF concentrations of ACE were observed between the three groups (p=0.0819). In NS patients, CSF concentrations of KL-6 were directly correlated with CSF albumin index (r=0.98; p<0.0001), albumin (r=0.979, p=0.0001), IgG (r=0.928, p=0.0009) and total protein concentrations (r=0.945, p=0.0004)., Discussion: KL-6 is a high MW protein, under physiological conditions it is unlikely to cross the blood-brain barrier. We found KL-6 in CSF from NS and not from ND and DM patients. The finding sustains the specificity of changes in KL-6 in this granulomatous disease, suggesting it as a candidate biomarker for recognition of NS.

MRI and clinical features of myelin oligodendrocyte glycoprotein (MOG)-antibody disease may overlap with those of other inflammatory demyelinating conditions posing diagnostic challenges, especially in non-acute phases and when serologic testing for MOG antibodies is unavailable or shows uncertain results. We aimed to identify MRI and clinical markers that differentiate non-acute MOG-antibody disease from aquaporin 4 (AQP4)-antibody neuromyelitis optica spectrum disorder and relapsing remitting multiple sclerosis, guiding in the identification of patients with MOG-antibody disease in clinical practice. In this cross-sectional retrospective study, data from 16 MAGNIMS centres were included. Data collection and analyses were conducted from 2019 to 2021. Inclusion criteria were: diagnosis of MOG-antibody disease; AQP4-neuromyelitis optica spectrum disorder and multiple sclerosis; brain and cord MRI at least 6 months from relapse; and Expanded Disability Status Scale (EDSS) score on the day of MRI. Brain white matter T2 lesions, T1-hypointense lesions, cortical and cord lesions were identified. Random forest models were constructed to classify patients as MOG-antibody disease/AQP4-neuromyelitis optica spectrum disorder/multiple sclerosis; a leave one out cross-validation procedure assessed the performance of the models. Based on the best discriminators between diseases, we proposed a guide to target investigations for MOG-antibody disease. One hundred and sixty-two patients with MOG-antibody disease [99 females, mean age: 41 (±14) years, median EDSS: 2 (0-7.5)], 162 with AQP4-neuromyelitis optica spectrum disorder [132 females, mean age: 51 (±14) years, median EDSS: 3.5 (0-8)], 189 with multiple sclerosis (132 females, mean age: 40 (±10) years, median EDSS: 2 (0-8)] and 152 healthy controls (91 females) were studied. In young patients (<34 years), with low disability (EDSS < 3), the absence of Dawson's fingers, temporal lobe lesions and longitudinally extensive lesions in the cervical cord pointed towards a diagnosis of MOG-antibody disease instead of the other two diseases (accuracy: 76%, sensitivity: 81%, specificity: 84%, P < 0.001). In these non-acute patients, the number of brain lesions < 6 predicted MOG-antibody disease versus multiple sclerosis (accuracy: 83%, sensitivity: 82%, specificity: 83%, P < 0.001). An EDSS < 3 and the absence of longitudinally extensive lesions in the cervical cord predicted MOG-antibody disease versus AQP4-neuromyelitis optica spectrum disorder (accuracy: 76%, sensitivity: 89%, specificity: 62%, P < 0.001). A workflow with sequential tests and supporting features is proposed to guide better identification of patients with MOG-antibody disease. Adult patients with non-acute MOG-antibody disease showed distinctive clinical and MRI features when compared to AQP4-neuromyelitis optica spectrum disorder and multiple sclerosis. A careful inspection of the morphology of brain and cord lesions together with clinical information can guide further analyses towards the diagnosis of MOG-antibody disease in clinical practice., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Significance: Increased plasma concentrations of total homocysteine (tHcy; mild-moderate hyperhomocysteinemia: 15-50 μ M tHcy) are considered an independent risk factor for the onset/progression of various diseases, but it is not known about how the increase in tHcy causes pathological conditions. Recent Advances: Reduced homocysteine (HSH ∼1% of tHcy) is presumed to be toxic, unlike homocystine (∼9%) and mixed disulfide between homocysteine and albumin (HSS-ALB; homocysteine [Hcy]-albumin mixed disulfide, ∼90%). This and other notions make it difficult to explain the pathogenicity of Hcy because: (i) lowering tHcy does not improve pathological outcomes; (ii) damage due to HSH usually emerges at supraphysiological doses; and (iii) it is not known why tiny increments in plasma concentrations of HSH can be pathological. Critical Issues: Albumin may have a role in Hcy toxicity, because HSS-ALB could release toxic HSH via thiol-disulfide (SH/SS) exchange reactions in cells. Similarly, thiol-disulfide exchange processes of reduced albumin (albumin with free SH group of Cys34 [HS-ALB]) or N -homocysteinylated albumin are plausible alternatives for initiating Hcy pathological events. Adverse effects of albumin and other data reviewed here suggest the hypothesis of a role of albumin in Hcy toxicity. Future Directions : HSS-ALB might be involved in disruption of the antioxidant/oxidant balance in critical tissues (brain, liver, kidney). Since homocysteine-albumin mixed disulfide is a possible intermediate of thiol-disulfide exchange reactions, we suggest that homocysteinylated albumin could be a new pathological factor, and that studies on the redox role of albumin and mixed disulfide production via thiol-disulfide exchange reactions could offer new therapeutic insights for reducing Hcy toxicity.

Background: Patients with multiple sclerosis (pwMS) treated with anti-CD20 or fingolimod showed a reduced humoral response to SARS-CoV-2 vaccines., Objective: In this study we aimed to monitor the risk of breakthrough SARS-CoV-2 infection in pwMS on different disease-modifying therapies (DMTs)., Methods: Data on the number of vaccinated patients and the number of patients with a breakthrough infection were retrospectively collected in 27 Italian MS centers. We estimated the rate of breakthrough infections and of infection requiring hospitalization per DMT., Results: 19,641 vaccinated pwMS were included in the database. After a median follow-up of 8 months, we observed 137 breakthrough infections. Compared with other DMTs, the rate of breakthrough infections was significantly higher on ocrelizumab (0.57% vs 2.00%, risk ratio (RR) = 3.55, 95% CI = 2.74-4.58, p  < 0.001) and fingolimod (0.58% vs 1.62%, RR = 2.65, 95% CI = 1.75-4.00, p  < 0.001), while there were no significant differences in any other DMT group. In the ocrelizumab group the hospitalization rate was 16.7% versus 19.4% in the pre-vaccination era (RR = 0.86, p  = 0.74) and it was 3.9% in all the other DMT groups versus 11.9% in the pre-vaccination period (RR = 0.33, p  = 0.02)., Conclusions: The risk of breakthrough SARS-CoV-2 infections is higher in patients treated with ocrelizumab and fingolimod, and the rate of severe infections was significantly reduced in all the DMTs excluding ocrelizumab.

Objective: Chronic comorbidities are common in people with multiple sclerosis (PwMS), thus worsening their prognosis and quality of life, and increasing disease burden. The aim of the present study was to evaluate the prevalence of common comorbidities in PwMS in Tuscany (Central Italy) and to compare it with the general population., Methods: The prevalence of comorbidities, including diabetes, chronic obstructive pulmonary disease (COPD), hypertension, stroke, heart failure (HF), cardiac infarction and ischemic heart disease (IHD), was assessed in PwMS and in general population resident in Tuscany, aged > 20 years, using administrative data., Results: In total, we identified 8,274 PwMS. Among them, 34% had at least one comorbidity, with hypertension being the most common (28.5%). Comparing PwMS with the general population, PwMS had a higher frequency of hypertension and stroke when considering the whole group, and of diabetes, COPD, and IHD when considering sex and age subgroups. This increased risk was especially evident in the young and intermediate age groups, where multiple sclerosis may play an important role as risk factor for some comorbidities. In PwMS, as well as in the general population, prevalence of chronic diseases was higher in males and increased with age., Conclusions: Comorbidities frequently coexist with multiple sclerosis and they may have an impact on this complex disease, from the health, clinical, and socioeconomic points of view. Therefore, a routine screening of chronic comorbidities should be a crucial step in clinical practice, as well as the promotion of healthy lifestyles to prevent the onset and to reduce their burden., (© 2022. The Author(s).)

Background: Multiple sclerosis (MS) is characterized by phenotypical heterogeneity, partly resulting from demographic and environmental risk factors. Socio-economic factors and the characteristics of local MS facilities might also play a part., Methods: This study included patients with a confirmed MS diagnosis enrolled in the Italian MS and Related Disorders Register in 2000-2021. Patients at first visit were classified as having a clinically isolated syndrome (CIS), relapsing-remitting (RR), primary progressive (PP), progressive-relapsing (PR), or secondary progressive MS (SP). Demographic and clinical characteristics were analyzed, with centers' characteristics, geographic macro-areas, and Deprivation Index. We computed the odds ratios (OR) for CIS, PP/PR, and SP phenotypes, compared to the RR, using multivariate, multinomial, mixed effects logistic regression models., Results: In all 35,243 patients from 106 centers were included. The OR of presenting more advanced MS phenotypes than the RR phenotype at first visit significantly diminished in relation to calendar period. Females were at a significantly lower risk of a PP/PR or SP phenotype. Older age was associated with CIS, PP/PR, and SP. The risk of a longer interval between disease onset and first visit was lower for the CIS phenotype, but higher for PP/PR and SP. The probability of SP at first visit was greater in the South of Italy., Discussion: Differences in the phenotype of MS patients first seen in Italian centers can be only partly explained by differences in the centers' characteristics. The demographic and socio-economic characteristics of MS patients seem to be the main determinants of the phenotypes at first referral., (© 2022. The Author(s).)

Background: In this study we aimed to monitor the risk of breakthrough SARS-CoV-2 infection in patients with MS (pwMS) under different DMTs and to identify correlates of reduced protection., Methods: This is a prospective Italian multicenter cohort study, long-term clinical follow-up of the CovaXiMS (Covid-19 vaccine in Multiple Sclerosis) study. 1855 pwMS scheduled for SARS-CoV-2 mRNA vaccination were enrolled and followed up to a mean time of 10 months. The cumulative incidence of breakthrough Covid-19 cases in pwMS was calculated before and after December 2021, to separate the Delta from the Omicron waves and to account for the advent of the third vaccine dose., Findings: 1705 pwMS received 2 m-RNA vaccine doses, 21/28 days apart. Of them, 1508 (88.5%) had blood assessment 4 weeks after the second vaccine dose and 1154/1266 (92%) received the third dose after a mean interval of 210 days (range 90-342 days) after the second dose. During follow-up, 131 breakthrough Covid-19 infections (33 during the Delta and 98 during the Omicron wave) were observed. The probability to be infected during the Delta wave was associated with SARS-CoV-2 antibody levels measured after 4 weeks from the second vaccine dose (HR=0.57, p < 0.001); the protective role of antibodies was preserved over the whole follow up (HR=0.57, 95%CI=0.43-0.75, p < 0.001), with a significant reduction (HR=1.40, 95%CI=1.01-1.94, p=0.04) for the Omicron cases. The third dose significantly reduced the risk of infection (HR=0.44, 95%CI=0.21-0.90,p=0.025) during the Omicron wave., Interpretation: The risk of breakthrough SARS-CoV-2 infections is mainly associated with reduced levels of the virus-specific humoral immune response., Funding: Supported by FISM - Fondazione Italiana Sclerosi Multipla - cod. 2021/Special-Multi/001 and financed or co-financed with the '5 per mille' public funding., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: To evaluate mortality for Parkinson's disease (PD) in Italy during a long time period (1980-2015) and to discuss the role of possible general and specific influencing factors., Methods: Based on mortality data provided by the Italian National Institute of Statistics, sex- and age-specific crude mortality rates were computed, for the whole country and for its main geographical sub-areas. Rates were standardized using both direct (annual mortality rates AMRs) and indirect (standardized mortality rates SMRs) methods. SMRs were used to evaluate geographical differences, whereas AMRs and joinpoint linear regression analysis to study mortality trends., Results: Considering the entire period, highest mortality rates were observed in males (AMR/100,000: 9.0 in males, 5.25 in females), in North-West and Central Italy (SMR > 100). Overall PD mortality decreased from mid-eighties onwards and then rapidly reversed the trend in the period 1998-2002, rising up to a maximum in 2015, with some differences according to sex and geographical areas., Conclusions: Several factors may have contributed to the rapid inversion of decreasing trend in mortality observed in the last part of XX century. Possible explanations of this rising trend are related to the increasing burden of PD (especially in males and in certain Italian regions), caused by different factors as population aging, physiological prevalence rise due to incidence exceeding mortality, and growing exposure to environmental or occupational risk factors. In addition, the accuracy of death certificate compilation could account for geographical differences and for the temporal trend. The role of levodopa and recently introduced dopaminergic drugs is also discussed., (© 2021. Fondazione Società Italiana di Neurologia.)

Background: In patients with Multiple Sclerosis (pwMS) disease-modifying therapies (DMTs) affects immune response to antigens. Therefore, post-vaccination serological assessments are needed to evaluate the effect of the vaccine on SARS-CoV-2 antibody response., Methods: We designed a prospective multicenter cohort study enrolling pwMS who were scheduled for SARS-Cov-2 vaccination with mRNA vaccines (BNT162b2, Pfizer/BioNTech,Inc or mRNA-1273, Moderna Tx,Inc). A blood collection before the first vaccine dose and 4 weeks after the second dose was planned, with a centralized serological assessment (electrochemiluminescence immunoassay, ECLIA, Roche-Diagnostics). The log-transform of the antibody levels was analyzed by multivariable linear regression., Findings: 780 pwMS (76% BNT162b2 and 24% mRNA-1273) had pre- and 4-week post-vaccination blood assessments. 87 (11·2%) were untreated, 154 (19·7%) on ocrelizumab, 25 (3·2%) on rituximab, 85 (10·9%) on fingolimod, 25 (3·2%) on cladribine and 404 (51·7%) on other DMTs. 677 patients (86·8%) had detectable post-vaccination SARS-CoV-2 antibodies. At multivariable analysis, the antibody levels of patients on ocrelizumab (201-fold decrease (95%CI=128-317), p < 0·001), fingolimod (26-fold decrease (95%CI=16-42), p < 0·001) and rituximab (20-fold decrease (95%CI=10-43), p < 0·001) were significantly reduced as compared to untreated patients. Vaccination with mRNA-1273 resulted in a systematically 3·25-fold higher antibody level (95%CI=2·46-4·27) than with the BNT162b2 vaccine (p < 0·001). The antibody levels on anti-CD20 therapies correlated to the time since last infusion, and rituximab had longer intervals (mean=386 days) than ocrelizumab patients (mean=129 days)., Interpretation: In pwMS, anti-CD20 treatment and fingolimod led to a reduced humoral response to mRNA-based SARS-CoV-2 vaccines. As mRNA-1273 elicits 3·25-higher antibody levels than BNT162b2, this vaccine may be preferentially considered for patients under anti-CD20 treatment or fingolimod. Combining our data with those on the cellular immune response to vaccines, and including clinical follow-up, will contribute to better define the most appropriate SARS-CoV-2 vaccine strategies in the context of DMTs and MS., Funding: FISM[2021/Special-Multi/001]; Italian Ministry of Health'Progetto Z844A 5 × 1000'., Competing Interests: Declaration of Competing Interest Caleri F received personal compensations from Merck, Biogen, Genzyme, Roche, Teva. Clerico M received grants and consulting fees from Merck, Biogen, Novartis, Sanofi-Genzyme, Roche, Almirall. Cordioli C received personal compensations from Merck, Biogen, Novartis, Roche, Almirall. Di Sapio A received consulting fees from Novartis, Biogen, Genzyme. Franciotta D received personal honoraria from Merck, Biogen, Sanofi-Genzyme, Roche. Frau J received consulting fees from Biogen, Sanofi-Genzyme, Almirall. Inglese received consulting fees from Merck, Biogen, Novartis, Sanofi-Genzyme, Roche. Iodice received personal honoraria from Merck, Biogen, Sanofi-Genzyme, Roche. Landi received consulting fees from Merck, Biogen, Novartis, Sanofi-Genzyme, Roche, Teva, Mylan, Bristol-Celgene. Laroni received consulting fees from Merck, Biogen, Novartis, Sanofi-Genzyme, Roche. Salvetti received consulting fees from Merck, Biogen, Novartis, Sanofi-Genzyme, Roche. Serrati received grants from Neopharmed. Sormani received consulting fees from Merck, Biogen, Novartis, Sanofi-Genzyme, Roche, Celgene, Geneuro, GSK, Medday, Immunic. Uccelli participated in advisory boards for Biogen, Roche. Ulivelli received consulting fees from Biogen, Novartis, Serono. Battaglia MA, Brichetto G, Callari G, Carmisciano L, Cordera S, Da Rin G, Ferrò MT, Gandoglia I, Gazzola P Lapucci C, Liberatore G, Mannironi A, Marinelli F, Pasquali L, Perego G, Repice AM, Schiavetti I, Signoriello E, Stromillo ML, Tassinari T, have nothing to disclose., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

It is likely that when using an artificially augmented hand with six fingers, the natural five plus a robotic one, corticospinal motor synergies controlling grasping actions might be different. However, no direct neurophysiological evidence for this reasonable assumption is available yet. We used transcranial magnetic stimulation of the primary motor cortex to directly address this issue during motor imagery of objects' grasping actions performed with or without the Soft Sixth Finger (SSF). The SSF is a wearable robotic additional thumb patented for helping patients with hand paresis and inherent loss of thumb opposition abilities. To this aim, we capitalized from the solid notion that neural circuits and mechanisms underlying motor imagery overlap those of physiological voluntary actions. After a few minutes of training, healthy humans wearing the SSF rapidly reshaped the pattern of corticospinal outputs towards forearm and hand muscles governing imagined grasping actions of different objects, suggesting the possibility that the extra finger might rapidly be encoded into the user's body schema, which is integral part of the frontal-parietal grasping network. Such neural signatures might explain how the motor system of human beings is open to very quickly welcoming emerging augmentative bioartificial corticospinal grasping strategies. Such an ability might represent the functional substrate of a final common pathway the brain might count on towards new interactions with the surrounding objects within the peripersonal space. Findings provide a neurophysiological framework for implementing augmentative robotic tools in humans and for the exploitation of the SSF in conceptually new rehabilitation settings., (© 2021. The Author(s).)

Background: If Parkinson's Disease (PD) may represent a risk factor for Coronavirus disease 2019 (COVID-19) is debated and there are few data on the direct and indirect effects of this pandemic in PD patients., Objective: In the current study we evaluated the prevalence, mortality and case-fatality of COVID-19 in a PD cohort, also exploring possible risk factors. We also aimed to investigate the effect of lockdown on motor/non-motor symptoms in PD patients as well as their acceptability/accessibility to telemedicine., Method: A case-controlled survey about COVID-19 and other clinical features in PD patients living in Tuscany was conducted. In non-COVID-19 PD patients motor/non-motor symptoms subjective worsening during the lockdown as well as feasibility of telemedicine were explored., Results: Out of 740 PD patients interviewed, 7 (0.9%) were affected by COVID-19, with 0.13% mortality and 14% case-fatality. COVID-19 PD patients presented a higher presence of hypertension (p < 0.001) and diabetes (p = 0.049) compared to non-COVID-19. In non-COVID-19 PD population (n = 733) about 70% did not experience a subjective worsening of motor symptoms or mood, anxiety or insomnia. In our population 75.2% of patients was favorable to use technology to perform scheduled visits, however facilities for telemedicine were available only for 51.2% of cases., Conclusion: A higher prevalence of COVID-19 respect to prevalence in Tuscany and Italy was found in the PD population. Hypertension and diabetes, as for general population, were identified as risk factors for COVID-19 in PD. PD patients did not experience a subjective worsening of symptoms during lockdown period and they were also favorable to telemedicine, albeit we reported a reduced availability to perform it.

Objective: The presence of a cochlear implant is being considered an absolute contraindication for experiments and/or treatments. We aimed to verify TMS (Transcranial Magnetic Stimulation) compatibility of a new generation of cochlear implants., Methods: In a series of experiments, we test if MED-EL cochlear implants -compatible with stable fields of magnetic resonance imaging scanning- are fully resistant even to rapidly varying magnetic fields as those generated by single pulses and low and high-frequency trains of repetitive TMS (rTMS) applied with a figure of eight coil and different magnetic stimulators., Results: With a TMS intensity equal or below 2.2 Tesla (T) the cochlear implant and all its electronic components remain fully functional, even when the combination of frequency, intensity and number of pulses exceeds the currently available safety guidelines. Induced forces on the implant are negligible. With higher magnetic fields (i.e., 3.2 T), one device was corrupted., Conclusions: Results exclude the risk of electronic damaging, demagnetizing or displacements of the studied cochlear implants when exposed to magnetic fields of up to 2.2 T delivered through a focal coil., Significance: They open the way to use focal rTMS protocols with the aim of promoting neural plasticity in auditory networks, possibly helping the post-implant recovery of speech perception performance., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Background and Objective: In a proof-of-concept study, we aimed to verify whether the wearable haptic anklets, a device that delivers personalized suprathreshold alternating exteroceptive stimulation at the anklets on demand, may improve the quality of walking, including the freezing of gate (FOG), in idiopathic Parkinson's disease (PD) patients. The clinical relevance of the presented device as a walking pacemaker to compensate the disturbed locomotion through the generation of a more physiological internal walking rhythm should be verified in a dedicated clinical trial., Methods: We tested 15 patients diagnosed as idiopathic PD, during their regular treatment regimen. Patients were evaluated during walking with the device switched on and off, personalized at their most comfortable cadence. Stride velocity, variance, and length, as well as FOG episode duration during walking or turning of 180°, were quantified by an optical high-performance motion capture VICON system., Results: The alternating, rhythmic, sensory stimulation significantly improved either walking velocity or reduced inter-stride variance. Effects were more variable on stride length. The significant reduction of FOG episodes' duration correlated with clinical severity of scales rating gate and balance. No safety problems occurred., Conclusions: The WEARHAP-PD device, whose Technology Readiness Level (TRL) is 6, significantly improved some walking abilities (walking velocity and stride variance) and reduced the duration of FOG episodes in idiopathic PD patients. Unlike the traditional auditory and visual explicit cues that require the user's allocation of attention for correct functioning, the interaction of the patients with the surrounding environment was preserved, due to the likely implicit processing of haptic stimuli.

Background: The epidemiology of Multiple Sclerosis (MS) is relevant for health-services planning. Most of MS prevalence and incidence studies in Italy referred to specific geographical areas and periods, whereas mortality data are routinely collected at the national level. The aim was to assess MS mortality trend and geographical differences in Italy from 1980 to 2015., Methods: Mortality data were provided by the Italian Institute of Statistics. Due to a low number of annual deaths, mortality data were analysed for both the entire period under study and for sub-periods. Temporal trends were first evaluated using age-adjusted mortality rates (AMRs) comparing each sub-period with the initial one. Then, the annual percent change in mortality was estimated through the joinpoint regression model. Spatial differences between 5 main geographical areas were evaluated using standardized mortality ratios (SMRs)., Results: During the study period, 4,959 deaths for males and 7,434 for females were observed. The higher overall AMR was observed for females (F:0.71 vs. M: 0.56 per 100,000 persons per year). Analysing mortality by gender and geographical area, SMRs 〈 100 were observed in South Italy for both sexes, and in Central Italy for males only, whereas SMRs 〉 100 for Islands for both sexes, and in North-East and North-West for females only. The analysis of the mortality trend through AMRs calculated for sub-periods revealed no difference between the first and the last period for males, whereas a significant increase in mortality was observed for females. The joinpoint regression analysis showed a significant decrease in mortality up to 1995 for males (APC -3.23%) and up to 1999 for females, (APC -1.01%), followed by a significant increase for both sexes, but more marked for females (APC +1.9% M, +2.34% F)., Conclusion: The increasing trend of mortality for MS, especially for females, may reflect the increase in the prevalence of MS and the improvement in the quality of diagnosis or coding of the cause of death., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background and study purpose: to describe the comorbidity of celiac disease among a large cohort of multiple sclerosis patients in Tuscany., Methods: the association of celiac disease among multiple sclerosis adult patients (n=2050) was retrospectively evaluated., Results: 13 patients were diagnosed with celiac disease, the female:male ratio was 3.3:1 and the median age at diagnosis was 34.2 years (SD 13). Seventy-seven per cent of subjects complained about gastrointestinal symptoms. IgA anti- transglutaminase was positive in 85 % of cases and there was 70 % of villous atrophy., Conclusions: the frequency of celiac disease among multiple sclerosis patients examined was lower than in the general population, 0.6 % vs 1 %)(p = 0.65).

Background and Rationale: An increase of prevalence and incidence of multiple sclerosis (MS) has been reported in several countries, especially taking into account a long-term evaluation. This increasing trend often reflects improved case identification and ascertainment due to the refinement of diagnostic criteria. The aim of this study was to update the prevalence rate of MS in Tuscany (central Italy) as of 2017, and to assess if there has been an increasing trend of prevalence in this Region considering a short period of analysis, from 2014 to 2017., Methods: To capture prevalent cases, a case-finding algorithm based on administrative data, previously created and validated, was used. As data sources, we considered hospital discharge records, drug-dispensing records, disease-specific exemptions from copayment to health care, home and residential long-term care, and inhabitant registry., Results: As of January 1, 2017, 7809 cases were identified, of which 69.4% were females and 30.6% were males. Considering temporal variation, an increasing trend was observed, with standardized rates rising from 189.2 in 2014 to 208.7 per 100,000 in 2017., Conclusions: Results confirm that prevalence increases every year, probably mainly due to the difference between incidence and mortality, resulting in an increasing trend. Moreover, administrative data may accurately identify MS patients in a routinary way and monitor this cohort along disease care pathways.

Transcranial magnetic stimulation was used to investigate corticospinal output changes in 10 professional piano players during motor imagery of triad chords in C major to be "mentally" performed with three fingers of the right hand (thumb, index, and little finger). Five triads were employed in the task; each composed by a stable 3rd interval (C4-E4) and a varying third note that could generate a 5th (G4), a 6th (A4), a 7th (B4), a 9th (D5), or a 10th (E5) interval. The 10th interval chord was thought to be impossible in actual execution for biomechanical reasons, as long as the thumb and the index finger remained fixed on the 3rd interval. Chords could be listened from loudspeakers, read on a staff, or listened and read at the same time while performing the imagery task. The corticospinal output progressively increased along with task demands in terms of mental representation of hand extension. The effects of audio, visual, or audiovisual musical stimuli were generally similar, unless motor imagery of kinetically impossible triads was required. A specific three-effector motor synergy was detected, governing the representation of the progressive mental extension of the hand. Results demonstrate that corticospinal facilitation in professional piano players can be modulated according to the motor plan, even if simply "dispatched" without actual execution. Moreover, specific muscle synergies, usually encoded in the motor cortex, emerge along the cross-modal elaboration of musical stimuli and in motor imagery of musical performances.

Objective: Verify whether Percutaneous Transluminal Angioplasty (PTA) may affect neural conduction properties in Multiple Sclerosis (MS) patients, thereby modifying patients' disability, with prospective neurophysiological, urodynamic, clinical and subjective well-being evaluations., Methods: In 55 out of 72 consecutively screened MS patients, the following procedures were carried out before (T0), at 2-6 months (T1) and at 6-15 months (T2) after a diagnostic phlebography, eventually followed by the PTA intervention if chronic cerebrospinal venous insufficiency (CCSVI) was diagnosed: clinical/objective evaluation (Expanded Disability Status Scale, EDSS), ratings of subjective well-being, evaluation of urodynamic functions and multimodal EPs (visual, acoustic, upper and lower limbs somatosensory and motor evoked potentials)., Results: The number of dropouts was relatively high, and a complete set of neurophysiological and clinical data remained available for 37 patients (19 for urological investigations). The subjective well-being score significantly increased at T1 and returned close to basal values at T2, but their degree of objective disability did not change. Nevertheless, global EP-scores (indexing the impairment in conductivity of central pathways in multiple functional domains) significantly increased from T0 (7.9 ± 6.0) to T1 (9.2 ± 6.3) and from T0 to T2 (9.8 ± 6.3), but not from T1 and T2 (p > 0.05). Neurogenic urological lower tract dysfunctions slightly increased throughout the study., Conclusions: The PTA intervention did not induce significant changes in disability in the present cohort of MS patients, in line with recent evidence of clinical inefficacy of this procedure., Significance: Absence of multimodal neurophysiological and functional testing changes in the first 15 months following PTA suggests that conduction properties of neural pathways are unaffected by PTA. Current findings suggest that the short-lived (2-6 months), post-PTA, beneficial effect on subjective well-being measures experienced by MS patients is likely related to a placebo effect., (Copyright © 2018 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Background: Italy is a high-risk area for multiple sclerosis with 110,000 prevalent cases estimated at January 2016 and 3400 annual incident cases. To study multiple sclerosis epidemiology, it is preferable to use population-based studies, e.g., with a registry. A valid alternative to obtain data on entire population is from administrative sources., Objective: To estimate the incidence of multiple sclerosis in Tuscany using a case-finding algorithm based on administrative data., Methods: In a previous study, we calculated the prevalence in Tuscany using a validated case-finding algorithm based on administrative data. Incident cases were identified as a subset of prevalent cases among those patients not traced in the years before the analysis period, and the date of the first multiple sclerosis-related claim was considered the incidence date of multiple sclerosis diagnosis. We examined the period 2011-2015., Results: We identified 1147 incident cases with annual rates ranged from 5.60 per 100,000 in 2011 to 6.58 in 2015., Conclusions: We found a high incidence rate, similarly to other Italian areas, especially in women, that may explain the increasing prevalence in Tuscany. To confirm this data and to calculate the possible bias caused by our inclusion method, we will validate our algorithm for incident cases.

Background: Knowledge concerning the predictors of social security benefits and the proportion of Multiple Sclerosis (MS) patients receiving these benefits is very limited., Objective: To estimate the likelihood of receiving social security benefits for Italian MS patients., Methods: From September 2014 to November 2015, we interviewed MS outpatients from two Italian MS clinics to collect information regarding their personal data, clinical and working history, and access to social security benefits. We performed both univariate and multivariable analyses to evaluate the predictors for receiving social security benefits., Results: We interviewed 297 patients, with a mean age of 49.5 (± 10.7) years; 71.4% were females. About 73% of patients had a relapsing-remitting (RR) course and the median EDSS score was 2.5 (IQR 1.5-6). About 75% of MS patients received a full exemption from co-payments, while the proportions of people who enjoyed each of the other social security benefits were lower, ranging from 8.8% (car adaptation) to 32% (disable badge). At multivariable analysis, the probability of obtaining each of the benefits was significantly associated with the EDSS score: walking aids (OR 3.9), care allowance (OR 3.6), disabled badge (OR 2.4), exemption from co-payment (OR 1.6) and allowed off work permit (OR 1.7). Only the probability of obtaining an allowed off work permit was also influenced by comorbidities (OR 2.9) and a higher education (OR 2.2)., Conclusion: Except for full exemption from co-payments, the proportions of MS patients who enjoyed social security benefits seem to be limited in our study sample. The EDSS score is the strongest predictor of the probability of receiving all the benefits. Only a small proportion of patients received care allowance and working permits, probably because such benefits are only granted to people with a high level of disability. On the other hand, the low proportion of patients who enjoyed fiscal benefits for home and car adaptations could have been influenced by the way such benefits are granted in our country., (Copyright © 2018. Published by Elsevier B.V.)

F 4 -neuroprostanes (F 4 -NeuroPs) are non-enzymatic oxidized products derived from docosahexaenoic acid (DHA) and are suggested to be oxidative damage biomarkers of neurological diseases. However, 128 isomers can be formed from DHA oxidation and among them, 4(RS)-4-F 4t -NeuroP (4-F 4t -NeuroP) and 10(RS)-10-F 4t -NeuroP (10-F 4t -NeuroP) are the most studied. Here, we report the identification and the clinical relevance of 4-F 4t -NeuroP and 10-F 4t -NeuroP in plasma of four different neurological diseases, including multiple sclerosis (MS), autism spectrum disorders (ASD), Rett syndrome (RTT), and Down syndrome (DS). The identification and the optimization of the method were carried out by gas chromatography/negative-ion chemical ionization tandem mass spectrometry (GC/NICI-MS/MS) using chemically synthesized 4-F 4t -NeuroP and 10-F 4t -NeuroP standards and in oxidized DHA liposome. Both 4-F 4t -NeuroP and 10-F 4t -NeuroP were detectable in all plasma samples from MS (n = 16), DS (n = 16), ASD (n = 9) and RTT (n = 20) patients. While plasma 10-F 4t -NeuroP content was significantly higher in patients of all diseases as compared to age and gender matched healthy control subjects (n = 61), 4-F 4t -NeuroP levels were significantly higher in MS and RTT as compared to healthy controls. Significant positive relationships were observed between relative disease severity and 4-F 4t -NeuroP levels (r = 0.469, P <0.0001), and 10-F 4t -NeuroP levels (r = 0.757, P < 0.0001). The study showed that the plasma amount ratio of 10-F 4t -NeuroP to 4-F 4t -NeuroP and the plasma amount as individual isomer can be used to discriminate between different brain diseases. Overall, by comparing the different types of disease, our plasma data indicates that 4-F 4t -NeuroP and 10-F 4t -NeuroP: i) are biologically synthesized in vivo and circulated, ii) are related to clinical severity of neurological diseases, iii) are useful to identify shared pathogenetic pathways in distinct brain diseases, and iv) appears to be distinctive for different neurological conditions, thus representing potentially new biological disease markers. Our data strongly suggest that in vivo DHA oxidation follows preferential chemical rearrangements according to different brain diseases., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Tuscany (Central Italy) is a high-risk area for multiple sclerosis (MS) with a prevalence of 188 cases per 100,000 at 2011, and it is characterized by a heterogeneous geographic distribution of this disease. Our objective was to update prevalence at 2013 and to evaluate the presence of spatial clusters in Tuscany. The MS prevalence was evaluated on 31 December 2013 using a validated case-finding algorithm, based on administrative data. To identify spatial clusters, we calculated standardized morbidity ratios (SMRs) for each Tuscan administrative municipality. In addition to the classical approach, we applied the hierarchical Bayesian model to overcome random variability due to the presence of small number of cases per municipality. We identified 7330 MS patients (2251 males and 5079 females) with an overall prevalence of 195.4/100,000. The SMR for each Tuscan municipality ranged from 0 to 271.4, but this approach produced an extremely non-homogeneous map. On the contrary, the Bayesian map was much smoother than the classical one. The posterior probability (PP) map showed prevalence clusters in some areas in the province of Massa-Carrara, Pistoia, and Arezzo, and in the municipalities of Siena, Florence, and Barberino Val d'Elsa. Our prevalence data confirmed that Tuscany is a high-risk area, and we observed an increasing trend during the time. Using the Bayesian method, we estimated area-specific prevalence in each municipality reducing the random variation and the effect of extreme prevalence values in small areas that affected the classical approach.

Background: Dysfunctions of the upper limbs occur in the 66% of multiple sclerosis (MS) patients. To date, no data, about the persistence of the effects of a rehabilitation treatment and no prognostic markers of functional improvement, have been established., Aim: The aim of this study was to define clinical data supporting the efficacy of a rehabilitation treatment in MS patients with upper limb impairment and to find prognostic factors for functional improvement., Design: Pre-post comparison prospective study., Setting: Two tertiary Italian MS centres: Rome and Siena., Population: Twenty-five consecutive MS patients were tested for eligibility., Methods: We multidimensionally evaluated 25 consecutive patients with MS-related upper limbs impairment through clinical objective, patient-oriented and neurophysiological measures pre and post a16-week rehabilitation treatment on upper limb sensorimotor function., Results: We found a significant improvement in the Nine Hole Peg Test (9-HPT) at either sides, both at an immediate post-training visit (T1) (left: P=0.018, right: P=0.004) and at a 12-week postintervention assessment visit (T2) (left: P=0.033, right: P=0.022). We also found a positive correlation between the 12-week post-training changes in the 9-HPT and the N14-P20 interpeak of the somatosensory evoked potentials, (rho=0.374, P=0.008)., Conclusions: Our study demonstrates that a rehabilitation treatment can lead to an improvement of the upper limb motor performance in MS patients which continues to persist even after 3 months of treatment-discontinuation suggesting a possible role of rehabilitation in neuroplasticity changes. Moreover, we found, in the latency of the N14-P20 interpeak, a possible prognostic marker for the effects of a upper limb rehabilitation treatment in MS patients., Clinical Rehabilitation Impact: The N14-P20 interpeak could be used as a prognostic marker of the effects of rehabilitation of the upper limb.

The toxicity risk of hyperhomocysteinemia is prevented through thiol drug administration which reduces plasma total homocysteine (tHcy) concentrations by activating thiol exchange reactions. Assuming that cysteine (Cys) is a homocysteinemia regulator, the hypothesis was verified in healthy and pathological individuals after the methionine loading test (MLT). The plasma variations of redox species of Cys, Hcy, cysteinylglycine, glutathione and albumin (reduced, HS-ALB, and at mixed disulfide, XSS-ALB) were compared in patients with cerebral small vessels disease (CSVD) (n = 11), multiple sclerosis (MS) (n = 12) and healthy controls (n = 11) at 2-4-6 h after MLT. In MLT-treated subjects, the activation of thiol exchange reactions provoked significant changes over time in redox species concentrations of Cys, Hcy, and albumin. Significant differences between controls and pathological groups were also observed. In non-methionine-treated subjects, total Cys concentrations, tHcy and thiol-protein mixed disulfides (CSS-ALB, HSS-ALB) of CSVD patients were higher than controls. After MLT, all groups displayed significant cystine (CSSC) increases and CSS-ALB decreases, that in pathological groups were significantly higher than controls. These data would confirm the Cys regulatory role on the homocysteinemia; they also explain that the Cys-Hcy mixed disulfide excretion is an important point of hyperhomocysteinemia control. Moreover, in all groups after MLT, significant increases in albumin concentrations, named total albumin (tALB) and measured as sum of HS-ALB (spectrophometric), and XSS-ALB (assayed at HPLC) were observed. tALB increases, more pronounced in healthy than in the pathological subjects, could indicate alterations of albumin equilibria between plasma and other extracellular spaces, whose toxicological consequences deserve further studies.

Neuromodulation refers to invasive, minimally invasive or non-invasive techniques to stimulate discrete cortical or subcortical brain regions with therapeutic purposes in otherwise intractable patients: for example, thousands of advanced Parkinsonian patients, as well as patients with tremor or dystonia, benefited by deep brain stimulation (DBS) procedures (neural targets: basal ganglia nuclei). A new era for DBS is currently opening for patients with drug-resistant depression, obsessive-compulsive disorders, severe epilepsy, migraine and chronic pain (neural targets: basal ganglia and other subcortical nuclei or associative fibres). Vagal nerve stimulation (VNS) has shown clinical benefits in patients with pharmacoresistant epilepsy and depression. Non-invasive brain stimulation neuromodulatory techniques such as repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) are also being increasingly investigated for their therapeutic potential in several neurological and psychiatric disorders. In this review, we first address the most common neural targets of each of the mentioned brain stimulation techniques, and the known mechanisms of their neuromodulatory action on stimulated brain networks. Then, we discuss how DBS, VNS, rTMS and tDCS could impact on the function of brainstem centres controlling vital functions, critically reviewing their acute and long-term effects on brain sympathetic outflow controlling heart function and blood pressure. Finally, as there is clear experimental evidence in animals that brain stimulation can affect autonomic and heart functions, we will try to give a critical perspective on how it may enhance our understanding of the cortical/subcortical mechanisms of autonomic cardiovascular regulation, and also if it might find a place among therapeutic opportunities in patients with otherwise intractable autonomic dysfunctions., (© 2016 The Author(s).)

Background: Multiple Sclerosis (MS) epidemiology in Italy is mainly based on population-based prevalence studies. Administrative data are an additional source of information, when available, in prevalence studies of chronic diseases such as MS. The aim of our study is to update the prevalence rate of MS in Tuscany (central Italy) as at 2011 using a validated case-finding algorithm based on administrative data., Methods: The prevalence was calculated using an algorithm based on the following administrative data: hospital discharge records, drug-dispensing records, disease-specific exemptions from copayment to health care, home and residential long-term care and inhabitant registry. To test algorithm sensitivity, we used a true-positive reference cohort of MS patients from the Tuscan MS register. To test algorithm specificity, we used another cohort of individuals who were presumably not affected by MS., Results: As at December 31, 2011, we identified 6,890 cases (4,738 females and 2,152 males) with a prevalence of 187.9 per 100,000. The sensitivity of algorithm was 98% and the specificity was 99.99%., Conclusions: We found a prevalence higher than the rates present in literature. Our algorithm, based on administrative data, can accurately identify MS patients; moreover, the resulting cohort is suitable to monitor disease care pathways., (© 2015 S. Karger AG, Basel.)

Parkinson's disease (PD) is a major worldwide public health problem with a prevalence that is expected to increase dramatically in the coming decades. Because administrative data are useful for epidemiologic and health service studies, we aimed to define procedural algorithms to identify PD patients (on a regional basis) using these data. We built two a priori algorithms, respecting privacy laws, with increasing theoretical specificity for PD including: (1) a hospital discharge diagnosis of PD; (2) PD-specific exemption; (3) a minimum of two separate prescriptions of an antiparkinsonian drug. The two algorithms differed for drugs included. Sensitivities were tested on an opportunistic sample of 319 PD patients from the databases of 5 regional movement disorders clinics. The estimated prevalence of PD in the sample population from Tuscany was 0.49 % for algorithm 1 and 0.28 % for algorithm 2. Algorithm 1 correctly identified 291 PD patients (sensitivity 91.2 %), and algorithm 2 identified 242 PD patients (sensitivity 75.9 %). We developed two reproducible algorithms demonstrating increasing theoretical specificity with good sensitivity in identifying PD patients based on an evaluation of administrative data. This may represent a low-cost strategy to reliably follow up a large number of PD patients as a whole for evaluating the effects of therapies, disease progression and prevalence.

In ten healthy subjects and in ten patients suffering from Multiple Sclerosis (MS), we investigated the cortical functional changes induced by a standard fatiguing repetitive tapping task. The Cortical Silent Period (CSP), an intracortical, mainly GABAB-mediated inhibitory phenomenon, was recorded by two different hand muscles, one acting as prime mover of the fatiguing index-thumb tapping task (First Dorsal Interosseous, FDI) and the other one not involved in the task but sharing largely overlapping central, spinal, and peripheral innervation (Abductor Digiti Minimi, ADM). At baseline, the CSP was shorter in patients than in controls. As fatigue developed, CSP changes involved both the "fatigued" FDI and the "unfatigued" ADM muscles, suggesting a cortical spread of central fatigue mechanisms. Chronic therapy with amantadine annulled differences in CSP duration between controls and patients, possibly through restoration of more physiological levels of intracortical inhibition in the motor cortex. These inhibitory changes correlated with the improvement of fatigue scales. The CSP may represent a suitable marker of neurophysiological mechanisms accounting for central fatigue generation either in controls or in MS patients, involving corticospinal neural pools supplying not only the fatigued muscle but also adjacent muscles sharing an overlapping cortical representation.

Background: Individual factors in multiple sclerosis (MS) patients may modify the reliability of health-related quality of life (HRQOL) assessment. Knowledge of these effects may enable physicians to identify patients at risk for poor perceived health., Objective: To investigate what individual factors may interact with MS symptoms and their severity to modify the reliability of HRQOL assessment; to explore the predictive values of the significant variables identified., Methods: HRQOL was assessed in 57 patients by the 36-Item Short Form Health Survey (SF-36). The Physical Component Summary and Mental Component Summary were dichotomized and applied as dependent variables for logistic regression analysis. The Functional Independence Measure (FIM), Expanded Disability Status Scale (EDSS), Fatigue Severity Scale (FSS), Cognitive Behavioral Assessment (CBA) and specific individual factors were tested as independent variables. Two-way contingency tables were used to calculate the predictive values., Results: Unemployment, smoking, and night waking were the most significant individual factors. Introversion, physical pain and difficulty falling asleep were also significant. EDSS-total ≥2, EDSS-pyramidal ≥2, FIM ≤123, FSS ≥5, depressive manifestations and bowel/bladder dysfunction were significant MS-related determinants. Sensitivity and specificity differed widely for each variable., Conclusions: Individual factors have relevance in HRQOL assessment. Their identification may help physicians construct the patient's risk profile. Sensitivity and specificity add weight to the significance of variables., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: Repetitive transcranial magnetic stimulation (rTMS) of the motor cortex activates corticospinal neurons mainly through the depolarization of cortico-cortical axons belonging to interneurons of superficial layers., Objective: We used single-fiber electromyography (SFEMG) to estimate the "central jitter" of activation latency of interneural pools from one pulse of TMS to another., Methods: We evaluated 10 healthy subjects and one patient with multiple sclerosis. By recording SFEMG evoked activity from the left first dorsal interosseous (FDI), we first used a standard repetitive electrical 3 Hz stimulation of the ulnar nerve at the wrist to calculate the mean consecutive difference from at least 10 different potentials. The same procedure was applied during 3 Hz repetitive TMS of the contralateral motor cortex. The corticospinal monosynaptic connection of the FDI and the selectivity of SFEMG recording physiologically justified the subtraction of the "peripheral jitter" from the whole cortico-muscular jitter, obtaining an estimation of the actual "central jitter.", Results: All subjects completed the study. The peripheral jitter was 28 μs ± 6 and the cortico-muscular jitter was 344 μs ± 97. The estimated central jitter was 343 ± 97 μs. In the patient the central jitter was 846 μs, a value more than twice the central jitter in healthy subjects., Conclusion: Current results demonstrate that the evaluation of the central component of the cumulative cortico-muscular latency variability in healthy subjects is feasible with a minimally invasive approach. We present and discuss this methodology and provide a "proof of concept" of its potential clinical applicability in a patient with multiple sclerosis., (Copyright © 2014 Elsevier Inc. All rights reserved.)

In hyperhomocysteinemic patients, after reaction with homocysteine-albumin mixed disulfides (HSS-ALB), mesna (MSH) forms the mixed disulfide with Hcy (HSSM) which can be removed by renal clearance, thus reducing the plasma concentration of total homocysteine (tHcy). In order to assess the HSS-ALB dethiolation via thiol exchange reactions, the distribution of redox species of cysteine, cysteinylglycine, homocysteine and glutathione was investigated in the plasma of healthy subjects: (i) in vitro, after addition of 35 μM reduced homocysteine (HSH) to plasma for 72 h, followed by MSH addition (at the concentration range 10-600 μM) for 25 min; (ii) in vivo, after oral treatment with methionine (methionine, 200 mg/kg body weight, observation time 2-6 h). In both experiments the distribution of redox species, but not the total amount of each thiol, was modified by thiol exchange reactions of albumin and cystine, with changes thermodynamically related to the pKa values of thiols in the corresponding mixed disulfides. MSH provoked a dose-response reversal of the redox state of aged plasma, and the thiol action was confirmed by in vivo experiments. Since it was observed that the dimesna production could be detrimental for the in vivo optimization of HSSM formation, we assume that the best plasma tHcy lowering can be obtained at MSH doses producing the minimum dimesna concentration in each individual.

Similarly to subjects with degenerative parkinsonism, (123)I-FP-CIT SPECT has been reported either normal or abnormal in patients with drug-induced parkinsonism (DIP), challenging the notion that parkinsonism might be entirely due to post-synaptic D2-receptors blockade by antipsychotic drugs. In a previous multicenter cross-sectional study conducted on a large sample of patients with schizophrenia, we identified 97 patients who developed parkinsonism with a similar bi-modal distribution of DAT-SPECT. In this longitudinal study, we reported clinical and imaging features associated with progression of motor disability over 2-year follow-up in 60 out of those 97 patients with schizophrenia and parkinsonism who underwent (123)I-FP-CIT SPECT at baseline evaluation (normal SPECT=33; abnormal SPECT=27). As second end-point, chronic response to levodopa over a 3-month period was tested in a subgroup of subjects. Motor Unified Parkinson's Disease Rating Scale (UPDRS) at follow-up significantly increased in patients with abnormal SPECT. Specifically, a 6-point worsening was demonstrated in 18.5% of the subjects with abnormal SPECT and in none of the subjects with normal SPECT. Levodopa treatment improved motor UPDRS only in the group with abnormal SPECT. After adjustment for possible confounders, linear regression analysis demonstrated that abnormal SPECT findings at baseline were the only predictor of motor disability progression and of better outcome of levodopa treatment. Our results support the notion that a degenerative disease might underlie parkinsonism in a minority of schizophrenic patients chronically exposed to antipsychotics. Functional imaging of the dopamine transporter can be helpful to select this patient sub-group that might benefit from levodopa therapy., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Event-related repetitive transcranial magnetic stimulation (rTMS) can dynamically interfere with the memory encoding of complex visual scenes. Here, we investigated the critical time elapsing from stimulus presentation to the formation of an effective memory trace by delivering rTMS (900 ms at 20 Hz) during the encoding of visual scenes at different poststimulus delays (from 100 to 500 ms) in 28 healthy volunteers. The stimulation delay showed a robust inverse correlation with the correct retrieval of encoded images. In particular, rTMS stimulation delivered with a delay of 500 ms and lasting for 400 ms after stimulus offset resulted in a huge drop in retrieval accuracy. Such a timing suggests that rTMS affects the formation of long-term memory through interference with postperceptual executive processes, rather than with perceptual analysis of the stimuli. The effect was specific for stimulation of the left dorsolateral prefrontal cortex (DLPFC), whereas rTMS applied to the right DLPFC, vertex (active control site), as well as sham stimulation (placebo) did not affect accuracy. These results confirm the crucial role of the left DLPFC in encoding and provide novel information about the critical timing of its engagement in the formation, consolidation, and maintenance of the memory trace.

Background: Internal Jugular Veins (IJVs) are the principle outflow pathway for intracranial blood in clinostatism condition. In the seated position, IJVs collapse, while Vertebral Veins (VVs) increase the venous outflow and partially compensate the venous drainage. Spinal Epidural Veins are an additional drainage pathway in the seated position. Colour- Doppler-Sonography (CDS) examination is able to demonstrate IJVs and VVs outflow in different postural and respiratory conditions. The purpose of this study was to evaluate CDS quantification of the cerebral venous outflow (CVF) in healthy subjects and patients with multiple sclerosis (MS)., Methodology/principal Findings: In a group of 27 healthy adults (13 females and 14 males; mean age 37.8 ± 11.2 years), and 52 patients with MS (32 females and 20 males; mean age 42.6 ± 12.1 years), CVF has been measured in clinostatism and in the seated position as the sum of the flow in IJVs and VVs. The difference between CVF in clinostatism and CVF in the seated position (ΔCVF) has been correlated with patients' status (healthy or MS), and a number of clinical variables in MS patients. Statistical analysis was performed by Fisher's exact test, non-parametric Mann-Whitney U test, ANOVA Kruskal-Wallis test, and correntropy coefficient. The value of ΔCVF was negative in 59.6% of patients with MS and positive in 96.3% of healthy subjects. Negative ΔCVF values were significantly associated with MS (p<0.0001). There was no significant correlation with clinical variables., Conclusions/significance: Negative ΔCVF has a hemodynamic significance, since it reflects an increased venous return in the seated position. This seems to be a pathologic condition. In MS patients, a vascular dysregulation resulting from involvement of the autonomous nervous system may be supposed. ΔCVF value should be included in the quantitative CDS evaluation of the cerebral venous drainage, in order to identify cerebral venous return abnormalities.

Increases in plasma concentrations of total homocysteine (tHcy) have recently been reported in multiple sclerosis (MS) as the alteration of the methionine cycle for the onset of autoimmune diseases. Homocysteine (Hcy) and cysteine (Cys) are generated by the methionine cycle and transsulfuration reactions. Their plasma levels are subjected to complex redox changes by oxidation and thiol/disulfide (SH/SS) exchange reactions regulated by albumin. The methionine loading test (MLT) is a useful in vivo test to assay the functionality of the methionine cycle and transsulfuration reactions. Time courses of redox species of Cys, cysteinylglycine (CGly), Hcy, and glutathione have been investigated in plasma of MS patients versus healthy subjects after an overnight fasting, and 2, 4, and 6 h after an oral MLT (100 mg/kg body weight), to detect possible dysfunctions of the methionine cycle, transsulfuration reactions and alterations in plasma distribution of redox species. After fasting, the MS group showed a significant increase in cysteine-protein mixed disulfides (bCys) and total Cys (tCys). While plasma bCys and tCys in MS group remained elevated after methionine administration when compared to control, cystine (oxCys) increased significantly with respect to control. Although increased plasma concentrations of bCys and tCys at fasting might reflect an enhance of transsulfuration reactions in MS patients, this was not confirmed by the analysis of redox changes of thiols and total thiols after MLT. This study has also demonstrated that albumin-dependent SH/SS exchange reactions are a potent regulation system of thiol redox species in plasma.

A number of cortical and spinal excitability variables have been tested in a patient with Stiff Person Syndrome (SPS), before and after immunotherapy with mycophenolate mofetil, intravenous immunoglobulin and corticosteroids, which normalized plasma levels of anti-GAD antibodies and dramatically improved the clinical picture. The overlapping time-course of neurophysiological, clinical and bio-umoral findings suggests that immunotherapy might have changed GABA/Glutamate balance at cortical level, favoring the former, as reflected by normalization of the startle reflex, lengthening of the cortical silent period and clear-cut reduction of intracortical facilitation to paired-pulse transcranial magnetic stimulation. This represents the first report investigating effects of immunotherapy on cortical excitability in SPS.

Background: The investigation of a wide set of transcranial magnetic stimulation (TMS)-related variables in both hemispheres might help to identify a pattern of cortical excitability changes in posttraumatic stress disorder (PTSD) patients, reflecting gamma-amino-butiric acid (GABA)/glutamate balance and dysfunction, and to determine whether some of these variables are related to clinical features., Methods: In 20 drug-naive PTSD patients without comorbidity and 16 matched healthy control subjects we tested bilaterally with standard TMS procedures: resting motor threshold (RMT) to single-pulse TMS (reflecting ion channel function), paired-pulse short-latency intracortical inhibition (SICI; mainly reflecting GABA(A) function) and intracortical facilitation (ICF; mainly reflecting glutamatergic function), single-pulse cortical silent period (CSP; mainly reflecting GABA(B)-ergic function), and paired-pulse short-latency afferent inhibition (SAI; reflecting cholinergic mechanisms and their presynaptic GABA(A)-mediated modulation)., Results: The PTSD patients showed widespread impairment of GABA(A)-ergic SICI, which was reversed toward facilitation in both hemispheres in one-half of the patients, marked increase of glutamatergic ICF in the right hemisphere, and right-sided impairment of SAI. Illness duration and avoidance symptoms but not anxiety correlated with right-lateralized dysfunctions of cortical excitability., Conclusions: Although the neurobiological complexity of each TMS variable makes current results theoretical, the pattern of cortical excitability accompanying PTSD symptoms suggests a bilateral decrease of the GABA(A)-ergic function. This prevails in the right hemisphere, in association with a relative prevalence of the glutamatergic tone, a new finding that current neuroimaging investigations cannot provide due to the lack of reliable glutamate tracers. Results might help to disclose new pathophysiological aspects of PTSD symptoms, providing a rationale for future neuromodulatory strategies of treatment.