Grey Matter Atrophy and its Relationship with White Matter Lesions in Patients with Myelin Oligodendrocyte Glycoprotein Antibody-associated Disease, Aquaporin-4 Antibody-Positive Neuromyelitis Optica Spectrum Disorder, and Multiple Sclerosis.

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 cm3); AQP4+NMOSD in the occipital cortex (32.83 cm3); and RRMS diffusely in the GM (260.61 cm3). MOGAD showed more pronounced temporal cortex atrophy than RRMS (6.71 cm3), whereas AQP4+NMOSD displayed greater occipital cortex atrophy than RRMS (19.82 cm3). RRMS demonstrated more pronounced deep GM atrophy in comparison with MOGAD (27.90 cm3) and AQP4+NMOSD (47.04 cm3). 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.

The role of ethnicity and native-country income in multiple sclerosis: the Italian multicentre study (MS-MigIT).

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.

Krebs von den Lungen-6 (KL-6) in cerebrospinal fluid from neurosarcoidosis patients.

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.

Data monitoring roadmap. The experience of the Italian Multiple Sclerosis and Related Disorders Register.

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.

Antibody response elicited by the SARS-CoV-2 vaccine booster in patients with multiple sclerosis: Who gains from it?

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.

Clinical and MRI measures to identify non-acute MOG-antibody disease in adults.

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.

Does Risk of Hyperhomocysteinemia Depend on Thiol-Disulfide Exchange Reactions of Albumin and Homocysteine?

Significance: Increased plasma concentrations of total homocysteine (tHcy; mild-moderate hyperhomocysteinemia: 15-50 µM 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.

Prevalence of chronic comorbidities in people with multiple sclerosis: descriptive study based on administrative data in Tuscany (Central Italy).

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.

Breakthrough SARS-CoV-2 infections in MS patients on disease-modifying therapies.

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.

Breakthrough SARS-CoV-2 infections after COVID-19 mRNA vaccination in MS patients on disease modifying therapies during the Delta and the Omicron waves in Italy.

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.

Mortality of Parkinson's disease in Italy from 1980 to 2015.

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.

Effect of SARS-CoV-2 mRNA vaccination in MS patients treated with disease modifying therapies.

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'.

Emerging of new bioartificial corticospinal motor synergies using a robotic additional thumb.

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.

Feasibility of TMS in patients with new generation cochlear implants.

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.

Prevalence and impact of COVID-19 in Parkinson's disease: evidence from a multi-center survey in Tuscany region.

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.

Wearable haptic anklets for gait and freezing improvement in Parkinson's disease: a proof-of-concept study.

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.

Mortality trend for multiple sclerosis in Italy during the period 1980-2015.

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.

Association of celiac disease in patients with multiple sclerosis in Tuscany.

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).

Increasing prevalence of multiple sclerosis in Tuscany, Italy.

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.

Cross-Modal Audiovisual Modulation of Corticospinal Motor Synergies in Professional Piano Players: A TMS Study during Motor Imagery.

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.