Simultaneous quantification of natural and inducible regulatory T-cell subsets during interferon-ß therapy of multiple sclerosis patients.

BACKGROUND: The mechanisms underlying the therapeutic activity of interferon-ß in multiple sclerosis are still not completely understood. In the present study, we evaluated the short and long-term effects of interferon-ß treatment on different subsets of regulatory T cells in relapsing-remitting multiple sclerosis patients biologically responsive to treatment because of mixovirus resistance protein A inducibility. METHODS: In this prospective longitudinal study, subsets of natural regulatory T cells (naïve, central memory and effector memory) and inducible regulatory T cells (Tr1), as well as in vitro-induced regulatory T cells (Tr1-like cells), were simultaneously quantified by flow cytometry in samples prepared from 148 therapy-naïve multiple sclerosis patients obtained before and after 6, 12, 18, and 24 months of interferon-ß-1a treatment. mRNA for interleukin-10 and Tr1-related genes (CD18, CD49b, and CD46, together with Cyt-1 and Cyt-2 CD46-associated isoforms) were quantified in Tr1-like cells. RESULTS: Despite profound inter-individual variations in the modulation of all regulatory T-cell subsets, the percentage of natural regulatory T cells increased after 6, 12, and 24 months of interferon-ß treatment. This increase was characterized by the expansion of central and effector memory regulatory T-cell subsets. The percentage of Tr1 significantly enhanced at 12 months of therapy and continued to be high at the subsequent evaluation points. Patients experiencing relapses displayed a higher percentage of naïve regulatory T cells and a lower percentage of central memory regulatory T cells and of Tr1 before starting interferon-ß therapy. In addition, an increase over time of central memory and of Tr1 was observed only in patients with stable disease. However, in vitro-induced Tr1-like cells, prepared from patients treated for 24 months, produced less amount of interleukin-10 mRNA compared with pre-treatment Tr1-like cells. CONCLUSION: Interferon-ß induces the expansion of T regulatory subsets endowed with a high suppressive activity, especially in clinically stable patients. The overall concurrent modulation of natural and inducible regulatory T-cell subsets might explain the therapeutic effects of interferon-ß in multiple sclerosis patients.

Non-amnestic mild cognitive impairment and sleep complaints: a bidirectional relationship?

BACKGROUND: Prior studies documented that several sleep disorders may coexist in patients affected by Mild Cognitive Impairment (MCI) and Alzheimer disease (AD), and have a strong bidirectional relationship with cognitive decline. AIM: To assess the self-reported sleep quality and daytime sleepiness among subjects affected by MCI and AD at early-stage and healthy controls, and to verify if sleep disturbances might be an indicator of specific cognitive deficits. METHODS: 139 patients (102 MCI, 37 AD) underwent comprehensive neuropsychological, functional, and behavioral assessment, which also included Epworth Sleepiness Scale (ESS) and Pittsburgh Sleep Quality Index (PSQI). 80 healthy elderly subjects were used as controls. MCI patients have been divided into Good Sleepers and Bad Sleepers, depending on their reported sleep quality (PSQI global score ≤5/>5). RESULTS: MCI patients experienced more subjective daytime sleepiness than AD matches. As for the subjective sleep quality among MCI patients, 54% of Bad Sleepers met diagnostic criteria for non-amnestic MCI; vice-versa, 73% of Good Sleepers were diagnosed with amnestic-MCI (p = 0.005), independently of depression and anxiety. CONCLUSIONS: MCI patients complain of daytime sleepiness and dysfunction more than AD patients; among MCI patients, Bad Sleepers appear mainly characterized by a non-amnestic cognitive profile.

Unprescribed cannabinoids and multiple sclerosis: a multicenter, cross-sectional, epidemiological study in Lombardy, Italy.

INTRODUCTION: Cannabinoids are approved for spasticity and pain in multiple sclerosis (MS). In 2017 the prevalence of current users in the Italian general population was 10.2%, while data on Italian MS patients are limited. METHODS: From March 2022 to February 2023, we conducted a multicenter, cross-sectional study. Adult MS patients completed an anonymous online survey. The primary outcome was the estimated prevalence of unprescribed cannabis current use. Cannabis use patterns and associations with clinical and socio-demographical variables were investigated. The binomial method was used to estimate 95% confidence interval (95% CI) for primary outcome. RESULTS: 5620 patients were invited and 2024 (36.0%) were included (mean age 45.2 years, females 64.5%). Relapsing remitting form was the most frequent (77.3%). Median expanded disability status scale (EDSS) was 2.0. The proportion of current users was 15.5% (95% CI 13.9-17.1) and 36.4% of them disclosed to their physician their unprescribed cannabis use. 15.0% patients were former users while 69.5% never used cannabis. Current users more frequently reported a medical use (i.e., current medical users) compared to former users (p < 0.001). 41.1% of never users would use cannabis if it was legal. Young age, being male, and a free marital status were associated with current use. Current medical users had higher disability, spasticity and pain, reduced quality of life, concomitant neurological/psychiatric drugs and analgesics use. Unprescribed cannabis appeared relatively safe, with limited addiction risk, and reported clinical benefits, including concomitant medications reduction. CONCLUSION: Unprescribed cannabis use is common in patients with MS in Italy, with observed prevalence seemingly superior to the general population, often intended for medical use and without the disclosure to the treating physician, although with potential clinical benefits.

Patients with multiple sclerosis choose a collaborative role in making treatment decision: results from the Italian multicenter SWITCH study.

BACKGROUND: Clinicians are increasingly recognizing the importance of shared decision-making in complex treatment choices, highlighting the importance of the patient's rationale and motivation for switching therapies. This study aimed to evaluate the association between different modalities of changing multiple sclerosis (MS) treatments, cognitive profile and attitude and preferences of patients concerning treatment choice. METHODS: This multicenter cross-sectional study was conducted at 28 Italian MS centers in the period between June 2016 and June 2017. We screened all MS patients treated with any DMT, with a treatment compliance of at least 80% of therapy administered during the 3 last months who needed to modify MS therapy because of efficacy, safety or other reasons during a follow-up visit. At the time of switching the symbol digit modalities test (SDMT) and the Control Preference Scale (CPS) were evaluated. According to the CPS, patients were classified as "active" (i.e. who prefer making the medical decision themselves), "collaborative" (i.e. who prefer decisions be made jointly with the physician), or "passive" (i.e. who prefer the physician make the decision). RESULTS: Out of 13,657 patients recorded in the log, 409 (3%) changed therapy. Of these, 336 (2.5%) patients, 69.6% were female and with mean age 40.6 ± 10.5 years, were enrolled. According to the CPS score evaluation, a significant high percentage of patients (51.1%) were considered collaborative, 74 patients (22.5%) were passive, and 60 (18.2%) patients were active. Stratifying according to CPS results, we found a higher SDMT score among collaborative patients compared to active and passive ones (45.8 ± 12.3 versus 41.0 ± 13.2 versus 41.7 ± 12.8, p < 0.05). CONCLUSION: In this study, the CPS evaluation showed that more than 50% of patients who needed to change therapy chose a "collaborative" role in making treatment decision. Cognitive profile with SDMT seems to correlate with patients' preference on treatment decision, showing better scores in collaborative patients.

Neurologic manifestations in 1760 COVID-19 patients admitted to Papa Giovanni XXIII Hospital, Bergamo, Italy.

OBJECTIVES: Evidences from either small series or spontaneous reporting are accumulating that SARS-CoV-2 involves the Nervous Systems. The aim of this study is to provide an extensive overview on the major neurological complications in a large cohort of COVID-19 patients. METHODS: Retrospective, observational analysis on all COVID-19 patients admitted from February 23rd to April 30th, 2020 to ASST Papa Giovanni XXIII, Bergamo, Italy for whom a neurological consultation/neurophysiological assessment/neuroradiologic investigation was requested. Each identified neurologic complication was then classified into main neurologic categories. RESULTS: Of 1760 COVID-19 patients, 137 presented neurologic manifestations that manifested after COVID-19 symptoms in 98 pts and was the presenting symptom in 39. Neurological manifestations were classified as: (a) cerebrovascular disease [53 pts (38.7%)] including 37 ischemic and 11 haemorrhagic strokes, 4 transient ischemic attacks, 1 cerebral venous thrombosis; (b) peripheral nervous system diseases [31 (22.6%)] including 17 Guillain-Barrè syndromes; (c) altered mental status [49 (35.8%)] including one necrotizing encephalitis and 2 cases with RT-PCR detection of SARS-Cov-2 RNA in CSF; (d) miscellaneous disorders, among whom 2 patients with myelopathy associated with Ab anti-SARS-CoV-2 in CSF. Patients with peripheral nervous system involvement had more frequently severe ARDS compared to patients with cerebrovascular disease (87.1% vs 42%; difference = 45.1% 95% CI 42.0-48.2; χ2= 14.306; p < 0.0002) and with altered mental status (87.1% vs 55.6%; difference = 31.5% 95% CI 27.5-37.5%; χ2= 7.055; p < 0.01). CONCLUSION: This study confirms that involvement of nervous system is common in SARS-CoV-2 infection and offers clinicians useful information for prevention and prompt identification in order to set the adequate therapeutic strategies.

Clinical and patient determinants of changing therapy in relapsing-remitting multiple sclerosis (SWITCH study).

BACKGROUND: clinical factors and frequency of disease-modifying therapy (DMT) changes/interruptions in relapsing-remitting multiple sclerosis (RRMS) patients have not been well defined. The aim of this study was to describe reasons of MS treatment modifications in a large cohort of Italian MS patients. METHODS: this multicenter, cross-sectional non interventional study (SWITCH) conducted at 28 Italian MS centers, screened, by visit/telephone contact between June 2016 and June 2017, all RRMS patients receiving stable DMT treatment and enrolled patients with change in DMT treatment. RESULTS: out of 13,657 recorded in the log, 409 (3%) changed therapy. Of these, 336 (2.5%), met the study criteria and were considered eligible. Among 303 (90.2% of 336) patients switching, the most common reason was "lack of efficacy" (58.4% of 303). Among 30 (8.9%) patients who interrupted treatment temporarily, the most common reason was pregnancy (40.0% of 30). Out of 3 (0.9%) patients who discontinued treatment permanently, 2 (66.7%) had as first reason as "patient decision". Multivariate analysis showed that EDSS was the only variable with statistically significant effect on changing treatments (r = 8.33; p-value of Type III Sum of Squares = 0.016). CONCLUSION: in our study, 303 (90.2% of eligible patients) switched treatment, 30 (8.9%) interrupted treatment temporarily, and 3 (0.9%) discontinued treatment permanently. Efficacy remains the main driving force behind switching behavior, as the primary aim of treatment is to be disease free or reduce disease activity.

Erythroblastaemia in natalizumab-treated patients with multiple sclerosis.

BACKGROUND: Natalizumab is a monoclonal antibody that significantly reduces the occurrence of relapses in relapse-remitting multiple sclerosis (RRMS) patients. Early papers on the clinical use of natalizumab in RRMS patients reported erythroblastemia as occasional and transient. OBJECTIVES: to determine the prevalence and absolute count of erythroblasts (nucleated red blood cells, NRBCs) in peripheral blood of RRMS patients in different treatment groups and healthy controls from the same geographic area using the same equipment for laboratory analysis. METHODS: We retrospectively evaluated the samples of 203 consecutive RRMS patients including 26 subjects on natalizumab, 17 on fingolimod, 72 on interferon, 41 on glatiramer acetate, 47 treatment-naïve and 240 healthy controls from the same geographic area. Blood samples were processed using an XN-9000-Hematology Analyzer and subsequent microscopic verification. In the natalizumab-treated patients we performed an additional analysis in order to detect the expression of CD34+ cells in peripheral blood, as confirmation of a bone marrow mobilization. RESULTS: The prevalence of patients with NRBCs positivity was significantly higher in natalizumab-treated patients (92%) compared with the other treatment groups and healthy controls (0%) (p<0.0005). The median absolute NRBCs count was significantly higher in natalizumab-treated patients (median 0.020, p<0.0005) than in the other treatment groups and healthy controls. Natalizumab-treated patients also had higher levels of white blood cells than all other groups and lower haemoglobin levels than healthy subjects (p<0.01), but no morphologic alterations were evident at a subsequent review of red blood cells, platelets and white blood cells. CD34+ cells levels were consistent with mobilization of haematopoietic stem cells from the bone marrow (median 8 cells/µL, IQR 5-12). CONCLUSIONS: We confirm erythroblastaemia as a frequent finding of natalizumab treatment in RRMS patients. More extended knowledge and adequate long-term observation of this phenomenon are essential to better understand any pathological implication.

Assessment of the Incremental Diagnostic Value of Florbetapir F 18 Imaging in Patients With Cognitive Impairment: The Incremental Diagnostic Value of Amyloid PET With [18F]-Florbetapir (INDIA-FBP) Study.

IMPORTANCE: Cerebral amyloidosis is a key abnormality in Alzheimer disease (AD) and can be detected in vivo with positron emission tomography (PET) ligands. Although amyloid PET has clearly demonstrated analytical validity, its clinical utility is debated. OBJECTIVE: To evaluate the incremental diagnostic value of amyloid PET with florbetapir F 18 in addition to the routine clinical diagnostic assessment of patients evaluated for cognitive impairment. DESIGN, SETTING, AND PARTICIPANTS: The Incremental Diagnostic Value of Amyloid PET With [18F]-Florbetapir (INDIA-FBP) Study is a multicenter study involving 18 AD evaluation units from eastern Lombardy, Northern Italy, 228 consecutive adults with cognitive impairment were evaluated for AD and other causes of cognitive decline, with a prescan diagnostic confidence of AD between 15% and 85%. Participants underwent routine clinical and instrumental diagnostic assessment. A prescan diagnosis was made, diagnostic confidence was estimated, and drug treatment was provided. At the time of this workup, an amyloid PET/computed tomographic scan was performed, and the result was communicated to physicians after workup completion. Physicians were asked to review the diagnosis, diagnostic confidence, and treatment after the scan. The study was conducted from August 5, 2013, to December 31, 2014. MAIN OUTCOMES AND MEASURES: Primary outcomes were prescan to postscan changes of diagnosis, diagnostic confidence, and treatment. RESULTS: Of the 228 participants, 107 (46%) were male; mean (SD) age was 70.5 (7) years. Diagnostic change occurred in 46 patients (79%) having both a previous diagnosis of AD and an amyloid-negative scan (P < .001) and in 16 (53%) of those with non-AD diagnoses and an amyloid-positive scan (P < .001). Diagnostic confidence in AD diagnosis increased by 15.2% in amyloid-positive (P < .001; effect size Cohen d = 1.04) and decreased by 29.9% in amyloid-negative (P < .001; d = -1.19) scans. Acetylcholinesterase inhibitors and memantine hydrochloride were introduced in 61 (65.6%) patients with positive scan results who had not previously received those drugs, and the use of the drugs was discontinued in 6 (33.3%) patients with negative scan results who were receiving those drugs (P < .001). CONCLUSIONS AND RELEVANCE: Amyloid PET in addition to routine assessment in patients with cognitive impairment has a significant effect on diagnosis, diagnostic confidence, and drug treatment. The effect on health outcomes, such as morbidity and mortality, remains to be assessed.

Glatiramer acetate-induced hepatitis in a young female patient with multiple sclerosis.

We report the first Italian case of glatiramer acetate-related acute hepatotoxicity. A 25-years-old woman suffering from multiple sclerosis presented acute hepatitis after eight months of treatment. Neither infective, nor autoimmune markers were detected. Liver biopsy histology was consistent with drug-induced acute injury. Liver function tests became normal after eight weeks of treatment discontinuation. This report points out the importance of monitoring liver function during the first year of treatment with glatiramer acetate.

Odor identification deficit predicts clinical conversion from mild cognitive impairment to dementia due to Alzheimer's disease.

The aim of this study was to analyze the relationship between olfactory and cognitive functions in subjects affected by mild cognitive impairment (MCI) and to investigate whether olfactory deficits might reflect the likelihood of conversion from MCI to dementia. In this longitudinal study conducted on a sample of MCI outpatients, CA-SIT Smell Identification Test was administered to 88 MCI subjects and 46 healthy control subjects. MCI subjects have been divided into two groups, considering smell identification performances: 40% had normal performances (MCI olfactory-normal), whereas 60% had a moderate olfaction deficit (MCI olfactory-impaired). At 2-year follow-up, the 47% of MCI olfactory-impaired subjects and the 11% of MCI olfactory-normal subjects progressed to dementia. In a logistic regression model, a lower score in MMSE (95%, OR 1.9; IC 1.23-3.01; p = .004) and a pathological smell identification at baseline (95%, OR 5.1; IC 1.16-22.6; p = .03) were independently associated with the progression to dementia within 2 years. This study confirms that smell identification testing may be useful in high-risk settings to identify patients at risk for developing dementia.