The cerebrospinal fluid (CSF)/serum quotient of albumin (QAlb) is the most used biomarker for the evaluation of blood-cerebrospinal fluid barrier (B-CSF-B) permeability. For years QAlb was considered ...only as an age-related parameter but recently it has also been associated to sex. The aim of the present study was to explore the impact of sex in the determination of B-CSF-B dysfunction.
The analysis was retrospectively conducted on subjects consecutively admitted to the neurological ward. CSF and serum albumin levels were measured by immunonephelometry and pathological QAlb thresholds were considered: 6.5 under 40 years, 8.0 in the age 40-60 and 9.0 over 60 years.
1209 subjects were included in the study. 718 females and 491 males (age: 15-88 years): 24.6% of patients had a diagnosis of multiple sclerosis, 23.2% suffered from other inflammatory neurological diseases, 24.6% were affected by non-inflammatory neurological diseases, and for 27.6% of patients the final neurological diagnosis could not be traced. Dysfunctional B-CSF-B was detected more frequently (44 vs. 20.1%, p < 0.0001) and median QAlb value were higher (7.18 vs. 4.87, p < 0.0001) in males than in females in the overall study population and in all disease subgroups. QAlb and age were positively correlated both in female (p < 0.0001) and male (p < 0.0001) patients, however the slopes of the two regression lines were not significantly different (p = 0.7149), while the difference between the elevations was extremely significant (p < 0.0001) with a gap of 2.2 units between the two sexes. Finally, in a multivariable linear regression analysis increased age and male sex were independently associated with higher QAlb in the overall study population (both p < 0.001) and after stratification by age and disease group.
Accordingly, identification and validation of sex-targeted QAlb thresholds should be considered as a novel tool in an effort to achieve more precision in the medical approach.
Objectives:
The aim of this study was to characterize multiple sclerosis (MS) patients exposed to dimethyl fumarate (DMF) and to evaluate the predictors of therapeutic response. In addition, the ...study offers a picture of how DMF use has changed over the past few years in naive or switcher patients.
Methods:
In this observational monocentric study, we examined the prescription flow of DMF in MS patients categorized as naive or switchers (for safety/tolerability, ineffectiveness, and de-escalation strategy) from 2015 to 2019. Clinical and magnetic resonance imaging data of DMF-treated patients were analyzed, and NEDA-3 status at 24 months was evaluated by the three assessment components (absence of clinical relapses, no Expanded Disability Status Scale progression, no radiological activity). Determinants of therapeutic response were also evaluated using regression analysis.
Results:
The sample included 595 MS patients exposed to DMF categorized as naive (158; 26.5%) and switchers for reasons of safety/tolerability (198; 33.3%), inefficacy (175; 29.4%), and de-escalation strategy (64; 10.8%). A 15% increase in DMF use in naive and horizontal shift groups was observed in the last 3 years of observation, whereas there was a drop, with prescription passed from ~20% to <5%, as an exit strategy from second-line therapies. NEDA-3 status was calculated for 340 patients after 24 months of DMF treatment and achieved in 188 (55.3%) of these. Analyzing the predictors of DMF response, we observed that lower annualized relapse rate (ARR) in 2 years pretreatment hazard ratio (HR) = 0.49,
p
= 0.001 and being naive patients (HR = 1.38,
p
= 0.035) were associated with achievement of NEDA-3. Analogously, ARR in 2 years pretreatment affected the NEDA-3 achievement at 24 months in patients of the de-escalation group (HR = 0.07,
p
= 0.041), also indicating an effect related to the DMF initiation within 3 months (HR = 1.24,
p
= 0.029).
Conclusion:
Our findings confirm DMF as a handy drug with broad clinical utility, with greater benefits for naive patients and horizontal switchers. Additionally, an increase in the flow of DMF prescriptions in these two groups of patients was also observed in our cohort.
Monitoring immune responses to SARS-CoV-2 vaccination and its clinical efficacy over time in Multiple Sclerosis (MS) patients treated with disease-modifying therapies (DMTs) help to establish the ...optimal strategies to ensure adequate COVID-19 protection without compromising disease control offered by DMTs. Following our previous observations on the humoral response one month after two doses of BNT162b2 vaccine (T1) in MS patients differently treated, here we present a cross-sectional and longitudinal follow-up analysis six months following vaccination (T2, n=662) and one month following the first booster (T3, n=185). Consistent with results at T1, humoral responses were decreased in MS patients treated with fingolimod and anti-CD20 therapies compared with untreated patients also at the time points considered here (T2 and T3). Interestingly, a strong upregulation one month after the booster was observed in patients under every DMTs analyzed, including those treated with fingolimod and anti-CD20 therapies. Although patients taking these latter therapies had a higher rate of COVID-19 infection five months after the first booster, only mild symptoms that did not require hospitalization were reported for all the DMTs analyzed here. Based on these findings we anticipate that additional vaccine booster shots will likely further improve immune responses and COVID-19 protection in MS patients treated with any DMT.
Background
The etiology of pediatric-onset multiple sclerosis is unknown although putative genetic and environmental factors appear to be involved. Among children multiple sclerosis onset occurs ...closer to the susceptibility window thank in adults and the exposure to etiological environmental factors is more informative. An Italian multicentre case-control study (the PEDiatric Italian Genetic and enviRonment ExposurE, PEDIGREE study) was designed to investigate environmental exposures in pediatric-onset multiple sclerosis and their interaction with genetics.
Objectives
To collect evidence on exposures to environmental risk factors in pediatric-onset multiple sclerosis, a questionnaire was developed for the Italian population (PEDIGREE Questionnaire) and is presented.
Methods
PEDIGREE Questionnaire develops from an existing tool used in case-control studies on pediatric-onset multiple sclerosis in US Americans, and was translated, adapted and tested for the contents perceived relevance, acceptability, feasibility and reliability in a population of Italian pediatric subjects and their parents recruited from clinics and general population.
Results
PEDIGREE Questionnaire contents were overall deemed relevant by the study population, acceptable for 100% participants and feasible for at least 98%. PEDIGREE Questionnaire degree of reliability ranged 56% to 72%.
Conclusion
PEDIGREE Questionnaire proves to be an efficient tool to assess environmental exposures in the Italian pediatric population. We encourage the dissemination of population-specific questionnaires and shared methodology to optimize efforts in MS etiological research.
Introduction
While the determinants influencing self-perceived health-related quality of life (spHRQoL) in persons with multiple sclerosis (pwMS) and severe physical impairment have been well ...investigated, their impact on pwMS with mild disability is poorly addressed. We aimed to investigate possible drivers of spHRQoL among Sardinian pwMS with an EDSS lower than 2.5.
Methods
A sample of 87 fully ambulatory (EDSS < 2.5) pwMS were included after screening for major cognitive impairment. spHRQoL was measured with the Italian version of 36-Item Short Form Health Survey (SF-36). The Physical Component Summary (PCS) and Mental Component Summary (MCS) were used as dependent variables for univariate analysis with Cognitive Behavioral Assessment (CBA) and specific individual factors as independent variables. Subsequent multivariate general linear models (GLMs) for PCS and MCS respectively were run after stepwise regression. Normative data referring to Italian population were used for comparison.
Results
As compared to normative data, no statistically significant difference was found for PCS, while MCS was reduced. Multivariate GLMs showed a significant association between lower PCS scores and presence of psychosomatic symptoms, older age and fatigue (
p
< 0.05). Furthermore, a significant association was shown between lower MCS scores and presence of anxiety (
p
< 0.001).
Conclusion
Mood, presence of psychosomatic symptoms, fatigue and age can have a relevant impact on spHRQoL in people with mildly disabling MS and should be considered in the management of such individuals.
•Disease-modifying therapies (DMTs) exert an effect on the gut microenvironment.•Defining the effects of DMTs on microbiota is difficult due to several confounding factors.•This review summarizes ...recent evidence on the gut microbiome changes during DMTs exposition.
Growing evidence has suggested the involvement of gut microbiota in the pathophysiology of multiple sclerosis (MS). Disease-modifying therapies (DMTs) exert a parallel effect on the gut microenvironment with subsequent modulation of the intestinal and systemic immune system. Herein, we summarize the current literature on the effect of DMTs on the gut microbiome and possible implications for MS.
All the literature available in PubMed on the effects of DMTs on the gut microbiota composition in patients with MS was reviewed. We used multiple combinations of the following keywords: “multiple sclerosis; demyelinating disease; gut microbiome; microbiome; brain-gut axis; diet; fecal microbiome; disease modifying therapy; immunomodulator; interferon; glatiramer acetate; teriflunomide; dimethyl fumarate; natalizumab; alemtuzumab; anti-CD20; fingolimod”. All the original research articles available in English were included in this narrative review.
Ten original full-text articles were considered eligible, including seven case-control and three cohort studies. First-line DMTs, including oral and subcutaneous treatments (dimethyl fumarate, glatiramer acetate, and interferon β 1b) were considered, while a small number of patients with MS were under natalizumab, fingolimod and anti-CD20 treatments.
Emerging evidence reported changes in the gut microbiome during exposition to DMTs. However, the association between DMTs exposure and microbial changes was mostly indirect, and the results of the different studies needed to be more consistent. The mitigation of methodological bias is necessary for future studies to allow the identification of a “microbial signature” related to MS pathophysiology, the role of DMTs, and possible prognostic implications.
Background
Common genes implicated in amyotrophic lateral sclerosis (ALS) development may also influence its progression rate. The C9orf72 mutations featured a faster progression rate while the ...European SOD1 mutations were associated with a slower progression. In this study, we assessed the relationship between TARDBP and ALS progression/survival.
Methods
ALS incident patients (2010–2019) were diagnosed by El Escorial revised criteria and staged over the disease course by the King’s staging system. Disease progression was analysed by Kaplan–Meier survival curves and Cox regression models, with survival measured from symptom onset to death/tracheostomy or censor date.
Results
The study population included 76 patients carrying TARDBP mutations (A382T/G295S), 28 patients carrying the C9orf72 GGGGCC expansion, and 158 patients who had no evidence of causative genetic mutations (nmALS group). TARDBP patients reached death/tracheostomy later than C9orf72 and nmALS patients, independently of possible prognostic indicators (sex, age at ALS onset, diagnostic delay, phenotype at onset, and family history of ALS). On King’s staging, the time elapsed between disease onset (King’s stage 1) and involvement of the second body region (King’s stage 2B) was similar in TARDBP and nmALS patients but longer in TARDBP than in C9orf72 patients. TARDBP patients reached King’s stages 3 and 4 later than C9orf72 and nmALS patients.
Conclusions
TARDBP patients have a better survival/prognosis than C9orf72-positive and nmALS patients. King’s staging also suggested that the higher survival rate and the slower progression associated with the TARDBP mutation could mainly be attributed to the longer time elapsed between King’s stages 2B to 3.
Introduction/Aims
Several microgeographic clusters of higher/lower incidence of amyotrophic lateral sclerosis (ALS) have been identified worldwide. Differences in the distribution of local factors ...were proposed to explain the excess ALS risk, whereas the contribution of known genetic/epigenetic factors remains unclear. The aim is to identify restricted areas of higher risk in Sardinia and to assess whether age, sex, and the most common causative genetic mutations in Sardinia (C9orf72 and TARDBP mutations) contributed to the variation in the ALS risk.
Methods
We performed an ad hoc analysis of the 10‐y population‐based incident cohort of ALS cases from a recent study of a large Sardinian area. Cluster analysis was performed by age‐ and sex‐adjusted Kulldorff's spatial scan statistic.
Results
We identified a statistically significant cluster of higher ALS incidence in a relatively large area including 34 municipalities and >100,000 individuals. The investigated genetic mutations were more frequent in the cluster area than outside. Regardless of the genetic mutations, the excess of ALS risk was significantly associated with either sex or with age ≥ 65 y. Finally, an additive interaction between older age and male sex contributed to the excess of ALS risk in the cluster area but not outside.
Discussion
Our analysis demonstrated that known genetic factors, age, and sex may contribute to microgeographic variation in ALS incidence. The significant additive interaction between older age and male sex we found in the high‐incidence cluster could suggest the presence of a third factor connecting the analyzed risk factors.
Background
While amyotrophic lateral sclerosis (ALS) incidence has increased during the last decades, structured evidence on increased prevalence is lacking. After reporting a significant yearly ...increase of ALS incidence over a 10-year period, we checked for increased prevalence in Southern Sardinia over a quinquennium.
Methods
ALS patients (El Escorial Criteria) recruited from the study area and followed at ALS Centre, University of Cagliari, were included. Prevalence was computed for January 1, 2015 and January 1, 2019 and was calculated for the overall ALS population as well as for tracheostomized and non-tracheostomized patients.
Results
We observed a non-significant trend for greater ALS prevalence in 2019 than in 2015 (18.31 per 100,000 vs. 15.26 per 100,000; rate ratio: 1.83,
p
= 0.01). By contrast, a significantly raising 2015 to 2019 ALS prevalence was observed in tracheostomized patients. No significant difference could be detected in non-tracheostomized.
Conclusions
We provided the highest prevalence rate to date reported in the worldwide literature, and also showed a non-significant raising ALS prevalence in the Sardinian population over a quinquennium. The trend in raising ALS prevalence was likely due to extended survival due to invasive interventions.
Objective
Several studies have demonstrated a higher frequency of seizures and epilepsy in Alzheimer's disease and other forms of dementia as compared with healthy elderly individuals. However, ...incidence and prevalence of epilepsy in the general population of dementia are unknown since most previous studies were performed in secondary‐tertiary referral centres. In addition, all prior studies but one provided “period” rather than “point” prevalence estimates.
Methods
We assessed point prevalence estimate of epileptic manifestations requiring antiepileptic medication in patients Alzheimer's disease, vascular dementia, and fronto‐temporal dementia from a secondary clinical setting.
Results
Point prevalence estimates were 6.4% (95% CI: 1.5 to 11.3) in Alzheimer's disease, 8.9% (95% CI: 1.4 to 16.4), in vascular dementia, and 6% (95% CI: 1.3 to 10.7) in fronto‐temporal dementia, rates that were greater than those observed in the healthy elderly population. Regardless of the etiology of dementia, epilepsy was characterized by unprovoked seizures that lacked distinguishing clinical features.
Significance
These findings support epilepsy as part of the spectrum of dementia. The similar point prevalence of definite epilepsy requiring AED treatment in Alzheimer's disease and non Alzheimer dementias raised the possibility of similar underlying mechanism of epileptogenesis. Although this was not a population‐based study, accurate point prevalence data from clinic setting would be important to better define the burden of epilepsy in dementia and the demands on health services to manage the condition.
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