Risk of stroke with different levels of leisure-time physical activity: a systematic review and meta-analysis of prospective cohort studies.

BACKGROUND: Leisure-time physical activity (LTPA) protects against vascular diseases. Whether and to what extent different levels of LTPA, including lower ones, benefit stroke prevention is still unclear. METHODS: We searched prospective cohort studies, indexed on PubMed and Scopus, published in English up to 22 April 2023, that investigated, in a general healthy population, the relationship between different predefined LTPA levels, compared with inactivity, and the risk of any type of stroke. We applied random effect modelling for meta-analyses and meta-regression to control for the impact of age and sex. RESULTS: Out of 3064 screened articles, 15 articles on 16 cohorts of subjects were included in meta-analyses, with a total of 752 050 followed-up subjects. Mean follow-up was 125.7±77.5 months. Included studies identified three (none, below target and ideal) to five (none, insufficient, low, moderate and intense) levels of LTPA. In the five studies identifying three levels of LTPA, compared with no LTPA, below target (risk ratio (RR)=0.82, 95% CI=0.75 to 0.88) and ideal LTPA significantly reduced stroke risk (RR=0.71, 95% CI=0.58 to 0.86).Lower levels of LTPA also mitigated stroke risk in studies reporting on four (n=6; RR=0.73, 95% CI=0.62 to 0.87 favouring moderate LTPA over no LTPA) and five levels (n=2; RR=0.71, 95% CI=0.58 to 0.88 favouring moderate LTPA over no LTPA). The benefits of LTPA were independent of age and sex. CONCLUSIONS: According to our results, all levels of LTPA can be beneficial for stroke prevention, including levels currently regarded as low or insufficient. People should be encouraged to be physically active even at the lowest levels. PROSPERO REGISTRATION NUMBER: CRD42023425302.

Adherence to riluzole therapy in patients with amyotrophic lateral sclerosis in three Italian regions-The CAESAR study.

PURPOSE: Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disease. Riluzole may increase survival and delay the need for mechanical ventilation. The CAESAR project ('Comparative evaluation of the efficacy and safety of drugs used in rare neuromuscular and neurodegenerative diseases', FV AIFA project 2012-2013-2014) involves evaluating prescribing patterns, and analysing effectiveness and comparative safety of drugs, in patients with neurodegenerative diseases. The aim of this study is to evaluate adherence to riluzole in patients with ALS during the first year of use, identifying adherence clusters. METHODS: A retrospective cohort study was conducted using administrative data from Latium, Tuscany, and Umbria. We identified subjects with a new diagnosis of ALS between 2014 and 2019, with the first dispensation of riluzole within 180 days of diagnosis. We considered a two-year look-back period for the characterization of patients, and we followed them from the date of first dispensing of riluzole for 1 year. We calculated 12 monthly adherence measures, through a modified version of the Medication Possession Ratio, estimating drug coverage with Defined Daily Dose. Adherence trajectories were identified using a three-step method: (1) calculation of statistical measures; (2) principal component analysis; (3) cluster analysis. Patient characteristics at baseline and during follow-up were described and compared between adherence groups identified. RESULTS: We included 264 ALS patients as new users of riluzole in Latium, 344 in Tuscany, and 63 in Umbria. We observed a higher frequency of males (56.2%) and a mean age of 67.4 (standard deviation, SD, 10.4) in the overall population. We identified two clusters in all regions: one more numerous, including adherent patients (60%, 74%, 88%, respectively), and another one including patients who discontinued therapy (40%, 26%, 12%, respectively). In Tuscany patients discontinuing riluzole more frequently died (28.6% vs. 15.4%, p-value <0.01). Additionally, low-adherers had a higher frequency of central nervous system disorders (69.0% vs. 52.5%, p-value 0.01), and a greater use of non-pharmacological treatments (p-values ≤0.01 for invasive ventilation and tracheostomy). We did not observe any differences in Lazio, whereas in Umbria we observed a higher use of drugs for dementia-related psychiatric problems among low-adherers (57.1% vs. 7.8%, respectively, p-value <0.01), although with small numbers. CONCLUSION: Most ALS patients who start riluzole adhere to therapy during the first year. Patients who discontinue therapy early show greater fragility and mortality.

Frequency and characterization of cognitive impairments in patients diagnosed with paediatric central nervous system tumours: a systematic review.

Background: This systematic review has been conducted with the aim of characterizing cognitive deficits and analyzing their frequency in survivors of paediatric Central Nervous System tumours. Materials and methods: All literature published up to January 2023 was retrieved searching the databases "PubMed", "Cochrane", "APA PsycInfo" and "CINAHL". The following set of pre-defined inclusion criteria were then individually applied to the selected articles in their full-text version: i) Retrospective/prospective longitudinal observational studies including only patients diagnosed with primary cerebral tumours at ≤ 21 years (range 0-21); ii) Studies including patients evaluated for neuro-cognitive and neuro-psychological deficits from their diagnosis and/or from anti-tumoral therapies; iii) Studies reporting standardized tests evaluating patients' neuro-cognitive and neuro-psychological performances; iv) Patients with follow-ups ≥ 2 years from the end of their anti-tumoral therapies; v) Studies reporting frequencies of cognitive deficits. Results: 39 studies were included in the analysis. Of these, 35 assessed intellectual functioning, 30 examined memory domains, 24 assessed executive functions, 22 assessed attention, 16 examined visuo-spatial skills, and 15 explored language. A total of 34 studies assessed more than one cognitive function, only 5 studies limited their analysis on a single cognitive domain. Attention impairments were the most recurrent in this population, with a mean frequency of 52.3% after a median period post-treatment of 11.5 years. The other cognitive functions investigated in the studies showed a similar frequency of impairments, with executive functions, language, visuospatial skills and memory deficits occurring in about 40% of survivors after a similar post-treatment period. Longitudinal studies included in the systematic review showed a frequent decline over time of intellectual functioning. Conclusions: Survivors of paediatric Central Nervous System tumours experience cognitive sequelae characterized by significant impairments in the attention domain (52.3%), but also in the other cognitive functions. Future studies in this research field need to implement more cognitive interventions and effective, but less neurotoxic, tumour therapies to preserve or improve neurocognitive functioning and quality of life of this population.

An updated overview of recent and ongoing deep brain stimulation (DBS) trials in patients with dementia: a systematic review.

BACKGROUND: Dementia affects more than 55 million people worldwide. Several technologies have been developed to slow cognitive decline: deep brain stimulation (DBS) of network targets in Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) have been recently investigated. OBJECTIVE: This study aimed to review the characteristics of the populations, protocols, and outcomes of patients with dementia enrolled in clinical trials investigating the feasibility and efficacy of DBS. MATERIALS AND METHODS: A systematic search of all registered RCTs was performed on Clinicaltrials.gov and EudraCT, while a systematic literature review was conducted on PubMed, Scopus, Cochrane, and APA PsycInfo to identify published trials. RESULTS: The literature search yielded 2122 records, and the clinical trial search 15 records. Overall, 17 studies were included. Two of 17 studies were open-label studies reporting no NCT/EUCT code and were analysed separately. Of 12 studies investigating the role of DBS in AD, we included 5 published RCTs, 2 unregistered open-label (OL) studies, 3 recruiting studies, and 2 unpublished trials with no evidence of completion. The overall risk of bias was assessed as moderate-high. Our review showed significant heterogeneity in the recruited populations regarding age, disease severity, informed consent availability, inclusion, and exclusion criteria. Notably, the standard mean of overall severe adverse events was moderately high (SAEs: 9.10 ± 7.10%). CONCLUSION: The population investigated is small and heterogeneous, published results from clinical trials are under-represented, severe adverse events not negligible, and cognitive outcomes uncertain. Overall, the validity of these studies requires confirmation based on forthcoming higher-quality clinical trials.

Potentially inappropriate drug use in myasthenia gravis: a real-world population-based cohort study in Italy.

Introduction: To evaluate the use of pyridostigmine in presence of contraindications, and the use of concomitant potentially contraindicated drugs in a cohort of patients affected by Myasthenia Gravis (MG) in the Italian Regions of Lazio, Tuscany, and Umbria. Methods: This is a retrospective cohort study. A multivariate logistic regression model was used to evaluate the determinants of pyridostigmine and of potentially contraindicated drugs use in MG patients. Results: Among 591 incident pyridostigmine users affected by MG, 91 (15.4%) had at least one of the contraindications considered at the first prescription of pyridostigmine. Patients prescribed with pyridostigmine in presence of contraindications were more frequently affected by diabetes, obesity, and renal diseases. Age 75+ years (odds ratio, OR 4.94, 95% confidence interval, CI 1.60-15.22 for Latium; OR 3.78, 95%CI: 1.26-11.34 for Tuscany; OR 5.83, 95%CI 1.19-28.52 for Umbria), the presence of at least one specific comorbidity (OR 3.93; 95%CI 1.68-9.17 for Latium), and polytherapy (6+ drugs, OR 4.90, 95%CI: 1.35-17.85 for Tuscany) were found to be significantly associated with pyridostigmine use in presence of contraindications. Among patients affected by MG, 1,483 (62.6%) were treated with potentially contraindicated drugs in the first year of follow-up (67.06.9% in Latium; 59% in Tuscany; 57.6% in Umbria). Patients aged 75+ years, those with at least one specific complication or comorbidity, and those exposed to polytherapy were more likely to be treated with a potential contraindicated drug. Conclusion: Among incident users of pyridostigmine, more than 15% of patients have at least one of the contraindications considered, and among patients diagnosed with MG, in the first year of follow-up >60% of subjects were treated with potentially contraindicated drugs.

The Italian fund for Alzheimer's and other dementias: strategies and objectives to face the dementia challenge.

The Italian Fund for Alzheimer's and other dementias was approved and signed in December 2021. The Fund is financed with 15 million euros in three years. The main goal is to provide new strategies in the field of dementia with a Public Health perspective. The Fund includes eight main activities that will be monitored and supervised by the Italian National Institute of Health: 1) development of a guideline for the assessment, management and support for people with dementia and their families/carers; 2) updating of the Dementia National Plan (DNP); 3) implementation of the documents of the DNP; 4) conducting surveys dedicated to the Italian Dementia Services; 5) promotion of dementia prevention strategies; 6) training strategies for healthcare professionals, families and caregivers; 7) creation of a National Electronic Record for Dementia; 8) evaluation and monitoring of activities promoted by Regions and Autonomous Provinces in the field of dementia, together with the dementia National Permanent Table. These activities are outlined in detail in the present paper.

Computer-Based Cognitive Training in Children with Primary Brain Tumours: A Systematic Review.

Background: Late neurocognitive sequelae are common among long-term brain tumour survivors, resulting in significantly worse quality of life. Cognitive rehabilitation through specific APP/software for PC/tablets represents an innovative intervention spreading in recent years. In this study, we aim to review the current evidence and trends regarding these innovative approaches. Methods: A systematic literature review was performed. Inclusion criteria were: (i) Studies recruiting patients diagnosed with any brain tumour before 21 years of age; (ii) studies assessing the role of digital interventions on cognitive outcomes. Case reports, case series, reviews, letters, conference proceedings, abstracts, and editorials were excluded. Results: Overall, nine studies were included; 152 patients (67.8% males) with brain tumours underwent a digital intervention. The mean age at diagnosis and the intervention enrolment ranged from 4.9 to 9.4 years and 11.1 to 13.3 years, respectively. The computer-based software interventions employed were: Cogmed, Captain's Log, Fast ForWord, and Nintendo Wii. Most of these studies assessed the effects of cognitive training on working memory, attention, and performance in daily living activities. Conclusions: The studies suggest that this type of intervention improves cognitive functions, such as working memory, attention, and processing speed. However, some studies revealed only transient positive effects with a significant number of dropouts during follow-up. Trials with greater sample sizes are warranted. Motivating families and children to complete cognitive interventions could significantly improve cognitive outcomes and quality of life.

Safety and Efficacy of Monoclonal Antibodies for Alzheimer's Disease: A Systematic Review and Meta-Analysis of Published and Unpublished Clinical Trials.

BACKGROUND: Monoclonal antibodies (mAbs) are currently among the most investigated targets for potential disease-modifying therapies in Alzheimer's disease (AD). OBJECTIVE: Our objectives were to identify all registered trials investigating mAbs in MCI due to AD or AD at any stage, retrieve available published and unpublished data from all registered trials, and analyze data on safety and efficacy outcomes. METHODS: A systematic search of all registered trials on ClinicalTrials.gov and EUCT was performed. Available results were searched on both platforms and on PubMed, ISI Web of Knowledge, and The Cochrane Library. RESULTS: Overall, 101 studies were identified on 27 mAbs. Results were available for 50 trials investigating 12 mAbs. For 18 trials, data were available from both published and unpublished sources, for 21 trials only from published sources, and for 11 trials only from unpublished sources. Meta-analyses of amyloid-related imaging abnormalities (ARIA) events showed overall risk ratios of 10.65 for ARIA-E and of 1.75 for ARIA-H. The meta-analysis of PET-SUVR showed an overall significant effect of mAbs in reducing amyloid (SMD -0.88), but when considering clinical efficacy, data on CDR-SB showed that treated patients had a statistically significant but clinically non-relevant lower worsening (MD -0.15). CONCLUSION: Our results suggest that the risk-benefit profile of mAbs remains unclear. Research should focus on clarifying the effect of amyloid on cognitive decline, providing data on treatment response rate, and accounting for minimal clinically important difference. Research on mAbs should also investigate the possible long-term impact of ARIA events, including potential factors predicting their onset.

A nationwide survey of Italian Centers for Cognitive Disorders and Dementia on the provision of care for international migrants.

BACKGROUND: More than 500,000 dementia cases can be estimated among migrants living in Europe. There is the need to collect "real world" data on the preparedness of healthcare services to support the inclusion of migrants in the public health response to dementia. The present study aimed (i) to estimate the number of migrants referred to Italian memory clinics (Centers for Cognitive Disorders and Dementia [CCDDs]) and (ii) to identify possible barriers and resources for the provision of diversity-sensitive care. METHODS: A survey of all Italian CCDDs was conducted between December 2020 and April 2021. An online questionnaire was developed to obtain information on the number of migrants referred to Italian CCDDs in 2019, the challenges encountered in the diagnostic approach, and possible facilitators in the provision of care. RESULTS: Overall, 343 of the 570 contacted CCDDs completed the survey questionnaire (response rate: 60.2%). Nearly 4527 migrants were referred to these services in 2019. Migrants accounted for a median 1.1% (IQR: 0.9%-2.8%) of overall CCDD referrals. More than one-third of respondents reported that the number of migrants referred to their facilities had increased in the last 5 years. The overall quality of the migrants' cognitive assessment was deemed to be very poor or insufficient in most cases. A minority of CCDDs had translated information material on dementia and reported the possibility to contact cultural mediators and interpreters. CONCLUSIONS: A relevant number of migrants are being referred to Italian CCDDs that are still not adequately prepared to deliver diversity-sensitive care and support.

Use of Biomarkers in Ongoing Research Protocols on Alzheimer's Disease.

The present study aimed to describe and discuss the state of the art of biomarker use in ongoing Alzheimer's disease (AD) research. A review of 222 ongoing phase 1, 2, 3, and 4 protocols registered in the clinicaltrials.gov database was performed. All the trials (i) enrolling subjects with clinical disturbances and/or preclinical diagnoses falling within the AD continuum; and (ii) testing the efficacy and/or safety/tolerability of a therapeutic intervention, were analyzed. The use of biomarkers of amyloid deposition, tau pathology, and neurodegeneration among the eligibility criteria and/or study outcomes was assessed. Overall, 58.2% of ongoing interventional studies on AD adopt candidate biomarkers. They are mostly adopted by studies at the preliminary stages of the drug development process to explore the safety profile of novel therapies, and to provide evidence of target engagement and disease-modifying properties. The biologically supported selection of participants is mostly based on biomarkers of amyloid deposition, whereas the use of biomarkers as study outcomes mostly relies on markers of neurodegeneration. Biomarkers play an important role in the design and conduction of research protocols targeting AD. Nevertheless, their clinical validity, utility, and cost-effectiveness in the "real world" remain to be clarified.