Fondazione Istituto Neurologico Nazionale Casimiro Mondino

AimThe TACHIS study (from the ancient Greek adjective "tachýs" meaning rapid) aimed to evaluate eptinezumab effectiveness and tolerability in routine clinical practice, integrating patient-reported outcomes and use of International Headache Society (IHS)-endorsed categories of migraine control by treatment.BackgroundEptinezumab is the only intravenous anti-calcitonin gene related peptide (CGRP) monoclonal antibody (mAb) approved for migraine prevention. While its efficacy has been demonstrated in RCTs, real-world evidence in patients with prior preventive treatment failures is still limited.MethodsTACHIS is a prospective, multicenter, observational study conducted in Italy. Adults with episodic or chronic migraine initiating eptinezumab were followed for 24 weeks. Primary outcomes included change from baseline in monthly migraine days (MMDs) and ≥50% responder rate. Secondary outcomes included changes from baseline in acute medication use, Migraine Disability Assessment (MIDAS) and Headache Impact Test-6 (HIT-6) and IHS-defined residual burden categories. Logistic regression identified factors of response status.ResultsA total of 128 patients were included (82% female; 82% chronic migraine). MMDs decreased overall by 5.7 days (95% CI: -7.2 to -4.3) at week 12 and 6.9 (95% CI: -8.5 to -5.2) at week 24 (p < 0.001). A ≥ 50% response was achieved in 43.8% and 48.2% of patients at weeks 12 and 24, respectively. Over 40% of patients achieved optimal or modest migraine control. CGRP targeted therapy-naïve patients experienced significant greater benefit, though non-naïve patients also improved. Female sex and chronic migraine diagnosis were independently associated with response at 12 weeks. Adverse events were infrequent (4.7%) and mild, with no discontinuations due to safety concerns.ConclusionsEptinezumab demonstrated effectiveness and tolerability in a real-world population of patients with migraine and prior preventive treatment failures. The integration of migraine control metrics provides a comprehensive evaluation of therapeutic impact and supports eptinezumab use in routine care.Trial RegistrationThe TACHIS study was preregistered on clinicaltrial.gov, NCT06409845.

The measurement of fluid biomarkers such as phosphorylated tau at threonine 181 (pTAU181), amyloid-β 40 (Aβ40), and Aβ42 is a routine medical examination that contributes to achieving an accurate diagnosis within the Alzheimer's disease (AD) clinical continuum. The aim of this study is to compare the concentration of these biomarkers in CSF and plasma and determine their relationship with the patients' clinical variant and profile. Patients were diagnosed following the NIA-AA criteria. Plasma and CSF were obtained from healthy controls (HC), mild cognitive impairment (MCI non-AD), MCI displaying positive AD markers (MCI-AD), and AD patients. Biomarker levels were assessed using the LUMIPULSE® G600II instrument (Fujirebio, Japan). Data showed a significant increase in pTAU181 concentration, specifically in the progression from MCI non-AD to AD conditions. The opposite trend was observed for Aβ42 and Aβ42/Aβ40. Furthermore, these biomarker trends appeared to change consistently with variations in the MMSE score, highlighting the relevance of plasma in detecting changes in patients' cognitive function. Considering the clinical variant, atypical patients displayed the highest pTAU181 and lowest Aβ42 levels, consistent with their lower MMSE scores. Lastly, the posterior cortical atrophy (PCA) profile showed higher pTAU181 and lower Aβ42 levels when compared to other profiles. Nevertheless, these last results are to be cautiously interpreted given the limited number of samples included in the analysis. Hence, further analyses on larger cohorts are needed to better define the role of these biomarkers in distinguishing between patients' clinical variants.

Patient engagement in cancer care is increasingly recognized as essential for improving clinical outcomes. Nurses play a crucial role in fostering patient engagement, yet there is a lack of validated instruments to assess which nursing behaviors are most effective in promoting engagement from the patient's perspective. This study aimed to develop and test the psychometric characteristics of the Nurses' Behavioral Engagement Scale, a tool designed to measure nursing behaviors that support patient engagement in oncology settings, from patients' point of view. The study followed a three-phase exploratory sequential mixed-methods design. In the first phase, 53 items were generated based on findings from a previous qualitative study and a systematic review of the literature. In the second phase, the items underwent content validation through a modified e-Delphi procedure with 19 experts in oncology nursing, patient engagement, tool development, and linguistics. Forty-eight items were deemed relevant and tested in the third phase with a sample of 250 cancer patients to evaluate construct validity, internal consistency, and convergent validity. Exploratory Factor Analysis revealed a four-factor structure, collectively explaining 70.0% of the total variance: Factor 1 - Acknowledgment of Patient's Uniqueness, Factor 2 - Meeting Patient's Knowledge Expectations, Factor 3 - Fostering Patient's Motivation, and Factor 4 - Valuing Patient's Informal Caregivers. The final Nurses' Behavioral Engagement Scale comprises 29 items. Internal consistency was excellent, with Cronbach's alpha coefficients of 0.953, 0.890, 0.942, and 0.920 for the four factors, respectively. The Nurses' Behavioral Engagement Scale demonstrated significant and meaningful correlations with the Health Care Climate Questionnaire and items assessing satisfaction with nursing care, supporting its convergent validity. The Nurses' Behavioral Engagement Scale provides a psychometrically sound measure of nursing behaviors that promote patient engagement in oncology care. This tool has the potential to inform targeted interventions and quality improvement initiatives, ultimately enhancing patient-centered care and improving health outcomes in cancer patients.

Spinal muscular atrophy (SMA) is a severe neurological disease caused by mutations in the SMN1 gene, characterized by early onset and degeneration of lower motor neurons. Understanding early neurodevelopmental defects in SMA is crucial for optimizing therapeutic interventions. Using spinal cord and cerebral organoids generated from multiple SMA type 1 male donors, we revealed widespread disease mechanisms beyond motor neuron degeneration. Single-cell transcriptomics uncovered pervasive alterations across neural populations, from progenitors to neurons, demonstrating SMN-dependent dysregulation of neuronal differentiation programs. Multi-electrode array (MEA) analysis identified consistent hyperexcitability in both spinal and brain organoids, establishing altered electrical properties as a central nervous system-wide feature of pathogenesis. Early administration of an optimized antisense oligonucleotide (ASO) that increased SMN levels rescued morphological and functional deficits in spinal cord organoids across different genetic backgrounds. Importantly, this early intervention precisely corrected aberrant splicing in here identified SMN1 targets enriched at critical nodes of neuronal differentiation. Our findings demonstrate that early developmental defects are core features of SMA pathogenesis that can be prevented by timely therapeutic intervention, providing insights for optimizing treatment strategies.

Autoimmune nodopathy (AN) is a disabling peripheral nerve disorder mediated by four pathogenic autoantibodies targeting the node of Ranvier: anti-neurofascin-155 (Nfasc155); anti-Nfasc155 and Nfasc186 (PanNfasc); anti-contactin-1; and anti-contactin-associated protein 1 autoantibodies. Several autoantibody detection assays exist; however, which assay yields the best performance remains unclear. We evaluated the performance of five diagnostic assays individually and in combinations to identify a gold standard assay for diagnosing AN and improve diagnostic accuracy. Sera from 290 individuals from a European cohort, including healthy controls and patients with Guillain-Barré syndrome, chronic inflammatory demyelinating polyradiculoneuropathy, monoclonal gammopathy, Charcot-Marie-Tooth disease, and AN were tested using five diagnostic assays for AN: ImmunoDOT (D-tek, Mons, Belgium); ELISA; an in-house cell-based assay (CBA); a commercial CBA (Euroimmun, Bussy-Saint-Martin, France); and peripheral nerve immunohistochemistry (IHC). The sensitivity (Se) and specificity (Sp) of the individual assays and their combinations were estimated using Bayesian latent class analysis. The overall Se was 84% (95% credibility interval [CI], 79-88) for ImmunoDOT, 86% (81-90) for ELISA, 96% (93-98) for the in-house CBA, 92% (89-96) for the commercial CBA, and 91% (87-94) for IHC. For all assays, the overall Sp was ≥ 97%. Among the tested assays, in-house CBA showed the best performance, with the highest Se and Sp. The assay combinations demonstrated excellent analytical performance (Se ≥ 91% and Sp ≥ 98%). Inter-laboratory validation revealed excellent repeatability, with a Gwet's agreement coefficient of >0.94 for most assays. Our research suggests that combining two assays, CBA and ImmunoDOT enhances the accuracy of AN diagnosis. This approach can facilitate the establishment of standardized assays for AN diagnosis and aid in the better differentiation of AN from other similar pathologies.

Pregnancy constitutes a critical window of vulnerability during which maternal and environmental exposures may shape fetal development through epigenetic mechanisms. While prenatal maternal anxiety and exposure to green spaces have been independently associated with child neurodevelopment, their potential interactive effects on neonatal epigenetic profiles remain largely unexplored. This study examined the independent and interactive effects of maternal trait anxiety and residential green space exposure during pregnancy on neonatal DNA methylation (DNAm) of the brain-derived neurotrophic factor (BDNF) gene. A sample of 110 mother-infant dyads was enrolled at delivery. Maternal trait anxiety was assessed using the Stait-Trait Anxiety Inventory (STAI-Y) and infants' BDNF DNAm at birth was assessed in 11 CpG sites in buccal cells. Prenatal residential addresses were geocoded and green space availability within 300, 500, and 1000 m buffers was calculated using the CLCplus Backbone 2021 land cover dataset. Hierarchical linear regression models were adjusted for infant sex and prenatal exposure to PM2.5. Results indicated that higher maternal trait anxiety was associated with increased BDNF DNAm at four CpG sites only among infants with lower exposure to green space within a 300 m buffer. This association was not significant at higher levels of greenness, suggesting a neuroprotective effect of natural environments during gestation. Findings provide novel evidence that urban green space may buffer the biological impact of maternal anxiety on neonatal BDNF methylation. This highlights the importance of integrating psychological and environmental-level exposures to elucidate early-life determinants of neurodevelopment.

Migraine is a common neurological disorder that predominantly affects women during their reproductive years, presenting unique challenges in the context of pregnancy, breastfeeding, and pregnancy planning. In the present review, we intend to summarize those challenges and propose possible solutions. Women with migraine, particularly those with aura, face an increased risk of pregnancy-related complications, including preeclampsia, stroke, and preterm birth, highlighting the need for careful monitoring throughout gestation. When migraine persists during pregnancy, management should prioritize non-pharmacological approaches, with a strong emphasis on lifestyle modifications and behavioral therapies. In some settings, non-invasive neuromodulation may also be a reasonable option. However, disabling migraine should not be left untreated and may require pharmacological management. Pharmacological treatments should be chosen primarily based on safety considerations, as many migraine medications are not suitable for use during pregnancy. Given the limited safety data available for several treatments, shared decision-making between patients and healthcare providers is essential. During breastfeeding, medication selection should focus on minimizing infant exposure while ensuring effective migraine control for the mother. In women of childbearing potential, caution is needed when prescribing certain migraine treatments, as unplanned pregnancies can occur. Special considerations should also be given to those requiring preventive treatment while planning pregnancy. Given the complexities of migraine management in this population, an individualized approach is crucial to balancing maternal well-being with fetal and infant safety.

Attentional resources are crucial in determining whether and how a specific stimulus is selected for further processing from a multitude of concurrent inputs. Within this framework, multisensory integration enhances the salience of environmental stimuli amplifying perceptual responses to events. According to the race model, competition among sensory modalities in multisensory stimulation resembles a race; thus, when bimodal or trimodal stimulation elicits faster responses compared to unimodal stimulation, the model's prediction is violated. The present study aimed to validate a technological device capable of delivering unimodal, bimodal and trimodal stimulation, and to investigate perceptual processes and attentional dynamics by applying the race model to multisensory data, utilizing a previous multisensory attentional paradigm. Our findings provide compelling evidence of facilitatory attentional capture by multisensory events, as reflected in faster detection times compared to unisensory stimuli. Notably, this advantage is most pronounced in the initial segment of the cumulative distribution function, where responses are less influenced by higher cognitive mechanisms. Additionally, manipulation of perceptual load created an interfering effect in preliminary analyses, not found within the race model. The Tech-PAD proves to be a valuable tool for replicating and expanding research paradigms. The results reinforce previous findings and extend the multisensory advantage to the trimodal condition, including the tactile modality. Furthermore, this study highlights the role of attentional control mechanisms in multisensory environments, particularly in the early stages of sensory perception. The findings are interpreted in relation to attentional mechanisms and cognitively efficient strategies, offering new insights into the optimization of sensory processing.

To evaluate the effect of erenumab treatment beyond monthly migraine days in patients with high-frequency episodic migraine who did not respond to at least one previous migraine preventive treatment. Reduction in monthly migraine days has been the efficacy standard for migraine preventive treatments; however, it does not fully capture the holistic benefit of the therapy. Erenumab, a monoclonal antibody targeting the calcitonin gene-related peptide pathway, has demonstrated reduction in monthly migraine days and improvement in function in patients with episodic and chronic migraine. In this phase 4, interventional, double-blind, randomized, placebo-controlled, multicenter, global study, treatment with erenumab was assessed over 4 months in adults with high-frequency episodic migraine. The study was conducted at 61 sites located across North America and Europe between September 2020 and October 2023. Patients with ≥1 qualifying oral triptan-treated migraine attack at baseline were randomized to receive erenumab 140 mg or placebo subcutaneously once monthly. The primary endpoint was change from baseline in mean monthly hours of at least moderate headache pain intensity over months 1, 2, and 3; secondary endpoints included change from baseline in mean monthly function, mean monthly duration of at least moderate pain intensity in migraine attacks, and mean monthly peak migraine pain intensity. Safety outcomes were also assessed. Of 512 randomized patients, 510 received erenumab 140 mg (n = 254) or placebo (n = 256) once monthly. Demographics and baseline characteristics were balanced between the two treatment arms. Erenumab 140 mg was superior to placebo in reducing duration of moderate or severe headache pain intensity over months 1, 2, and 3 (least squares mean [95% confidence interval {CI}] difference, -7.95 [-11.45, -4.46]; p < 0.001). Compared with placebo, erenumab significantly reduced migraine functional impact as assessed by the four domains of the Migraine Functional Impact Questionnaire, with a least squares mean (95% CI) difference of -7.36 (-10.80, -3.92) for physical functioning, -7.10 (-10.34, -3.87) for usual activities, -6.82 (-10.37, -3.27) for social functioning, and - 7.05 (-10.76, -3.34) for emotional functioning (p < 0.001 for all domains). Significant reductions with erenumab compared with placebo were also observed in duration of at least moderate pain intensity in residual or break-through migraine attacks (least squares mean [95% CI] difference, -1.07 [-1.92, -0.22]; p = 0.013) and peak migraine pain intensity (-0.48 [-0.85, -0.11]; p = 0.011). Incidence of grade 3 adverse events was 1.6% with erenumab and 1.2% with placebo; no grade 4 or fatal adverse events were reported in either treatment arm. Findings from the EMBRACE study demonstrated that treatment with erenumab in patients with high-frequency episodic migraine can provide positive therapeutic effects on ictal burden and pain, with residual migraine attacks tending to be shorter and less painful, with less overall impact.