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.

Insulin resistance has been proposed as a modifiable risk factor for cognitive impairment and Alzheimer's disease (AD). However, its relationship with clinical and biological markers of AD remains unclear. This study investigated the associations between insulin resistance, cerebrospinal fluid (CSF) biomarkers of AD and cognitive performance in a Memory Clinic cohort. Two hundred individuals were enrolled among consecutive subjects referred for cognitive evaluation. All of them underwent neuropsychological assessments, blood sampling, and lumbar puncture for CSF collection. Insulin resistance was assessed using the Homeostatic Model Assessment for Insulin Resistance (HOMA), derived from fasting insulin and glucose levels. CSF biomarkers of amyloidopathy, tauopathy and neurodegeneration were quantified using chemiluminescent enzyme immunoassays. Participants were classified as AD or non-AD, and individuals with diabetes were excluded from the analyses. No significant differences in HOMA were observed between AD and non-AD groups, and insulin resistance was not significantly associated with CSF biomarkers of AD. However, within the AD group, individuals with dementia exhibited significantly higher insulin resistance than those with mild cognitive impairment. Across the full sample, insulin resistance was negatively correlated with global cognition. In the AD group, multiple linear regression analyses adjusted for age, sex, education, and CSF biomarkers confirmed that insulin resistance independently predicted cognitive performance. These findings suggest that insulin resistance is associated with more severe cognitive impairment in individuals within the AD continuum through mechanisms largely independent of core AD pathophysiology. Nevertheless, addressing insulin resistance may represent a promising avenue for therapeutic intervention or risk reduction in cognitive disorders.

Falls are one of the most common and devastating effects of neurological diseases, especially in patients with stroke outcomes, Parkinson’s Disease (PD), and Multiple Sclerosis (MS). To prevent negative outcomes and guide tailored rehabilitation, it is necessary to identify risk factors early. The current study aims to assess whether and how the risk of falling is related to spatiotemporal and kinematic parameters in stroke, PD, and MS. It also seeks to determine how these factors can help manage patients and identify more personalized and appropriate rehabilitation treatments. Ninety patients with neurological disorders (stroke, PD, and MS) underwent eight weeks of home-based rehabilitation using the ARC Intellicare device or following a paper-based protocol. At baseline (T0) and at the end of the protocol (T2), they were assessed using the Silver Index of the hunova® robotic platform to evaluate fall risk, and instrumental gait analysis to record spatiotemporal and kinematic parameters of walking. Statistical analysis showed moderate and significant correlations between the Silver Index and gait spatiotemporal parameters such as stance and swing phase, both in affected (T0, p = 0.007; T2, p = 0.017) and unaffected side (T0, p = 0.022; T2, p = 0.008), double support in affected side (T0, p = 0.002; T2, p = 0.005), cycle length in affected (T0, p = 0.007; T2, p = 0.003) and unaffected side (T0, p = 0.008; T2, p = 0.003), and cadence (T0, p = 0.025; T2, p = 0.003) in stroke patients. No significant results emerged in the PD and MS. No population showed significant correlations between the Silver Index and gait kinematic parameters. The Silver Index may reflect distinct patterns of instability in post-stroke gait, but in PD and MS, multiple factors influence the risk of falling that instrumental gait analysis cannot fully capture, requiring a more extensive and multidimensional approach that includes cognitive aspects.

The spontaneous firing activity of substantia nigra (SN) dopaminergic (DA) neurons is finely tuned by the autocrine inhibition mediated by D2 DA autoreceptors (D2-ARs) that activate GIRK2 channels. Despite this regulatory mechanism, the vulnerability of SN DA neurons may nevertheless increase due to an altered spontaneous firing activity of DA neurons, Ca2+ dishomeostasis, mitochondrial stress, high dendritic arborization, aggregation of α-synuclein (α-syn), α-syn mutations, reduced levels of calbindin protein, etc. Although the intraneuronal accumulation and the spreading of misfolded α-syn is a hallmark of full-blown Parkinson's disease, the effects produced by α-syn aggregation on neuronal functionality at the early onset of neurodegeneration are still of debate. We previously reported that α-syn oligomers in the extracellular medium drastically inhibit the firing rate of midbrain neurons and significantly impair burst generation and network synchronization. Here, by combining conventional electrophysiology and cutting-edge technology of micro-graphitized diamond micro-electrode arrays, we confirm that exogenous α-syn effectively slows down the firing rate of SN DA neurons, but it also selectively upregulates Cav2.2 (N-type) Ca2+ currents and consequently Ca2+-dependent DA release. Thus, our data uncover a novel regulatory mechanism in SN DA neurons and demonstrate that exogenous α-syn alters the interplay among Ca2+ entry, spontaneous firing and DA release causing DA accumulation in the extracellular milieu and intracellular Ca2+ overload. Both processes may represent a target for future investigations to better understand the initial phases of SN DA neuron degeneration. KEY POINTS: We combined conventional electrophysiology and micro-graphitized diamond multi-electrode arrays to investigate the effect of exogeneous α-synuclein on cultured midbrain dopaminergic neurons isolated from substantia nigra. α-Synuclein oligomers slow down the firing rate of dopaminergic neurons and up-regulate Cav2.2 (N-type) Ca2+ currents. Raised Cav2.2 currents in turn increase the depolarization-evoked dopamine release and the frequency of quantal exocytotic events. Overall, this mechanism causes dopamine accumulation in the extracellular milieu and intracellular Ca2+ overload.

Background: Migraine attacks typically emerge in predisposed individuals after exposure to heterogeneous stimuli that vary widely across patients. A system-level perspective highlights migraine as a disturbance of homeostasis and allostasis: the brain integrates multiple inputs and generates adaptive responses to maintain physiological stability, but sustained physiological or paraphysiological stressors may impose excessive allostatic load. When compensatory mechanisms become energetically costly or insufficient, an “allostatic reset” may occur, clinically manifesting as a migraine attack. Within this framework, the concept of a migraine trigger is better viewed as a threshold modulator rather than a deterministic cause, i.e., a stimulus that lowers the attack threshold in susceptible individuals. Nutrition is among the most frequently implicated domains, including fasting, dehydration, specific foods and additives, and overall dietary patterns. Methods: This narrative review synthesizes current evidence on dietary exposures as potential migraine precipitants and modulators of disease course. Results: The most frequently reported food-related triggers include fasting, dehydration, alcohol, coffee and caffeine withdrawal, chocolate, milk and dairy products, processed and cured meats rich in nitrites and nitrates, citrus fruits, tea, onions, tomatoes, ice cream, nuts, spicy foods, and ultra-processed foods. Food additives such as monosodium glutamate, aspartame, sulfites, and other artificial sweeteners have also been repeatedly implicated, alongside dietary histamine and biogenic amines. Importantly, several studies suggest that overall dietary patterns, characterized by high glycemic load, irregular meal timing, excessive sugar and saturated fat intake, or ultra-processed foods, may exert a greater influence on migraine susceptibility than single food items. Conclusions: Overall, the literature is fragmented and often contradictory, with a frequent mismatch between patient-reported triggers and results from blinded challenge studies, underscoring the roles of recall bias, expectancy effects, and prodromal symptoms (e.g., food cravings) misattributed to causation. Inter- and intra-individual variability – shaped by genetic background, metabolic state, gut-brain axis mechanisms, and comorbidities – suggests that “one-size-fits-all” dietary restrictions are inappropriate. Rather than endorsing broad exclusion lists, current evidence supports personalized trigger identification and prioritization of protective dietary patterns, regular hydration, and consistent meal timing to reduce attack susceptibility and overall disease burden.

OBJECTIVE:Stigma remains a major determinant of impaired quality of life (QoL) in people with epilepsy (PwE). We aimed to investigate perceptions of epilepsy-related stigma in the Italian general population, assess knowledge of epilepsy and seizure first aid, and identify factors associated with stigmatizing attitudes. METHODS:We conducted a cross-sectional, anonymized online survey using a structured questionnaire. The instrument comprised four sections: (1) sociodemographic characteristics; (2) epilepsy-related knowledge and perceptions; (3) seizure first aid (12 items on correct and incorrect actions during a seizure, summarized into the Seizure First Aid Knowledge Score (SAFE score - range 0-12); and (4) stigma assessment using the validated Stigma Scale of Epilepsy (SSE). Multivariate linear regression was used to explore predictors of stigma. RESULTS:A total of 1159 individuals completed the survey (mean age 36.9 ± 16.2 years; 64.6% women). SSE demonstrated excellent internal consistency (Cronbach's α = 0.89-0.90). Women reported higher stigma than men (53.1 ± 16.8 vs. 48.6 ± 17.6; p < 0.001). Participants from Southern Italy had significantly higher SSE scores compared to Central or Northern regions (53.4 ± 17.5 vs. 48.1 ± 16.4 and 49.8 ± 16.0; p < 0.001). Healthcare professionals reported lower stigma compared with PwE, relatives, or individuals without epilepsy (47.6 ± 17.2 vs. 55.6 ± 18.1, 51.8 ± 16.0, and 52.0 ± 17.2; p = 0.023). A higher SAFE score was inversely associated with stigma (β = -0.89, p = 0.013). Although most participants recognized appropriate first aid measures, misconceptions persisted: 38.1% endorsed inserting hands into the mouth during seizures, and 24.5% considered physical restraint appropriate. SIGNIFICANCE:Stigma persists in Italy, particularly among women and residents of Southern regions. Tailored educational interventions may both improve seizure safety and mitigate stigma, ultimately enhancing QoL for PwE. PLAIN LANGUAGE SUMMARY:Epilepsy is often associated with negative attitudes that can affect the well-being of people living with the condition. In this study, we surveyed adults across Italy to understand how epilepsy is perceived, how much people know about seizure first aid, and how stigma varies across different groups. We found that stigma remains common, especially among women and people living in Southern Italy, while better knowledge of how to help during a seizure was linked to lower stigma. These results highlight the importance of public education to improve understanding, safety, and social inclusion.

Medication-overuse headache (MOH) is a frequent, disabling, and largely preventable secondary headache disorder, most associated with pre-existing migraine. Since many patients rely on over-the-counter medications and experience long delays before specialist referral, community pharmacists represent key frontline professionals in the identification, counseling, and prevention of medication overuse and MOH. However, data on pharmacists’ knowledge and practices regarding migraine and MOH in Italy are still lacking. We conducted a nationwide, cross-sectional survey among Italian pharmacists and pharmacy students using a structured, self-administered questionnaire. The survey assessed demographic characteristics, knowledge of migraine and MOH, dispensing and counseling practices, screening for medication overuse, and referral behaviors. A composite scoring system, the Migraine and Medication Overuse Headache Knowledge and Awareness Scale (MMKAS; range 0–23), was developed by expert consensus to evaluate knowledge and professional behavior. Group comparisons were conducted using independent t-tests or Mann–Whitney U tests and categorical variables were analyzed using chi-square tests with standardized residual post-hoc analysis. For comparisons across more than two groups, one-way ANOVA or Kruskal–Wallis tests were applied, followed by adjusted post-hoc tests. A multivariable linear regression model was performed to identify independent predictors of total MMKAS scores. Internal consistency was evaluated using Cronbach’s α coefficient. A total of 271 participants were included (mean age 40.8 ± 11.4 years; 15.5

Cognitive impairment is a major non-motor feature of Parkinson's disease (PD). Alzheimer's disease CSF biomarkers-amyloid-β (Aβ42, Aβ42/40), phosphorylated tau (p-tau) and total tau (t-tau)-may influence both cognitive and motor outcomes, but their role in relation to Parkinson's disease phenotype or progression remains unclear. Moreover, few studies have investigated these associations using extensive neuropsychological batteries. The aim of the study was to examine the associations between CSF Alzheimer's disease biomarkers, domain-specific neuropsychological performance and motor impairment in Parkinson's disease and to evaluate their predictive value for longitudinal changes. Seventy-eight Parkinson's disease patients underwent extensive neuropsychological examination, along with motor evaluation and Alzheimer's disease CSF biomarkers quantification. Fifty-two patients completed follow-up motor assessment and 43 repeated cognitive evaluation after 18-24 months. Correlation and regression models adjusted for demographic and clinical covariates were applied. Thirty-nine patients were classified as mild cognitive impaired (PD-MCI), mostly with multidomain impairment. Amyloid-β biomarkers were associated with poorer attention, working memory, executive and language performance. Tau proteins were inversely associated with motor scores. PD-MCI patients tended to experience greater motor decline than cognitive unimpaired subjects. Over time, higher p-tau and t-tau predicted global cognitive decline (MMSE), while lower Aβ42/40 predicted worsening in verbal memory and reasoning. Higher t-tau and lower baseline MMSE independently predicted greater motor deterioration. CSF Alzheimer's disease biomarkers showed domain-specific relationships with cognitive function and predicted both neuropsychological decline and motor progression. Combining detailed neuropsychological profiling with Alzheimer's disease biomarkers assessment may improve identification of high-risk patients and support integrated biological definitions of Parkinson's disease.

In experimental models of Parkinson's disease (PD), chronic Levodopa (L-DOPA) induces abnormal involuntary movements (AIMs) similar to L-DOPA-induced dyskinesias (LIDs) and psychiatric disturbances associated with a lack of homeostatic synaptic downscaling in striatal spiny projection neurons (SPNs) and dysfunctional neuroimmune responses. Continuous Theta-Burst Stimulation (cTBS), a transcranial magnetic stimulation protocol that inhibits neuronal activity, is a promising non-invasive brain stimulation treatment for LIDs and addiction, whose mechanisms are still unclear. In this study, we investigated the subcortical effects of chronic cTBS during a two-week pulsatile L-DOPA treatment in 6-hydroxydopamine-lesioned rats, a well-established PD model. Six weeks post-lesion, axial, limb, and orolingual AIMs were measured using a validated scoring scale. Synaptic depotentiation of striatal SPNs was investigated ex vivo using the whole-cell patch-clamp recording technique in the dorsolateral striatum. Cytokine levels in the cerebrospinal fluid (CSF) were quantified with magnetic Luminex multiplex assays. Glial reactivity was assessed by immunofluorescence and confocal microscopy, while RNAscope in situ hybridization identified cytokine-expressing glial cells. Chronic cTBS reduced L-DOPA-induced AIMs incidence and intensity, restored long-term potentiation and synaptic depotentiation in striatal SPNs, and prevented excessive increases in glial reactivity associated with pulsatile L-DOPA. In CSF, proinflammatory cytokines were downregulated, with the most substantial reduction observed for Interleukin-1β (IL-1β), while the anti-inflammatory cytokine IL-10 was increased. RNAscope shows that IL-1β upregulation mainly originated from dysregulated microglia. These findings highlight the critical role of microglial activation and IL-1β signaling in LIDs development and support cTBS as an effective strategy to mitigate L-DOPA-induced motor complications while preserving corticostriatal synaptic integrity.

Chimeric antigen receptor T-cell (CAR-T) therapies targeting CD19 have revolutionized the treatment of B-cell malignancies, but their use is frequently complicated by immune effector cell-associated neurotoxicity syndrome (ICANS). The underlying mechanisms include endothelial dysfunction, blood–brain barrier disruption, and neuroinflammation. Circulating biomarkers of neuronal and astroglial injury, such as neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP), may provide insight into ICANS pathophysiology and serve as predictive tools. We conducted a retrospective study of 34 adult patients treated with anti-CD19 CAR-T cells for B-cell malignancies. Serum NfL and GFAP were measured at infusion (day 0) and day 7 using ultrasensitive immunoassays. Baseline GFAP and NfL levels correlated with endothelial activation markers, including mEASIX and lactate dehydrogenase, but not with demographic variables. ICANS of any grade occurred in 34

Migraine is common in people with multiple sclerosis (PwMS) and substantially contributes to disability and impaired quality of life. Although (CGRP)–targeting therapies have reshaped migraine prevention, evidence on their use in PwMS remains scarce, particularly in people receiving concomitant disease-modifying therapies (DMTs). We retrospectively collected data from 17 Italian multiple sclerosis (MS) centers on adult PwMS with comorbid migraine treated with anti-CGRP monoclonal antibodies or gepants in addition to stable DMTs. Monthly headache days (MHDs) and total number of analgesics per month were compared between treatment initiation and last follow-up. MS activity was assessed through clinical relapses, Expanded Disability Status Scale (EDSS), and MRI findings. A ≥ 50

BACKGROUND:Neuroinflammatory and systemic immune mechanisms are increasingly recognized as contributors to migraine pathophysiology. However, peripheral markers of inflammation remain underexplored. This study aimed to evaluate systemic immune alterations in patients with migraine through complete blood count (CBC) parameters and derived inflammatory indices, comparing findings with healthy controls (HCs). METHODS:We conducted a cross-sectional analysis of peripheral blood samples, assessing leukocyte subtypes including absolute and relative (percentage-%) values, hemoglobin, and platelet levels. Inflammatory indices, including neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and systemic immune-inflammation index (SII), were calculated. Migraine features were collected. RESULTS:A total of 409 subjects were included: 179 HCs, 194 with episodic migraine (EM), and 36 with chronic migraine (CM). Regarding inflammatory indices, SII significantly differed among EM, CM, and HCs (p = 0.024). In particular, in post hoc analyses, it was significantly higher in CM (514.20 ± 250.57) vs. HCs (423.14 ± 221.69) (p = 0.019) and in CM compared to EM (448.28 ± 266.53, p = 0.044). Similarly, neutrophil% significantly differed among the three groups (p = 0.022), and was higher in patients with CM (58.69 ± 9.57) vs. HCs (54.81 ± 8.86, p = 0.019) and in patients with CM vs. EM (55.39 ± 9.77, p = 0.016). Lymphocyte% differed among the three groups (p = 0.047), and it was lower in CM (31.51 ± 8.27) vs. HCs (34.55 ± 8.24, p = 0.047). CONCLUSIONS:Systemic immune dysregulation appears to be associated with migraine, particularly CM. Alterations in neutrophil and lymphocyte distributions, as well as increased SII, may represent peripheral correlates of central neuroinflammation. These findings suggest that simple, routinely available blood-derived markers could help identify inflammatory endophenotypes in migraine, warranting validation in larger, prospective studies.

OBJECTIVES:Super-refractory status epilepticus (SRSE) is a neurological emergency with high morbidity and mortality. Cenobamate, a novel antiseizure medication, may be helpful in managing SRSE, but evidence is limited. METHODS:This retrospective case series reports the use of cenobamate as add-on therapy in the management of three cases of SRSE. RESULTS:Median age at status epilepticus (SE) onset was 28 years (range 27-75). The etiologies of SRSE included one case of febrile infection-related epilepsy syndrome (FIRES), one patient with a probable genetic etiology (SCN7A variant of uncertain significance), and one case of unknown etiology. Cenobamate was introduced at a median of 27 days (range 13-103) after SE onset. Resolution of SRSE was observed after a median of 7 days (range 3-30) once cenobamate was started. Median dose of cenobamate at SRSE cessation was 25 mg/day (range 12.5-50 mg/day), and the median maintenance dose at the time of discharge was 200 mg/day (range 100-400 mg/day). Two patients died and one patient achieved functional independence. No severe medication side effects, specifically drug reaction with eosinophilia and systemic symptoms (DRESS), were observed. DISCUSSION:Cenobamate may have a role in the management of SRSE. Further studies are needed to define the optimal timing of initiation, titration strategy, and target dose of cenobamate in the context of SE.

AimCalcitonin gene-related peptide (CGRP), vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating peptide (PACAP) play a crucial role in migraine pathophysiology. In recent years, anti-CGRP(R) monoclonal antibodies (mAbs) have emerged as the first targeted and highly effective therapy for migraine. This study aimed to assess any changes in plasma CGRP levels following prophylactic treatment with anti-CGRP(R) mAbs and to compare CGRP dynamics between anti-receptor (erenumab) and anti-ligand (galcanezumab, fremanezumab) therapies. Secondary objectives were: (i) to evaluate changes in VIP and PACAP plasma levels following treatment with anti-CGRP(R) mAbs and (ii) to investigate whether baseline or post-treatment plasma levels of CGRP, VIP and PACAP were associated with clinical response to anti-CGRP(R) monoclonal antibody therapy.MethodsBetween February 2022 and February 2023, we enrolled 56 migraine patients who initiated prophylaxis with either erenumab (26 patients), galcanezumab (16 patients) or fremanezumab (14 patients). Responders were defined as those achieving a ≥50% reduction in monthly migraine days after six months. Blood samples were collected at baseline and at each follow-up visit (baseline, T0; three months, T1; six months, T2; 12 months, T3). Plasma levels of CGRP, VIP and PACAP were measured using a validated radioimmunoassay and commercially available enzyme-linked immunosorbent assay kits.ResultsOverall, 80.3% (45 out of 56) of patients responded to anti-CGRP(R) mAbs. No correlation was found between baseline CGRP, VIP and PACAP plasma levels and clinical response to anti-CGRP(R) mAbs therapy. Regarding CGRP trend, significant differences were found between patients treated with the anti-receptor monoclonal antibody (erenumab) and those receiving anti-ligand therapies. In patients treated with erenumab, CGRP levels did not show a significant change over the treatment period (T1-T3), whereas, in the galcanezumab group, CGRP levels significantly decreased as early as T1 (p < 0.01). CGRP longitudinal assessment of the fremanezumab group were excluded due to assay interference with the drug. VIP and PACAP plasma levels remained stable over time for all treatments, with no significant differences between responders and non-responders.ConclusionsGalcanezumab reduced CGRP plasmatic levels already after three months, whereas erenumab did not affect significantly CGRP plasmatic levels. VIP and PACAP levels were not influenced by the therapy.

Parkinson's disease (PD) is a neurodegenerative disorder marked by loss of substantia nigra dopaminergic neurons. Epidemiological evidence indicates that lifelong physical activity reduces both PD incidence and slows disease progression. Here, we examine how voluntary exercise induces long-lasting neuroprotection of the corticostriatal function in a murine model of α-synuclein-driven nigrostriatal pathology. In preformed fibril (PFF)-injected mice, long-lasting voluntary wheel running prevents degeneration of nigrostriatal dopaminergic terminals and improves motor performances. Intensive exercise normalizes spontaneous glutamatergic transmission and preserves corticostriatal long-term potentiation (LTP) in striatal spiny projection neurons. Exercise-induced LTP is dependent on activation of dopamine (DA) DA1, GluN2B-expressing NMDA and CB1 endocannabinoid (eCB) receptors. Pharmacological modulation of exercise-induced plasticity shows that, while in physiological conditions eCBs regulate synaptic depotentiation, persistence of LTP in active α-syn mice occurs independently of the eCB system, highlighting a critical interaction between DA and eCBs in long-term synaptic regulation. These findings identify voluntary exercise as a robust neuroprotective intervention with therapeutic relevance for early PD.

AimTo assess whether the timing of atogepant administration influences its tolerability and effectiveness over 12 weeks in patients with episodic and chronic migraine in a real-world setting.MethodsThis is a post-hoc analysis of the STAR study, a prospective, Italian, multicenter study evaluating atogepant 60 mg for migraine prevention. Data were collected at baseline (T0) and after the first 12 weeks (T3) of treatment. Patients were grouped by administration timing (morning vs. evening) and by administration with or without food. Changes in monthly headache days (MHDs), monthly migraine days (MMDs), and Migraine Disability Assessment (MIDAS) were measured. Tolerability was evaluated via adverse events (AEs). Linear mixed-effects models (LMMs) were used.ResultsEighty-one patients (86% females, mean age 50.8 ± 13.7 years) were included. At T3, MMDs decreased from 16.6 to 9.7 (p < 0.001) and MHDs from 19.8 to 11.9 (p < 0.001); 60% of patients achieved ≥50% reduction in MMDs. AEs occurred in 34 (42%) participants. Atogepant was taken in the morning by 57% and in the evening by 43% of patients. Fifty-seven out of 81 participants (70.4%) took atogepant with food. No significant differences in MMDs, MHDs, or AEs emerged between morning and evening users. Evening users had higher baseline MIDAS scores (estimated marginal means [EMMs]: 69.9 vs. 39.9, p = 0.034) that showed a greater reduction compared to morning users (F(1,63) = 6.29, p = 0.015), reaching similar final scores after 12 weeks (EMMs: 25.1 vs. 23.8). No difference in atogepant effectiveness and tolerability according to intake with or without food, except for a reduction in MHDs for patients who took atogepant without food (EMMs from 21.3 to 9.9 vs with food: EMMs from 18.4 to 12.7; F(1,79) = 8.553, p = 0.005).ConclusionsAtogepant significantly reduced migraine burden over 12 weeks in a real-world setting. Overall, the timing of atogepant administration did not affect its effectiveness or tolerability. However, a greater reduction in MIDAS scores was observed among evening users. Whether this reflects a pharmacological advantage or a ceiling effect remains unclear. Taking atogepant without food was associated with a significantly greater reduction in MHDs, whereas changes in MMDs and MIDAS scores did not differ between groups. Long-term and dedicated studies are needed to evaluate and confirm these findings.Trial RegistrationThe main study (STAR) was preregistered on clinicaltrial.gov, NCT06414044.

Dopaminergic drugs represent the cornerstone in the symptomatic management of Parkinson's disease motor manifestations, although their long-term use is associated with the appearance of motor fluctuations and dyskinesias. The correlation between pulsatile plasmatic levels of dopaminergic drugs and motor complications suggested that a central continuous dopaminergic stimulation (CDS) could prevent their development. Therefore, several methods have been implemented to provide more stable plasmatic levels of dopaminergic drugs and obtain a continuous drug delivery (CDD). Nevertheless, CDD does not necessarily mean CDS, since other peripheral pharmacokinetic factors intervene before the striatal dopamine release, along with central pharmacodynamic mechanisms. Here, we provide an overview of the different pharmacological approaches taken over time to reach CDS, with limitations and questions that remain open.