Writing abilities can be interpreted within dual-route models, which distinguish lexical and sublexical processes. The present study aimed to validate a novel writing to dictation test to assess both lexical and sub-lexical spelling abilities in an Italian population. A sample of 392 healthy participants provided robust normative data, revealing significant effects of age, education, and sex on spelling performance. Test-retest analyses indicated satisfactory reliability and minimal learning effects. The clinical feasibility of the test was explored in patients with amnestic Mild Cognitive Impairment (MCI) and Alzheimer's disease (AD). MCI patients mainly showed selective difficulties in spelling words with unpredictable orthography, suggesting early lexical impairment, whereas AD patients exhibited more severe and heterogeneous deficits involving both lexical and sublexical processes. Qualitative error analysis revealed multiple dysgraphic patterns, particularly in the AD group. Spelling performance did not significantly correlate with other cognitive domains, which may suggest a relative specificity of writing impairment. While the test provides a useful tool for assessing spelling abilities and characterizing writing to dictation disorders in neurodegenerative conditions, limitations related to sample stratification and socio-demographic representation were noted. The study underscores the importance of including standardized writing to dictation assessments in neuropsychological evaluations.

Glioblastoma is a highly malignant and refractory brain tumor with limited treatment options and poor prognosis. Although antibody-drug conjugate (ADC) have shown potential in glioblastoma therapy, their clinical utility is hampered by off-target toxicity. This study aimed to develop a novel NAD(P)H:quinone oxidoreductase 1 (NQO1)-responsive ADC, NRBM-25, to enhance targeting specificity and safety, and to investigate its antitumor mechanisms. NRBM-25 was constructed using an NQO1-enzyme-responsive linker to conjugate a vascular endothelial growth factor-targeting antibody with the cytotoxic payload monomethyl auristatin E, enabling tumor-specific activation. The NQO1-dependent activation mechanism was validated in isogenic and native cell models. In vitro and in vivo, NRBM-25 exhibited potent and selective cytotoxicity against NQO1-high glioblastoma cells while sparing NQO1-low normal cells. The conjugate induced dual modes of cell death-apoptosis and ferroptosis-accompanied by mitochondrial dysfunction, oxidative stress, and cell cycle arrest. In animal models, NRBM-25 significantly inhibited tumor growth, prolonged survival with minimal systemic toxicity, and outperformed temozolomide at medium-to-high doses. This approach of using an enzyme-dependent linker to dually induce apoptosis and ferroptosis offers a potential strategy to overcome treatment resistance, representing a new exploration in ADC-based therapy for glioblastoma. SIGNIFICANCE STATEMENT: A novel antibody-drug conjugate targeting glioblastoma was developed, which uses a tumor-specific enzyme activation mechanism and demonstrates favorable safety and antitumor efficacy in preclinical models. This candidate represents a new exploration in antibody-drug conjugate-based therapy for glioblastoma.

Dementia is a neurodegenerative disorder marked by cognitive decline affecting daily activities, including various conditions, however, early detection and classification of dementia using EEG signals is crucial. Hence, a novel "Dynamic Bayesian Morlet-Hilbert Consensus Spectrum Optimization" is proposed to enhance the accuracy of dementia diagnosis, specifically for Alzheimer's Disease and Mild Cognitive Impairment. Additionally, Cholinergic System Dysfunction, characterized by non-uniform brain degeneration, complicates EEG feature extraction due to heterogeneous neural activity patterns, and existing models struggle to accurately interpret these patterns. Thus, a novel Adaptive Morlet Consensus Beamforming Transform is introduced to capture heterogeneous neural activity patterns and adapt to complex brain regions, thereby improving the identification of biomarkers associated with cholinergic system dysfunction. Furthermore, existing models often overlook the striatum due to its intricate structure and the cholinergic system's impact on cognitive functions, making it challenging to accurately assess cholinergic dysfunction. So, a novel Multilayer Adaptive Dynamic Causal Frequency Decomposition is introduced to detect subtle variations in brain function, improving the identification of early-stage dementia-related changes linked to cholinergic system dysfunction. Moreover, the striatum, a complex structure with subregions, exhibits varying impacts of cholinergic dysfunction, causing significant variability in cognitive and motor functions. Therefore, a novel Bayesian Hilbert-ElasticNet Spectrum Optimization is introduced to effectively capture the spectral and temporal dynamics of EEG signals to classify subtle variations in dementia. The results demonstrate that the methodology significantly improves classification performance, achieving an accuracy of 98.23%, along with precision and F1-Score rates of 98.84% and 97.52%, respectively, while minimizing RMSE and enhancing processing efficiency.

Spinal cord injury (SCI) disrupts the local microenvironmental niche, resulting in persistent neuroinflammation, vascular dysfunction, and impaired neuronal regeneration, presenting a significant challenge for tissue repair. In this context, hydrogels offer a versatile strategy for targeted and sustained therapeutic delivery and localized microenvironmental modulation. To facilitate niche restoration following SCI, we developed a bioinspired platform by integrating KTPSLEQRTVYAKGGIKRGK-brain-derived neurotrophic factor mimetic peptides (TPS-BDNF) into a dopamine-modified gelatin methacryloyl hydrogel. In vitro and in vivo studies demonstrated that the proposed hydrogel exhibits optimal injectability, shear-thinning behavior, and intrinsic antioxidant and anti-inflammatory properties, thereby facilitating minimally invasive delivery and localized microenvironment modulation. Furthermore, the TPS-BDNF endows the multifunctional hydrogel with sustained neurotrophic and pro-angiogenic cues that promote the restoration of the neurovascular niche and subsequent functional recovery after SCI. In summary, the bioinspired hydrogel offers a promising, clinically translatable approach to synergistic niche remodeling for the restoration of neuronal function following SCI. STATEMENT OF SIGNIFICANCE: The gelatin methacryloyl (GelMA) /dopamine/Polyethylene glycol-conjugated KTPSLEQRTVYAKGGIKRGK-brain-derived neurotrophic factor mimetic peptides (TPS-BDNF) (GDP) hydrogel represents a significant advance for spinal cord injury (SCI) therapy by simultaneously promoting neurogenesis and angiogenesis while delivering strong anti-inflammatory and antioxidant effects. By integrating TPS-BDNF with a GelMA-based matrix, GDP remodels the lesion microenvironment, enhances endogenous neural stem cell mobilization and neuronal differentiation, and improves functional recovery in SCI animals, all with injectable, controllable release and minimal systemic toxicity. This platform holds strong potential for translation to human SCI treatment.

Diabetes and obesity are associated with poorer outcomes after ischemic stroke; however, it remains unclear whether this results from increased neuronal susceptibility to injury or from vascular dysfunction induced by metabolic syndrome. To minimize the contribution of vascular factors, we used a model of photoinduced thrombosis (PT) in cortical vessels, which generates lesions of reproducible size and is less dependent on collateral blood flow. PT was induced in wild-type (WT) mice, as well as in ob/ob (leptin-deficient) and db/db (leptin receptor-deficient) mice. Magnetic resonance imaging (MRI) revealed that PT produced comparable infarct volumes in all mouse groups. Several genes associated with inflammation and activation of microglia and macroglia in the peri-infarct area (Cst7, Ccl3, Tlr2, Gfap) exhibited similar expression patterns across all three mouse strains, while transcriptional response to cerebral ischemia of Tnfa, Cxcl9, Il6, Cox2, Mmp3, and Bdnf genes depended on the genotype. Overall, despite individual differences in the expression profiles of certain genes, disruption of leptin signaling (whether due to leptin deficiency or leptin receptor deficiency) caused no genotype-specific exacerbation of stroke-induced injury. Assessment of post-stroke neurological deficits revealed substantial differences in absolute scores between WT and ob/ob or db/db mice, attributable to baseline disparities in body weight and motor activity. In db/db mice, normalization of post-stroke neurological status scores to pre-injury values revealed a more pronounced relative functional decline compared to ob/ob mice, suggesting impairments in early compensatory mechanisms and an important role of leptin signaling in neuroplasticity rather than in the extent of acute neuronal damage. Thus, under conditions that minimize vascular complications, neither leptin deficiency nor leptin receptor deficiency exacerbated acute ischemic brain damage or neuroinflammation.

Lance-Adams syndrome is a severe and disabling posthypoxic myoclonus in humans. Its underlying mechanisms are still unknown. We aimed to develop a new animal model of Lance-Adams syndrome. We performed our procedures on Sprague-Dawley rats monitored for basic cardiorespiratory parameters. The Group 1 was sedated and submitted to hypoxia in a dedicated cage where oxygen was replaced with nitrogen. The Groups 2 and 3 were sedated, intubated, ventilated, and submitted to anoxia with the replacement of oxygen by nitrogen in the ventilatory circuit, either continuously (Group 2) or intermittently (Group 3). Rats benefited from cardiopulmonary resuscitation. Each rat was evaluated daily for spontaneous, wandering-induced, and auditory stimuli-induced myoclonic jerks, for the latter using a quantitative myoclonus score. In the Group 1 (n = 19), the duration of hypoxia was 25 ± 20 min for the surviving animals (n = 14/19) and minimal partial pressure of oxygen in the cage was 7.2 ± 0.8%. In the Group 2 (n = 38), the duration of anoxia was 5.6 ± 1.9 min for the surviving animals (n = 23/38). In the Group 3 (n = 30), the total duration of anoxia was 15 ± 3.5 min in the surviving animals (n = 15/30). These three procedures did not allow for generating a myoclonic phenotype. Some refinements of hypoxic/anoxic procedures are still needed to develop an animal model of posthypoxic myoclonus that would be a precious tool to understand better the pathophysiology of Lance-Adams syndrome.

Aging-induced neurodegeneration is characterized by cognitive impairment, elevated oxidative stress, neuroinflammation, synaptic loss, and neuronal death. Atraric acid (AA), a phenolic compound obtained from lichens, is reported to have potent anti-inflammatory and antioxidant effects in various disease models. However, aging-induced cognitive impairment and dementia are still not elucidated. To fill this gap, we investigated AA (20 mg/kg/day, intraperitoneally (i.p.) for 4 weeks) against D-galactose (D-gal) (120 mg/kg/day, i.p. for 8 weeks)-induced brain senescence and memory dysfunction in mice. Behavioral tests, including NOR, MWM, and Y-maze, were conducted to assess cognitive function, followed by biochemical and immunofluorescence analyses. AA restored the BDNF/TrkB/Akt signaling axis disrupted by D-gal administration. Furthermore, immunoblotting for Nrf-2 and HO-1 revealed elevated expression in the mouse cortex and hippocampus. AA also enhanced antioxidant enzymes, including glutathione (GSH), glutathione S-transferase (GST), catalase (CAT), and superoxide dismutase (SOD), while reducing lipid peroxidation (LPO), thereby supporting its antioxidant role. Moreover, D-gal enhanced NF-kB-mediated neuroinflammation, apoptotic markers including caspase-3 and PARP-1, and suppressed synaptic proteins (SNAP-23 and PSD-95). Interestingly, these expression aberrations were reversed upon AA administration. Histological analyses using Nissl and Fluoro-Jade B staining further supported neuronal protection in the cortex and hippocampus. Collectively, these findings suggest that AA exerts neuroprotective effects against D-gal-induced aging and cognitive decline by reducing oxidative stress, neuroinflammation, neuronal apoptosis, and enhancing synaptic plasticity through BDNF/TrkB/Akt/CREB signaling.

Major depressive disorder is a leading cause of disability worldwide, with significant challenges in treatment response, adherence and functional recovery. Despite the availability of numerous antidepressants, a substantial proportion of patients fail to achieve remission with initial therapy, underscoring the need for effective first-line treatment options. Desvenlafaxine, a serotonin-noradrenaline reuptake inhibitor, has demonstrated efficacy and safety in major depressive disorder, while its pharmacokinetic properties result in minimal drug-drug interactions. This narrative review evaluates clinical evidence supporting the use of desvenlafaxine as a first-line treatment and examines patient subgroups that may benefit most from this antidepressant. A comprehensive literature review was conducted to evaluate the evidence on desvenlafaxine in the treatment of major depressive disorder. This was supplemented by clinical insights discussed during a virtual advisory board meeting held on 16 December, 2024, attended by the authors-psychiatrists from Italy, Germany, Spain, Ireland and Portugal-together with representatives from Neuraxpharm, who market desvenlafaxine. The available evidence suggests that desvenlafaxine offers early symptom relief, sustained efficacy across diverse major depressive disorder symptom clusters, and benefits for patients with anhedonia, fatigue, cognitive dysfunction and functional impairment. Its tolerability and safety profile, including a lower risk of weight gain and drug-drug interactions, contributes to its ease of use and improved adherence. Based on the authors' clinical consensus, desvenlafaxine may be particularly suitable for working-age adults, perimenopausal and menopausal women, those with general medical comorbidities or polypharmacy concerns, and individuals requiring an antidepressant with a broad mechanism of action. In addition, its predictable pharmacokinetics make it a practical choice in primary care settings. While most current guidelines typically recommend selective serotonin reuptake inhibitors as first-line treatment, the favourable tolerability profile and efficacy of desvenlafaxine across diverse symptom clusters may support its consideration as a first-line option in select patient populations.

Tauopathies are pathologies wherein phosphorylated insoluble tau aggregates in neurons, leading to dysfunction and degeneration. Positron emission tomography (PET) enables measurement of in vivo tau, with second-generation radiotracers such as [[18]F]MK6240 showing high tau affinity with minimal off-target binding. While tauopathies are commonly linked to age-related neurodegenerative diseases, notably Alzheimer's disease (AD), evidence suggests pathophysiological cascades may begin long before clinical onset. Increasingly, tau is recognized in pathologies affecting younger individuals, including autosomal dominant AD, Niemann-Pick disease type C, chronic traumatic encephalopathy, and epilepsy, thus highlighting the importance of normative data in non-geriatric populations. Here, we present a dataset of 33 young to middle-age healthy adults (mean age 34.0 ± 10.4 years, 12 female) with [[18]F]MK6240 PET data and T1w magnetic resonance imaging. Longitudinal data are also available in a subset of 9 participants with a minimum follow-up time of 1 year. Our dataset aims to support imaging biomarker studies on younger individuals potentially at risk for AD and to advance work in tauopathies affecting non-geriatric populations generally excluded from neurodegeneration studies.

Tracheoesophageal fistula (TEF) in adults is an uncommon but clinically significant condition that poses considerable challenges in anesthetic management. Most acquired cases are associated with prolonged mechanical ventilation, trauma, malignancy, or corrosive injury, with postintubation injury being a well-recognized etiology. We report a 29-year-old male who developed TEF following prolonged ventilatory support for traumatic brain injury. He presented with dysphagia, regurgitation, and intermittent vomiting. Chest computed tomography revealed chronic bronchitis, emphysema, and bilateral pneumonic changes with partial right lung consolidation. Pulmonary function testing showed moderate-to-severe restrictive ventilatory dysfunction. Esophagography confirmed a fistulous communication at the T4 level, with contrast entering the right bronchus. In view of the risk of gas leak through the fistula associated with pneumoperitoneum during laparoscopic surgery, an open surgical approach was planned. Anesthesia was induced with propofol and succinylcholine. To achieve one-lung ventilation and bypass the right-sided defect, a left-sided double-lumen tube was inserted under videolaryngoscopic guidance, and its position was confirmed using fiber-optic bronchoscopy. Anesthesia was maintained with sevoflurane, with strategies aimed at minimizing positive pressure-related complications. The intraoperative course remained stable without significant events. The patient was monitored postoperatively in the intensive care unit, and recovery was uneventful following confirmation of repair integrity. This case highlights the importance of meticulous airway and ventilation planning in TEF, emphasizing that fistula characteristics and underlying pulmonary status are critical determinants of anesthetic strategy.

Cerebral malaria (CM), the most severe neurological manifestation of Plasmodium infection, is characterized by microglial activation that plays a pivotal role in initiating pathogenic neuroinflammatory cascades. Tunneling nanotubes (TNTs) are dynamic F-actin-based intercellular connections which transfer mitochondria and pathogenic factors. Although TNTs have been implicated in various neuropathological conditions, their precise involvement in CM pathogenesis, particularly in relation to microglial activation, remains undefined. In this study, single-cell RNA-sequencing (scRNA-seq) revealed significant dysregulation of TNT-associated genes and actin cytoskeleton pathway remodeling in microglia of ECM model. In vitro studies demonstrated that Plasmodium-infected red blood cells (pRBCs)-stimulated primary microglia formed extensive F-actin-rich tunneling nanotubes, which mediated the bidirectional transfer for mitochondria and facilitated intercellular trafficking of lysosomal contents and malarial pigment. These TNT-mediated intercellular communication amplified microglial activation, as evidenced by: (i) lipid peroxidation, (ii) mitochondrial dysfunction, and (iii) autophagosome (LC3+) accumulation. This process further amplifies neuroinflammation through TNFα/IL-6 secretion and expansion of CD45high microglial populations. Pharmacological TNT inhibition restores microglial homeostasis in ECM model. In conclusion, TNTs mediate neuroinflammation in the ECM model by transferring mitochondria and malarial pigment between microglia. Although mitochondrial transfer may transiently support cellular homeostasis, progressive malarial pigment accumulation triggers lipid metabolism dysregulation and amplified neuroinflammation. Inhibiting TNTs formation attenuates microglial hyperactivation, highlighting targeted regulation of TNT-mediated intercellular communication as a potential therapeutic approach for CM-associated neuropathology.

Although sleep deprivation (SD) is clinically associated with numerous neuropsychiatric disorders, its underlying molecular correlates remain unclear. Because extended wakefulness is accompanied by increased neuronal activity and network firing, SD may be associated with a hyperactive neural state. This study aimed to test the hypothesis that SD shares transcriptomic signatures induced by neuronal hyperexcitation and to identify the gene pathways and cell types associated with these signatures. Publicly available transcriptomic datasets were analyzed, including 32 SD and 23 neuronal hyperexcitation transcriptomic datasets. These datasets were systematically compared using the Running Fisher algorithm across multiple mouse brain regions and rodent neuronal hyperexcitation models. The analysis revealed significant positive transcriptomic overlaps between SD and neuronal hyperexcitation models (p ≤ 0.05 in 73% of cross-model comparisons). In addition, neuronal hyperexcitation datasets collected within 1-12 h after seizure induction showed stronger transcriptomic similarity to SD than those collected 24 h or later. The shared transcriptomic signature was significantly enriched for pathways associated with neuronal plasticity, immune response, and inflammation. Key overexpressed genes common to both conditions included immediate early genes (IEGs) such as Egr1, Fos, and Arc, as well as inflammation-associated genes such as Ptgs2 and Junb. Comparisons between SD single-cell and neuronal hyperexcitation datasets indicated that the shared signature was most strongly enriched in microglia and neurons, with additional contributions from endothelial cells and astrocytes. Microglia showed enrichment of stress- and immune-response genes, neurons exhibited IEG and plasticity-related signatures, and endothelial cells expressed metabolism-associated genes. Together, these findings indicate that SD is associated with a transcriptomic state resembling acute neuronal hyperexcitation, characterized by activation of neuronal plasticity-, neuroinflammatory-, and metabolism-related pathways. This shared molecular signature provides a transcriptomic framework linking sleep loss to molecular processes implicated in neuropsychiatric disorders and suggests that acute neuronal hyperexcitation-related molecular processes may contribute to SD-associated brain dysfunction.