Abstract: Background: Age-related hearing loss (HL) is a significant independent risk factor for Alzheimer's disease (AD), yet the molecular mechanisms underlying this comorbidity and the comparative efficacy of hearing interventions on cognitive outcomes remain unclear. This study aims to integrate clinical evidence and molecular data to address these gaps. Objective:To conduct a systematic review and network meta-analysis (NMA) to: 1) compare the effects of hearing interventions on cognitive function in AD patients; 2) identify and rank key microRNAs (miRNAs) associated with AD-HL comorbidity; 3) explore heterogeneity sources; and 4) cross-validate findings with independent clinical sequencing data. Methods: We systematically searched PubMed, Web of Science, Embase, and Cochrane Library up to May 2025. Included studies involved AD patients with/without HL, re-porting cognitive scores (MoCA, MMSE, AVLT) or miRNA expression data. A NMA was performed to rank interventions (cochlear implants-CI, hearing aids-HA, no in-tervention-NI) and miRNAs using surface under the cumulative ranking (SUCRA) curves. Heterogeneity was assessed via subgroup analysis and meta-regression. Pooled miRNA expression results were cross-validated against an independent clinical se-quencing dataset (LC-P20240110033, n=16) using intraclass correlation coefficient (ICC) and Bland-Altman plots. Results: Twelve studies (2,137 patients) were included. HL was significantly associated with worse cognitive function (MoCA: SMD = -0.82, 95% CI: -1.15 to -0.49; AVLT delayed recall: SMD = -1.12, 95% CI: -1.56 to -0.68). NMA revealed CI (SUCRA=0.89) was superior to HA (SUCRA=0.62) and NI (SUCRA=0.09) for preserving MoCA scores. Among nine differentially expressed miRNAs, hsa-miR-6875-5p was the most consistent biomarker (pooled FC = 1.52, 95% CI: 1.04–2.23), showing excellent agreement with sequencing data (FC = 3.29; ICC = 0.82, 95% CI: 0.67–0.91). Heterogeneity was significantly influenced by miRNA detection platform (p=0.04) and HL severity (p=0.03).Conclusion: This study demonstrates that HL exacerbates cognitive decline in AD in a dose-dependent manner. Cochlear implants may offer superior cognitive protection compared to hearing aids. The consistently dysregulated hsa-miR-6875-5p emerges as a promising cross-modal biomarker, bridging clinical observation and molecular pathology in AD-HL comor-bidity.

Abstract: A PIEZO2 variant was shown recently to protect against Alzheimer’s disease in the Hispanic population. This analysis implicates the potentially critical role of Piezo2 in Alzheimer’s disease pathophysiology. Another recent research mimicked acquired Piezo1 channelopathy by PIEZO1 manipulation. This study also showed that phosphatidylinositol 4,5-bisphosphate (PIP2) administration ameliorated brain capillary endothelial Piezo1 channelopathy in a mouse model of Alzheimer’s disease. However, the initiating microdamage is suggested to be in the prefrontal cortex further upstream of pathophysiology, namely an irreversible Piezo2 channelopathy of glutamatergic terminals that should fine modulate oxytocin release along stressful ultradian events. Implication of Piezo2 in the defensive arousal response reveals an underlying body-wide Piezo2 system of which the proposed prefrontal Piezo2 channelopathy posits a critical locus. PIP2 is emerging as a potential treatment method of Piezo channelopathy in Alzheimer’s disease, however the challenge remains how it could be administered more precisely to affected brain areas.

Abstract: Low-dose radiation (LDR) has emerged as a promising therapeutic modality for Alzheimer’s Disease (AD). Although different irradiation protocols have been explored, the optimal parameters for maximizing therapeutic efficacy remain unclear. Radiation energy has been shown to influence radiobiological responses, with more pronounced effects at lower energy ranges. We therefore investigated whether kilovoltage LDR (KLDR) provides superior therapeutic efficacy compared with megavoltage LDR (MLDR) in an AD mouse model (3xTg-AD). To this end, we directly compared the efficacy of MLDR and KLDR in AD mice to identify an optimal irradiation strategy for LDR treatment with potential relevance to clinical translation in AD. X-rays with 110-kV or 6-MV energy were applied to the brain of early-stage AD mice (3xTg-AD, 26-28 weeks age) (0.6 Gy × 5 fractions for 2.5 weeks). After LDR treatment, cognitive function was assessed in AD mice using passive avoidance (PA) test and novel object recognition (NOR) test. In addition, different molecular markers associated with inflammation, amyloid-beta (Aβ) plaques, tau burden, and neuronal and synaptic degeneration, were analyzed in the brain of AD mice. KLDR (110 kV) significantly inhibited cognitive decline in AD mice, as demonstrated by both the PA and NOR tests. In addition, KLDR significantly reduced hippocampal levels of GFAP, Iba-1, and pro-inflammatory cytokines (TNF-α and IL-1β), along with marked decreases in Aβ and tau levels. Furthermore, the expression levels of Aβ40 and Aβ42 were quantified by ELISA following KLDR and MLDR treatment, revealing a statistically significant reduction in the KLDR group. The degeneration of neurons and synapses was significantly suppressed also at the kilovoltage energy level. Conversely, MLDR (6 MV) exerted minimal effects and did not produce statistically significant improvements. Taken together, our findings demonstrate that radiation energy level is a key determinant of LDR therapeutic efficacy in AD mice, with KLDR showing significantly greater effectiveness in improving AD-related pathological features than MLDR. Therefore, KLDR may be recommended as a novel radiation protocol for AD treatment.

Abstract: Neuroinflammation has emerged as a central mechanism in the pathogenesis of epilepsy, particularly in drug-resistant epilepsy (DRE), where conventional antiseizure medications fail to achieve adequate control. Accumulating evidence indicates that inflammatory processes within the central nervous system contribute not only to seizure initiation but also to their perpetuation and pharmacoresistance. Among the key cellular mediators that play a pivotal role in neuroinflammation is microglia, which are the resident immune cells of the brain. In response to neuronal injury, infection, or recurrent seizures, microglia undergo activation and adopt diverse phenotypes ranging from pro-inflammatory to neuroprotective states. However, sustained or dysregulated microglial activation promotes the release of pro-inflammatory cytokines, chemokines, and reactive oxygen species, thereby exacerbating neuronal hyperexcitability, disrupting synaptic function, and facilitating epileptogenesis. Recent researches have increasingly focused on targeting microglial activation as a therapeutic strategy in DRE. Preclinical and clinical studies have explored a range of anti-inflammatory interventions, including cytokine inhibitors, modulators of microglial signaling pathways such as Toll-like receptor and NF-κB pathways, and repurposed agents like minocycline and corticosteroids. Additionally, emerging therapies aimed at selectively modulating microglial phenotypes, shifting from pro-inflammatory to neuroprotective states, offer promising avenues for intervention. Despite these advances, challenges remain in translating these strategies into routine clinical practice, including issues of specificity, timing of intervention, and potential systemic side effects. Therapeutically, targeting microglial activation holds significant promise for addressing the unmet needs in DRE by not only reducing seizure frequency but also potentially modifying disease progression. A deeper understanding of microglial biology and its interaction with neuronal networks may facilitate the development of precision therapies tailored to inflammatory profiles in epilepsy. This review highlights the evolving landscape of microglia-targeted therapies and underscores their potential as a novel and complementary approach in the management of drug-resistant epilepsy.

Abstract: Background: The Testamentary Capacity Assessment Tool (ΤCAT) is a brief instrument with good psychometric properties, specifically designed for the assessment of testamentary capacity (TC) in individuals with dementia. It assesses memory, perception of financial matters and judgment, as well as cognitive functions, such as theory of mind, not measured by other traditional tools. Additionally, it does not require collateral sources of financial information. Aim of the present study was to provide an updated report on the use of the TCAT in research and systematic review studies. Methods: This narrative review includes studies that have used the TCAT for clinical use, validation in different culture, and comparison with the two other specialized TC assessment tools. The Pubmed database was searched using the keyword “Testamentary Capacity Assessment Tool”. Results: The TCAT has been validated in healthy Italian population and was found to be a useful adjunct instrument for TC assessment in older adults. Another study demonstrated its clinical utility in patients with acute ischemic stroke. A systematic review compared the TCAT to the other two existing specialized TC assessment tools, namely the Testamentary Capacity Instrument (TCI) and the Testamentary Definition Statement (TDS) and highlighted the superiority of the TCAT in clinical practice. Conclusions: TCAT is a useful, specialized screening tool that is easily applicable in clinical practice by both experts and non-experts. Further studies are recommended across different cultures, in both healthy and cognitively impaired adults, to support its standardized use in forensic and clinical settings.

Abstract: The DMD gene is well known for its product dystrophin, a large rod-shaped protein that plays a critical role in muscular membrane strength and integrity. Mutations affecting dystrophin lead to Duchenne muscular dystrophy, a fatal X-linked disease characterized by muscular weakness and breakdown. In addition to the full-length dystrophin product that is most often associated with disease, the DMD gene also encodes for multiple shorter isoforms of dystrophin with diverse functions. One isoform in particular, Dp71, has been increasingly found to play a wide variety of roles throughout the body. In this review, we consolidate the numerous studies on Dp71 to provide a comprehensive foundation for future work. We outline and summarize the current state of knowledge on the role of Dp71 in the brain, the retina, and skeletal muscles. We also explore Dp71-based therapies currently being tested in the pre-clinical landscape.

Abstract: Background: We investigated whether combining sural nerve sensory conduction study (s-SCS) and tibial nerve SEPs (t-SEPs) improves diagnostic accuracy for peripheral sensory neuropathy. Methods: We retrospectively reviewed 74 consecutive cases (114 lower limbs) of patients suspected of having neuropathy or radiculoneuropathy who underwent s-SCS and t-SEPs between July 2021 and December 2024. Abnormal s-SCS was defined as an amplitude <3.8 µV or a conduction velocity <39.3 m/s. Abnormal t-SEPs were defined as the failure to evoke N20, N20 latency >24.37 ms, the failure to evoke P37, or P37 latency >44.35 ms. Results: No cases showed s-SCS abnormalities with normal t-SEPs. Group 1 (G1) had normal s-SCS and normal t-SEPs, which were observed in 31 limbs (27.2%). Group 2 (G2) had normal s-SCSs and abnormal t-SEPs, which were found in 45 limbs (39.5%). Subgroups of G2 included normal N20 with abnormal P37, abnormal N20 with normal P37 and N20/P37 abnormalities. Group 3 (G3) had abnormal s-SCSs with abnormal t-SEPs, which was seen in 38 limbs (33.3%). Conclusions: Electrophysiological testing reveals normal distal and proximal sensory nerves in G1, suggesting preserved sensory nerve function. The distal sensory nerves are normal in G2. However, abnormal N20/P37 and abnormal N20 with nP37 indicate proximal sensory nerve involvement. Normal N20 with abnormal P37 indicates posterior column dysfunction. In G3, both the distal and proximal sensory nerve segments are abnormal. Therefore, adding t-SEPs to s-SCSs allows us to evaluate the full length of the peripheral nerves, which is useful for diagnosis and assessing treatment efficacy.

Abstract: Background: Post-stroke cognitive impairment (PSCI) is a common complication affecting a substantial proportion of stroke survivors and is associated with reduced functional independence, poorer rehabilitation outcomes, and increased caregiver burden. Early identification of patients at risk remains challenging. Neurofilament Light Chain (NfL), a marker of neuroaxonal injury, has emerged as a potential blood-based biomarker in neurological disorders.Objective: To systematically evaluate prospective evidence on NfL as a predictor of cognitive impairment following ischemic or hemorrhagic stroke.Methods: A systematic review was conducted in accordance with PRISMA Guidelines. PubMed, Cochrane Library, and ScienceDirect were searched for prospective cohort studies assessing plasma or serum NfL levels and subsequent cognitive outcomes in adult stroke patients. Eligible studies evaluated cognitive outcomes using validated assessment tools during follow-up. Due to methodological heterogeneity across studies, findings were synthesized narratively due to methodological heterogeneity.Results: Seven prospective cohort studies involving 2,907 stroke patients were included. Most studies measured NfL within 24-48 hours after stroke onset and assessed cognitive outcomes between 3 and 12 months. Across studies, elevated baseline NfL levels were consistently associated with an increased risk of PSCI and lower cognitive scores. In multivariable analyses, NfL remained independently predictive after adjustment for age, stroke severity, and infarct volume. Reported discriminative performance ranged from AUC 0.672 to 0.865, indicating moderate to good predictive ability.Conclusion: Blood-based NfL measurement is consistently associated with post-stroke cognitive impairment. These findings support circulating Nfl as a promising biomarker for early risk stratification of PSCI in stroke survivors.

Abstract: Interdisciplinary research is needed on the biomechanical and structural pathways that might explain why people with connective tissue disorders like hypermobile Ehlers-Danlos Syndrome (hEDS) are particularly susceptible to Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and ME/CFS-like presentations of Long COVID. In particular, research is needed on the role that disordered fascia and lymphatic system dysfunction might play in the pathophysiology of ME/CFS and Long COVID. Research is also needed on the role that spinal conditions like craniocervical instability and Chiari Malformation might play in obstructing outflow from the glymphatic system.

Abstract: The review explores the development of non-implantable vestibular devices designed to address postural instability, particularly in aging populations and patients with vestibular hypofunction. It establishes that balance relies on complex sensory integration and that the functional decline of this system creates a significant medical need. Three principal technological strategies are examined: sensory substitution devices, galvanic vestibular stimulation (GVS), and immersive visual feedback systems. Sensory substitution devices, which convert balance data into auditory, tactile, or electrotactile cues, demonstrate significant promise. Examples like vibrotactile belts provide feedback that reduces postural sway, enhancing stability and patient confidence. Parallel to this, GVS—using electrical currents applied to the mastoids—emerges as a potent non-invasive method to modulate vestibular pathways, improving balance control and even inducing neuroplastic changes, especially with stochastic “noisy” signals. Most recently develop devices include augmented and virtual reality technologies offer innovative visual feedback, creating enriched rehabilitation environments that accelerate recovery by promoting sensory reweighting and neural adaptation. The review concludes that while implantable prostheses are advancing, non-invasive devices offer versatile, affordable and complementary solutions for balance restoration. Future success of non-invasive alternatives hinges on developing more sophisticated stimulation protocols that account for the complexity of natural movement and individual patient contexts, ultimately expanding therapeutic options for vestibular disorders.

Abstract: Background: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterised by progressive motor neuron loss and neuroinflammation. Current disease-modifying therapies provide only marginal benefit, and microglial NLRP3 inflammasome hyperactivation has emerged as a key pathological amplifier common to all ALS genetic and sporadic subtypes. Colchicine, an anti-inflammatory alkaloid approved for gout and pericarditis, potently inhibits NLRP3 assembly through tubulin disruption and direct blockade of ASC oligomerisation. Hypothesis and Aims: We hypothesise that low-dose colchicine can attenuate microglial NLRP3-driven neuroinflammation in ALS, thereby slowing motor neuron loss and disease progression. We present a mechanistic synthesis of the NLRP3 pathway in ALS, review available clinical and preclinical evidence for colchicine in neuroinflammatory diseases, and propose a precision biomarker-stratified clinical trial design. Methods and Evidence: We performed a systematic review of published literature on NLRP3 inflammasome activation in ALS, colchicine’s pharmacology and safety profile, and relevant clinical trial evidence including the Co-ALS randomised controlled trial. Candidate biomarkers for patient stratification and outcome monitoring were identified from the literature. Results: NLRP3 inflammasome activation is documented across ALS subtypes including SOD1, C9orf72, and TDP-43 proteinopathies. Colchicine inhibits NLRP3 at multiple points, reduces IL-1β and IL-18 release, and crosses the blood–brain barrier. The Co-ALS trial demonstrated acceptable safety and tolerability of colchicine in ALS patients. Chitotriosidase-1 (CHIT1) plasma levels are validated as an accessible microglial activation biomarker. We propose a Phase 2b biomarker-stratified trial incorporating CHIT1, plasma neurofilament light (NfL), and plasma NLRP3 as stratification and outcome measures. Conclusions: Colchicine represents a biologically plausible, affordable, and safe candidate for repurposing in ALS via NLRP3 inhibition. The gap between mechanistic evidence and clinical design can be bridged by incorporating neuroinflammatory biomarkers into future trials. High-CHIT1 patients are predicted to derive maximum benefit and should be prioritised for recruitment.

Abstract: Background: Essential tremor (ET) is increasingly recognized as a heterogeneous disorder that may present with additional parkinsonian or cerebellar features, complicating its differential diagnosis from Parkinson’s disease (PD) and degenerative ataxia (DA). Oculomotor assessment has been proposed as a potential tool for identifying disease-specific patterns. Methods: We evaluated eye movement parameters in 50 patients with ET (including subgroups with parkinsonian and/or cerebellar signs), 50 patients with PD, 42 patients with degenerative ataxias, and 42 healthy controls. Reflexive, pace-induced, and cued saccades were recorded using saccadometry, while smooth pursuit and fixation were assessed with electrooculography. Group comparisons focused on saccadic metrics and the frequency of abnormalities. Results: Hypometria of pace-induced saccades was observed in patients with PD (32.0%) and degenerative ataxias (57.1%) but was not detected in any ET subgroup, including those with parkinsonian or cerebellar features. Reflexive saccade hypometria was less frequent in ET patients with parkinsonian features compared to PD (50.0% vs. 66.0%, p = 0.016). Other oculomotor parameters showed substantial overlap between groups. Conclusions: ET patients, including those with additional parkinsonian or cerebellar signs, exhibit partially distinct oculomotor features compared with PD and degenerative ataxias, particularly in pace-induced saccades. These findings require confirmation in larger, well-characterized cohorts.

Abstract:

Impulse Control Disorders (ICDs) are increasingly recognized non-motor complications in PD patients with multiple negative consequences for the individual and caregivers. ICDs are frequently observed in PD patients treated with dopaminergic agents, however not all patients develop these behavioral disorders, suggesting that other factors may increase susceptibility for PD-ICDs. This review aims to analyze current knowledge on the genetic background of ICDs. For this narrative review article, we searched PubMed and Scopus databases for peer-reviewed research, review articles, and meta-analyses regarding the role of genetics in ICDs, published in the English language with no time restrictions. References of the selected articles for possible additional articles were also screened in order to include most of the key recent evidence. This review pinpoints the critical role of genes that encode for enzymes, transporters and receptors that participate in the dopaminergic system, in ICD pathogenesis. Glutamate receptor, ionotropic, N-methyl-d-aspartate 2B (GRIN2B), involved in the glutamatergic pathway and hydroxytryptamine receptor 2A (HTR2A) and tryptophan hydroxylase 2 (TPH2) involved in the serotoninergic pathways, are also highlighted as important risk factors, as well as Opioid receptor kappa 1 (OPRK1) and Opioid receptor Mu 1 (OPRM1) that participate in the opioid system. Early recognition of genetic factors that increase susceptibility for ICDs in PD patients is awaited to increase diagnostic accuracy and expedite individualized treatment.

Abstract: It is hypothesized that in most cases of sporadic late-onset Alzheimer’s disease (LOAD), the abnormally-elevated cholesterol level in brain neurons represents a critical caus­ative factor that drives the pathogenic processes of LOAD. Specifically, it is hypothesized that the abnormally-elevated neuronal cholesterol will disrupt mitochondrial structure and metabolic activity, resulting in ATP deficiency as well as reduced formation of neuroactive metabolic intermediates (such as mevalonate and geranylgeraniol) along the cholesterol synthesis pathway in brain neurons. In addition, the abnormally-elevated neuronal cholesterol will cause direct neuronal damage as well as other pathogenic changes in the brain, including increased formation and aggregation of amyloid (Aβ) plaques. It is speculated that Aβ accumulation and plaque formation in a majority of LOAD cases only represent a characteristic secondary pathological change, and are usually not the driving force in the pathogenesis of LOAD. As discussed in this paper, the abnormally-elevated neuronal cholesterol in conjunction with ATP deficiency and lack of neuroactive metabolic intermediates will not only cause learning and memory impairment, but will also reduce the formation of cholinergic vesicles and induce tauopathy. It is expected that these pathogenic changes are more readily seen initially in ischemia-sensitive neurons in the hippocampus and posterior parietal cortex, which is then followed by progressive neurodegenerative and atrophic changes in many other brain regions along with progressive cognitive decline. As explained in this paper, ApoE4 is a major risk factor in LOAD because ApoE4 has a drastically reduced ability than ApoE2 and ApoE3 to efflux excess cholesterol out of neurons. Overall, there is a large body of direct, indirect and circumstantial clinical and experimental evidence which jointly supports the cholesterol-centered hypothesis on the etiology and pathogenesis of LOAD.

Abstract: Folate receptor-alpha (FRα) transports folate to germline cells and across the placental and blood-brain barrier to the brain. FRα autoantibodies (FRαAb) occur in ~70% of autistic children devoid of genetic defects, and ~1/3 of their asymptomatic parents. Folinic acid circumvents blocked folate transport. In children positive for FRαAb whose parents tested negative for FRαAb, high dose folinic acid treatment before 3 ½ years, results in improved outcome (88%). High autism prevalence with poor outcome (29%) is observed when mothers or both parents are positive for FRαAb. We postulated that folinic acid treatment of parents before and during pregnancy may reduce the risk of autism in further offspring. In a prospective open label pilot study, parents with positive FRαAb wishing to have further children, took daily levo-folinic acid (3.75 mg) or an equivalent dose of dl-folinic acid (7.5 mg) three months before conception and throughout pregnancy. Among five families where all mothers and three fathers tested positive for FRαAb, folinic acid prevented autism in all 7 children born. This contrasts significantly (Fisher’s exact test p=0.011) with the high autism prevalence of 54 % in offspring from 28 untreated families where either only mothers (n=15) or both parents (n=13) had FRαAb. Therefore, folinic acid intervention before and throughout pregnancy, in parents positive for FRαAb, may reduce the risk of autism in their offspring.

Abstract: Fibromyalgia (FM) is a complex syndrome associated with chronic widespread pain and with various other symptoms, including sleep and mood disturbances. Its under-lying causes are not fully understood, and the lack of diagnostic blood tests and im-aging, along with the absence of definitive treatments, makes management challenging. Recent studies showed that immunoglobulins in the blood of FM patients activate satellite glial cells (SGCs) in mouse dorsal root ganglia (DRG), leading to pain behaviors in mice after passive transfer. Here, we aimed to determine whether serum from FM patients activates mouse SGCs in DRGs and other ganglia that may be involved in FM’s diverse symptoms. Serum from FM patients (N=15) and healthy controls (HC, N=8) was collected. Sera were incubated with different types of mouse sensory ganglia: DRG, trigeminal ganglion (TG), the nodose ganglion (NG), and the superior cervical sympathetic ganglion (Sup-CG). SGC activation was assessed by immunostaining of SGCs for the glial activation marker glial fibrillary acidic protein (GFAP). We compared this response between male and female mice. All the ganglia tested, DRG, TG, NG, and Sup-CG, showed induced upregulation of GFAP labeling in SGCs after incubation with FM serum compared with HC, indicating SGC activation by the se-rum. Similar responses were observed in both male and female mice. We conclude that serum from FM patients contains factor(s) that can activate SGCs across various types of mouse ganglia, which may reflect the diverse symptom profile of FM. These findings provide objective evidence of pathogenic factor(s) that could serve as a foundation for a diagnostic method for FM and require further purification and identification, hopefully paving the way for future targeted FM therapy.

Abstract:

Background/Objectives: Radial extracorporeal shock wave therapy (rESWT) is used to treat neuromuscular disorders such as spasticity, but the mechanisms by which rESWT modulates muscle tone remain incompletely understood. One proposed mechanism involves mechanical perturbation of the neuromuscular junction (NMJ), particularly destabilization of acetylcholine receptor clusters in the postsynaptic membrane. Because rapsyn knockout mice are not viable, Caenorhabditis elegans (C. elegans) provides an alternative model through its rapsyn homolog RPY-1. This study examined whether loss of RPY-1 alters locomotor responses of C. elegans to radial extracorporeal shock wave (rESW) exposure. Methods: Wild-type worms and rpy-1 knockout worms (rpy-1-KOs) were exposed to defined numbers of rESWs. Locomotor behavior was quantified using automated tracking of parameters describing speed, trajectory and body-wave dynamics. Results: rESW exposure produced pronounced alterations in locomotor behavior across all parameters analyzed. After normalization to genotype-specific baseline values (because baseline locomotion differed between genotypes), wild-type worms and rpy-1-KOs responded similarly to moderate exposure levels. In contrast, higher exposure levels produced stronger locomotor impairment in rpy-1-KOs than in wild-type worms. Locomotor impairment was most pronounced immediately after exposure but improved during the subsequent recovery period of three hours. Conclusions: rESWs induced strong but largely reversible locomotor alterations in C. elegans during the first hours after exposure. The stronger impairment observed in rpy-1-KOs at higher exposure levels suggests that absence of the rapsyn homolog increased the vulnerability of the neuromuscular system of C. elegans to stronger mechanical perturbation induced by rESWs.

Abstract: The transition from relapsing-remitting multiple sclerosis (RRMS) to secondary-progressive multiple sclerosis (SPMS) represents an ambiguous transition period characterized by diagnostic delays and a shifting therapeutic window. While inflammatory relapses are well-managed, the underlying neurodegeneration often remains undetected until substantial disability has accrued. This review evaluated the shift from traditional metrics, such as the Expanded Disability Status Scale (EDSS), toward more sensitive, multimodal monitoring strategies. We described characteristic MRI findings in SPMS and addressed the impact of comorbidities that frequently confound the diagnosis of disease transition. Furthermore, we evaluated the predictive potential of emerging fluid biomarkers and gut microbial signatures in identifying the early RRMS-to-SPMS transition. Finally, we described the current therapeutic landscape and emerging immunomodulatory interventions. Diagnosing SPMS remains a clinical challenge due to comorbidities and the lack of a singular definitive marker. Moving toward high-sensitivity imaging and molecular biomarkers is essential for the early initiation of treatments and improved patient outcomes.

Abstract: Recent Phase 3 clinical trials of selective kappa-opioid peptide (KOP) receptor antagonists – aticaprant (Johnson & Johnson, VENTURA trial, 2025) and navacaprant (Neumora, KOASTAL-1 trial, 2025) – failed to demonstrate sufficient clinical efficacy in treatment-resistant depression (TRD). We propose two hypotheses that could explain these setbacks: (1) neutral antagonists may be poorly effective in patients with TRD due to constitutive KOP receptor hyperactivation and (2) the KOP receptor paralog – nociceptin opioid peptide (NOP) receptor – can effectively compensate for KOP receptor blockade decreasing the magnitude of clinical efficacy. We hypothesize that functional redundancy provided by NOP receptor signaling requires dual KOP/NOP blockade to achieve clinically meaningful improvement in reward function. Recent insights gained from paralogous compensation in drug-resistant tumors underscore the need for dual-target approaches. We propose that future studies, if successful, may yield a novel pharmacological class targeting opioid-mediated hedonic suppression, advocating for the development of opioid inverse agonists (such as norBNI), pan-antagonists (such as AT-076), and combinations of selective blockers.

Abstract: Introduction The artery of Davidoff and Schechter (ADS) is a dural branch of the posterior cerebral artery that supplies the falcotentorial junction and posterior tentorium. It can be a major feeder in dural arteriovenous fistulas, tumors, and uncommon aneurysms in this area. This study examines documented human cases of the ADS to provide a comprehensive understanding of its anatomy, pathological correlations, and neurosurgical and therapeutic consequences. Methods We conducted a systematic review of PubMed, Scopus, and ScienceDirect from inception to December 2025, focusing on human, English-language studies with eponymous ADS terms and combinations of posterior cerebral artery dural/meningeal branches, tentorial or falcotentorial pathology, and dAVFs/meningiomas. Results Twenty-three studies met the inclusion criteria, including 54 patients with ADS-related vascular lesions published between 1974 and 2025. The average age was 51.1 years (range 13-79), and 46.3% of patients were male. Headache was the most commonly reported symptom (44.4%), followed by altered awareness (11.1%), tinnitus (9.3%), visual/ocular symptoms (9.3%), and ataxia (9.3%). All lesions were dural shunts or related vascular diseases in the falcotentorial-tentorial-falcine/posterior fossa region, with falcotentorial dAVF (19/54; 35.2%) and tentorial dAVF (16/54; 29.6%) predominating. ADS laterality was 35.2% left, 29.6% right, and 11.1% bilateral. Transarterial embolization was the most common treatment (75.9%), with surgery and transvenous embolization being used less frequently. Major consequences were primarily in ischemia infarction (7.4%). Favorable outcomes were achieved in most patients, complete recovery in 44.4% and clinical improvement in 20.4%. Conclusions This systematic study will provide clinicians with a consolidated reference on ADS architecture, disease involvement, and procedural risks, allowing them to plan neurosurgical and neurointerventional procedures more effectively.