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Known as the most prevailing complication of herpes zoster (HZ), postherpetic neuralgia (PHN) can lead to long-term skin discomfort. Current medications for PHN remain suboptimal with incomplete relief and potential side effects. Low-level light therapy (LLLT) has been increasingly explored as a non-invasive modality for treating PHN, but the mechanistic basis and clinical implications have not been synthesized in a translational framework. In this review, we explore the pathophysiological mechanisms of PHN and the biological mechanisms of LLLT, integrating current mechanistic insights with available clinical evidence. We summarize the experimental and clinical literature evaluating LLLT for PHN and related neuropathic pain models, mainly focusing on mechanisms across peripheral tissues, dorsal root ganglia, and neuro-immune aspects, as we evaluate therapeutic parameters and outcomes from available clinical studies. Current evidence suggests that PHN is associated with dorsal root ganglion (DRG) inflammation, peripheral cutaneous neuroinflammation, loss of cutaneous innervation, and ion channel dysregulation. These changes comprehensively lead to hyperexcitable neurons with a lower sensory threshold. Across neuropathic pain models, LLLT elevates mechanical and thermal pain thresholds, attenuates inflammatory cytokine signaling, and promotes an immune cell phenotype shift toward an anti-inflammatory profile including M1-to-M2 macrophage polarization. LLLT also stabilizes membrane excitability by restoring Na⁺/K⁺-ATPase activity and modulating calcium dynamics, while supporting peripheral nerve repair via axonal regeneration. Clinically, administering LLLT to patients with PHN resulted in significant pain reduction, and early intervention may also reduce its incidence. By integrating experimental and clinical research, LLLT serves as a promising approach for PHN owing to its efficacy for anti-inflammation, neuronal regeneration and ion modulation.

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by social communication deficits, restricted interests, and repetitive behaviors. Emerging evidence links several autism susceptibility genes to the nonsense-mediated decay (NMD) pathway, which maintains the homeostasis of gene transcription and protein translation in the nervous system. However, the role of Suppressor with morphogenetic effect on genitalia 7 (Smg7), an essential NMD factor, in brain function and ASD remains largely unknown. Here, we generated an Emx1-Cre-mediated conditional Smg7 knockout (Smg7cko) mouse model to investigate its neurological consequences. We found that both male and female Smg7cko mice exhibited autism-like behaviors, including impaired social interaction and communication, repetitive behaviors, anxiety-like traits, and learning and memory deficits. These phenotypes were accompanied by neuronal hyperexcitability and increased dendritic spine density in layer II/III pyramidal neurons of the hippocampus and the medial prefrontal cortex (mPFC). Notably, Smg7 deletion led to pronounced upregulation of Protein Kinase D1 (PKD1) transcripts, an NMD target, in these brain regions. Strikingly, adeno-associated virus (AAV)-mediated PKD1 knockdown (AAVsh-PKD1) in the hippocampus and mPFC significantly rescued social deficits in Smg7-deficient mice. Together, these findings identify Smg7 as a key regulator of neuronal function and behavior, and reveal PKD1 upregulation as a pathogenic mechanism underlying ASD-like phenotypes, providing new insight into NMD deficiency in ASD pathophysiology and a potential therapeutic target.

Cerebral ischemia-reperfusion (I/R) injury remains a major therapeutic challenge, primarily due to complex mechanisms involving oxidative stress and apoptosis. Growth arrest and DNA damage-inducible protein α (Gadd45α), a stress sensor linked to cellular stress responses, has been implicated in I/R injury, yet its precise role in ischemic stroke is incompletely understood. This study aimed to elucidate the function and underlying mechanisms of Gadd45α in cerebral I/R injury using both in vivo and in vitro models. In rats subjected to middle cerebral artery occlusion (MCAO) and in neurons exposed to oxygen-glucose deprivation/reperfusion (OGD/R), Gadd45α expression was significantly upregulated. Lentivirus-mediated knockdown of Gadd45α (sh-Gadd45α) reduced infarct volumes, improved neurological function and increased miniature excitatory postsynaptic current (mEPSC) amplitude. In primary cortical neurons exposed to OGD/R, Gadd45α knockdown decreased reactive oxygen species (ROS) production, DNA damage, and apoptosis, while Gadd45α overexpression exacerbated these effects. Mechanistically, Gadd45α directly interacts with forkhead box O1 (FOXO1) and positively regulates its transcriptional activity. Gadd45α knockdown attenuated the ischemia-induced upregulation of both total FOXO1 and its phosphorylated form (p-FOXO1), thereby suppressing FOXO1 signaling and mitigating cerebral I/R injury. Furthermore, FOXO1 overexpression reversed the neuroprotective effects of Gadd45α silencing, confirming that FOXO1 acts as a critical downstream mediator. These findings demonstrate that Gadd45α silencing alleviates cerebral I/R injury by suppressing FOXO1 signaling, suggesting the Gadd45α/FOXO1 axis as a promising therapeutic target for ischemic stroke.

Down syndrome (DS), or trisomy 21 (T21), represents the most common genetic cause of intellectual disability worldwide and is associated with a wide range of medical, developmental, and neurodegenerative conditions, including a universal predisposition to early-onset Alzheimer's disease (AD). Since its establishment in 2014, the Trisomy 21 Research Society (T21RS) has provided a global forum for advancing DS research across disciplines and promoting translational efforts to improve health and quality of life. Every two years, T21RS hosts an international scientific meeting that brings together researchers, clinicians, self-advocates, families, and industry stakeholders. In 2024, the 5th T21RS International Conference was held in Rome, Italy, from June 5 to 8, under the theme "Promoting Research Excellence in Down Syndrome." The meeting brought together about 500 scientists from 26 countries across five continents, and more than 900 attendees overall, including families and caregivers. The scientific program featured 5 keynote lectures, 2 satellite meetings, 17 symposia, 7 nano symposia, 2 workshops, and 1 industry-focused session, totaling more than 150 oral presentations. More than 230 abstracts were presented as posters. The conference covered research across the lifespan of individuals with DS, spanning genomic and epigenetic regulation, molecular and cellular mechanisms, preclinical and experimental models, cognition and behavior, neurodevelopment, aging and neurodegeneration, co-occurring medical conditions, and therapeutic interventions. Dedicated sessions focused on capacity-building in DS research and societal engagement were established. Significantly, T21RS promoted inclusivity by supporting 60 young investigator fellowships, providing childcare awards, and organizing a two-day program for families and caregivers in collaboration with Italian DS associations. This proceeding summarizes the main scientific highlights of the 5th T21RS International Conference, reflecting the latest advances in DS biology, clinical research, biomarker development, and therapeutic innovation.

Traumatic brain injury (TBI) can lead to lasting neurological and emotional effects. Latent Toxoplasma gondii (T. gondii) infection, prevalent worldwide, may exacerbate these outcomes by altering immune and neurochemical pathways. This cross-sectional observational study investigated whether chronic T. gondii infection is associated with structural brain differences and long-term outcomes in survivors of moderate-to-severe TBI ≥ 10 years post-injury. 89 TBI survivors (≥10 years post-injury) were recruited from a tertiary-centre database; 35 (39%) tested positive for latent T. gondii via plasma IgG. Thirty-two age- and sex-matched controls without TBI were included (25% T. gondii-seropositive). Nonparametric regression analyses adjusted for age, sex, and intracranial volume, with false discovery rate corrections applied. Primary outcomes were MRI-based measures of white matter microstructure, cortical thickness, and subcortical volumes. Secondary outcomes included neuropsychological assessments of anxiety, depression, cognition, and TBI blood biomarkers. Within the TBI group, T. gondii-positive individuals had reduced fibre density and increased diffusivity in the posterior corpus callosum, increased cortical thickness (insula, cuneus), and reduced brainstem volume. They also reported higher anxiety and mediation analysis showed brainstem volume partially mediated the link between infection and anxiety. Within controls, T. gondii infection was not significantly associated with anxiety, cognition, white matter microstructure, or blood biomarkers. However, controls with T. gondii infection did have increased cortical thickness in the left inferior temporal gyrus and reduced volume in the left caudate compared to their uninfected counterparts. Taken together, latent T. gondii infection may alter brain structure and exacerbate anxiety in chronic TBI. These findings support considering infection status in TBI prognostics and call for further research into its mechanistic and clinical implications.

Dementia affects over 55 million people worldwide, with Alzheimer's disease (AD) comprising most cases. Because curative therapies remain unavailable, there is an urgent need for prevention strategies that target modifiable risk factors. Behavioral interventions-particularly sleep improvement and physical activity-can independently benefit cognition, brain function, and cardiometabolic health, yet their combined (potentially synergistic) effects and scalable delivery models remain underexplored. This exploratory, hypothesis-generating, three-arm randomized controlled trial will evaluate: (1) whether improvements in sleep metrics are associated with improvements in cognitive performance and biomarker panels reflecting brain and cardiometabolic health; (2) the effects of structured, moderate-intensity aerobic and anaerobic exercise on cognitive performance and biomarker panels; (3) the combined effects of sleep and exercise interventions on cognitive performance and biomarker panels, including potential synergy; and (4) the role of light exposure as a modulator of sleep parameters. Over 8 weeks at a single site, 60 community-dwelling adults, aged 55-80 years, with and without mild cognitive impairment, will be randomized to exercise-only, sleep-only, or combined sleep-plus-exercise interventions. Programs will be delivered in-person and/or using Elemind Neuromodulation headbands, Fitbit trackers, and Lys light sensors. Cognitive function will be assessed with the Digital Neuro-Signature Platform, and plasma biomarkers will index cardiometabolic health and AD-related neuropathology. Findings will inform larger, multi-site trials targeting modifiable AD risk factors using scalable, digital, and decentralized intervention platforms. ClinicalTrials.gov NCT04855630; https://clinicaltrials.gov/study/NCT04855630 . Registration date 04/19/2021.

Recent modern characterizations of human meningeal lymphatic vessels have reframed long-standing views of central nervous system neurofluid drainage. However, gross anatomical data on lymphatic vessels remains sparse. In this cadaveric study, we combined dissections and immunohistochemical analysis in formalin-fixed human body donors to characterize lymphatic vessels associated with cervical spinal nerves. Using manual, low-pressure peroxide-dye injections via the thoracic duct and left jugular lymphatic trunk, we effervesced and identified candidate lymphatic pathways extending toward the head and neck, highlighting vessels accompanying cervical spinal nerves at the interface between the vertebral canal and surrounding soft tissues. Dye-identified vessels and adjacent dural and perineural tissues were harvested and processed for D2-40 immunohistochemistry, targeting the lymphatic endothelial marker podoplanin. Across four of nine donors, we observed D2-40-positive, thin-walled luminal structures within epineurial and peridural compartments at the craniovertebral junction, along cervical intervertebral foramina, and near brachial plexus roots, consistent with lymphatic vessels. These findings identify D2-40-positive vessel profiles consistent with lymphatic vasculature extending along spinal nerves without directly demonstrating intradural channels or cerebrospinal fluid outflow. They provide an anatomical framework for future studies probing how cervical lymphatic networks at CNS interfaces contribute to neurofluid drainage, immune cell trafficking, and neurological disease.

Age-related musculoskeletal diseases (ARMDs), including sarcopenia, osteoporosis, and osteoarthritis, may contribute to declines in intrinsic capacity and co-occur with neurodegenerative disorders such as Parkinson's disease (PD). We examined the association between ARMDs and PD risk. In 362,656 UK Biobank participants (mean age 56.48 years; median follow-up 13.65 years), ARMDs were assessed individually and cumulatively. Cox models estimated PD risk, adjusting for demographic, lifestyle, and genetic factors. Subgroup and sensitivity analyses were conducted to ensure robustness. A nested case-control analysis further explored the relationship between the duration of ARMDs exposure and the odds of PD diagnosis. Multivariable regression models assessed the associations between ARMDs and brain structure, including cortical, gray matter, and white matter integrity. During follow-up, 2,057 participants developed PD. Sarcopenia (hazard ratio [HR]: 1.74, 95% confidence interval [CI]: 1.45-2.08, P&#x2009;<&#x2009;0.001) and osteoporosis (HR: 1.76, 95% CI: 1.34-2.32, P&#x2009;<&#x2009;0.001) were independently associated with higher PD risk. PD risk increased with the number of ARMDs (HR 1.30, 95% CI 1.19-1.41; Ptrend<0.001) and the odds of PD diagnosis was highest within 5 years of the ARMDs diagnosis (odds ratio [OR] 2.19, 95% CI: 1.59-2.96, P&#x2009;<&#x2009;0.001). Neuroimaging analysis indicated that ARMDs were associated with widespread and significant brain structural alterations, including in regions related to motor control. ARMDs are linked to elevated PD risk and brain structural changes. Interventions targeting musculoskeletal health may help preserve intrinsic capacity and delay or prevent PD onset in aging populations.

Loss-of-function (LOF) variants in KCNQ2, encoding the potassium channel subunit Kv7.2, cause a spectrum of neonatal epilepsies ranging from self-limiting familial neonatal epilepsy (SeLFNE) to severe developmental and epileptic encephalopathy (DEE). To dissect the developmental consequences of Kv7.2 LOF, we conducted a longitudinal and multimodal comparative analysis in a human neuronal model generated from patients with KCNQ2-DEE and KCNQ2-SeLFNE. KCNQ2-LOF variants induced a biphasic dysfunction at both single-cell and network levels, characterized by early Kv7-driven hyperexcitability accompanied by a clear reduction M-current density, which was rescued by acute Retigabine treatment. At later stages, intrinsic excitability and M-current normalized, yet network activity diverged further from control trajectories, indicating compensatory and ultimately maladaptive network remodeling. Transcriptomic analysis mirrored this biphasic dynamic trajectory, revealing an initial upregulation followed by a subsequent downregulation of synaptic genes. Structural analysis showed a steeper decline in presynaptic density alongside a distal shift in the axon initial segment (AIS) throughout maturation, and impaired AIS plasticity at later stages. Overall, KCNQ2-LOF variants disrupt human neuronal maturation through dynamic, biphasic changes in function, gene expression and structure, offering insights into disease mechanisms and therapeutic options.

The autoimmune nodopathy affecting the node of Ranvier was formerly classified within the spectrum of chronic inflammatory demyelinating polyradiculoneuropathy. However, as a result of comprehensive pathological and immunological investigations conducted in recent years, it has increasingly been recognized as a distinct clinical entity. To date, there have been no reported cases linking autoimmune nodopathy at the node of Ranvier with anti-CNTN2 antibodies. This paper presents a case study demonstrating such an association, detailing the clinical and electrophysiological features, and thereby contributing to the global understanding and recognition of this condition. The patient, a 48-year-old female of Han nationality, was admitted to the intensive care unit (ICU) after experiencing a period of unconsciousness, accompanied by a high-grade fever lasting over 4&#xa0;h. Diagnostic evaluations, including blood tests and imaging studies, indicated the presence of heat stroke and coagulation dysfunction. The therapeutic interventions administered included endotracheal intubation and mechanical ventilation, continuous cooling with electric ice blankets and ice caps, treatments to correct coagulopathy, and aggressive fluid resuscitation. Following these interventions, the patient regained consciousness, and her body temperature returned to normal. However, upon cessation of mechanical ventilation, she exhibited limb weakness and produced indistinct vocalizations, although she was capable of sound production. Routine electromyography identified peripheral nerve injury of the axonal type, while cerebrospinal fluid analysis revealed protein-cell dissociation. Laboratory assays of both blood and cerebrospinal fluid samples tested positive for the anti-CNTN2 antibody IgG. Given the limited availability of effective therapeutic research for this condition at the time, intravenous immunoglobulin therapy was administered with the patient's informed consent, although it did not result in significant improvement of her symptoms. Clinically, impairments in limb motor abilities, dysarthria, respiratory insufficiency, protein-cell dissociation within the cerebrospinal fluid, and early axonal degeneration as evidenced by electromyography are critical diagnostic criteria for autoimmune nodopathy of the Ranvier nodes in patients who test seropositive for anti-CNTN2 antibodies. For individuals presenting with these phenotypes and suspected of having Guillain-Barr&#xe9; syndrome or chronic inflammatory demyelinating polyradiculoneuropathy, it is essential to conduct comprehensive assessments for node, paranode, and juxtaparanode antibodies, along with their specific subtypes, to refine therapeutic strategies.

ObjectiveTo evaluate the clinical and cost-effectiveness of SHARE TO CARE (S2C), a complex intervention for hospital-wide, systematic implementation of shared decision making.MethodsWe analyzed clinical effectiveness, health care resource utilization, and implementation costs of S2C from the statutory health insurance perspective using a quasi-experimental difference-in-differences approach with evidence from the Department of Neurology. Clinical outcomes included inpatient hospital admissions, emergency department admissions, and rates of standard and advanced imaging procedures. Implementation costs comprised those related to the conception, development, process integration, ongoing support, and auditing of S2C. Health care utilization data covered inpatient and outpatient care, pharmaceuticals, therapeutic services, assistive devices, and nursing care. We conducted sensitivity analyses to account for uncertainties.FindingsS2C was associated with a reduction in inpatient hospital admissions, emergency department admissions, and imaging rates in the intervention group. The cost analyses aligned with these findings, showing reduced total costs and health care resource utilization in the intervention group. Although none of the estimates reached the predefined thresholds for statistical significance, the primary analysis yielded weak evidence (P&#x2009;<&#x2009;0.1) of a reduction in emergency department admissions in the intervention group. Overall, savings outweighed the costs of implementing S2C, suggesting cost-effectiveness.ConclusionsS2C has the potential to reduce emergency department admissions and overall health care costs from the statutory health insurance perspective. Further research should investigate generalizability, the timing of the treatment effect, and potential biases introduced by the COVID-19 pandemic. The demonstrated effects of shared decision making (SDM) have encouraged statutory health insurances in Germany to offer additional reimbursement for clinics certified under the S2C program. The S2C model illustrates how payers and providers can collaborate to facilitate the nationwide implementation of SDM.HighlightsThe implementation of SHARE TO CARE (S2C) was associated with a statistically nonsignificant reduction in emergency department admissions after 1 y from the statutory health insurance perspective, based on data from the Department of Neurology.The cost savings from reduced health care utilization outweighed the implementation costs, and despite not reaching statistical significance, the results support the potential cost-effectiveness of S2C.S2C has the potential for nationwide implementation as a systematic form of shared decision making.Future research should investigate the generalizability of the results to other health care settings.

Autosomal recessive microcephaly encompasses a group of rare neurogenetic disorders in which microcephaly presents at birth or postnatally as part of a syndromic disorder. Autosomal recessive microcephaly is both clinically and genetically heterogeneous, with numerous genes associated. In the present study, we investigated the genetic basis of likely autosomal recessive microcephaly in a cohort of five unrelated consanguineous and non-consanguineous Pakistani families presenting with microcephaly, intellectual disability, and developmental delay. Whole-exome sequencing was performed on one affected individual from each family. Candidate variants identified by WES were subsequently validated by Sanger sequencing, and segregation analysis was performed in all available affected and unaffected family members. We identified five homozygous pathogenic variants, including three novel variants: ASPM (NM_018136.5:c.1669_1670del p.(Ser557Leufs*2)), CDK5RAP2 (NM_018249.6:c.199del p.(Ile67Serfs*4)), and VPS13B (NM_152564.5:c.8230&#xa0;C&#x2009;>&#x2009;T (p.Gln2744*)). Alongside, two previously reported homozygous variants in ASPM (NM_018136.5:c.9190&#xa0;C&#x2009;>&#x2009;T p.(Arg3064*) & NM_018136.5:c.3978G&#x2009;>&#x2009;A p.(Trp1326*)). All variants matched a suspected autosomal recessive inheritance pattern, segregated within their respective families, and were absent or very rare in proxy population genetic databases. The results expand the genetic spectrum of autosomal recessive microcephaly within the Pakistani population and highlight the importance of whole exome sequencing in diagnosing rare neurodevelopmental disorders and understanding genetic diversity.

Guillain-Barr&#xe9; syndrome (GBS) is an autoimmune disorder characterized by acute peripheral demyelination, leading to progressive muscle weakness and sensory loss. While CD4&#x207a; T cells and circulating macrophages are implicated in autoimmune neuropathies, the compositional dynamics and activation mechanisms of circulating immune cells remain elusive. Here, we performed single-cell RNA sequencing (scRNA-seq) on peripheral blood mononuclear cells (PBMC) from 3 GBS patients and 2 healthy controls. A total of 51358 cells in the PBMC dataset passed the quality control. In addition, immune cell activation and recruitment were validated using mouse model single-cell datasets and rat transcriptome datasets. We delineate a T-cell differentiation-chemokine secretion axis that operates as a pathogenic hub in inflammatory neuropathy. This data resource provides an indispensable foundation for developing immunomodulatory therapies in Guillain-Barr&#xe9; syndrome.

Global developmental delay (GDD) and intellectual disability (ID) are common neurodevelopmental disorders with a strong genetic basis. However, comprehensive large-cohort analyses integrating genotype-phenotype correlations and functional mechanisms remain limited. This study aimed to systematically characterize the clinical and genetic spectrum of GDD/ID in a large single-center cohort and to explore the functional attributes of disease-causing genes. We retrospectively analyzed 1024 children diagnosed with GDD or ID who underwent genetic testing, including trio whole-exome sequencing (trio-WES), proband-only WES, and clinical exome sequencing. Clinical phenotypes were categorized, and functional enrichment analyses were conducted for genes associated with diagnostic and probable diagnostic results. A genetic diagnosis was achieved in 48.1% of patients, with trio-WES demonstrating a significantly higher diagnostic yield than proband-only approaches. Pathogenic variants mainly comprised single-nucleotide variants and copy number variants. Identified genes were predominantly involved in protein homeostasis, synaptic and ion channel function, epigenetic regulation, and key developmental signaling pathways. Distinct genotype-phenotype associations were observed among clinical subgroups, including enrichment of synaptic-related genes in epilepsy-associated GDD/ID and epigenetic regulatory genes in patients with facial dysmorphism. &#xa0;This study provides a comprehensive characterization of the genetic landscape of GDD/ID in a large single-center cohort and identifies distinct genotype-phenotype correlations and convergent molecular pathways underlying these disorders. &#x2022; Global developmental delay (GDD) and intellectual disability (ID) are highly heterogeneous neurodevelopmental disorders with a strong genetic basis. &#x2022; We report a large single-center cohort of 1024 children with GDD/ID, providing a comprehensive overview of the genetic landscape and diagnostic yield of different sequencing strategies. &#x2022; Our study systematically integrates genotype-phenotype correlations with functional pathway analyses, highlighting key molecular mechanisms underlying GDD/ID and supporting refined molecular stratification.

Impaired memory function is a frequent yet understudied symptom in kidney transplant recipients. In part, this knowledge gap reflects the lack of scalable, sensitive, and low-burden tools for quantifying memory function in large clinical populations. The aim of this study is to evaluate a brief, remote memory assessment and to examine memory function and its clinical correlates in kidney transplant recipients compared with healthy controls. In this cross-sectional study, we demonstrate a remote, minimally burdensome memory screener, the Seattle-Groningen Memory Assessment, which estimates a patient's speed of forgetting from paired-associate learning. Participants aged 22-86 years from a large transplant cohort completed an eight-minute online memory test. Memory performance was compared between kidney transplant recipients (n = 556) and kidney donors (n = 408). Associations with demographic, clinical, and physiological variables were examined using regression analyses. Here, we show that the memory score derived from an eight-minute session is a reliable and accurate measure of an individual's ability for long-term retention. Kidney transplant recipients show more forgetting than donors. Memory scores are sensitive to demographic factors, including age and education level, and are associated with self-reported sleep quality, fatigue, and health-related quality of life. On the physiological level, more forgetting in recipients is linked to higher monocyte, neutrophil, reticulocyte, and white blood cell counts, as well as lower ferritin and greater iron deficiency. This work highlights the potential of computational memory assessment as a minimally burdensome and reliable tool for detecting cognitive impairment in complex clinical populations. Such tools may enable scalable monitoring of cognitive health and improve the detection of subtle cognitive changes relevant for disease progression and treatment evaluation. Memory problems are commonly reported by people who receive a kidney transplant, but they are often difficult to measure with traditional cognitive or neuropsychological tests. In this study, we evaluated a brief online memory task that can be completed at home in about eight minutes. The test measures how quickly newly learned information is forgotten over time. More than 500 kidney transplant recipients and about 400 kidney donors completed the assessment. We found that transplant recipients, on average, forgot information more quickly than donors. Memory performance was also related to factors such as age, education, sleep quality, fatigue, and several blood markers linked to inflammation and iron levels. Our findings suggest that short digital memory tests may offer a practical way to monitor cognitive health in people with complex medical conditions and could support future research and clinical care.