NeuroSci

Melancholia remains a severe and complex form of depression. One possible avenue to a better understanding of melancholia and potentially improved methods of treating it, is via examination of the profiles of brain electrical activity of patients suffering from melancholia. However, apart from work using fMRI, relatively little is known about the electrophysiological basis of melancholia despite the potential for this to inform targeted effective treatments such as Transcranial Magnetic Stimulation. To better understand the state of research regarding EEG variables and melancholia, a systematic review was undertaken. Results indicated that there was a large degree of complexity in the association between melancholia and various EEG parameters, and that many specific aspects of brain electrical activity remain under-studied. Suggestions are made for future research. Full article

Background: Creating antibiograms solely for adults may overestimate resistance of antimicrobials for certain pathogens in children. The Canadian Paediatric Society comments that areas with no cephalosporin-resistant Streptococcus pneumoniae cases should consider ceftriaxone or cefotaxime monotherapy for meningitis, despite most experts recommending adding vancomycin. The present study created age-specific antibiograms using LifeLabs data to report incidences of resistant bacterial meningitis pathogens at the regional level to determine the need for duo-coverage. Methods: Data of common bacterial meningitis pathogen susceptibility was collected from 1 January 2023 to 31 December 2024, in the LifeLabs community laboratory on Vancouver Island. Results: Most Streptococcus pneumoniae isolates (78/83) were susceptible to ceftriaxone using the meningitis breakpoint; the remaining five isolates showed intermediate susceptibility to ceftriaxone. There was a significant difference when comparing S. pneumoniae susceptibility using penicillin-meningitis and penicillin-non-meningitis breakpoints (82% vs. 99%, respectively; p < 0.05). There was a significant difference between the three age groups (<18 years, 18–50 years, >50 years) when analyzing ciprofloxacin susceptibility of isolates [82% (n = 462), 77% (n = 2452), 75% (n = 8352), respectively, p < 0.05]. Conclusions: Ceftriaxone should remain the drug of choice for community-acquired bacterial meningitis and might be sufficient as a monotherapy for pneumococcal meningitis on Vancouver Island. The age-specific differences in E. coli susceptibilities to ciprofloxacin showed the importance of age-specific antibiograms. Full article

The human spinal cord is increasingly recognized as an active and adaptable component of sensorimotor function, contributing to motor control, pain modulation, and recovery after neurological injury. Within this framework, the Hoffmann reflex (H-reflex) has evolved from a classical electrophysiological phenomenon into a useful probe of spinal circuit function. Rather than reflecting motoneuron excitability alone, H-reflex amplitude and modulation arise from the interaction of Ia afferent transmission, presynaptic inhibition, homosynaptic depression, and interneuronal networks that regulate sensorimotor gain in a state-dependent manner. This review synthesizes classical and contemporary evidence to position the H-reflex as an indirect measure of spinal inhibitory function in humans. We integrate physiological mechanisms with findings from studies in chronic pain syndromes, spasticity, Parkinson’s disease, and recovery after central nervous system injury, where alterations in spinal inhibitory processes have been described. We further discuss methodological and conceptual challenges that limit clinical translation, including state dependence, protocol heterogeneity, and the lack of normative reference frameworks. Finally, we outline directions for integrating H-reflex paradigms with complementary approaches to improve the interpretation of spinal circuit function and its relation to clinical phenomena. Framed in this context, the H-reflex can be considered a valuable experimental and translational tool, whose utility depends on careful methodological implementation and physiologically informed interpretation. Full article

Background: Acute focal neurological deficits require rapid differentiation between ischemic stroke and stroke mimics to avoid treatment delays and inappropriate therapy. Seizures, including ictal deficits, status epilepticus, and post-ictal/Todd’s phenomena, are among the most challenging mimics. This review summarizes the role of multimodal neuroimaging in distinguishing acute ischemic stroke from seizure-related deficits. Methods: We performed a focused narrative review of neuroimaging findings in acute stroke mimics, emphasizing non-contrast computed tomography (CT), CT angiography, CT perfusion, magnetic resonance imaging (MRI), including diffusion weighted imaging (DWI), apparent diffusion coefficient (ADC), fluid attenuated inversion recovery (FLAIR), and arterial spin labeling (ASL) sequences. Imaging patterns, diagnostic pitfalls, and practical clues for hyperacute stroke pathways were synthesized. Results: Acute ischemic stroke is typically suggested by vascular-territorial abnormalities, including arterial occlusion or stenosis, territorial hypoperfusion, and congruent DWI/ADC restriction. Seizure-related deficits more often show non-territorial cortical perfusion changes, ictal or status-related hyperperfusion, reversible MRI abnormalities, and absence of arterial occlusion. However, post-ictal hypoperfusion, peri-ictal diffusion restriction, and reperfusion-related hyperperfusion may overlap with ischemic patterns. Conclusions: A multimodal approach integrating vascular imaging, perfusion distribution, DWI/ADC, ASL, clinical timing, and EEG findings can improve diagnostic accuracy in the stroke–seizure differential without delaying treatment in true acute ischemic stroke. Full article

Background: The nationally advertised mass media campaign Act-FAST UK, delivered in multiple waves since its launch in 2009, has increased public awareness of stroke symptoms. However, many stroke patients still delay in calling for help and reach the hospital too late to receive emergency treatments. The reasons for this cognitive dissonance between recognition of symptoms and urgent seeking of emergency medical services (EMS) are unclear. Aims: This study aimed to quantify cognitive, psychological, and knowledge-based barriers to help-seeking in patients with acute stroke or transient ischaemic attack (TIA), as well as in intervening witnesses, and to examine their association with the use of EMS as the initial point of contact. Methods: We interviewed patients admitted to a hyperacute stroke unit with a stroke or transient ischaemic attack (TIA) from 2013 to 2016. People who contacted emergency services on the patient’s behalf (intervening witnesses (IWs)) were also interviewed when available. Reasons given for delays in calling for help were related to correct symptom recognition, and whether/at what time, emergency services were contacted after symptoms onset. Results: A total of 602 patients (429 with stroke, 173 with TIA) along with 128 witnesses who intervened in calling for help in those cases (IWs) were interviewed. In the subset of patients with both measures available, there was a strong positive correlation between NIHSS score and number of FAST symptoms (Spearman’s rho = 0.645, p < 0.001), providing supportive evidence for the use of FAST symptom count as a proxy measure of stroke severity. A total of 469 (77.9%) of the patients were aware of a media education campaign about stroke, but only 145 (24.1%) had attributed their own symptoms to stroke at onset. However, correct self-diagnosis of stroke was not associated with direct calls to the EMS (OR 1.43, 95% CI 0.84–2.45). Cognitive, psychological or emotional barriers to help-seeking, as reported by prior published studies, were reported by 463 (81.2%) of the patients we interviewed but in only 63 (53.3%) of the IWs (p < 0.001). Amongst the patient cohort, “not thinking symptoms were serious” (275, 45.7%) and “waiting to see if symptoms would go away” (285, 47.3%) were most strongly negatively associated with EMS use (OR 0.52, 95% CI 0.32–0.84 and OR 0.34, 95% CI 0.21–0.55, respectively). Only 55 (9.1%) of the patients interviewed had been aware of any time-critical stroke treatment prior to their stroke. Eighteen stroke patients (4.2%) reached hospital in time to receive thrombolysis, but an additional 170 (39%) could have been considered for this treatment (i.e., had no apparent other contraindications from a notes review) had they arrived within 4 h of symptom onset. Conclusions: Future public education campaigns may be more effective if they specifically address factors associated with delays in calling for help after stroke symptoms and emphasise the existence of emergency treatments, which are also time-critical. More effective public education may have the potential to increase the proportion of patients arriving in time to benefit from such treatments. Full article

Objective: Evaluate the test–retest reliability of quadriceps corticospinal excitability and intracortical excitability using transcranial magnetic stimulation (TMS). Design: A test–retest observational cohort study. Methods: Twelve healthy adults attended two laboratory sessions, seated with their knee at 90 degrees and fitted with electrodes on the rectus femoris (RF), vastus lateralis (VL) and vastus medialis (VM). TMS was used to assess the active motor threshold (AMT), motor evoked potential (MEP) amplitude, short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF). Individual results were calculated as the mean and median of the 10 trials of each measure for MEP, SICI and ICF. Intraclass correlation coefficients were calculated. Results: All muscles showed good or excellent reliability for the mean and median measures of the MEP amplitude (ICC ≥ 0.820) as well as the AMT of the RF (ICC = 0.991). SICI showed good reliability in the mean and median measures of the RF and the mean measure of the VL (ICC ≥ 0.809), moderate reliability in both measures of the VM (ICC ≥ 0.655) and was not significant for the median measure of the VL (ICC = 0.513). ICF showed excellent reliability in the mean measure of each muscle and median measure of the RF (ICC ≥ 0.906), with good reliability in the median measure of the VL (ICC = 0.888) and moderate reliability in the median measure of the VM (ICC = 0.719). Conclusion: The mean of an individual’s quadriceps corticospinal excitability and intracortical excitability have good or excellent reliability for every TMS measure, in every muscle (except SICI of the VM). With the previous reliability of TMS measures mostly investigating the upper limbs, these results offer important context for neurophysiological research in the quadriceps. Full article

Drug-resistant epilepsy (DRE) secondary to viral brain infections (VBI) may have multiple seizure foci, making it not amenable to surgical resection but could respond to responsive neurostimulation (RNS). We aimed to evaluate characteristics of DRE patients with a VBI history who did or did not respond to RNS therapy; 9 patients met criteria. Four out of 9 patients were responders to RNS therapy with ≥50% of seizure-frequency reduction at an average 39-month follow-up. Five patients were non-responders, an average 47-month follow-up. Two responders had a prior destructive surgery. Four non-responders had a prior neurosurgery including 1 focal resection, 2 vagus nerve stimulation, and 1 prior RNS. Patients in the responder group had shorter DRE duration prior to RNS placement than in the non-responder group (average 11.0 years versus 14.4 years). Three responders and four non-responders had a history of focal to bilateral tonic–clonic seizures (FBTC) pre-RNS. Post-RNS, all responders and 2 non-responders stopped experiencing FBTC. Our study demonstrates that RNS therapy could be effective in patients with DRE secondary to VBI, even if the patients failed previous surgical intervention(s). Patients in both responder and non-responder groups had reduction of convulsive seizures. These findings should be considered preliminary observations due to a small sample-size. Full article

Objective: We aimed to determine whether sexual experience modulates the soleus H-reflex in male rats and to assess the specific contribution of vermis lobules 6a and 7 to cerebellar-dependent spinal plasticity. Methods: Thirty-six male Wistar rats were divided into sexually inexperienced (SI) and sexually experienced (SE) groups and assigned to one of three cerebellar conditions: intact control, lobule 6a lesion, or lobule 7 lesion. SE rats underwent repeated mating sessions until they achieved efficient copulatory performance. Subsequently, targeted electrolytic lesions were made, and electromyographic recordings of the soleus H-reflex were obtained under urethane anesthesia to quantify H-wave amplitude and temporal parameters. Results: The global linear mixed model yielded no significant main effects of sexual experience, cerebellar condition, or their interaction on H-wave amplitude. Planned contrasts revealed a near-significant trend toward higher H-wave amplitude in sexually experienced intact animals compared with inexperienced controls (p = 0.061, Cohen’s d = 0.592, 95% CI [−1.44, 0.04] V), and significant amplitude reductions following lobule 6a (p = 0.029, d = 1.450, 95% CI [0.13, 2.33] V) and lobule 7 (p = 0.002, d = 2.256, 95% CI [0.74, 3.08] V) lesions specifically in sexually experienced animals. Neither sexual experience nor lesions significantly affected H-wave latency or duration, suggesting that modulation primarily targets synaptic excitability rather than axonal conduction. M-wave latency showed a significant effect of sexual experience (p = 0.026, d = 1.405, 95% CI [0.03, 0.45] ms). Conclusions: Sexual experience appears to be associated with cerebellar-dependent modulation of soleus H-reflex excitability; lobules 6a and 7 of the cerebellar vermis contribute to this effect specifically in experienced animals. Shorter M-wave latency in experienced animals suggests parallel peripheral motor reorganization. Adequately powered confirmatory studies are needed to characterize the mechanisms underlying this association. Full article

Background: Parkinson’s disease and dementia are major neurodegenerative disorders that substantially contribute to disability, dependency, and mortality worldwide. Although prior CDC WONDER studies have separately evaluated Parkinson’s disease and dementia mortality trends, fewer analyses have examined national mortality patterns in which both conditions are recorded on death certificates simultaneously over extended time periods. Methods: We analyzed U.S. death certificates from 1999 through 2025 using the CDC WONDER Multiple Cause of Death database, identifying deaths among adults aged ≥45 years in which both Parkinson’s disease (ICD-10 G20) and dementia-related codes (F01, F03, G30, G31) were recorded anywhere on the certificate. This operational definition captures co-recorded diagnoses and does not identify clinically confirmed Parkinson’s disease dementia. Age-adjusted mortality rates (AAMRs) per 100,000 were standardized to the 2000 U.S. standard population, a method that controls for shifts in population age structure over time and allows valid temporal comparisons independent of absolute population growth. Joinpoint regression was used to quantify trends. Sensitivity analyses excluded 2025 provisional data and the COVID-19 period (1999–2019). Results: A total of 337,721 deaths were identified. Overall AAMR increased from 5.75 (95% CI: 5.60–5.90) in 1999 to 11.15 (95% CI: 10.98–11.32) in 2025 (AAPC: 2.07; p = 0.002). A sharp transient increase occurred in 2020, attributable to pandemic-related factors including disproportionate COVID-19 mortality among older adults with neurodegenerative conditions, care disruptions, and changes in death-certificate coding practices. Following this pandemic-era peak, AAMRs declined significantly through 2025 and should be interpreted cautiously given provisional data. Males (AAPC: 2.14), non-Hispanic White individuals (AAPC: 2.29), the Midwest region (AAPC: 2.65), and non-metropolitan areas carried the highest mortality burden. Mortality was greatest among adults aged ≥85 years. Conclusion: Population-level death rates involving co-recorded Parkinson’s disease and dementia demonstrated significant temporal changes over the study period, with marked demographic and geographic disparities. These findings reflect death-certificate surveillance data and cannot establish clinical co-occurrence, causal relationships, or individual disease risk. Full article

Introduction: Neurosurgery has evolved from an anatomy-driven analog discipline into a digitally augmented field supported by multimodal imaging, neuronavigation, intraoperative imaging, neurophysiological monitoring, robotics, augmented reality, and artificial intelligence. Objective: To examine how this transition has altered professional responsibility, informed consent, training, and medico-legal accountability in neurosurgical practice. Methods: We performed a structured narrative review of the literature on digital neurosurgery and its ethical and professional implications, focusing on publications from 1990 onward and supplemented by landmark historical papers. Sources were selected for relevance to cranial, spinal, skull base, stereotactic, and neuro-oncological neurosurgery, and then synthesized into thematic domains including brain shift, eloquent cortex preservation, stereotactic accuracy, intraoperative neurophysiology, workflow integration, equity, and liability. Results: Digital systems improve lesion localization, function-preserving surgery, stereotactic precision, documentation, and training, but they also introduce new vulnerabilities related to registration error, brain shift, platform dependence, data overload, cost, cybersecurity, deskilling, and diffuse accountability. Conclusions: Digital augmentation expands rather than diminishes the neurosurgeon’s responsibility. The neurosurgeon remains accountable for surgical indication, interpretation of technology-generated information, intraoperative override, and communication of technology-specific risks. The central ethical challenge is to integrate digital tools without weakening patient-centered judgment. Full article

Fatigue monitoring and detection are crucial for improving efficiency and safety due to their influence on reducing cognitive and physical performance that may result in safety-related incidents. This paper proposes a filter bank-based approach that decomposes electroencephalography (EEG) signals into delta, theta, alpha, beta, and gamma sub-bands for feature extraction to enhance fatigue detection using a wearable EEG-based brain–computer interface (BCI). The study utilized a publicly available EEG dataset from 40 participants collected with a dry-EEG headband while performing two cognitive tasks: a Cognitive Vigilance Task (CVT) and a Multi-Modal Integration Task (MMIT). The data was previously investigated for stress detection on the MMIT. In this study, we investigate fatigue detection on the CVT. Subjects who were not fatigued post-CVT were iteratively removed. Two models were trained with five models to classify the fatigued state from the non-fatigued state, one using features extracted from a broadband filter approach and the other from the proposed filter bank approach. Leave-one-subject-out cross-validation yielded accuracies of 75.8% $\pm$10.4% (95% confidence interval) from the broadband filter approach, and 86.4% $\pm$8.3% (95% confidence interval) from the proposed filter bank approach, yielding an overall increase of 10.6%. These results demonstrate the potential of filter bank-based feature extraction for fatigue detection in wearable EEG-based BCI systems. Full article

Periventricular nodular heterotopia (PVNH) is a genetically heterogeneous malformation of cortical development with variable neurological outcomes. Among recessive forms, ARFGEF2-related disorder is uniquely characterised by the association of diffuse PVNH and progressive microcephaly. We describe a two-year-old boy born to consanguineous parents who presented with severe developmental delay, hypotonia, progressive microcephaly, and infantile-onset epileptic spasms with developmental regression. Brain MRI showed extensive bilateral PVNH associated with callosal hypoplasia and ventriculomegaly. EEG revealed dysmature background activity with multifocal epileptiform discharges and runs of asynchronous fast activity during sleep. Genetic testing identified a novel homozygous nonsense variant in ARFGEF2. The clinical course was characterised by drug-resistant epilepsy and multisystemic involvement, including feeding difficulties and recurrent respiratory infections. To contextualise this case, we performed a comprehensive review of previously reported patients, further delineating the clinical, neuroradiological, and electroclinical spectrum of ARFGEF2-related disorder. This case highlights progressive microcephaly as a key distinguishing feature of ARFGEF2-related PVNH and underscores the importance of early genetic diagnosis to guide targeted surveillance for extra-CNS complications and multidisciplinary care. Full article

Since 1999, sellar xanthogranulomas (XGs) have been recognized as a distinct pathological entity characterized by cholesterol clefts, macrophages, chronic inflammatory infiltrates with multinucleated giant cells, necrotic debris, and hemosiderin, suggesting a chronic inflammatory process with repetitive intralesional bleeding. This study aims to characterize the clinical phenomenology of the rare XG entity and to explore its correlation with other lesions. A retrospective screening was conducted of 628 sellar surgeries performed during the 2007–2024 period at a major communal hospital in Berlin and 529 surgeries between 2015 and 2024 at Ulm University. Eight XGs were analyzed. Eight XGs (0.6% of 1157 surgeries) showed mixed intra- and suprasellar localization. Visual deficits and endocrinological insufficiencies were the most common symptoms (four out of eight each). Visual recovery was favorable (three out of four complete, one out of four marked improvement), whereas endocrinological recovery was limited (one out of four). One patient experienced recurrence. Intraoperatively, seven out of eight lesions contained characteristic fluid described as ‘golden water of Gdansk.’ Postoperatively, transient arginine vasopressin deficiency occurred in four out of eight patients. The illustrative case demonstrated transformation of a Rathke’s cleft cyst, while two cases were associated with pituitary adenomas. Sellar XGs are benign, chronic inflammatory and hemorrhagic lesions with low recurrence risk. Their frequent association with other sellar pathologies supports a secondary reactive origin. Full article

Introduction: Delirium is associated with worse outcomes in critically ill patients. Factors that could reduce delirium are patients’ environment and maintaining circadian cycles, but whether certain room characteristics improve the incidence of delirium is unclear. Our objective was to investigate whether the presence of windows or doors in patients’ rooms is associated with lower rates of delirium. Methods: In this retrospective, cohort study, adult, medical patients admitted to the Intensive Care Unit (ICU) between 1 January 2024 and 1 July 2024 were identified. Clinical and room characteristics were collected. The primary outcome was the development of Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) positive status. Secondary outcomes included ICU and hospital length of stay (LOS) and mortality. Results: Four hundred fifty-eight (458) patients met inclusion criteria (mean age 61.7 +/− 16.4 years; 51.3% male). In the adjusted multivariate analysis, neither the presence of windows (aOR 2.2; 95% CI 0.7–6.2; p = 0.155) nor closed-format rooms (aOR 0.1; 95% CI 0.0–1.2; p = 0.077) were significantly associated with CAM-ICU positivity. Although an initial association was observed between the presence of windows and increased hospital LOS (aMR 1.4; 95% CI 1.1–1.8; p = 0.008), this did not maintain statistical significance after False Discovery Rate (FDR) correction (q > 0.05). No significant associations were found for other secondary outcomes, including ICU mortality or ICU LOS. Conclusion: Room characteristics were not significantly associated with delirium or secondary outcomes after FDR correction. However, given the study’s limited power to detect moderate differences, these findings do not definitively rule out an architectural influence on delirium and warrant further investigation in larger cohorts. Studies with more discrete measurement of room characteristics are needed to investigate these associations further. Full article

Background: Peripheral neuropathy is a common and clinically heterogeneous neurological condition caused by metabolic, inflammatory, toxic, or traumatic factors and is associated with sensory deficits, neuropathic pain, motor impairment, and reduced functional capacity. Management remains challenging and often requires multimodal therapeutic approaches, as pharmacological monotherapy frequently provides incomplete symptom control. Objective: This narrative review explores the conceptual rationale for combining galantamine with iontophoresis and Black Sea brine-based therapy as a potential multimodal strategy for peripheral neuropathy management. Main Findings: Galantamine, a reversible acetylcholinesterase inhibitor and positive allosteric modulator of nicotinic acetylcholine receptors, has demonstrated neuroprotective, neuromodulatory, and anti-inflammatory properties in experimental settings. Iontophoresis may provide a non-invasive method for targeted local drug delivery while reducing systemic exposure. Black Sea brine, widely used in Bulgarian balneological and rehabilitation practice, has been associated with improved circulation, pain reduction, and neuromuscular support. The reviewed evidence suggests biologically plausible complementary mechanisms; however, no direct clinical studies evaluating the combined intervention were identified. Limitations: Current evidence is indirect and derived from separate investigations of galantamine, iontophoresis, and brine-based therapy, as well as heterogeneous historical and regional sources. Therefore, the proposed combination should be considered hypothesis-generating rather than evidence-established. Conclusions: The combination of galantamine, iontophoresis, and Black Sea brine represents a potentially interesting multimodal concept for peripheral neuropathy rehabilitation. Well-designed preclinical and clinical studies are required to determine safety, feasibility, optimal treatment parameters, and therapeutic efficacy. Full article

Peripheral artery disease (PAD) is found in 10.9% of patients with ischaemic stroke (IS). This cross-sectional study was performed to investigate the prevalence of PAD and its risk factors among acute IS patients in Singapore. Patients admitted for IS were recruited. Data was collected on sex, age, body mass index (BMI), history of hypertension, diabetes mellitus (DM), hypercholesterolaemia, cigarette smoking, prior stroke (PS) and ischaemic heart disease (IHD). IS was classified as a lacunar infarct (LI) or non-lacunar infarct (NLI) based on neuroimaging. Carotid intima–medial thickening (IMT) and carotid plaques (CP) were determined by ultrasonography. The ankle–brachial Index (ABI) was calculated in both lower limbs; PAD was diagnosed if the ABI was ≤0.9 in any limb. The estimated sample size was 150 subjects. In total, 150 subjects were recruited; the mean age was 62.7 ± 10.2 years, 44.7% were female, and the mean BMI was 24.1 ± 4.1. A total of 63.3% reported hypertension, 42.7% DM, 30.0% hypercholesterolaemia, 38.0% smoking, 18.7% PS, and 6.0% IHD. A total of 30.7% had IMT, 77.3% had CP, and 8.0% had carotid stenosis ≥50%. LI occurred in 64.7%. PAD was diagnosed in 22.0% (95% CI 16.1–29.3). On univariate analysis, based on vascular risk factors alone, PAD was associated with age (p = 0.03), hypercholesterolaemia (p = 0.03), and IHD (p = 0.004). On logistic regression, PAD was only associated with IHD (aOR 6.42, 95% CI 1.25–32.84; p = 0.03). When IMT and CP were added to the model, the association with IHD remained (aOR 5.45, 95% CI 1.03–28.71; p = 0.045). When the results of neuroimaging were added, the association was only with NLI (aOR 2.78, 95% CI 1.09–7.14; p = 0.03). This study found a high prevalence of PAD among Asian patients with IS. It was associated with a non-lacunar infarction. Full article

Neurofilaments (NFs) are the predominant type IV intermediate filaments in differentiated neurons, functioning not just as static scaffolds, but as active drivers of radial axonal growth and nerve conduction velocity. While their physical properties are well characterized, a critical gap remains in synthesizing how their dynamic assembly and developmental subunit switching directly dictate neurodegenerative outcomes. This review breaks down the molecular architecture and stepwise kinetic assembly of NFs, detailing their role in polarized transport and the formation of a protective viscoelastic gel network within axons. We specifically highlight the physiological expression switching of early subunits, such as alpha-internexin and peripherin, during neuronal maturation, a process often overlooked in traditional structural reviews. By examining how specific gene mutations and aberrant hyperphosphorylation trigger axonal transport jams and protein aggregation, we map the direct pathways leading to amyotrophic lateral sclerosis (ALS) and Charcot–Marie–Tooth (CMT) disease. Finally, we emphasize that a precise mechanistic decoding of NF structural dynamics and their pathological disruption is essential for understanding the fundamental etiology of these neurodegenerative conditions. Full article

Recent advances in neurodegenerative disease research increasingly support the existence of multiple trajectory signatures underlying the heterogeneity of cognitive decline syndromes. Originally proposed in Parkinson’s disease, the brain-first and body-first models have emerged as conceptual frameworks to explain variability in disease onset, prodromal features, and progression across dementia-related disorders. Brain-first phenotypes are defined by the early emergence of central nervous system pathology and cognitive symptoms, whereas body-first phenotypes are characterized by prominent peripheral or autonomic dysfunctions that precede central involvement. Within this perspective, neurodegeneration is not viewed as a uniform, brain-restricted process, but a dynamic interaction between central, peripheral, and network-level mechanisms. Integrating central and peripheral biomarkers, autonomic physiology, and alterations in functional connectivity provides a coherent framework for interpreting phenotypic heterogeneity and prodromal dysregulation across dementia syndromes. Current evidence supporting brain-first and body-first trajectories is largely associative, and their clinical translation requires rigorous validation. Accordingly, this narrative perspective review aims to provide a critical and integrative conceptual framework that synthesizes existing evidence, identifies unresolved questions, and outlines research priorities for trajectory-based stratification, rather than offering a definitive diagnostic classification or pharmacological evaluation. The present work adopts a conceptual and mechanistic perspective rather than a clinically prescriptive or trial-oriented one. Its aim is to articulate a generative framework capable of producing testable hypotheses about disease trajectories and biomarker constellations across neurodegenerative syndromes. Full article

Background: Only a subset of cannabis users develop persistent psychosis, implying that genetic vulnerability modulates risk. HLA-DR/DQ variation is a strong non-dopaminergic risk locus for schizophrenia, but its role in cannabis-related psychosis is unclear. Methods: We studied 296 cannabis users from Romanian psychiatric services, grouped as non-psychosis (0), non-schizophrenia psychosis (1) and schizophrenia (2). High-resolution HLA-DRB1, DRB3/4/5 and inferred DRB1-DQB1 haplotypes were tested using Fisher’s exact tests with FDR correction in a universal contrast (0 vs. 1+2) and 0-1-2 pairwise comparisons, with Firth logistic regression and resampling as supportive analyses. Results: In the universal analysis, DRB1*16, DRB5 and the DRB1*16-DQB1*05 haplotype were associated with roughly two- to threefold higher odds of psychosis, whereas DRB1*07 and DRB4/DRB3 paralogs showed protective effects or trends. In the 0-1-2 contrasts, DRB1*16 was enriched in non-schizophrenia psychosis. DRB4/DRB3 paralogs were under-represented in schizophrenia relative to both cannabis users without psychosis and those with non-schizophrenia psychosis, suggesting a schizophrenia-specific protective association. Firth models supported effect directions but were underpowered. Conclusions: HLA class II immunogenetic background may modify psychosis risk among cannabis users: DRB5/DRB1*16-containing backgrounds were associated with increased vulnerability, whereas DRB4/DRB3 paralogs were associated with reduced schizophrenia risk in this cohort. These findings are hypothesis-generating, do not establish causality, and warrant replication in larger cohorts. Full article