Neurology International

13 pages, 524 KB

Open AccessArticle

Plasma Neurofilament Light Chain Is Associated with Cognitive Functions but Not Patient-Reported Outcomes in Multiple Sclerosis

by Valerio Nicolella, Federica Novarella, Fabrizia Falco, Carmela Polito, Rosa Sirica, Evelina La Civita, Vincenzo Criscuolo, Giuseppe Corsini, Antonio Luca Spiezia, Alessia Castiello, Antonio Carotenuto, Maria Petracca, Roberta Lanzillo, Giuseppe Castaldo, Vincenzo Brescia Morra, Daniela Terracciano and Marcello Moccia

Neurol. Int. 2025, 17(9), 144; https://doi.org/10.3390/neurolint17090144 - 9 Sep 2025

Abstract

Objective: We aimed to explore associations between plasma neurofilament light chain (pNfL) and cognition through patient-reported outcomes (PROs) in multiple sclerosis (MS). Methods: In this cross-sectional study, we included 211 people with MS (PwMS) and collected data from pNfL (fully automated chemiluminescent enzyme [...] Read more.

Objective: We aimed to explore associations between plasma neurofilament light chain (pNfL) and cognition through patient-reported outcomes (PROs) in multiple sclerosis (MS). Methods: In this cross-sectional study, we included 211 people with MS (PwMS) and collected data from pNfL (fully automated chemiluminescent enzyme immunoassay), EDSS, education, cognition (the Symbol Digit Modalities Test (SDMT), California Verbal Learning Test-II (CVLT II), and Brief Visuospatial Memory Test–Revised (BVMT-R)), the Modified Fatigue Impact Scale (MFIS), Beck Depression Inventory (BDI-II), Beck Anxiety Inventory (BAI), and Pittsburgh Sleep Quality Index (PSQI). Results: On multivariate linear regression models, higher educational attainment was significantly associated with lower pNfL (high school: Coeff = −0.22, 95% CI = −0.41 to −0.04, p = 0.019; university: Coeff = −0.22, 95% CI = −0.42 to −0.02, p = 0.030). In logistic regression models, the likelihood of having pNfL levels above normal thresholds increased by 56% for each one-point increment in the EDSS score (OR = 1.56, 95% CI = 1.23 to 1.98, p < 0.001) and was 2.5 times greater in individuals with impaired SDMT (OR = 2.50, 95% CI = 2.20 to 5.21, p = 0.014). No statistically significant associations were observed between pNfL and CVLT-II, BVMT-R, BDI-II, MFIS, BAI, or PSQI. Conclusions: Neuro-axonal damage in people with MS manifests clinically as increased disability and reduced attention and processing speed. However, these effects may be mitigated by greater brain resilience, as suggested by the protective role of higher educational attainment. The PROs assessed in this study showed no significant associations with pNfL levels, possibly due to measurement errors and heterogeneity, with limited sensitivity to neuro-axonal damage. Full article

(This article belongs to the Section Aging Neuroscience)

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15 pages, 869 KB

Open AccessReview

Pericapsular Nerve Group Block Versus Lumbar Epidural Block for Pain Management After Hip Surgeries with a Focus on Pediatric Patients: A Narrative Review

by Shahab Ahmadzadeh, Hunter M. Schwab, Mary O’Dell Duplechin, Kalob M. Broocks, Jon D. Hirsch, Joseph Drinkard and Sahar Shekoohi

Neurol. Int. 2025, 17(9), 142; https://doi.org/10.3390/neurolint17090142 - 8 Sep 2025

Abstract

Pediatric hip surgeries are associated with moderate to high levels of pain, which, in severe cases can lead to opioid prescription and use. There is a growing focus on reducing post-operative pain in these patients to decrease the need for opioids, as well [...] Read more.

Pediatric hip surgeries are associated with moderate to high levels of pain, which, in severe cases can lead to opioid prescription and use. There is a growing focus on reducing post-operative pain in these patients to decrease the need for opioids, as well as increase early mobilization for recovery. Conventional methods of pain relief using opioids can have unwanted negative impacts on pediatric patients such as respiratory depression, nausea, confusion, and the concerning possibility for the development of dependence. Likewise, traditional methods of anesthesia, like the lumbar epidural block, can have unwanted systemic side effects, such as hypotension, urinary retention, arrhythmias, and spinal abscesses. These complications can lead to longer hospital stays and delayed recovery. This review analyzes the efficacy of a newer regional anesthesia technique, the pericapsular nerve group (PENG) block, in comparison to the lumbar epidural block. This technique utilizes precision-based anesthesia to selectively block the articular branches to the hip joint while avoiding the main trunks of the femoral and obturator nerves. Additionally, with the utilization of high-resolution ultrasound to guide the blocks, providers can increasingly count on proper insertion and predictable anesthetic spread. The result is a motor-sparing blockade that shows promise in allowing earlier mobilization and better functional recovery times after pediatric hip surgeries. Full article

(This article belongs to the Section Pain Research)

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13 pages, 4892 KB

Open AccessCase Report

Hyperkinetic Movement Disorder in KARS1-Related Disease: An Illustrative Video-Recorded Case and Narrative Literature Review

by Veronica Ferasin, Arianna Raicich, Caterina Ancora, Ilaria Bonemazzi, Alessandro Di Paola, Ignazio D’Errico, Margherita Nosadini, Claudio Ancona, Maria Federica Pelizza, Matteo Cassina and Irene Toldo

Neurol. Int. 2025, 17(9), 143; https://doi.org/10.3390/neurolint17090143 - 7 Sep 2025

Abstract

Background: Aminoacyl-tRNA synthetases (ARSs) are a group of enzymes responsible for the first step of protein translation. Among them, the KARS1 gene encodes lysyl-tRNA synthetase 1, an enzyme essential for charging tRNA-Lys with lysine in both the cytoplasm and mitochondria. Mutations in KARS1 [...] Read more.

Background: Aminoacyl-tRNA synthetases (ARSs) are a group of enzymes responsible for the first step of protein translation. Among them, the KARS1 gene encodes lysyl-tRNA synthetase 1, an enzyme essential for charging tRNA-Lys with lysine in both the cytoplasm and mitochondria. Mutations in KARS1 are associated with a wide range of clinical phenotypes, including leukoencephalopathy, hereditary deafness, peripheral neuropathies, and multisystemic involvement. Methods: We hereby report a detailed case study of a 15-month-old boy presenting at age 5 months with developmental delay, microcephaly, hypotonia, sensorineural deafness, retinopathy, visual impairment, nystagmoid eye movements, and hepatic and immuno-hematological abnormalities. In addition, he exhibited a severe hyperkinetic movement disorder, not previously reported in the literature, and developed epilepsy at 13 months. Genetic testing identified two rare compound heterozygous variants in the KARS1 gene. Results: With this report, we aim to contribute to the expanding of both the clinical phenotype and the allelic spectrum of lysyl-tRNA synthetase-related disorders. Our study also includes a review of previously described KARS1 cases presenting with movement disorders. Conclusions: Our findings further highlight the importance of assessing systemic involvement and performing brain and spinal neuroimaging, as well as implementing genetic screening, in infants presenting with global developmental delay, sensory deficits, and movement disorders—features that may suggest a mitochondrial disorder such as those involving ARS mutations. Full article

(This article belongs to the Special Issue New Insights into Movement Disorders)

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21 pages, 1777 KB

Open AccessFeature PaperReview

Cannabinoids in Chronic Pain: Clinical Outcomes, Adverse Effects and Legal Challenges

by Aleksandar Sic, Conor George, Daniela Ferrer Gonzalez, Vasilis-Spyridon Tseriotis and Nebojsa Nick Knezevic

Neurol. Int. 2025, 17(9), 141; https://doi.org/10.3390/neurolint17090141 - 5 Sep 2025

Abstract

Cannabinoids have gained increasing attention as potential therapeutic agents in chronic pain management. Their mechanisms of action, mediated through CB1 and CB2 receptors, provide a pharmacological alternative to conventional analgesics. The evidence is strongest for neuropathic pain and multiple sclerosis-related spasticity, while the [...] Read more.

Cannabinoids have gained increasing attention as potential therapeutic agents in chronic pain management. Their mechanisms of action, mediated through CB1 and CB2 receptors, provide a pharmacological alternative to conventional analgesics. The evidence is strongest for neuropathic pain and multiple sclerosis-related spasticity, while the results for fibromyalgia, osteoarthritis, and musculoskeletal pain remain inconsistent. The average pain reduction is modest, often not exceeding 0.5–1.0 points on a 10-point scale, and therapeutic gains are offset by safety concerns. Quantitative data show that discontinuation rates range from 4.3% at low-dose CBD to 12.9% at high-dose CBD, compared with 3.5% on placebo, while nabiximols (THC + CBD spray) are associated with dizziness in 25% of patients, somnolence in 8%, and treatment discontinuation in 12%. High-dose CBD also carries a measurable risk of hepatotoxicity. Regulatory heterogeneity further constrains trial feasibility, scalability, and patient access, with disparities evident across the United States, Europe, Canada, and Australia. Overall, cannabinoids provide modest, condition-specific analgesia and should be considered adjunctive rather than first-line options, reserved for patients unresponsive to conventional therapy. Future progress requires standardized formulations, harmonized international regulations, long-term safety data, and large-scale randomized controlled trials to clarify their role in evidence-based pain management. Full article

(This article belongs to the Section Pain Research)

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23 pages, 1536 KB

Open AccessArticle

Epidemiological and Clinical Characteristics of Acute Stroke in a Multi-Ethnic South Asian Population

by Kim H. Tran, Naveed Akhtar, Yahia Imam, Md Giass Uddin, Sujatha Joseph, Deborah Morgan, Blessy Babu, Ryan Ty Uy and Ashfaq Shuaib

Neurol. Int. 2025, 17(9), 140; https://doi.org/10.3390/neurolint17090140 - 5 Sep 2025

Abstract

Objective: Stroke is one of the leading causes of death and disability worldwide. Compared to developed countries, the prognosis of stroke is less favourable in developing countries. The objective of this study is to identify inter-ethnic variation in risk profiles and stroke outcomes [...] Read more.

Objective: Stroke is one of the leading causes of death and disability worldwide. Compared to developed countries, the prognosis of stroke is less favourable in developing countries. The objective of this study is to identify inter-ethnic variation in risk profiles and stroke outcomes amongst Bangladeshi, Indian, Nepalese, Pakistani, and Sri Lankan expatriates living in Qatar. Methods: Data from the Qatar Stroke Registry were retrospectively analyzed from April 2014 to June 2025. A total of 8825 patients were included. The chi-square test was used to analyze sociodemographic variables, while the Kruskal–Wallis test was used to analyze continuous variables. Post hoc analysis was performed. Multivariate logistic regression and multivariate multiple regression were used to identify the predictors associated with poor clinical outcomes and mortality at 90 days. Results: Ischemic stroke was the predominant stroke type in all groups, with Nepalese patients presenting with stroke at a younger age, whilst Pakistanis tended to be older (p < 0.001). In terms of stroke outcomes, Nepalese patients had the highest proportion of a poor functional outcome at 90 days as well as NIHSS at discharge (p < 0.05). However, Bangladeshis had the highest proportion of mortality at 90 days compared to the other cohorts. Multivariable logistic regression revealed that undiagnosed dyslipidemia, Nepalese ethnicity, and moderate and severe NIHSS admission scores were independent predictors of a poor functional outcome at 90 days, whilst male sex and prior antidiabetic therapy were protective factors (p < 0.001). In terms of mortality at 90 days, only a severe NIHSS admission score (>10) was a significant predictor (p < 0.001). A severe NIHSS admission score was also the only predictive factor of mortality and poor functional outcome at 90 days (p < 0.05). Conclusions: There was a significant variation in stroke presentation and outcomes among South Asian subpopulations in Qatar, suggesting the importance of tailored public health strategies as a uniform approach to stroke care is insufficient for this diverse population. Full article

(This article belongs to the Section Movement Disorders and Neurodegenerative Diseases)

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12 pages, 892 KB

Open AccessArticle

Relationship Between Each of the Four Major Motor Symptoms and At-Home Physical Activity in Individuals with Parkinson’s Disease: A Cross-Sectional Study

by Yuichi Hirakawa, Hiroaki Sakurai, Kazuya Takeda, Soichiro Koyama, Masanobu Iwai, Ikuo Motoya, Yoshikiyo Kanada, Nobutoshi Kawamura, Mami Kawamura and Shigeo Tanabe

Neurol. Int. 2025, 17(9), 139; https://doi.org/10.3390/neurolint17090139 - 3 Sep 2025

Abstract

Background/Objectives: Individuals with Parkinson’s disease (PD) often experience four major motor symptoms—tremor, rigidity, bradykinesia, and postural instability/gait disorder. Although these symptoms have been shown to affect activities of daily living, their impact on the level of at-home physical activity (PA) in this [...] Read more.

Background/Objectives: Individuals with Parkinson’s disease (PD) often experience four major motor symptoms—tremor, rigidity, bradykinesia, and postural instability/gait disorder. Although these symptoms have been shown to affect activities of daily living, their impact on the level of at-home physical activity (PA) in this population remains unexplored. We aimed to investigate the relationship between the four major motor symptoms of PD and at-home PA in these individuals. Methods: This retrospective cross-sectional study included 17 individuals with PD. We examined the relationship between the Movement Disorder Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale Part 3 score and the time spent in three PA intensities (sedentary behavior, light PA [LPA], and moderate-to-vigorous PA) within the home. Pearson’s correlation coefficient was used for statistical analysis. Results: In the initial step analysis, a significant negative correlation was observed between the overall motor symptom score and the time spent in LPA inside the home (r_s [95% confidence interval]: −0.72 [−0.93 to −0.25]; p < 0.01). In the second step analysis, a significant negative correlation was observed between the bradykinesia score and the time spent in LPA inside the home (r_s: −0.74 [−0.92 to −0.30]; p < 0.01). Conclusions: Among the four major motor symptoms, only the severity of bradykinesia influenced the time spent in LPA inside the home. Thus, rehabilitation treatment focusing on bradykinesia may be beneficial for increasing the time spent in LPA inside the home for individuals with PD. Full article

(This article belongs to the Section Movement Disorders and Neurodegenerative Diseases)

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12 pages, 6471 KB

Open AccessArticle

The Effects of Co-Culturing ND7/23 Sensory Neuron-like Cells and IFRS1 Schwann Cells on Myelination: A Single-Arm Nonrandomized Study

by Shizuka Takaku and Kazunori Sango

Neurol. Int. 2025, 17(9), 138; https://doi.org/10.3390/neurolint17090138 - 1 Sep 2025

Abstract

Background/Objectives: Co-culture models of neurons and Schwann cells have been used to explore the mechanisms of myelination during development, axonal regeneration after injury, and the pathogenesis of various demyelinating neuropathies. A spontaneously immortalized Fischer rat Schwann cell line 1 (IFRS1), established from [...] Read more.

Background/Objectives: Co-culture models of neurons and Schwann cells have been used to explore the mechanisms of myelination during development, axonal regeneration after injury, and the pathogenesis of various demyelinating neuropathies. A spontaneously immortalized Fischer rat Schwann cell line 1 (IFRS1), established from the primary culture of adult Fischer344 rat peripheral nerves, can myelinate neurites in co-cultures with primary cultured dorsal root ganglion neurons and neuronal cell lines, such as nerve growth factor (NGF)-primed PC12 cells and NSC-34 motor neuron-like cells. In this study, we aimed to establish a stable co-culture system using IFRS1 cells and ND7/23 sensory neuron-like cells. Methods: ND7/23 cells were seeded at a low density (2 × 10³/cm²) and maintained for 7 days in serum-containing medium supplemented with NGF (10 ng/mL) and the Rho kinase inhibitor Y27632 (5 μM) to promote neurite elongation. The cells were then treated with the anti-mitotic agent mitomycin C (1 μg/mL) for 12–16 h to suppress proliferative activity. Following this, the cells were co-cultured with IFRS1 cells (2 × 10⁴/cm²) and maintained at 37 °C in serum-containing medium supplemented with ascorbic acid (50 μg/mL), NGF (10 ng/mL), and ciliary neurotrophic factor (10 ng/mL). Results: Double-immunofluorescence staining performed on day 21 of the co-culture revealed myelin protein 22- or myelin basic protein-immunoreactive IFRS1 cells surrounding βIII tubulin-immunoreactive neurites emerging from ND7/23 cells. Myelin formation was further confirmed via Sudan Black B staining and electron microscopy. Conclusions: This co-culture system may provide a valuable tool for studying the processes of myelination in the peripheral nervous system, as well as the pathogenesis of various sensory neuropathies and potential novel therapeutic approaches for these conditions. Full article

(This article belongs to the Collection Exclusive Papers from the Editorial Board Members (EBMs) of Neurology International)

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16 pages, 7412 KB

Open AccessArticle

Carpal Tunnel Syndrome in the Very Elderly: Clinical, Electrodiagnostic, and Ultrasound Features in a Cohort of 187 Patients

by Lisa B. E. Shields, Vasudeva G. Iyer, Theresa Kluthe, Yi Ping Zhang and Christopher B. Shields

Neurol. Int. 2025, 17(9), 137; https://doi.org/10.3390/neurolint17090137 - 30 Aug 2025

Abstract

Background/Objectives: Elderly patients with carpal tunnel syndrome (CTS) have more severe clinical, ultrasonic, and electrodiagnostic (EDX) findings compared to younger patients. Thenar weakness and atrophy are more common at initial presentation in the elderly population with CTS. Methods: This is a retrospective review [...] Read more.

Background/Objectives: Elderly patients with carpal tunnel syndrome (CTS) have more severe clinical, ultrasonic, and electrodiagnostic (EDX) findings compared to younger patients. Thenar weakness and atrophy are more common at initial presentation in the elderly population with CTS. Methods: This is a retrospective review of 187 very elderly patients (aged 80 years and older) with EDX confirmation of CTS. We describe the clinical, EDX, and US features in these patients and compare the severity of the median nerve entrapment at the carpal tunnel (CT) by EDX findings to a middle-aged cohort (ages 40–50 years). Results: The total number of very elderly hands with CTS was 289 (187 patients total, with bilateral symptoms in 102 patients). Of the 289 hands, thenar atrophy was observed in 75 (26.0%) hands, weakness of the abductor pollicis brevis (APB) muscle was detected in 178 (61.6%) hands, and pinprick decrease/loss was noted in 265 (91.7%) hands. Of the total 289 hands, 57 (66.3%) hands’ median nerve stimulation did not evoke compound muscle action potentials over the APB and second lumbrical muscles. Sensory nerve action potentials were not detected in 211 (76.2%) hands. Comparing the sensitivities of various US measurements in diagnosing CTS, the cross-sectional area at the CT inlet had the highest sensitivity among the various measurements. As the CSA at the CT inlet increases, the odds of a greater CTS severity by EDX studies also increase (OR = 1.109, p-value = 0.001). The very elderly patients with CTS more frequently had more severe CTS compared to the middle-aged patients with CTS (chi-squared = 102.65₃, p-value < 0.001). Conclusions: The very elderly patients appear to seek medical care only when the CTS has become severe. The primary care physicians should look for signs and symptoms of CTS in the very elderly and encourage prompt treatment. Surgeons should be cognizant of the differences in the clinical, EDX, and US studies in the very elderly patient cohort with CTS. US is highly useful in evaluating CTS when the EDX studies become non-localizing in severe CTS, as often seen in the very elderly patients. Full article

(This article belongs to the Section Movement Disorders and Neurodegenerative Diseases)

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20 pages, 1484 KB

Open AccessArticle

Novel Computed Tomography Perfusion and Laboratory Indices as Predictors of Long-Term Outcome and Survival in Acute Ischemic Stroke

by Eray Halil, Kostadin Kostadinov, Nikoleta Traykova, Neli Atanasova, Kiril Atliev, Elizabet Dzhambazova and Penka Atanassova

Neurol. Int. 2025, 17(9), 136; https://doi.org/10.3390/neurolint17090136 - 27 Aug 2025

Abstract

Background/Objectives: Acute ischemic stroke is a leading cause of mortality and long-term disability globally, with limited reliable early predictors of functional outcomes and survival. This study aimed to assess the prognostic value of two novel predictors: the hypoperfusion intensity ratio calculated from mean [...] Read more.

Background/Objectives: Acute ischemic stroke is a leading cause of mortality and long-term disability globally, with limited reliable early predictors of functional outcomes and survival. This study aimed to assess the prognostic value of two novel predictors: the hypoperfusion intensity ratio calculated from mean transit time and time-to-drain maps (HIR-MTT–TTD), derived from computed tomography perfusion (CTP) imaging parameters, and the Inflammation–Coagulation Index (ICI), which integrates systemic inflammatory (C-reactive protein and white blood cell count) and hemostatic (D-dimer) markers. Methods: This prospective, single-center observational study included 60 patients with acute ischemic stroke treated with intravenous thrombolysis and underwent pre-treatment CTP imaging. HIR-MTT–TTD evaluated collateral status and perfusion deficit severity, while ICI integrated C-reactive protein (CRP), white blood cell (WBC) count, and D-dimer levels. Functional outcomes were assessed using the National Institutes of Health Stroke Scale (NIHSS), Barthel Index, and modified Rankin Scale (mRS) at 24 h, 3 months, and 1 year. Results: Of 60 patients, 53.3% achieved functional independence (mRS 0–2) at 1 year. Unadjusted Cox models showed HIR-MTT–TTD (HR = 6.25, 95% CI: 1.48–26.30, p = 0.013) and ICI (HR = 1.08, 95% CI: 1.00–1.17, p = 0.052) were associated with higher 12-month mortality, worse mRS, and lower Barthel scores. After adjustment for age, BMI, smoking status, and sex, these associations became non-significant (HIR-MTT–TTD: HR = 2.83, 95% CI: 0.37–21.37, p = 0.314; ICI: HR = 1.07, 95% CI: 0.96–1.19, p = 0.211). Receiver operating characteristic (ROC) analysis indicated moderate predictive value, with ICI (AUC = 0.756, 95% CI: 0.600–0.867) outperforming HIR-MTT–TTD (AUC = 0.67, 95% CI: 0.48–0.83) for mortality prediction. Conclusions: The study introduces promising prognostic tools for functional outcomes. Elevated HIR-MTT–TTD and ICI values were independently associated with greater initial stroke severity, poorer functional recovery, and increased 1-year mortality. These findings underscore the prognostic significance of hypoperfusion intensity and systemic thrombo-inflammation in acute ischemic stroke. Combining the use of the presented indices may enhance early risk stratification and guide individualized treatment strategies. Full article

(This article belongs to the Section Movement Disorders and Neurodegenerative Diseases)

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19 pages, 3496 KB

Open AccessArticle

Sulbactam: A β–Lactam Compound with Neuroprotective Effects in Epilepsy

by Fang-Chia Chang, Chiung-Hui Liu, Wen-Chieh Liao, Yu-Shiuan Tzeng, Ru-Yin Tsai, Li-Ho Tseng, Ching-Sui Hung, Shey-Lin Wu and Ying-Jui Ho

Neurol. Int. 2025, 17(9), 135; https://doi.org/10.3390/neurolint17090135 - 27 Aug 2025

Abstract

Background: The pathophysiology of epilepsy is characterized by increased neuronal activity due to an excess of the excitatory neurotransmitter glutamate and a deficiency in the inhibitory neurotransmitter gamma–aminobutyric acid (GABA). Epilepsy presents with seizures, neuronal loss, and hyperactivity in the subthalamic nucleus (STN). [...] Read more.

Background: The pathophysiology of epilepsy is characterized by increased neuronal activity due to an excess of the excitatory neurotransmitter glutamate and a deficiency in the inhibitory neurotransmitter gamma–aminobutyric acid (GABA). Epilepsy presents with seizures, neuronal loss, and hyperactivity in the subthalamic nucleus (STN). Astrocytes play a crucial role by absorbing extracellular glutamate through glutamate transporter–1 (GLT–1), thereby reducing neuronal excitation. Upregulating the expression of astrocytic GLT–1 is a promising therapeutic strategy for epilepsy. Sulbactam (SUL), a β–lactam antibiotic, has been demonstrated to exert neuroprotective effects by upregulating GLT–1 expression. Objectives: This study investigated the impact of SUL on neuronal and behavioral changes in epilepsy by using a pentylenetetrazol (PTZ)-induced rat model of epilepsy. Methods: Rats were treated with saline, SUL (50 and 150 mg/kg), or a combination of SUL and the GLT–1 blocker dihydrokainate (DHK) for 20 days. Subsequently, behavioral tasks were conducted to assess recognition, anxiety, and memory. Results: Histological analyses revealed that SUL ameliorated neuronal deficits, increased astrocytic GLT–1 expression, and reduced hyperactivity in the STN. Additionally, SUL promoted astrocyte proliferation, indicating a new dimension of its neuroprotective properties. However, the beneficial effects of SUL were prevented by DHK. Conclusions: This pioneering study highlights multiple benefits of SUL, including seizure suppression, increased GLT–1 expression, and astrocyte proliferation, underscoring its high potential as a treatment for epilepsy. Full article

(This article belongs to the Topic Applications of Biomedical Technology and Molecular Biological Approach in Brain Diseases, 2nd Edition)

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30 pages, 2859 KB

Open AccessReview

Deciphering the Structural Biology of GFAP: Connotations of Its Potency in Presaging the Diagnosis for Traumatic Brain Injury and AD

by Sri Harsha Kanuri and Prapthi Jayesh Sirrkay

Neurol. Int. 2025, 17(9), 134; https://doi.org/10.3390/neurolint17090134 - 26 Aug 2025

Abstract

In Alzheimer’s disease, accumulation of Aβ and tau aggregates in the limbic and cortical regions of the brain forms the pathological basis for the onset of memory loss and cognitive abnormalities. The neuronal desecration inflicted by these toxic pile-ups will rouse the onset [...] Read more.

In Alzheimer’s disease, accumulation of Aβ and tau aggregates in the limbic and cortical regions of the brain forms the pathological basis for the onset of memory loss and cognitive abnormalities. The neuronal desecration inflicted by these toxic pile-ups will rouse the onset of innate immune defense mechanisms including astrogliosis within the neuronal milieu. A potential ramification of astrogliosis is the overproduction and spillage of GFAP into the brain circulation. Execution of GFAP vital physiological functions rests upon the preservation of its filamentous structure as well as its cytoskeletal interactions. Any anomaly that hampers the structural integrity of GFAP will engender filament disassembly, cytoplasmic aggregation, and decreased solubility with the resultant deleterious consequences. The potency of GFAP as a reliable biomarker in the blood also rests on its ability to navigate the glymphatic excretory pathways and spill into the systemic circulation. Recent reports have suggested GFAP is a dependable marker for auguring subtle disease changes in traumatic brain injury (TBI) and AD. However, pathological anomalies such abnormal structural integrity, cleavage, impaired drainage pathways, and alternative isoforms will lessen its potency and thwarts its ability from becoming a full-fledged and stable biomarker for neurological diseases. Understanding the GFAP biology, including factors that influence its structural integrity and excretory pathways, will be crucial and this review underscores these sections in a succinct manner. Thorough comprehension of GFAP biology is the principal step in unearthing its potential as a powerful marker for auguring disease initiation, and progression in TBI and AD. Full article

(This article belongs to the Section Brain Tumor and Brain Injury)

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20 pages, 948 KB

Open AccessArticle

High-Accuracy Classification of Parkinson’s Disease Using Ensemble Machine Learning and Stabilometric Biomarkers

by Ana Carolina Brisola Brizzi, Osmar Pinto Neto, Rodrigo Cunha de Mello Pedreiro and Lívia Helena Moreira

Neurol. Int. 2025, 17(9), 133; https://doi.org/10.3390/neurolint17090133 - 26 Aug 2025

Abstract

Background: Accurate differentiation of Parkinson’s disease (PD) from healthy aging is crucial for timely intervention and effective management. Postural sway abnormalities are prominent motor features of PD. Quantitative stabilometry and machine learning (ML) offer a promising avenue for developing objective markers to [...] Read more.

Background: Accurate differentiation of Parkinson’s disease (PD) from healthy aging is crucial for timely intervention and effective management. Postural sway abnormalities are prominent motor features of PD. Quantitative stabilometry and machine learning (ML) offer a promising avenue for developing objective markers to support the diagnostic process. This study aimed to develop and validate high-performance ML models to classify individuals with PD and age-matched healthy older adults (HOAs) using a comprehensive set of stabilometric parameters. Methods: Thirty-seven HOAs (mean age 70 ± 6.8 years) and 26 individuals with idiopathic PD (Hoehn and Yahr stages 2–3, on medication; mean age 66 years ± 2.9 years), all aged 60–80 years, participated. Stabilometric data were collected using a force platform during quiet stance under eyes-open (EO) and eyes-closed (EC) conditions, from which 34 parameters reflecting the time- and frequency-domain characteristics of center-of-pressure (COP) sway were extracted. After data preprocessing, including mean imputation for missing values and feature scaling, three ML classifiers (Random Forest, Gradient Boosting, and Support Vector Machine) were hyperparameter-tuned using GridSearchCV with three-fold cross-validation. An ensemble voting classifier (soft voting) was constructed from these tuned models. Model performance was rigorously evaluated using 15 iterations of stratified train–test splits (70% train and 30% test) and an additional bootstrap procedure of 1000 iterations to derive reliable 95% confidence intervals (CIs). Results: Our optimized ensemble voting classifier achieved excellent discriminative power, distinguishing PD from HOAs with a mean accuracy of 0.91 (95% CI: 0.81–1.00) and a mean Area Under the ROC Curve (AUC ROC) of 0.97 (95% CI: 0.92–1.00). Importantly, feature analysis revealed that anteroposterior sway velocity with eyes open (V-AP) and total sway path with eyes closed (TOD_EC, calculated using COP displacement vectors from its mean position) are the most robust and non-invasive biomarkers for differentiating the groups. Conclusions: An ensemble ML approach leveraging stabilometric features provides a highly accurate, non-invasive method to distinguish PD from healthy aging and may augment clinical assessment and monitoring. Full article

(This article belongs to the Section Movement Disorders and Neurodegenerative Diseases)

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22 pages, 2429 KB

Open AccessArticle

The Role of Pre-Operative Biopsy in Malignant Peripheral Nerve Sheath Tumours: A Review and Retrospective Series with a Management Algorithm from a Single-Center Experience

by Francesca Vincitorio, Leonardo Bradaschia, Enrico Lo Bue, Alice Antico, Paolo Titolo, Bruno Battiston, Diego Garbossa and Fabio Cofano

Neurol. Int. 2025, 17(9), 132; https://doi.org/10.3390/neurolint17090132 - 22 Aug 2025

Abstract

Background/Objectives: Peripheral nerve tumours are commonly encountered in clinical practice. Although most are benign, a subset can exhibit aggressive and invasive behaviour, evolving into malignant peripheral nerve sheath tumours (MPNSTs). Due to their rarity and overlapping features with benign lesions, MPNSTs are [...] Read more.

Background/Objectives: Peripheral nerve tumours are commonly encountered in clinical practice. Although most are benign, a subset can exhibit aggressive and invasive behaviour, evolving into malignant peripheral nerve sheath tumours (MPNSTs). Due to their rarity and overlapping features with benign lesions, MPNSTs are frequently misdiagnosed during the initial evaluation. Preoperative biopsy may aid in distinguishing malignant from benign lesions. This single-center study aimed to develop and validate a diagnostic algorithm—based on a systematic literature review and institutional case series—to assess the role of preoperative biopsy in the diagnostic workflow. Methods: A systematic review of the literature was conducted in accordance with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, covering the period from 1998 to 2024. Additionally, a retrospective case series of patients with peripheral nerve lesions treated at the authors’ institution between January 2018 and June 2024 was analysed. Results: Forty-eight articles met the inclusion criteria and were categorized into five key domains: radiological features of MPNSTs, associated risk factors and genetic conditions, the role of preoperative biopsy, use of radiotherapy, and general clinical management strategies. The proposed diagnostic algorithm was applied to a series of 36 patients, four of whom met the criteria for preoperative biopsy. In three of these cases, early diagnosis of MPNSTs was achieved. Conclusions: Preoperative biopsy appears to be a safe and cost-effective tool for the early identification of MPNSTs. Early diagnosis may facilitate the use of neoadjuvant therapies—such as radiotherapy or chemotherapy—potentially enabling more radical surgical resection and improving overall patient outcomes. Full article

(This article belongs to the Section Brain Tumor and Brain Injury)

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13 pages, 1439 KB

Open AccessArticle

Safety and Effectiveness of Unilateral Transcranial Magnetic Resonance-Guided Focused Ultrasound in Essential Tremor: One-Year Single-Center Real-World Results

by Salvatore Iacono, Cesare Gagliardo, Domenico Gerardo Iacopino, Giuseppe Schirò, Rosario Maugeri, Sergio Mastrilli, Valentina Picciolo, Eleonora Bruno, Maurizio Marrale, Massimo Midiri and Marco D’Amelio

Neurol. Int. 2025, 17(8), 131; https://doi.org/10.3390/neurolint17080131 - 21 Aug 2025

Abstract

Background/Objectives: Essential tremor (ET) is the most common movement disorder worldwide. It negatively affects patients’ activities of daily living (ADL) and quality of life. Unilateral transcranial magnetic resonance-guided focused ultrasound (tcMRgFUS) thalamotomy has been proven as a highly effective and safe treatment [...] Read more.

Background/Objectives: Essential tremor (ET) is the most common movement disorder worldwide. It negatively affects patients’ activities of daily living (ADL) and quality of life. Unilateral transcranial magnetic resonance-guided focused ultrasound (tcMRgFUS) thalamotomy has been proven as a highly effective and safe treatment option for patients with refractory ET. The aims of this study are to explore the effectiveness and safety of tcMRgFUS thalamotomy in patients with ET in a real-world setting. Methods: Patients who underwent tcMRgFUS thalamotomy at the University Hospital of Palermo were prospectively enrolled. Scores obtained by Quality of Life in Essential Tremor Questionnaire (QUEST) and The Essential Tremor Rating Assessment Scale (TETRAS) were compared before and after tcMRgFUS thalamotomy. Predictors of tcMRgFUS thalamotomy effectiveness were explored by multivariable Cox regression analyses. All the adverse events (AEs) during and after the procedure were collected. Results: Fifty patients were included (80% male; median age at tcMRgFUS 67.4 years). After procedure, the QUEST score decreased by 46.2%, while TETRAS-ADL and TETRAS Performance (TETRAS-PE) decreased by 52.2% and 51.8%, respectively. Temperature peak and longitudinal lesion diameter positively correlated with the magnitude of QUEST and TETRAS-PE reduction. A higher baseline TETRAS-PE score predicted a good prognosis (HR = HR 6.6 [95% CI: 2.1–21.3]; p = 0.001). AEs were mild to moderate and transient, while permanent AE was observed only in one case. Conclusions: This real-world study confirms the higher effectiveness and the favorable safety profile of tcMRgFUS thalamotomy in patients with ET by reducing the tremor-related interference in quality of life, disability in ADL, and tremor severity. Full article

(This article belongs to the Section Movement Disorders and Neurodegenerative Diseases)

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9 pages, 519 KB

Open AccessArticle

Validation of the Charlotte Large Artery Occlusion Endovascular Therapy Outcome Score in a Modern Cohort of Thrombectomy Patients

by Rahul R. Karamchandani, Liang Wang, Hongmei Yang, Dale Strong, Jeremy B. Rhoten, Jonathan D. Clemente, Gary Defilipp, Elizabeth A. Adelman, William R. Stetler and Andrew W. Asimos

Neurol. Int. 2025, 17(8), 130; https://doi.org/10.3390/neurolint17080130 - 21 Aug 2025

Abstract

Background/Objectives: The Charlotte Large artery occlusion Endovascular therapy Outcome Score (CLEOS) predicts neurological outcomes after endovascular thrombectomy (EVT). Given recent expanded indications for EVT, we evaluated CLEOS in a modern cohort of thrombectomy patients. Methods: We retrospectively analyzed consecutive, anterior circulation EVT patients [...] Read more.

Background/Objectives: The Charlotte Large artery occlusion Endovascular therapy Outcome Score (CLEOS) predicts neurological outcomes after endovascular thrombectomy (EVT). Given recent expanded indications for EVT, we evaluated CLEOS in a modern cohort of thrombectomy patients. Methods: We retrospectively analyzed consecutive, anterior circulation EVT patients from January to December 2024 at multiple centers. The primary outcome was a 90-day modified Rankin Scale (mRS) score of 4–6. We compared primary outcome rates between the original CLEOS derivation cohort and the validation cohort. The area under the curve (AUC) was calculated for CLEOS and compared to other prognostic scales. Results: In the 347 included patients, the mean age was 67.6 (14.9) years, the median National Institutes of Health Stroke Scale (NIHSS) was 15 (10–20), and 137 (42.2%) had a 90-day mRS score of 4–6. A similar proportion of patients in the validation cohort and the derivation cohort achieved the primary outcome (39% each, p = 0.957). The AUC for CLEOS (0.7416, 95% confidence interval [CI] 0.688–0.795) was superior to that of the Pittsburgh Response to Endovascular therapy (AUC 0.681, 95% CI 0.624–0.738, p < 0.01) and Stroke Prognostication using Age and NIHSS (AUC 0.5982, 95% CI 0.556–0.640, p < 0.01), while a trend was observed compared to Houston Intra-Arterial Therapy-2 (AUC 0.6999, 95% CI 0.644–0.756, p = 0.0657) and Totaled Health Risk in Vascular Events (AUC 0.7046, 95% CI 0.560–0.759, p = 0.07). CLEOS ≥ 700 predicted the primary outcome in 16/19 (84.2%) patients. Conclusions: CLEOS performed well in our modern cohort of thrombectomy patients. Prognostic scales such as CLEOS may be useful in guiding conversations and setting expectations with family members pre- and post-thrombectomy. Full article

(This article belongs to the Section Brain Tumor and Brain Injury)

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10 pages, 946 KB

Open AccessBrief Report

High-Level Exposure of Testosterone During Mouse Pregnancy Impairs the Offspring Social Behavior by Interrupting Neurexin–Neuroligin Binding

by Nan Yagishita-Kyo and Sosuke Yagishita

Neurol. Int. 2025, 17(8), 129; https://doi.org/10.3390/neurolint17080129 - 16 Aug 2025

Abstract

Background/Objectives: The onset of autism spectrum disorder (ASD) is thought to be related to fetal testosterone (TSTN) levels or the binding of neurexin (Nrxn) to neuroligin (Nlgn), as per some studies. However, the underlying molecular mechanisms remain unclear. We found that high [...] Read more.

Background/Objectives: The onset of autism spectrum disorder (ASD) is thought to be related to fetal testosterone (TSTN) levels or the binding of neurexin (Nrxn) to neuroligin (Nlgn), as per some studies. However, the underlying molecular mechanisms remain unclear. We found that high concentrations of TSTN interrupt Nrxn–Nlgn binding in the neonatal brain, causing impaired social behavior. Methods: We reproduced high concentrations of TSTN in the womb by injecting TSTN into pregnant mice, followed by the quantification of Nrxn–Nlgn binding in the neonatal brain. We also explored the sociability and social novelty preferences of male and female offspring. Results: Nrxn–Nlgn binding in the neonatal brain decreased after TSTN injection. Furthermore, male mice showed impairment in social novelty, whereas female mice showed impairments in both social novelty and sociability following TSTN injection. Conclusions: This study revealed that high concentrations of TSTN during brain development interrupted Nrxn–Nlgn binding and led to impairments in social behavior. Full article

(This article belongs to the Section Aging Neuroscience)

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16 pages, 504 KB

Open AccessArticle

Correlation of Neuroimaging Biomarkers and Pharmacogenetic Profiles in Optimizing Personalized Therapy in Children and Adolescents with Psychotic Disorders

by Adriana Cojocaru, Adina Braha, Nicoleta Ioana Andreescu, Alexandra Florina Șerban, Codrina Mihaela Levai, Iulius Jugănaru, Iuliana Costea, Lavinia Hogea, Marius Militaru, Iuliana-Anamaria Trăilă and Laura Alexandra Nussbaum

Neurol. Int. 2025, 17(8), 128; https://doi.org/10.3390/neurolint17080128 - 14 Aug 2025

Abstract

Background/Objectives: Psychotic disorders with childhood or adolescent onset pose major therapeutic challenges due to their complex etiology and variable treatment response. While pharmacogenetics and neuroimaging biomarkers have independently shown potential for guiding therapy, their combined utility remains underexplored. This study aimed to investigate [...] Read more.

Background/Objectives: Psychotic disorders with childhood or adolescent onset pose major therapeutic challenges due to their complex etiology and variable treatment response. While pharmacogenetics and neuroimaging biomarkers have independently shown potential for guiding therapy, their combined utility remains underexplored. This study aimed to investigate whether integrating CYP2D6 pharmacogenetic profiles with structural neuroimaging findings can enhance personalized treatment and predict clinical outcomes in pediatric psychotic disorders. Methods: This prospective observational study included 63 children and adolescents (10–18 years) with DSM-5 diagnosed psychotic disorders. All patients underwent baseline MRI and standardized clinical assessments (PANSS, CGI, GAF). CYP2D6 genotyping was performed in 31 patients (49.2%), categorizing them as extensive (EMs) or intermediate metabolizers (IMs). Patients were treated with atypical antipsychotics and followed for 18 months. Outcomes included symptom severity, global functioning, and side-effect profiles. Results: EM patients demonstrated superior clinical improvement, as evidenced by a reduction in PANSS scores (from 118 to 40) and a corresponding increase in GAF scores (from 39 to 76), compared to the IM and non-tested groups. IM patients exhibited a higher prevalence of MRI abnormalities and slower response. Significant correlations emerged between CYP2D6 genotype, MRI findings, and treatment outcomes (p < 0.001). Combined biomarker profiles enhanced the prediction of therapeutic response and tolerability. Conclusions: Integrating CYP2D6 pharmacogenetic data with neuroimaging biomarkers provides valuable guidance for personalizing antipsychotic treatment in pediatric psychosis. This approach improves clinical outcomes and reduces adverse effects. Future research should further explore the integration of multimodal biomarkers in larger, longitudinal cohorts to optimize individualized psychiatric care for this vulnerable population. Full article

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13 pages, 1495 KB

Open AccessArticle

Exploring Left Atrial Appendage Thrombi in Large Vessel Occlusion Stroke by Cardiac CT: Thrombus Features, LAA Characteristics and the Impact of Direct Oral Anticoagulation

by Karim Mostafa, Sarah Krutmann, Cosima Wünsche, Naomi Larsen, Alexander Seiler, Hatim Seoudy, Domagoj Schunk, Olav Jansen and Patrick Langguth

Neurol. Int. 2025, 17(8), 127; https://doi.org/10.3390/neurolint17080127 - 11 Aug 2025

Abstract

Background: Large vessel occlusion (LVO) strokes account for a significant proportion of ischemic strokes and are often cardioembolic in origin, particularly following atrial fibrillation (AF) with thrombus formation in the left atrial appendage (LAA). Although direct oral anticoagulation (DOAC) therapy reduces stroke risk [...] Read more.

Background: Large vessel occlusion (LVO) strokes account for a significant proportion of ischemic strokes and are often cardioembolic in origin, particularly following atrial fibrillation (AF) with thrombus formation in the left atrial appendage (LAA). Although direct oral anticoagulation (DOAC) therapy reduces stroke risk in AF, anatomical and flow-related factors may still allow thrombi to form and persist, revealing the limitations of anticoagulation in high-risk patients. Examining structural and hemodynamic factors contributing to thrombus persistence is essential for optimizing patient management. Methods: We retrospectively analyzed 169 AF patients with LVO stroke who underwent cardiac CT (cCT) during acute stroke assessment. Patients were categorized based on the presence or absence of persistent LAA thrombi and further stratified by DOAC status. LAA volume, blood stasis and left ventricular (LV) diameter were measured. Thrombi were assessed using Hounsfield Unit (HU) analysis to evaluate potential differences in thrombus composition. Logistic regression analysis was performed to identify independent predictors of thrombus persistence with adjustment for DOAC therapy. Results: Persistent LAA thrombi were identified in 23 patients (13.6%). Patients with thrombi had significantly higher rates of stasis (p = 0.004), larger left ventricular diameters (p = 0.0019) and higher LAA volumes (p = 0.004). When adjusted for DOAC therapy, larger LAA volume (OR 1.05, p = 0.011), presence of LAA stasis (OR 6.14, p = 0.013) and increased LV diameter (OR 1.06, p = 0.006) were independent predictors of thrombus persistence. Thrombus size and HU values did not differ significantly between DOAC and non-DOAC groups. Notably, 30.4% of patients with persistent thrombi were on adequate DOAC therapy. Conclusions: LAA volume, stasis and LV enlargement predict thrombus persistence in the LAA of AF patients with LVO stroke, even under adequate DOAC therapy. These findings highlight the potential need for alternative antithrombotic strategies, including interventional LAA occlusion, and warrant further investigation into individualized stroke prevention in high-risk AF populations. Full article

(This article belongs to the Special Issue Towards an All-Inclusive Paradigm for Acute Stroke Treatment—Challenges and Innovations)

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11 pages, 741 KB

Open AccessArticle

Effect of Cilostazol in the Expression of Biomarkers and Neurological Outcome Following Experimentally Induced Cerebrovascular Accident—Experimental Protocol

by Christiana Anastasiadou, Stavroula Kastora, Alkistis Kapelouzou, Anastasios Papapetrou, Angelos Megalopoulos, Nikolaos Kostomitsopoulos, Efthymios Paronis, Andreas Lazaris, George Geroulakos, Christos Liapis, Nikolaos Saratzis and John Kakisis

Neurol. Int. 2025, 17(8), 126; https://doi.org/10.3390/neurolint17080126 - 11 Aug 2025

Abstract

Objective: Several strategies have been described for stroke prevention, and the most commonly used medication is aspirin. Cilostazol, which is a substance with a pleiotropic effect, is still not well investigated. In this study, we aimed to delineate the effects of mono- and [...] Read more.

Objective: Several strategies have been described for stroke prevention, and the most commonly used medication is aspirin. Cilostazol, which is a substance with a pleiotropic effect, is still not well investigated. In this study, we aimed to delineate the effects of mono- and combinatorial pre-treatment upon neurological status and biomarkers, namely protein S100b, GFAP, procalcitonin, and galectin-3, following stroke. Methods: Twelve-week-old Sprague–Dawley rats were randomly assigned to four groups, each containing six rats: control group (normal saline), cilostazol group (30 mg/kg/daily), aspirin group (10 mg/kg/daily), and aspirin/cilostazol group. Each substance was administered by gavage for four weeks. All animals were subjected to cerebral ischemia for 2 h using intraluminal middle cerebral artery occlusion. A neurological examination was performed, serum concentrations of biomarkers were determined, and the animals were then sacrificed. Results: All treatment groups exhibited variations in the severity of immediate neurological presentation. Unlike the control group, where all rats presented with severe focal neurology or mortality, most rats in the treatment groups displayed no to moderate focal neurology. Moreover, the aspirin/cilostazol group consistently exhibited significantly lower levels in the studied biomarkers compared to other groups. Conclusions: Co-administration of cilostazol and aspirin significantly ameliorates the immediate expression of the studied biomarkers. Further large-scale studies are needed to investigate the effect of combined therapy for primary and secondary prevention of stroke, using not only serum biomarkers but other specific clinical and laboratory endpoints. Full article

(This article belongs to the Special Issue Innovations in Acute Stroke Treatment, Neuroprotection, and Recovery)

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