Neurology International

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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11 pages, 5327 KB

Open AccessCase Report

Coexisting Subdural Hematoma in Cerebral Amyloid Angiopathy: A Case Series

by Matija Zupan, Lara Straus, Tomaž Velnar, Matic Bošnjak, Ulf Jensen-Kondering, Bruno Splavski and Senta Frol

Neurol. Int. 2025, 17(8), 125; https://doi.org/10.3390/neurolint17080125 - 7 Aug 2025

Abstract

Background: Cerebral amyloid angiopathy (CAA) is a common cause of spontaneous intracerebral hemorrhage (ICH) in elderly individuals, and it is characterized by the deposition of amyloid β protein (Aß) in the walls of small-caliber cortical and leptomeningeal vessels. The diagnostic criteria for CAA [...] Read more.

Background: Cerebral amyloid angiopathy (CAA) is a common cause of spontaneous intracerebral hemorrhage (ICH) in elderly individuals, and it is characterized by the deposition of amyloid β protein (Aß) in the walls of small-caliber cortical and leptomeningeal vessels. The diagnostic criteria for CAA highlight its association with spontaneous lobar hemorrhage, convexity subarachnoid hemorrhage (SAH), and cortical superficial siderosis but not with subdural hematoma (SDH). This article presents a three-patient case series of CAA who experienced a lobar ICH associated with an SDH, underscoring a potentially under-recognized correlation between an acute ICH and coexistent SDH. Case presentation: We present a case series of three patients in a single university medical center who experienced acute-onset lobar ICH with a concurrent SDH, treated with evacuation. Histopathological examination established the diagnosis of CAA in all three cases. This case series underscores a potentially under-recognized association between an acute ICH and coexistent SDH in the context of CAA. Conclusions: Considering our findings, we emphasize the possibility that SDH may be a more frequent manifestation of CAA than previously recognized. Therefore, patients with CAA who initially present with acute SDH may be underdiagnosed, consequently leading to delayed identification and missed opportunities for proper risk assessment and management. Full article

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

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12 pages, 2779 KB

Open AccessArticle

Clinical and Electrodiagnostic Correlations of Ultrasound-Detected Markedly Enlarged Median Nerve at the Wrist

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

Neurol. Int. 2025, 17(8), 124; https://doi.org/10.3390/neurolint17080124 - 7 Aug 2025

Abstract

Background/Objectives: This is a retrospective review of 36 patients with electrodiagnostic (EDX) confirmation of carpal tunnel syndrome (CTS) and ultrasound (US) detection of marked median nerve enlargement (defined as a cross-sectional area [CSA] of 40 mm² or greater) at the wrist. Methods: [...] Read more.

Background/Objectives: This is a retrospective review of 36 patients with electrodiagnostic (EDX) confirmation of carpal tunnel syndrome (CTS) and ultrasound (US) detection of marked median nerve enlargement (defined as a cross-sectional area [CSA] of 40 mm² or greater) at the wrist. Methods: We describe the clinical, electrodiagnostic (EDX), and US findings in these patients and discuss the pathophysiologic basis of a markedly enlarged median nerve. Results: The markedly enlarged median nerve was detected by US in a total of 39 hands (36 patients, with 3 bilateral). Of the 39 hands, thenar atrophy was observed in 15 (38.5%) hands, and pinprick loss in the median nerve distribution was noted in all hands. Moderately severe or severe median nerve entrapment at the carpal tunnel (CT) was confirmed by EDX studies in 21 (53.8%) and 16 (41.0%) hands, respectively. A total of 12 (30.8%) hands had no compound muscle action potentials (CMAPs) over the abductor pollicis brevis muscle, and sensory nerve action potentials (SNAPs) were not detected in 31 (79.5%) hands. The wrist CSA was between 40 and 44 mm² in 20 (51.3%) hands, between 45 and 49 mm² in 13 (33.3%) hands, and 50 mm² or greater in 6 (15.4%) hands. Conclusions: The implications of the markedly enlarged median nerve for surgical management of CTS are unknown, and future prospective studies are needed. Full article

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

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14 pages, 1391 KB

Open AccessArticle

Correlation of Neurodegenerative Biomarkers and Functional Outcome in Patients with Relapsing–Remitting Multiple Sclerosis

by Elina Polunosika, Monta Feldmane, Daina Pastare, Joel Simren, Kaj Blennow, Nauris Zdanovskis, Henrik Zetterberg, Renars Erts and Guntis Karelis

Neurol. Int. 2025, 17(8), 123; https://doi.org/10.3390/neurolint17080123 - 7 Aug 2025

Abstract

Background and Objectives: Multiple sclerosis (MS) is a chronic autoimmune, inflammatory, and neurodegenerative central nervous system disease. Neurodegeneration plays a central role in long-term disease progression. Materials and Methods: This cross-sectional study examined the relationship between neurodegenerative biomarkers, namely plasma neurofilament [...] Read more.

Background and Objectives: Multiple sclerosis (MS) is a chronic autoimmune, inflammatory, and neurodegenerative central nervous system disease. Neurodegeneration plays a central role in long-term disease progression. Materials and Methods: This cross-sectional study examined the relationship between neurodegenerative biomarkers, namely plasma neurofilament light chain (pNfL) levels and MRI-derived brain volume measurements, and clinical outcomes in 49 patients with relapsing–remitting multiple sclerosis (RRMS). Plasma NfL levels were quantified using Simoa technology, while MRI data was analyzed via FreeSurfer to measure volumes of grey and white matter, specific brain structures, and ventricular sizes. Cognitive performance was assessed using the Symbol Digit Modalities Test (SDMT) and Brief Visuospatial Memory Test-Revised (BVMT-R). Disability was evaluated using the Expanded Disability Status Scale (EDSS). Results: The results indicated significant positive correlations between SDMT scores and volumes of grey matter, white matter, and various subcortical structures, suggesting that preserved brain volume is linked to better cognitive performance. Negative correlations were observed between SDMT scores and ventricular volumes, as well as between SDMT scores and EDSS scores, implying that cognitive decline corresponds with structural brain deterioration and increased disability. No significant associations were found between BVMT-R scores and imaging data or disability measures. Plasma NfL levels showed significant correlations with early disease relapses and enlargement of the third and fourth ventricles, but not with brain volume, cognitive tests, or EDSS scores. Conclusions: These findings indicate that MRI-based brain volumetrics, particularly grey and white matter measures, are stronger indicators of cognitive function and disability in RRMS than plasma NfL. Full article

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

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14 pages, 541 KB

Open AccessReview

Foreign Language Syndrome: Neurological and Psychiatric Aspects

by Ansam Eghzawi, Ali Madha and Rany Aburashed

Neurol. Int. 2025, 17(8), 122; https://doi.org/10.3390/neurolint17080122 - 6 Aug 2025

Abstract

Foreign Language Syndrome (FLS) is a rare neuropsychiatric condition characterized by the sudden, involuntary use of a non-native language, with concurrent loss or suppression of the native language. Distinct from Foreign Accent Syndrome (FAS), FLS often arises acutely following anesthesia, brain injury, or [...] Read more.

Foreign Language Syndrome (FLS) is a rare neuropsychiatric condition characterized by the sudden, involuntary use of a non-native language, with concurrent loss or suppression of the native language. Distinct from Foreign Accent Syndrome (FAS), FLS often arises acutely following anesthesia, brain injury, or psychological stress. Although neuroimaging typically reveals no structural pathology, functional disconnection within bilingual language control systems has been hypothesized. Case reports suggest contributions from both neurological disruptions—such as transient cortical dysfunction—and psychiatric mechanisms, including dissociation and conversion phenomena. This review synthesizes the clinical features, diagnostic strategies, neurocognitive models, and psychiatric interpretations of FLS. It emphasizes the importance of multidisciplinary evaluation and treatment and outlines prognosis patterns. The need for longitudinal follow-up, functional imaging studies, and centralized case databases is highlighted to better understand the pathophysiology and clinical management of this enigmatic syndrome. Full article

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

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23 pages, 4728 KB

Open AccessArticle

A Web-Deployed, Explainable AI System for Comprehensive Brain Tumor Diagnosis

by Serra Aksoy, Pinar Demircioglu and Ismail Bogrekci

Neurol. Int. 2025, 17(8), 121; https://doi.org/10.3390/neurolint17080121 - 4 Aug 2025

Abstract

Background/Objectives: Accurate diagnosis of brain tumors is one of the most important challenges in neuro-oncology since tumor classification and volumetric segmentation inform treatment planning. Two-dimensional classification and three-dimensional segmentation deep learning models can augment radiological workflows, particularly if paired with explainable AI techniques [...] Read more.

Background/Objectives: Accurate diagnosis of brain tumors is one of the most important challenges in neuro-oncology since tumor classification and volumetric segmentation inform treatment planning. Two-dimensional classification and three-dimensional segmentation deep learning models can augment radiological workflows, particularly if paired with explainable AI techniques to improve model interpretability. The objective of this research was to develop a web-based brain tumor segmentation and classification diagnosis platform. Methods: A diagnosis system was developed combining 2D tumor classification and 3D volumetric segmentation. Classification employed a fine-tuned MobileNetV2 model trained on a glioma, meningioma, pituitary tumor, and normal control dataset. Segmentation employed a SegResNet model trained on BraTS multi-channel MRI with synthetic no-tumor data. A meta-classifier MLP was used for binary tumor detection from volumetric features. Explainability was offered using XRAI maps for 2D predictions and Gaussian overlays for 3D visualizations. The platform was incorporated into a web interface for clinical use. Results: MobileNetV2 2D model recorded 98.09% classification accuracy for tumor classification. 3D SegResNet obtained Dice coefficients around 68–70% for tumor segmentations. The MLP-based tumor detection module recorded 100% detection accuracy. Explainability modules could identify the area of the tumor, and saliency and overlay maps were consistent with real pathological features in both 2D and 3D. Conclusions: Deep learning diagnosis system possesses improved brain tumor classification and segmentation with interpretable outcomes by utilizing XAI techniques. Deployment as a web tool and a user-friendly interface made it suitable for clinical usage in radiology workflows. Full article

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

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20 pages, 2238 KB

Open AccessReview

The Pathogenesis and Medical Treatment of Depression: Opportunity and Challenge

by Mengjiao Xu, Zhiyu Zhang, Zhoudong Zhang, Dong Liu, Yanguo Shang, Chenglun Tang, Weipeng Wang, Huanqiu Li, Bengang You, Hanjie Ying and Tao Shen

Neurol. Int. 2025, 17(8), 120; https://doi.org/10.3390/neurolint17080120 - 4 Aug 2025

Abstract

Depression is a common mental disorder with high economic burden, characterized by high disability and mortality rates. The etiology of depression remains unclear to date, and there are various hypotheses regarding the pathogenesis of depression in clinical practice, including the monoamine neurotransmitter hypothesis, [...] Read more.

Depression is a common mental disorder with high economic burden, characterized by high disability and mortality rates. The etiology of depression remains unclear to date, and there are various hypotheses regarding the pathogenesis of depression in clinical practice, including the monoamine neurotransmitter hypothesis, the hypothalamic–pituitary–adrenal (HPA) axis dysregulation hypothesis, the inflammatory cytokine hypothesis, and the neurotrophic factor hypothesis. These theories offer specific directional aid in the clinical management of individuals suffering from depression. Medicinal intervention stands as a critical approach within the spectrum of depression treatments, and this article reviews the specific mechanisms of different hypotheses on the pathogenesis of depression in recent years, as well as the research progress on related therapeutic drugs. Full article

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13 pages, 2174 KB

Open AccessArticle

Characterization of QuantiFERON-TB-Plus Results in Patients with Tuberculosis Infection and Multiple Sclerosis

by Elisa Petruccioli, Luca Prosperini, Serena Ruggieri, Valentina Vanini, Andrea Salmi, Gilda Cuzzi, Simonetta Galgani, Shalom Haggiag, Carla Tortorella, Gabriella Parisi, Alfio D’Agostino, Gina Gualano, Fabrizio Palmieri, Claudio Gasperini and Delia Goletti

Neurol. Int. 2025, 17(8), 119; https://doi.org/10.3390/neurolint17080119 - 2 Aug 2025

Abstract

Background: Disease-modifying drugs (DMDs) for multiple sclerosis (MS) slightly increase the risk of tuberculosis (TB) disease. The QuantiFERON-TB-Plus (QFT-Plus) test is approved for TB infection (TBI) screening. Currently, there are no data available regarding the characterization of QFT-Plus response in patients with MS. [...] Read more.

Background: Disease-modifying drugs (DMDs) for multiple sclerosis (MS) slightly increase the risk of tuberculosis (TB) disease. The QuantiFERON-TB-Plus (QFT-Plus) test is approved for TB infection (TBI) screening. Currently, there are no data available regarding the characterization of QFT-Plus response in patients with MS. Objectives: This study aimed to compare the magnitude of QFT-Plus responses between patients with MS and TBI (MS-TBI) and TBI subjects without MS (NON-MS-TBI). Additionally, discordant responses to TB1/TB2 stimulation were documented. Results were evaluated considering demographic and clinical data, particularly the impact of DMDs and the type of TB exposure. Methods: Patients with MS (N = 810) were screened for TBI (2018–2023). Thirty (3.7%) had an MS-TBI diagnosis, and 20 were recruited for the study. As a control group, we enrolled 106 NON-MS-TBI. Results: MS-TBI showed significantly lower IFN-γ production in response to TB1 (p = 0.01) and TB2 stimulation (p = 0.02) compared to NON-MS-TBI. The 30% of TB2 results of MS-TBI fell into the QFT-Plus grey zone (0.2–0.7 IU/mL). Only 7% of NON-MS-TBI showed this profile (p = 0.002). Conclusions: MS-TBI had a lower QFT-Plus response and more borderline results compared to NON-MS-TBI. Future studies should clarify the significance of the borderline results in this vulnerable population to improve QFT-Plus accuracy regarding sensitivity, specificity, and TB prediction. Full article

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14 pages, 2132 KB

Open AccessArticle

Measuring Myotonia: Normative Values and Comparison with Myotonic Dystrophy Type 1

by Andrea Sipos, Milán Árvai, Dávid Varga, Brigitta Ruszin-Perecz, József Janszky, Nándor Hajdú and Endre Pál

Neurol. Int. 2025, 17(8), 118; https://doi.org/10.3390/neurolint17080118 - 31 Jul 2025

Abstract

Introduction: Myotonia is a rare neuromuscular condition characterized by impaired muscle relaxation. In this study, we provide normative values for clinical tests related to myotonia in the Hungarian population and compare them to patients with myotonic dystrophy type 1 (DM1). Methods: Relaxation tests [...] Read more.

Introduction: Myotonia is a rare neuromuscular condition characterized by impaired muscle relaxation. In this study, we provide normative values for clinical tests related to myotonia in the Hungarian population and compare them to patients with myotonic dystrophy type 1 (DM1). Methods: Relaxation tests (10 eye openings, tongue extension, and palm openings), handgrip strength, and the nine-hole peg test were conducted on 139 healthy individuals and 31 patients with DM1. Results: We observed non-significant declines in handgrip strength and relaxation tests with age (p < 0.05). Significant differences were found between controls (n:139) and patients with DM1 (n = 31) in all tests (p < 0.05). Sex differences were noted in the healthy population: men (n:68/139) had stronger handgrip (mean of men 42.45 ± 1.15 vs. women 24.3 ± 0.9) and slower relaxation tests (mean of eye openings in men 3.6 ± 0.2 vs. in women 4.2 ± 0.2, tongue extensions in men 3.7 ± 0.2 vs. in women 4.2 ± 0.2, palm openings in men 4 ± 0.2 vs. in women 4.9 ± 0.2 However, these differences were not present among patients with DM1. Discussion: Normal values for relaxation tests across different age groups were established. These results might be useful for further clinical investigations. Our study supports the usage of averages of healthy population instead of age groups of relaxation tests and their clinical relevance in the evaluation of patients with myotonia. Full article

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

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13 pages, 1698 KB

Open AccessReview

Systematic Review of Parkinsonism in Cerebrotendinous Xanthomatosis

by Jennifer Hanson and Penelope E. Bonnen

Neurol. Int. 2025, 17(8), 117; https://doi.org/10.3390/neurolint17080117 - 30 Jul 2025

Abstract

Background: Cerebrotendinous Xanthomatosis (CTX) is a rare, inherited metabolic disease caused by pathogenic variants in CYP27A1. The clinical presentation of this progressive disease includes cognitive deficits, ataxia, peripheral neuropathy, and pyramidal signs, as well as bilateral cataracts and tendon xanthomas. In some [...] Read more.

Background: Cerebrotendinous Xanthomatosis (CTX) is a rare, inherited metabolic disease caused by pathogenic variants in CYP27A1. The clinical presentation of this progressive disease includes cognitive deficits, ataxia, peripheral neuropathy, and pyramidal signs, as well as bilateral cataracts and tendon xanthomas. In some cases, CTX also includes parkinsonism. The goals of this study are to develop a data source that provides improved characterization and awareness of parkinsonism in CTX. Methods: We conducted a systematic review of the literature according to PRISMA guidelines to identify all published individuals diagnosed with CTX and parkinsonism. Clinical signs, imaging findings and treatment response to both chenodeoxycholic acid and dopaminergic medications were examined for 72 subjects. Results: The average age of onset of parkinsonism in these CTX patients was 42 years, illustrating the early onset nature of parkinsonism in CTX. Functional dopaminergic imaging revealed the loss of presynaptic dopaminergic neurons in the substantia nigra which points to neurodegeneration of the dopaminergic system as the underlying pathophysiology for parkinsonism in CTX. Brain MRI showed abnormalities in the basal ganglia in 38% of subjects. MRI also showed abnormalities in the cerebellum in 88% of subjects which is typical for CTX and can be utilized to distinguish subjects with CTX and parkinsonism from individuals with other forms of atypical parkinsonism. Dopaminergic medication mitigated parkinsonism signs in most individuals with CTX. Conclusion: CTX is a neurometabolic disease that can result in levodopa-responsive parkinsonism that should be included in the differential for atypical parkinsonism. Full article

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

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