Current Neuropharmacology - Online First

Depression is a common mental disorder, often accompanied by suicidal ideation (SI). Modified electroconvulsive therapy (MECT) is widely used as an effective treatment for severe depression, especially when pharmacotherapy has failed. However, concerns regarding the potential cardiovascular effects of MECT have prompted further investigation.

A total of 100 patients with depressive disorders undergoing MECT were recruited in this study. Among them, 70 had suicide ideation (SI group) and 30 did not (non-SI group). Electrocardiogram (ECG) recordings were obtained before MECT and on the second day after several sessions of MECT treatment.

After treatment with MECT, no significant differences were observed in ECG parameters, including PR intervals, QT intervals, and heart rates. However, a significant interaction between time and group on PR intervals was observed (F(1,98)=5.5, p=0.02). Specifically, patients in the non-SI group exhibited a slight increase in PR intervals compared with baseline values, whereas those in the SI group showed a slight decrease. More importantly, significant differences were observed between the SI and non-SI groups (Z= 2.3, p=0.02). Further linear regression analysis showed that, after controlling for gender and medication types (antidepressants versus antipsychotics), the presence of suicide ideation was independently associated with changes in PR intervals following MECT treatment (β= 0.20, t= 2.04, p= 0.04).

Our findings suggested a significant interaction between time and group on PR intervals after treatment with MECT in patients.

Considering that the within-group changes did not reach statistical significance, future research with a large sample size is warranted to focus on the differential effects of MECT on ECG indicators in depressed patients with or without suicide ideation.

The mechanisms of neurodegeneration common to many neurodegenerative diseases include oxidative stress, mitochondrial dysfunctions, excitotoxicity, and others. Beyond the broad spectrum of strategies for developing neuroprotective agents that target stage-specific mechanisms in each neurodegenerative disease, considerable attention is also being given to approaches aimed at developing compounds that can effectively modulate general pathogenic mechanisms and enhance the overall resilience of neuronal cells to cell death induction.

This review discusses some of the results on new multitarget multipharmacophore agents with neuroprotective effects, particularly through their influence on mitochondrial permeability transition and antioxidant properties. We conducted comprehensive online searches on PubMed to gather the latest data on multitarget multipharmacophore agents consisting of pre-defined pharmacophores that have already demonstrated neuroprotective properties.

To create compounds with a desirable spectrum of biological activity, an approach based on the conjugation of specific structural fragments of pharmacologically active substances into a single molecular entity could be used. Core fragments of compounds that have already demonstrated neuroprotective properties due to mitochondrial and antioxidant mechanisms of action can be used as neuroactive scaffolds.

The combination of several pharmacophores in one molecule may not only result in the mere addition of the useful properties of each component, but may also give rise to new types of biological activity. The examples of the appearance of new properties in such multipharmacophore compounds, not inherent in the reference agents, discussed in our review, may be considered a prospective approach for creating a novel generation of neuroprotective agents.

Preclinical and clinical studies reported that 3,4-methylenedioxymeth-amphetamine (MDMA, ‘ecstasy’) can cause adverse effects in the central nervous system (CNS). Recently, preclinical studies have demonstrated that certain psychoactive substances may exacerbate the noxious central effects of MDMA when co-administered, including substances that are contained as adulterants in tablets sold as MDMA in the illegal market. Since the quality and quantity of adulterants in tablets sold as MDMA vary based on factors, such as the year and the geographical region of production, this may result in diverse health risks for people who use MDMA.

This review provides a concise overview of: i) composition of tablets sold as MDMA in Continental Europe, UK, USA and Australia in the post COVID-19 pandemic period; ii) recent preclinical and clinical findings about the central effects of the psychoactive adulterants most commonly found in tablets sold as MDMA in the above areas; and iii) the possible adverse CNS effects of these adulterants in humans when taken in combination with MDMA.

We systematically searched PubMed, Scopus, and Web of Science for studies published between 2020 and 2025 using terms related to “adulterants”, “MDMA tablets composition,” “COVID-19”. Eligible articles were screened for quality, with emphasis on recent, high-impact contributions. Extracted papers included cytotoxicity studies, neurobehavioral outcomes, and mechanistic insights.

Tablets sold as MDMA are frequently and differently adulterated in Continental Europe, the UK, the USA, and Australia.

The possible interactions between MDMA and psychoactive adulterants contained in tablets sold as MDMA deserve attention, since they may potentially explain some of the noxious neurological and psychiatric effects that have been described in people who use MDMA.

Ongoing public health efforts and expansion of drug checking are essential to properly inform MDMA users about the risks associated with psychoactive contaminants, first responders, healthcare professionals, and the general public about the possible detrimental consequences for health associated with the use of MDMA obtained from illicit sources and unintended contaminant consumption.

Medical cannabis has gained growing attention as a potential treatment for children with Autism Spectrum Disorder (ASD), particularly in cases where conventional pharmacological approaches have proven ineffective. Emerging evidence suggests that cannabinoid-based therapies may alleviate Attention Deficit Hyperactivity Disorder (ADHD) related symptoms in children with ASD. The objective of this study is to evaluate changes in ADHD symptoms over six months of treatment with a CBD-rich cannabis oil, using the Conners' Teacher Rating Scale as the assessment tool.

This was a prospective, single-arm, open-label study conducted at a single center. A total of 109 children and young adults diagnosed with ASD and ADHD symptoms were recruited between November 2019 and April 2021. Of these, 53 participants were assessed by their schoolteachers using the Conners' Teacher Rating Scale (CTRS) questionnaire, both before and after a three- to six-month treatment period with a CBD-rich, cannabis oil-based product. Blood samples were collected before and after treatment to measure cannabinoid levels, including CBD, 6-OH-CBD, 7-COOH-CBD, and 7-OH-CBD.

Significant improvements were observed in the following categories: anxious-shyness, perfectionism, ADHD index, emotional lability, and hyperactivity-impulsivity (p < 0.001). Additional trends toward improvement were identified in oppositional behavior (p = 0.009), cognitive inattention (p = 0.009), hyperactivity (p = 0.006), the Conners’ Global Index (p = 0.007), and DSM-IV inattention scores (p = 0.003). No significant correlations were found between cannabinoid dosage or blood levels and changes in CTRS scores, except for emotional lability, where higher CBD concentrations were predictive of greater symptom improvement.

This is the first prospective study to evaluate the effects of CBD-rich cannabis on ADHD symptoms in children with ASD using standardized teacher-based Assessments (CTRS). The findings indicate improvements in core behavioral domains. While previous studies have focused primarily on parent-reported outcomes or small-scale trials, our results support emerging evidence on the role of cannabinoids in modulating attention and emotional regulation. The main limitations of the study were its open-label design.

CBD-rich cannabis oil may reduce ADHD symptoms in children with ASD. These findings support the need for future clinical trials to validate efficacy and determine optimal dosing.

To investigate hemodynamic and blood oxygen metabolism and their associations with disease progression, dopaminergic transporter (DAT) activity, and glucose uptake in patients with Parkinson’s disease (PD).

This cross-sectional study included 73 patients with PD (mean age: 61.10 years) and 67 healthy controls (mean age: 58.99 years). Oxygen metabolism parameters—deoxygenated hemoglobin (Cdeoxy), oxygen extraction fraction (OEFrel), deoxygenated cerebral blood volume (dCBV), and R2* were measured using qMRI. DAT availability and glucose metabolism were assessed using PET with [18F]FP-CIT and [18F]FDG, respectively. Regional analyses were conducted using standardized brain atlases.

Compared with the controls patients with PD exhibited elevated Cdeoxy, OEFrel, and R2* in the substantia nigra, whereas Cdeoxy and dCBV levels were reduced in the bilateral caudate nucleus and frontal cortex (p < 0.05). The Hoehn-Yahr (H-Y) 2.5–3 subgroup exhibited higher levels of Cdeoxy and OEFrel in the left putamen than the H-Y 1-2 subgroup (p < 0.05). In the H-Y 1-2 subgroup, Cdeoxy, OEFrel, and R2* correlated with UPDRS scores in the substantia nigra and red nucleus (p < 0.05). In advanced stages (H-Y stages 2.5-3), significant correlations were observed in the striatal structures/the left dorsolateral putamen/posterior right caudate (p < 0.05). OEFrel and R2* values were positively correlated with glucose metabolism in the left putamen and right caudate. (p < 0.05).

qMRI demonstrated alterations in hemodynamics and oxygen metabolism in patients with PD, particularly within the nigrostriatal system, suggesting that metabolic indicators could serve as supplementary biomarkers for diagnosing and monitoring the progression of PD.

Olanzapine-associated metabolic adverse effects lead to medication discontinuation and non-compliance in Schizophrenia (SCZ). This study aimed to examine the efficacy of a low dose of olanzapine in combination with sertraline in mitigating metabolic adverse effects by reducing the olanzapine dose in first-episode SCZ (FE-SCZ) patients.

This randomized clinical trial with a blinded endpoint design was conducted among FE-SCZ patients. During a 12-week treatment, 196 patients with FE-SCZ were randomly assigned to the combined low-dose olanzapine/sertraline (OS group) or standard-dose olanzapine (control group). The body weight and levels of fasting glucose and blood lipids were determined at baseline and the end of weeks 4, 8, 12, and 24. Additionally, the clinical symptoms were also assessed at baseline and follow-up.

Relative to the control group, the OS group had a lower percentage of weight gain from baseline to week 24 across two thresholds (7% and 10%) for changes in bodyweight (100% vs. 97.8%; 98.7% vs. 28.3%). In addition, combination treatment mitigated olanzapine-associated weight gain and other metabolic abnormalities compared with the control group (all p < 0.01). Notably, clinical symptom improvements were similar between the two treatment groups.

Our study suggests that low-dose olanzapine/sertraline combination therapy was correlated with significantly less weight gain and improved other metabolic parameter levels than standard-dose olanzapine in patients with FE-SCZ. Clinical symptom improvements in the combination group were comparable to those of the olanzapine monotherapy group.

These findings suggest a potential strategy to improve medication adherence and overall patient outcomes by mitigating metabolic side effects.

ClinicalTrials.gov, NCT04076371.

There is a need to search for new treatment options not only for depression but also for its concomitant diseases. Particularly, depression and metabolic health abnormalities often coexist, while inflammation and microbiota imbalance may play a part in their pathophysiological overlap. Thus, trials of interventions targeting the microbiota may result in establishing a safe adjunctive treatment option. This secondary analysis aimed to assess the effect of a probiotic formulation on inflammatory parameters in adult patients with depressive disorders depending on baseline clinical and immunometabolic characteristics.

The parent trial was a two-arm, 60-day, prospective, randomized, double-blind, controlled study. The probiotic formulation contained Lactobacillus helveticus Rosell^®-52 and Bifidobacterium longum Rosell^®-175. The change in inflammatory parameters after the intervention in the context of baseline lifestyle, clinical, metabolic, and inflammatory parameters was assessed.

In per-protocol analysis, data from 88 participants were finally analyzed. Probiotic supplementation decreased the levels of C-reactive protein (CRP) compared to placebo by 21.3% with a small effect size (p = .047, d = .249). There were no significant differences in complete blood count-derived parameters or in tumor necrosis factor-α levels. The impact of probiotics was different when stratified by baseline metabolic syndrome (MetS) presence, liver steatosis non-invasive biomarkers, chronic low-grade inflammation status, and antidepressant use.

The intake of probiotics by people with depression may offer some improvement in lowering CRP levels, especially in patients with comorbid MetS, liver abnormalities, or the use of antidepressants. The future potential of probiotic supplementation in the management of depression seems to be targeted at individuals with comorbidities of metabolic diseases, particularly suspected liver steatosis. Furthermore, patients treated with antidepressants may gain additional advantages from probiotic use, not only in terms of alleviating depression, but also in decreasing inflammation.

Due to the preliminary character of our results, we emphasize the need for future studies in this area. ClinicalTrials.gov identifier: NCT04756544.

Acute studies have shown that TRPV1 agonists have improved both the biomechanics and neurophysiology of the swallowing response. The aim of this study was to assess the effect of a two-week treatment with capsaicin in older patients with oropharyngeal dysphagia (OD).

A prospective, double-blind, randomized clinical trial was conducted. A total of 51 older patients with OD (PAS > 2) were included and treated for two weeks with 10 mL capsaicin 10 µM before meals (three times a day). Videofluoroscopy was used to examine swallowing biomechanics, and pharyngeal sensory (pSEP) and motor evoked potentials (pMEP) were used to assess neurophysiological responses. Salivary neuropeptides SP and CGRP were quantified using ELISA.

The mean age of patients was 78.51 ± 6.04 years. The 32 patients treated with capsaicin showed a significant reduction in PAS score (4.7 ± 1.7 vs 3.9 ± 1.5, p = 0.02), time to LVC (405.3 ± 124.2 ms vs. 366.6 ± 154.4 ms, p = 0.04), and latency of the N1 peak of pSEPs (88.3 ± 17.1 ms vs 74.4 ± 17.6 ms, p = 0.007) and had significant changes in brain activation. Improvement in time to LVC correlated significantly with N1 peak latency (p = 0.03), and salivary substance P increased by 75.8%. In contrast, the biomechanics and neurophysiology of the swallowing response in the 19 patients of the placebo group did not show significant improvement.

Two weeks of capsaicin stimulation in older patients with OD were found to improve sensory and motor swallowing functions by enhancing pharyngeal sensitivity and reducing the time to LVC.

Capsaicin administered over 2 weeks was found to improve swallowing safety and the biomechanics and neurophysiology of the swallowing response. TRPV1 agonists could be the basis of long-term pharmacological treatments for OD.

Treatment-resistant depression (TRD) is a severe psychiatric condition that may increase the risk of suicidal thoughts and self-harming behaviors. Intranasal esketamine has emerged as an effective treatment for TRD, also addressing depression-related emergencies such as suicidal ideation.

This retrospective observational study analyzed 26 outpatients with TRD treated with adjunctive intranasal esketamine alongside ongoing oral antidepressants for 4 weeks. Suicidal ideation and behaviors were assessed using the Columbia-Suicide Severity Rating Scale (C-SSRS), and depressive symptoms were evaluated with the Montgomery-Åsberg Depression Rating Scale (MADRS) at baseline, week 2, and week 4. Statistical analyses included repeated-measures ANOVA and subgroup analyses by gender and baseline self-harm profile.

Esketamine significantly reduced suicidal ideation and depressive symptoms from baseline to week 2 and week 4 (all p<.001). Additionally, non-suicidal self-harm declined, exhibiting gender-specific patterns: women demonstrated a faster reduction in non-suicidal self-harm, whereas men showed slower improvement in suicidal self-harm. A strong correlation between depressive symptoms and suicidality confirmed their interplay.

In our real-world TRD sample, adjunctive intranasal esketamine led to a rapid and sustained reduction in suicidality and depressive symptoms, with distinct gender-related patterns in self-harm trajectories. These findings may inform individualized monitoring strategies. Limitations include the small sample size, retrospective design, and lack of a control group.

Esketamine rapidly improved suicidality and depression in TRD, with preliminary evidence suggesting gender-specific responses, and highlighting the importance of tailored interventions to maximize outcomes. Further research is needed to confirm these differences, explore the long-term effects, and understand the underlying mechanisms.

The nerve growth factor (NGF) is a crucial neurotrophic factor with the ability to induce neuronal differentiation. However, whether NGF-loaded exosomes (Exo-NGF) can alleviate neuropathic pain in chronic constriction injury (CCI) rats remains unclear.

A neuropathic pain model was established using CCI rats. The pain was assessed using the von Frey test and the hot plate test. Exo-NGF was collected from HEK293 cells transfected with an NGF plasmid. The diameter of Exo-NGF was determined using transmission electron microscopy. Protein levels of inflammatory factors, including IL-18, IL-1β, and TNF-α, were measured using enzyme-linked immunosorbent assay, and their mRNA levels were evaluated using qPCR. The NOD-like receptor family pyrin domain-containing protein 3 (NLRP3) protein levels were determined using immunostaining and Western blot.

NGF protein and mRNA were highly expressed in Exo-NGF. The mRNA in Exo-NGF was successfully delivered into neural stem cells and promoted their differentiation. Injection of Exo-NGF into the spinal dorsal horn significantly alleviated mechanical allodynia and thermal hyperalgesia. Additionally, Exo-NGF reduced levels of IL-18, IL-1β, and TNF-α. NLRP3 and its key components, including apoptosis-associated speck-like protein and caspase-1, were also reduced by Exo-NGF treatment in CCI rats.

Our findings highlight the therapeutic potential of exosome-based NGF delivery for treating chronic pain conditions.

Exo-NGF significantly alleviates neuropathic pain by suppressing inflammation and NLRP3 activation.

Clozapine, after its introduction, reshaped the landscape of Treatment-Resistant Schizophrenia (TRS) treatment, becoming the first-line treatment for that condition. However, many patients fail to respond to this drug alone. Clozapine-resistant schizophrenia (CRS) is associated with a more severe clinical presentation than TRS, manifesting in exacerbated symptoms and significantly diminished quality of life. The complex nature of CRS has prompted the development of augmentation strategies, which most commonly include another antipsychotic. The present multicenter observational study aimed to assess and compare the efficacy of Lurasidone augmentation alongside clozapine versus other second-generation antipsychotic combinations in patients with a schizophrenia spectrum disorder.

A total of 45 patients with a diagnosis of a schizophrenia spectrum disorder and labeled as “treatment resistant” were included. Functional and psychometric assessments were made at the baseline, one month, and six months after the treatment. A linear mixed-effect regression was performed along with other appropriate statistical analyses.

A significant improvement over time was observed in the two groups for both the clinical and functional outcomes assessed, demonstrating the efficacy of a proper augmentation strategy in CRS management. Moreover, significantly lower psychiatric ward admissions were observed in the lurasidone group (p<.05).

Our findings suggest that lurasidone augmentation in CRS offers significant improvements in psychopathological domains similar to alternative augmentation strategies.

Although further studies are needed to confirm our findings, lurasidone’s favorable side-effect profile should be considered.

Increasing evidence indicates a connection between Alzheimer’s disease (AD) and endothelial dysfunction. Given the lack of a definitive cure for AD, the purpose of this research was to explore the impact of a short incubation with plasma samples obtained from 30 patients with sporadic AD and 21 age- and sex-matched control subjects on cultured human aortic endothelial cells (HAECs), as well as to assess the effects of resveratrol (RSV) supplementation to the plasma.

Specifically, the study analyzed: the production of nitric oxide (NO) and peroxynitrite; the activities of superoxide dismutase (SOD) and Na⁺/K⁺-ATPase; membrane fluidity; and levels of thiobarbituric acid-reactive substances (TBARS).

When incubated with AD plasma, cells showed a decrease in NO levels, enzymatic activities, and membrane fluidity, as well as an increase in peroxynitrite and TBARS production, compared to those exposed to plasma from healthy controls. In contrast, supplementation with RSV-enriched plasma, reduced reactive oxygen species (ROS) levels, and enhanced SOD activity. RSV also improved endothelial function, by increasing membrane fluidity, Na^+/K⁺-ATPase activity, and enhancing NO production and bioavailability, potentially benefiting cerebral perfusion.

Though preliminary, our findings highlight the critical role played by vascular health in Alzheimer’s disease, and the potential impact of resveratrol in maintaining the endothelial integrity, thus mitigating the progression of AD .

In conclusion, our study supports the use of dietary natural compounds to reduce oxidative stress and prevent or reverse vascular endothelial dysfunction associated with AD.

Ginsenoside Rg2 (GRg2), a naturally occurring triterpenoid derived from ginseng rhizomes, exhibits neuroprotective properties. Neuroinflammation is recognized as one of the key pathogenic mechanisms underlying Alzheimer's disease (AD). This research aims to investigate the beneficial effects of GRg2 on AD and explore its potential mechanisms.

In APP/PS1 mice, cognitive and behavioral assessments were first performed. Subsequently, brain tissue analyses were performed using immunohistochemical analysis and Western blot. A combined analysis of the gut microbiome and metabolomics was conducted to explore potential mechanisms. Finally, key findings were further validated through immunofluorescence and enzyme-linked immunosorbent assay.

GRg2 enhanced learning, memory, and cognitive functions. And inhibits the deposition of β-amyloid and phosphorylated tau. GRg2 effectively inhibits the production of Bacteroides and Helicobacter. In addition, it reduced the levels of pyruvaldehyde and trimethylamine N-oxide, metabolites closely related to neuroinflammation. GRg2 effectively inhibited the activation of astrocytes and microglia in the brains of APP/PS1 mice, and also reduced the expression of neuroinflammatory mediators IL-6, IL-1β, and TNF-α.

The findings of this study substantiate the neuroprotective efficacy of GRg2, providing a novel therapeutic strategy and theoretical foundation for natural product-based interventions against AD.

GRg2 improves cognitive function and mitigates AD pathology, which is at least partially attributed to its regulation of gut microbiota and metabolites, as well as its anti-neuroinflammatory effects.

Recent evidence increasingly supports a potential role of Perivascular Macrophages (PVMs), a unique subpopulation of brain immune cells, in the pathogenesis of Alzheimer’s disease (AD). Strategically positioned at the brain-vasculature interface, PVMs sense the redox status, modulate immunity, and potentially influence ferroptosis—an iron-dependent form of regulated cell death increasingly implicated in AD. However, whether the involvement of PVMs in AD pathology specifically entails mechanisms related to the crosstalk between immunometabolism and ferroptosis, and the precise molecular pathways linking PVMs, immunometabolism, and ferroptosis to AD, remains unclear.

We first obtained single-cell RNA sequencing data of PVMs from AD patients and control subjects via the GEO database, identified Differentially Expressed Genes (DEGs), and applied Mendelian Randomization (MR), with robustness validated via leave-one-out analysis to pinpoint key genes among the DEGs with causal relevance to AD. Next, we identified ferroptosis-related genes within these key genes and examined their associations with immune cell infiltration and immunometabolic signaling pathways, while also predicting their regulatory transcription factors to inform potential therapeutic strategies.

We identified 149 DEGs in PVMs between AD and control groups, which were primarily enriched in immune and metabolic pathways. MR analysis established eight genes (ACSL1, SPATA6, RAB31, NIBAN1, HDAC4, GRAMD1B, GCC2, and DENND3) as causally and negatively associated with AD risk (IVW analysis identified all P < 0.05, with robustness confirmed by leave-one-out analysis), with ACSL1 being recognized as a known ferroptosis driver. Immune cell infiltration analysis revealed significant differences in monocyte and neutrophil proportions in AD, with DENND3 identified as the sole gene significantly correlated with monocyte abundance. The Key genes demonstrated distinct associations with immunometabolic pathways: GRAMD1B expression was positively associated with PI3K/AKT/mTOR signaling, whereas both NIBAN1 and SPATA6 showed enrichment in cells with high Notch signaling activity. ACSL1 exhibited robust associations with multiple pathways implicated in ferroptosis, including the IL-6/JAK/STAT3, interferon-γ, TGF-β, bile acid metabolism, and cholesterol homeostasis pathways, suggesting potential mechanisms that mediate the crosstalk between immunometabolism and ferroptosis. Transcription factor analysis highlighted shared regulation by CEBPD and the SP1/2/3/4 family, indicating convergent transcriptional control of these genes.

This study identifies eight key genes in PVMs that may protect against AD through mechanisms involving the interplay between immunometabolism and ferroptosis. Our findings provide novel insights into the function of PVMs in AD pathophysiology and suggest potential therapeutic targets for this devastating neurodegenerative disease.

Genetic variations in the microtubule-associated protein tau (MAPT) gene play a central role in Alzheimer's disease (AD) pathogenesis. Two major MAPT haplotypes, H1 and H2, show differential associations with tau expression and AD risk. However, data from Middle Eastern populations remain limited, restricting our understanding of population-specific disease susceptibility patterns and therapeutic responses.

We conducted a comprehensive literature review using PubMed, Scopus, and Web of Science databases. Search terms included “MAPT haplotype,” “Alzheimer's disease,” “H1 H2,” “tau pathology,” and “pharmacogenetics.” We analyzed peer-reviewed articles published between 2000 and 2024, focusing on studies reporting haplotype frequencies, MAPT expression levels, APOE interactions, and clinical outcomes. This review synthesizes published data without generating new experimental results.

The H1 haplotype consistently associates with increased MAPT expression, tau accumulation, and elevated AD risk, particularly in APOE ε4 noncarriers. Conversely, the H2 haplotype appears protective, correlating with reduced tau burden and slower cognitive decline. Notably, recent reports reveal significant overrepresentation of the H2 haplotype in the Jordanian population compared to European and East Asian cohorts, where H2 frequency is substantially lower or absent. This distinct genetic architecture suggests altered regional AD risk profiles.

The elevated H2 frequency in Jordan represents a unique population-specific genetic signature that may influence regional AD susceptibility patterns. These findings challenge current risk models predominantly based on European populations and suggest the need for population-tailored approaches in neurodegenerative disease research. The naturally H2-enriched Jordanian cohort provides an exceptional opportunity to investigate protective mechanisms against tau pathology.

MAPT haplotype distributions show significant population variation with important implications for AD risk assessment and therapeutic targeting. The high H2 frequency in Jordan warrants integration into personalized medicine frameworks and population-specific disease models, potentially informing more effective regional prevention and treatment strategies.

Frontotemporal dementia (FTD) is the third most frequent dementia and the leading dementia subtype in individuals under 65. The discovery of C9orf72 (chromosome 9 open reading frame 72) GGGGCC abnormal expansion is a major genetic cause of both FTD and amyotrophic lateral sclerosis (ALS), linking these diseases along a clinicopathological spectrum. This study aimed to depict the research landscape of C9orf72 in FTD over the past decade, track emerging research hotspots, and provide insights into under-researched areas.

Based on the Web of Science database, a bibliometric analysis was conducted to explore publication trends, key contributors, funding sources, journal categories, co-authorship networks, and keyword co-occurrence, clustering, and bursts.

A total of 1,220 articles were identified, with sustained output of over 100 articles annually. The majority of contributions and funding support came from North America and Europe. Hot research themes included hexanucleotide repeats, nucleocytoplasmic transport, disease mechanisms, and therapeutic targets.

North America and Europe were highly productive, supported by higher regional prevalence, genetic burden, and robust funding. Ploy-GR in cerebrospinal fluid has emerged as a diagnostic biomarker. Pathogenic mechanisms remain complex, involving both gain- and loss-of-function effects. Metformin and antisense oligonucleotides were considered as potential therapeutics. Further research is needed in underrepresented populations and on the translational potential of emerging molecular targets.

This study offers a comprehensive overview of current trends and future directions over the past decade in C9orf72-related FTD research, allowing researchers—particularly those new to the area—to quickly understand the current landscape.