Search Results (423)

Background/Objectives: Neurodegenerative cerebellar ataxia (CA) is a movement disorder caused by progressive cell death in the cerebellum. Motor imagery represents a potential therapeutic tool to improve motor function by “exercising” brain regions associated with movement, without the need for overt activity. This study assessed the feasibility of combining motor imagery with real-time functional magnetic resonance imaging neurofeedback (rt-fMRI-NF) to improve motor function in CA. Methods: During finger tapping conditions, 16 participants with CA pushed a button at the same frequency in time with cross flashing at 1 Hz or 4 Hz, and this information was used to train the model. During motor imagery, participants imagined finger tapping while undergoing rt-fMRI-NF with visual feedback, steering them toward activating their motor circuit. Afterwards, they completed finger tapping again. FMRI analysis compared successful motor imagery trials versus all other imagery events. Brain activity on successful trials was covaried with pre–post rt-fMRI-NF tapping improvement scores. Results: Tapping was more accurate at 1 Hz than 4 Hz, and larger tapping error rates correlated with greater movement impairments. While not significant at the group level, 9 of the 16 participants improved tapping accuracy following rt-fMRI-NF. The size of motor improvements correlated with successful motor imagery activity at 1 Hz in the frontal lobe, insula, parietal lobe, basal ganglia, and cerebellum. Motor improvements were not associated with neurological impairment severity, mood, cognition, or imagery vividness. Conclusions: Feasibility was demonstrated for motor imagery therapy with neurofeedback to potentially improve fine motor precision in people with CA. Brain regions relevant to this process may be considered for targets of non-invasive therapeutic interventions. Full article

Background: Autism spectrum disorder (ASD) is a highly prevalent neurodevelopmental condition influenced by both genetic and non-genetic factors, although the underlying pathomechanisms remain unclear. We systematically analyzed microRNA (miRNA) expression and associated functional pathways in ASD to evaluate their potential as prenatal/postnatal, diagnostic, and prognostic biomarkers. Methods: Peripheral blood mononuclear cells from 12 Sicilian patients with ASD (eight with normal cognitive function) and 15 healthy controls were analyzed using small RNA sequencing. Differential expression analysis was performed with DESeq2 (|fold change| ≥ 1.5; adjusted p ≤ 0.05). Functional enrichment and network analyses were conducted using Ingenuity Pathway Analysis, focusing on Diseases and Biofunctions. Results: 998 miRNAs were differentially expressed in ASD, 424 upregulated and 553 downregulated. Enriched pathways were primarily associated with psychological and neurological disorders. Network analysis highlighted three principal interaction clusters related to inflammation, cell survival and mechanotransduction, synaptic plasticity, and neuronal excitability. Four miRNAs (miR-296-3p, miR-27a, miR-146a-5p, and miR-29b-3p) emerged as key regulatory candidates. Conclusions: The marked divergence in miRNA expression between ASD and controls suggests distinct regulatory patterns, thus reinforcing the central involvement of inflammatory, autoimmune, and infectious mechanisms in ASD, mediated by miRNAs regulating S100 family genes, neuronal migration, and synaptic communication. However, rather than defining a predictive biomarker panel, this study identified candidate miRNAs and regulatory networks that may be relevant to ASD pathophysiology. As such, further validation in appropriately powered cohorts with predictive modeling frameworks are warranted before any biomarker or diagnostic implications can be inferred. Full article

Transcranial magnetic stimulation (TMS) is a non-invasive neuromodulation technique that utilizes magnetic fields to induce cortical electric currents, enabling both the measurement and modulation of neuronal activity. Initially developed as a diagnostic tool, TMS now serves dual roles in clinical neurology, offering insight into neurophysiological dysfunctions and the therapeutic modulation of abnormal cortical excitability. This review examines key TMS outcome measures, including motor thresholds (MT), input–output (I/O) curves, cortical silent periods (CSP), and paired-pulse paradigms such as short-interval intracortical inhibition (SICI), short-interval intracortical facilitation (SICF), intracortical facilitation (ICF), long interval cortical inhibition (LICI), interhemispheric inhibition (IHI), and short-latency afferent inhibition (SAI). These biomarkers reflect underlying neurotransmitter systems and can aid in differentiating neurological conditions. Diagnostic applications of TMS are explored in Parkinson’s disease (PD), dystonia, essential tremor (ET), Alzheimer’s disease (AD), and mild cognitive impairment (MCI). Each condition displays characteristic neurophysiological profiles, highlighting the potential for TMS-derived biomarkers in early or differential diagnosis. Therapeutically, repetitive TMS (rTMS) has shown promise in modulating cortical circuits and improving motor and cognitive symptoms. High- and low-frequency stimulation protocols have demonstrated efficacy in PD, dystonia, ET, AD, and MCI, targeting the specific cortical regions implicated in each disorder. Moreover, the successful application of TMS in differentiating and treating AD and MCI underscores its clinical utility and translational potential across all neurodegenerative conditions. As research advances, increased attention and investment in TMS could facilitate similar diagnostic and therapeutic breakthroughs for other neurological disorders that currently lack robust tools for early detection and effective intervention. Moreover, this review also aims to underscore the importance of maintaining standardized TMS protocols. By highlighting inconsistencies and variability in outcomes across studies, we emphasize that careful methodological design is critical for ensuring the reproducibility, comparability, and reliable interpretation of TMS findings. In summary, this review emphasizes the value of TMS as a distinctive, non-invasive approach to probing brain function and highlights its considerable promise as both a diagnostic and therapeutic modality in neurology—roles that are often considered separately. Full article

Background: The interplay between neuronutrition, physical activity, and mental health for enhancing brain resilience to stress and overall human health is widely recognized. The use of brain mapping via quantitative-EEG (qEEG) comparative analysis enables researchers to identify deviations or abnormalities and track the changes in neurological patterns when a targeted drug or specific nutrition is administered over time. High-functioning mild-to-borderline intellectual disorders (MBID) and autism spectrum disorder (ASD) constitute leading global public health challenges due to their high prevalence, chronicity, and profound cognitive and functional impact. Objective: The objectives of the present study were twofold: first, to characterize an extremely vulnerable group of children with functioning autism symptoms, disclosing their overall pattern of cognitive abilities and areas of difficulty, and second, to investigate the relevance of the effects of a mushroom (Hericium erinaceus) biomass dietary supplement on improvement on neurocognitive behavior. Methods: This study used qEEG to compare raw data with a normative database to track the changes in neurological brain patterns in 147 children with high-functioning autistic attributes when mushroom H. erinaceus biomass supplement was consumed over 6 and 12 months. Conclusions: H. erinaceus biomass in children with pervasive developmental disorders significantly improved the maturation of the CNS after 6 to 12 months of oral use, decreased the dominant slow-wave activity, and converted slow-wave activity to optimal beta1 frequency. Therefore, despite the lack of randomization, blinding, and risk of bias, due to a limited number of observations, it may be concluded that the H. erinaceus biomass may generate a complex effect on the deficits of the autism spectrum when applied to high-functioning MBID children, representing a safe and effective adjunctive strategy for supporting neurodevelopment in children. Full article

Background: Irisin, an exercise-induced myokine, has emerged as a potent neuroprotective factor, though a systematic synthesis of its role across neurological disorders is lacking. This review systematically evaluates clinical and preclinical evidence on irisin’s association with neurological diseases and its underlying mechanisms. Methods: Following PRISMA 2020 guidelines, a systematic search of PubMed/MEDLINE, Scopus, Web of Science, Embase, and Cochrane Library was conducted. The review protocol was prospectively registered in PROSPERO. Twenty-one studies were included, comprising predominantly preclinical evidence (n = 14), alongside clinical observational studies (n = 6), and a single randomized controlled trial (RCT) investigating irisin in cerebrovascular diseases, Parkinson’s disease (PD), Alzheimer’s disease (AD), and other neurological conditions. Eligible studies were original English-language research on irisin or FNDC5 and their neuroprotective effects, excluding reviews and studies without direct neuronal outcomes. Risk of bias was independently assessed using SYRCLE, the Newcastle–Ottawa Scale, and RoB 2, where disagreements between reviewers were resolved through discussion and consensus. Results were synthesized narratively, integrating mechanistic, pre-clinical, and clinical evidence to highlight consistent neuroprotective patterns of irisin across disease categories. Results: Clinical studies consistently demonstrated that reduced circulating irisin levels predict poorer outcomes. Lower serum irisin was associated with worse functional recovery and post-stroke depression after ischemic stroke, while decreased plasma irisin in PD correlated with greater motor severity, higher α-synuclein, and reduced dopamine uptake. In AD, cerebrospinal fluid irisin levels were significantly correlated with global cognitive efficiency and specific domain performance, and correlation analyses within studies suggested a closer association with amyloid-β pathology than with markers of general neurodegeneration. However, diagnostic accuracy metrics (e.g., AUC, sensitivity, specificity) for irisin as a standalone biomarker are not yet established. Preclinical findings revealed that irisin exerts neuroprotection through multiple mechanisms: modulating microglial polarization from pro-inflammatory M1 to anti-inflammatory M2 phenotype, suppressing NLRP3 inflammasome activation, enhancing autophagy, activating integrin αVβ5/AMPK/SIRT1 signaling, improving mitochondrial function, and reducing neuronal apoptosis. Irisin administration improved outcomes across models of stroke, PD, AD, postoperative cognitive dysfunction, and epilepsy. Conclusions: Irisin represents a critical mediator linking exercise to brain health, with consistent neuroprotective effects across diverse neurological conditions. Its dual ability to combat neuroinflammation and directly protect neurons, demonstrated in preclinical models, positions it as a promising therapeutic candidate for future investigation. Future research must prioritize the resolution of fundamental methodological challenges in irisin measurement, alongside investigating pharmacokinetics and sex-specific effects, to advance irisin toward rigorous clinical evaluation. Full article

The intestinal microbiota, a diverse community of microorganisms residing in the human gut, recently attracted considerable attention as a contributing factor to various neurological disorders, including Alzheimer’s Disease (AD). Within the established framework of the gut–brain axis (GBA) concept, it is commonly suggested that dysbiosis, through microbial metabolites entering the brain, affect the cognitive functions in patients with AD. However, evidence for such a role of dysbiosis remains largely associative, and the complexity of the communication channels between the gut and the brain is not fully understood. Moreover, the new players of the GBA are emerging and the AD concept is constantly evolving. The objective of this narrative review is to synthesize the current evidence on the humoral, endocrine, immune, and neural communication mechanisms linking the gut and brain in AD and highlight newly discovered GBA messengers such as microRNAs, extracellular vesicles, T-cells, and the intestinal hormones, including emerging neuroprotective role for glucagon-like peptide-1 (GLP-1). Based on this knowledge, we aimed to develop a conceptual understanding of the GBA function in health and AD. We specify that, in AD, the GBA goes beyond a disrupted microbiome, but operates in conjunction with impaired intestinal secretion, motility, barrier permeability, and neuroinflammatory signaling. These factors are associated with the dysfunction of the hypothalamic–pituitary axis, altered somatic and autonomic neuronal gut regulation, and abnormal, due to memory problems, behavioral aspects of food intake. Identifying the individual profile of key molecular and cellular players contributing to an unbalanced GBA should optimize existing approaches or propose new approaches for the complex therapy of AD. Full article

Background: Brain-derived neurotrophic factor (BDNF) is a key regulator of neuroplasticity, cognitive function, and mental health. Exercise is proposed as a non-pharmacological strategy to enhance BDNF; however, findings across neurological and non-neurological disorders remain inconsistent, and the influence of exercise type or dose-related parameters remains unclear. Objective: This meta-analysis evaluated the effects of exercise interventions on peripheral BDNF levels in individuals with neurological (e.g., multiple sclerosis, cognitive impairment, schizophrenia, depression) and non-neurological (e.g., obesity, type 2 diabetes, cancer) disorders, and examined whether outcomes varied by disease category, exercise modality, or dose. Methods: A systematic search of Web of Science, PubMed, ScienceDirect, Scopus, and Cochrane was conducted up to 1 October 2025. Eligible randomized controlled trials (RCTs) and the quality of evidence were assessed using the PEDro scale and the GRADE approach, respectively. Random-effects models were applied, with subgroup analyses (neurological vs. non-neurological; exercise type; duration and assay type), meta-regressions (duration, frequency, session length), and publication bias tests (funnel plot, Begg’s test, Egger’s regression, and trim-and-fill). Results: Nineteen RCTs, including 850 participants, were analyzed. According to low-quality evidence, exercise significantly increased peripheral BDNF (SMD = 1.03, 95% CI: [0.56–1.49, p < 0.0001). Effects did not differ significantly between neurological (SMD = 0.91, 95% CI: 0.31–1.50) and non-neurological (SMD = 1.23, 95% CI: 0.47–1.99) conditions (Q (1) = 0.44, p = 0.51). Subgroup analyses revealed significant improvements for resistance exercise (SMD = 1.57, 95% CI: 0.91–2.23), followed by aerobic (SMD = 1.44, 95% CI: 0.36–2.52) and combined exercise (SMD = 0.55, 95% CI: 0.21–0.89). Meta-regressions showed no moderating effects of duration (β = 0.0101, p = 0.834), weekly frequency (β = 0.1464, p = 0.648), minutes per session (β = −0.0124, p = 0.233) or total weekly minutes (β = 0.0005, p = 0.919) apart from age and baseline BDNF level factors (β = 0.0348, p = 0.020; β = −0.035, p = 0.0258). Publication bias tests indicated minimal publication bias, with adjusted effects remaining robust. Conclusions: Exercise interventions have been shown to increase peripheral BDNF significantly across diverse clinical populations. In particular, resistance and aerobic exercise protocols accounted for the exploratory component, whereas simple dose-related factors did not explain the variability. These findings are consistent with the biological plausibility of exercise-induced neuroplasticity and underscore the need for larger, pre-registered RCTs with harmonized biomarker protocols to strengthen clinical translation. However, the certainty of evidence is limited by small sample sizes and the frequent lack of blinding of participants and assessors across included trials. Full article

Background/Objectives: Beyond respiratory problems, COVID-19 can cause a variety of symptoms, such as neurological disorders caused by biological and psychological factors. Brain fog (BF), a post-illness cognitive impairment that many patients report, can be evaluated with reaction time (RT) testing. Response latency is measured by RT, which can be either simple (sRT) or complex (cRT). This study focuses on how COVID-19 affects cognitive function, with particular attention on RT changes, BF prevalence, and implications for daily life. Methods: The study included 599 participants from Bosnia and Herzegovina, Croatia and Serbia. RT was measured using PsyToolkit and participants completed a COVID-19-associated BF questionnaire. Participants who experienced BF after their latest COVID-19 infection rated its severity using a visual analogue scale (VAS). Additional clinical data were obtained from medical records. Results: BF was reported by 40% of participants post-COVID-19. Men reported it less frequently but found it more disruptive. RT progressively declined post-infection, reaching peak impairment at 15 weeks, following recovery, with RT normalizing by six months. Conclusions: COVID-19 is linked to temporary RT impairment, peaking at 15 weeks post-infection and resolving by six months, independent of BF presence. This study emphasizes the need for a biopsychosocial approach to BF management. Easily available RT assessments should be incorporated into routine clinical practice. Full article

Background/Objectives: Parkinson’s disease (PD) is an adult-onset neurodegenerative disorder whose pathogenesis is still not completely understood. Several lines of evidence suggest that alterations in epigenetic architecture may contribute to the development of this condition. Here, we present a pilot DNA methylation study from peripheral blood in a cohort of Sicilian PD patients and matched controls. Peripheral tissue analysis has previously been shown to reflect molecular and functional profiles relevant to neurological diseases, supporting their validity as a proxy for studying brain-related epigenetic mechanisms. Methods: We analyzed 20 PD patients and 20 healthy controls (19 males and 21 females overall), matched for sex, with an age range of 60–87 years (mean 72.3 years). Peripheral blood DNA was extracted and processed using the Illumina Infinium MethylationEPIC v2.0 BeadChip, which interrogates over 935,000 CpG sites across the genome, including promoters, enhancers, CpG islands, and other regulatory elements. The assay relies on sodium bisulfite conversion of DNA to detect methylation status at single-base resolution. Results: Epigenome-wide association study (EWAS) data allowed for multiple levels of analysis, including immune cell-type deconvolution, estimation of biological age (epigenetic clocks), quantification of stochastic epigenetic mutations (SEMs) as a measure of epigenomic stability, and differential methylation profiling. Immune cell-type inference revealed an increased but not significant proportion of monocytes in PD patients, consistent with previous reports. In contrast, epigenetic clock analysis did not reveal significant differences in biological age acceleration between cases and controls, partially at odds with earlier studies—likely due to the limited sample size. SEMs burden did not differ significantly between groups. Epivariations reveal genes involved in pathways known to be altered in dopaminergic neuron dysfunction and α-synuclein toxicity. Differential methylation analysis, however, yielded 167 CpG sites, of which 55 were located within genes, corresponding to 54 unique loci. Gene Ontology enrichment analysis highlighted significant overrepresentation of pathways with neurological relevance, including regulation of synapse structure and activity, axonogenesis, neuron migration, and synapse organization. Notably, alterations in KIAA0319, a gene involved in neuronal migration, synaptic formation, and cortical development, have previously been associated with Parkinson’s disease at the gene expression level, while methylation changes in FAM50B have been reported in neurotoxic and cognitive contexts; our data suggest, for the first time, a potential epigenetic involvement of both genes in Parkinson’s disease. Conclusions: This pilot study on a Sicilian population provides further evidence that DNA methylation profiling can yield valuable molecular insights into PD. Despite the small sample size, our results confirm previously reported findings and highlight biological pathways relevant to neuronal structure and function that may contribute to disease pathogenesis. These data support the potential of epigenetic profiling of peripheral blood as a tool to advance the understanding of PD and generate hypotheses for future large-scale studies. Full article

Neurological and neurodegenerative diseases encompass a wide range of conditions affecting the central nervous system, leading to progressive dysfunction and damage. These diseases, such as Alzheimer’s, Parkinson’s, and some cerebral organic acidurias, often result in debilitating symptoms impacting motor control, cognitive function, and sensory processing. Research into their complex etiologies, including the role of energy and redox homeostasis, is crucial for developing effective diagnostics and therapeutic interventions. Despite the current lack of effective treatments for many neurological and neurodegenerative disorders, nutraceuticals are garnering significant interest. These food-derived compounds offer benefits beyond basic nutrition, primarily due to their ability to modulate intracellular processes that are known to be disrupted in these diseases. This study reviews the neuroprotective potential of several nutraceuticals, specifically creatine, acetyl-L-carnitine, melatonin, and resveratrol, as promising adjuvants to therapeutic interventions in neurological and neurodegenerative diseases. Full article

Oxidative stress (OS) reflects a pathologic imbalance between excessive production of reactive oxygen species (ROS) and insufficient antioxidant defenses. Growing evidence indicates that a healthy gut microbiota (GM) is essential for regulating redox homeostasis, whereas gut dysbiosis contributes to elevated ROS levels and oxidative damage in DNA, lipids, and proteins. This redox disequilibrium initiates a cascade of cellular disturbances—including synaptic dysfunction, altered receptor activity, excitotoxicity, mitochondrial disruption, and chronic neuroinflammation—that can, in turn, impair cognitive and social functioning in metabolic and neuropsychiatric disorders via epigenetic mechanisms. In this review, we synthesize current knowledge on (1) how OS contributes to cognitive and social deficits through epigenetic dysregulation; (2) the role of disrupted one-carbon metabolism in epigenetically mediated neurological dysfunction; and (3) mechanistic links between leaky gut, OS, altered GM composition, and GM-derived epigenetic metabolites. We also highlight emerging microbiota-based therapeutic strategies capable of mitigating epigenetic abnormalities and improving cognitive and social outcomes. Understanding the OS–microbiota–epigenetic interplay may uncover new targetable pathways for therapies aimed at restoring brain and behavioral health. Full article

Introduction: Infantile Refsum disease (IRD) is considered one of the milder phenotypes within the Zellweger Spectrum Disorders (ZSDs), a group of peroxisomal biogenesis disorders characterized by a generalized impairment of peroxisomal function. Pathognomonic features of IRD are growth retardation, hearing and cognitive impairment, neuromuscular problems, and craniofacial anomalies. Due to the relatively short lifespan, severe dental anomalies have not been previously reported in association with this disorder. This case report describes a rare manifestation of multiple impacted teeth and near complete edentulism in an adult patient diagnosed with Infantile Refsum disease (IRD). Material and Methods: The patient, a 24-year-old female, presented with a skeletal Class III malocclusion, severe maxillary hypoplasia, and complete impaction of the permanent dentition. The diagnosis of Infantile Refsum disease (IRD) was genetically confirmed and was associated with both neurological and dermatological manifestations. Conclusions: This case underscores that severe disturbances in tooth eruption and impaction may represent underrecognized manifestations of metabolic and genetic disorders such as Infantile Refsum disease (IRD). Dental professionals should remain vigilant to the potential association between systemic conditions and delayed or failed tooth eruption, emphasizing the need for interdisciplinary management and further investigation. Full article

Background: Wolfram syndrome (WS) is an ultrarare neuroendocrine disorder caused by pathogenic variants in WFS1, frequently leading to progressive neurological, autonomic, and cognitive impairment. Anticipating neurological trajectories remains challenging due to marked phenotypic variability and limited genotype–phenotype data. Methods: Forty-five genetically confirmed patients with WS were evaluated between 1998 and 2024 in Spain. All WFS1 variants were systematically classified by exon, zygosity, protein-level functional impact, and predicted wolframin production (Classes 0–3). Machine learning models (Random Forests with engineered gene–gene interaction terms) were applied to predict neurological manifestations and identify the strongest genetic determinants of symptom severity. Results: Neurological involvement was present in 93% of patients. The most prevalent manifestations were absence of gag reflex (67%), gait instability (64%), dysphagia (60%), and sialorrhea (60%), followed by dysmetria (56%), impaired tandem gait (53%), anosmia (44%), dysarthria (44%), and adiadochokinesia (42%). Most symptoms emerged in early adulthood (23–26 years), whereas cognitive decline occurred later (29.9 ± 12.2 years). Homozygosity for truncating variants—particularly c.409_424dup16 (Val142fsX110)—and complete loss of wolframin production (Class 0; 67–83% across symptoms) were the strongest predictors of early and severe neurological involvement. Machine learning models achieved high discrimination for ataxia, gait instability, and absent gag reflex (AUC 0.63–0.86; calibrated AUC up to 0.97), identifying Mut1_Protein_Class and Mut2_Protein_Class as dominant predictors across all phenotypes, followed by coherent secondary effects from zygosity × exon interaction terms (Prod_mgm). Conclusions: Integrating detailed genetic classification with machine learning methods enables accurate prediction of neurological outcomes in WS. Protein-level dysfunction and allele interaction structure are the principal drivers of neurological vulnerability. This framework enhances precision diagnosis and offers a foundation for individualized surveillance, clinical risk stratification, and future therapeutic trial design in WFS1-related disorders. Full article

Background and Clinical Significance: Wilson disease is a rare autosomal recessive disorder of copper metabolism that can initially present with psychiatric symptoms, leading to delays in accurate diagnosis and treatment. Adult-onset cases may be misdiagnosed as primary psychiatric disorders, particularly when hepatic signs are subtle or absent. Early recognition is critical to prevent irreversible neurological and hepatic damage. Case Presentation: A 48-year-old Hispanic male developed persecutory delusions, cognitive decline, and ultimately catatonia over a three-year period. He was initially diagnosed with a primary psychiatric disorder and treated with antipsychotics, which caused severe extrapyramidal side effects. Further evaluation revealed markedly abnormal liver function tests, low serum ceruloplasmin, and elevated 24 h urinary copper excretion. Brain MRI showed characteristic findings of Wilson disease, and liver biopsy confirmed the diagnosis. The patient was started on trientine and zinc sulfate, but progressive hepatic dysfunction necessitated liver transplantation. Following a successful transplant, the patient experienced significant neurological and psychiatric recovery. Conclusions: This case underscores the importance of considering Wilson disease in patients presenting with atypical or treatment-resistant psychiatric symptoms, particularly when accompanied by abnormal liver function or intolerance to antipsychotics. Timely, multidisciplinary evaluation is essential to avoid misdiagnosis and initiate appropriate therapy. Early intervention can significantly improve both psychiatric and medical outcomes in Wilson disease. Full article

Lafora disease is a fatal neurodegenerative disorder caused by loss-of-function mutations in the EPM2A or EPM2B genes, which encode laforin and malin, respectively. These mutations lead to the accumulation of intracellular inclusions of abnormal glycogen, known as Lafora bodies, the hallmark of the disease. Symptoms typically begin in early adolescence with seizures and rapidly progress to cognitive and motor decline, ultimately resulting in dementia and death within a decade of onset. Disruption of Epm2a or Epm2b in mice causes neuronal degeneration and Lafora body accumulation in the brain and other tissues. Epm2a^−/− and Epm2b^−/− mice exhibit motor and memory impairments, epileptic activity, and molecular and histological abnormalities. We previously demonstrated that intracerebroventricular delivery of a recombinant adeno-associated virus carrying EPM2A significantly improved pathology in Epm2a^−/− mice. In this study, we tested recombinant adeno-associated virus-mediated delivery of the human EPM2B gene in Epm2b^−/− mice. The treatment partially improved neurological, molecular, and histopathological outcomes, although some pathological features persisted. Importantly, our findings reveal differences between EPM2A- and EPM2B-based gene therapies, highlighting the need to better understand their distinct mechanisms. Despite limitations, our study provides new insights into the complexity of targeting EPM2B mutations in Lafora disease. Full article