Neurodegenerative and neurodevelopmental neurological disorders represent a growing global health burden, characterized by progressive neuronal dysfunction, cognitive decline, and impaired functional outcomes. Increasing evidence highlights neuroinflammation as a central pathophysiological mechanism linking mitochondrial dysfunction, oxidative stress, microbiota dysbiosis, and synaptic impairment across diverse neurological conditions. This narrative review was conducted using a structured literature search approach, incorporating major biomedical databases to enhance transparency and reproducibility. This review synthesizes contemporary evidence on mechanistic pathways underlying neuroinflammation-mediated neurodegeneration and critically evaluates emerging neuroprotective therapeutic strategies. Particular emphasis is placed on mitochondrial transfer approaches, novel circulating and imaging biomarkers, and integrative neurotechnological innovations such as artificial intelligence-driven neuroimaging analytics. While several therapeutic approaches demonstrate promise in preclinical models, most remain at early experimental or translational stages, with limited validation in large-scale human studies. Current findings suggest that targeting neuroimmune signaling cascades, restoring mitochondrial bioenergetics, and modulating gut-brain axis interactions may provide synergistic neuroprotective benefits. The review proposes a multidimensional precision-medicine framework incorporating biomarker-guided therapeutic selection and interdisciplinary care models. Future research priorities include longitudinal biomarker validation, randomized clinical trials of mitochondrial-based therapies, and integration of digital neurodiagnostic platforms to enhance early disease detection. Despite these advances, significant gaps remain in clinical translation, standardization of biomarkers, and long-term therapeutic safety, necessitating cautious interpretation of emerging evidence.
Aim: Attention deficit hyperactivity disorder (ADHD) is a common condition impacting approximately 5% of children and 3–4% of adults in the United Kingdom (UK). While it cannot be cured, treatment has been shown to positively impact the difficulties associated with ADHD. However, ADHD is widely underdiagnosed and undertreated in the UK. This paper reports the results of a model developed to estimate pharmacological treatment rates by area across National Health Service (NHS) integrated care systems (ICSs) in England, health boards in Scotland and Wales, and health & social care trusts (HSCTs) in Northern Ireland. Methods: The model used the UK general population and ADHD prevalence data to estimate the number of patients with ADHD in each area. Prescription data for medicines licensed for the treatment of ADHD were then used to estimate the number of patients who are untreated and treated, and the percentage treatment rates by area. The analysis was descriptive, focusing on quantifying geographic variation in treatment rates. Results: Nationally, the estimated proportions of children and young people (CYP; 5–17 years) and adults (18–65 years) treated were 26.6% and 15.6%, respectively, of the expected ADHD populations. Treatment rates by ICS or health board in England, Scotland, and Wales ranged from 11.7% to 60.6% for the CYP population and 8.6% to 24.8% for the adult population (data for Northern Ireland were not available by age group). Overall treatment rates (ages 5–65 years) in Northern Ireland ranged from 6.7% in the lowest-ranking HSCT to 31.1% in the highest-ranking HSCT. Conclusions: In the UK, there is currently a high degree of geographic variation across all NHS systems and a generally low level of treatment of ADHD, especially in adults. Up to a 4.6-fold difference in pharmacological treatment rates was observed between NHS service provider areas.
Stroke remains a leading cause of long-term disability worldwide, and selective serotonin reuptake inhibitors (SSRIs), beyond their established role in treating post-stroke depression, have been investigated for potential neurorestorative effects through modulation of neuroplasticity, cortical excitability, and synaptic remodeling. This narrative mini-review summarizes the current clinical evidence on the use of SSRIs for motor recovery, cognitive recovery, and global functional outcomes after stroke. Early small-scale studies, particularly with fluoxetine, suggested improvements in motor performance and neurophysiological markers of plasticity, generating interest in a possible disease-modifying role. However, subsequent large multicenter randomized controlled trials failed to demonstrate benefits on global functional outcomes and instead reported an increased risk of adverse events, including fractures, falls, seizures, and hyponatremia. Evidence for other SSRIs remains limited, heterogeneous, and largely inconclusive. The observed discrepancy between mechanistic plausibility and neutral clinical outcomes may reflect limitations in outcome sensitivity, patient heterogeneity, differences in stroke subtypes, and suboptimal alignment between biological targets and clinical endpoints. Overall, current data do not support the routine use of SSRIs as neurorestorative agents in non-depressed stroke patients. Future research should focus on biomarker-guided patient selection, optimized timing of intervention, and the use of domain-specific outcome measures more closely aligned with neuroplasticity mechanisms, in order to clarify whether serotonergic modulation may have a selective, context-dependent role in post-stroke recovery.
Aim: Cerebral palsy (CP), a prevalent pediatric neurological disorder, involves significant motor and sensory impairments requiring long-term, multifaceted management. Action observation therapy (AOT), a novel neurorehabilitation approach, activates the mirror neurons through task observation. Evidence for AOT remains inconclusive for CP despite promising results in other populations. The study aimed to investigate the effects of AOT on functional performance, specifically mobility and balance, in spastic CP. Methods: 28 spastic CP children, eligible based on the Gross Motor Function Classification System (GMFCS) and Modified Ashworth Scale (MAS), were randomly assigned to an experimental group receiving video-based AOT plus task-oriented physiotherapy or to a control group receiving the same task-oriented physiotherapy protocol with therapist demonstration but without video-based action observation. Both groups received an 8-week play-based, task-oriented physiotherapy program. The experimental group additionally received video-based AOT before performing the tasks, whereas the control group received therapist demonstration without video-based observation. Functional outcomes were assessed at baseline and after the intervention using the Pediatric Balance Scale (PBS) and the Gross Motor Function Measure-88 (GMFM-88). Within- and between-group differences were analyzed using the Wilcoxon Signed-Rank test and the Mann-Whitney U test, respectively. Results: Both groups showed significant within-group improvements in PBS and GMFM-88 scores after the intervention (p < 0.05). However, post-intervention comparisons did not show a significant difference between the experimental and control groups. The play-based format appeared to support engagement and functional gains in both groups. Conclusions: AOT led to clinical improvements without a statistically significant dominance over the conventional approach, suggesting AOT might be more beneficial with increased dosage or multimodal approaches (ClinicalTrials.gov identifier: NCT06672328).
Microglia, the resident immune cells of the central nervous system, are increasingly recognized as key regulators of neural development, synaptic plasticity, and behavior. In addition to their classical role in immune surveillance, microglia actively shape neuronal circuits and influence cognitive and emotional functions across the life span. Accumulating evidence now implicates aberrant or chronic microglial activation as a central mechanism underlying neuroinflammation-associated behavioral and cognitive disturbances in a wide range of neuropsychiatric disorders, including major depressive disorder, schizophrenia, autism spectrum disorder, posttraumatic stress disorder, and attention-deficit/hyperactivity disorder. This narrative review synthesizes preclinical and clinical findings linking dysregulated microglial activation to brain pathology of neuropsychiatric disorders, with particular emphasis on cytokine signaling, oxidative stress, synaptic remodeling, and gut–brain–microglia interactions. This review discusses how sustained microglial priming and excessive inflammatory responses disrupt neurotransmitter systems, impair synaptic integrity, and alter neural network connectivity in brain regions critical for emotion regulation, cognition, and social behavior. Advances in neuroimaging, including TSPO-PET and multimodal approaches, have enabled in vivo assessment of microglial activation in humans, strengthening translational relevance. Furthermore, this review evaluates emerging therapeutic strategies aimed at modulating microglial function, including pharmacological immunomodulators, CSF1R-based depletion and repopulation approaches, lifestyle interventions, and novel cell-based and vesicle-based therapies. Finally, this review highlights key translational challenges, particularly species-specific differences between mouse and human microglia, and proposes future directions for precision neuroimmune interventions. Collectively, the evidence reviewed here positions microglia as both mechanistic drivers and therapeutic targets in neuropsychiatric disorders rooted in chronic neuroinflammation.
Aim: Spinal cord injury (SCI) disrupts autonomic regulation of the gastrointestinal tract, resulting in altered motility, microbial dysbiosis, and decreased production of short-chain fatty acids such as butyrate, a metabolite with neuroprotective properties. This study aimed to evaluate the effects of SCI level and severity on gut microbiota composition and butyrate concentration, and to determine the impact of symbiotic supplementation with Enterococcus faecium and agave inulin on microbial and metabolic recovery. Methods: Twenty female Sprague Dawley rats were randomized into five groups: Sham, thoracic five moderate (T5M), thoracic five severe (T5S), thoracic nine moderate (T9M), and thoracic nine severe (T9S). Fecal samples were collected four weeks post-injury and again after four weeks of daily symbiotic administration. Butyrate levels were quantified by gas chromatography, and microbial composition was analyzed by 16S ribosomal RNA (16S rRNA) sequencing (V3–V4 region). Locomotor recovery was assessed weekly using the Basso, Beattie, and Bresnahan (BBB) scale. Results: All SCI groups displayed significant dysbiosis compared with Sham, characterized by decreased relative abundance of butyrate-producing genera such as Clostridium at week four, as confirmed in the main dataset. Following symbiotic supplementation, Bifidobacterium, Lactobacillus, and Clostridium levels showed partial restoration, although responses varied by injury site and severity. The T9M group demonstrated the most consistent recovery of butyrate-producing taxa; however, butyrate concentration decreased after treatment, while T9S showed a significant increase in butyrate concentration, and T5S exhibited minimal change. Motor recovery was greatest in T9M, followed by T9S and T5M, with no significant improvement in T5S. Conclusions: SCI level and severity strongly influenced microbial dysbiosis, butyrate metabolism, and motor recovery. Symbiotic supplementation partially restored butyrate-producing bacterial taxa, with the most pronounced metabolic and functional benefits observed in the T9M group. These findings support a level-dependent role of gut-brain axis modulation as a potential therapeutic strategy after SCI.
Aim: This study aimed to redefine post-stress depressive pathogenesis through a novel five-disease multimorbidity trajectory model (brain1-coronary-brain2-gastro-enteric; B1CB2GE) and to evaluate the multifunctional anchoring effects of Bupleurum chinense Shugan-San (BSS) and its absorbed compounds (ACs), including meranzin hydrate (MH), in AFS (acute forced swimming) male Sprague-Dawley rats. Methods: Temporal multimorbidity trajectories of B1CB2GE clusters were established in AFS rats and compared with single-disease models using 10 integrative analytic methods, including dynamic cluster trajectory modeling, biochemical profiling, and pharmacokinetic-pharmacodynamic (PK-PD) correlation analyses. A multi-cell experiment was used as a proxy for the in vivo system, whereas H-ECs (H2O2-treated endothelial cells) were used as a proxy for the multicellular system. Circulatory biomarkers related to oxidative, endothelial, and inflammatory (OEI) impairment, brain-derived neurotrophic factor (BDNF) levels, and cecal butyrate contents were measured. The role of the ghrelin (Ghr) receptor was examined using the antagonist D-Lys3-GHRP-6 (D-Lys). Forced-swim test, gastric emptying, enteric transit, and coronary flow were used to characterize post-AFS multimorbidity trajectory phenotypes in animals. Results: Fifteen minutes after AFS, distinct temporal B1CB2GE multimorbidity clusters emerged with normalized ranking values: G 15.31 > B2 1.17 > B1 0.85 > C 0.49 > E 0.32. These clusters were accurately anchored by BSS and its five tailored sets of 1–10 ACs, demonstrating multifunctional modulation ranging from 53.23% to 156.32%, with optimal anchoring efficiency of 96.37–104.14%. MH, a representative multifunctional compound, exhibited the strongest prokinetic and OEI-restorative effects, elevating BDNF and cecal butyrate levels. These therapeutic effects were abolished by D-Lys, confirming a Ghr-dependent mechanism. Conclusions: This study introduces a multimorbidity trajectory framework (B1CB2GE) for modeling post-stress depression and demonstrates that Shugan-like herbal formulas such as BSS effectively anchor dynamic multimorbidity progression via multifunctional compounds like MH. These findings provide a systems-pharmacology basis for understanding and treating complex comorbid depressive disorders through multifunctional anchoring herbal therapeutics.
Norepinephrine (NE), a central catecholamine neurotransmitter synthesized primarily in the locus coeruleus (LC), plays a critical role in regulating arousal, attention, emotional processing, and stress responsiveness. While contemporary personality neuroscience has established the role of NE in acute psychological states, its contribution to stable personality traits remains underexplored. This review synthesizes neurobiological, psychological, genetic, and psychopharmacological evidence to propose a NE-personality continuum that links tonic and phasic dynamics of the LC-NE system to enduring individual differences in alertness, anxiety, and adaptability. Alertness is associated with optimal noradrenergic tone and efficient phasic signaling, which enhances the signal-to-noise ratio and attentional focus. Anxiety arises from chronic hyperactivation or dysregulated NE release, particularly involving excessive α1- and β-adrenergic receptor activity and impaired modulation from the prefrontal cortex. Adaptability denotes a harmonious interaction between the limbic system and prefrontal cortex, which facilitates cognitive flexibility and emotional regulation in response to changing environmental demands. The connection between NE activity and personality traits follows an inverted U-shaped pattern. Low tone leads to apathy and less engagement, moderate tone helps with resilience and optimal functioning, and high tone leads to hypervigilance and rigidity. This model combines findings from fundamental neuroscience and clinical research to provide a physiologically based framework for understanding how long-term variations in noradrenergic regulation affect personality traits, as described in established trait theories. The findings underline the feasibility of adding noradrenergic biomarkers and pharmaceutical therapies into clinical practice, as well as the importance of longitudinal and multimodal research to determine trait-level causality. This is especially important for understanding how to use these elements to improve treatment plans for personality disorders.
This Perspective explores why hyperbaric oxygen therapy (HBOT) deserves closer clinical and scientific attention as a possible treatment for ischemic stroke and a potential neuroprotective strategy in chronic central nervous system disorders, especially multiple sclerosis and other progressive or age-related neurological conditions. While HBOT is not yet widely accepted for these indications, three factors justify reconsideration: its strong safety profile, a biologically plausible mechanistic rationale, and recurrent signals of benefit from selected neurological studies. We review HBOT’s historical development, current accepted indications, and evidence that adverse effects are generally mild, uncommon, and reversible under modern protocols. In neurology, efficacy remains unproven, yet interest persists due to preliminary findings and repeated patient-reported improvements. A central argument is that the main barrier to progress is not safety, but evidence generation. Conventional randomized controlled trials face major challenges: difficult blinding, wide variation in dosing protocols, and uncertainty about meaningful outcomes in chronic neurological disease. Moreover, HBOT is non-patentable, which limits commercial investment and leaves a potentially valuable intervention underexplored. Mechanistically, we move beyond explanations centred solely on oxygen delivery or oxidative stress. As a working hypothesis, neurological benefits may partly arise from cumulative adaptive responses—including a rebound hormesis following repeated hyperoxic exposure. We conclude with a pragmatic research agenda: continuous, low-cost physiological monitoring in patients already receiving HBOT, coupled with a medium-term goal of adequately powered efficacy trials.
Aim: To assess the effect of a synbiotic supplement composed of Enterococcus faecium and agave inulin on cognitive function in older adults with mild cognitive impairment (MCI). Methods: In a triple-blind randomized crossover trial, nineteen adults aged 64–85 years with MCI received either the synbiotic or an isocaloric vehicle for eight weeks, followed by a three-week washout and treatment crossover. Cognitive outcomes were assessed at baseline, after the first intervention, and after crossover using the Modified Mini-Mental State Examination (MMSE), Rey-Osterrieth Complex Figure Test (RCFT; copy and memory), and Abbreviated Instrument for Expectations of Self-Efficacy for Daily Activities in Older Adults (AERAC) self-efficacy scale. Paired and unpaired Student’s t-tests were used for statistical comparisons (p < 0.05). Results: The synbiotic group showed significant improvement relative to baseline across all domains: MMSE (p = 0.05), AERAC (p = 0.005), RCFT-copy (p = 0.03), and RCFT-memory (p = 0.03). Post-treatment comparisons between groups also favored the synbiotic, with significant differences in MMSE (p = 0.001), AERAC (p = 0.001), RCFT-copy (p = 0.0095), and RCFT-memory (p = 0.001). After crossover, cognitive gains were sustained and reproduced. MMSE scores reached 17.89 ± 1.45 in the synbiotic-first group versus 18.20 ± 0.63 in the control-first group (p < 0.001). RCFT-copy remained high (29.83 ± 4.18 vs. 29.52 ± 5.60, p = 0.0157), while RCFT-memory scores differed (17.56 ± 6.73 vs. 17.20 ± 3.29, p = 0.0005). AERAC scores continued to improve during crossover (82.60 ± 10.49 vs. 85.46 ± 8.28, p < 0.001). No adverse effects occurred. Conclusions: Synbiotic supplementation significantly improved global cognition, visuoconstructive ability, memory, and functional self-efficacy in older adults with MCI. Benefits persisted beyond the initial intervention and were replicated when the control group received the synbiotic, supporting its potential as a safe and effective strategy to mitigate age-related cognitive decline.
The NEUROD2 gene encodes a transcription factor essential for neuronal differentiation and cortical development. Pathogenic variants cause a rare autosomal dominant neurodevelopmental disorder with variable expressivity, typically presenting in early infancy with developmental delay, epilepsy, and behavioral abnormalities. We report a newborn girl carrying a de novo heterozygous missense variant NM_006160.4:c.790G>A, p.(Ala264Thr), located outside the canonical basic helix-loop-helix (bHLH) domain. Soon after birth, she presented respiratory depression, hypotonia, feeding difficulties, and electrographic seizures. Magnetic resonance imaging (MRI) showed subcortical white matter hyperintensity, and the electroencephalogram (EEG) revealed abnormal background activity. During follow-up, epilepsy was controlled, but neurodevelopmental delay with autistic features emerged. This case represents the earliest reported clinical onset associated with NEUROD2 variants and expands the phenotypic and mutational spectrum. It highlights that variants outside known hotspots can cause severe disease and supports including NEUROD2 in the differential diagnosis of neonatal neurological impairment.
Background: Atrial fibrillation (AF) substantially increases the risk of ischemic stroke (IS), underscoring the need for effective anticoagulation strategies. Direct oral anticoagulants (DOACs) have largely supplanted vitamin K antagonists (VKAs) due to their favorable safety profile and ease of use. Factor XI (FXI) inhibitors, which target the intrinsic coagulation pathway, are emerging as potential alternatives that may offer reduced bleeding risk. This systematic review evaluates the efficacy and safety of FXI inhibitors compared with DOACs for stroke prevention in AF. Methods: A total of 20 studies fulfilled the inclusion criteria, comprising 11 randomized controlled trials (RCTs), five systematic reviews or meta-analyses, and four narrative, cohort, or modeling studies. Eligible investigations compared FXI inhibitors with DOACs in patients diagnosed with AF. The primary outcomes assessed were stroke or systemic embolism, major bleeding, and all-cause mortality. Methodological quality was evaluated according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) framework, the revised Cochrane Risk of Bias 2 (RoB 2) tool for RCTs, and the Newcastle-Ottawa Scale (NOS). Results: FXI inhibitors were associated with a significant reduction in major bleeding [relative risk (RR) 0.31; 95% confidence interval (CI) 0.21–0.46] and clinically relevant non-major bleeding (RR 0.66; 95% CI 0.47–0.93) compared with DOACs. Conversely, FXI inhibitors demonstrated an increased risk of stroke or systemic embolism (RR 3.17; 95% CI 2.18–4.62), as observed in the OCEANIC-AF trial [hazard ratio (HR) 3.79; 95% CI 2.46–5.83]. No significant difference was noted in all-cause mortality (RR 0.85; 95% CI 0.67–1.08). Limited evidence suggests that FXI inhibitors may also reduce bleeding-related hospitalizations. Discussion: FXI inhibitors provide a favorable bleeding profile but are less effective than DOACs for stroke prevention in patients with AF. Further long-term RCTs are warranted to delineate their role, particularly in populations at high risk of bleeding.
Background: Fully immersive virtual reality (IVR) is an emerging technology approach for cognitive training in individuals with mild cognitive impairment (MCI) and dementia. While interest in fully IVR continues to grow, it remains unclear the extent of effectiveness and the key components that contribute to successful implementation. This study aimed to explore the effectiveness of fully IVR cognitive training for individuals with MCI or dementia from previous research literature. Methods: A scoping review was conducted using a systematic search strategy based on the population, concept, and context framework. Results: Out of the 816 records identified, 123 full texts were screened, and eight studies were included in the review. The included studies all involved participants completing a cognitive training intervention using fully IVR headsets, with cognitive outcomes measured before and after the intervention. The most consistent improvements across the included studies were executive function, memory, and visuospatial abilities. Only two studies explicitly referenced a theoretical model. Discussion: Fully IVR cognitive training demonstrates promise for improving specific cognitive domains in individuals living with MCI or dementia. However, inconsistencies in outcomes and limited theoretical grounding highlight the need for further exploration. Broader considerations are discussed in the discussion section.
Phycocyanobilin (PCB), the covalently bound chromophore of the cyanobacterial protein C-phycocyanin (CPC), is recognized as a bioactive molecule with neuroprotective and anti-inflammatory properties. PCB and CPC, frequently coexisting in Spirulina extracts or experimental formulations, have demonstrated beneficial effects in preclinical models of multiple sclerosis, ischemic stroke, and Alzheimer’s disease. Reported mechanisms include attenuation of oxidative stress, reduction of neuroinflammation, and preservation of mitochondrial function, thereby contributing to a reparative microenvironment within the central nervous system. PCB can be obtained through two complementary approaches: Extraction from cyanobacterial biomass, where it remains covalently bound to CPC, and heterologous biosynthesis in Escherichia coli (E. coli), which enables production of free PCB as a high-purity, scalable linear tetrapyrrole suitable for translational applications. This mini-review summarizes current evidence on the neuroprotective actions of PCB and CPC, highlights their molecular targets, and discusses biotechnological advances that support their potential role in remyelination. By bridging natural pigment pharmacology with recombinant production strategies, PCB is positioned as a multitarget candidate of growing interest for the development of future neuroprotective and neurorepair therapies.
Background: Acquired brain injury (ABI) often causes long-lasting impairments in written language and handwriting that limit autonomy and daily functioning. Despite their relevance, these deficits have received limited research attention compared with spoken language disorders. The present work aims to systematically review interventions designed to improve reading, writing, and handwriting abilities in individuals with ABI. Methods: Following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, PubMed, American Psychological Association (APA) PsycINFO, Cochrane Library, Web of Science, and Google Scholar were searched from inception to 1 November 2025. Eligible studies were randomized or non-randomized clinical trials (non-RCTs) involving adults or adolescents with ABI and documented written language impairments. Risk of bias was assessed using the Risk of Bias 2 tool (RCTs) and Risk of Bias in Non-randomized Studies—of Interventions tool (non-RCTs). Results: Twelve studies met inclusion criteria (2 RCTs, 10 non-RCTs), all conducted in post-stroke populations, highlighting the absence of evidence from other ABI aetiologies. Three main intervention categories emerged: (1) Behavioral treatments, which consistently improved trained spelling and functional writing, with some advantages for errorless learning in maintaining gains. (2) Technology-assisted approaches, including assistive software, digital spelling aids, and handwriting-focused programs, which showed feasibility, high usability, and improvements in accuracy, legibility, and motor fluency. (3) Neuromodulation, with one RCT showing that dual-site transcranial direct current stimulation can modestly enhance behavioral writing therapy. Most non-RCTs showed serious or critical risk of bias, and sample sizes were small, limiting generalizability. Discussion: Current evidence—although preliminary and restricted to post-stroke ABI—indicates that behavioral, technological, and neuromodulatory interventions can improve aspects of written language and handwriting after ABI. However, the available literature is characterized by small samples, substantial methodological variability, and a paucity of standardized and ecologically valid outcome measures. High-quality, adequately powered trials with standardized, functional outcomes are urgently needed, particularly in non-stroke ABI populations.
Neurodevelopmental Disorder with Regression, Abnormal Movements, Loss of Speech, and Seizures (NEDAMSS) is an ultra-rare, progressive neurological disorder, with more than 60 individuals described in the medical literature. It is caused by de novo mutations in the interferon regulatory factor 2 binding protein-like (IRF2BPL) gene, leading to early-onset symptoms including seizures, developmental delays, intellectual disability, and other severe neurological impairments, typically beginning in infancy or early childhood. This review aims to consolidate and refine current knowledge on NEDAMSS, focusing on the molecular functions of IRF2BPL, the spectrum of clinical features, and underlying disease mechanisms. A comprehensive understanding of NEDAMSS is essential for guiding the development of targeted interventions and therapeutic strategies to improve patient outcomes. By integrating current findings, we focus both on the progress made and the gaps that remain in research, providing a foundation for future studies to advance diagnosis, treatment, and overall patient care. We reviewed the published literature through studies available up to 2025 to synthesize current knowledge on clinical features, genetics, and proposed disease mechanisms. Reported phenotypes show substantial heterogeneity, and current genotype-phenotype correlations remain limited by small cohorts and inconsistent reporting. Key next steps include standardized phenotyping, natural history studies, and biomarker development to enable trial-ready outcome measures and accelerate targeted therapy development.
Background: Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease affecting the central nervous system, the cause of which remains unknown. Environmental, genetic, and immunological factors are considered risk factors. MS has no cure; therefore, therapy focuses on reducing the number of outbreaks, controlling symptoms, and therapies aimed at modifying the course of the disease. Innovative strategies that promote remyelination and repair of damaged brain tissue are under investigation. This review aims to compile and systematize the available knowledge on the multifactorial nature of MS, highlighting the main risk factors. It also discusses the mechanisms underlying the pathogenesis of the disease, current therapies, and prospects, presenting a comprehensive overview of the effect of various drugs on remyelination and repair of central nervous system damage. Methods: A comprehensive literature search, guided by Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) standards, was conducted across PubMed, Cochrane Library, Web of Science, and ClinicalTrials.gov to identify relevant clinical trials. Of the studies retrieved, 13 were selected for this review. These trials specifically explored integrated therapeutic approaches, combining pharmacological and non-pharmacological interventions, for managing MS. Results: The results reflect the multifactorial nature of MS and the existence of several promising therapies to combat inflammation and demyelination, as well as to promote remyelination. Reducing inflammation remains the main target, but new approaches such as clemastine, liothyronine, interleukin (IL)-2, N-acetylglucosamine, and intracranial transplantation of fetal human neural precursor cells have shown promising results. Discussion: Currently, the therapies available for MS target the peripheral immune system. Therefore, more studies are needed on treatment therapies that combine immunomodulation of the peripheral and central nervous systems to reduce the neurological disability of patients. It is also concluded that the therapies were safe and were well tolerated, given the occurrence of a small number of adverse events.
Neurodegenerative disorders such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and ischemic stroke cause progressive and often irreversible neuronal loss, leading to major functional disability. Conventional pharmacological therapies primarily offer symptomatic relief and fail to promote neuro-restoration. Stem cell-derived exosomes have recently gained attention as acellular, regenerative biologics capable of modulating inflammation, enhancing synaptic repair, and facilitating neural recovery. These nanoscale vesicles carry bioactive molecules, including microRNAs (miRNAs) and growth factors, that replicate many of the paracrine benefits of stem cells without the associated risks of tumorigenicity or immune rejection. The objective of this review is to critically evaluate recent evidence on the neuroprotective, immunomodulatory, and translational mechanisms of stem cell-derived exosomes in major neurodegenerative and cerebrovascular disorders, highlighting their clinical relevance and therapeutic potential. Preclinical studies suggest that exosome administration may restore mitochondrial function, reduce oxidative stress, and support neuronal survival, with associated improvements in cognitive and motor outcomes in experimental models of AD, PD, and stroke. Exosomal miRNAs such as miR-21, miR-124, and miR-133b mediate neuroprotective effects through phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt), mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK), and nuclear factor erythroid 2-related factor 2 (Nrf2) signaling, while miR-146a promotes immunomodulation by suppressing pro-inflammatory cytokines and facilitating microglial repair phenotypes. Early-phase clinical studies primarily demonstrate feasibility and short-term safety, with exploratory signals of neurological improvement that require confirmation in adequately powered trials. Despite challenges in standardization and regulation, exosome-based therapy represents a scalable, safe, and clinically translatable strategy for neuro-regeneration, with significant promise for future management of brain network disorders.
Neurodegenerative diseases, including Alzheimer’s, Parkinson’s, Huntington’s, and Amyotrophic Lateral Sclerosis, are characterized by multifactorial pathologies that extend beyond neuronal loss to include neuroinflammation, oxidative stress, mitochondrial dysfunction, and glial dysregulation. Despite extensive research, disease-modifying therapies remain elusive, hindered by late diagnosis, limited availability of specific biomarkers, and the persistent dominance of reductionist, single-target strategies. This comprehensive and informative review provides a critical synthesis of integrated neuroprotective strategies, with particular focus on glial mechanisms and biomarker-guided interventions. Therapeutic emphasis is placed on coordinated mechanisms targeting both neurons and non-neuronal cells, such as astrocytes, microglia, and oligodendrocytes. Emerging strategies are reported to include modulation of synaptic plasticity and neurotransmission, delivery of neurotrophic factors, activation of intrinsic cytoprotective pathways (e.g., Nrf2 signaling), restoration of proteostasis, and induction of regeneration via cellular reprogramming. Glial cells are discussed as therapeutic targets involved in inflammation, metabolism, myelination, and neuronal survival. Advances in predictive, preventive, personalized, and participatory (P4) medicine, supported by genomics, multi-omics, imaging, and real-world data, are presented as accelerating biomarker discovery and enabling earlier and more precise stage-specific interventions. Future success in combating neurodegeneration will depend on integrated approaches that combine protective, supportive, and regenerative strategies, appropriate for disease stage and patient profile. By reframing neuroprotection as a systemic, multicellular endeavor, this review highlights the potential to not only extend life expectancy, but also preserve meaningful quality of life in individuals affected by neurodegenerative diseases.
Neurodevelopmental disorders form a considerable group in the DSM-5, the diagnostic mental disorders manual employed in numerous regions. Some disorders are identified with biomedical tests while those from unknown sources are verified with behavioural scales. They are ubiquitous in youths, significantly impacting their behaviours and lives. They begin in early development and persist mostly throughout their lifespan with chronogeneity, i.e., changes over time. They often form comorbidities, adding to the complexity by creating “new” phenotypes at the intersection. The article aims to provide clinically critical views of ADHD and the added burden of alexithymia comorbidities with profound effects on developmental language disorder (DLD) and autism. The noted problem is the DSM-5’s mental health categorical measure of disease identification of the disorders’ symptoms, but the neglect of comorbidity. The article’s guiding theory is the adoption of the dimensional approach in addressing the target disorders, and the Vygotskian social interactional and linguistic-cognitive learning theory in proposing dimensional treatments. The ADHD including alexithymia in these disorders exhibit commonalities: 1. all are dimensional conditions rather than categorical ones requiring dimensional approaches as these include the entire continuum; 2. all show accompanying developmental language and learning limitations, and 3. all have histories of literacy acquisition problems that impact their academic trajectory while sabotaging their executive functions (EFs) development and undermining the affected individuals and the clinicians’ treatment efforts. The suggested interventions target multiple ages based on the Vygotskian social-interactional learning theory acknowledging cognitive development as language and knowledge transmitted via psychosocial interactions facilitating the internalization of education that actively forges learners’ character, psychology, and behaviours. They are meant to address their conditions’ dimensionality, remediate cognitive linguistic lags, alleviate symptoms, and substitute ineffective learning and thinking habits with more functional ones. Issues to be addressed in developing a clinical plan complete the review.
