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Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, neuroinflammation, and accumulation of amyloid-beta plaques and tau tangles. Emerging research emphasizes the gut-brain axis as a key modulator of AD pathogenesis, with gut microbiota influencing neuroimmune, neurochemical, and metabolic pathways. This review examines the therapeutic and preventive potential of probiotics, live beneficial microorganisms, in modulating the gut-brain axis to mitigate AD progression. Modifying gut microbiota presents a novel, potentially modifiable approach to influence AD pathophysiology and improve cognitive outcomes, offering insights for adjunctive clinical strategies. A systematic literature search was conducted across PubMed, Scopus, Web of Science, Google Scholar, and Cochrane Library for studies published up to July 2025. Studies were classified by design, sample size, follow-up duration, cognitive and biomarker outcomes, and risk of bias, following Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines to ensure transparency and reproducibility. Preclinical studies indicate that probiotics can regulate gut microbiota, reduce oxidative stress, suppress neuroinflammation, and enhance synaptic plasticity, improving cognition in animal models. Clinical trials suggest potential benefits in humans, including improved memory scores and reduced inflammatory biomarkers, though limited sample sizes, trial duration, and strain variability constrain conclusions. Overall, probiotics demonstrate promise as an adjunctive intervention in AD. Further long-term, strain-specific, and large-scale clinical studies are needed to confirm efficacy, establish causality, and optimize therapeutic strategies.
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, neuroinflammation, and accumulation of amyloid-beta plaques and tau tangles. Emerging research emphasizes the gut-brain axis as a key modulator of AD pathogenesis, with gut microbiota influencing neuroimmune, neurochemical, and metabolic pathways. This review examines the therapeutic and preventive potential of probiotics, live beneficial microorganisms, in modulating the gut-brain axis to mitigate AD progression. Modifying gut microbiota presents a novel, potentially modifiable approach to influence AD pathophysiology and improve cognitive outcomes, offering insights for adjunctive clinical strategies. A systematic literature search was conducted across PubMed, Scopus, Web of Science, Google Scholar, and Cochrane Library for studies published up to July 2025. Studies were classified by design, sample size, follow-up duration, cognitive and biomarker outcomes, and risk of bias, following Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines to ensure transparency and reproducibility. Preclinical studies indicate that probiotics can regulate gut microbiota, reduce oxidative stress, suppress neuroinflammation, and enhance synaptic plasticity, improving cognition in animal models. Clinical trials suggest potential benefits in humans, including improved memory scores and reduced inflammatory biomarkers, though limited sample sizes, trial duration, and strain variability constrain conclusions. Overall, probiotics demonstrate promise as an adjunctive intervention in AD. Further long-term, strain-specific, and large-scale clinical studies are needed to confirm efficacy, establish causality, and optimize therapeutic strategies.
DOI: https://doi.org/10.37349/ent.2025.1004120
This article belongs to the special issue Role of Microbiota in Neurological Diseases
Parkinson’s disease (PD) is a devastating neurodegenerative condition characterized primarily by the degeneration of the dopaminergic neurons in the substantia nigra, causing motor dysfunction and many non-motor symptoms. Available pharmacological treatments and therapies provide symptomatic relief but do not halt the progression of PD. Gene therapy has been recognized as a valuable therapeutic frontier, providing the possibility of disease modification by targeting the underlying molecular and cellular mechanisms of PD. The parts of the methodology used for gene therapy entail the delivery of genetic material into particular regions of the brain with the aid of viral vectors to improve the synthesis of dopamine, maintain the integrity of neurons, or control pathological pathways. Recent clinical trials have shown promising efficacy and safety profiles for many gene therapy methods, consisting of those targeting enzymes in the biosynthesis of dopamine [e.g., L-amino acid decarboxylase (AADC)], synuclein alpha pathology, and neurotrophic factors [e.g., growth-derived neurotrophic factor (GDNF)]. However, in spite of these developments, there are limitations in vector delivery and prolonged expression of genes, as well as patient-specific responses. This review highlights the present landscape of gene therapy in PD, discussing the latest successes, ongoing clinical trials, and future perspectives that could shape therapeutic paradigms for PD.
Parkinson’s disease (PD) is a devastating neurodegenerative condition characterized primarily by the degeneration of the dopaminergic neurons in the substantia nigra, causing motor dysfunction and many non-motor symptoms. Available pharmacological treatments and therapies provide symptomatic relief but do not halt the progression of PD. Gene therapy has been recognized as a valuable therapeutic frontier, providing the possibility of disease modification by targeting the underlying molecular and cellular mechanisms of PD. The parts of the methodology used for gene therapy entail the delivery of genetic material into particular regions of the brain with the aid of viral vectors to improve the synthesis of dopamine, maintain the integrity of neurons, or control pathological pathways. Recent clinical trials have shown promising efficacy and safety profiles for many gene therapy methods, consisting of those targeting enzymes in the biosynthesis of dopamine [e.g., L-amino acid decarboxylase (AADC)], synuclein alpha pathology, and neurotrophic factors [e.g., growth-derived neurotrophic factor (GDNF)]. However, in spite of these developments, there are limitations in vector delivery and prolonged expression of genes, as well as patient-specific responses. This review highlights the present landscape of gene therapy in PD, discussing the latest successes, ongoing clinical trials, and future perspectives that could shape therapeutic paradigms for PD.
DOI: https://doi.org/10.37349/ent.2025.1004119
This article belongs to the special issue Parkinson's Disease: Principal Targets and Interventional Mechanisms
Tau phosphorylated at threonine 217 (p-tau217) has moved from research novelty to clinical reality, but its greatest value lies in dynamic monitoring, not static stratification. The pace of adoption of the plasma measurement of p-tau217 now demands clear guidance on optimal use. Two complementary evidence strands inform this perspective. First, a multi-cohort evaluation of a commercial assay shows high concordance with amyloid and tau reference standards and supports a pragmatic three-zone interpretation, rule-out, indeterminate, and rule-in, that can streamline diagnostic pathways while preserving accuracy. Second, longitudinal analyses in amyloid-positive individuals reveal that the most informative property of p-tau217 is dynamic: steeper rises occur in those who decline faster, whereas baseline values substantially overlap across outcome groups. These findings show that plasma p-tau217 levels can be a complementary tool for triage, enrichment, and longitudinal monitoring, but not as a time-stable baseline stratifier for defining trial cohorts or assessing therapeutic efficacy. Stratification should instead anchor to independent, stable measures such as tau burden measured by positron emission tomography (PET), structural magnetic resonance imaging (MRI), and cognitive history, reducing misclassification and avoiding circular validation. Comparable scrutiny should be applied to other p-tau biomarkers and to composite measures, such as the p-tau217/Aβ1–42 ratio, to rigorously define their risk-benefit profile, guide therapeutic evaluation, and maximize translational impact.
Tau phosphorylated at threonine 217 (p-tau217) has moved from research novelty to clinical reality, but its greatest value lies in dynamic monitoring, not static stratification. The pace of adoption of the plasma measurement of p-tau217 now demands clear guidance on optimal use. Two complementary evidence strands inform this perspective. First, a multi-cohort evaluation of a commercial assay shows high concordance with amyloid and tau reference standards and supports a pragmatic three-zone interpretation, rule-out, indeterminate, and rule-in, that can streamline diagnostic pathways while preserving accuracy. Second, longitudinal analyses in amyloid-positive individuals reveal that the most informative property of p-tau217 is dynamic: steeper rises occur in those who decline faster, whereas baseline values substantially overlap across outcome groups. These findings show that plasma p-tau217 levels can be a complementary tool for triage, enrichment, and longitudinal monitoring, but not as a time-stable baseline stratifier for defining trial cohorts or assessing therapeutic efficacy. Stratification should instead anchor to independent, stable measures such as tau burden measured by positron emission tomography (PET), structural magnetic resonance imaging (MRI), and cognitive history, reducing misclassification and avoiding circular validation. Comparable scrutiny should be applied to other p-tau biomarkers and to composite measures, such as the p-tau217/Aβ1–42 ratio, to rigorously define their risk-benefit profile, guide therapeutic evaluation, and maximize translational impact.
DOI: https://doi.org/10.37349/ent.2025.1004118
Healthcare professionals, especially those in rehabilitation, are increasingly vulnerable to occupational burnout, particularly in the post-pandemic landscape. This review synthesizes existing literature on the prevalence of burnout, possible contributing factors, resilience mechanisms, and interventions tailored to physiotherapists and related disciplines. A narrative review was carried out by combing through databases including PubMed, Scopus, and Web of Science for literature published between 2020 and 2025. The studies focused on burnout, mental health, and resilience among rehabilitation professionals were included in the review. Burnout remains prevalent, with emotional exhaustion and reduced personal growth commonly reported. Risk factors include lack of support, excessive workload, and exposure to workplace bullying. Protective mechanisms entail individual resilience behaviors, social support, and institutional strategies such as regulated supervision and workload management. Addressing burnout in rehabilitation settings requires a dual approach—strengthening individual factors and directing systemic organizational reforms. Embedding resilience education into the training core curriculum and workplace code of conduct may boost mental well-being.
Healthcare professionals, especially those in rehabilitation, are increasingly vulnerable to occupational burnout, particularly in the post-pandemic landscape. This review synthesizes existing literature on the prevalence of burnout, possible contributing factors, resilience mechanisms, and interventions tailored to physiotherapists and related disciplines. A narrative review was carried out by combing through databases including PubMed, Scopus, and Web of Science for literature published between 2020 and 2025. The studies focused on burnout, mental health, and resilience among rehabilitation professionals were included in the review. Burnout remains prevalent, with emotional exhaustion and reduced personal growth commonly reported. Risk factors include lack of support, excessive workload, and exposure to workplace bullying. Protective mechanisms entail individual resilience behaviors, social support, and institutional strategies such as regulated supervision and workload management. Addressing burnout in rehabilitation settings requires a dual approach—strengthening individual factors and directing systemic organizational reforms. Embedding resilience education into the training core curriculum and workplace code of conduct may boost mental well-being.
DOI: https://doi.org/10.37349/ent.2025.1004117
Aim:
Post-exertional malaise (PEM) has been a challenging construct to measure, particularly with self-report instruments, which have the benefits of being less expensive and less invasive than cardiopulmonary exercise tests. Existing PEM questionnaires have often been used for diagnostic purposes and less frequently as outcome measures. Few self-report PEM measures address comprehensive PEM domains, including types of triggers, duration of symptoms, delayed symptom onset, number of symptoms, frequency and severity of symptoms, as well as whether pacing or other strategies reduce or eliminate PEM. Without characterizing these features, salient aspects of PEM would be overlooked. However, efforts to assess all these domains can be time-consuming and potentially burdensome.
Methods:
The current study offers investigators a brief but comprehensive instrument of critical PEM domains, called the DePaul Symptom Questionnaire (DSQ)-PEM-2, to assess PEM. Validation data were derived from a large sample of individuals with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).
Results:
The DSQ-PEM-2 was developed using an existing dataset of individuals with ME, CFS, or both ME and CFS, allowing comprehensive coverage of key PEM domains.
Conclusions:
The DSQ-PEM-2 can be used either for diagnostic purposes or as an outcome measure. The instrument’s time frames for symptom manifestation can be adapted to suit a variety of research or clinical contexts. Future validation studies need to include a healthy control group.
Aim:
Post-exertional malaise (PEM) has been a challenging construct to measure, particularly with self-report instruments, which have the benefits of being less expensive and less invasive than cardiopulmonary exercise tests. Existing PEM questionnaires have often been used for diagnostic purposes and less frequently as outcome measures. Few self-report PEM measures address comprehensive PEM domains, including types of triggers, duration of symptoms, delayed symptom onset, number of symptoms, frequency and severity of symptoms, as well as whether pacing or other strategies reduce or eliminate PEM. Without characterizing these features, salient aspects of PEM would be overlooked. However, efforts to assess all these domains can be time-consuming and potentially burdensome.
Methods:
The current study offers investigators a brief but comprehensive instrument of critical PEM domains, called the DePaul Symptom Questionnaire (DSQ)-PEM-2, to assess PEM. Validation data were derived from a large sample of individuals with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).
Results:
The DSQ-PEM-2 was developed using an existing dataset of individuals with ME, CFS, or both ME and CFS, allowing comprehensive coverage of key PEM domains.
Conclusions:
The DSQ-PEM-2 can be used either for diagnostic purposes or as an outcome measure. The instrument’s time frames for symptom manifestation can be adapted to suit a variety of research or clinical contexts. Future validation studies need to include a healthy control group.
DOI: https://doi.org/10.37349/ent.2025.1004116
Exercise may be one of the most potent tools for protecting the brain—but only through active participation can its benefits be realized. This perspective provides a brief overview of current research avenues and key insights into the role of physical activity and exercise in preventing and mitigating chronic and neurodegenerative diseases and promoting optimal health across the population. The perspective opens with a summary of key findings on how exercise supports brain health and cognitive well-being. It then draws on rodent model studies which shed light on the molecular mechanisms behind these benefits. The paper addresses challenges in translating this research into effective, real-world exercise programs and introduces a new framework aimed at fostering global, inclusive initiatives. This transformative approach is designed to reach individuals across all ages, backgrounds, and health statuses. A central theme throughout is the critical role of psychological factors in exercise adherence—highlighting the need to tackle these barriers if scientific advances are to translate into meaningful benefits for diverse populations.
Exercise may be one of the most potent tools for protecting the brain—but only through active participation can its benefits be realized. This perspective provides a brief overview of current research avenues and key insights into the role of physical activity and exercise in preventing and mitigating chronic and neurodegenerative diseases and promoting optimal health across the population. The perspective opens with a summary of key findings on how exercise supports brain health and cognitive well-being. It then draws on rodent model studies which shed light on the molecular mechanisms behind these benefits. The paper addresses challenges in translating this research into effective, real-world exercise programs and introduces a new framework aimed at fostering global, inclusive initiatives. This transformative approach is designed to reach individuals across all ages, backgrounds, and health statuses. A central theme throughout is the critical role of psychological factors in exercise adherence—highlighting the need to tackle these barriers if scientific advances are to translate into meaningful benefits for diverse populations.
DOI: https://doi.org/10.37349/ent.2025.1004115
This article belongs to the special issue Empower Yourself - Physical Activity as Prevention and Rehabilitation of Neurological and Psychiatric Diseases
Aim:
Pain and overuse syndromes are common problems among musicians. The prevalence of musculoskeletal complaints in professional musicians ranges from 62% to 93%. Excessive muscle tension, rigidity, weakness, and stiffness in various anatomical regions such as the arm, neck, and lower back are common complaints. This study investigates the prevalence and severity of musculoskeletal symptoms, such as the amount and distribution of pain in the cranio-cervical-mandibular complex, the presence of bruxism and temporomandibular noises in conservatory clarinet students.
Methods:
A 36-item questionnaire regarding the presence of musculoskeletal symptoms was sent to all clarinet students at Italian conservatories.
Results:
From the analysis of the responses of 100 students, the occurrence of pain was not related to experience and was higher during non-musical activities (70%) than during performance (38%) (P = 0.001). Female players reported higher levels of pain using a 0–10 numeric rating scale: 4 during performance, 5 during non-musical activities, while males scored 3 in both conditions. A slight positive correlation emerged between pain and years of study (P = 0.03). The most painful regions were those of the posterior neck (29–45%) and the masseter muscle (28–31%). Temporomandibular noises were prevalent in female students (female 43%, male 22%, P = 0.005) and were often associated with bruxism (P = 0.015).
Conclusions:
Clarinet students should be informed about the symptoms they may experience, but also about the prevention of these symptoms and the techniques to improve clarinet performance.
Aim:
Pain and overuse syndromes are common problems among musicians. The prevalence of musculoskeletal complaints in professional musicians ranges from 62% to 93%. Excessive muscle tension, rigidity, weakness, and stiffness in various anatomical regions such as the arm, neck, and lower back are common complaints. This study investigates the prevalence and severity of musculoskeletal symptoms, such as the amount and distribution of pain in the cranio-cervical-mandibular complex, the presence of bruxism and temporomandibular noises in conservatory clarinet students.
Methods:
A 36-item questionnaire regarding the presence of musculoskeletal symptoms was sent to all clarinet students at Italian conservatories.
Results:
From the analysis of the responses of 100 students, the occurrence of pain was not related to experience and was higher during non-musical activities (70%) than during performance (38%) (P = 0.001). Female players reported higher levels of pain using a 0–10 numeric rating scale: 4 during performance, 5 during non-musical activities, while males scored 3 in both conditions. A slight positive correlation emerged between pain and years of study (P = 0.03). The most painful regions were those of the posterior neck (29–45%) and the masseter muscle (28–31%). Temporomandibular noises were prevalent in female students (female 43%, male 22%, P = 0.005) and were often associated with bruxism (P = 0.015).
Conclusions:
Clarinet students should be informed about the symptoms they may experience, but also about the prevention of these symptoms and the techniques to improve clarinet performance.
DOI: https://doi.org/10.37349/ent.2025.1004114
Aim:
Epilepsy is associated with cognitive and neuropsychiatric impairments, affecting attention, memory, executive functions, and emotional well-being. While these impairments are well-documented in general epilepsy populations, limited research focuses on economically active young adults who face unique cognitive demands in competitive academic and professional environments. The objective of this research was to evaluate the cognitive and neuropsychiatric outcomes in economically active young adults with epilepsy compared to matched controls.
Methods:
An observational, analytical, case-control study was conducted at a secondary medical center in Mexico. Participants included 25 patients with well-controlled epilepsy and 25 matched controls. Cognitive function was assessed using the Montreal Cognitive Assessment (MoCA) and Addenbrooke’s Cognitive Examination III (ACE-III). Anxiety and depression were evaluated using the Beck Anxiety Inventory and Patient Health Questionnaire-9 (PHQ-9). Statistical analysis included Student’s T-test and Chi-square for cognitive scores and Wilcoxon rank-sum tests for non-parametric data.
Results:
Cognitive impairments were significantly more frequent in patients with epilepsy than in controls, particularly in attention (p = 0.041), episodic memory (p = 0.048), clock drawing (p = 0.004), and cube copying (p < 0.001). Verbal (p = 0.011) and semantic fluency (p = 0.027) were also affected. No significant differences were observed in anxiety (p = 0.221) or depression (p = 0.800) between groups.
Conclusions:
Economically active young adults with well-controlled epilepsy showed significant cognitive impairments, particularly in attention, memory, visuospatial, and executive functions, independent of anxiety and depression levels. This study underscores the need for comprehensive cognitive and neuropsychiatric evaluations in epilepsy treatment, regardless of seizure control. It advocates for targeted cognitive rehabilitation and a holistic approach to epilepsy care beyond seizure frequency control.
Aim:
Epilepsy is associated with cognitive and neuropsychiatric impairments, affecting attention, memory, executive functions, and emotional well-being. While these impairments are well-documented in general epilepsy populations, limited research focuses on economically active young adults who face unique cognitive demands in competitive academic and professional environments. The objective of this research was to evaluate the cognitive and neuropsychiatric outcomes in economically active young adults with epilepsy compared to matched controls.
Methods:
An observational, analytical, case-control study was conducted at a secondary medical center in Mexico. Participants included 25 patients with well-controlled epilepsy and 25 matched controls. Cognitive function was assessed using the Montreal Cognitive Assessment (MoCA) and Addenbrooke’s Cognitive Examination III (ACE-III). Anxiety and depression were evaluated using the Beck Anxiety Inventory and Patient Health Questionnaire-9 (PHQ-9). Statistical analysis included Student’s T-test and Chi-square for cognitive scores and Wilcoxon rank-sum tests for non-parametric data.
Results:
Cognitive impairments were significantly more frequent in patients with epilepsy than in controls, particularly in attention (p = 0.041), episodic memory (p = 0.048), clock drawing (p = 0.004), and cube copying (p < 0.001). Verbal (p = 0.011) and semantic fluency (p = 0.027) were also affected. No significant differences were observed in anxiety (p = 0.221) or depression (p = 0.800) between groups.
Conclusions:
Economically active young adults with well-controlled epilepsy showed significant cognitive impairments, particularly in attention, memory, visuospatial, and executive functions, independent of anxiety and depression levels. This study underscores the need for comprehensive cognitive and neuropsychiatric evaluations in epilepsy treatment, regardless of seizure control. It advocates for targeted cognitive rehabilitation and a holistic approach to epilepsy care beyond seizure frequency control.
DOI: https://doi.org/10.37349/ent.2025.1004113
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating multisystem disorder affecting an estimated 0.4% to 2.5% of community populations. Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and marked metabolic heterogeneity underscore its complex pathophysiology. The hypothalamic peptides hypocretin-1 and -2 (also known as orexin-A and orexin-B), synthesized by neurons in the lateral hypothalamus, regulate sleep-wake cycles, arousal, autonomic function, and energy homeostasis. This integrative review aimed to synthesize current evidence on hypothalamic orexinergic dysfunction in ME/CFS and assess its potential as a biomarker framework for stratification in precision medicine. The review followed Whittemore and Knafl’s five-stage methodology. Comprehensive searches were conducted across PubMed, Scopus, Web of Science, and OpenAlex up to April 2025, supplemented by manual screening of reference lists. Data extraction and synthesis were performed using constant comparison techniques to integrate quantitative outcomes with theoretical insights. Twenty-seven studies met the inclusion criteria, consistently reporting reduced orexin-A levels in individuals with ME/CFS and variable orexin-B responses indicative of biomarker potential. Neuroendocrine findings, including alterations in cortisol and adrenocorticotropic hormone levels, along with inflammatory profiles, confirmed the involvement of neuroimmune interactions. Multi-omics analyses further delineated distinct patient subtypes characterized by unique molecular signatures. Hypothalamic orexinergic dysfunction emerges as a central feature of ME/CFS, with orexin-B representing a promising candidate biomarker. The integration of orexin profiling with multi-omics data and machine learning strategies provides a viable pathway towards precision-medicine interventions for this heterogeneous condition.
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating multisystem disorder affecting an estimated 0.4% to 2.5% of community populations. Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and marked metabolic heterogeneity underscore its complex pathophysiology. The hypothalamic peptides hypocretin-1 and -2 (also known as orexin-A and orexin-B), synthesized by neurons in the lateral hypothalamus, regulate sleep-wake cycles, arousal, autonomic function, and energy homeostasis. This integrative review aimed to synthesize current evidence on hypothalamic orexinergic dysfunction in ME/CFS and assess its potential as a biomarker framework for stratification in precision medicine. The review followed Whittemore and Knafl’s five-stage methodology. Comprehensive searches were conducted across PubMed, Scopus, Web of Science, and OpenAlex up to April 2025, supplemented by manual screening of reference lists. Data extraction and synthesis were performed using constant comparison techniques to integrate quantitative outcomes with theoretical insights. Twenty-seven studies met the inclusion criteria, consistently reporting reduced orexin-A levels in individuals with ME/CFS and variable orexin-B responses indicative of biomarker potential. Neuroendocrine findings, including alterations in cortisol and adrenocorticotropic hormone levels, along with inflammatory profiles, confirmed the involvement of neuroimmune interactions. Multi-omics analyses further delineated distinct patient subtypes characterized by unique molecular signatures. Hypothalamic orexinergic dysfunction emerges as a central feature of ME/CFS, with orexin-B representing a promising candidate biomarker. The integration of orexin profiling with multi-omics data and machine learning strategies provides a viable pathway towards precision-medicine interventions for this heterogeneous condition.
DOI: https://doi.org/10.37349/ent.2025.1004112
MicroRNAs (miRNAs) are small, non-coding RNA molecules that play a pivotal role in post-transcriptional gene regulation, influencing various biological processes such as cell division, proliferation, and apoptosis. Recent research has illuminated the significant involvement of miRNAs in neurological disorders, which encompass a wide range of conditions affecting both the central and peripheral nervous systems. These disorders, including neurodegenerative diseases like Alzheimer’s and Parkinson’s, as well as psychiatric conditions such as depression and schizophrenia, impose a substantial burden on global health. Dysregulated miRNAs contribute to disease pathogenesis by modulating neuronal differentiation and related signaling cascades. This review explores the biogenesis of miRNAs and their dysregulation in neurological disorders, highlighting specific miRNAs that serve as potential biomarkers and therapeutic targets. For instance, decreased levels of miR-125b-5p and miR-26b-5p in cerebrospinal fluid have been associated with Alzheimer’s disease progression. In Parkinson’s disease, distinct profiles of dysregulated miRNAs have been identified, including miR-7-5p and miR-153-3p, which target α-synuclein. Furthermore, studies have demonstrated the potential of miRNA-based therapies to modulate disease processes and improve clinical outcomes. This review critically evaluates current therapeutic strategies for miRNA delivery in neurological disorders, focusing on advanced platforms such as nanocarriers, exosomes, viral vectors, and ligand-mediated systems designed to overcome the blood-brain barrier. We also explore the future of miRNA research in the context of precision medicine, highlighting the importance of targeted delivery, safety optimization, and integration of patient-specific molecular profiles. A comprehensive understanding of miRNA-regulated networks will be essential for developing innovative diagnostics and personalized treatments for neurodegenerative and neuroinflammatory diseases.
MicroRNAs (miRNAs) are small, non-coding RNA molecules that play a pivotal role in post-transcriptional gene regulation, influencing various biological processes such as cell division, proliferation, and apoptosis. Recent research has illuminated the significant involvement of miRNAs in neurological disorders, which encompass a wide range of conditions affecting both the central and peripheral nervous systems. These disorders, including neurodegenerative diseases like Alzheimer’s and Parkinson’s, as well as psychiatric conditions such as depression and schizophrenia, impose a substantial burden on global health. Dysregulated miRNAs contribute to disease pathogenesis by modulating neuronal differentiation and related signaling cascades. This review explores the biogenesis of miRNAs and their dysregulation in neurological disorders, highlighting specific miRNAs that serve as potential biomarkers and therapeutic targets. For instance, decreased levels of miR-125b-5p and miR-26b-5p in cerebrospinal fluid have been associated with Alzheimer’s disease progression. In Parkinson’s disease, distinct profiles of dysregulated miRNAs have been identified, including miR-7-5p and miR-153-3p, which target α-synuclein. Furthermore, studies have demonstrated the potential of miRNA-based therapies to modulate disease processes and improve clinical outcomes. This review critically evaluates current therapeutic strategies for miRNA delivery in neurological disorders, focusing on advanced platforms such as nanocarriers, exosomes, viral vectors, and ligand-mediated systems designed to overcome the blood-brain barrier. We also explore the future of miRNA research in the context of precision medicine, highlighting the importance of targeted delivery, safety optimization, and integration of patient-specific molecular profiles. A comprehensive understanding of miRNA-regulated networks will be essential for developing innovative diagnostics and personalized treatments for neurodegenerative and neuroinflammatory diseases.
DOI: https://doi.org/10.37349/ent.2025.1004111
Aim:
Our previous research (Abstract, J Vessels Circ. 2021;2) suggested an increased risk of thrombotic events, including ischemic strokes, in patients with COVID-19. This study aims to determine the mortality rate and its predictors in patients with stroke and concurrent COVID-19 infection.
Methods:
A retrospective analysis was conducted on stroke patients admitted to three Iranian referral hospitals within a 3-month period during the COVID-19 pandemic (COV-pos and COV-neg groups). The mortality rate was compared to a similar period one year before the pandemic (non-COV group). The Cox proportional hazards model was used to assess the independent and interactive effects of various variables on mortality.
Results:
Among 124 stroke admissions, 59 (47.6%) had confirmed COVID-19 infection. The COV-pos group had a significantly higher initial NIHSS score (P = 0.001) compared to other groups. Mortality rates were 49.2%, 24.2%, and 17.3% in the COV-pos, COV-neg, and non-COV groups, respectively (P < 0.001). Posterior cerebral artery (PCA) stroke (HR = 65.099), internal carotid artery (ICA) stroke (HR = 19.102), and a history of diabetes mellitus (HR = 3.824) were identified as the most significant predictors of mortality in patients with stroke and COVID-19 infection.
Conclusions:
Stroke patients with COVID-19 infection exhibited a significantly higher mortality rate compared to patients without COVID-19. The type of stroke involving the PCA or ICA and a history of diabetes emerged as the strongest predictors of mortality in the studied population.
Aim:
Our previous research (Abstract, J Vessels Circ. 2021;2) suggested an increased risk of thrombotic events, including ischemic strokes, in patients with COVID-19. This study aims to determine the mortality rate and its predictors in patients with stroke and concurrent COVID-19 infection.
Methods:
A retrospective analysis was conducted on stroke patients admitted to three Iranian referral hospitals within a 3-month period during the COVID-19 pandemic (COV-pos and COV-neg groups). The mortality rate was compared to a similar period one year before the pandemic (non-COV group). The Cox proportional hazards model was used to assess the independent and interactive effects of various variables on mortality.
Results:
Among 124 stroke admissions, 59 (47.6%) had confirmed COVID-19 infection. The COV-pos group had a significantly higher initial NIHSS score (P = 0.001) compared to other groups. Mortality rates were 49.2%, 24.2%, and 17.3% in the COV-pos, COV-neg, and non-COV groups, respectively (P < 0.001). Posterior cerebral artery (PCA) stroke (HR = 65.099), internal carotid artery (ICA) stroke (HR = 19.102), and a history of diabetes mellitus (HR = 3.824) were identified as the most significant predictors of mortality in patients with stroke and COVID-19 infection.
Conclusions:
Stroke patients with COVID-19 infection exhibited a significantly higher mortality rate compared to patients without COVID-19. The type of stroke involving the PCA or ICA and a history of diabetes emerged as the strongest predictors of mortality in the studied population.
DOI: https://doi.org/10.37349/ent.2025.1004109
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.
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.
DOI: https://doi.org/10.37349/ent.2025.1004110
This article belongs to the special issue Advances in the Pathogenesis, Diagnosis and Treatment of Attention Deficit Hyperactivity Disorder
Aim:
Aging and early Alzheimer’s disease (AD) affect pattern separation (PS) based mnemonic discrimination in humans. PS function involves the dentate gyrus (DG), a brain region producing new neurons during adulthood. Aging and AD presumably affect PS and DG function through different mechanisms, although it has never been clearly shown within the same study. Passive immunotherapy targeting β-amyloid peptides (Aβ) was used to determine the relative contribution of abnormal levels of Aβ to early PS deficits in two mouse models of aging and amyloid pathology, and potential involvement of adult neurogenesis.
Methods:
Female Tg2576 mice were tested in a spatial PS task from the age of three months to determine the age of onset of PS deficits. A cohort of five-month-old female Tg2576 mice and a cohort of 20-month-old male C57BL/6J mice were treated with passive immunization for four weeks, and then tested for PS performance. ELISA assays were used to quantify Aβ levels in CA3/DG regions of these mouse models. DG recruitment during PS testing was assessed with an Egr-1 ex vivo imagery. The contribution of adult-born neurons to a potential rescue of PS performances was evaluated using bromodeoxyuridine and doublecortin co-immunostainings.
Results:
Spatial PS deficits appeared first in four-month-old female Tg2576 mice, an early pre-plaque stage of Alzheimer pathology. Aβ immunotherapy restored PS performance in Tg2576 mice, but not in aged male C57BL/6J mice. PS impairments were associated with an overactivation of the DG in both models and a potentially abnormal level of immature adult-born neurons in Tg2576 mice.
Conclusions:
Alleviation of PS deficits following Aβ immunotherapy in Tg2576 mice is associated with reduced DG activation and improved adult-born neurons maturation. The absence of beneficial effects in aged mice suggests that PS deficits in aging and AD may be related to different underlying mechanisms.
Aim:
Aging and early Alzheimer’s disease (AD) affect pattern separation (PS) based mnemonic discrimination in humans. PS function involves the dentate gyrus (DG), a brain region producing new neurons during adulthood. Aging and AD presumably affect PS and DG function through different mechanisms, although it has never been clearly shown within the same study. Passive immunotherapy targeting β-amyloid peptides (Aβ) was used to determine the relative contribution of abnormal levels of Aβ to early PS deficits in two mouse models of aging and amyloid pathology, and potential involvement of adult neurogenesis.
Methods:
Female Tg2576 mice were tested in a spatial PS task from the age of three months to determine the age of onset of PS deficits. A cohort of five-month-old female Tg2576 mice and a cohort of 20-month-old male C57BL/6J mice were treated with passive immunization for four weeks, and then tested for PS performance. ELISA assays were used to quantify Aβ levels in CA3/DG regions of these mouse models. DG recruitment during PS testing was assessed with an Egr-1 ex vivo imagery. The contribution of adult-born neurons to a potential rescue of PS performances was evaluated using bromodeoxyuridine and doublecortin co-immunostainings.
Results:
Spatial PS deficits appeared first in four-month-old female Tg2576 mice, an early pre-plaque stage of Alzheimer pathology. Aβ immunotherapy restored PS performance in Tg2576 mice, but not in aged male C57BL/6J mice. PS impairments were associated with an overactivation of the DG in both models and a potentially abnormal level of immature adult-born neurons in Tg2576 mice.
Conclusions:
Alleviation of PS deficits following Aβ immunotherapy in Tg2576 mice is associated with reduced DG activation and improved adult-born neurons maturation. The absence of beneficial effects in aged mice suggests that PS deficits in aging and AD may be related to different underlying mechanisms.
DOI: https://doi.org/10.37349/ent.2025.1004108
Polyunsaturated fatty acids (PUFAs) are critical for human health, serving as key components of cellular membranes and regulators of various physiological functions. Since the body can endogenously synthesize only a small amount of these fatty acids from precursors, adequate dietary intake is essential. This article discusses the vital role of omega-3 fatty acids, particularly docosahexaenoic acid (DHA), in fetal brain development, with maternal omega-3 intake during pregnancy linked to improved neurodevelopment and long-term cognitive outcomes. However, variability in study findings highlights the need for further research to clarify DHA’s mechanisms of action. This article explores recent findings indicating that insufficient omega-3 levels during pregnancy disrupt key neurodevelopmental processes, particularly microglial function, potentially elevating the risk of cognitive impairments and neurodevelopmental disorders, highlighting the need for further research to confirm these effects and elucidate underlying mechanisms and long-term consequences. Ensuring adequate maternal omega-3 intake is vital for supporting healthy brain development and reducing these risks. Additionally, DHA and eicosapentaenoic acid (EPA) show promise in treating pediatric depression by modulating the gut-brain axis, reducing neuroinflammation, and restoring autonomic nervous system function—mechanisms implicated in depression. While omega-3 supplementation holds potential as an adjunctive treatment for pediatric major depressive disorder (MDD), further research is necessary to refine dosing strategies and explore underlying mechanisms, ultimately advancing neuropsychiatric care.
Polyunsaturated fatty acids (PUFAs) are critical for human health, serving as key components of cellular membranes and regulators of various physiological functions. Since the body can endogenously synthesize only a small amount of these fatty acids from precursors, adequate dietary intake is essential. This article discusses the vital role of omega-3 fatty acids, particularly docosahexaenoic acid (DHA), in fetal brain development, with maternal omega-3 intake during pregnancy linked to improved neurodevelopment and long-term cognitive outcomes. However, variability in study findings highlights the need for further research to clarify DHA’s mechanisms of action. This article explores recent findings indicating that insufficient omega-3 levels during pregnancy disrupt key neurodevelopmental processes, particularly microglial function, potentially elevating the risk of cognitive impairments and neurodevelopmental disorders, highlighting the need for further research to confirm these effects and elucidate underlying mechanisms and long-term consequences. Ensuring adequate maternal omega-3 intake is vital for supporting healthy brain development and reducing these risks. Additionally, DHA and eicosapentaenoic acid (EPA) show promise in treating pediatric depression by modulating the gut-brain axis, reducing neuroinflammation, and restoring autonomic nervous system function—mechanisms implicated in depression. While omega-3 supplementation holds potential as an adjunctive treatment for pediatric major depressive disorder (MDD), further research is necessary to refine dosing strategies and explore underlying mechanisms, ultimately advancing neuropsychiatric care.
DOI: https://doi.org/10.37349/ent.2025.1004107
Background:
High-intensity training (HIT) increases walking speed for individuals with chronic stroke. Several recent studies have examined its application for those in the subacute phase following a stroke. This systematic review examines the application of HIT in the subacute phase following a stroke.
Methods:
A systematic search for studies that compared HIT (defined as 60–84% heart rate reserve or 77–93% heart rate maximum) to lower-intensity training, conventional physical therapy, placebo, or no intervention in adults 0–6 months post stroke. Randomized or quasi-randomized controlled trials, cohort studies, and case-controlled studies published in peer-reviewed journals in English were included. The primary outcome of interest was walking speed; the secondary outcome was walking endurance. Two independent evaluators performed literature selection, data extraction, and assessed study quality using the revised Cochrane risk-of-bias tool. Reporting followed PRISMA guidelines.
Results:
Of 1,642 studies initially retrieved, 10 studies with a total of 677 participants were included. All experimental groups showed an average positive change in self-selected walking speed (range: 0.20–0.56 m/s). HIT resulted in statistically significant improvements in walking speed versus comparison interventions in 4 studies. Eight studies that measured walking endurance found an average increase of 60 to 197 m following HIT.
Discussion:
HIT demonstrated superior outcomes in self-selected walking speed and walking endurance for individuals in the subacute phase post stroke, both immediately following intervention and at follow-up. These findings align with the clinical practice guideline (CPG) for chronic stroke patients. Further randomized clinical trials are needed to strengthen the evidence.
Background:
High-intensity training (HIT) increases walking speed for individuals with chronic stroke. Several recent studies have examined its application for those in the subacute phase following a stroke. This systematic review examines the application of HIT in the subacute phase following a stroke.
Methods:
A systematic search for studies that compared HIT (defined as 60–84% heart rate reserve or 77–93% heart rate maximum) to lower-intensity training, conventional physical therapy, placebo, or no intervention in adults 0–6 months post stroke. Randomized or quasi-randomized controlled trials, cohort studies, and case-controlled studies published in peer-reviewed journals in English were included. The primary outcome of interest was walking speed; the secondary outcome was walking endurance. Two independent evaluators performed literature selection, data extraction, and assessed study quality using the revised Cochrane risk-of-bias tool. Reporting followed PRISMA guidelines.
Results:
Of 1,642 studies initially retrieved, 10 studies with a total of 677 participants were included. All experimental groups showed an average positive change in self-selected walking speed (range: 0.20–0.56 m/s). HIT resulted in statistically significant improvements in walking speed versus comparison interventions in 4 studies. Eight studies that measured walking endurance found an average increase of 60 to 197 m following HIT.
Discussion:
HIT demonstrated superior outcomes in self-selected walking speed and walking endurance for individuals in the subacute phase post stroke, both immediately following intervention and at follow-up. These findings align with the clinical practice guideline (CPG) for chronic stroke patients. Further randomized clinical trials are needed to strengthen the evidence.
DOI: https://doi.org/10.37349/ent.2025.1004106
Neuroinflammation is a hallmark of various neurodegenerative and neuropsychiatric disorders, driven by complex interactions between neurotransmitter receptors and immune signaling pathways. Among these, heteroreceptor complexes—functional assemblies formed by the physical interaction of different G protein-coupled or ionotropic receptor subtypes within the same membrane microdomain—play a crucial role in modulating synaptic activity, neuroimmune responses, and inflammatory cascades. For example, the A2A-D2 receptor complex modulates dopaminergic signaling in the striatum and has been implicated in Parkinson’s disease pathology. These receptor-receptor interactions influence key signaling pathways involving dopamine, serotonin, glutamate, adenosine, and cannabinoid systems, thereby contributing to the pathophysiology of Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, schizophrenia, and depression. Dysregulation of heteroreceptor complexes disrupts neuronal homeostasis, exacerbates neuroinflammatory responses, and influences microglial and astrocytic activation. Understanding the molecular mechanisms governing these interactions, including allosteric modulation and biased agonism, offers novel therapeutic avenues for targeting neuroinflammation. Pharmacological strategies, such as selective allosteric modulators, biased agonists, and receptor-specific ligands, aim to restore heteroreceptor function and mitigate neuroinflammatory damage. Emerging clinical trials—such as those evaluating A2A receptor antagonists like istradefylline for Parkinson’s disease and 5-HT2A antagonists for schizophrenia—have shown promising neuroprotective and anti-inflammatory effects, although larger-scale, long-term studies are needed to confirm efficacy. This review highlights the pivotal role of heteroreceptor complexes in neuroinflammation, discusses their therapeutic potential, and underscores the need for further research into their functional dynamics to develop effective interventions for neurodegenerative and neuropsychiatric diseases.
Neuroinflammation is a hallmark of various neurodegenerative and neuropsychiatric disorders, driven by complex interactions between neurotransmitter receptors and immune signaling pathways. Among these, heteroreceptor complexes—functional assemblies formed by the physical interaction of different G protein-coupled or ionotropic receptor subtypes within the same membrane microdomain—play a crucial role in modulating synaptic activity, neuroimmune responses, and inflammatory cascades. For example, the A2A-D2 receptor complex modulates dopaminergic signaling in the striatum and has been implicated in Parkinson’s disease pathology. These receptor-receptor interactions influence key signaling pathways involving dopamine, serotonin, glutamate, adenosine, and cannabinoid systems, thereby contributing to the pathophysiology of Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, schizophrenia, and depression. Dysregulation of heteroreceptor complexes disrupts neuronal homeostasis, exacerbates neuroinflammatory responses, and influences microglial and astrocytic activation. Understanding the molecular mechanisms governing these interactions, including allosteric modulation and biased agonism, offers novel therapeutic avenues for targeting neuroinflammation. Pharmacological strategies, such as selective allosteric modulators, biased agonists, and receptor-specific ligands, aim to restore heteroreceptor function and mitigate neuroinflammatory damage. Emerging clinical trials—such as those evaluating A2A receptor antagonists like istradefylline for Parkinson’s disease and 5-HT2A antagonists for schizophrenia—have shown promising neuroprotective and anti-inflammatory effects, although larger-scale, long-term studies are needed to confirm efficacy. This review highlights the pivotal role of heteroreceptor complexes in neuroinflammation, discusses their therapeutic potential, and underscores the need for further research into their functional dynamics to develop effective interventions for neurodegenerative and neuropsychiatric diseases.
DOI: https://doi.org/10.37349/ent.2025.1004105
This article belongs to the special issue GPCR Heteroreceptor Complexes as Key Players in Neuroprotection
Neurodegenerative diseases represent a significant and growing challenge to public health worldwide. Current therapeutic strategies often fall short in halting or reversing disease progression, highlighting the urgent need for novel approaches. Extracellular vesicles (EVs) have garnered attention as potential therapeutic agents due to their role in intercellular communication and their ability to transport bioactive cargo, including proteins, nucleic acids, and lipids. This review provides a comprehensive overview of the biology of EVs, their involvement in neurodegenerative diseases, and the potential for EV-based therapies. We discuss the different types of EVs, their biogenesis, and their cargo composition, emphasizing their relevance to neurological processes such as protein misfolding, neuroinflammation, and oxidative stress. Preclinical studies investigating EVs as carriers of therapeutic cargo and their ability to promote neuronal survival and regeneration are examined, with a focus on evidence from animal models of neurodegenerative disorders. We explore the use of EVs in the treatment of neurodegenerative diseases, including ongoing clinical trials, methods for EV isolation and modification, and future perspectives on personalized EV-based therapies designed to meet the unique needs of individual patients. Overall, this review highlights the potential of EVs as a promising avenue for neurodegenerative disease therapy, while also addressing key research gaps and translational hurdles that need to be overcome for their successful clinical implementation.
Neurodegenerative diseases represent a significant and growing challenge to public health worldwide. Current therapeutic strategies often fall short in halting or reversing disease progression, highlighting the urgent need for novel approaches. Extracellular vesicles (EVs) have garnered attention as potential therapeutic agents due to their role in intercellular communication and their ability to transport bioactive cargo, including proteins, nucleic acids, and lipids. This review provides a comprehensive overview of the biology of EVs, their involvement in neurodegenerative diseases, and the potential for EV-based therapies. We discuss the different types of EVs, their biogenesis, and their cargo composition, emphasizing their relevance to neurological processes such as protein misfolding, neuroinflammation, and oxidative stress. Preclinical studies investigating EVs as carriers of therapeutic cargo and their ability to promote neuronal survival and regeneration are examined, with a focus on evidence from animal models of neurodegenerative disorders. We explore the use of EVs in the treatment of neurodegenerative diseases, including ongoing clinical trials, methods for EV isolation and modification, and future perspectives on personalized EV-based therapies designed to meet the unique needs of individual patients. Overall, this review highlights the potential of EVs as a promising avenue for neurodegenerative disease therapy, while also addressing key research gaps and translational hurdles that need to be overcome for their successful clinical implementation.
DOI: https://doi.org/10.37349/ent.2025.1004104
This article belongs to the special issue Breakthroughs in Mechanisms and Treatments for Neurodegenerative Diseases
The diagnosis of attention deficit hyperactivity disorder (ADHD) poses several diagnostic problems, as is widely acknowledged. The name points to two symptoms only, which are unspecific and embedded in many more neuropsychological symptoms. The additional deficits, such as problems with orientation, memory, cognition, emotion, autonomic nervous regulation, and motor dysfunctions, can be more important for patients in their daily lives than attention and hyperactivity. The general term “neurodevelopmental disorder (6A0)” in the International Classification of Diseases (ICD-11) is more appropriate and should be used instead. A further question is, when a dysfunction, such as inattention, becomes a clinical sign. As outlined in the International Classification of Functioning, Disability and Health (ICF), the context and the associated impairment decide on the clinical relevance of dysfunctions. Accordingly, the diagnosis of neurodevelopmental disorders must start with the description of context requirements, then assess capacity restrictions, and finally relate these to neuropsychological deficits. Subdimensions of neurodevelopmental disorders, as listed in ICD-11, are of no additional benefit, as they are comorbid merging syndromes.
The diagnosis of attention deficit hyperactivity disorder (ADHD) poses several diagnostic problems, as is widely acknowledged. The name points to two symptoms only, which are unspecific and embedded in many more neuropsychological symptoms. The additional deficits, such as problems with orientation, memory, cognition, emotion, autonomic nervous regulation, and motor dysfunctions, can be more important for patients in their daily lives than attention and hyperactivity. The general term “neurodevelopmental disorder (6A0)” in the International Classification of Diseases (ICD-11) is more appropriate and should be used instead. A further question is, when a dysfunction, such as inattention, becomes a clinical sign. As outlined in the International Classification of Functioning, Disability and Health (ICF), the context and the associated impairment decide on the clinical relevance of dysfunctions. Accordingly, the diagnosis of neurodevelopmental disorders must start with the description of context requirements, then assess capacity restrictions, and finally relate these to neuropsychological deficits. Subdimensions of neurodevelopmental disorders, as listed in ICD-11, are of no additional benefit, as they are comorbid merging syndromes.
DOI: https://doi.org/10.37349/ent.2025.1004103
This article belongs to the special issue Advances in the Pathogenesis, Diagnosis and Treatment of Attention Deficit Hyperactivity Disorder
Chronic upper limb pain is rather common among people in general and is characterized by a complex diagnosis due to the wide variety of factors that are involved in its development. In terms of treatment, pharmacology and manual therapy have classically been the most used options. However, based on current evidence, recommendations are more inclined to apply multimodal treatments, mainly with exercise therapy and pain education, based on the patient-centered care model. This case report details the evaluation and treatment of a 23-year-old woman with chronic upper limb pain using a multimodal physical therapy with a biobehavioral approach. The intervention lasted 12 weeks with a total of 9 sessions, in which manual therapy, therapeutic exercise, pain neuroscience education, motion representation methods, and sensory retraining were applied. The treatment resulted in a substantial improvement in the patient’s health condition. This case report indicates that a multimodal physical therapy treatment based on a biobehavioral approach may offer benefits in reducing pain symptoms and enhancing somatosensory, motor-functional, and affective-cognitive abilities in patients with chronic upper limb pain, as observed in the described case. Accordingly, this treatment can be a therapeutic option for patients with chronic upper limb pain.
Chronic upper limb pain is rather common among people in general and is characterized by a complex diagnosis due to the wide variety of factors that are involved in its development. In terms of treatment, pharmacology and manual therapy have classically been the most used options. However, based on current evidence, recommendations are more inclined to apply multimodal treatments, mainly with exercise therapy and pain education, based on the patient-centered care model. This case report details the evaluation and treatment of a 23-year-old woman with chronic upper limb pain using a multimodal physical therapy with a biobehavioral approach. The intervention lasted 12 weeks with a total of 9 sessions, in which manual therapy, therapeutic exercise, pain neuroscience education, motion representation methods, and sensory retraining were applied. The treatment resulted in a substantial improvement in the patient’s health condition. This case report indicates that a multimodal physical therapy treatment based on a biobehavioral approach may offer benefits in reducing pain symptoms and enhancing somatosensory, motor-functional, and affective-cognitive abilities in patients with chronic upper limb pain, as observed in the described case. Accordingly, this treatment can be a therapeutic option for patients with chronic upper limb pain.
DOI: https://doi.org/10.37349/ent.2025.1004102
Stroke is the third leading cause of death and disability in industrialized countries. The estimated costs of stroke to the healthcare system are $85 billion in the United States and $40 billion in the European Union. Despite the extensive research over the past decades, only therapies aimed at restoring blood flow to the affected area have been successful. However, the high risk of causing intracranial hemorrhage limits the application of this type of therapy to a small number of patients. Several studies have shown that, in addition to its well-known regulatory function in erythropoiesis, erythropoietin (EPO) is a potent neuroprotective agent against ischemic stroke. However, the use of EPO to treat stroke requires long-term protocols, high doses, and multiple administrations, which may cause thromboembolic complications due to increased hematocrit and blood viscosity, making EPO treatment unsuitable. To mitigate these adverse effects, various EPO analogues with neuroprotective properties but lacking erythropoietic activity have been investigated. This review aims to provide an overview of the protective mechanisms of EPO and its derivatives in the treatment of stroke.
Stroke is the third leading cause of death and disability in industrialized countries. The estimated costs of stroke to the healthcare system are $85 billion in the United States and $40 billion in the European Union. Despite the extensive research over the past decades, only therapies aimed at restoring blood flow to the affected area have been successful. However, the high risk of causing intracranial hemorrhage limits the application of this type of therapy to a small number of patients. Several studies have shown that, in addition to its well-known regulatory function in erythropoiesis, erythropoietin (EPO) is a potent neuroprotective agent against ischemic stroke. However, the use of EPO to treat stroke requires long-term protocols, high doses, and multiple administrations, which may cause thromboembolic complications due to increased hematocrit and blood viscosity, making EPO treatment unsuitable. To mitigate these adverse effects, various EPO analogues with neuroprotective properties but lacking erythropoietic activity have been investigated. This review aims to provide an overview of the protective mechanisms of EPO and its derivatives in the treatment of stroke.
DOI: https://doi.org/10.37349/ent.2025.1004101
This article belongs to the special issue Interdisciplinary Approach to Therapeutic Strategies of Neuroprotection in Present and Future
