@article {pmid41051689,
year = {2025},
author = {Azam, HMH and Mumtaz, M and Rödiger, S and Schierack, P and Hussain, N and Aisha, A},
title = {MicroRNAs in neurodegenerative diseases: from molecular mechanisms to clinical biomarkers, detection methods and therapeutic strategies-advances and challenges.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {},
number = {},
pages = {},
pmid = {41051689},
issn = {1590-3478},
abstract = {Neurodegenerative diseases (NDDs) pose significant challenges in early detection and treatment due to their complex pathophysiology and heterogeneous clinical presentations. MicroRNAs (miRNAs), small noncoding RNAs that regulate gene expression, have emerged as promising diagnostic biomarkers and therapeutic targets in NDDs. Pathological examination of affected tissues reveals early synaptic dysfunction, protein misfolding, and neuroinflammation occur prior to overt clinical symptoms, highlighting the importance of sensitive diagnostics approaches in prodromal stages. This review summarizes for researchers on the role of miRNAs in NDDs by examining their diagnostic potential in biofluids such as blood and cerebrospinal fluid, and their therapeutic applicability through inhibition or replacement strategies. Literature from peer-reviewed databases was assessed with a focus on recent advances in molecular detection platforms, computational modeling of miRNA-mRNA interactions, and preclinical/clinical investigations.More than 2600 human miRNAs have been identified, collectively regulating over half of mammalian protein-coding genes. Quantitative methodologies, particularly reverse transcription quantitative PCR (RT-qPCR), enable reliable miRNA profiling, facilitating early diagnosis and prognosis of NDDs. Therapeutic strategies, including antagomirs, mimics, sponges and viral or non-viral delivery systems, show promise in modulating disease pathways. However, significant challenges remain, including variability in miRNA extraction and quantification protocols, off-target effects, delivery barriers across the blood brain barrier and limited reproducibility across studies. MiRNAs represent a class of molecular tools with potential to transform diagnostics and therapeutics in NDDs. Future research should prioritize methodological standardization, validation in large multicenter cohorts, and improved computational approaches to elucidate miRNA-mediated regulatory networks in NDDs. Replication studies and translational research are essential harnessing the the full clinical utility of miRNAs in the management of Alzheimer disease, Parkinson disease and other NDDs. Graphical Abstract.},
}

@article {pmid41050540,
year = {2025},
author = {Bøgard, H and Green Knakkergaard, S and Simonÿ, C and Tang, LH and Christensen, JR and Dalhoff Pedersen, A and Luijk, A and Gundtoft Roikjær, S},
title = {Implementation of cross-sectoral rehabilitation in the Nordic countries: a scoping review.},
journal = {Frontiers in health services},
volume = {5},
number = {},
pages = {1662230},
pmid = {41050540},
issn = {2813-0146},
abstract = {INTRODUCTION: Rehabilitation needs are rising in the Nordic countries due to an aging population and declining health profiles. Nordic healthcare systems share common features, including universal access, organization, and substantial tax-based financing. Due to the organization of the healthcare system, patients often experience transitions between sectors as part of the rehabilitation program. This fragmented setup undermines the continuity and quality of rehabilitation, making implementation more difficult. To inform future implementation processes, this scoping review examines the factors that influence cross-sectoral rehabilitation in settings with comparable healthcare systems.

METHODS: This Scoping review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews. The search strategy aimed to identify published, peer-reviewed primary studies on interventions implemented in adult rehabilitation within Nordic countries. Data were charted following Levac et al.'s framework and analyzed using Elo & Kyngäs' content analysis to identify factors influencing implementation. Key study characteristics and implementation approaches were synthesized narratively and in tables.

RESULTS: Thirty-six papers were identified. Most studies described the implementation of rehabilitation transitioning from the secondary to the primary sector. A top-down implementation approach was predominantly reported and appears more facilitating than a bottom-up approach. Implementation of rehabilitation across sectors is influenced by an interplay of factors: (1) Organization & Resources: alignment of context with intervention, involvement from front-line personnel, time & resources, the workplace itself, and managers, and (2) Collaboration & Communication, including knowledge and competence, attitudes, communication, patients, and families.

CONCLUSION: While this scoping review conveys that collaboration, communication, resources, and organization have a central role affecting the implementation of cross-sectoral rehabilitation, it further identifies knowledge gaps, such as the lack of the patients' perspective, the use of a framework or other systematic approach to ensure the success of the implementation.},
}

@article {pmid41047006,
year = {2025},
author = {Stefano, GB and Büttiker, P and Weissenberger, S and Raboch, J and Anders, M},
title = {Semaglutide and the pathogenesis of progressive neurodegenerative disease: the central role of mitochondria.},
journal = {Frontiers in neuroendocrinology},
volume = {},
number = {},
pages = {101217},
doi = {10.1016/j.yfrne.2025.101217},
pmid = {41047006},
issn = {1095-6808},
abstract = {While mitochondria provide critical energy resources, mitochondrial dysfunction can lead to both metabolic and neurodegenerative disorders. Primary mitochondrial disorders (e.g., Leigh syndrome) are uniformly associated with profound neurodegeneration. Recent studies have also implicated mitochondrial dysfunction as a central feature of progressive neurodegenerative diseases, notably Alzheimer's disease, Parkinson's disease, Amyotrophic Lateral Sclerosis, and Huntington's Disease. In addition to its profound impact on metabolic disease, the glucagon-like peptide-1 receptor agonist, semaglutide, has significant neuroprotective features and may limit the progression of one or more of these disorders. These observations might be explained at least in part by the impact of this drug on mitochondrial function and energy production. Collectively, these observations highlight disrupted energy homeostasis as a critical feature of neurodegenerative disease and suggest novel targets for the development of much-needed new neuropharmaceutical strategies.},
}

@article {pmid41046979,
year = {2025},
author = {Puspita, L and Deline, M and Shim, JW},
title = {DUAL SMAD INHIBITION AS A VERSATILE PLATFORM IN HUMAN PLURIPOTENT STEM CELL-BASED NEUROSCIENCE AND REGENERATIVE MEDICINE.},
journal = {Molecules and cells},
volume = {},
number = {},
pages = {100284},
doi = {10.1016/j.mocell.2025.100284},
pmid = {41046979},
issn = {0219-1032},
abstract = {Dual SMAD inhibition is a robust and widely adopted protocol for directing human pluripotent stem cells (hPSCs) toward neuronal lineages by blocking transforming growth factor-beta and bone morphogenetic protein pathways. Suppressing TGF-β and BMP signaling enables efficient and reproducible induction of neuroectoderm, serving as the foundation for generating diverse brain region-specific neuronal subtypes. This review outlines the mechanistic basis and major achievements of the dual SMAD inhibition strategy, including its application in two recent clinical trials for Parkinson's disease, and its role in preclinical studies targeting conditions, such as spinal cord injury, retinal degeneration, and amyotrophic lateral sclerosis. In addition to its significant contribution to the generation of transplantation-ready grafts from hPSCs, the protocol serves as a valuable platform for disease modeling across various neurological and metabolic disorders. The key strengths include high efficiency, technical simplicity that enables precise control of cell fate using small molecules, versatility in both two- and three-dimensional culture systems, and reproducibility across various hPSC lines. This review also addresses key limitations, such as restricted gliogenic capacity and limited neural progenitor cell expansion. Future research should focus on incorporating emerging technologies to advance stem cell-based applications. Overall, dual SMAD inhibition represents a powerful and versatile platform for stem cell-based neuroscience and regenerative medicine.},
}

@article {pmid41042709,
year = {2025},
author = {Hall, HK and Austin, E and Hutchinson, K and Cheek, C and Clay-Williams, R},
title = {A Systematic Review of Management of Cramping Pain in Patients with Amyotrophic Lateral Sclerosis.},
journal = {European neurology},
volume = {},
number = {},
pages = {1},
doi = {10.1159/000548820},
pmid = {41042709},
issn = {1421-9913},
abstract = {BACKGROUND/INTRODUCTION: Pain, particularly cramping, in people living with Amyotrophic Lateral Sclerosis (ALS) is often underrecognized and under-treated. Despite affecting over 70% of people living with ALS (plwALS), cramping pain remains inadequately managed due to its complex nature and the difficulties plwALS face in communicating their symptoms as the disease progresses. This systematic review explores both pharmacological and non-pharmacological treatments for cramping pain in ALS, aiming to assess and compare their efficacy.

METHODS: The systematic review was conducted following PRISMA guidelines and the protocol was registered with PROSPERO (ID CRD42024521649). A comprehensive search was performed across MEDLINE, Embase, Scopus, and Cochrane databases from inception until February 1, 2024, using specific search terms related to ALS and cramping.

RESULTS: The search resulted in the identification of 368 studies. After duplicates were removed, abstracts screened, and full texts reviewed, nine studies were included. Pharmacological interventions such as Mexiletine demonstrated significant reductions in cramp frequency and intensity in several trials, with varying doses showing distinct levels of effectiveness. Other medications like Dronabinol and Levetiracetam were also tested but showed limited efficacy in reducing cramp severity. Among non-pharmacological options, supervised exercise programs, particularly those incorporating stretching and functional mobility, were effective in reducing cramping pain intensity, while unsupervised home exercise programs did not show significant improvements.

CONCLUSION: The review demonstrates the scarcity of high-quality research on cramping pain management in ALS. Mexiletine emerged as the most promising pharmacological intervention, providing notable relief, while supervised exercise therapy demonstrated beneficial effects.},
}

@article {pmid41037122,
year = {2025},
author = {Thakur, A and Sharma, R and Sharma, R and Devi, A},
title = {Neurodegeneration and aging: pathophysiology, diagnosis, and therapeutic targets.},
journal = {Inflammopharmacology},
volume = {},
number = {},
pages = {},
pmid = {41037122},
issn = {1568-5608},
abstract = {Aging is the greatest risk factor for AD, ALS, PD, FTD, and HD. Neurons in the brain experience many changes as people age, negatively affecting their structure and function. It examines the key processes behind brain aging, such as age-related death of cells, failure of the cells' powerhouses, oxidative stress, incorrect protein shapes, brain inflammation, difficulty in cleaning the brain, and deterioration of blood vessels, and shows their impact on neurodegeneration. With age, there are difficulties in brain-blood circulation, less synaptic change, and fewer new neurons, which make the disease even worse. Informed by human and animal trials, we see that mitochondria work less efficiently in aging brain cells, while oxidative damage to DNA increases doubly to triply. In addition, too much tau, amyloid-β, and α-synuclein building up is tied to declining mental abilities in the elderly. We further evaluate new tests that help with early detection and classification, for example, using biomarkers in cerebrospinal fluid (CSF), blood panels, detailed brain scans, and AI algorithms. It stresses that more aging-specific trials, better integration of multi-omics, and increased interest in research on the gut-brain axis are important. The communication between the aging of the body and the brain is also explained. This article covers the main cellular, molecular, and clinical issues linked to brain aging and highlights important future research areas needed to develop effective treatments for aging people.},
}

@article {pmid41032625,
year = {2025},
author = {Rosenberg, GM and Murray, KA and Sawaya, MR and Jiang, YX and Geschwind, DH and Eisenberg, DS},
title = {Genetic and structural aspects of amyloid diseases.},
journal = {Science translational medicine},
volume = {17},
number = {818},
pages = {eadp3378},
doi = {10.1126/scitranslmed.adp3378},
pmid = {41032625},
issn = {1946-6242},
mesh = {Humans ; *Amyloidosis/genetics ; *Amyloid/chemistry/genetics/metabolism ; Mutation/genetics ; Animals ; },
abstract = {The conversion of proteins into insoluble fibrillar aggregates known as amyloid occurs in a wide variety of diseases, e.g., Alzheimer's disease, amyotrophic lateral sclerosis, systemic transthyretin amyloidosis, and multisystem atrophy. There are more than 60 disease-associated amyloid-forming proteins, and amyloid formation can occur sporadically or can be induced or accelerated by genetic mutations. This Review discusses structural mechanisms by which genetic changes promote amyloid formation and thereby influence disease outcomes. By dividing amyloid-forming proteins into six types according to the genetic mutations they carry and analyzing mutation-induced structural changes in amyloid fibrils, a better understanding of inheritance patterns of amyloid diseases (amyloidoses) can be obtained.},
}

Humans
*Amyloidosis/genetics
*Amyloid/chemistry/genetics/metabolism
Mutation/genetics
Animals

@article {pmid40581671,
year = {2025},
author = {Ono, S and Nakamura, M and Ikegami, T and Kajiyama, Y and Kume, K and Takahashi, Y and Takahashi, M and Mochizuki, H and Mizusawa, H and Kawakami, H and Yakushiji, Y},
title = {Spinocerebellar ataxia type 2 followed by amyotrophic lateral sclerosis due to a pure CAG repeat expansion in ATXN2: a case report and literature review.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {46},
number = {10},
pages = {5417-5421},
pmid = {40581671},
issn = {1590-3478},
mesh = {Humans ; Middle Aged ; *Amyotrophic Lateral Sclerosis/genetics/complications/diagnostic imaging ; Female ; *Ataxin-2/genetics ; *Spinocerebellar Ataxias/genetics/complications/diagnostic imaging ; *Trinucleotide Repeat Expansion/genetics ; Magnetic Resonance Imaging ; },
abstract = {BACKGROUND: Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant cerebellar ataxia caused by abnormal CAG expansions (≥ 34 repeats) in the ATXN2 gene (ATXN2), whereas intermediate CAG expansions (27-33 repeats) have been linked to amyotrophic lateral sclerosis (ALS).

CASE DESCRIPTION: A 53-year-old woman with longstanding cerebellar ataxia developed progressive upper limb weakness and muscle atrophy at the age of 51 years. On neurological examination, she was found to have ataxic dysarthria, slow saccadic eye movements, tongue atrophy with fasciculations, muscle atrophy and weakness in both upper limbs, hyperreflexia with Babinski's sign, and limb and gait ataxia. Brain magnetic resonance imaging (MRI) showed brainstem and cerebellar atrophy. Genetic analysis identified an expanded CAG-repeat of 39/22 in ATXN2, and screening for other known ALS-related gene mutations was negative, leading to a diagnosis of both SCA2 and ALS associated with ATXN2.

CONCLUSIONS: SCA2 is typically associated with uninterrupted CAG-repeat expansions, whereas ALS-related ATXN2 expansions usually contain at least one CAA triplet. However, despite carrying an uninterrupted CAG-repeat expansion, this patient developed ALS. This case shows that ALS can emerge several decades after SCA2 onset, even in patients with pure CAG-repeats, underscoring the need for long-term monitoring in SCA2 patients. Further research is needed to clarify the roles of repeat length, CAA interruptions, and other factors in ATXN2-related ALS.},
}

Humans
Middle Aged
*Amyotrophic Lateral Sclerosis/genetics/complications/diagnostic imaging
Female
*Ataxin-2/genetics
*Spinocerebellar Ataxias/genetics/complications/diagnostic imaging
*Trinucleotide Repeat Expansion/genetics
Magnetic Resonance Imaging

@article {pmid41024175,
year = {2025},
author = {Bamber, R and Carlton, J and McDermott, C and Stavroulakis, T},
title = {Understanding health-related quality of life of informal carers in amyotrophic lateral sclerosis: a scoping review and conceptual framework.},
journal = {Health and quality of life outcomes},
volume = {23},
number = {1},
pages = {90},
pmid = {41024175},
issn = {1477-7525},
support = {NIHR301648//National Institute for Health and Care Research/ ; NIHR301648//National Institute for Health and Care Research/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/nursing ; *Quality of Life/psychology ; *Caregivers/psychology ; Patient Reported Outcome Measures ; },
abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a rapidly progressive, life-limiting neurodegenerative disease. Informal carers provide extensive support, significantly impacting their health-related quality of life (HRQoL). Current HRQoL measurement using person-reported outcome measures (PROMs) in ALS carers lacks consistency and comprehensiveness, hindering robust assessment and synthesis. There is evident need for a comprehensive conceptual framework of HRQoL, to fully capture the multidimensional nature of caregiving in ALS. Such a framework is essential to inform research and clinical practice, ensuring relevant measurement and meaningful clinical discussions. This study aimed to develop this evidence-based framework.

METHODS: This study comprised two stages. Firstly, a scoping review was undertaken in March 2024 using Medline, Embase, and CINAHL to identify primary articles exploring HRQoL in ALS carers. Qualitative, mixed methods and quantitative articles using multi-item PROMs to assess HRQoL in informal ALS carers were included. Relevant themes and subthemes were extracted from articles and PROMs and mapped onto an existing conceptual framework for people with ALS (Quality of Life in ALS, QuALS), which covers physical, psychological, and social HRQoL domains in people with ALS. The Carer-QuALS framework was subsequently developed and refined using existing literature and consultation with ALS carers. PROMs within this review were then indexed against the finalised Carer-QuALS framework.

RESULTS: From 715 search results, 82 articles and 44 PROMs were eligible for inclusion. One new subtheme 'physical caring activities' emerged, while seven subthemes lacked support from the literature. In three structured consultation sessions, nine ALS carers, reviewed the draft Carer-QuALS framework (consisting of seven themes and 43 subthemes). Based on their input, one new subtheme 'privacy' was added, six subthemes were removed, and one was retained, despite lacking support from review literature. The final Carer-QuALS framework includes 37 subthemes: 8 physical, 6 social, and 23 psychological.

CONCLUSIONS: This review presents a comprehensive conceptual framework encompassing the multidimensional impact of ALS caregiving on the HRQoL of informal carers. The framework provides a resource that can be used by researchers, clinicians, and patient advocacy groups for multiple purposes (e.g., to support PROM selection to measure HRQoL, to guide future PROM development, and to facilitate discussions between informal carers and clinicians).},
}

Humans
*Amyotrophic Lateral Sclerosis/psychology/nursing
*Quality of Life/psychology
*Caregivers/psychology
Patient Reported Outcome Measures

@article {pmid41022359,
year = {2025},
author = {Liu, C and Lai, FF and Zhang, T and Mao, KJ and Wan, HT and He, Y},
title = {Roles and therapeutic potential of PARP-1 in neurodegenerative diseases.},
journal = {Biochemical pharmacology},
volume = {},
number = {},
pages = {117373},
doi = {10.1016/j.bcp.2025.117373},
pmid = {41022359},
issn = {1873-2968},
abstract = {Poly(ADP-ribose) polymerase 1 (PARP-1) was first discovered in the 1960 s, and over the past few decades, there has been growing evidence that PARP-1 plays a key role in neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. With DNA damage detection and repair as its main function, PARP-1 is activated by regulation in the early stages of neurodegenerative diseases, quickly and effectively repairs mild DNA damage, and protects nerve cells from death. However, as the disease progresses, severe DNA damage causes PARP-1 to overactivate, resulting in neuronal cell death, including apoptosis, necrosis, and parthanatos, further exacerbating the disease progression. PARP-1 is also involved in the pathological process of neurodegenerative diseases, such as pathological protein aggregation, neuroinflammation, mitochondrial dysfunction, autophagy disorder, and damage to the blood-brain barrier. According to a large number of studies, PARP-1 inhibition has shown great therapeutic potential for neurodegenerative diseases, and the development of PARP-1 inhibitors has received increasing attention. Here, we review the role of PARP-1 in the process of neurodegenerative diseases and summarize the latest research progress and application of PARP-1 inhibitors in neurodegenerative diseases.},
}

@article {pmid41019550,
year = {2025},
author = {Chen, KQ and Cao, WJ and Liu, Z and Liu, RZ},
title = {Mini-review: Processed red meat intake and risk of neurodegenerative diseases.},
journal = {Frontiers in nutrition},
volume = {12},
number = {},
pages = {1663647},
pmid = {41019550},
issn = {2296-861X},
abstract = {Neurodegenerative diseases (NDDs) are a group of disorders characterized by the progressive loss of neurons in specific areas of the central nervous system. In recent years, more and more research has focused on the influence of diet on NDDs. As a common food, processed red meat is widely consumed worldwide. Many studies have shown that processed red meat may increase the risk of cancer, diabetes and cardiovascular disease. Unfortunately, it is unclear whether processed red meat affects NDDs. Therefore, we reviewed the existing literature on the role of processed meats in NDDs. We concluded that intake of processed meat may have an adverse effect on NDDs.},
}

@article {pmid41018945,
year = {2025},
author = {Vucic, S and Shahrizaila, N and Kano, O and Menon, P and Agustini, S and Kulkantrakorn, K and Atchayaram, N and Lee, YC and Prado, MB and Ng, KWP and Chai, J and Son, B and Talman, P and Nghia, HTT and Tuan, LTQ and Shibuya, K and Izumi, Y and Atsuta, N and Henderson, RD and Cui, L and Liu, M and Ohnmar, O and Rabani, R and Hong, YH and Sung, JJ and Fan, D and Raykar, V and Kuwabara, S and Kim, SH and Sobue, G and Kiernan, MC},
title = {Pan-Asian consortium for treatment and research in ALS (PACTALS) guidelines for management of amyotrophic lateral sclerosis.},
journal = {The Lancet regional health. Western Pacific},
volume = {62},
number = {},
pages = {101684},
pmid = {41018945},
issn = {2666-6065},
abstract = {The Pan-Asian Consortium for Treatment and Research in ALS (PACTALS) guidelines were developed for the management of amyotrophic lateral sclerosis (ALS) patients living in the Asia-Pacific countries, taking into consideration the ethnic, racial and economic diversity of the region. The majority of patients reside in low-income (limited-resource setting) and middle-income countries. Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology was utilised for development of the PACTALS management guidelines. Nine broad research questions, divided into sections, were addressed. Evidence was derived from existing Cochrane reviews, systematic reviews, meta-analysis, and randomized controlled trials (RCT) along with consensus when evidence was limited. Recommendations were provided for diagnostic pathways, use of disease modifying therapies, appropriateness of multidisciplinary care models, management of respiratory dysfunction, communication and nutrition, addressing symptoms that affect the quality of life, managing cognitive, behavioural and emotional symptoms as well as appropriate implementation of palliative care services and addressing end-of-life issues. The PACTALS guidelines provide a much-needed framework for the management of ALS patients living in the Asia-Pacific region. The management guidelines will be updated as the treatment landscape evolves and evidence of novel management approaches becomes available.},
}

@article {pmid41017972,
year = {2025},
author = {Feng, J and Hu, X and Liu, J and Wang, W and Chen, L and Pang, R and Zhang, A},
title = {Akkermansia muciniphila in neurological disorders: mechanisms and therapeutic potential via the gut-brain axis.},
journal = {Frontiers in neuroscience},
volume = {19},
number = {},
pages = {1650807},
pmid = {41017972},
issn = {1662-4548},
abstract = {In recent years, the role of Akkermansia muciniphila (A. muciniphila) in neurological diseases has attracted increasing attention. As a probiotic, A. muciniphila is closely associated with host health, metabolism, and immunity, demonstrating therapeutic potential in various conditions such as obesity, atherosclerosis, inflammatory bowel disease, diabetes, and liver disorders. In the context of neurological diseases, A. muciniphila significantly influences the host brain through the microbiota-gut-brain axis (MGBA). This review summarizes the roles and mechanisms of A. muciniphila and its active components (e.g., the outer membrane protein Amuc_1100, extracellular vesicles AmEVs, and short-chain fatty acids SCFAs) in various neurological disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), depression, cerebral palsy (CP), epilepsy (EP), autism spectrum disorder (ASD), and amyotrophic lateral sclerosis (ALS). It exerts protective effects by enhancing the intestinal barrier, regulating lipid metabolism, producing SCFAs, secreting neuroactive substances, and inhibiting neuroinflammation, thereby suggesting novel therapeutic avenues for neurological disorders. However, due to limited data from large-scale human clinical trials and the complexity of disease mechanisms and host-microbiota interactions, its clinical translation faces considerable challenges. Future efforts should focus on multicenter randomized controlled trials and in-depth mechanistic studies utilizing technologies such as metabolomics to facilitate evidence-based clinical application.},
}

@article {pmid41011076,
year = {2025},
author = {Della Toffola, J and Ricci, E and Quagliotto, M and Manganotti, P and Benussi, A},
title = {Non-Invasive Brain Stimulation for Amyotrophic Lateral Sclerosis: Current Evidence and Future Perspectives.},
journal = {Medicina (Kaunas, Lithuania)},
volume = {61},
number = {9},
pages = {},
pmid = {41011076},
issn = {1648-9144},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/physiopathology ; *Transcranial Magnetic Stimulation/methods/trends/standards ; *Transcranial Direct Current Stimulation/methods/trends/standards ; Brain/physiopathology ; },
abstract = {Background and Objectives: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting the upper and lower motor neurons, with a bleak prognosis and few treatment options. Non-invasive brain stimulation (NIBS) techniques, such as repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS), represent emerging approaches aimed at modulating cortical hyperexcitability, a relevant pathogenetic mechanism in ALS. Materials and Methods: A systematic review of the literature was conducted following the PRISMA guidelines, exploring the Scopus and PubMed databases from April to June 2025 with terms related to ALS and NIBS. A total of 18 relevant studies were selected from the initial 708 articles, analysing stimulation protocols, clinical and neurophysiological outcomes, and associated biomarkers; their validity was assessed using the revised Cochrane risk-of-bias (RoB2) tool. Results: The selected studies were extremely heterogeneous, with NIBS techniques, including magnetic (rTMS, cTBS, tSMS) and electrical (tDCS) stimulation, showing variable effects. Low-frequency protocols (1 Hz rTMS) and cTBS showed a slight slowing of clinical progression, while prolonged home stimulation with tDCS and tSMS showed more significant improvements in terms of efficacy, tolerability, and adherence. The main limitations concern the heterogeneity of patients and protocols and the lack of standardised biomarkers, which is why the analysis remained at a descriptive level. The use of telemonitoring and caregiver training are essential to ensure safety and accessibility. Conclusions: NIBS represents a promising therapeutic approach for ALS, but further multicentre, standardised studies with prolonged follow-up are needed. Future strategies should include customisation of stimulation, combination with other therapies, and extension of application to pre-symptomatic phases.},
}

Humans
*Amyotrophic Lateral Sclerosis/therapy/physiopathology
*Transcranial Magnetic Stimulation/methods/trends/standards
*Transcranial Direct Current Stimulation/methods/trends/standards
Brain/physiopathology

@article {pmid41009734,
year = {2025},
author = {Genchi, G and Catalano, A and Carocci, A and Sinicropi, MS and Lauria, G},
title = {Copper, Cuproptosis, and Neurodegenerative Diseases.},
journal = {International journal of molecular sciences},
volume = {26},
number = {18},
pages = {},
doi = {10.3390/ijms26189173},
pmid = {41009734},
issn = {1422-0067},
mesh = {*Copper/metabolism/toxicity ; Humans ; *Neurodegenerative Diseases/metabolism/etiology/pathology ; Animals ; Homeostasis ; },
abstract = {Copper is a vital micronutrient for animals and plants acting as a crucial cofactor in the synthesis of numerous metabolic enzymes and contributing to mitochondrial respiration, metabolism, oxido-reductive reactions, signal transmission, and oxidative and nitrosative damage. In the cells, copper may exist in the Cu[+] and Cu[++] oxidation states and the interconversion between these two states may occur via various redox reactions regulating cellular respiration, energy metabolism, and cell growth. The human body maintains a low level of copper, and copper deficiency or copper excess may adversely affect cellular functions; therefore, regulation of copper levels within a narrow range is important for maintaining metabolic homeostasis. Recent studies identified a new copper-dependent form of cell death called cuproptosis. Cuproptosis occurs due to copper binding to lipoylated enzymes (for instance, pyruvate dehydrogenase and α-ketoglutarate dehydrogenase) in the tricarboxylic acid Krebs cycle. In recent years, extensive studies on copper homeostasis and copper-induced cell death in degenerative disorders, like Menkes, Wilson, Alzheimer, Parkinson's, Huntington's diseases, and Amyotrophic Lateral Sclerosis, have discussed the therapeutic potential of targeting cuproptosis. Copper contamination in the environment, which has increased in recent years due to the expansion of agricultural and industrial activities, is associated with a wide range of human health risks. Soil used for the cultivation of grapes has a long history of copper-based fungicide application (the Bordeaux mixture is rich in copper) resulting in copper accumulation at levels capable of causing toxicity in plants that co-inhabit the vineyards. Phytoremediation, which uses plants and biological solutions to remove toxic heavy metals and pesticides and other contaminants from soil and water, is an environmentally friendly and cost-effective technology used for the removal of copper. It requires plants to be tolerant of high levels of copper and capable of accumulating metal copper in plants' aerial organs and roots. This review aims at highlighting the importance of copper as an essential metal, as well as its involvement in cuproptosis and neurodegenerative diseases.},
}

*Copper/metabolism/toxicity
Humans
*Neurodegenerative Diseases/metabolism/etiology/pathology
Animals
Homeostasis

@article {pmid41009457,
year = {2025},
author = {Scognamiglio, A and Corvino, A and Caliendo, G and Fiorino, F and Perissutti, E and Santagada, V and Severino, B},
title = {Druggability of Sodium Calcium Exchanger (NCX): Challenges and Recent Development.},
journal = {International journal of molecular sciences},
volume = {26},
number = {18},
pages = {},
doi = {10.3390/ijms26188888},
pmid = {41009457},
issn = {1422-0067},
mesh = {*Sodium-Calcium Exchanger/metabolism/antagonists & inhibitors/chemistry ; Humans ; Animals ; Protein Isoforms/metabolism ; Calcium/metabolism ; },
abstract = {Na[+]/Ca[2+] exchangers (NCXs) are membrane transporters crucial for calcium homeostasis in excitable tissues, particularly in the central nervous system. Growing evidence indicates that NCX dysfunction contributes to calcium overload and neuronal damage in several neurological conditions. Thus, pharmacological modulation of NCX isoforms (NCX1, NCX2, and NCX3) has emerged as a potential therapeutic strategy for disorders such as stroke, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), and Parkinson's disease (PD). However, the identification of selective modulators directed at specific NCX isoforms, or even different splice variants, remains challenging and limits their clinical validation. This Review aims to provide an updated overview of small-molecule NCX modulators, described over the last two decades. Chemical structures, mechanisms of action, and isoform specificity are discussed, along with the most commonly used biological assays for their functional evaluation.},
}

*Sodium-Calcium Exchanger/metabolism/antagonists & inhibitors/chemistry
Humans
Animals
Protein Isoforms/metabolism
Calcium/metabolism

@article {pmid41008559,
year = {2025},
author = {Steffan, D and Pezzini, C and Esposito, M and Franco-Romero, A},
title = {Mitochondrial Aging in the CNS: Unravelling Implications for Neurological Health and Disease.},
journal = {Biomolecules},
volume = {15},
number = {9},
pages = {},
doi = {10.3390/biom15091252},
pmid = {41008559},
issn = {2218-273X},
mesh = {Humans ; *Mitochondria/metabolism/pathology/genetics ; *Neurodegenerative Diseases/metabolism/pathology/genetics ; *Aging/metabolism/pathology ; *Central Nervous System/metabolism/pathology ; Animals ; DNA, Mitochondrial/genetics/metabolism ; Oxidative Stress ; Reactive Oxygen Species/metabolism ; Mitophagy ; Mitochondrial Dynamics ; },
abstract = {Mitochondrial aging plays a central role in the functional decline of the central nervous system (CNS), with profound consequences for neurological health. As the brain is one of the most energy-demanding organs, neurons are particularly susceptible to mitochondrial dysfunction that arises with aging. Key features of mitochondrial aging include impaired mitochondrial dynamics, reduced mitophagy, increased production of reactive oxygen species (ROS), and accumulation of mitochondrial DNA (mtDNA) mutations. These alterations dramatically compromise neuronal bioenergetics, disrupt synaptic integrity, and promote oxidative stress and neuroinflammation, paving the path for the development of neurodegenerative diseases. This review also examines the complex mechanisms driving mitochondrial aging in the central nervous system (CNS), including the disruption of mitochondrial-organelle communication, and explores how mitochondrial dysfunction contributes to neurodegenerative diseases, such as Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis. By synthesizing current evidence and identifying key knowledge gaps, we emphasize the urgent need for targeted strategies to restore mitochondrial function, maintain cognitive health, and delay or prevent age-related neurodegeneration.},
}

Humans
*Mitochondria/metabolism/pathology/genetics
*Neurodegenerative Diseases/metabolism/pathology/genetics
*Aging/metabolism/pathology
*Central Nervous System/metabolism/pathology
Animals
DNA, Mitochondrial/genetics/metabolism
Oxidative Stress
Reactive Oxygen Species/metabolism
Mitophagy
Mitochondrial Dynamics

@article {pmid41008528,
year = {2025},
author = {Tian, Z and Jin, F and Geng, Z and Xu, Z and Shao, Q and Liu, G and Ji, X and Liu, J},
title = {Unraveling the Mystery of Hemoglobin in Hypoxia-Accelerated Neurodegenerative Diseases.},
journal = {Biomolecules},
volume = {15},
number = {9},
pages = {},
doi = {10.3390/biom15091221},
pmid = {41008528},
issn = {2218-273X},
support = {20230484436//the Beijing Nova Program/ ; CX23YQ01//the Chinese Institutes for Medical Research, Beijing/ ; 22JCZXJ00190//Beijing-Tianjin-Heibei Basic Research Cooperation Project/ ; },
mesh = {Humans ; *Neurodegenerative Diseases/metabolism/pathology ; *Hemoglobins/metabolism ; *Hypoxia/metabolism/complications ; Animals ; Mitochondria/metabolism ; },
abstract = {Hypoxic stress is increasingly recognized as a convergent pathological factor in various age-related neurodegenerative diseases (NDDs), encompassing both acute events such as stroke and traumatic brain injury (TBI), and chronic disorders including Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS). Recent studies have revealed that hemoglobin (Hb), beyond its classical oxygen-transport function, exhibits unexpected expression and functional relevance within the central nervous system. Notably, both cerebral and circulating Hb appear to be dysregulated under hypoxic and aging conditions, potentially influencing disease onset and progression of these diseases. However, Hb's impact on neurodegeneration appears to be context-dependent: in acute NDDs, it may exert neuroprotective effects by stabilizing mitochondrial and iron homeostasis, whereas in chronic NDDs, aberrant Hb accumulation may contribute to toxic protein aggregation and neuronal dysfunction. This review provides an integrative overview of the emerging roles of Hb in hypoxia-related NDDs, highlighting both shared and distinct mechanisms across acute and chronic conditions. We further discuss potential therapeutic implications of targeting Hb-related pathways in NDDs and identify key gaps for future investigation.},
}

Humans
*Neurodegenerative Diseases/metabolism/pathology
*Hemoglobins/metabolism
*Hypoxia/metabolism/complications
Animals
Mitochondria/metabolism

@article {pmid41008332,
year = {2025},
author = {Bernetti, C and Cea, L and Buoso, A and Greco, F and Rossi, M and Pilato, F and Calandrelli, R and Di Gennaro, G and Di Lazzaro, V and Zobel, BB and Mallio, CA},
title = {A Comprehensive Overview of Subacute Combined Degeneration: MRI Diagnostic Challenges and Treatment Pathways.},
journal = {Brain sciences},
volume = {15},
number = {9},
pages = {},
doi = {10.3390/brainsci15090972},
pmid = {41008332},
issn = {2076-3425},
abstract = {Subacute combined degeneration (SCD) is a neurological disorder primarily caused by vitamin B12 deficiency. This condition leads to progressive demyelination and axonal damage, predominantly affecting the dorsal and lateral columns of the spinal cord. This review provides a comprehensive overview of SCD, detailing its complex etiology, pathophysiology, and clinical presentation. We highlight the critical role of magnetic resonance imaging (MRI) in the diagnostic process, discussing both the characteristic spinal cord findings and the more subtle intracranial abnormalities. Furthermore, we address the diagnostic challenges presented by conditions that mimic SCD in MRI, such as multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS). We conclude by outlining current treatment pathways and identifying key areas for future research, including the use of advanced neuroimaging techniques and the potential for new therapeutic approaches. This updated synthesis aims to provide a clear framework for clinicians and researchers to better understand and manage SCD.},
}

@article {pmid41007730,
year = {2025},
author = {Schreiner, TG and Menéndez-González, M and Schreiner, OD and Ciobanu, RC},
title = {Intrathecal Therapies for Neurodegenerative Diseases: A Review of Current Approaches and the Urgent Need for Advanced Delivery Systems.},
journal = {Biomedicines},
volume = {13},
number = {9},
pages = {},
doi = {10.3390/biomedicines13092167},
pmid = {41007730},
issn = {2227-9059},
abstract = {Neurodegenerative diseases (NDDs) pose an immense global health burden, and developing effective treatments is hindered by the blood-brain barrier (BBB). Intrathecal (IT) administration of therapeutics directly into the cerebrospinal fluid (CSF) bypasses the BBB, offering a promising avenue for antisense oligonucleotides (ASOs), gene therapies, antibodies, and stem cells for these disorders. This review synthesizes the current landscape of IT therapies for Alzheimer's disease, Parkinson's disease, Huntington's disease, and Amyotrophic Lateral Sclerosis based on the current literature and ClinicalTrials.gov. We highlight key trials and approaches, including the success of ASOs in spinal muscular atrophy and recent progress in other NDDs. However, the efficacy of these novel treatments is often constrained by the limitations of first-generation IT delivery systems, which struggle with uneven distribution, systemic leakage, and the demands of modern biologics. Drawing from recent analyses, we underscore the critical shortcomings of current devices and point out the innovations needed in shaping next-generation systems: subcutaneous access ports, CSF flow platforms, AI-driven adaptive dosing, nanoporous membranes, intrathecal pseudodelivery, and hydrogel scaffolds. We conclude by emphasizing the urgent need for these advanced IT drug delivery systems, alongside rigorous comparative assessments, cost-benefit analyses, and clear regulatory pathways to fully realize the potential of emerging CNS therapies and transform NDD management.},
}

@article {pmid41005573,
year = {2025},
author = {Marlow, TR and Bowden, KM and Collins, MO and Shaw, PJ},
title = {The potential role of misfolded wild-type SOD1 protein in sporadic amyotrophic lateral sclerosis (ALS): a review of the evidence.},
journal = {Neurobiology of disease},
volume = {},
number = {},
pages = {107124},
doi = {10.1016/j.nbd.2025.107124},
pmid = {41005573},
issn = {1095-953X},
abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterised by the selective loss of motor neurons in the motor cortex, brainstem and spinal cord. In 1993, the first ALS-linked gene mutations were identified in the Cu,Zn superoxide dismutase (SOD1) gene, which account for approximately 20 % of familial ALS cases. The mechanism of toxicity in this subset of patients is thought to arise from a gain-of-toxic function from the protein's propensity to misfold and aggregate into cytoplasmic inclusions. Immunohistochemical studies have shown that misfolded wildtype SOD1 (wtSOD1) is also detected in the motor neurons and glial cells of ALS patients without SOD1 mutations. It is proposed that disrupted, or aberrant, posttranslational modifications cause wtSOD1 to adopt a toxic conformation similar to that of the mutant protein. Subsequent mechanistic studies have shown that this misfolded wtSOD1 can disrupt cellular function and lead to motor neuron death through pathways similar to those observed in mutant SOD1-ALS. Given the limited neuroprotective treatments currently available that can effectively slow or reverse disease progression, targeting a pathogenic mechanism that features in both familial and sporadic ALS cases represents a promising therapeutic approach for a broader patient population. This review examines the growing body of evidence that supports or challenges the role of misfolded wtSOD1 in the pathophysiology of sporadic ALS and explores the potential implications of this mechanism in disease progression. Understanding how misfolded wtSOD1 contributes to disease pathogenesis provides new opportunities for developing more widely available treatments for this devastating disease.},
}

@article {pmid41004063,
year = {2025},
author = {Dellarole, IL and Lombardo, A and Ciullini, A and Cazzaniga, FA and Domina, R and Bacınoğlu, MB and Moda, F},
title = {Seed Amplification Assays as Powerful Tools for Detecting Peripheral Biomarkers in Prion-Like Diseases.},
journal = {Sub-cellular biochemistry},
volume = {112},
number = {},
pages = {293-320},
pmid = {41004063},
issn = {0306-0225},
mesh = {Humans ; *Biomarkers/metabolism/blood/cerebrospinal fluid ; *Prion Diseases/diagnosis/metabolism ; *Prions/metabolism ; *Nucleic Acid Amplification Techniques/methods ; Neurodegenerative Diseases/diagnosis ; },
abstract = {Seed amplification assays (SAAs) are highly sensitive and advanced techniques originally developed for the study and diagnosis of prion diseases. Thanks to their remarkably high sensitivity and specificity, SAAs are now widely employed in both research and clinical settings for prion detection, especially in peripheral tissues of patients with prion disorders. Many neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, dementia with Lewy bodies, frontotemporal dementia, and amyotrophic lateral sclerosis, show prion-like mechanisms involving the misfolding and self-propagation of pathological proteins. As a result, SAAs are being adapted and refined for clinical use to improve the diagnosis of these conditions. This includes detecting traces of pathological proteins in cerebrospinal fluid as well as in minimally or noninvasively collected samples, such as blood, urine, skin, and olfactory mucosa. This chapter offers an overview of the role of SAAs in the clinical diagnosis of neurodegenerative diseases.},
}

Humans
*Biomarkers/metabolism/blood/cerebrospinal fluid
*Prion Diseases/diagnosis/metabolism
*Prions/metabolism
*Nucleic Acid Amplification Techniques/methods
Neurodegenerative Diseases/diagnosis

@article {pmid41002898,
year = {2025},
author = {Truong, TT and Singh, AA and Bang, NV and Vu, NMH and Na, S and Choi, J and Oh, J and Mondal, S},
title = {Mitochondria-Associated Membrane Dysfunction in Neurodegeneration and Its Effects on Lipid Metabolism, Calcium Signaling, and Cell Fate.},
journal = {Membranes},
volume = {15},
number = {9},
pages = {},
doi = {10.3390/membranes15090263},
pmid = {41002898},
issn = {2077-0375},
support = {//This work was supported by a Research Grant of Pukyong National University (2023)/ ; },
abstract = {Mitochondria-associated membranes (MAMs) are essential for cellular homeostasis. MAMs are specialized contact sites located between the endoplasmic reticulum (ER) and mitochondria and control apoptotic pathways, lipid metabolism, autophagy initiation, and calcium signaling, processes critical to the survival and function of neurons. Although this area of membrane biology remains understudied, increasing evidence links MAM dysfunction to the etiology of major neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS). MAMs consist of a network of protein complexes that mediate molecular exchange and ER-mitochondria tethering. MAMs regulate lipid flow in the brain, including phosphatidylserine and cholesterol; disruption of this process causes membrane instability and impaired synaptic function. Inositol 1,4,5-trisphosphate receptor-voltage-dependent anion channel 1 (IP3R-VDAC1) interactions at MAMs maintain calcium homeostasis, which is required for mitochondria to produce ATP; dysregulation promotes oxidative stress and neuronal death. An effective therapeutic approach for altering neurodegenerative processes is to restore the functional integrity of MAMs. Improving cell-to-cell interactions and modulating MAM-associated proteins may contribute to the restoration of calcium homeostasis and lipid metabolism, both of which are key for neuronal protection. MAMs significantly contribute to the progression of neurodegenerative diseases, making them promising targets for future therapeutic research. This review emphasizes the increasing importance of MAMs in the study of neurodegeneration and their potential as novel targets for membrane-based therapeutic interventions.},
}

@article {pmid41002740,
year = {2025},
author = {Bardhan, M and Anand, A and Javed, A and Chilo, MA and Khan, N and Garg, T and Surana, A and Huang, H and Samim, MM and Suresh, V and Khare, A and Menon, B and Kundu, T},
title = {Polymorphism of Melanocortin Receptor Genes-Association with Inflammatory Traits and Diseases.},
journal = {Diseases (Basel, Switzerland)},
volume = {13},
number = {9},
pages = {},
doi = {10.3390/diseases13090305},
pmid = {41002740},
issn = {2079-9721},
abstract = {Melanocortin receptors (MCRs) are responsible for various functions ranging from skin pigmentation, regulation of appetite, stress response and cognition, steroid synthesis, and energy balance to cellular regeneration and immunomodulation. The genetic polymorphism with tissue distribution ranging from the brain, limbic system, and adrenal cortex to neutrophils, monocytes, and macrophages is evident in MCRs. The mutations in MC1R, MC2R, MC3R, and MC4R genes are associated with risk of melanoma, familial glucocorticoid deficiency, obesity, and type 2 diabetes mellitus, respectively. Meanwhile, MC1R, MC2R, and MC5R genes are involved in the risk of major depressive disorder. Melanocortin receptors are involved in different inflammatory disorders, i.e., atopic dermatitis, autoimmune uveitis, sarcoidosis, respiratory diseases, multiple sclerosis, scleroderma, inflammatory bowel disease, amyotrophic lateral sclerosis, Alzheimer's disease, arthritis, and reperfusion injury. Several newer therapeutic agents related to MCRs have numerous advantages over the current anti-inflammatory drugs, demonstrating therapeutic relevance. Among them, α-MSH analogs play a role in atopic dermatitis and scleroderma, and MC1R agonist Dersimelagon has shown effectiveness in systemic sclerosis. The FDA has recently approved the repository corticotropin injection (RCI) to treat sarcoidosis. The FDA has also approved various melanocortin agonists, i.e., Bremelanotide, Afamelanotide, and Setmelanotide, for the treatment of hypoactive sexual desire disorder, Erythropoietic protoporphyria, and obesity, due to pro-opiomelanocortin and leptin receptor deficiency, respectively. Therefore, this review aims to summarize the function and genetic polymorphism of melanocortin receptors, regulatory pathways involving MCRs, and the existing evidence of the prime effect of MCRs on inflammatory responses via different mechanisms and their potential therapeutic use in inflammatory diseases.},
}

@article {pmid40999441,
year = {2025},
author = {Abdi, K and Foroughi, Z and Najafi, Z and Afshari, M},
title = {Challenges and solutions to effective stewardship of rehabilitation services: a scoping review.},
journal = {BMC health services research},
volume = {25},
number = {1},
pages = {1211},
pmid = {40999441},
issn = {1472-6963},
support = {IR.USWR.REC.1402.099//University of Social Welfare and Rehabilitation Sciences/ ; },
mesh = {Humans ; *Rehabilitation/organization & administration ; Iran ; *Delivery of Health Care/organization & administration ; Health Policy ; },
abstract = {BACKGROUND AND AIM: Strong and effective stewardship is a fundamental function of health systems. However, rehabilitation services often receive insufficient attention due to the limited priority assigned to them by governments and health systems. In many countries-particularly low- and middle-income nations-this neglect has resulted in fragmented and poorly coordinated rehabilitation services across various sectors, with inconsistent service delivery influenced by the internal policies of individual institutions. This study investigates the broader barriers to rehabilitation services, analyzes their implications for stewardship, and proposes solutions to improve governance and system coordination.

METHOD: In this scoping review of studies conducted in Iran and globally, we identified factors and strategies for effective stewardship of rehabilitation services using Arksey and O'Malley's framework. Searches were performed in English databases (PubMed, Web of Science, and Scopus) and Persian databases (SID and Magiran), as well as the Google Scholar search engine, utilizing relevant English keywords and their Persian equivalents. Data were analyzed through a qualitative methodology employing directed content analysis. Additionally, Veillard et al.'s Health System Stewardship Framework was utilized to identify and analyze the challenges and solutions implemented in other countries.

FINDINGS: From a total of 38 published articles on rehabilitation services, six themes, eight sub-themes, 81 challenges, and 74 solutions were identified. The challenges included the ineffectiveness of the fragmented rehabilitation structure and stewardship, the absence of a comprehensive plan, and inadequate coordination and communication. Proposed solutions from these studies included establishing a central regulatory and governance body; developing rehabilitation services that recognize rehabilitation as a population-based strategy for health and well-being across a wide range of health conditions throughout the continuum of care and throughout life; and creating databases to track individuals with disabilities and the rehabilitation services provided to them.

CONCLUSION: Effective stewardship of integrated rehabilitation services necessitates service continuity, coordinated policymaking, and active stakeholder engagement. A cohesive governance structure, bolstered by a robust information system, is crucial for evidence-based decision-making. Aligning policies with operational plans fosters collaboration and improves service efficiency.},
}

Humans
*Rehabilitation/organization & administration
Iran
*Delivery of Health Care/organization & administration
Health Policy

@article {pmid40992439,
year = {2025},
author = {Tien Vo, TT and Tsai, MH and Cheng, CY and Wang, YL and Lee, WJ and Lee, IT},
title = {The oral microbiome-redox-inflammation axis in neurodegeneration: mechanistic insights and therapeutic perspectives.},
journal = {Biochemical pharmacology},
volume = {242},
number = {Pt 3},
pages = {117362},
doi = {10.1016/j.bcp.2025.117362},
pmid = {40992439},
issn = {1873-2968},
abstract = {The oral microbiome is a highly diverse and metabolically active ecosystem that plays a pivotal role in maintaining oral and systemic homeostasis. Disruption of this balance, referred to as oral dysbiosis, has been increasingly implicated in the pathogenesis of neurodegenerative diseases (NDs) such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Although the precise molecular mechanisms remain incompletely defined, accumulating evidence indicates that oxidative stress and redox signaling act as central mediators linking microbial imbalance to neuroinflammatory responses and progressive neuronal dysfunction. In this review, we critically synthesize interdisciplinary findings on the oral microbiome-brain axis, emphasizing redox-sensitive pathways that mediate communication between oral pathogens and the central nervous system. We discuss how reactive oxygen species (ROS), generated by microbial metabolites and pathogen-associated molecular patterns, activate various signaling cascades, thereby exacerbating neuroinflammation and glial activation. We further evaluate evidence that oral dysbiosis contributes to blood-brain barrier (BBB) disruption, peripheral immune priming, and chronic neuroimmune dysregulation. By integrating mechanistic, cellular, and clinical perspectives, we identify oxidative stress and redox signaling as critical biological bridges between oral dysbiosis and neurodegeneration. This framework highlights not only the translational potential of targeting redox pathways and the oral microbiome for preventive and therapeutic strategies but also the need for future research to clarify causal relationships and validate clinical applications.},
}

@article {pmid40795649,
year = {2025},
author = {Rabbani, MG and Alif, SM and Zhou, Z and Ryan, J and Karim, MN},
title = {Association between higher serum uric acid levels and cognitive function: a systematic review and meta-analysis.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {80},
number = {10},
pages = {},
doi = {10.1093/gerona/glaf174},
pmid = {40795649},
issn = {1758-535X},
mesh = {Humans ; *Uric Acid/blood ; *Cognition/physiology ; Male ; Female ; Cross-Sectional Studies ; Biomarkers/blood ; },
abstract = {BACKGROUND: Serum uric acid (SUA) levels may be associated with cognitive function, but findings have been inconsistent, potentially varying by cognitive domain and sex. We aimed to determine the association of SUA and different domains of cognitive function.

METHODS: Five electronic databases were searched to identify relevant peer-reviewed articles. Studies investigating the association between SUA levels and cognitive function were included. Standardized mean difference (SMD) was calculated, and separate meta-analyses were conducted for each of the domains. Risk of bias was assessed using the Newcastle-Ottawa Quality Assessment Scale. Between-study heterogeneity was investigated through subgroup analysis and a meta-regression model using study-level covariates.

RESULTS: Ten prospective cohort and 16 cross-sectional studies were eligible for inclusion, but only a subset of these studies was included in each meta-analysis. Pooled estimates from cross-sectional studies showed that higher SUA levels were significantly associated with better global cognition (n = 6, SMD = 2.27, 95% CI, 1.18-3.35), and learning and memory (n = 4, SMD = 1.49, 95% CI, 1.12-1.87). Sensitivity analysis, excluding the study conducted on amyotrophic lateral sclerosis patients, resulted in better performance estimates for executive function (n = 4, SMD = 0.51, 95% CI, 0.47-0.55) and language (n = 2, SMD = 0.75, 95% CI, 0.71-0.79). The pooled result from 2 prospective cohort studies found a positive relationship between SUA levels and attention (SMD = 0.22, 95% CI, 0.07-0.36). Serum uric acid levels were associated with executive function and learning and memory in males, and with language in females.

CONCLUSIONS: Higher SUA levels were associated with better global cognitive performance executive function, learning and memory, attention and language. These findings highlight low SUA levels as a potentially useful biomarker for cognitive decline.},
}

Humans
*Uric Acid/blood
*Cognition/physiology
Male
Female
Cross-Sectional Studies
Biomarkers/blood

@article {pmid40983949,
year = {2025},
author = {Cheng, S and Xiao, B and Luo, Z},
title = {Glycosylation in neuroinflammation: mechanisms, implications, and therapeutic strategies for neurodegenerative diseases.},
journal = {Translational neurodegeneration},
volume = {14},
number = {1},
pages = {47},
pmid = {40983949},
issn = {2047-9158},
support = {2022YFC2503802//the National Key Research and Development Program of China/ ; z027001//The National Multidisciplinary Cooperative Diagnosis and Treatment Capacity Project for Major Diseases of Xiangya Hospital, Central South University/ ; 2021SK4001//the Innovative Construction Foundation of Hunan Province/ ; 2023JJ30924//the National Natural Science Foundation of Hunan province, China/ ; B202303076019//Scientific research project of Health Commission of Hunan Province/ ; },
mesh = {Humans ; Glycosylation ; *Neurodegenerative Diseases/metabolism/immunology/therapy ; Animals ; *Neuroinflammatory Diseases/metabolism ; Inflammation/metabolism ; Microglia/metabolism ; },
abstract = {Neuroinflammation is a key pathological mechanism underlying neurodegenerative diseases, and intricately interacts with protein glycosylation. Emerging evidence suggests that aberrant glycosylation disrupts immune homeostasis, activates microglia, and promotes the release of inflammatory mediators, thereby exacerbating neuroinflammatory responses. In addition, the inflammatory microenvironment can further dysregulate glycosylation patterns, creating a vicious cycle that amplifies disease pathology. Although the regulatory role of glycosylation in neuroinflammation associated with neurodegenerative diseases has been recognized, the precise molecular and cellular mechanisms remain incompletely understood. This review systematically examines the complex crosstalk between glycosylation and neuroinflammation, with a particular focus on the critical roles of glycosylation in key neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis. We explore how glycosylation abnormalities contribute to disease pathogenesis through effects on immune recognition, protein aggregation, and cellular functions. Understanding the molecular underpinnings of these diseases may pave the way for the development of therapeutic strategies targeting glycosylation pathways, ultimately improving clinical outcomes for patients.},
}

Humans
Glycosylation
*Neurodegenerative Diseases/metabolism/immunology/therapy
Animals
*Neuroinflammatory Diseases/metabolism
Inflammation/metabolism
Microglia/metabolism

@article {pmid40981102,
year = {2025},
author = {Juranek, JK and Kordas, B and Podlasz, P and Bossowska, A and Banach, M},
title = {Current Evidence on the Involvement of RAGE-Diaph1 Signaling in the Pathology and Treatment of Neurodegenerative Diseases-An Overview.},
journal = {Pathophysiology : the official journal of the International Society for Pathophysiology},
volume = {32},
number = {3},
pages = {},
doi = {10.3390/pathophysiology32030043},
pmid = {40981102},
issn = {1873-149X},
abstract = {Neurodegenerative diseases are a group of disorders characterized by the progressive deterioration of the structure and function of central nervous system neurons and include, among others, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), Parkinson's (PD), Alzheimer's (AD), and Huntington's (HD) diseases. And while all these diseases seem to have different genetic and environmental components, growing evidence shows that they share common underlying pathological features such as increased neuroinflammation and excessive oxidative stress. RAGE, the receptor for advanced glycation end-products, is a signal transduction receptor, and its activation triggers an increase in proinflammatory molecules, oxidative stressors, and cytokines. Diaph1, protein diaphanous homolog 1, is an actin modulator and an intracellular ligand of RAGE. Studies demonstrated that RAGE and Diaph1 act together, and their downstream signaling pathways play a role in neurodegeneration. Here, based on current evidence and our own research, we provide an overview of the RAGE-Diaph1 signaling and discuss the therapeutic potential of targeted therapy aimed at RAGE-Diaph1 signaling inhibition in the prevention and treatment of neurodegenerative diseases.},
}

@article {pmid40977745,
year = {2025},
author = {Wang, J and Li, Y and Xia, Y},
title = {C/EBPβ as a master regulator of inflammasome signaling in neurodegenerative diseases: mechanisms and therapeutic implications.},
journal = {Frontiers in immunology},
volume = {16},
number = {},
pages = {1656165},
pmid = {40977745},
issn = {1664-3224},
mesh = {Humans ; *Inflammasomes/metabolism/immunology ; *Neurodegenerative Diseases/metabolism/immunology/therapy/etiology ; Animals ; *Signal Transduction ; *CCAAT-Enhancer-Binding Protein-beta/metabolism/genetics ; },
abstract = {CCAAT/enhancer-binding protein beta (C/EBPβ), a key transcription factor, plays a central role in regulating inflammasome signaling in neurodegenerative diseases (NDs). This review synthesizes the mechanisms by which C/EBPβ modulates neuroinflammation and its potential as a therapeutic target. We conducted a comprehensive systematic review spanning January 1995 to June 2025, systematically querying Google Scholar and PubMed with the following keywords: neuroinflammation, inflammasome activation, C/EBPβ, therapeutic targeting, and neurodegenerative diseases. C/EBPβ exists in three isoforms-LAP1, LAP2, and LIP-each with distinct functions in inflammasome activation. In Alzheimer's disease (AD), C/EBPβ drives tau cleavage and Aβ pathology through the AEP axis and exacerbates neuroinflammation by upregulating APOE4. In Parkinson's disease (PD), C/EBPβ silencing reduces α-synuclein aggregation and dopaminergic neuron loss by suppressing the NLRP3 inflammasome. In Amyotrophic Lateral Sclerosis (ALS), C/EBPβ is hypothesized to contribute to TDP-43-associated inflammasome activation, though this requires further validation. In Multiple Sclerosis (MS), C/EBPβ may influence microglial activation and neuroinflammation, as shown in experimental autoimmune encephalomyelitis models. Modulators of the C/EBPβ-inflammasome axis include endogenous regulators like gut-derived metabolites and pharmacological interventions such as small-molecule inhibitors. Therapeutic strategies targeting C/EBPβ hold promise for mitigating neuroinflammation and neurodegeneration, though challenges remain in achieving isoform-specific targeting and blood-brain barrier penetration. Future directions include CRISPR-based editing and biomarker development for personalized therapies.},
}

Humans
*Inflammasomes/metabolism/immunology
*Neurodegenerative Diseases/metabolism/immunology/therapy/etiology
Animals
*Signal Transduction
*CCAAT-Enhancer-Binding Protein-beta/metabolism/genetics

@article {pmid40976462,
year = {2025},
author = {Shi, M and Chu, F and Zhu, J},
title = {Stem cells therapy in neurodegenerative and neuroimmune diseases: current status of treatments and future prospects.},
journal = {Pharmacological research},
volume = {},
number = {},
pages = {107960},
doi = {10.1016/j.phrs.2025.107960},
pmid = {40976462},
issn = {1096-1186},
abstract = {Neurodegenerative and neuroimmune diseases, such as multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS) share a common pathologic hallmark i.e. loss of neurons in the central nervous system (CNS), despite diverse pathological manifestations. These diseases present major challenges to global health due to incurable or extremely difficult to treat, imposing a heavy burden on society and families. Stem cell therapy, as a novel promising approach for treating various neurological diseases, harnesses the regenerative potential of stem cells to repair damaged neural tissues and circuits, and has become the only hope for patients to recover their health or delay the deterioration of disease symptoms. In recent years, researchers have successfully generated neurons from multiple types of stem cells, and good curative effects have been achieved in their animal models and in clinical trials. This comprehensive review elaborates on the relevant content of stem cell biology, focuses on conducting an in-depth analysis of the current application status of various stem cells in major neurodegenerative and neuroimmune diseases including MS, AD, PD and ALS, kindling the hope for the development of stem cell-based cell therapies in neurological diseases.},
}

@article {pmid40972344,
year = {2025},
author = {Del Moro, L and Brunetta, E and Gershwin, ME and Selmi, C},
title = {Microglia and myeloperoxidase in neuroinflammatory and neurodegenerative diseases.},
journal = {Current opinion in immunology},
volume = {97},
number = {},
pages = {102660},
doi = {10.1016/j.coi.2025.102660},
pmid = {40972344},
issn = {1879-0372},
abstract = {The dogma of an impenetrable blood-brain barrier (BBB) has given way to the view that resident immune cells within the central nervous system respond to a variety of blood-borne soluble factors, particularly cytokines, and play an important functional role. In particular, microglia cells contribute to the regulation of neuroinflammation, with both protective and pathological roles. Specific microglia activation states variably influence the progression of neuroinflammatory and neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis. Significant evidence indicates that gut microbiota-derived products regulate microglial function across the lifespan and influence the BBB. Myeloperoxidase (MPO) catalyzes the conversion of hydrogen peroxide and chloride ions into hypochlorous acid, a potent oxidant implicated in oxidative tissue damage and modulation of inflammatory signaling. Elevated MPO levels in the central nervous system have been correlated with human disease and the dysregulation of MPO activity in microglia is particularly detrimental, as it amplifies the oxidative stress, disrupts the BBB integrity, and potentiates the neuroinflammatory cascades through the activation of transcription factors like NF-κB. Targeting MPO activity through selective inhibitors or antioxidant strategies may attenuate microglial activation and reduce neuroinflammation, highlighting its potential as a therapeutic target, but the regulatory mechanisms governing MPO expression in microglia and its interplay with other inflammatory mediators remain poorly understood. New research efforts into the relationship between gut microbiota, microglia, MPO, and neuroinflammation are essential to unravel the complexities of neuropathology in a variety of conditions beyond neurodegenerative diseases.},
}

@article {pmid40969213,
year = {2025},
author = {Ciechanover, A and Livneh, I},
title = {Protein quality control systems in neurodegeneration - culprits, mitigators, and solutions?.},
journal = {Frontiers in neurology},
volume = {16},
number = {},
pages = {1604076},
pmid = {40969213},
issn = {1664-2295},
abstract = {A key hallmark of neurodegenerative diseases (NDDs) is the formation of neurotoxic protein aggregates, which are considered to reflect inadequate protein quality control (PQC). In agreement with this fundamental pathophysiologic characteristic, the two main cellular systems responsible for cellular protein removal - the ubiquitin-proteasome system (UPS) and autophagy - have been extensively studied in the context of NDD. The involvement of these proteolytic machineries was interpreted in different ways - some pointed them as dysfunctional systems that may underlie pathogenesis, while others suggested they fulfill protective roles which delay the clinical presentation of these diseases. Perhaps not surprisingly, the growing body of knowledge concerning the different types of NDD portrays a more complex picture, and no distinct generalization can be made regarding the contribution of either the neurotoxic protein substrate(s) or proteolytic system(s) to the development of NDD. For instance, in Parkinson's disease, the toxic aggregation of α-synuclein, Parkinson's canonical culprit protein, can stem from seemingly unrelated events. Among them, alterations in α-synuclein itself, a mutation in Parkin - an E3 ubiquitin ligase targeting proteins and organelles to proteasomal and lysosomal degradation, respectively, as well as a mutation in LRRK2 - a kinase postulated to be linked with α-synuclein through their common removal by chaperone-mediated autophagy. Also, in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), the toxic aggregation of one protein - TDP-43 - can result from defects in other proteins, some of which are related to proteostasis, such as the shuttle protein Optineurin and the E3 ubiquitin ligase VCP. In contrast, ALS and FTLD demonstrate how common abnormalities leading to neurotoxic aggregate formation, may present clinically in profoundly different ways, from motor dysfunction to behavioral changes. In Alzheimer's Disease, the leading cause for dementia, rare cases were linked directly with PQC as they are caused by a mutation in one of the genes encoding ubiquitin itself, while the majority of cases were not directly linked to components of the two main proteolytic systems. All-in-all, the UPS and autophagy are heavily intertwined with NDD, either as part of the problem or as mitigating factors, and hopefully - as platforms for future therapeutics. In this review, we shall dissect NDDs from the perspective of protein turnover pathways, aiming to track both common and unique patterns of PQC failure in this group of diseases, which differ significantly from one another both in their clinical manifestations and affected anatomic regions, yet share the common trait of abnormal protein accumulation. We shall review some of the mechanistic understandings concerning protein aggregation in NDDs, describing the interactions of aggregated proteins with the UPS and autophagy, discuss recent controversies around the protein aggregates' hypothesis, and point to implications for developing therapeutic strategies.},
}

@article {pmid40962156,
year = {2025},
author = {Yipeng, X and Guiqian, W and Qiaochu, Z and Tengjie, H and Yan, Z and Hai, H and Jing, Z},
title = {Molecular mechanisms by which mitochondrial dysfunction drives neuromuscular junction degeneration in amyotrophic lateral sclerosis.},
journal = {Neurobiology of disease},
volume = {},
number = {},
pages = {107103},
doi = {10.1016/j.nbd.2025.107103},
pmid = {40962156},
issn = {1095-953X},
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder marked by progressive degeneration of motor neurons and early deterioration of neuromuscular junctions (NMJs). Increasing evidence indicates that mitochondrial dysfunction plays a pivotal role in driving NMJ degeneration in ALS.

OBJECTIVE: This review aims to comprehensively summarize the molecular mechanisms by which mitochondrial defects contribute to NMJ instability, with a particular focus on bioenergetics, calcium homeostasis, oxidative stress, and impaired mitochondrial biogenesis.

CONCLUSION: Mitochondrial dysfunction is a core driver of NMJ degeneration in ALS. Targeting mitochondrial biogenesis and metabolism-particularly through the PGC-1α pathway-represents a promising strategy to preserve NMJ integrity and slow disease progression.},
}

@article {pmid40958782,
year = {2025},
author = {Sun, LC and Li, WS and Chen, W and Zhao, DQ and Zhang, X and Li, CX and Ren, Z},
title = {Frontiers and Emerging Trends in Edaravone Research: A Bibliometric Analysis of Molecular Basis and Clinical Studies Using CiteSpace and VOSviewer.},
journal = {Journal of multidisciplinary healthcare},
volume = {18},
number = {},
pages = {5743-5758},
pmid = {40958782},
issn = {1178-2390},
abstract = {PURPOSE: Edaravone is a potent free-radical scavenger and antioxidant that has been widely investigated for its therapeutic potential in neurodegenerative diseases and oxidative stress-related conditions. Although previous studies have explored its molecular structure, pharmacological effects, and clinical applications, a comprehensive bibliometric analysis of its research trends and future directions remains lacking.

METHODS: This study employed bibliometric methods to analyze edaravone-related publications from 2000 to 2024, using the Web of Science Core Collection database. The analysis examined publication trends; contributions by countries, institutions, and authors; and keyword clustering. Data visualization tools, such as CiteSpace and VOSviewer, were utilized to identify research clusters and emerging trends in edaravone research.

RESULTS: The findings revealed a significant increase in edaravone-related publications, with China, Japan, and the United States as the leading contributors. Notable researchers, including Abe K and Yoshino H, have made substantial contributions to this field. Four major research clusters were identified: free radical scavenging, cerebral infarction, amyotrophic lateral sclerosis, and oxidative stress. Emerging trends suggest a growing interest in edaravone dexbornel for acute ischemic stroke treatment, as well as its potential applications in blood-brain barrier interactions and Alzheimer's disease.

CONCLUSION: This bibliometric analysis highlights the growing interest in edaravone and its potential clinical application, particularly in neuroprotection. While this study provides valuable insights into current research trends, future studies should incorporate a broader range of sources and languages to obtain a more comprehensive understanding of the impact and scope of edaravone.},
}

@article {pmid40958089,
year = {2025},
author = {Zhang, M and Lin, Y and Wei, H and Ju, Q and Gao, T and Zhang, Y and Shen, L and Sun, C},
title = {The membrane receptor CD44: roles in neurodegenerative diseases.},
journal = {Expert opinion on therapeutic targets},
volume = {},
number = {},
pages = {},
doi = {10.1080/14728222.2025.2563243},
pmid = {40958089},
issn = {1744-7631},
abstract = {INTRODUCTION: With the increasing prevalence of aging populations, the incidence of neurodegenerative diseases continues to rise, posing a serious threat to human health and quality of life. Owing to the highly complex pathogenesis of these disorders, the identification of effective therapeutic targets remains a major challenge. CD44, a cell surface glycoprotein, plays a central role in regulating cell proliferation, survival, adhesion, and migration. Emerging evidence further indicates that CD44 contributes to NF-κB activation, thereby amplifying inflammatory responses.

AREAS COVERED: Given its central role in neuroinflammation, CD44 has attracted increasing attention as a potential therapeutic target for neurodegenerative diseases. This review explores the involvement of CD44 in amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), and Parkinson's disease (PD), with particular emphasis on its contributions to neuroinflammatory processes, neuronal survival, and pathological protein aggregation.

EXPERT OPINION: Chronic low-grade neuroinflammation is a major driver of neurodegenerative diseases, including ALS, AD, and PD. Growing evidence implicates CD44 as a key contributor to disease pathogenesis, with several studies reporting significantly elevated CD44 expression in affected patients. These findings highlight the role of CD44 in disease progression and suggest that targeting CD44-mediated inflammation may offer a promising therapeutic strategy for neurodegenerative disorders.},
}

@article {pmid40955309,
year = {2025},
author = {Wang, L and Feng, L and Ning, B and Wang, Z and Dai, C and Li, M},
title = {Natural Products from Chinese Medicine Targeting NF-κB Signaling: Emerging Therapeutic Avenues for Neurodegenerative Diseases.},
journal = {Drug design, development and therapy},
volume = {19},
number = {},
pages = {8135-8159},
pmid = {40955309},
issn = {1177-8881},
mesh = {Humans ; *NF-kappa B/metabolism/antagonists & inhibitors ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Biological Products/pharmacology/chemistry ; *Medicine, Chinese Traditional ; Signal Transduction/drug effects ; Animals ; *Drugs, Chinese Herbal/pharmacology/chemistry ; },
abstract = {This review summarizes recent advances in leveraging natural products from Chinese medicine to modulate the nuclear factor kappa B (NF-κB) signaling pathway for the prevention and treatment of neurodegenerative diseases (NDDs), focusing specifically on Alzheimer's disease (AD), Parkinson's disease (PD), and Amyotrophic lateral sclerosis (ALS). NF-κB proteins regulate cellular biological activity by binding to promoter regions in the nucleus and transcribing various protein-coding genes. Emerging evidence indicates that NF-κB plays a pivotal role in driving key hallmarks of NDD progression, including neuroinflammation, oxidative stress, mitochondrial dysfunction, and dysregulation of the cell cycle. Natural products from Chinese medicine exert modulatory effects on NF-κB signaling through diverse pharmacological mechanisms, ultimately improving cognitive and motor impairments in preclinical NDDs models. The pleiotropic nature of natural products derived from traditional Chinese medicine (TCM)-which operate through subunit-specific modulation of NF-κB-underscores their potential as next-generation therapeutics. Investigating the intricate regulation of NF-κB by natural products from Chinese medicine will not only enrich our understanding of the pathogenesis of NDDs but also establish a theoretical foundation for the development of new therapeutic drugs for NDDs, providing innovative strategies for prevention and treatment.},
}

Humans
*NF-kappa B/metabolism/antagonists & inhibitors
*Neurodegenerative Diseases/drug therapy/metabolism
*Biological Products/pharmacology/chemistry
*Medicine, Chinese Traditional
Signal Transduction/drug effects
Animals
*Drugs, Chinese Herbal/pharmacology/chemistry

@article {pmid40952592,
year = {2025},
author = {Chen, C and Wang, GQ and Li, DD and Zhang, F},
title = {Microbiota-gut-brain axis in neurodegenerative diseases: molecular mechanisms and therapeutic targets.},
journal = {Molecular biomedicine},
volume = {6},
number = {1},
pages = {64},
pmid = {40952592},
issn = {2662-8651},
support = {No. 82160690//National Natural Science Foundation of China/ ; No. ZK [2021]-014//Science and Technology Foundation of Guizhou Province/ ; No. 2020-39//Collaborative Innovation Center of Chinese Ministry of Education/ ; },
mesh = {Humans ; *Neurodegenerative Diseases/therapy/microbiology/metabolism/etiology ; *Gastrointestinal Microbiome ; *Brain/metabolism ; Animals ; Dysbiosis ; Probiotics/therapeutic use ; *Brain-Gut Axis ; },
abstract = {The microbiota-gut-brain axis (MGBA) is an intricate bidirectional communication network that links intestinal microbiota with the central nervous system (CNS) through immune, neural, endocrine, and metabolic pathways. Emerging evidence suggests that dysregulation of the MGBA plays pivotal roles in the onset and progression of neurodegenerative diseases. This review outlines the key molecular mechanisms by which gut microbes modulate neuroinflammation, blood-brain barrier integrity, protein misfolding, and neuronal homeostasis. We discuss how microbial metabolites, such as short-chain fatty acids, tryptophan derivatives, and bile acids, interact with host to influence CNS functions. Disease-specific features are described across Alzheimer's disease, Parkinson's disease, Multiple sclerosis, and Amyotrophic lateral sclerosis, emphasizing the distinct and overlapping pathways through which gut dysbiosis may contribute to pathogenesis. We further explore the translational potential of microbiota-targeted therapies, including probiotics, fecal microbiota transplantation, dietary interventions, and small-molecule modulators. While preclinical results are promising, clinical trials reveal considerable variability, highlighting the need for personalized approaches and robust biomarkers. Challenges remain in deciphering causal relationships, accounting for inter-individual variability, and ensuring reproducibility in therapeutic outcomes. Future research should integrate multi-omics strategies, longitudinal human cohorts, and mechanistic models to clarify the role of the MGBA in neurodegeneration. Collectively, understanding the MGBA provides a transformative perspective on neurodegenerative disease mechanisms and offers innovative therapeutic avenues that bridge neurology, microbiology, and precision medicine.},
}

Humans
*Neurodegenerative Diseases/therapy/microbiology/metabolism/etiology
*Gastrointestinal Microbiome
*Brain/metabolism
Animals
Dysbiosis
Probiotics/therapeutic use
*Brain-Gut Axis

@article {pmid40951906,
year = {2025},
author = {Telec, W and Al-Saad, S and Karbowski, L and Kłosiewicz, T and Baszko, A},
title = {Postshock Pacing in Cardiac Arrest: A Concise Review.},
journal = {Emergency medicine international},
volume = {2025},
number = {},
pages = {9067144},
pmid = {40951906},
issn = {2090-2840},
abstract = {Following an administered shock in cardiac arrest, the heart commonly experiences a short phase of inability to efficiently perfuse. Despite being a commonly used feature in the ICD population, postshock pacing (PSP) is yet to be adequately explored for its utility in this pulseless phase. Notably, an overwhelming proportion of available data for transcutaneous pacing in spontaneous cardiac arrest stem from the 1980s and 1990s and revolve largely around nonshockable, as opposed to shockable rhythms. The lack of large-scale clinical trials assessing the efficacy of transcutaneous PSP and the considerable advancements in technology and training facilities since the 1990s indicates a need for reevaluation of current understanding of PSP and its applicability in cardiac arrest. Shedding light into the possible implications of transcutaneous PSP in emergency setting cardiac arrest may not only reshape the current protocols of ALS but also carry the potential of improving survival rates. This concise review serves as a summary of the existing knowledge on the subject of PSP and reveals further possible directions for the development of this therapy.},
}

@article {pmid40949612,
year = {2025},
author = {Gao, L and Wang, J and Bi, Y},
title = {Nanotechnology for Neurodegenerative Diseases: Recent Progress in Brain-Targeted Delivery, Stimuli-Responsive Platforms, and Organelle-Specific Therapeutics.},
journal = {International journal of nanomedicine},
volume = {20},
number = {},
pages = {11015-11044},
pmid = {40949612},
issn = {1178-2013},
abstract = {Neurodegenerative diseases-including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis-are characterized by progressive neuronal loss and complex pathological mechanisms such as protein aggregation, mitochondrial dysfunction, and neuroinflammation. Conventional therapies offer limited efficacy due to the blood-brain barrier (BBB) and lack of targeted delivery. Nanotechnology has emerged as a transformative strategy for precise brain-targeted treatment. This review summarizes recent advances in nanoparticle-based drug delivery systems, including polymeric nanoparticles, liposomes, inorganic nanomaterials, and biomimetic carriers, highlighting their design features, BBB-penetration mechanisms, and disease-specific applications. Emphasis is placed on stimuli-responsive nanocarriers that react to pH, reactive oxygen species, or enzyme activity, enabling site-specific drug release. Additionally, organelle-targeting strategies-particularly those directed at mitochondria and lysosomes-are explored for their role in subcellular precision therapy. The integration of diagnostic and therapeutic modalities in theranostic nanoplatforms is also discussed. By consolidating preclinical progress and emerging technologies, this review offers insights into the future of nanomedicine in treating neurodegenerative diseases and lays the groundwork for clinical translation.},
}

@article {pmid40949164,
year = {2025},
author = {Roczkowsky, A and Rachubinski, RA and Hobman, TC and Power, C},
title = {Peroxisomes as emerging clinical targets in neuroinflammatory diseases.},
journal = {Frontiers in molecular neuroscience},
volume = {18},
number = {},
pages = {1642590},
pmid = {40949164},
issn = {1662-5099},
abstract = {Peroxisomes are membrane-bounded organelles that contribute to a range of physiological functions in eukaryotic cells. In the central nervous system (CNS), peroxisomes are implicated in several vital homeostatic functions including, but not limited to, reactive oxygen species signaling and homeostasis; generation of critical myelin sheath components (including ether phospholipids); biosynthesis of neuroprotective docosahexaenoic acid; breakdown of neurotoxic metabolites (such as very-long chain fatty acids); and, intriguingly, glial activation and response to inflammatory stimuli. Indeed, peroxisomes play a critical role in modulating inflammatory responses and are key regulators of the mitochondrial antiviral signaling (MAVS) protein-mediated response to infections. The importance of peroxisomes in CNS physiology is exemplified by the peroxisome biogenesis disorders (PBDs), a spectrum of inherited disorders of peroxisome assembly and/or abundance, that are characterized in part by neurological manifestations ranging from severe cerebral malformations to vision and hearing loss, depending on the individual disorder. Recently, peroxisome dysfunction has been implicated in neurological diseases associated with neuroinflammation including Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis, and Parkinson's disease while also contributing to the pathogenesis of neurotropic viruses including SARS-CoV-2, Human Pegivirus, HIV-1 and Zika virus. In the present review, we examine the diverse roles that peroxisomes serve in CNS health before reviewing more recent studies investigating peroxisome dysfunction in inflammatory brain disorders and also highlight potential peroxisomal targets for diagnostic biomarkers and therapeutic interventions.},
}

@article {pmid40943341,
year = {2025},
author = {Yang, EJ},
title = {The Emerging Role of the Brain-Gut Axis in Amyotrophic Lateral Sclerosis: Pathogenesis, Mechanisms, and Therapeutic Perspectives.},
journal = {International journal of molecular sciences},
volume = {26},
number = {17},
pages = {},
pmid = {40943341},
issn = {1422-0067},
support = {(KIOM) KSN2224011//KIOM/ ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive loss of motor neurons. Although genetic and environmental factors are established contributors, recent research has highlighted the critical role of the gut-brain axis (GBA) in ALS pathogenesis. The GBA is a bidirectional communication network involving neural, immune, and endocrine pathways that connect the gut microbiota with the central nervous system. Dysbiosis in ALS disrupts this axis, leading to increased intestinal permeability, neuroinflammation, and excitotoxicity. Notably, reductions in butyrate-producing bacteria, alterations in microbial metabolites, and enhanced NLRP3 inflammasome activation have been observed in patients with ALS. These changes may precede motor symptoms, suggesting a potential causative role. Interventions targeting the microbiome, such as dietary modulation, have shown promise in delaying disease onset and reducing inflammation. However, the clinical evidence remains limited. Given that gut dysbiosis may precede neurological symptoms, microbiota-targeted therapies offer a novel and potentially modifiable approach to ALS treatment. Understanding the role of GBA in ALS will open new avenues for early diagnosis and intervention. Further clinical trials are required to clarify the causal links and evaluate the efficacy of microbiome-based interventions. Understanding the brain-gut-microbiota axis in ALS could lead to new diagnostic biomarkers and therapeutic strategies.},
}

@article {pmid40905633,
year = {2025},
author = {Verdés, S and Navarro, X and Bosch, A},
title = {Targeting Amyotrophic Lateral Sclerosis with Gene Therapy: From Silencing Genes to Enhancing Neuroprotection.},
journal = {Human gene therapy},
volume = {36},
number = {17-18},
pages = {1173-1198},
doi = {10.1177/10430342251372898},
pmid = {40905633},
issn = {1557-7422},
abstract = {Gene therapy is emerging as a transformative approach for treating amyotrophic lateral sclerosis (ALS), a progressive and fatal neurodegenerative disease. While gene replacement has shown a groundbreaking success in spinal muscular atrophy, the complexity of ALS-due to frequent gain-of-function mutations and a heterogeneous etiology-presents significant challenges. Importantly, approximately 90% of ALS cases are sporadic, with unknown genetic mutation, further complicating patient stratification and therapeutic targeting. As a result, gene therapy strategies must often address multiple pathological mechanisms simultaneously. So far, current gene therapy strategies aim to either suppress toxic gene expression or promote neuroprotection, predominantly via viral-mediated delivery systems. This review will provide an overview of emerging preclinical and clinical gene therapy approaches for ALS, focusing on two main strategies: gene silencing and neuroprotection. Gene silencing techniques, including antisense oligonucleotides (ASOs), viral-mediated RNA interference, and gene editing, have demonstrated efficacy in reducing mutant gene expression, particularly in SOD1 and C9orf72 models, although clinical translation has so far yielded limited success. The recent Food and Drug Administration's approval of the ASO therapy Qalsody for SOD1-ALS underscores the clinical potential of these approaches. Neuroprotective strategies aim to enhance motor neuron survival through delivery of trophic factors, often targeting both central and peripheral tissues to harness retrograde transport mechanisms. We will discuss the advantages and limitations of various delivery vectors, targeting specificity, timing of intervention, and translational challenges, alongside current clinical trial data. This review aims to synthesize how these approaches may converge to address the multifaceted nature of ALS and guide the development of next-generation therapeutics.},
}

@article {pmid40943213,
year = {2025},
author = {Liu, D and Yu, S and Ji, B and Peng, Q and Gao, J and Zhang, J and Guo, Y and Hu, M},
title = {Molecular Mechanisms of Herbicide Resistance in Rapeseed: Current Status and Future Prospects for Resistant Germplasm Development.},
journal = {International journal of molecular sciences},
volume = {26},
number = {17},
pages = {},
doi = {10.3390/ijms26178292},
pmid = {40943213},
issn = {1422-0067},
support = {2023ZD0404203//Science and Technology Innovation 2030 Major Program/ ; 31901503//National Natural Science Foundation of China/ ; CARS-12//Agriculture Research System of China/ ; CX (23) 1001//Jiangsu Provincial Agricultural Science and Technology Independent Innovation Fund/ ; BE2021405//Jiangsu Province Key Research and Development Project/ ; },
abstract = {Rapeseed (Brassica napus) is a globally important oilseed crop whose yield and quality are frequently limited by weed competition. In recent years, there have been significant advances in our understanding of herbicide-resistance mechanisms in rapeseed and in the development of herbicide-resistant rapeseed germplasm. Here, we summarize the molecular mechanisms of resistance to three herbicides: glyphosate, glufosinate, and acetolactate synthase (ALS) inhibitors. We discuss progress in the identification of new resistance genes and the development of herbicide-resistant rapeseed germplasm, from the initial identification of natural mutants to artificial mutagenesis screening, introduction of exogenous resistance genes, and gene editing. In addition, we describe how synthetic biology and directed protein evolution will contribute to precision-breeding efforts in the near future. This is the first review to systematically integrate non-target resistance mechanisms and the potential applications of multi-omics and AI technologies for breeding of herbicide-resistant rapeseed, together with strategies for managing the risks associated with gene flow, the evolution of herbicide-resistant weeds, and the occurrence of volunteer plants resulting from deployment of herbicide-resistant rapeseed. By synthesizing current knowledge and future trends, this review provides guidance for safe, effective, and innovative approaches to the sustainable development of herbicide-resistant rapeseed.},
}

@article {pmid40943143,
year = {2025},
author = {Calcagnile, M and Alifano, P and Damiano, F and Pontieri, P and Del Giudice, L},
title = {A Perspective on the Role of Mitochondrial Biomolecular Condensates (mtBCs) in Neurodegenerative Diseases and Evolutionary Links to Bacterial BCs.},
journal = {International journal of molecular sciences},
volume = {26},
number = {17},
pages = {},
doi = {10.3390/ijms26178216},
pmid = {40943143},
issn = {1422-0067},
support = {project 'NutrAge' (project nr. 7022)//CNR-DISBA/ ; FOE-2019 DBA.AD003.139//CNR/ ; },
abstract = {Biomolecular condensates (BCs), formed through liquid-liquid phase separation (LLPS), are membraneless compartments that dynamically regulate key cellular processes. Beyond their canonical roles in energy metabolism and apoptosis, Mitochondria harbor distinct BCs, including mitochondrial RNA granules (MRGs), nucleoids, and degradasomes, that coordinate RNA processing, genome maintenance, and protein homeostasis. These structures rely heavily on proteins with intrinsically disordered regions (IDRs), which facilitate the transient and multivalent interactions necessary for LLPS. In this review, we explore the composition and function of mitochondrial BCs and their emerging involvement in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, and Huntington's disease. We provide computational evidence identifying IDR-containing proteins within the mitochondrial proteome and demonstrate their enrichment in BC-related functions. Many of these proteins are also implicated in mitochondrial stress responses, apoptosis, and pathways associated with neurodegeneration. Moreover, the evolutionary conservation of phase-separating proteins from bacteria to mitochondria underscores the ancient origin of LLPS-mediated compartmentalization. Comparative analysis reveals functional parallels between mitochondrial and prokaryotic IDPs, supporting the use of bacterial models to study mitochondrial condensates. Overall, this review underscores the critical role of mitochondrial BCs in health and disease and highlights the potential of targeting LLPS mechanisms in the development of therapeutic strategies.},
}

@article {pmid40940798,
year = {2025},
author = {Li, L and Zheng, X and Ma, H and Zhu, M and Li, X and Sun, X and Feng, X},
title = {TREM2 in Neurodegenerative Diseases: Mechanisms and Therapeutic Potential.},
journal = {Cells},
volume = {14},
number = {17},
pages = {},
doi = {10.3390/cells14171387},
pmid = {40940798},
issn = {2073-4409},
abstract = {Neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), represent significant global health challenges, affecting millions and straining healthcare systems. These disorders involve progressive neuronal loss and cognitive decline, with incompletely elucidated underlying mechanisms. Chronic neuroinflammation is increasingly recognized as a critical contributor to disease progression. The brain's resident immune cells, microglia, are central to this inflammatory response. When overactivated, microglia and other immune cells, such as peripheral macrophages, can exacerbate inflammation and accelerate disease development. Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) is a transmembrane receptor of the immunoglobulin superfamily that demonstrates high expression on microglia in the central nervous system. TREM2 serves a vital role in regulating phagocytosis, synaptic pruning, and energy metabolism. This review examines the functions of TREM2 in neurodegenerative diseases and its potential as a therapeutic target, aiming to inform future treatment strategies.},
}

@article {pmid40940752,
year = {2025},
author = {Lee, JH and Chang, W and Min, SS and Song, DY and Yoo, HI},
title = {Beyond Support Cells: Astrocytic Autophagy as a Central Regulator of CNS Homeostasis and Neurodegenerative Diseases.},
journal = {Cells},
volume = {14},
number = {17},
pages = {},
doi = {10.3390/cells14171342},
pmid = {40940752},
issn = {2073-4409},
support = {2023//Eulji University/ ; RS-2024-00438628//Korea Health Industry Development Institute/Republic of Korea ; },
abstract = {Autophagy is a fundamental catabolic pathway critical for maintaining cellular homeostasis in the central nervous system (CNS). While neuronal autophagy has been extensively studied, growing evidence highlights the crucial roles of astrocytic autophagy in CNS physiology and pathology. Astrocytes regulate metabolic support, redox balance, and neuroinflammatory responses. These functions are closely linked to autophagic activity. The disruption of astrocytic autophagy contributes to synaptic dysfunction, chronic inflammation, myelin impairment, and blood-brain barrier instability. Dysregulation of astrocytic autophagy has been implicated in the pathogenesis of multiple neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. This review summarizes the molecular mechanisms of autophagy in astrocytes and delineates its role in intercellular communication with neurons, microglia, oligodendrocytes, and endothelial cells. Furthermore, we will discuss current pharmacological approaches targeting astrocytic autophagy, with particular attention to repurposed agents such as rapamycin, lithium, and caloric restriction mimetics. Although promising in preclinical models, therapeutic translation is challenged by the complexity of autophagy's dual roles and cell-type specificity. A deeper understanding of astrocytic autophagy and its crosstalk with other CNS cell types may facilitate the development of targeted interventions for neurodegenerative diseases.},
}

@article {pmid40938039,
year = {2025},
author = {Baroni, A and Moulton, C and Cristina, M and Sansone, L and Belli, M and Tasciotti, E},
title = {Nano- and Microplastics in the Brain: An Emerging Threat to Neural Health.},
journal = {Nanomaterials (Basel, Switzerland)},
volume = {15},
number = {17},
pages = {},
pmid = {40938039},
issn = {2079-4991},
support = {[Ricerca corrente]//Italian Ministry of Health/ ; },
abstract = {Nano- and microplastics (NMPs), with nanoplastics posing higher risks due to their smaller size and greater capacity for cellular and subcellular penetration, are being referred to as ubiquitous environmental neurotoxicants, due to their ability to pass through biological barriers, including the blood-brain barrier (BBB) and nasal olfactory epithelium, and to remain lodged in neural tissue. Upon uptake, such particles disturb neuronal homeostasis by multiple converging pathways, including oxidative stress, mitochondrial dysfunction, pathological protein aggregation, and chronic neuroinflammation, all closely involved with the molecular signatures of neurodegenerative disorders (Alzheimer's, Parkinson's, Amyotrophic Lateral Sclerosis-ALS). In addition to their neurotoxicity, recent findings suggest that NMPs could disturb synaptic communication and neuroplasticity, thereby compromising the brain's capacity to recover from an injury, a trauma, or neurodegeneration, thus impacting the progression of the disease, our ability to treat it and eventually the efficacy of rehabilitation approaches. Despite these findings, our understanding remains hampered by analytical issues, the scarcity of standard detection methods, and a total lack of longitudinal studies in humans. This review combines multidisciplinary evidence on brain-plastic interactions and calls for accelerated advances in our ability to monitor bioaccumulation in humans, and to integrate neurotoxicology paradigms in the assessment of this underappreciated but growing threat to brain health.},
}

@article {pmid40931498,
year = {2025},
author = {Alemán-Villa, KM and Armienta-Rojas, DA and Camberos-Barraza, J and Rábago-Monzón, ÁR and Camacho-Zamora, A and Osuna-Ramos, JF and Magaña-Gómez, JA and Guadrón-Llanos, AM and Calderón-Zamora, L and Norzagaray-Valenzuela, CD and Valdez-Flores, MA and Picos-Cárdenas, VJ and De la Herrán-Arita, AK},
title = {Neuroinflammation across the spectrum of neurodegenerative diseases: mechanisms and therapeutic frontiers.},
journal = {Neuroimmunomodulation},
volume = {},
number = {},
pages = {1-33},
doi = {10.1159/000548021},
pmid = {40931498},
issn = {1423-0216},
abstract = {Neuroinflammation has emerged as a central and dynamic component of the pathophysiology underlying a wide range of neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and multiple sclerosis. Far from being a secondary consequence of neuronal damage, inflammatory processes (mediated by microglia, astrocytes, peripheral immune cells, and associated molecular mediators) actively shape disease onset, progression, and symptomatology. This review synthesizes current knowledge on the cellular and molecular mechanisms that govern neuroinflammatory responses, emphasizing both shared and disease-specific pathways. We examine how innate and adaptive immune interactions contribute to neuronal vulnerability and neurodegenerative cascades, and explore the reciprocal communication between systemic and central immune compartments. Particular attention is given to emerging therapeutic strategies aimed at modulating neuroinflammation, including immunomodulatory drugs, glial-targeted interventions, and novel delivery platforms. By integrating findings across disciplines and disease models, we outline key translational challenges and propose future directions to harness neuroinflammation as a therapeutic target in the era of precision medicine. Ultimately, a deeper understanding of neuroimmune dynamics holds promise for redefining both the diagnosis and treatment of neurodegenerative disorders.},
}

@article {pmid40928564,
year = {2025},
author = {Davidow, D and Paul, L and Jones, B and Hohlfeld, A and Rasenyalo, S and Dane, K and Shill, IJ and Hendricks, S},
title = {Player-Level Tackle Training Interventions in Tackle-Collision Sports: A Systematic Scoping Review.},
journal = {Sports medicine - open},
volume = {11},
number = {1},
pages = {103},
pmid = {40928564},
issn = {2199-1170},
abstract = {BACKGROUND: In tackle-collision sports, the tackle has the highest incidence, severity, and burden of injury. Head injuries and concussions during the tackle are a major concern within tackle-collision sports. To reduce concussion and head impact risk, evaluating optimal tackle techniques to inform tackle-related prevention strategies has been recommended. The purpose of this study was to perform a systematic scoping review of player-level tackle training intervention studies in all tackle-collision sports.

METHODS: The Arksey and O'Malley's five-stage scoping review process and Levac et al.'s framework were used, along with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis extension for Scoping Reviews (PRISMA-ScR) checklist. The main inclusion criteria were that the study included an intervention aimed at improving a player's tackle abilities, and the intervention had to be delivered/implemented at the player-level in a training setting.

RESULTS: Thirteen studies were included in this review, seven studies in American Football (54%), followed by a combined cohort of rugby union and rugby league players (three studies; 23%), rugby union (two studies; 15%), and one study reported on a rugby league cohort (8%). Studies focused primarily on the tackler, with the intervention incorporating a form of instruction or feedback, delivered through video or an expert coach. Other interventions included an 8-week strength and power training programme, designing practice sessions based on baseline data, and helmetless training in American Football. All interventions demonstrated a favourable change in the outcome measured-which included tackler and ball-carrier kinematics based on motion capture video, tackler proficiency scoring, tackling task analysis, head impact frequencies by xPatch head-impact sensor technology, head impact kinematics using head-impact sensors (helmet or skin patches) and football tackle kinematics with motion capture systems or video.

CONCLUSION: This review shows that a range of studies have been undertaken focusing on player-level training interventions. The quality of studies were rated as 'good', and all studies showed improvements in outcome measures. Coaches and policy makers should ensure tackle technique is profiled alongside other player characteristics, and an evidence-based approach to improving player tackling is adopted, improving both performance and reducing injury risk.

KEY POINTS: Only 13 studies tested or implemented interventions at the player level in tackle-collision sports. The focus of the studies was primarily on the tackler, with the interventions incorporating a form of instruction or feedback, which was delivered through video or an expert coach. Other interventions included an 8-week strength and power training programme, designing practice sessions based on baseline data, and helmetless training in American Football. All interventions demonstrated a favourable change in the outcome measure and provide coaches and policymakers with tackle training insights.

REGISTRATION: The systematic scoping review was prospectively registered with OSF (registration number: https://doi.org/10.17605/OSF.IO/V3KZC).},
}

@article {pmid40924345,
year = {2025},
author = {Kutlubaev, MA and Pervushina, EV and Kiernan, MC},
title = {The nature of fatigue in amyotrophic lateral sclerosis: a systematic review and meta-analysis.},
journal = {Acta neurologica Belgica},
volume = {},
number = {},
pages = {},
pmid = {40924345},
issn = {2240-2993},
abstract = {OBJECTIVES: Patients diagnosed with amyotrophic lateral sclerosis (ALS) typically describe symptoms of fatigue. Despite this frequency, the underlying mechanisms of fatigue are poorly understood, and are likely multifactorial. To help clarify mechanisms, the present systematic review was undertaken to determine the risk factors related to fatigue in ALS.

METHODS: A systematic review was conducted using PubMed and Google Scholar databases using key words. From a total of 40,014 articles, 18 articles were included in the final review, following PRISMA guidelines. Meta-regression and subgroup analyses were conducted to study the relationship between fatigue in ALS and different covariates.

RESULTS: Eighteen studies were included in the analysis. A number of factors were investigated, including age, sex, disease severity and duration, site of disease onset, neurophysiological parameters, and respiratory symptoms, depression and anxiety, sleep disorders, and pain. Combined analyses established that participants with ALS who reported fatigue had more severe disease, as confirmed by lower functional rating scores, than those who did not report fatigue. The remaining factors including depression, anxiety and pain, were not found to be related to the onset of fatigue in ALS. Overall, fatigue worsened quality of life in patients diagnosed with ALS.

DISCUSSION: Fatigue in ALS appears to be particularly associated with progressive neurological deficit and disability, linked to both central and peripheral neuromuscular mechanisms.},
}

@article {pmid40922888,
year = {2025},
author = {Kademani, A and Avraam, C and Montenegro, D and Paloh, A and Somannagari, N and Gupta, A and Lafi, AW and Algaba, AE and Islam, R and Fahima, C and Siddiqui, HF},
title = {Exploring the Emerging Role of Stem Cell Therapy in Neurodegenerative Diseases and Spinal Cord Injury: A Narrative Review.},
journal = {Cureus},
volume = {17},
number = {8},
pages = {e89629},
pmid = {40922888},
issn = {2168-8184},
abstract = {Neurodegenerative diseases and spinal cord injuries (SCI) pose a significant burden on the healthcare system globally. Diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease precipitate cognitive, motor, and behavioral deficits. Parallelly, spinal cord injuries produce sensory and motor deficits, which are burdensome psychologically, socially, and economically. Current management strategies focus only on symptomatic relief, with no definitive cure. Stem cells have been explored for regenerative therapy. This review focuses on developments, limitations, and future potential of stem cell therapy. Stem cells affect the central nervous system via neuroprotective mechanisms, immunomodulatory effects, and mitigation of oxidative stress. The clinical implications of stem cell therapy in treating neurodegenerative diseases and SCI are debatable due to varied outcomes. Challenges related to sample size, long-term follow-up, and assessment of adverse effects should be mitigated in future research. Researchers are currently exploring optimal stem cell types along with various transplantation strategies. Biomaterials integrated with stem cells are a novel approach for treating neurodegenerative diseases and spinal cord injuries. Certain genetic modifications have shown improved results. Screening patients to ascertain better responses to therapy has proven to be a challenge. Other complications include graft vs. host reaction and degeneration of transplanted neurons due to pathogenesis and tumorigenesis. However, the majority of the potential stem cell therapeutic avenues are in the preclinical stage and are being tested on animal models. Guidelines pertaining to ethical concerns and regulatory frameworks need to be established to unfold the full potential of stem cell therapy in the clinical setting. Recent advances also show an increased need to formulate patient-specific approaches to treatment, ranging from stem cell selection to the technique of transplantation. Ongoing clinical trials can address the current challenges and leverage emerging technologies, leading to definitive treatments for neurodegenerative diseases and spinal cord injuries.},
}

@article {pmid40922457,
year = {2025},
author = {Eroglu, E and Harmanci, N},
title = {Emerging Molecular Targets in Neurodegenerative Disorders: New Avenues for Therapeutic Intervention.},
journal = {Basic & clinical pharmacology & toxicology},
volume = {137},
number = {4},
pages = {e70107},
doi = {10.1111/bcpt.70107},
pmid = {40922457},
issn = {1742-7843},
mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/physiopathology/metabolism/genetics ; Animals ; *Molecular Targeted Therapy ; Autophagy/drug effects ; Drug Development ; },
abstract = {Neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and frontotemporal dementia represent a significant global health burden with limited therapeutic options. Current treatments are primarily symptomatic and fail to modify disease progression, emphasizing the urgent need for novel, mechanism-based interventions. Recent advances in molecular neuroscience have identified several non-classical pathogenic pathways, including neuroinflammation, mitochondrial dysfunction, impaired autophagy and proteostasis, synaptic degeneration and non-coding RNA dysregulation. In this focused review, we highlight emerging molecular targets such as TREM2, NLRP3, mTOR, TFEB, PINK1 and SIRT3, which offer promising avenues for therapeutic intervention. We also address challenges in target validation and translational drug development, while proposing future research directions that may facilitate the design of more effective treatments. A deeper understanding of these molecular mechanisms is essential for developing disease-modifying strategies to combat neurodegeneration.},
}

Humans
*Neurodegenerative Diseases/drug therapy/physiopathology/metabolism/genetics
Animals
*Molecular Targeted Therapy
Autophagy/drug effects
Drug Development

@article {pmid39708835,
year = {2025},
author = {Davalos, L and Kushlaf, H},
title = {Advances in Disease-Modifying Therapeutics for Chronic Neuromuscular Disorders.},
journal = {Seminars in respiratory and critical care medicine},
volume = {46},
number = {3},
pages = {250-258},
doi = {10.1055/a-2463-3385},
pmid = {39708835},
issn = {1098-9048},
mesh = {Humans ; *Neuromuscular Diseases/drug therapy/physiopathology/therapy ; Chronic Disease ; Myasthenia Gravis/drug therapy ; },
abstract = {Neuromuscular disorders can cause respiratory impairment by affecting the muscle fibers, neuromuscular junction, or innervation of respiratory muscles, leading to significant morbidity and mortality. Over the past few years, new disease-modifying therapies have been developed and made available for treating different neuromuscular disorders. Some of these therapies have remarkable effectiveness, resulting in the prevention and reduction of respiratory complications. For myasthenia gravis (MG), efgartigimod, ravulizumab, rozanolixizumab, and zilucoplan have been Food and Drug Administration (FDA)-approved for the treatment of acetylcholine receptor (AChR) antibody-positive generalized MG in the past 2 years. Rozanolixiumab is also approved for treating MG caused by muscle-specific tyrosine kinase (MuSK) antibodies. The new MG therapeutics target the complement system or block the neonatal fragment crystallizable (Fc) receptors (FcRn), leading to significant clinical improvement. For spinal muscular atrophy (SMA), nusinersen (intrathecal route) and risdiplam (oral route) modify the splicing of the SMN2 gene, increasing the production of normal survival motor neuron (SMN) protein. Onasemnogene abeparvovec is a gene replacement therapy that encodes a functional SMN protein. All SMA medications, particularly onasemnogene abeparvovec, have led to clinically meaningful improvement. For late-onset Pompe disease (LOPD), avalglucosidase alfa has shown a greater improvement in respiratory function, ambulation, and functional outcomes in comparison to alglucosidase alfa, and cipaglucosidase alfa combined with miglustat has shown improvement in respiratory and motor function in a cohort of enzyme replacement therapy-experienced LOPD patients. Amyotrophic lateral sclerosis (ALS) remains a challenge. The two most recent FDA-approved medications, namely sodium phenylbutyrate and tofersen, may slow down the disease by a few months in a selected population but do not stop the progression of the disease.},
}

Humans
*Neuromuscular Diseases/drug therapy/physiopathology/therapy
Chronic Disease
Myasthenia Gravis/drug therapy

@article {pmid40920272,
year = {2025},
author = {Ku, JB and Pak, RJ and Ku, SS and Holland, RD and Kim, HS},
title = {Clinical Efficacy of Stem Cell Therapy in Neurotraumatic and Neurodegenerative Conditions: A Comparative Review.},
journal = {Tissue engineering and regenerative medicine},
volume = {},
number = {},
pages = {},
pmid = {40920272},
issn = {2212-5469},
abstract = {BACKGROUND: Neurotraumatic conditions, such as spinal cord injury, brain injury, and neurodegenerative conditions, such as amyotrophic lateral sclerosis, pose a challenge to the field of rehabilitation for its complexity and nuances in management. For decades, the use of cell therapy in treatment of neurorehabilitation conditions have been explored to complement the current, mainstay treatment options; however, a consensus for standardization of the cell therapy and its efficacy has not been reached in the medical community. This study aims to provide a comparative review on the very topic of cell therapy use in neurorehabilitation conditions in an attempt to bridge the gap in knowledge.

METHODS: Studies were searched from the PubMed database published from 2014 to 2024 employing the terms including but not exclusive to "spinal cord injury," "brain injury," "amyotrophic lateral sclerosis," "regenerative medicine," "cell therapy," and "stem cell." Following the PRISMA 2020 statement, the studies were screened, included, and excluded. Thirty three studies were identified and selected for this review.

RESULTS: Countless researchers investigated the efficacy of various stem cell products for the treatment of numerous neurotraumatic conditions, such as spinal cord injury, traumatic brain injury, and neurodegenerative conditions such as amyotrophic lateral sclerosis. The recent decade of studies suggest that in neurotraumatic conditions, bone-marrow-derived and neural stem cells can be effective, and in neurodegenerative conditions, such as ALS, mesenchymal and neural stem cells can be efficacious.

CONCLUSION: Emerging data from the latest research is encouraging to the patients suffering from neurotraumatic and neurodegenerative conditions, which present themselves as a need for further studies with improved standardization in study design, including cell source specification, differentiation and culture method, and outcome measures to ensure a wide applicability.},
}

@article {pmid40917070,
year = {2025},
author = {Xie, J and Xu, J and Tian, Z and Liang, J and Tang, H},
title = {Extended Insights Into Advancing Multi-Omics and Prognostic Methods for Cancer Prognosis Forecasting.},
journal = {Frontiers in bioscience (Landmark edition)},
volume = {30},
number = {8},
pages = {44091},
doi = {10.31083/FBL44091},
pmid = {40917070},
issn = {2768-6698},
mesh = {Humans ; Prognosis ; *Lung Neoplasms/genetics/pathology/therapy/diagnosis ; *Biomarkers, Tumor/genetics ; *Adenocarcinoma of Lung/genetics/pathology ; Genomics/methods ; Gene Expression Regulation, Neoplastic ; *Neoplasms/genetics ; Multiomics ; },
abstract = {Zhang et al.'s recent article utilizes comprehensive single-cell data to identify differences in tumor cell populations, highlighting the CKS1B+ malignant cell subcluster as a potential target for immunotherapy. It develops a prognostic and immunotherapeutic signature (PIS) based on this subcluster, demonstrating good performance in predicting lung adenocarcinoma (LUAD) prognosis. The study also validates the role of PSMB7 in LUAD progression. However, there are areas for improvement. There is a lack of clarity regarding the relationship between the CKS1B+ malignant cell subcluster and the PIS, particularly in terms of why PSMB7 was selected for functional studies. The sequencing data are retrospectively obtained from public databases and lack prospective clinical validation. It is suggested to collect LUAD patient tissues for RT-qPCR and RNA-seq analysis and seek external multi-center validations. Additionally, integrating emerging multi-omics methods is recommended to further validate the findings. Despite these limitations, the study represents progress in understanding LUAD and treatment strategies, and continuous evaluation and refinement of multi-omics and machine learning methods are expected for future research and clinical practice.},
}

Humans
Prognosis
*Lung Neoplasms/genetics/pathology/therapy/diagnosis
*Biomarkers, Tumor/genetics
*Adenocarcinoma of Lung/genetics/pathology
Genomics/methods
Gene Expression Regulation, Neoplastic
*Neoplasms/genetics
Multiomics

@article {pmid40855953,
year = {2025},
author = {Logroscino, G and Giannoni-Luza, S and Urso, D and Hamdi, N},
title = {Heterogeneity of frequencies of motor neuron disease across ethnicities and geographical areas: focus on Arabic countries in the Mediterranean area.},
journal = {Current opinion in neurology},
volume = {38},
number = {5},
pages = {588-595},
doi = {10.1097/WCO.0000000000001415},
pmid = {40855953},
issn = {1473-6551},
mesh = {Humans ; Mediterranean Region/epidemiology ; *Amyotrophic Lateral Sclerosis/epidemiology/ethnology/genetics ; Prevalence ; Incidence ; *Motor Neuron Disease/epidemiology/ethnology ; Registries ; Egypt/epidemiology ; Ethnicity ; },
abstract = {PURPOSE OF REVIEW: Although amyotrophic lateral sclerosis (ALS) epidemiology has been increasingly characterized in many regions, data from Arabic countries remain limited. This review aims to summarize the current knowledge on the burden of ALS in Arabic Mediterranean countries, with a particular focus on Egypt.

RECENT FINDINGS: ALS exhibits significant geographic and ethnic variability in terms of incidence, phenotype, and genetic background. Data from the Global Burden of Disease Study 2021 show that Egypt has one of the lowest age-standardized rates of ALS incidence, prevalence, and mortality in the Mediterranean basin. During the past three decades, Egypt has seen a notable decline in ALS-related Disability-Adjusted Life Years and deaths, in contrast to neighboring countries. A national registry has recently been initiated to enhance epidemiological surveillance in the country.

SUMMARY: ALS in Arabic Mediterranean countries presents a distinct epidemiological profile. These differences likely reflect a combination of genetic, demographic, and healthcare-related factors. Strengthening national registries and promoting regional collaborations will be crucial for gaining a deeper understanding of the determinants of ALS in these underrepresented populations.},
}

Humans
Mediterranean Region/epidemiology
*Amyotrophic Lateral Sclerosis/epidemiology/ethnology/genetics
Prevalence
Incidence
*Motor Neuron Disease/epidemiology/ethnology
Registries
Egypt/epidemiology
Ethnicity

@article {pmid40832750,
year = {2025},
author = {Erdi-Krausz, G and Shaw, PJ},
title = {Antisense oligonucleotide therapy in amyotrophic lateral sclerosis.},
journal = {Current opinion in neurology},
volume = {38},
number = {5},
pages = {574-580},
doi = {10.1097/WCO.0000000000001413},
pmid = {40832750},
issn = {1473-6551},
mesh = {*Amyotrophic Lateral Sclerosis/genetics/therapy/drug therapy ; Humans ; *Oligonucleotides, Antisense/therapeutic use ; Animals ; C9orf72 Protein ; Superoxide Dismutase-1 ; *Genetic Therapy/methods ; Superoxide Dismutase/genetics ; DNA-Binding Proteins/genetics ; },
abstract = {PURPOSE OF REVIEW: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with few treatment options available. The approval of tofersen, an antisense oligonucleotide, for SOD1 -ALS by the FDA and EMA may herald a new era of treatment in these patients.

RECENT FINDINGS: So far, trials against the most common genetic form of ALS, C9orf72 , have been unsuccessful, but new preclinical data may show a promising new direction to take. Clinical trials targeting other, more rare genetic mutations associated with familial ALS are currently underway. Other research assessing the use of ASOs to target aberrant splicing associated with sporadic forms of ALS has also produced promising results in preclinical models, using patient-derived induced cellular models and animal models. These therapies are focussed largely on alleviating and reversing TDP-43 pathology, opening up the possibility of not only arresting disease progression, but reversing neurodegeneration.

SUMMARY: ASO therapies have made some promising steps towards treating familial ALS, particularly SOD1 . Ongoing early clinical/preclinical phase research is underway to utilise this technology in other genetic mutations linked with ALS, as well as in sporadic cases.},
}

*Amyotrophic Lateral Sclerosis/genetics/therapy/drug therapy
Humans
*Oligonucleotides, Antisense/therapeutic use
Animals
C9orf72 Protein
Superoxide Dismutase-1
*Genetic Therapy/methods
Superoxide Dismutase/genetics
DNA-Binding Proteins/genetics

@article {pmid40832743,
year = {2025},
author = {Verde, F},
title = {Neurochemical biomarkers of amyotrophic lateral sclerosis: recent developments.},
journal = {Current opinion in neurology},
volume = {38},
number = {5},
pages = {614-619},
doi = {10.1097/WCO.0000000000001411},
pmid = {40832743},
issn = {1473-6551},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/metabolism/cerebrospinal fluid/blood ; *Biomarkers/blood/cerebrospinal fluid/metabolism ; *Neurofilament Proteins/cerebrospinal fluid/blood/metabolism ; DNA-Binding Proteins/blood ; tau Proteins/blood ; },
abstract = {REVIEW PURPOSE: To provide an overview of the recent developments in the field of neurochemical biomarkers of amyotrophic lateral sclerosis (ALS).

RECENT FINDINGS: Neurofilaments, especially NFL, have been confirmed to be good biomarkers for ALS. NFL may be diagnostically useful but its main role is as prognostic and pharmacodynamic biomarker. Inflammatory biomarkers, especially the chitinases, might also serve as pharmacodynamic biomarkers in treatment trials targeting neuroinflammation. GFAP could reflect cognitive-behavioural impairment. CSF dipeptides are diagnostic biomarkers for ALS caused by the C9ORF72 exanucleotide repeat expansion and may be used to confirm target engagement by experimental drugs. Levels of TDP-43 (virtually the ideal biomarker for ALS) in CSF and plasma have not been demonstrated to be consistently altered in ALS. However, promising advancements have been achieved in seed amplification assays for the protein, in its quantification in plasma extracellular vesicles, and in the measurement of CSF levels of a protein reflecting splicing dysfunction of TDP-43. Finally, blood phosphorylated tau has emerged as an ALS biomarker linked to lower motor neuron (or muscle) pathology.

SUMMARY: NFL is still the best neurochemical biomarker for ALS. However, substantial advances have been recently made, especially regarding detection of TDP-43 and blood phosphorylated tau.},
}

Humans
*Amyotrophic Lateral Sclerosis/diagnosis/metabolism/cerebrospinal fluid/blood
*Biomarkers/blood/cerebrospinal fluid/metabolism
*Neurofilament Proteins/cerebrospinal fluid/blood/metabolism
DNA-Binding Proteins/blood
tau Proteins/blood

@article {pmid40832740,
year = {2025},
author = {Lang, C},
title = {Sleep alterations in amyotrophic lateral sclerosis.},
journal = {Current opinion in neurology},
volume = {38},
number = {5},
pages = {606-613},
doi = {10.1097/WCO.0000000000001424},
pmid = {40832740},
issn = {1473-6551},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/physiopathology ; *Sleep Wake Disorders/etiology/physiopathology ; },
abstract = {PURPOSE OF REVIEW: This review summarizes recent evidence on sleep disturbances in amyotrophic lateral sclerosis (ALS), emphasizing their role as intrinsic features of the disease process rather than consequence of motor decline.

RECENT FINDINGS: Emerging data suggest that sleep disturbances such as sleep fragmentation, rapid eye movement sleep (REM) and non rapid eye movement sleep (NREM) alterations and circadian changes often precede classic motor symptoms. Structural and functional hypothalamic changes have been observed in early ALS, suggesting a direct role in sleep-wake dysregulation. In addition, impaired glymphatic clearance during sleep may contribute to neurodegeneration by impairing the removal of protein waste. Polysomnographic studies and cohort data support the presence of prodromal sleep abnormalities in both symptomatic patients and gene mutation carriers. Noninvasive ventilation has shown benefits not only in respiratory management but also in improving sleep quality and overall prognosis.

SUMMARY: Sleep alterations in ALS are increasingly recognized as early indicators and potential modulators of disease progression. The hypothalamus and the glymphatic system emerge as key contributors to these disturbances, highlighting sleep as a therapeutic target. Understanding the role of sleep in ALS pathophysiology may aid in earlier diagnosis and novel intervention strategies aimed at modifying disease course.},
}

Humans
*Amyotrophic Lateral Sclerosis/complications/physiopathology
*Sleep Wake Disorders/etiology/physiopathology

@article {pmid40772655,
year = {2025},
author = {He, J and Fan, D},
title = {Amyotrophic lateral sclerosis in Mainland China: clinical translational challenges and opportunities.},
journal = {Current opinion in neurology},
volume = {38},
number = {5},
pages = {596-605},
pmid = {40772655},
issn = {1473-6551},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/therapy/diagnosis ; China/epidemiology ; *Translational Research, Biomedical ; Biomarkers ; },
abstract = {PURPOSE OF REVIEW: Amyotrophic lateral sclerosis (ALS) imposes a growing medical and socioeconomic burden in China. This review synthesizes recent advances in understanding ALS epidemiology, biomarker discovery, therapeutic innovations, and policy frameworks in China. It highlights the urgency of addressing challenges, including fragmented healthcare resources, translational medicine gaps, and regional inequities, while emphasizing China's unique contributions to global ALS research.

RECENT FINDINGS: Chinese ALS cohorts exhibit distinct epidemiological profiles, including a younger mean age of onset and prolonged median survival. Policy initiatives, such as ALS inclusion in rare disease registries and insurance reforms, aim to reduce financial burdens of patients. Multimodal biomarker exploration has advanced integrated diagnostic models combining neurofilament light chain (NfL) and clinical data platforms. Neuroimaging and electrophysiological studies reveal glymphatic dysfunction, white matter degeneration, and neuromuscular junction abnormalities, with novel links to hepatic metabolism. Genomic analyses identify population-specific variants. Therapeutic innovations in China include not only biopharmaceuticals, but also integrative traditional Chinese medicine (TCM) approaches.

SUMMARY: China's ALS landscape is transitioning towards precision medicine through biomarker-guided diagnostics and multidisciplinary care models. Key priorities include establishing a national ALS registry, standardizing biomarker validation, and expanding clinical trials to bridge translational medicine gaps.},
}

Humans
*Amyotrophic Lateral Sclerosis/epidemiology/therapy/diagnosis
China/epidemiology
*Translational Research, Biomedical
Biomarkers

@article {pmid40772638,
year = {2025},
author = {Menge, S and Decker, L and Freischmidt, A},
title = {Genetics of ALS - genes and modifier.},
journal = {Current opinion in neurology},
volume = {38},
number = {5},
pages = {568-573},
pmid = {40772638},
issn = {1473-6551},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *Genetic Predisposition to Disease/genetics ; Mitochondria/genetics ; },
abstract = {PURPOSE OF REVIEW: Amyotrophic lateral sclerosis (ALS) is a complex genetic disorder, and the pace of discoveries is very rapid. This review aims at briefly summarizing our current knowledge, and at discussing the progress of the last two years.

RECENT FINDINGS: Common variation in numerous genes and variants in some nuclear-encoded mitochondrial genes were linked to an increased or modified risk of ALS, respectively. Mitochondrial function, i.e. specific mitochondrial haplotypes and loss-of-function variants in mitochondria-related genes, was identified as potent modifier of ALS survival, but not risk. Pioneering analyses of copy number variations in ALS-related genes revealed an increased load in ALS, but causality is unclear. A rare hyperactive variant of ER stress associated transcription factor CREB3 was linked to both substantially decreased ALS risk and slower disease progression. Furthermore, variants in IGFBP7 were linked to rare "ALS reversals", but existence of such phenotypes is controversial.

SUMMARY: Common variation increasing ALS risk contributes to our understanding of sporadic ALS, and novel structural variants have the potential to at least partly explain the missing heritability in ALS. Identification of mitochondrial function and ER stress signaling as potent disease modifiers provide valuable starting points for therapeutic approaches beyond targeting single causative genes.},
}

Humans
*Amyotrophic Lateral Sclerosis/genetics
*Genetic Predisposition to Disease/genetics
Mitochondria/genetics

@article {pmid40767546,
year = {2025},
author = {Dupuis, L and Robertson, J},
title = {Is amyotrophic lateral sclerosis less severe in mice than in humans?.},
journal = {Current opinion in neurology},
volume = {38},
number = {5},
pages = {581-587},
pmid = {40767546},
issn = {1473-6551},
mesh = {*Amyotrophic Lateral Sclerosis/genetics/physiopathology/pathology ; Animals ; Humans ; *Disease Models, Animal ; Mice ; Gene Knock-In Techniques ; Mice, Transgenic ; },
abstract = {PURPOSE OF REVIEW: We review here novel knock-in models of amyotrophic lateral sclerosis (ALS).

RECENT FINDINGS: Knock-in mouse models of various familial forms of ALS generally display a mild motor phenotype, with limited progression, that do not recapitulate the full-blown clinical picture of ALS.

SUMMARY: ALS is a devastating neurodegenerative disease in humans. Typically manifesting in the fifth or sixth decade of life, ALS leads to progressive motor dysfunction and death, usually within 2-5 years from symptom onset. A subset of ALS cases are dominantly inherited. Over the last 30 years, multiple mouse models of ALS have been generated, and recent advances in mouse genome editing techniques have enabled the generation of mouse strains carrying orthologous mutations in endogenous genes that mirror those causing familial forms of ALS. Intriguingly, many of these knock-in mouse models develop much milder phenotypes than patients with ALS carrying the same mutations. A full-blown ALS clinical phenotype seems to be only elicited upon overexpression of mutant genes beyond the endogenous levels. Here, we review these novel models and argue that these models could represent how ALS manifests in the mouse species. We also evaluate how these models could be used for characterizing mechanisms and preclinical drug evaluation.},
}

*Amyotrophic Lateral Sclerosis/genetics/physiopathology/pathology
Animals
Humans
*Disease Models, Animal
Mice
Gene Knock-In Techniques
Mice, Transgenic

@article {pmid40916690,
year = {2025},
author = {Sharma, S and Gupta, M and Sharma, S},
title = {Exploring Thiophene-Based Pharmacophores as Emerging Therapeutics for Neurodegenerative Disorders.},
journal = {Critical reviews in analytical chemistry},
volume = {},
number = {},
pages = {1-29},
doi = {10.1080/10408347.2025.2554239},
pmid = {40916690},
issn = {1547-6510},
abstract = {Neurodegenerative disorders (NDD) i.e., dementia of the Alzheimer's type, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis are a rising worldwide epidemic driven by aging populations and characterized by progressive neuronal impairment. In the face of symptomatic therapies, disease-modifying treatments are beyond reach, for many years, at least, owing to the multifactorial origin, including protein aggregation, oxidative stress, neuroinflammation, and neurotransmitter dysregulation. Here, we point out thiophene, a five-membered heterocyclic sulfur-containing scaffold, as an underinvestigated but highly versatile pharmacophore with great potential in therapeutics of NDD. Here, we provide a systematic review of thiophene derivatives identified between 2006 and 2024, highlighting that these compounds are capable of modulating the aggregation of amyloid-β, inhibiting acetylcholinesterase, alleviating oxidative stress, inhibiting the toxicity of α-synuclein, and restoring neurotransmitter homeostasis. Specific emphasis is placed on their structural malleability, blood-brain barrier penetrability, and multi-targeting, which collectively present advantages over traditional heterocyclic templates. Progress in the areas of structure-activity relationship (SAR)-motivated design, synthetic methods, molecular docking, and preclinical assessment is reviewed, leading to the establishment of lead thiophene scaffolds with micro or nanomolar-range activity. This review also provides future directions, such as the requirement of pharmacokinetic improvement, target verification, and translational research to bridge preclinical discoveries with clinical utility. This article collectively places thiophene derivatives as an innovative chemical platform for the design of next-generation drugs for neurodegenerative diseases.},
}

@article {pmid40914405,
year = {2025},
author = {Wang, J and Li, X and Yang, F and Guo, P and Ren, C and Duan, Z and Bi, M and Kong, Y and Zhang, Y and Lu, J},
title = {Exploration of endoplasmic reticulum stress-related gene markers in amyotrophic lateral sclerosis: a comprehensive analysis of bioinformatics and machine learning.},
journal = {Analytical biochemistry},
volume = {},
number = {},
pages = {115969},
doi = {10.1016/j.ab.2025.115969},
pmid = {40914405},
issn = {1096-0309},
abstract = {This study aimed to investigate potential biomarkers related to Endoplasmic reticulum (ER) stress in Amyotrophic lateral sclerosis (ALS) through a comprehensive bioinformatic approach. The gene expression profiles of ALS patients and healthy controls were downloaded from the Gene Expression Omnibus (GEO) database. ER stress-related genes were collected from the MSigDB databases and document literature. The "limma" R package was employed to detect the differentially expressed ER stress-related genes (DE-ERSGs). Three methods of machine learning were applied to select the hub DE-ERSGs. ROC curves were conducted to evaluate model performance. An external dataset was chosen to evaluate the diagnostic capability of hub genes. The CIBERSORT algorithm was used to evaluate the immune cell infiltration characteristics. Additionally, we constructed a systematic ceRNA regulatory network using Cytoscape software and predicted the possible drug candidates using the Enrichr platform. Molecular docking analysis was used to further validate the binding ability of the candidate drug molecules to the hub genes. Six hub DE-ERSGs (ABCA1, CKAP4, TOR1AIP1, MMP9, EDC4, and ALPP) were identified, and the related models performed well. These hub genes were concentrated in multiple pathways and related to various immune cells. Drugs such as nitroglycerin, diazepam, FENRETINIDE, and edaravone exhibited good binding affinity to the hub genes, indicating that they may be promising drugs for the management of ALS. This study revealed the essential role of ER stress in the pathogenesis of ALS from an integrative perspective, providing guidance for the development of new therapeutic targets and diagnostic strategies.},
}

@article {pmid40909873,
year = {2025},
author = {Wang, X and Dong, B and Gan, Q and Li, J and Wu, P and Guan, Y and Wang, J},
title = {Unraveling the Vicious Cycle: Oxidative Stress and Neurotoxicity in Neurodegenerative Diseases.},
journal = {FASEB bioAdvances},
volume = {7},
number = {8},
pages = {e70041},
pmid = {40909873},
issn = {2573-9832},
abstract = {Oxidative stress is characterized by an imbalance between the production and elimination of free radicals, where the rate of free radical generation surpasses the rate of their removal. This imbalance can lead to tissue and organ damage, contributing to the pathogenesis of various diseases. The nervous system, due to its high oxygen consumption, is particularly susceptible to oxidative stress. Numerous neurotoxins can induce neurotoxicity through oxidative stress, thereby contributing to the onset of neurodegenerative diseases, such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. Furthermore, neurotoxicity can exacerbate oxidative stress by disrupting mitochondrial metabolism and impairing the activity of antioxidant enzymes, thereby intensifying neurotoxic effects. This review examines the mechanisms underlying the interaction between oxidative stress and neurotoxicity and explores strategies to mitigate neurotoxicity by reducing oxidative stress, with the aim of informing future clinical approaches for the treatment of neurodegenerative diseases.},
}

@article {pmid40908745,
year = {2025},
author = {Pask, S and Okwuosa, C and Mohamed, A and Price, R and Young, J and Curtis, T and Henderson, S and Winter-Luke, I and Sunny, A and Chambers, RL and Greenley, S and Johansson, T and Bone, AE and Barclay, S and Higginson, IJ and Sleeman, KE and Murtagh, FE},
title = {Models, components and outcomes of palliative and end-of-life care provided to adults living at home: A systematic umbrella review of reviews.},
journal = {Palliative medicine},
volume = {},
number = {},
pages = {2692163251362567},
doi = {10.1177/02692163251362567},
pmid = {40908745},
issn = {1477-030X},
abstract = {BACKGROUND: There is growing demand for home-based palliative care because of patient preference, and increased number of deaths. Optimal models for community-based palliative and end-of-life care are unknown.

AIM: To identify, synthesise and describe review-level evidence to better understand models of palliative and end-of-life care for adults living at home, and examine components of these models and their association with outcomes.

DESIGN: Systematic umbrella review, using key concepts established a priori from Firth et al. and Brereton et al.''s model descriptions. Quality assessment used AMSTAR-2 or equivalent.

DATA SOURCES: MEDLINE, EMBASE, CINAHL, Cochrane Database, Epistemonikos (inception - 2024), supplemented by CareSearch, PROSPERO and citation searches.

RESULTS: From 6683 initial papers, n = 66 reviews were included. Seven models of care were identified; by setting (in-home, outpatient); type of professionals (specialist, integrated, non-specialist); or mode (telehealth, education/training). Components included: holistic person-centred assessment, skilled professionals, access to medicines/care/equipment, patient/family support, advance care planning, integration of services, virtual/remote technology and education. We categorised outcomes into: (i) patient outcomes, (ii) family/informal caregiver outcomes, (iii) professional outcomes and iv) service utilisation/cost outcomes. The 'in-home palliative care' model was most researched with good evidence of positive benefit. Specialist and integrated models of care were next most researched, with evidence of improved patient and service utilisation outcomes. Cost-effectiveness evidence was lacking.

CONCLUSION: This meta-level evidence supports provision of in-home palliative care, with most review level evidence showing positive effect on patient outcomes. There was also evidence to support specialist palliative care and integration of primary palliative care with specialist support.},
}

@article {pmid40907612,
year = {2025},
author = {Kumar, AP and Puthussery, DT},
title = {Regulation of PPAR-γ coactivator-1α and its implication in mitochondrial function and neurodegenerative diseases.},
journal = {Ageing research reviews},
volume = {112},
number = {},
pages = {102887},
doi = {10.1016/j.arr.2025.102887},
pmid = {40907612},
issn = {1872-9649},
abstract = {Peroxisome proliferator-activated receptor (PPAR)-γ coactivator (PGC)-1α, interacts with numerous transcription factors implicated in a wide spectrum of biological responses. It has been identified as a key player in the transcriptional regulation of many mitochondrial components. The activity of PGC1-α is regulated at multiple levels, such as gene expression, transcriptional, post-transcriptional, and post-translational modification. The purpose of this review is to highlight the data supporting PGC1-α-mediated regulation by transcriptional and post-translational modification. We summarize the mechanisms involved in PGC1-α regulation by phosphorylation (AMPK, p38 MAPK, Akt, and GSK3β), acetylation (GCN5, p300, and SRCC), and ubiquitination (E3-ubiquitin ligase). Moreover, the review focuses on the multidomain structure of PGC1-α, its expression in the brain, and the importance of PGC1-α-mediated mitochondrial functions. Mitochondrial dysfunction and impaired energy metabolism are key characteristics of neurodegenerative diseases like Alzheimer's, Huntington's, Parkinson's, amyotrophic lateral sclerosis, and multiple sclerosis. It is associated with reduced PGC1-α expression or activity, resulting in an imbalance in the maintenance of mitochondrial dynamics. In this backdrop, we additionally provide a comprehensive overview of the implication of PGC1-α in the pathogenesis of neurodegenerative disease. Overall, PGC1-α acts as a potential target for therapies to reduce mitochondrial dysfunction associated with neurodegenerative diseases and aid in neuroprotection.},
}

@article {pmid40906916,
year = {2025},
author = {Kakoty, V and Kang, JH and Lee, OH and Oh, DH and Ko, YT},
title = {Grueneberg Ganglion: An Unexplored Site for Intranasal Drug Delivery in Alzheimer's Disease.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.5c00376},
pmid = {40906916},
issn = {1948-7193},
abstract = {Neurological disorders such as Alzheimer's Disease, Parkinson's Disease, Huntington's Disease, Multiple Sclerosis, and Amyotrophic Lateral Sclerosis pose significant challenges for treatment. Reasons for the difficulty in finding cures for these conditions include complications in early diagnosis, progressive and irreversible neuronal damage, and the presence of the blood-brain barrier (BBB), which hinders the delivery of drugs to the affected areas of the brain. Intranasal (INL) drug administration has increasingly gained popularity among researchers for targeting neurological conditions, because of its ability to bypass the BBB. However, chronic INL administration leads to nasal mucosa irritation. Additionally, rapid mucociliary clearance, a lack of targeted drug delivery, increased enzymatic degradation, and tight junctions that obstruct drug transport limit the clinical applicability of the INL route. To overcome these challenges, a unique region in the rodent nose, known as the Grueneberg Ganglion (GG), can be considered to be a novel site for INL drug administration. GG is a small structure housed under the snout cartilage of the nasal septum, approximately 1.5 mm from the nasal opening in mice. It is directly connected to the main olfactory bulb through axons. This Perspective aims to expand knowledge on why GG may be a viable option for INL delivery to combat neurological conditions. For better understanding, we have explained the INL administration in GG, using Alzheimer's Disease and INL insulin therapy as a role model for the current review.},
}

@article {pmid40905723,
year = {2025},
author = {Peng, C and Maiuri, T and Truant, R},
title = {Tipping the PARylation scale: Dysregulation of PAR signaling in Huntington and neurodegenerative diseases.},
journal = {Journal of Huntington's disease},
volume = {},
number = {},
pages = {18796397251372667},
doi = {10.1177/18796397251372667},
pmid = {40905723},
issn = {1879-6400},
abstract = {Poly(ADP-ribosyl)ation (PARylation), a crucial post-translational modification, is catalyzed by ADP-ribosyltransferases (ARTs) and has significant implications in various cellular processes, including DNA damage response, cell signaling, and immune processes. Aberrant PAR signaling is implicated in numerous neurodegenerative diseases, including Alzheimer, Parkinson, amyotrophic lateral sclerosis, and cerebellar ataxia, where increased PAR levels and PARP1 activity are commonly observed. However, Huntington disease exhibits a unique characteristic: reduced PAR levels and impaired PARP1 activity even in prodromal phase. This finding challenges the prevailing understanding of PAR's role in neurodegeneration and suggests that dysregulation of PAR signaling, whether through overactivation or suppression, can lead to neuronal dysfunction. Herein, we discuss how this balance may impact neurodegenerative diseases, and possible connections between PAR signaling and emerging modifiers of disease onset identified by HD genome-wide association studies (GWAS).},
}

@article {pmid40905501,
year = {2025},
author = {Huang, Y and Wan, Y and Chen, J and Qin, M and Wang, J and Liang, H},
title = {Knowledge mapping of biomarkers in amyotrophic lateral sclerosis: a comprehensive bibliometric and visual analysis.},
journal = {Neurodegenerative disease management},
volume = {},
number = {},
pages = {1-17},
doi = {10.1080/17582024.2025.2554525},
pmid = {40905501},
issn = {1758-2032},
abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a severe neurodegenerative disease, and there is currently an urgent need to identify valuable biomarkers to accelerate diagnosis, optimize treatment and prognosis.

METHODS: To conduct a bibliometric analysis of publications related to "ALS biomarker" over the past 20 years, utilizing the subject search feature of the Web of Science Core Collection along with CiteSpace, VOSviewer, and Bibliometrix.

RESULTS: This review presents a 20-year bibliometric analysis of ALS biomarker research (2004-2024), analyzing 2535 publications showing rising trends. The United States led contributions, with Turner, Martin R as the most productive/cited author. Key research hotspots included cerebrospinal fluid, tdp-43, clinical trial, and neuroinflammation. Topics such as neurofilament light chain, machine learning, and exosomes could potentially represent the cutting edge of future research.

CONCLUSION: In summary, this study uses bibliometric analysis of ALS biomarker research to provide a forward-looking perspective on its future limitations and potential.},
}

@article {pmid40904199,
year = {2025},
author = {Isik, S and Osman, S and Yeman-Kiyak, B and Shamshir, SRM and Sanchez, NME},
title = {Advances in Neurodegenerative Disease Therapy: Stem Cell Clinical Trials and Promise of Engineered Exosomes.},
journal = {CNS neuroscience & therapeutics},
volume = {31},
number = {9},
pages = {e70577},
pmid = {40904199},
issn = {1755-5949},
mesh = {Humans ; *Exosomes/transplantation/metabolism ; *Neurodegenerative Diseases/therapy ; Animals ; *Stem Cell Transplantation/methods/trends ; *Clinical Trials as Topic/methods ; },
abstract = {AIM: This review provides a systematic evaluation of 94 stem cell clinical trials to treat neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease.

METHODS: Data were collected from using relevant search terms, focusing exclusively on stem cell therapy. Of the 8000+ participants in these trials, nearly 70% were enrolled in AD-related studies. Only three Phase 3 studies were conducted, and most trials were in the early phases (Phases 1 and 2). Mesenchymal stem cells, neural stem cells, induced pluripotent stem cells, and embryonic stem cells are used the most to treat neurodegenerative diseases. This review also explores the emerging fields of preclinical and clinical investigations of stem cell-derived exosome-based therapies for neurodegenerative diseases.

RESULTS: Exosomes can cross the blood-brain barrier to deliver therapeutic molecules directly to the brain, offering a less invasive alternative to stem cell transplantation. Mesenchymal stem cell-derived exosomes, in particular, have demonstrated significant potential in preclinical models by reducing neuroinflammation, oxidative stress, and promoting neuronal regeneration. Additionally, recent advances in exosome engineering, including surface modifications, therapeutic agent loading, and transgenic modifications, have improved targeting, stability, blood-brain barrier delivery, and neural cell interactions, enabling targeted and effective treatment. Exosome-based therapies are in the preliminary phases of clinical investigation, with only three clinical trials.

CONCLUSION: Given the increasing interest in exosome therapy, clinical investigations are expected to increase. This growth will be driven by ongoing advancements in exosome technology, a deeper understanding of their therapeutic potential, and escalating demand for innovative treatment strategies for neurodegenerative diseases.},
}

Humans
*Exosomes/transplantation/metabolism
*Neurodegenerative Diseases/therapy
Animals
*Stem Cell Transplantation/methods/trends
*Clinical Trials as Topic/methods

@article {pmid40903341,
year = {2025},
author = {Vedula, P and Ishizuka, K and Hayashida, A and Sueo, K and Sawa, A},
title = {Stress-induced nuclear GAPDH: Scientific update and clinical application.},
journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics},
volume = {},
number = {},
pages = {e00725},
doi = {10.1016/j.neurot.2025.e00725},
pmid = {40903341},
issn = {1878-7479},
abstract = {Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) is known as a moonlighting protein beyond its original glycolytic function. Stress-induced nuclear translocation of GAPDH has been reproducibly reported, which results in variety types of cellular responses, including cell death and dysfunction. Blocking this stress-induced cascade has been regarded as a target of drug discovery and development for human disease conditions, particularly for neurological and psychiatric diseases. There are promising small compounds that can block this cascade in cell and animal models. Nevertheless, the clinical trials for Parkinson's disease and amyotrophic lateral sclerosis with one of these compounds Omigapil were unsuccessful. Including these failure cases, this review article discussed the scientific frontline of GAPDH, particularly stress-induced nuclear GAPDH, and its potential for clinical applications.},
}

@article {pmid40901987,
year = {2025},
author = {Sun, Z and Li, C and Leitner, D and Wu, M and Zhang, J and Wisniewski, T and Ge, Y},
title = {Age-related Vascular Alterations in the Choroid Plexus: Novel Insights from Pathophysiology and Imaging Studies.},
journal = {Aging and disease},
volume = {},
number = {},
pages = {},
doi = {10.14336/AD.2025.0735},
pmid = {40901987},
issn = {2152-5250},
abstract = {The choroid plexus (ChP), a highly vascularized brain structure responsible for cerebrospinal fluid (CSF) production, undergoes significant age-related changes that may contribute to neurodegenerative diseases involving disrupted immune regulation, fluid homeostasis and waste clearance. Compared to other brain regions, vascular research on the ChP remains limited despite its critical role as a central interface between the blood and CSF. This review focuses on age-related vascular and structural alterations in the ChP from both histopathological and neuroimaging perspectives, and explores their impact on CSF dynamics, immune regulation, and the integrity of the blood-CSF barrier (BCSFB). Rather than shrinking, the aging ChP often enlarges due to dystrophic changes, as shown in volumetric MRI studies. Histological studies reveal epithelial degeneration, basement membrane thickening, and stromal fibrosis in the normal aging process. In dementia such as Alzheimer's disease (AD), proteomic studies have identified upregulation of AD- and immune-related proteins, along with downregulation of proteins linked to CSF clearance and metabolic support. Emerging high-resolution contrast-enhanced MRI techniques now allow in vivo visualization of microvascular changes within the ChP, shedding light on its normal and abnormal aging processes. Understanding these alterations is critical, as they may influence the onset and progression of various neurological diseases such as AD, Parkinson's disease (PD), normal pressure hydrocephalus, and amyotrophic lateral sclerosis (ALS). The recent advancements and challenges described in this study underscore the need for deeper investigation into ChP aging to inform future diagnostic and therapeutic strategies of neurodegenerative diseases.},
}

@article {pmid40900744,
year = {2025},
author = {Mani, S and Wasnik, S and Shandilya, C and Srivastava, V and Khan, S and Singh, KK},
title = {Pathogenic synergy: dysfunctional mitochondria and neuroinflammation in neurodegenerative diseases associated with aging.},
journal = {Frontiers in aging},
volume = {6},
number = {},
pages = {1615764},
pmid = {40900744},
issn = {2673-6217},
abstract = {The term "neurodegenerative diseases" (NDDs) refers to a range of aging-associated conditions, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Unique clinical symptoms and underlying pathological mechanisms distinguish each of these illnesses. Although these conditions vary, they share chronic neuroinflammation as a defining characteristic. Protein aggregation and mitochondrial dysfunction are believed to play a role in initiating the neuroinflammatory response and, subsequently, the development and course of these illnesses. Apart from providing energy to the cells, mitochondria are involved in the immunoinflammatory response associated with neurological disorders such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, and epilepsy. This involvement is attributed to controlling processes such as inflammasome activation and cell death. Under inflammatory conditions, the underlying regulatory mechanisms for these aging-associated disorders may include calcium homeostasis imbalance, mitochondrial oxidative stress, mitochondrial dynamics, and epigenetics. Various NDDs are linked to neuroinflammation and mitochondrial dysfunction. The linkages between these occurrences are becoming more apparent, but the etiology of these pathologic lesions is yet to be elucidated. This review examines the role of neuroinflammation and mitochondrial dysfunction in the growth and course of NDDs, emphasizing the possibility of identifying novel therapeutic targets to address aging-related neurodegenerative processes and retard the progression of these illnesses.},
}

@article {pmid40897992,
year = {2025},
author = {Quigley, SE and Quigg, KH and Goutman, SA},
title = {Genetic and Mechanistic Insights Inform Amyotrophic Lateral Sclerosis Treatment and Symptomatic Management: Current and Emerging Therapeutics and Clinical Trial Design Considerations.},
journal = {CNS drugs},
volume = {},
number = {},
pages = {},
pmid = {40897992},
issn = {1179-1934},
support = {R01NS120926/NH/NIH HHS/United States ; R01NS127188/NH/NIH HHS/United States ; R01TS000344/ACL/ACL HHS/United States ; R01TS000327//Centers for Disease Control and Prevention/Agency for Toxic Substances and Disease Registry/ ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting both upper and lower motor neurons. ALS is classically characterized by painless progressive weakness, causing impaired function of limbs, speech, swallowing, and respiratory function. The disease is fatal within 2-4 years, often the result of respiratory failure. The pathologic hallmark for a majority of ALS cases is aberrant cytoplasmic accumulations of the nuclear protein TAR-DNA binding protein (TDP-43). A total of 10-15% of ALS can be attributed to a single gene mutation, known as genetic or "familial" ALS, while the remainder of cases are termed nongenetic or "sporadic" although heritability has been measured in up to 37% in this population. Complex interactions between genetics, environment, and physiologic susceptibility are thought to contribute to disease. Management is primarily supportive in nature, though there are several approved treatments worldwide. This review details the mechanisms and evidence of approved disease-modifying treatments, relevant measures to track disease burden and progression used in clinical trials, and approaches to pharmacologic management of common symptoms in ALS. As there is not currently a cure for ALS, research into the complex pathophysiologic and genetic alterations contributing to disease is of great interest. This review further discusses the current understanding of genetic etiologies and altered physiology leading to disease, such as neuroinflammation, integrated stress response, aberrant proteostasis and mitochondrial dysfunction, among others. The translation of preclinical discoveries into current investigational therapeutics, novel therapeutic categories such as antisense oligonucleotides and stem cell transplantation, as well as future horizons harnessing the power of artificial intelligence in drug development and clinical trials are discussed.},
}

@article {pmid40895800,
year = {2025},
author = {D'Arrigo, C and Labbate, S and Galante, D},
title = {Boosting the Therapeutic Potential of Extracellular Vesicles Derived From Mesenchymal Stem Cells via Advanced Preconditioning for Neurodegenerative Disorders.},
journal = {Stem cells international},
volume = {2025},
number = {},
pages = {2616653},
pmid = {40895800},
issn = {1687-966X},
abstract = {Acute and chronic neurodegenerative conditions (NDs) are major causes of disability and mortality worldwide. Acute NDs encompass conditions such as stroke, traumatic brain injury (TBI), and spinal cord injury (SCI). On the other hand, chronic NDs include Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS). Currently, no definitive cure exists for these diseases, and available therapies focus primarily on slowing the progression of symptoms. Mesenchymal stem cells (MSCs), due to their multilineage differentiation capacity, immunomodulatory abilities, and regenerative properties, have gained attention in regenerative medicine. In recent years, extracellular vesicles (EVs) derived from MSCs have shown great promise as a cell-free therapeutic approach, eliminating the risks associated with direct MSCs use, such as tumorigenicity and poor cell survival after transplantation. EVs have emerged as powerful mediators of intercellular communication and tissue repair, exhibiting immunomodulatory, anti-inflammatory, and proregenerative properties. However, limitations such as low EVs yield and reduced efficacy due to MSCs replicative senescence restrict their therapeutic potential. Preconditioning strategies, including hypoxia, 3D cultures, and biochemical priming, have been explored in other fields to enhance EVs properties, yet their specific application to NDs remains under-reported. This review aims to address this gap by analyzing the preconditioning methods used to boost the therapeutic potential of MSCs-derived EVs for neurodegenerative diseases. These preconditioning strategies may enhance EVs yield, functional cargo, and targeted therapeutic efficacy for treating acute and chronic NDs.},
}

@article {pmid40891578,
year = {2025},
author = {Toyota, S},
title = {Expanding Chemistry of Expanded Helicenes.},
journal = {Chemistry (Weinheim an der Bergstrasse, Germany)},
volume = {},
number = {},
pages = {e02193},
doi = {10.1002/chem.202502193},
pmid = {40891578},
issn = {1521-3765},
support = {23K26637//Japan Society for the Promotion of Science/ ; 20H02721//Japan Society for the Promotion of Science/ ; 23H01944//Japan Society for the Promotion of Science/ ; },
abstract = {Expanded helicenes are interesting compounds created by modifying the original helicene structure through the incorporation of linearly fused benzene rings, enlarging the helical diameter. Motivated by Tilley et al.'s report of a key expanded helicene structure in 2017, several research groups have synthesized such nonplanar aromatic compounds, aiming to explore their impressive structures, properties, and chiroptical performance. This review highlights recent advances in the expanded helicene chemistry through experimental and theoretical studies. The shape and length of helical structures depend on the number and combination of angularly and linearly fused benzene rings. Helical structures are classified using notations, and specific compounds corresponding to each structural form, namely, hexagonal, triangular, rhombic, or others, are introduced herein. As an extension of the molecular design, examples of nonhexagonal and heteroaromatic ring-embedded expanded helicenes are presented. Specifically, this review focuses on how the diameters, lengths, and turn numbers of helical structures depend on dynamic processes involving helical inversion and chiroptical properties (circular dichroism (CD) and circularly polarized luminescence (CPL)). The characteristics and perspectives of this molecular design are also discussed.},
}

@article {pmid40891506,
year = {2025},
author = {Pir, GJ and Buddenkotte, J and Alam, MA and Own, A and Eck, RJ and Kraemer, BC and Mandelkow, E and Steinhoff, M},
title = {TDP-43 proteinopathies and neurodegeneration: insights from Caenorhabditis elegans models.},
journal = {The FEBS journal},
volume = {},
number = {},
pages = {},
doi = {10.1111/febs.70239},
pmid = {40891506},
issn = {1742-4658},
support = {11S-0117 180326//Qatar National Research Fund/ ; //Katharina Hardt Foundation/ ; F99AG088436/NH/NIH HHS/United States ; //Cure Alzheimer's Fund/ ; },
abstract = {TDP-linked proteinopathies, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and limbic-predominant age-related TDP-43 encephalopathy (LATE), are characterised by pathogenic deposits containing transactive response DNA-binding protein 43 (TDP-43) in the brain and spinal cord of patients. These hallmark pathological features are associated with widespread neuronal dysfunction and progressive neurodegeneration. TDP-43's role as an essential RNA/DNA-binding protein in RNA metabolism and gene expression regulation is clear, but deciphering the intricate pathophysiological mechanisms underpinning TDP-43-mediated neurodegeneration is paramount for developing effective therapies and novel diagnostic tools for early detection before frank neuronal loss occurs. The nematode Caenorhabditis elegans, with highly conserved TDP-43 orthologue TDP-1, serves as a powerful genetic model to investigate the molecular underpinnings of TDP-43 proteinopathies. Here, we provide a brief overview of the structural and functional characteristics of TDP-43 and TDP-1, highlighting their conserved roles in RNA metabolism, stress responses, and neurodegeneration. We then delve into the pathobiology of TDP-43, drawing insights from C. elegans models expressing either monogenic TDP-43 variants or bigenic combinations with ALS-associated risk genes, and discuss how these models have advanced our understanding of the pathomechanisms of TDP-43 proteinopathies. By employing its simplicity and genetic manipulability, we discuss how these models have helped identify chemical and genetic suppressors of TDP-43-induced phenotypes, including small molecules like Pimozide and the probiotic Lacticaseibacillus rhamnosus HA-114, now in clinical trials. This review underscores the translational value of C. elegans in unraveling the biochemical pathways and interactions in TDP-43 proteinopathies that perturb cellular physiology, potentially facilitating mechanism-based therapy development.},
}

@article {pmid40887101,
year = {2025},
author = {Guillot, SJ and Luppi, PH and Dupuis, L and Bolborea, M},
title = {Sleep in neurodegenerative diseases: A focus on melatonin, melanin-concentrating hormone and orexin.},
journal = {Journal of neuroendocrinology},
volume = {},
number = {},
pages = {e70085},
doi = {10.1111/jne.70085},
pmid = {40887101},
issn = {1365-2826},
support = {ANR-16-CE16-0015//Agence Nationale de la Recherche/ ; ANR-16-CE92-0031//Agence Nationale de la Recherche/ ; ANR-19-CE17-0016//Agence Nationale de la Recherche/ ; ANR-20-CE17-0008//Agence Nationale de la Recherche/ ; ANR-24-CE37-4064//Agence Nationale de la Recherche/ ; //TargetALS/ ; //Fondation Thierry Latran/ ; //Association Francaise de Recherche sur la sclérose latérale amyotrophique/ ; //Radala Foundation for ALS Research/ ; //ARSLA/ ; //University of Starsbourg fundation/ ; //Fondation Bettencourt Schueller/ ; DEQ20180339179//Fondation pour la Recherche Médicale/ ; //Axa Research Funds/ ; },
abstract = {Sleep and circadian rest-activity rhythm alterations are recognised as inherent clinical features of various neurodegenerative diseases. Traditionally viewed as secondary manifestations of neurodegeneration, recent studies have revealed that disruptions in circadian rhythm and sleep-wake cycles can precede clinical symptoms and significantly contribute to the underlying pathophysiological progression. In this review, we summarise recent research on the impact of sleep and circadian rhythm alterations in ageing and major neurodegenerative diseases, including Alzheimer's, Parkinson's, Huntington's, amyotrophic lateral sclerosis, and frontotemporal dementia, highlighting the roles of melatonin, orexin, and melanin-concentrating hormone (MCH) systems as key regulators at the intersection of sleep and neurodegeneration. We argue that sleep and circadian alterations may serve as early biomarkers and therapeutic targets for these diseases.},
}

@article {pmid40885478,
year = {2025},
author = {Hafiz, B and Aldahlawi, A and Ashqar, A and Hamzah, A and Alotaibi, Y and Bajunaid, K and Baeesa, S},
title = {Outcomes of Surgical Versus Endovascular Treatment of Spinal Dural Arteriovenous Fistula: A Systematic Review and Meta-Analysis.},
journal = {World neurosurgery},
volume = {},
number = {},
pages = {124420},
doi = {10.1016/j.wneu.2025.124420},
pmid = {40885478},
issn = {1878-8769},
abstract = {BACKGROUND: Spinal dural arteriovenous fistulas (SDAVFs) are the most prevalent type of spinal vascular malformation and can lead to progressive neurological impairments if left untreated. Endovascular embolization and microsurgical resection are treatment options, although the optimal treatment method remains a subject of debate.

OBJECTIVE: A comprehensive systematic review and meta-analysis to compare the endovascular and microsurgical treatment outcomes of SDAVFs.

METHODS: An exhaustive literature search was conducted in the PubMed, Embase, Scopus, and Web of Science databases, encompassing publications from 2014 to 2024. A total of 522 patients from seven studies (417 surgical and 105 endovascular) met the inclusion criteria. Information on post-treatment complications, recurrence/failure rates, and functional improvement as assessed by the Aminoff-Logue Scale (ALS) or modified ALS (mALS) was extracted. I[2] statistics were used to evaluate heterogeneity, and random-effects models were used to compute risk ratios (RRs) and odds ratios (ORs).

RESULTS: Compared to endovascular intervention, surgical treatment was linked to significantly lower rates of recurrence or treatment failure (RR: 0.19; 95% CI: 0.09-0.39; p < 0.001), especially in long-term follow-up and thoracic-level studies. With greater ALS/mALS gains and a higher percentage of patients achieving full or partial recovery, functional improvement favored surgery. Although complication types varied, complication rates were similar across modalities (OR: 0.84; 95% CI: 0.48-1.49). Asymmetry in funnel plots indicated possible publication bias in favor of successful surgical outcomes.

CONCLUSION: For SDAVFs, surgical ligation provides better long-term results than endovascular embolization in terms of neurological recovery and recurrence prevention. Even though both procedures are usually safe, surgery is the recommended first-line course of action due to the higher failure and recurrence rates linked to embolization, especially in patients with operable anatomy and progressive symptoms.},
}

@article {pmid40858858,
year = {2025},
author = {Loo, YS and Yusoh, NA and Yap, K and Ng, CS},
title = {Programmable self-replicating JEV nanotherapeutics redefine RNA delivery in ALS.},
journal = {Communications biology},
volume = {8},
number = {1},
pages = {1282},
pmid = {40858858},
issn = {2399-3642},
support = {PM010CNI000148//International Brain Research Organization (IBRO)/ ; },
mesh = {*Amyotrophic Lateral Sclerosis/therapy/genetics ; Humans ; Animals ; *Encephalitis Virus, Japanese/genetics/physiology ; *Oligonucleotides, Antisense/administration & dosage/genetics ; *Genetic Therapy/methods ; MicroRNAs/genetics ; Virus Replication ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron degeneration, leading to paralysis and respiratory failure. Current therapies offer limited benefits, highlighting the need for novel therapeutic strategies. Antisense oligonucleotides (ASO) and CRISPR/Cas9 gene editing hold promise, but their effective delivery to the central nervous system (CNS) remains a significant challenge. Here, a potential approach involves utilizing engineered Japanese encephalitis virus (JEV) as a self-replicating nanocarrier for targeted ASO delivery to motor neurons. By leveraging JEV's natural neurotropism and "Trojan horse" mechanism of immune cell-mediated CNS entry, this strategy overcomes the blood-brain and blood-spinal cord barriers (BBB/BSCB). Incorporation of ASO sequences within the JEV genome facilitates co-packaging and sustained therapeutic delivery, while microRNA (miRNA)-mediated attenuation may enhance safety and CNS specificity. This theoretical framework offers a potential paradigm shift in CNS gene therapy for ALS and other neurodegenerative diseases by enabling efficient, targeted, and sustained ASO delivery. However, experimental validation remains critical to assess its safety and therapeutic efficacy.},
}

*Amyotrophic Lateral Sclerosis/therapy/genetics
Humans
Animals
*Encephalitis Virus, Japanese/genetics/physiology
*Oligonucleotides, Antisense/administration & dosage/genetics
*Genetic Therapy/methods
MicroRNAs/genetics
Virus Replication

@article {pmid40884740,
year = {2025},
author = {Kalasa Anil Kumar, AP and Subair, S and Basthikoppa Shivamurthy, P and Ummar, S and Rajeev, AC and Raju, R},
title = {Decoding ATXN2 Phosphocode: Structural Insights and Therapeutic Opportunities in Disease.},
journal = {The protein journal},
volume = {},
number = {},
pages = {},
pmid = {40884740},
issn = {1875-8355},
abstract = {Ataxin-2 (ATXN2), a key RNA-binding protein, regulates RNA metabolism, stress granule formation, and neuronal homeostasis, with dysregulated phosphorylation contributing to Spinocerebellar Ataxia type 2 (SCA2), amyotrophic lateral sclerosis (ALS), and cancer. This review integrates structural biology, phosphoproteomics, and interactome analyses to map six critical phosphosites (S772, T741, S624, S684, S784, S889) within ATXN2's intrinsically disordered regions. Modulated by kinases GSK3β and CDK13 and phosphatases like INPP5F, these sites orchestrate interactions with RNA-binding partners (e.g., ATXN2L, FXR2, STAU2) and co-regulated proteins (e.g., TP53BP1, NUP153), driving pathogenesis through disrupted autophagy, nucleocytoplasmic transport, and stress granule dynamics. We propose targeted therapies, including GSK3β inhibitors for ALS, antisense oligonucleotides for SCA2, and MTOR modulators for cancer, to restore ATXN2 function. By elucidating phosphocode of ATXN2, this work highlights novel avenues for precision medicine in neurodegenerative and oncogenic diseases.},
}

@article {pmid40883656,
year = {2025},
author = {García-Parra, B and Guiu, JM and Povedano, M and Modamio, P},
title = {Geographic distribution of amyotrophic lateral sclerosis-related genes: a systematic review.},
journal = {Neurodegenerative disease management},
volume = {},
number = {},
pages = {1-7},
doi = {10.1080/17582024.2025.2554382},
pmid = {40883656},
issn = {1758-2032},
abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a rare motor neuron disease. There is no effective treatment, but disease-modifying therapies do exist. Objective. To identify the geographical distribution of ALS-related genes.

METHODS: A systematic review was conducted according to the PRISMA 2020 guidelines in PubMed and Web of Science. Inclusion criteria: patients with ALS, no age or gender restriction, English and Spanish languages, studies published until 31 July 2025.

RESULTS: Thirty-eight results were obtained, 32 were selected, 19 articles were assessed for eligibility, and 8 articles were included from databases. Three articles recommended by clinical experts were added, so 11 results were reviewed. This research showed that published articles on the geographic distribution of ALS-related genes are limited, particularly for underrepresented regions such as Africa.

CONCLUSION: The findings demonstrate the need for intensified international research to improve knowledge of the genetic epidemiology of ALS.},
}

@article {pmid40871062,
year = {2025},
author = {Yang, HM},
title = {Overcoming the Blood-Brain Barrier: Advanced Strategies in Targeted Drug Delivery for Neurodegenerative Diseases.},
journal = {Pharmaceutics},
volume = {17},
number = {8},
pages = {},
pmid = {40871062},
issn = {1999-4923},
support = {03-2025-0200//Seoul National University Hospital/ ; },
abstract = {The increasing global health crisis of neurodegenerative diseases such as Alzheimer's, Parkinson's, amyotrophic lateral sclerosis, and Huntington's disease is worsening because of a rapidly increasing aging population. Disease-modifying therapies continue to face development challenges due to the blood-brain barrier (BBB), which prevents more than 98% of small molecules and all biologics from entering the central nervous system. The therapeutic landscape for neurodegenerative diseases has recently undergone transformation through advances in targeted drug delivery that include ligand-decorated nanoparticles, bispecific antibody shuttles, focused ultrasound-mediated BBB modulation, intranasal exosomes, and mRNA lipid nanoparticles. This review provides an analysis of the molecular pathways that cause major neurodegenerative diseases, discusses the physiological and physicochemical barriers to drug delivery to the brain, and reviews the most recent drug targeting strategies including receptor-mediated transcytosis, cell-based "Trojan horse" approaches, gene-editing vectors, and spatiotemporally controlled physical methods. The review also critically evaluates the limitations such as immunogenicity, scalability, and clinical translation challenges, proposing potential solutions to enhance therapeutic efficacy. The recent clinical trials are assessed in detail, and current and future trends are discussed, including artificial intelligence (AI)-based carrier engineering, combination therapy, and precision neuro-nanomedicine. The successful translation of these innovations into effective treatments for patients with neurodegenerative diseases will require essential interdisciplinary collaboration between neuroscientists, pharmaceutics experts, clinicians, and regulators.},
}

@article {pmid40870005,
year = {2025},
author = {Jeong, J and Kim, J and Kim, MS},
title = {Dual Nature of Mitochondrial Integrated Stress Response: Molecular Switches from Protection to Pathology.},
journal = {Genes},
volume = {16},
number = {8},
pages = {},
pmid = {40870005},
issn = {2073-4425},
mesh = {Humans ; *Mitochondria/metabolism/pathology/genetics ; *Stress, Physiological ; Animals ; *Amyotrophic Lateral Sclerosis/metabolism/drug therapy/pathology/genetics ; },
abstract = {BACKGROUND: The mitochondrial integrated stress response (ISR) represents a fundamental cellular adaptation mechanism with dual protective and pathological roles. We critically analyzed current literature on ISR mechanisms, focusing on recent paradigm shifts including the 2020 discovery of the OMA1-DELE1-HRI axis, emerging controversies over context-dependent activation patterns, and the January 2025 clinical trial failures that have reshaped the therapeutic landscape.

METHODS: We reviewed recent literature (2020-2025) examining ISR mechanisms, clinical trials, and therapeutic developments through comprehensive database searches.

RESULTS: The field has evolved from simple linear pathway models to recognition of complex, context-dependent networks. Recent findings reveal that ISR activation mechanisms vary dramatically based on cellular metabolic state, with distinct pathways operating in proliferating versus differentiated cells. The "dark microglia" phenotype in neurodegeneration and DR5-mediated apoptotic switches exemplify pathological ISR manifestations, while adaptive responses include metabolic reprogramming and quality control enhancement.

CONCLUSIONS: The 2025 failures of DNL343 and ABBV-CLS-7262 in ALS trials underscore the need for precision medicine approaches that account for context-dependent ISR functions, temporal dynamics, and disease-specific mechanisms.},
}

Humans
*Mitochondria/metabolism/pathology/genetics
*Stress, Physiological
Animals
*Amyotrophic Lateral Sclerosis/metabolism/drug therapy/pathology/genetics

@article {pmid40869392,
year = {2025},
author = {Șerban, M and Toader, C and Covache-Busuioc, RA},
title = {Blueprint of Collapse: Precision Biomarkers, Molecular Cascades, and the Engineered Decline of Fast-Progressing ALS.},
journal = {International journal of molecular sciences},
volume = {26},
number = {16},
pages = {},
pmid = {40869392},
issn = {1422-0067},
mesh = {*Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology/diagnosis ; Humans ; *Biomarkers/metabolism ; Disease Progression ; Animals ; Mitochondria/metabolism ; Precision Medicine ; Neurofilament Proteins/metabolism ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is still a heterogeneous neurodegenerative disorder that can be identified clinically and biologically, without a strong set of biomarkers that can adequately measure its fast rate of progression and molecular heterogeneity. In this review, we intend to consolidate the most relevant and timely advances in ALS biomarker discovery, in order to begin to bring molecular, imaging, genetic, and digital areas together for potential integration into a precision medicine approach to ALS. Our goal is to begin to display how several biomarkers in development (e.g., neurofilament light chain (NfL), phosphorylated neurofilament heavy chain (pNfH), TDP-43 aggregates, mitochondrial stress markers, inflammatory markers, etc.) are changing our understanding of ALS and ALS dynamics. We will attempt to provide a framework for thinking about biomarkers in a systematic way where our candidates are not signals alone but part of a tethered pathophysiological cascade. We are particularly interested in the fast progressor phenotype, a devastating and under-characterized subset of ALS due to a rapid axonal degeneration, early respiratory failure, and very short life span. We will try to highlight the salient molecular features of this ALS subtype, including SOD1 A5V toxicity, C9orf72 repeats, FUS variants, mitochondrial collapse, and impaired autophagy mechanisms, and relate these features to measurable blood and CSF (biomarkers) and imaging platforms. We will elaborate on several interesting tools, for example, single-cell transcriptomics, CSF exosomal cargo analysis, MRI techniques, and wearable sensor outputs that are developing into high-resolution windows of disease progression and onset. Instead of providing a static catalog, we plan on providing a conceptual roadmap to integrate biomarker panels that will allow for earlier diagnosis, real-time disease monitoring, and adaptive therapeutic trial design. We hope this synthesis will make a meaningful contribution to the shift from observational neurology to proactive biologically informed clinical care in ALS. Although there are still considerable obstacles to overcome, the intersection of a precise molecular or genetic association approach, digital phenotyping, and systems-level understandings may ultimately redefine how we monitor, care for, and treat this challenging neurodegenerative disease.},
}

*Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology/diagnosis
Humans
*Biomarkers/metabolism
Disease Progression
Animals
Mitochondria/metabolism
Precision Medicine
Neurofilament Proteins/metabolism

@article {pmid40869205,
year = {2025},
author = {Lewandowski, D and Konieczny, M and Różycka, A and Chrzanowski, K and Owecki, W and Kalinowski, J and Stepura, M and Jagodziński, P and Dorszewska, J},
title = {Cathepsins in Neurological Diseases.},
journal = {International journal of molecular sciences},
volume = {26},
number = {16},
pages = {},
pmid = {40869205},
issn = {1422-0067},
mesh = {Humans ; *Cathepsins/metabolism ; Animals ; *Nervous System Diseases/metabolism/pathology ; Lysosomes/metabolism ; Biomarkers/metabolism ; },
abstract = {Cathepsins, a family of lysosomal proteases, play critical roles in maintaining cellular homeostasis through protein degradation and modulation of immune responses. In the central nervous system (CNS), their functions extend beyond classical proteolysis, influencing neuroinflammation, synaptic remodeling, and neurodegeneration. Emerging evidence underscores the crucial role of microglial cathepsins in the pathophysiology of several neurological disorders. This review synthesizes current knowledge on the involvement of cathepsins in a spectrum of CNS diseases, including Parkinson's disease, Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, epilepsy, Huntington's disease, and ischemic stroke. We highlight how specific cathepsins contribute to disease progression by modulating key pathological processes such as α-synuclein and amyloid-β clearance, tau degradation, lysosomal dysfunction, neuroinflammation, and demyelination. Notably, several cathepsins demonstrate both neuroprotective and pathogenic roles depending on disease context and expression levels. Additionally, the balance between cathepsins and their endogenous inhibitors, such as cystatins, emerges as a critical factor in CNS pathology. While cathepsins represent promising biomarkers and therapeutic targets, significant gaps remain in our understanding of their mechanistic roles across diseases. Future studies focusing on their regulation, substrate specificity, and interplay with genetic and epigenetic factors may yield novel strategies for early diagnosis and disease-modifying treatments in neurology.},
}

Humans
*Cathepsins/metabolism
Animals
*Nervous System Diseases/metabolism/pathology
Lysosomes/metabolism
Biomarkers/metabolism

@article {pmid40868276,
year = {2025},
author = {Voicu, V and Toader, C and Șerban, M and Covache-Busuioc, RA and Ciurea, AV},
title = {Systemic Neurodegeneration and Brain Aging: Multi-Omics Disintegration, Proteostatic Collapse, and Network Failure Across the CNS.},
journal = {Biomedicines},
volume = {13},
number = {8},
pages = {},
pmid = {40868276},
issn = {2227-9059},
abstract = {Neurodegeneration is increasingly recognized not as a linear trajectory of protein accumulation, but as a multidimensional collapse of biological organization-spanning intracellular signaling, transcriptional identity, proteostatic integrity, organelle communication, and network-level computation. This review intends to synthesize emerging frameworks that reposition neurodegenerative diseases (ND) as progressive breakdowns of interpretive cellular logic, rather than mere terminal consequences of protein aggregation or synaptic attrition. The discussion aims to provide a detailed mapping of how critical signaling pathways-including PI3K-AKT-mTOR, MAPK, Wnt/β-catenin, and integrated stress response cascades-undergo spatial and temporal disintegration. Special attention is directed toward the roles of RNA-binding proteins (e.g., TDP-43, FUS, ELAVL2), m6A epitranscriptomic modifiers (METTL3, YTHDF1, IGF2BP1), and non-canonical post-translational modifications (SUMOylation, crotonylation) in disrupting translation fidelity, proteostasis, and subcellular targeting. At the organelle level, the review seeks to highlight how the failure of ribosome-associated quality control (RQC), autophagosome-lysosome fusion machinery (STX17, SNAP29), and mitochondrial import/export systems (TIM/TOM complexes) generates cumulative stress and impairs neuronal triage. These dysfunctions are compounded by mitochondrial protease overload (LONP1, CLPP), UPR maladaptation, and phase-transitioned stress granules that sequester nucleocytoplasmic transport proteins and ribosomal subunits, especially in ALS and FTD contexts. Synaptic disassembly is treated not only as a downstream event, but as an early tipping point, driven by impaired PSD scaffolding, aberrant endosomal recycling (Rab5, Rab11), complement-mediated pruning (C1q/C3-CR3 axis), and excitatory-inhibitory imbalance linked to parvalbumin interneuron decay. Using insights from single-cell and spatial transcriptomics, the review illustrates how regional vulnerability to proteostatic and metabolic stress converges with signaling noise to produce entropic attractor collapse within core networks such as the DMN, SN, and FPCN. By framing neurodegeneration as an active loss of cellular and network "meaning-making"-a collapse of coordinated signal interpretation, triage prioritization, and adaptive response-the review aims to support a more integrative conceptual model. In this context, therapeutic direction may shift from damage containment toward restoring high-dimensional neuronal agency, via strategies that include the following elements: reprogrammable proteome-targeting agents (e.g., PROTACs), engineered autophagy adaptors, CRISPR-based BDNF enhancers, mitochondrial gatekeeping stabilizers, and glial-exosome neuroengineering. This synthesis intends to offer a translational scaffold for viewing neurodegeneration as not only a disorder of accumulation but as a systems-level failure of cellular reasoning-a perspective that may inform future efforts in resilience-based intervention and precision neurorestoration.},
}

@article {pmid40868211,
year = {2025},
author = {Flor, J and Silveira, AT and Martins, IA and Otero, LB and Silva, FM and Vizuete, AFK and Wink, MR and Rigatto, K},
title = {Biological Actions of Alamandine: A Scoping Review.},
journal = {Biomedicines},
volume = {13},
number = {8},
pages = {},
pmid = {40868211},
issn = {2227-9059},
abstract = {Objective: This scoping review aims to comprehensively map the existing literature on the mechanisms of action of Alamandine (ALA), a peptide within the renin-angiotensin system, and its effects across various physiological systems. Materials and Methods: Utilizing the Joanna Briggs Institute methodology, a thorough search of databases including PubMed, Embase, Scopus, and Web of Science was conducted up to 30 January 2025. The review focused on identifying studies that explore the biological and therapeutic roles of ALA in different contexts, incorporating in vivo, in vitro, and in silico research. Results: A total of 590 records were initially identified, with 25 meeting the eligibility criteria for inclusion in this review. China emerged as the leading contributor to the research in this area, with a significant focus on the cardiovascular system. The studies revealed that ALA exhibits a range of beneficial effects, including anti-inflammatory, vasodilatory, antifibrotic, and antiapoptotic actions. These effects are primarily mediated through the inhibition of the mitogen-activated protein kinase (MAPK) signaling pathway and modulation of the nitric oxide pathway. The review also highlighted AL's potential in mitigating oxidative stress and its implications in treating cardiovascular diseases, fibrosis, and cancer. Conclusions: The findings suggest that ALA holds significant therapeutic potential, offering antihypertensive, anti-inflammatory, antifibrotic, and anticancer benefits without notable adverse effects, warranting further research to explore its full potential and mechanism of action.},
}

@article {pmid40876427,
year = {2025},
author = {Ibrahim, SI and Zaher, DM and Hersi, FA and Hamouda, AO and Al Hindawi, MA and Omar, HA},
title = {Repurposing edaravone in oncology: Bridging antioxidant defense and immune modulation.},
journal = {International immunopharmacology},
volume = {164},
number = {},
pages = {115413},
doi = {10.1016/j.intimp.2025.115413},
pmid = {40876427},
issn = {1878-1705},
abstract = {Edaravone, a synthetic free radical scavenger originally approved for neurological disorders such as stroke and amyotrophic lateral sclerosis (ALS), is gaining attention for its emerging potential role in cancer. Beyond its well-established antioxidant properties, edaravone demonstrates significant anti-inflammatory and immunomodulatory activities, including the inhibition of key pathways such as NF-κB, JAK2/STAT3, and TLR4/IL-6, suggesting potential to modulate immune responses within the tumor microenvironment. This review discusses how edaravone disrupts oncogenic signaling, induces cell cycle arrest, and enhances apoptosis, particularly in cancer stem cells and therapy-resistant models. It also examines edaravone's dual role in combination therapies, where it may improve the cytotoxicity of chemotherapeutic and radiotherapeutic agents while simultaneously protecting normal tissues from treatment-induced toxicities. By linking mechanistic insights with therapeutic outcomes, this review highlights the rationale for repurposing edaravone as a potential adjuvant in cancer therapy. Although clinical data are currently limited, preliminary findings are encouraging and warrant further investigation into edaravone's potential use in cancer treatment regimens.},
}

@article {pmid40866928,
year = {2025},
author = {Tsang, VSK and Malaspina, A and Henson, SM},
title = {The metabolic intersection between immunosenescence and neuroinflammation in amyotrophic lateral sclerosis.},
journal = {Journal of inflammation (London, England)},
volume = {22},
number = {1},
pages = {36},
pmid = {40866928},
issn = {1476-9255},
support = {BBX009610/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the progressive loss of motor neurons. Although it is traditionally viewed as a neuron-centric disease, neurodegeneration is increasingly linked to immunosenescence and age-related immune dysfunction, but the mechanisms connecting immune ageing to neurodegeneration remain poorly understood. In this review, we explore how metabolic reprogramming, especially the loss of metabolic plasticity in senescent immune cells, drives neuroinflammation in ALS. Senescent immune cells, including microglia and T cells, exhibit mitochondrial dysfunction, redox imbalance, impaired autophagy, and altered nutrient-sensing pathways that impair their homeostatic and reparative capacities. These cells adopt a metabolically demanding pro-inflammatory phenotype, sustaining an inflammatory secretome while promoting glial activation and neuronal damage. Finally, we discuss how targeting immunometabolic pathways may offer new therapeutic opportunities to restore immune balance, mitigate neuroinflammation, and potentially slow ALS progression. Understanding the metabolic basis of immune ageing is essential for developing effective, age-tailored interventions for ALS.},
}

@article {pmid40863128,
year = {2025},
author = {Pawłowska, M and Kruszka, J and Porzych, M and Garbarek, J and Nuszkiewicz, J},
title = {Ketogenic Metabolism in Neurodegenerative Diseases: Mechanisms of Action and Therapeutic Potential.},
journal = {Metabolites},
volume = {15},
number = {8},
pages = {},
pmid = {40863128},
issn = {2218-1989},
abstract = {Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, are characterized by progressive neuronal loss and share key pathological features such as oxidative stress, mitochondrial dysfunction, and chronic neuroinflammation. Recent research has highlighted the potential of ketogenic metabolism, particularly the use of ketone bodies like β-hydroxybutyrate, as a therapeutic approach targeting these shared mechanisms. This review provides a comprehensive synthesis of current knowledge on the neuroprotective effects of ketogenic interventions, including both dietary strategies and exogenous ketone supplementation. We discuss how ketone bodies improve mitochondrial function, reduce reactive oxygen species, modulate inflammatory pathways, and influence neurotransmission and synaptic plasticity. Additionally, we examine experimental and clinical evidence supporting the application of ketogenic therapies in neurodegenerative diseases, highlighting disease-specific findings, benefits, and limitations. While preclinical data are robust and suggest meaningful therapeutic potential, clinical studies remain limited and heterogeneous, with challenges related to adherence, safety, and patient selection. The review also addresses the translational relevance of ketogenic strategies, considering their feasibility, combination with other therapies, and the need for personalized approaches based on genetic and metabolic profiles. By critically evaluating existing data, this article aims to clarify the mechanisms through which ketogenic metabolism may exert neuroprotective effects and to outline future directions for research and clinical application in the context of neurodegenerative disorders.},
}

@article {pmid40859959,
year = {2025},
author = {Mao, S and Qiao, R and Wang, Q and Shen, L and Li, D and Huo, X and Wang, J and Liu, K and Chen, W and Zhu, T and Zhang, B and Leng, S and Bai, Y},
title = {Activity and Heterogeneity of Astrocytes in Neurological Diseases: Molecular Mechanisms and Therapeutic Targets.},
journal = {MedComm},
volume = {6},
number = {9},
pages = {e70329},
pmid = {40859959},
issn = {2688-2663},
abstract = {Astrocytes, the most prevalent glial cells in the central nervous system (CNS), play crucial roles in maintaining CNS homeostasis and responding to various pathological stimuli. They play key roles in neural development, neurotransmission, neuroinflammation, metabolic support, and tissue repair. Recent advancements in single-cell sequencing have revealed the remarkable heterogeneity of astrocytes, with distinct subpopulations differentially contributing to disease progression in neurological disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, ischemic stroke, intracerebral hemorrhage, and multiple sclerosis. In addition, they play an important role in various behavioral neuropsychiatric disorders. This review highlights the dual roles of astrocytes in disease progression, driven by their diverse molecular profiles and functions. It outlines the key molecular mechanisms underlying astrocyte heterogeneity and their impact on neuroinflammation, neuronal support, and ionic balance regulation. Additionally, the review discusses potential therapeutic strategies targeting astrocytes to modulate these processes, aiming to improve treatment outcomes in neurological diseases. By elucidating the specific roles of astrocyte subsets in disease, this review seeks to advance the development of precision medicine for astrocyte-related neurological disorders.},
}

@article {pmid40856865,
year = {2025},
author = {Shandilya, C and Mani, S},
title = {Rho kinase isoforms in neurodegeneration: from cellular functions to therapeutic targets.},
journal = {Molecular biology reports},
volume = {52},
number = {1},
pages = {846},
pmid = {40856865},
issn = {1573-4978},
mesh = {Humans ; *rho-Associated Kinases/metabolism/antagonists & inhibitors/genetics ; *Neurodegenerative Diseases/metabolism/drug therapy ; Mitochondria/metabolism ; Animals ; Mitophagy ; Neurons/metabolism ; Protein Isoforms/metabolism ; Signal Transduction ; Reactive Oxygen Species/metabolism ; Mitochondrial Dynamics ; Isoenzymes/metabolism ; Oxidative Stress ; },
abstract = {Mitochondria serve as an important cellular organelle for maintaining neurotransmission and synaptic plasticity in neuronal cells by playing a key role in ATP generation, maintaining calcium homeostasis, and regulating the levels of reactive oxygen species (ROS), etc. The regulation of the dynamic nature of mitochondria, including their fission, fusion, and removal of damaged mitochondria by mitophagy, is also very important for neuronal health. Abnormalities in mitochondrial processes, including but not limited to fission, fusion, and mitophagy, are known to be associated with numerous neurodegenerative diseases (NDDs), such as Parkinson's disease (PD), Alzheimer's disease (AD), Amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD). In the recent past, the Rho kinase (ROCK) isoforms, particularly ROCK1 and ROCK2, have gained a lot of attention in NDDs, mainly for their role in regulating the dynamics of the mitochondria, mitophagy, and other cell signalling pathways. By adding phosphate groups to Drp1, ROCK1 is crucial in supporting excessive mitochondrial fission, causing the death of neuronal cells. On the other hand, ROCK2 inhibits Parkin-dependent mitophagy by inhibiting the PTEN protein, the activator of Parkin-dependent mitophagy. This impaired mitochondrial quality control via reduced mitophagic flux leads to oxidative stress and neuronal degeneration, the central pathological feature of NDDs. The inhibition of ROCK isoforms has shown great promise in neuroprotective effects, controlling the dynamics of mitochondria in neuronal cells, lowering inflammation, and improving motor and cognitive functions in preclinical models of different NDDs, indicating ROCK isoforms as an attractive therapeutic target in different NDDs. This review aims to highlight the therapeutic significance of targeting ROCK isoforms in different NDDs.},
}

Humans
*rho-Associated Kinases/metabolism/antagonists & inhibitors/genetics
*Neurodegenerative Diseases/metabolism/drug therapy
Mitochondria/metabolism
Animals
Mitophagy
Neurons/metabolism
Protein Isoforms/metabolism
Signal Transduction
Reactive Oxygen Species/metabolism
Mitochondrial Dynamics
Isoenzymes/metabolism
Oxidative Stress

@article {pmid40849485,
year = {2025},
author = {Helal, MM and AbouShawareb, H and Abbas, OH and Haddad, R and Zain, Y and Osman, ASA and Hassan, AK},
title = {GLP-1 receptor agonists in Parkinson's disease: an updated comprehensive systematic review with meta-analysis.},
journal = {Diabetology & metabolic syndrome},
volume = {17},
number = {1},
pages = {352},
pmid = {40849485},
issn = {1758-5996},
abstract = {Previous studies have demonstrated an increased risk of developing Parkinson's disease (PD) in patients with type 2 diabetes mellitus (T2DM), as well as more severe and rapid motor and non-motor deterioration in diabetic PD patients compared to their non-diabetic counterparts. Additional research has suggested that diabetic subjects treated with glucagon-like peptide-1 (GLP-1) receptor agonists exhibit a reduced incidence of PD compared to those receiving other anti-diabetic medications. GLP-1 receptor agonists are FDA-approved therapies for T2DM, and recent studies have explored their potential as repurposed treatments for neurodegenerative diseases, including PD, AD, and ALS, as well as cerebrovascular disorders. This systematic review aims to assess the available literature on the efficacy and safety profiles of GLP-1 receptor agonists in PD management. A comprehensive search of PubMed, Scopus, CENTRAL, Web of Science, Embase, and ClinicalTrials.gov was conducted to identify relevant studies. The primary outcomes of this review include motor impairment in PD, as assessed by MDS-UPDRS Part III, as well as motor complications (Part IV) and motor experiences of daily living (Part II), and the incidence of gastrointestinal and systemic side effects. Meta-analysis showed that GLP-1 receptor agonists significantly improved motor function, as reflected by MDS-UPDRS Part III scores in the ON state (mean difference = - 2.88; p = 0.01; I[2] = 30%), although they were associated with a higher incidence of adverse events across all safety outcomes. Findings and conclusions of this review will contribute to a clearer understanding of the therapeutic potential of GLP-1 receptor agonists in PD, guiding future clinical research and treatment strategies.},
}

@article {pmid40848858,
year = {2025},
author = {Chen, X and Ma, Y and Liu, H and Wang, Y},
title = {Multifunctional regulation and treatment of ubiquitin specific protease 10.},
journal = {Biochemical pharmacology},
volume = {242},
number = {Pt 1},
pages = {117251},
doi = {10.1016/j.bcp.2025.117251},
pmid = {40848858},
issn = {1873-2968},
abstract = {USP10 is a critical deubiquitinating enzyme within the ubiquitin-specific protease family, playing multifaceted roles in cellular physiology and disease pathogenesis. Structurally composed of a G3BP1-interacting motif, a N-terminal domain (mediating most protein interactions), and a catalytic USP domain (residues 415-795, catalytic triad C424-H736-D751), USP10 regulates diverse cellular pathways by stabilizing key proteins through deubiquitination. It exhibits context-dependent functional duality, particularly in cancer: USP10 promotes tumorigenesis in various cancers (e.g., glioblastoma, esophageal, pancreatic, breast cancers) by stabilizing oncoproteins like CCND1, YAP1, HDAC7, and RUNX1, enhancing proliferation, metastasis, and immune evasion. Conversely, it suppresses tumors (e.g., NSCLC, CRC, thyroid cancer) by stabilizing tumor suppressors like p53, PTEN, and Axin1, inhibiting pathways such as Wnt/β-catenin. Beyond oncology, USP10 contributes to neurodegenerative diseases (neuroprotective in PD/ALS, neurotoxic in AD via Tau stabilization), viral immunity (inhibits SARS-CoV-2 infection), inflammatory responses, male reproduction, and metabolic/cardiovascular disorders. Its regulatory mechanisms include phosphorylation (e.g., by AMPK, AKT, ATM) controlling subcellular localization and activity, and ubiquitination via USP13. USP10's therapeutic significance drives inhibitor development (Spautin-1, D1, Wu-5, P22077, Parthenolide), though cross-reactivity within the USP family due to conserved catalytic domains remains a challenge. Novel strategies like PROTACs and engineered ubiquitin variants (UbVs) offer promise for future selective targeting of USP10 dysregulation in diverse diseases. A comprehensive understanding of its structure and context-specific functions is essential for exploiting its full therapeutic potential.},
}

@article {pmid40840854,
year = {2025},
author = {Fernàndez-Bernal, A and Mota, N and Pamplona, R and Area-Gómez, E and Portero-Otin, M},
title = {Mission cholesterol: Uncovering its hidden role in ALS neurodegeneration.},
journal = {Biochimica et biophysica acta. Molecular basis of disease},
volume = {1871},
number = {8},
pages = {168021},
doi = {10.1016/j.bbadis.2025.168021},
pmid = {40840854},
issn = {1879-260X},
abstract = {Cholesterol is a central determinant of membrane architecture, signaling, and cellular homeostasis in the central nervous system (CNS). While historically viewed as a structural component, emerging evidence highlights its dynamic regulatory role in neuronal function, particularly through its compartmentalized synthesis, trafficking, and turnover. This review examines the complex landscape of cholesterol metabolism in the CNS, emphasizing the cooperative roles of astrocytes and neurons, the partitioning of biosynthetic pathways, and the barriers that distinguish brain cholesterol pools from peripheral sources. We focus on mitochondria-associated endoplasmic reticulum membranes (MAMs) as key regulatory platforms for cholesterol sensing, esterification, and signaling, underscoring their emerging role in neurodegenerative diseases. Disruptions in MAM integrity, lipid raft composition, and transcriptional regulation of cholesterol-handling genes have been linked to pathologies such as amyotrophic lateral sclerosis (ALS), particularly through the actions of TDP-43. By consolidating recent findings from lipidomics, cell biology, and disease models, we propose that cholesterol dyshomeostasis constitutes a shared mechanistic axis across diverse neurodegenerative conditions. Understanding this axis offers novel insights into the metabolic vulnerability of neurons and highlights cholesterol metabolism as a promising target for therapeutic intervention.},
}

@article {pmid40839108,
year = {2025},
author = {Mukherjea, N and Khandelwal, A and Saluja, R and Kalra, N},
title = {The Role of the human microbiome in neurodegenerative diseases: A Perspective.},
journal = {Current genetics},
volume = {71},
number = {1},
pages = {17},
pmid = {40839108},
issn = {1432-0983},
mesh = {Humans ; *Neurodegenerative Diseases/microbiology ; *Microbiota ; Parkinson Disease/microbiology ; *Gastrointestinal Microbiome ; Alzheimer Disease/microbiology ; Inflammasomes ; Inflammation/microbiology ; },
abstract = {Advances in diagnostics, therapeutics, and large-scale clinical studies have significantly expanded our understanding how human health is shaped by the microorganisms that colonize the body since birth. This article explores the rapidly evolving field of human microbiome research, focusing upon how microbial communities influence neurological health and contribute to the development of neurodegenerative diseases (NDs). Multiple factors, including age, lifestyle, and immunological memory, are recognized as major determinants of an individual's microbiome composition, which in turn can influence the onset and the progression of disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. These conditions have been linked to mechanisms including the aggregation of pathogenic proteins (e.g., amyloid-β and α-synuclein), inflammation driven by activation of the Toll-like receptor (TLR) signaling pathway, the NLRP3 inflammasome, as well as the modulatory effect of microbial metabolites such as short-chain fatty acids (SCFAs) and lipopolysaccharides (LPS). The article also highlights ongoing research and emerging strategies aimed at leveraging the human microbiome for better diagnosis, and management of NDs.},
}

Humans
*Neurodegenerative Diseases/microbiology
*Microbiota
Parkinson Disease/microbiology
*Gastrointestinal Microbiome
Alzheimer Disease/microbiology
Inflammasomes
Inflammation/microbiology

@article {pmid40838713,
year = {2025},
author = {Noor, SM and Reddy, DH and Srikanth, Y and Viswanadh, MK and Dumala, N and Chakravarthy, G and Nalluri, BN and Naryanarao, A and Duguluri, S and Yadagiri, G and Prasanna, VS and Sundaram, S and Gujjari, L and Ramakrishna, K},
title = {Morin hydrate: a comprehensive review on therapeutic potential in treating neurological diseases.},
journal = {Nutritional neuroscience},
volume = {},
number = {},
pages = {1-25},
doi = {10.1080/1028415X.2025.2544605},
pmid = {40838713},
issn = {1476-8305},
abstract = {Background: Morin hydrate is a polyphenolic flavonoid present in various vegetables, fruits, nuts, and sea products. It has been reported to offer multiple protective effects against a range of diseases, including cancer, cardiovascular, liver, neurological, metabolic, and renal disorders.Objective: This review highlights the molecular mechanisms and therapeutic potential of Morin in neurological diseases, including Parkinson's disease, Alzheimer's disease, traumatic brain injury, neuropathic pain, stroke, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, depression, anxiety, sleep, encephalopathy, schizophrenia, and psychosis, etc.Methods: The research and review articles were collected from the Pubmed, Scopus, Web of Science, and Google Scholar databases using 'Morin' and the above-mentioned neurological diseases as keywords.Results: The neuroprotective effects of Morin are primarily attributed to its ability to mitigate oxidative stress, inflammation, excitotoxicity, calcium dysregulation, mitochondrial dysfunction, neurotransmitter alterations, protein modifications, and enzymatic inhibition.Conclusion: Despite its promising pharmacological profile, the clinical adaptation of Morin for combating neurological diseases requires further validation through comprehensive preclinical and clinical investigations.},
}