Physiotherapy Management of Rheumatic Diseases

Introduction: Physiotherapy is an integral part of the non-drug treatment strategy for rheumatological conditions. The evidence for its effects is not formal. The objective was to evaluate the impact of physiotherapy in the management of rheumatological disorders. Methods: 6-month case-control study (December 15, 2021 to June 20, 2022) at Ignace Deen University Hospital (Conakry). Patients with rheumatological disease who received drug therapy and physiotherapy were included in the case group. Age- and sex-matched controls had rheumatological conditions, treated without physiotherapy. The evaluation questionnaires were used: WOMAC (osteoarthritis), EIFEL (low back pain), NDI (neck pain), SPADI (shoulder). Patients with heart failure, respiratory failure and/or skin infection were not included. Results: We collected 773 patients (389 cases and 384 controls) with a mean age of 53.8 years ± 12.2 with female predominance (56.8%). Patients were mainly followed for osteoarthritis (65.2%). Rheumatological conditions managed were knee-based (119;30.6%), lumbar spine (220;56.6%), shoulders (27;6.9%) and cervical spine (23;5.9%). For an average duration of 53.4 ± 12.2 minutes per session, patients had benefited from a median of 19 physiotherapy sessions. After 3 months, the baseline mean VAS of 6/10 improved to 2.2 ± 1.6 for cases and 5.7 ± 1.2 for controls. Functional capacity was improved (WOMAC: 41.8 ± 22.7 vs. 18.3 ± 7.3). The satisfaction of patients treated with physiotherapy was 20 times higher than in controls. Conclusion: Physiotherapy performed in the management of rheumatological conditions significantly reduced pain and improved functional capacity.

Application of Clinical Nursing Pathway in the Peri-Treatment Period of Immunoadsorption Therapy for Rheumatic Immune Diseases

Objective: The paper aims to investigate the clinical nursing pathway (CNP) in the application of immunosorption therapy in patients with rheumatic immune disease. Methods: Convenience sampling method was used to select inpatients who received immunoadsorption therapy from January 2020 to December 2022 in the rheumatology and Immunology department of a 3A hospital in Jingzhou City. 30 patients from January 2020 to June 2021 were selected as control group, and 30 patients from July 2021 to December 2022 were selected as observation group. The control group was given routine nursing. On the basis of the control group, the observation group used a clinical nursing pathway for intervention during the perioperative period of immunosorbent therapy. The incidence of adverse reactions, patient satisfaction, and nurse satisfaction during immunosorbent therapy between the control group and the observation group were compared. Results: After intervention, the incidence of adverse reactions in the observation group was significantly lower than that in the control group, while patient satisfaction and nurse satisfaction in the observation group were significantly higher than those in the control group. The results are all statistically significant (P Conclusion: Clinical nursing pathway is beneficial to reduce the incidence of adverse reactions in patients with immunoadsorption during peri-treatment and improve the satisfaction of patients and nurses.

IFIH1 and DDX58 gene variants in pediatric rheumatic diseases

BACKGROUND The IFIH1 gene codes the MDA5 protein and the DDX58 gene codes the RIG-I receptor.Both proteins are parts of the interferon(IFN)I signaling pathway and are responsible for antiviral defense and innate immune response.IFIH1 and DDX58 polymorphisms are associated with a spectrum of autoimmune diseases.Rare gain-of-function IFIH1 mutations have been found in Singleton-Merten and Aicardi-Goutières syndrome,while DDX58 mutation can cause atypical Singleton-Merten syndrome.AIM To characterize children with pediatric rheumatic diseases(PRD)carrying DDX58 or IFIH1 variants.METHODS Clinical exome sequencing was performed on 92 children with different PRD.IFIH1 and DDX58 variants have been detected in 14 children.IFN-I score has been analyzed and the clinical characteristics of patients have been studied.RESULTS A total of seven patients with systemic lupus erythematosus(SLE)(n=2),myelodysplastic syndrome with SLE features at the onset of the disease(n=1),mixed connective tissue disease(MCTD)(n=1),undifferentiated systemic autoinflammatory disease(uSAID)(n=3)have 5 different variants of the DDX58 gene.A common non-pathogenic variant p.D580E has been found in five children.A rare variant of uncertain significance(VUS)p.N354S was found in one patient with uSAID,a rare likely non-pathogenic variant p.E37K in one patient with uSAID,and a rare likely pathogenic variant p.Cys864fs in a patient with SLE.Elevated IFN-I score was detected in 6 of 7 patients with DDX58 variants.Seven patients had six different IFIH1 variants.They were presented with uSAID(n=2),juvenile dermatomyositis(JDM)(n=1),SLElike disease(n=1),Periodic fever with aphthous stomatitis,pharyngitis,and adenitis syndrome(n=1),and systemic onset juvenile idiopathic arthritis(n=1).Three patients have VUS p.E627X,one patient has benign variant p.I923V.Rare VUS p.R595H was detected in the JDM patient.Another rare VUS p.L679Ifs*2 and previously not reported variant p.V599Ffs*5 were detected in the patient with uSAID.One patient with uSAID has rare VUS p.T520A.All patients had elevated IFN-I scores.CONCLUSION Rare compound-heterozygous IFIH1 variant(p.L679Ifs*2 and p.V599Ffs*5),heterozygous IFIH1 variant(p.T520A)and heterozygous DDX58 variant(p.Cys864fs)are probably disease causative for uSAID and SLE.The majority of patients with different DDX58 and IFI1 variants had hyperactivation of the IFN I signaling pathway.

The role of exosomes in adult neurogenesis:implications for neurodegenerative diseases

Exosomes are cup-shaped extracellular vesicles with a lipid bilayer that is approximately 30 to 200 nm in thickness.Exosomes are widely distributed in a range of body fluids,including urine,blood,milk,and saliva.Exosomes exert biological function by transporting factors between different cells and by regulating biological pathways in recipient cells.As an important form of intercellular communication,exosomes are increasingly being investigated due to their ability to transfer bioactive molecules such as lipids,proteins,mRNAs,and microRNAs between cells,and because they can regulate physiological and pathological processes in the central nervous system.Adult neurogenesis is a multistage process by which new neurons are generated and migrate to be integrated into existing neuronal circuits.In the adult brain,neurogenesis is mainly localized in two specialized niches:the subventricular zone adjacent to the lateral ventricles and the subgranular zone of the dentate gyrus.An increasing body of evidence indicates that adult neurogenesis is tightly controlled by environmental conditions with the niches.In recent studies,exosomes released from different sources of cells were shown to play an active role in regulating neurogenesis both in vitro and in vivo,thereby participating in the progression of neurodegenerative disorders in patients and in various disease models.Here,we provide a state-of-the-art synopsis of existing research that aimed to identify the diverse components of exosome cargoes and elucidate the therapeutic potential of exosomal contents in the regulation of neurogenesis in several neurodegenerative diseases.We emphasize that exosomal cargoes could serve as a potential biomarker to monitor functional neurogenesis in adults.In addition,exosomes can also be considered as a novel therapeutic approach to treat various neurodegenerative disorders by improving endogenous neurogenesis to mitigate neuronal loss in the central nervous system.

Lactate metabolism in neurodegenerative diseases

Lactate,a byproduct of glycolysis,was thought to be a metabolic waste until the discovery of the Warburg effect.Lactate not only functions as a metabolic substrate to provide energy but can also function as a signaling molecule to modulate cellular functions under pathophysiological conditions.The Astrocyte-Neuron Lactate Shuttle has cla rified that lactate plays a pivotal role in the central nervous system.Moreover,protein lactylation highlights the novel role of lactate in regulating transcription,cellular functions,and disease development.This review summarizes the recent advances in lactate metabolism and its role in neurodegenerative diseases,thus providing optimal pers pectives for future research.

Antisense therapy:a potential breakthrough in the treatment of neurodegenerative diseases

Neurodegenerative diseases are a group of disorders characterized by the progressive degeneration of neurons in the central or peripheral nervous system.Currently,there is no cure for neurodegenerative diseases and this means a heavy burden for patients and the health system worldwide.Therefore,it is necessary to find new therapeutic approaches,and antisense therapies offer this possibility,having the great advantage of not modifying cellular genome and potentially being safer.Many preclinical and clinical studies aim to test the safety and effectiveness of antisense therapies in the treatment of neurodegenerative diseases.The objective of this review is to summarize the recent advances in the development of these new technologies to treat the most common neurodegenerative diseases,with a focus on those antisense therapies that have already received the approval of the U.S.Food and Drug Administration.

NADPH oxidase 4(NOX4)as a biomarker and therapeutic target in neurodegenerative diseases

Diseases like Alzheimer’s and Parkinson’s diseases are defined by inflammation and the damage neurons undergo due to oxidative stress. A primary reactive oxygen species contributor in the central nervous system, NADPH oxidase 4, is viewed as a potential therapeutic touchstone and indicative marker for these ailments. This in-depth review brings to light distinct features of NADPH oxidase 4, responsible for generating superoxide and hydrogen peroxide, emphasizing its pivotal role in activating glial cells, inciting inflammation, and disturbing neuronal functions. Significantly, malfunctioning astrocytes, forming the majority in the central nervous system, play a part in advancing neurodegenerative diseases, due to their reactive oxygen species and inflammatory factor secretion. Our study reveals that aiming at NADPH oxidase 4 within astrocytes could be a viable treatment pathway to reduce oxidative damage and halt neurodegenerative processes. Adjusting NADPH oxidase 4 activity might influence the neuroinflammatory cytokine levels, including myeloperoxidase and osteopontin, offering better prospects for conditions like Alzheimer’s disease and Parkinson’s disease. This review sheds light on the role of NADPH oxidase 4 in neural degeneration, emphasizing its drug target potential, and paving the path for novel treatment approaches to combat these severe conditions.

Emerging roles of exosomes in oral diseases progression

Oral diseases, such as periodontitis, salivary gland diseases, and oral cancers, significantly challenge health conditions due to their detrimental effects on patient's digestive functions, pronunciation, and esthetic demands. Delayed diagnosis and non-targeted treatment profoundly influence patients' prognosis and quality of life. The exploration of innovative approaches for early detection and precise treatment represents a promising frontier in oral medicine.

ATP-binding cassette transporters as possible targets for the intervention of neurodegenerative diseases

ATP-binding cassette(ABC)transporters are ubiquitous membrane-bound proteins that are responsible for the translocation of a broad spectrum of substrates across cellular membranes,including lipids,amino acids,nucleosides,sugars,and xenobiotics.Interestingly,ABC transporters are highly expressed in the brain.While their functions in the brain still need to be elucidated,several members are implicated in the pathogenesis of neurodegenerative diseases,including Alzheimer’s disease(AD),Parkinson’s disease(PD),and frontotemporal dementia.In this perspective,we will review current knowledge of ABC transporters in the central nervous system in terms of physiological functions and pathology in neurodegeneration.Furthermore,we will explore the possibilities of ABC transporters as potential targets in the development of therapeutics for neurodegenerative diseases.

Clinical associations of corneal neuromas with ocular surface diseases

Corneal neuromas,also termed microneuromas,refer to microscopic,irregula rly-shaped enlargements of terminal subbasal nerve endings at sites of nerve damage or injury.The formation of corneal neuromas results from damage to corneal nerves,such as following corneal pathology or corneal or intraocular surge ries.Initially,denervated areas of sensory nerve fibers become invaded by sprouts of intact sensory nerve fibers,and later injured axons regenerate and new sprouts called neuromas develop.In recent years,analysis of corneal nerve abnormalities including corneal neuromas which can be identified using in vivo confocal microscopy,a non-invasive imaging technique with microscopic resolution,has been used to evaluate corneal neuropathy and ocular surface dysfunction.Corneal neuromas have been shown to be associated with clinical symptoms of discomfort and dryness of eyes,and are a promising surrogate biomarker for ocular surface diseases,such as neuropathic corneal pain,dry eye disease,diabetic corneal neuropathy,neurotrophic keratopathy,Sjogren's syndrome,bullous keratopathy,post-refra ctive surgery,and others.In this review,we have summarized the current literature on the association between these ocular surface diseases and the presentation of corneal microneuromas,as well as elaborated on their pathogenesis,visualization via in vivo confocal microscopy,and utility in monitoring treatment efficacy.As current quantitative analysis on neuromas mainly relies on manual annotation and quantification,which is user-dependent and labor-intensive,future direction includes the development of artificial intelligence software to identify and quantify these potential imaging biomarkers in a more automated and sensitive manner,allowing it to be applied in clinical settings more efficiently.Combining imaging and molecular biomarkers may also help elucidate the associations between corneal neuromas and ocular surface diseases.

Morphological and biochemical characteristics associated with autophagy in gastrointestinal diseases

Autophagy is a cellular catabolic process characterized by the formation of double-membrane autophagosomes.Transmission electron microscopy is the most rigorous method to clearly visualize autophagic engulfment and degradation.A large number of studies have shown that autophagy is closely related to the digestion,secretion,and regeneration of gastrointestinal(GI)cells.However,the role of autophagy in GI diseases remains controversial.This article focuses on the morphological and biochemical characteristics of autophagy in GI diseases,in order to provide new ideas for their diagnosis and treatment.

Autophagy in neural stem cells and glia for brain health and diseases

Autophagy is a multifaceted cellular process that not only maintains the homeostatic and adaptive responses of the brain but is also dynamically involved in the regulation of neural cell generation,maturation,and survival.Autophagy facilities the utilization of energy and the microenvironment for developing neural stem cells.Autophagy arbitrates structural and functional remodeling during the cell differentiation process.Autophagy also plays an indispensable role in the maintenance of stemness and homeostasis in neural stem cells during essential brain physiology and also in the instigation and progression of diseases.Only recently,studies have begun to shed light on autophagy regulation in glia(microglia,astrocyte,and oligodendrocyte)in the brain.Glial cells have attained relatively less consideration despite their unquestioned influence on various aspects of neural development,synaptic function,brain metabolism,cellular debris clearing,and restoration of damaged or injured tissues.Thus,this review composes pertinent information regarding the involvement of autophagy in neural stem cells and glial regulation and the role of this connexion in normal brain functions,neurodevelopmental disorders,and neurodegenerative diseases.This review will provide insight into establishing a concrete strategic approach for investigating pathological mechanisms and developing therapies for brain diseases.

Correlation between the gut microbiome and neurodegenerative diseases:a review of metagenomics evidence

A growing body of evidence suggests that the gut microbiota contributes to the development of neurodegenerative diseases via the microbiota-gut-brain axis.As a contributing factor,microbiota dysbiosis always occurs in pathological changes of neurodegenerative diseases,such as Alzheimer’s disease,Parkinson’s disease,and amyotrophic lateral sclerosis.High-throughput sequencing technology has helped to reveal that the bidirectional communication between the central nervous system and the enteric nervous system is facilitated by the microbiota’s diverse microorganisms,and for both neuroimmune and neuroendocrine systems.Here,we summarize the bioinformatics analysis and wet-biology validation for the gut metagenomics in neurodegenerative diseases,with an emphasis on multi-omics studies and the gut virome.The pathogen-associated signaling biomarkers for identifying brain disorders and potential therapeutic targets are also elucidated.Finally,we discuss the role of diet,prebiotics,probiotics,postbiotics and exercise interventions in remodeling the microbiome and reducing the symptoms of neurodegenerative diseases.

The History of Controlling and Treating Infectious Diseases in Ancient China

Infectious diseases are the common enemies of mankind.In the course of historical development,they persistently threaten human health and safety.Even today,despite the developments in medical science,we cannot escape the fear and suffering caused by infectious diseases.Whether in ancient or modern times,the source of infection,route of transmission,and a susceptible population are the three key conditions for the prevalence and spread of infectious diseases.All factors closely related to these three conditions can affect the prevalence of infectious diseases.China is one of the cradles of world civilization.The ancient people accumulated a great deal of experience and lessons in the long struggle against infectious diseases.In the face of the current threat posed by widespread infectious disease,it is imperative to review and summarize ancient Chinese ideas and health policies on epidemic prevention and control to inspire contemporary efforts in the prevention and control of infectious disease.The combination of prevention-oriented epidemic prevention ideology and traditional medicine provides valuable insights,especially for impoverished and medically underserved regions.

Bridging the gap:Unveiling the crisis of physical inactivity in inflammatory bowel diseases

In this editorial we comment on the article titled“Inflammatory bowel diseases patients suffer from significant low levels and barriers to physical activity:The BE-FIT-IBD study”published in a recent issue of the World Journal of Gastroen-terology 2023;29(41):5668-5682.Inflammatory bowel diseases(IBD)are emerging as a significant global health concern as their incidence continues to rise on a global scale,with detrimental impacts on quality of life.While many advances have been made regarding the management of the disease,physical inactivity in these patients represents an underexplored issue that may hold the key for further and better understanding the ramifications of IBD.Chronic pain,fatigue,and fear of exacerbating symptoms promotes physical inactivity among IBD patients,while the lack of clear guidelines on safe exercise regimens contributes to a norm of physical inactivity.Physical activity(PA)is accepted to have a positive effect on disease outcomes and quality of life,while inactivity exacerbates comorbidities like cardiovascular disease and mental health disorders.The“BE-FIT-IBD”study,focusing on PA levels and barriers in IBD patients of Southern Italy,revealed that a significant proportion(42.9%)were physically inactive.This lack of PA is attributed to barriers such as fear of flare-ups and misconceptions about exercise exacerbating the disease.The study also highlighted the need for better communication between healthcare providers and patients regarding the benefits of PA and safe incorporation into lifestyles.Moreover,physical inactivity may also contribute to disability in IBD patients,having a great impact on employment status.Of note is the fact that IBD also comes with an important psychological burden with relevant evidence suggesting that regular PA can improve mood,reduce anxiety,and enhance mental health.The“BE-FIT-IBD”study advocated for the integration of PA into IBD management,emphasizing the bidirectional link between PA and IBD.Regular exercise can influence the course of IBD,potentially reducing symptom severity and prolonging remission periods.As such,it is mandatory that healthcare providers actively educate patients,dispel misconceptions,and tailor exercise recommendations to improve the quality of life and reduce IBD-related complications.

Prognostic Role of Preoperative Tricuspid Annular Plane Systolic Excursion (TAPSE) in Mitral Valve Replacement (MVR) for Rheumatic Mitral Stenosis Patients

Tricuspid annular plane systolic excursion has been proposed as a simple and reproducible parameter for quantitative assessment of the right ventricular ejection fraction. The prognostic importance of preoperative TAPSE in patients with mitral valve replacement for rheumatic mitral stenosis patients is still under focused. Therefore, the objective of the study was to predict the outcome after MVR in rheumatic mitral stenosis patients in relation to preoperative TAPSE. This comparative cross-sectional study was conducted at the Department of Cardiac Surgery, National Heart Foundation Hospital and Research Institute. A total of 72 patients of rheumatic mitral stenosis patients who underwent mitral valve replacement were included in the study. They were divided into two groups: Group A and B. Group A included 36 patients with TAPSE 0.05) except for the preoperative TAPSE. Mean TAPSE of Group A was 13.17 (±1.40) and Group B was 18.61 (±1.57), the difference was statistically significant (p 0.05). Among the postoperative complications, including postoperative atrial fibrillation was higher in Group A (30.56%) than Group B (11.11%), mean ventilation time was higher in Group A (27.78%) than Group B (5.56%), length of intensive care was higher in Group A (33.33%) than Group B (11.12%), and hospital stay was higher in Group A (25.0%) than Group B (5.56%), (p < 0.05). Higher preoperative TASPE could be used as a prognostic tool for MVR in rheumatic mitral stenosis patients in our settings.

Age-specific differences in the association between prediabetes and cardiovascular diseases in China:A national cross-sectional study

BACKGROUND Cardiovascular disease(CVD)is a leading cause of morbidity and mortality worldwide,the global burden of which is rising.It is still unclear the extent to which prediabetes contributes to the risk of CVD in various age brackets among adults.To develop a focused screening plan and treatment for Chinese adults with prediabetes,it is crucial to identify variations in the connection between prediabetes and the risk of CVD based on age.AIM To examine the clinical features of prediabetes and identify risk factors for CVD in different age groups in China.METHODS The cross-sectional study involved a total of 46239 participants from June 2007 through May 2008.A thorough evaluation was conducted.Individuals with prediabetes were categorized into two groups based on age.Chinese atherosclerotic CVD risk prediction model was employed to evaluate the risk of developing CVD over 10 years.Random forest was established in both age groups.SHapley Additive exPlanation method prioritized the importance of features from the perspective of assessment contribution.RESULTS In total,6948 people were diagnosed with prediabetes in this study.In prediabetes,prevalences of CVD were 5(0.29%)in the younger group and 148(2.85%)in the older group.Overall,11.11%of the younger group and 29.59% of the older group were intermediate/high-risk of CVD for prediabetes without CVD based on the Prediction for ASCVD Risk in China equation in ten years.In the younger age group,the 10-year risk of CVD was found to be more closely linked to family history of CVD rather than lifestyle,whereas in the older age group,resident status was more closely linked.CONCLUSION The susceptibility to CVD is age-specific in newly diagnosed prediabetes.It is necessary to develop targeted approaches for the prevention and management of CVD in adults across various age brackets.

Pathological and therapeutic effects of extracellular vesicles in neurological and neurodegenerative diseases

Extracellular vesicles are released by all cell types and contain proteins,microRNAs,mRNAs,and other bioactive molecules.Extracellular vesicles play an important role in intercellular communication and in the modulation of the immune system and neuroinflammation.The cargo of extra cellular vesicles(e.g.,proteins and microRNAs)is altered in pathological situations.Extracellular vesicles contribute to the pathogenesis of many pathologies associated with sustained inflammation and neuroinflammation,including cance r,diabetes,hype rammonemia and hepatic encephalopathy,and other neurological and neurodegenerative diseases.Extracellular vesicles may cross the blood-brain barrier and transfer pathological signals from the periphery to the brain.This contributes to inducing neuroinflammation and cognitive and motor impairment in hyperammonemia and hepatic encephalopathy and in neurodegenerative diseases.The mechanisms involved are beginning to be unde rstood.For example,increased tumor necrosis factor a in extracellular vesicles from plasma of hype rammonemic rats induces neuroinflammation and motor impairment when injected into normal rats.Identifying the mechanisms by which extracellular vesicles contribute to the pathogenesis of these diseases will help to develop new treatments and diagnostic tools for their easy and early detection.In contrast,extra cellular vesicles from mesenchymal stem cells have therapeutic utility in many of the above pathologies,by reducing inflammation and neuroinflammation and improving cognitive and motor function.These extra cellular vesicles recapitulate the beneficial effects of mesenchymal stem cells and have advantages as therapeutic tools:they are less immunoge nic,may not diffe rentiate to malignant cells,cross the blood-brain barrier,and may reach more easily target organs.Extracellular vesicles from mesenchymal stem cells have beneficial effects in models of ischemic brain injury,Alzheimer's and Parkinson's diseases,hyperammonemia,and hepatic encephalopathy.Extracellular vesicles from mesenchymal stem cells modulate the immune system,promoting the shift from a pro-inflammato ry to an anti-inflammatory state.For example,extracellular vesicles from mesenchymal stem cells modulate the Th17/Treg balance,promoting the anti-inflammatory Treg.Extracellular vesicles from mesenchymal stem cells may also act directly in the brain to modulate microglia activation,promoting a shift from a pro-inflammatory to an anti-inflammatory state.This reduces neuroinflammation and improves cognitive and motor function.Two main components of extracellular vesicles from mesenchymal stem cells which contribute to these beneficial effects are transforming growth factor-βand miR-124.Identifying the mechanisms by which extracellular vesicles from mesenchymal stem cells induce the beneficial effects and the main molecules(e.g.,proteins and mRNAs)involved may help to improve their therapeutic utility.The aims of this review are to summarize the knowledge of the pathological effects of extracellular vesicles in different pathologies,the therapeutic potential of extra cellular vesicles from mesenchymal stem cells to recover cognitive and motor function and the molecular mechanisms for these beneficial effects on neurological function.

Genome-edited rabbits:Unleashing the potential of a promising experimental animal model across diverse diseases

Animal models are extensively used in all aspects of biomedical research,with substantial contributions to our understanding of diseases,the development of pharmaceuticals,and the exploration of gene functions.The field of genome modification in rabbits has progressed slowly.However,recent advancements,particularly in CRISPR/Cas9-related technologies,have catalyzed the successful development of various genome-edited rabbit models to mimic diverse diseases,including cardiovascular disorders,immunodeficiencies,agingrelated ailments,neurological diseases,and ophthalmic pathologies.These models hold great promise in advancing biomedical research due to their closer physiological and biochemical resemblance to humans compared to mice.This review aims to summarize the novel gene-editing approaches currently available for rabbits and present the applications and prospects of such models in biomedicine,underscoring their impact and future potential in translational medicine.

Rethinking neurodegenerative diseases:neurometabolic concept linking lipid oxidation to diseases in the central nervous system

Currently,there is a lack of effective medicines capable of halting or reve rsing the progression of neurodegenerative disorde rs,including amyotrophic lateral sclerosis,Parkinson s disease,multiple sclerosis,or Alzheimer s disease.Given the unmet medical need,it is necessary to reevaluate the existing para digms of how to to rget these diseases.When considering neurodegenerative diseases from a systemic neurometabolic perspective,it becomes possible to explain the shared pathological features.This innovative approach presented in this paper draws upon exte nsive research conducted by the authors and researchers worldwide.In this review,we highlight the importance of metabolic mitochondrial dysfunction in the context of neurodegenerative diseases.We provide an overview of the risk factors associated with developing neurodegenerative disorders,including genetic,epigenetic,and environmental fa ctors.Additionally,we examine pathological mechanisms implicated in these diseases such as oxidative stress,accumulation of misfolded proteins,inflammation,demyelination,death of neurons,insulin resistance,dysbiosis,and neurotransmitter disturbances.Finally,we outline a proposal for the restoration of mitochondrial metabolism,a crucial aspect that may hold the key to facilitating curative therapeutic interventions for neurodegenerative disorders in forthcoming advancements.