Nutritional support teams increase percutaneous endoscopic gastrostomy uptake in motor neuron disease

AIM:To examine factors influencing percutaneous endoscopic gastrostomy(PEG) uptake and outcomes in motor neuron disease(MND) in a tertiary care centre.METHODS:Case notes from all patients with a confirmed diagnosis of MND who had attended the clinic at the Repatriation General Hospital between January 2007 and January 2011 and who had since died,were audited.Data were extracted for demographics(age and gender),disease characteristics(date of onset,bulbar or peripheral predominance,complications),date and nature of discussion of gastrostomy insertion,nutritional status [weight measurements,body mass index(BMI)],date of gastrostomy insertion and subsequent progress(duration of survival) and quality of life(QoL) [Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised(ALSFRS-R)].In addition,the type of clinician initiating the discussion regarding gastrostomy was recorded as Nutritional Support Team(involved in providing nutrition input viz Gastroenterologist,Speech Pathologist,Dietitian) and other(involved in non-nutritional aspects of patient care).Factors affecting placement and outcomes including length of survival,change in weight and QoL were determined.RESULTS:Case records were available for all 86 patients(49 men,mean age at diagnosis 66.4 years).Thirty-eight patients had bulbar symptoms and 48 had peripheral disease as their presenting feature.Sixty-six patients reported dysphagia.Thirty-one patients had undergone gastrostomy insertion.The major indications for PEG placement were dysphagia and weight loss.Nine patients required immediate full feeding,whereas 17 patients initially used the gastrostomy to supplement oral intake,4 for medication administration and 1 for hydration.Initially the PEG regime met 73% ± 31% of the estimated total energy requirements,increasing to 87% ± 32% prior to death.There was stabilization of weight in patients undergoing gastrostomy [BMI at 3 mo(22.6 ± 2.2 kg/m 2) and 6 mo(22.5 ± 2.0 kg/m 2) after PEG placement compared to weight at the time of the procedure(22.5 ± 3.0 kg/m 2)].However,weight loss recurred in the terminal stages of the illness.There was a strong trend for longer survival from diagnosis among MND in PEG recipients with limb onset presentation compared to similar patients who did not undergo the procedure(P = 0.063).Initial discussions regarding PEG insertion occurred earlier after diagnosis when seen by nutrition support team(NST) clinicians compared to other clinicians.(5.4 ± 7.0 mo vs 11.9 ± 13.4 mo,P = 0.028).There was a significant increase in PEG uptake(56% vs 24%,P = 0.011) if PEG discussions were initiated by the NST staff compared to other clinicians.There was no change in the ALSFRS-R score in patients who underwent PEG(pre 34.1 ± 8.6 vs post 34.8 ± 7.4),although in non-PEG recipients there was a nonsignificant fall in this score(33.7 ± 7.9 vs 31.6 ± 8.8).Four patients died within one month of the procedure,4 developed bacterial site infection requiring antibiotics and 1 required endoscopic therapy for gastric bleeding.Less serious complications attributed to the procedure included persistent gastrostomy site discomfort,poor appetite,altered bowel function and bloating.CONCLUSION:Initial discussion with NST clinicians increases PEG uptake in MND.Gastrostomy stabilizes patient weight but weight loss recurs with advancing disease.

Therapeutic opportunities and challenges of induced pluripotent stem cells-derived motor neurons for treatment of amyotrophic lateral sclerosis and motor neuron disease

Amyotrophic lateral sclerosis（ALS） and motor neuron diseases（MNDs） are progressive neurodegenerative diseases that affect nerve cells in the brain affecting upper and lower motor neurons（UMNs/LMNs）, brain stem and spinal cord. The clinical phenotype is characterized by loss of motor neurons（MNs）, muscular weakness and atrophy eventually leading to paralysis and death due to respiratory failure within 3–5 years after disease onset. No effective treatment or cure is currently available that halts or reverses ALS and MND except FDA approved drug riluzole that only modestly slows the progression of ALS in some patients. Recent advances in human derived induced pluripotent stem cells have made it possible for the first time to obtain substantial amounts of human cells to recapitulate in vitro “disease in dish” and test some of the underlying pathogenetic mechanisms involved in ALS and MNDs. In this review, I discussed the opportunities and challenges of induced pluropotent stem cells-derived motor neurons for treatment of ALS and MND patients with special emphasis on their implications in finding a cure for ALS and MNDs.

Cerebellar pathology in motor neuron disease:neuroplasticity and neurodegeneration

Amyotrophic lateral sclerosis is a relentlessly progressive multi-system condition.The clinical picture is dominated by upper and lower motor neuron degeneration,but extra-motor pathology is increasingly recognized,including cerebellar pathology.Post-mortem and neuroimaging studies primarily focus on the chara cterization of supratentorial disease,des pite emerging evidence of cerebellar degeneration in amyotrophic lateral sclerosis.Cardinal clinical features of amyotrophic lateral sclerosis,such as dysarthria,dysphagia,cognitive and behavioral deficits,saccade abnormalities,gait impairment,respiratory weakness and pseudobulbar affect are likely to be exacerbated by co-existing cerebellar pathology.This review summarizes in vivo and post mortem evidence for cerebellar degeneration in amyotrophic lateral scle rosis.Structural imaging studies consistently capture cerebellar grey matter volume reductions,diffusivity studies readily detect both intra-cerebellar and cerebellar peduncle white matter alte rations and functional imaging studies commonly report increased functional connectivity with supratentorial regions.Increased functional connectivity is commonly interpreted as evidence of neuro plasticity representing compensatory processes despite the lack of post-mortem validation.There is a scarcity of post-mortem studies focusing on cerebellar alte rations,but these detect pTDP-43 in cerebellar nuclei.Ce rebellar pathology is an overloo ked facet of neurodegeneration in amyotrophic lateral sclerosis despite its contribution to a multitude of clinical symptoms,wides p read connectivity to spinal and supratentorial regions and putative role in compensating for the degeneration of primary motor regions.

Astrocyte Function and Role in Motor Neuron Disease:A Future Therapeutic Target?

星形胶质细胞是中枢神经系统中数量最多的细胞,从引导轴突、突触支持到控制血-脑脊液屏障及脑血流,发挥多种作用。发挥这些作用需要通过大量不同类型的星形胶质细胞进行。本文对星形胶质细胞的功能,尤其是保持突触平衡、调节神经元信号传导、保护氧化损伤下的神经元和决定内源性神经前体细胞分化方面的作用进行综述。本文还重点讨论近年星形胶质细胞在运动神经元病(MND)中的作用方面的研究,强调其在细胞替代治疗中作为治疗靶标和治疗剂的潜能。在20%家族性MND中涉及到的铜锌超氧化物歧化酶(SOD1)基因,其必须表达在胶质细胞和运动神经元中来诱导小鼠疾病模型的疾病状态。在星形胶质细胞中选择性减少突变SOD1(mSOD1)不会影响疾病发作,可延缓疾病进展;但减少运动神经元中的mSOD1可推迟疾病发作,延缓早期病程,对寿命无影响。这提示胶质细胞在MND中可作为潜在的治疗靶标。然而,对星形胶质细胞特异性标志物、前体细胞、亚型的认识缺乏意味着对其发育/分化、应对损伤的了解落后于对其功能的认识。只有深入理解这些问题才能有效运用星形胶质细胞靶向或替代治疗慢性中枢神经系统疾病,如MND。

Lower and upper motor neuron involvement and their impact on disease prognosis in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis is a fatal neurodegenerative disease characterized by progressive muscle wasting,breathing and swallowing difficulties resulting in patient’s death in two to five years after disease onset.In amyotrophic lateral sclerosis,both upper and lower motor neurons of the corticospinal tracts are involved in the process of neurodegeneration,accounting for great clinical heterogeneity of the disease.Clinical phenotype has great impact on the pattern and rate of amyotrophic lateral sclerosis progression and overall survival prognosis.Creating more homogenous patient groups in order to study the effects of drug agents on specific manifestations of the disease is a challenging issue in amyotrophic lateral sclerosis clinical trials.Since amyotrophic lateral sclerosis has low incidence rates,conduction of multicenter trials requires certain standardized approaches to disease diagnosis and staging.This review focuses on the current approaches in amyotrophic lateral sclerosis classification and staging system based on clinical examination and additional instrumental methods,highlighting the role of upper and lower motor neuron involvement in different phenotypes of the disease.We demonstrate that both clinical and instrumental findings can be useful in evaluating severity of upper motor neuron and lower motor neuron involvement and predicting the following course of the disease.Addressing disease heterogeneity in amyotrophic lateral sclerosis clinical trials could lead to study designs that will assess drug efficacy in specific patient groups,based on the disease pathophysiology and spatiotemporal pattern.Although clinical evaluation can be a sufficient screening method for dividing amyotrophic lateral sclerosis patients into clinical subgroups,we provide proof that instrumental studies could provide valuable insights in the disease pathology.

Quo vadis motor neuron disease?

Motor neuron disease(MND), also known as amyotrophic lateral sclerosis, is a relentlessly progressive neurodegenerative condition that is invariably fatal, usually within 3 to 5 years of diagnosis. The aetiopathogenesis of MND remains unresolved and no effective treatments exist. The only Food and Drug Administration approved disease modifying therapy is riluzole, a glutamate antagonist, which prolongs survival by up to 3 mo. Current management is largely symptomatic/supportive. There is therefore a desperate and unmet clinical need for discovery of disease mechanisms to guide novel therapeutic strategy. In this review, we start by introducing the organizational anatomy of the motor system, before providing a clinical overview of its dysfunction specifically in MND. We then summarize insights gained from pathological, genetic and animal models and conclude by speculating on optimal strategies to drive the step change in discovery, which is so desperately needed in this arena.

New trends in treatment of muscle fatigue throughout rehabilitation of elderlies with motor neuron diseases

Muscle fatigue is a problem in rehabilitation,particularly in elderlies and patients with motor neuron diseases.There are high contradictions in the effectiveness of the used methods to decrease muscle fatigue during rehabilitation.They mainly concentrate on increasing rest periods,decreasing training load,or using an ascending intensity of manner of exercise.The training should focus on the newly discovered sensory system of muscle fatigue because of the important role of the sensory system in driving the motor system.Thus,this editorial provides insight on using proprioceptive training to enhance the sensory system of muscle fatigue.

Motor Neuron Disease Associated with Voltage-Gated Potassium Channel Antibodies

Introduction: Antibodies to voltage-gated potassium channels have been implicated in causing a host of peripheral and central nervous system disorders. However, the presence of these antibodies has not been previously associated with motor neuropathy. We describe the first case of acquired motor neuron disease associated with voltage-gated potas-sium channel antibodies. Case Report: The patient is an 81-year-old female who developed signs and symptoms of an idiopathic motor neuron disease. The patient was found to have increased antibodies to voltage-gated potassium chan-nels in the absence of a known metastatic or autoimmune process. Magnetic resonance imaging of the cervical spine demonstrated increased signal in the anterior horn regions of the cervical and upper thoracic spinal cord on T2-weighted imaging. The patient’s disease progression was refractory to both intravenous immunoglobulin and ster-oid therapy. Conclusion: Voltage-gated potassium channels may be causal or simply associated with motor neuron disease;this relationship needs to be elucidated. Testing for these antibodies may be warranted in cases of idiopathic rapidly progressing motor neuron disease.

Catheter-related infections caused by Mycobacterium abscessus in a patient with motor neurone disease:A case report

BACKGROUND Mycobacterium abscessus(M.abscessus)is a rapidly growing mycobacterium and ubiquitous in the environment,which infrequently causes disease in humans.However,it can cause cutaneous or respiratory infections among immunocompromised hosts.Due to the resistance to most antibiotics,the pathogen is formidable and difficult-to-treat.CASE SUMMARY Here,we present a case of catheter-related M.abscessus infections in a patient with motor neurone disease.Catheter and peripheral blood cultures of the patient showed positive results during Gram staining and acid-fast staining.The alarm time of catheter blood culture was 10.6 h earlier than that of peripheral blood.After removal of the peripherally inserted central catheter,secretion and catheter blood culture were positive.M.abscessus was identified by matrix-assisted laser desorption ionization-time of flight mass spectrometry and 16S rDNA sequencing.CONCLUSION For catheter-related M.abscessus infection,rapid diagnosis and timely and adequate antimicrobial therapy are crucial.

Pathogenesis of motor neuron disease

OBJECTIVE: To summarize and analyze the factors and theories related to the attack of motor neuron disease, and comprehensively investigate the pathogenesis of motor neuron disease. DATA SOURCES: A search of Pubmed database was undertaken to identify articles about motor neuron disease published in English from January 1994 to June 2006 by using the keywords of 'neurodegenerative diseases'. Other literatures were collected by retrieving specific journals and articles. STUDY SELECTION: The data were checked primarily, articles related to the pathogenesis of motor neuron disease were involved, and those obviously irrelated to the articles were excluded. DATA EXTRACTION: Totally 54 articles were collected, 30 of them were involved, and the other 24 were excluded. DATA SYNTHESIS: The pathogenesis of motor neuron disease has multiple factors, and the present related theories included free radical oxidation, excitotoxicity, genetic and immune factors, lack of neurotrophic factor, injury of neurofilament, etc. The studies mainly come from transgenic animal models, cell culture in vitro and patients with familial motor neuron disease, but there are still many restrictions and disadvantages. CONCLUSION: It is necessary to try to find whether there is internal association among different mechanisms, comprehensively investigate the pathogenesis of motor neuron diseases, in order to provide reliable evidence for the clinical treatment.

Mills’syndrome is a unique entity of upper motor neuron disease with N-shaped progression:Three case reports

BACKGROUND Mills’syndrome is an extremely rare degenerative motor neuron disorder first described by Mills in 1900,but its nosological status is still not clear.We aimed to analyze the clinical features of Mills’syndrome.CASE SUMMARY Herein,we present 3 cases with similar features as those described in Mills’original paper and review the related literature.Our patients showed middle-and older-age onset,with only upper motor neuron symptoms evident throughout the course of the disease.Spastic hemiplegia began in the lower extremity with a unique progressive pattern.CONCLUSION We consider that Mills’syndrome is a unique entity of motor neuron disorder with an N-shaped progression.Clinicians should maintain a high index of suspicion for the diagnosis of Mills’syndrome when the onset involves lower extremity paralysis without evidence of lower motor neuron or sensory involvement.

Treatment of Motor Neuron Disease with Qi-invigorating Herbs——A Report of 31 Cases

The motor neuron disease (MND) refers to a group of progressive diseases with unknown reasons, which attacks the cells of the anterior horn of the spinal cord, the motor nuclei of the brain stem cranial nerves and the pyramidal cells of the cerebral motor cortex. It is characterized in clinic by atrophy of the muscles, myasthenia and even death due to paralysis of the respiratory muscle. Currently, there is still no any effective cure for this illness. 50-70% of the victims will die in 3 to 5 years, and the survival time for those with brain stem injuries is no more than two years.1 Since 1996, the authors have treated 31 cases of motor neuron disease with large dosage of qi-invigorating drugs in accordance with Prof. Liu Mocai's experience, and obtained certain therapeutic effects. A report follows.……

Amylotrophic Lateral Sclerosis-Like Motor Impairment in Prion Diseases

Neurodegenerative diseases are collective diseases that affect different parts of the brain with common or distinct disease phenotype. In almost all of the Prion diseases, motor impairments that are characterized by motor derangement, apathy, ataxia, and myoclonus are documented and again are shared by motor neuron diseases (MND). Proteins such as;B-Cell lymphoma 2 (BCL2), Copper chaperone for superoxide dismutase (CCS), Amyloid beta precursor protein (APP), Amyloid Precursor-Like Protein1/2 (APLP1/2), Catalase (CAT), and Stress induced phosphoprotein 1 (STIP1), are common interactomes of Prion and superoxide dismutase 1 (SOD1). Although there is no strong evidence to show the interaction of SOD1 and Prion, the implicated common interacting proteins indicate the potential bilateral interaction of those proteins in health and disease. For example, down-regulation of Heat shock protein A (HSPA5), a Prion interactome, increases accumulation of misfolded SOD1 leading to MND. Loss of Cu uptake function disturbs normal function of CCS. Over-expressed proteasome subunit alpha 3 (PSMA3) could fatigue its normal function of removing misfolded proteins. Studies showed the increase in CAT and lipid oxidation both in Prion-knocked out animal and in catalase deficiency cases. Up regulation, down regulation or direct interaction with their interactomes are predicted molecular mechanisms by which Prion and SOD exert their effect. The loss of protective function or the gain of a novel toxic property by the principal proteins is shared in Prion and MND. Thus, it might be possible to conclude that the interplay of proteins displayed in both diseases could be a key phenomenon in motor dysfunction development.

Effects of a Cocktail Supplement of Ginkgo Biloba and Acai Extract on Cognitive Symptoms of Parkinson’s Disease

Parkinson’s Disease (PD) is a neurodegenerative disorder characterized by motor and non-motor symptoms, including cognitive impairment. Current treatments often involve synthetic drugs with significant side effects and potential for dependency. This study investigates the effects of a natural supplement combination of Ginkgo Biloba and Acai Extract on cognitive symptoms in a 77-year-old male with PD. The participant underwent a three-month supplementation regimen, with cognitive function assessed using the Montreal Cognitive Assessment (MoCA) test before and after the intervention. The results indicated an improvement in cognitive scores, suggesting that the combination of Ginkgo Biloba and Acai Extract may offer a promising alternative or adjunct to conventional PD treatments. This study highlights the potential of natural supplements in managing PD symptoms and calls for further research with larger sample sizes to confirm these findings. Human data was performed in accordance with the Declaration of Helsinki by the Roxbury District IRB Board (IRB Number: IRB00011767).

Mitochondria Dynamically Transplant into Cells in Vitro and in Mice and Rescue Aerobic Respiration of Mitochondrial DNA-Depleted Motor Neuron NSC-34

It has been reported that transplantation of pheochromocytoma P12 and hepatoma cells’ mitochondria improve the locomotive activity and prevent disease progress in experimental Parkinson’s disease rats. To prepare for mitochondrial transplantation study in human neurodegenerative diseases, we select human fibroblasts as mitochondrial donor because that fibroblasts share many characteristics with mesenchymal stromal cells (MSCs). We isolate human primary fibroblasts and develop a mitochondrial DNA (mtDNA)-depleted mouse motor neuron NSC-34 cells (NSC-34 ρ° cells). Fibroblast and NSC-34 cell’s mitochondria are co-cultured with NSC-34 ρ° cells. Mitochondrial transplantation is observed by fluorescent microscopy. Gene expression is determined by polymerase chain reaction (PCR) and real time PCR (qPCR). Also, mitochondria are injected to mice bearing mammary adenocarcinoma 4T1 cells. We find results as following: 1) There are abundant mitochondria in fibroblasts (337 ± 80 mitochondria per fibroblast). 42.4% of viable mitochondria are obtained by using differential centrifugation. The isolated mitochondria actively transplant into NSC-34 ρ° cells after co-culture. 2) Fibroblasts transfer mitochondria to human mammary adenocarcinoma MCF-7 cells. 3) There is no expression of HLA-I antigen in fibroblast’s mitochondria indicating they can be used for allogeneic mitochondrial transplantation without HLA antigen match. 4) PCR and qPCR show that NSC-34 ρ° cells lose mitochondrially encoded cytochrome c oxidase I (MT-CO1) and mitochondrially encoded NADH dehydrogenase 1 (MT-ND1) and upregulate expression of glycolysis-associated genes hexokinase (HK2), glucose transporter 1 (SLC2A1) and lactate dehydrogenase A (LDHA). 5) Transplantation of NSC-34 mitochondria restores MT-CO1 and MT-ND1 and downregulates gene expression of HK2, SLC2A1 and LDHA. 6) Normal mammary epithelial mitochondria successfully enter to 4T1 cells in mice. Subcutaneous injection of mitochondria is safe for mice. In summary, mitochondrial transplantation replenishes mtDNA and rescues aerobic respiration of diseased cells with mitochondrial dysfunction. Human primary fibroblasts are potential mitochondrial donor for mitochondrial transplantation study in human neurodegenerative diseases.

SYNGR4 and PLEKHB1 deregulation in motor neurons of amyotrophic lateral sclerosis models: potential contributions to pathobiology

Amyotrophic lateral sclerosis is the most common adult-onset neurodegenerative disease affecting motor neurons. Its defining feature is progressive loss of motor neuron function in the cortex, brainstem, and spinal cord, leading to paralysis and death. Despite major advances in identifying genes that can cause disease when mutated and model the disease in animals and cellular models, it still remains unclear why motor symptoms suddenly appear after a long pre-symptomatic phase of apparently normal function. One hypothesis is that age-related deregulation of specific proteins within key cell types, especially motor neurons themselves, initiates disease symptom appearance and may also drive progressive degeneration. Genome-wide in vivo cell-type-specific screening tools are enabling identification of candidates for such proteins. In this minireview, we first briefly discuss the methodology used in a recent study that applied a motor neuron-specific RNASeq screening approach to a standard model of TAR DNA-binding protein-43(TDP-43)-driven amyotrophic lateral sclerosis. A key finding of this study is that synaptogyrin-4 and pleckstrin homology domain-containing family B member 1 are also deregulated at the protein level within motor neurons of two unrelated mouse models of mutant TDP-43 driven amyotrophic lateral sclerosis. Guided by what is known about molecular and cellular functions of these proteins and their orthologs, we outline here specific hypotheses for how changes in their levels might potentially alter cellular physiology of motor neurons and detrimentally affect motor neuron function. Where possible, we also discuss how this information could potentially be used in a translational context to develop new therapeutic strategies for this currently incurable, devastating disease.

脑源性神经营养因子介导帕金森病的运动防治:作用与机制

背景:运动干预作为经济有效的非物理疗法,可有效上调脑源性神经营养因子表达进而防治帕金森病发生发展,但目前关于靶向脑源性神经营养因子的运动治疗策略在延缓帕金森病发生发展的潜在作用机制尚不明晰。目的:以脑源性神经营养因子和帕金森病的关系为切入点,分析帕金森病病理状态下运动对脑源性神经营养因子表达的特异性调控作用及机制,梳理脑源性神经营养因子介导下不同运动方式对帕金森病的改善效果,并阐明靶向脑源性神经营养因子的运动治疗策略在防治帕金森病的潜在作用机制,旨在为运动防治帕金森病提供新的理论依据。方法:以“帕金森病,脑源性神经营养因子,神经保护,多巴胺,神经元异常凋亡,神经炎症反应,突触可塑性,运动”等为中文检索词;以“Parkinson’s disease,BDNF,Neuroprotection,neuroinflammation,synaptic plasticity”等为英文检索词,分别检索中国知网、万方数据库、PubMed和Web of Science数据库,搜寻各数据库建库至2024年2月发表的所有研究文献,根据纳排标准共获得核心相关文献98篇。结果与结论:①在帕金森病理背景下,运动可通过促进肌因子鸢尾素大量分泌,并降低色氨酸-犬尿氨酸代谢途径紊乱特异性调控脑源性神经营养因子表达。②有氧运动,尤其是特殊有氧运动(动物:旋转杆步行/人类:北欧健走)以及多模式运动可显著上调脑源性神经营养因子表达,进而改善帕金森病的运动症状,此外脑源性神经营养因子还介导身心运动(太极拳)对帕金森病患者认知障碍和睡眠障碍等非运动症状的有效调节。③运动诱导的高表达脑源性神经营养因子可能通过上调抗炎因子白细胞介素10、神经生长因子β和转化生长因子β表达,下调促炎因子肿瘤坏死因子α及白细胞介素1β表达,并抑制核转录因子κB信号通路表达降低小胶质细胞活性减轻神经炎症反应;增加酪氨酸羟化酶活性以促进多巴胺合成释放,并通过下调基质金属蛋白酶3及糖原合成酶激酶3β表达抑制α-突触核蛋白在丝氨酸129位点的磷酸化修饰,以防止神经异常凋亡;诱导突触效能的长时程增强发生,促进突触后致密区蛋白95及突触素大量表达以改善突触可塑性,发挥神经保护作。④鉴于脑源性神经营养因子在帕金森病发病进程及治疗中发挥重要作用,靶向脑源性神经营养因子的运动治疗策略将有助于推动帕金森病疾病“运动+药物”精准医疗的发展。但由于目前研究采用的运动处方较为单一,且研究焦点主要围绕运动症状而缺乏对非运动症状的考察,因此亟待学者采用更加统一和系统的运动处方,围绕非有氧运动类型对同一批帕金森病患者进行长期纵向跟踪研究,以此完善帕金森病运动防治领域研究的不足。

Insights into spinal muscular atrophy from molecular biomarkers

Spinal muscular atrophy is a devastating motor neuron disease characterized by severe cases of fatal muscle weakness.It is one of the most common genetic causes of mortality among infants aged less than 2 years.Biomarker research is currently receiving more attention,and new candidate biomarkers are constantly being discovered.This review initially discusses the evaluation methods commonly used in clinical practice while briefly outlining their respective pros and cons.We also describe recent advancements in research and the clinical significance of molecular biomarkers for spinal muscular atrophy,which are classified as either specific or non-specific biomarkers.This review provides new insights into the pathogenesis of spinal muscular atrophy,the mechanism of biomarkers in response to drug-modified therapies,the selection of biomarker candidates,and would promote the development of future research.Furthermore,the successful utilization of biomarkers may facilitate the implementation of gene-targeting treatments for patients with spinal muscular atrophy.

Dysfunction of autophagy as the pathological mechanism of motor neuron disease based on a patient-specific disease model

Autophagy is the main catabolic pathway in cells for the degradation of impaired proteins and organelles. Accumulating evidence supports the hypothesis that dysfunction of autophagy, leading to an imbalance of proteostasis and the accumulation of toxic proteins in neurons, is a central player in the pathogenesis of neurodegenerative diseases such as Alzheimer＇s disease, Parkinson＇s disease, and amyotrophic lateral sclerosis （ALS）. The clinical pathology of ALS is complex and many genes associated with autophagy and RNA processing are mutated in patients with the familial form. But a causal relationship between autophagic dysfunction and ALS has not been fully established. More importantly, studies on the pathological mechanism of ALS are mainly based on animal models that may not precisely recapitulate the disease itself in human beings. The development of human iPSC techniques allows us to address these issues directly in human cell models that may profoundly influence drug discovery for ALS.

Eiehavioral Symptoms in Motor Neuron Disease and Their Negative Impact on Caregiver Burden

Background： The spectrum of abnormal behaviors in amyotrophic lateral sclerosis/motor neuron disease （ALS/MND） has been described, but its practical meaning, namely its impact on caregiver burden, has not been clearly documented in Chinese population. This study aimed to assess the distribution of abnormal behaviors in Chinese population, and to analyze the relationship between behavior changes and caregivcr burden. Methods： Sixty-five patients with ALS/MND have been consecutively enrolled into registry platform of Peking Union Medical College Hospital. An investigation was performed to these patients and their caregivers using the revised ALS function rating scale, Frontal Behavioral Inventory-ALS version, the Frontal Assessment Battery, and the Caregiver Burden Inventory. Results： Twenty-eight （43.1%） patients displayed abnormal behaviors of varying degrees, with one fulfilling the diagnostic criteria of frontotemporal lobe degeneration. Irritability, logopenia, and inflexibility ranked top 3 of abnormal behavior list. Correlation analysis revealed that the degree of behavioral change and frontal cognitive status were significantly associated with caregiver burden, with more extensive impact from disinhibitive behaviors. Analysis of covariance analysis showed that after associated factors were corrected, caregivers of patients with moderate to severe behavior change reported significantly heavier developmental burden, physical burden, and total burden than those with no behavioral change. Conclusions： Nettrobehavioral symptoms could present in around 40% of Chinese patients with ALS/MND, and the distribution of these behaviors was also unique. Besides, abnormal behaviors were highly related to caregivers＇ burden.