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Cerebellar pathology in motor neuron disease:neuroplasticity and neurodegeneration

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Neural Regeneration Research 2022年第11期17卷 2335-2341页

作者： Rangariroyashe H.Chipika Grainne Mulkerrin Pierre-François Pradat Aizuri Murad Fabrice Ango Cédric Raoul Peter Bede Computational Neuroimaging Group Biomedical Sciences InstituteTrinity College DublinDublinIreland Pitié-Salpêtrière University Hospital Sorbonne UniversityParisFrance The Neuroscience Institute of Montpellier(INM) INSERMCNRSMontpellierFrance

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.

关键词： amyotrophic lateral sclerosis ataxia cerebellum magnetic resonance imaging motor neuron disease neuroimaging neuroplasticity pathology primary lateral sclerosis pseudobulbar affect

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

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Neural Regeneration Research 2022年第1期17卷 65-73页

作者： Maria N.Zakharova Anna A. Abramova Research Center of Neurology MoscowRussia

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.

关键词： amyotrophic lateral sclerosis biomarkers of progression classification diagnostic biomarkers disease heterogeneity electrodiagnostic medicine electromyography motor neuron disease neuroimaging

Eiehavioral Symptoms in motor neuron disease and Their Negative Impact on Caregiver Burden

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Chinese Medical Journal 2015年第17期128卷 2295-2300页

作者： Bo Cui Li-Ying Cui Ming-Sheng Liu Xiao-Guang Li Jun-Fang Ma Jia Fang Oino-Yun Ding Department of Neurology Peking Union Medical College Hospital Chinese Academy of Medical Sciences Beijing 100730 China Neurosciences Center Chinese Academy of Medical Sciences Beijing 100730 China

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.

关键词： Amyotrophic Lateral Sclerosis Behavioral Symptoms Caregiver Burden motor neuron disease

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

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Neural Regeneration Research 2017年第5期12卷 723-736页

作者： Manoj Kumar Jaiswal Molecular Imaging and Neuropathology Division New York State Psychiatry Institute Columbia University New York NY USA Department of Psychiatry Columbia University New York NY USA

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.

关键词： iPSCs stem cells human patients ALS mitochondria motor neuron disease disease modeling neurodegeneration gene editing transplantation drug screening

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

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Neuroscience Bulletin 2015年第4期31卷 445-451页

作者： Dan-Jing Yang Liang Zhu Jie Ren Rong-Jie Ma Hongwen Zhu Jun Xu Advanced Institute of Translational Medicine Tongji University East Hospital Tongji University School of Medicine Tianjin Hospital Tianjin Academy of Integrative Medicine

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.

关键词： motor neuron disease iPSC autophagy amyotrophic lateral sclerosis spinal muscular atrophy

Metabolic deficit and motor neuron disease

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Metabolic deficit and motor neuron disease

The active role of glial cells in familial and sporadic motor neuron disease

中国神经科学学会第四次会员代表大会暨第八届全国学术会议

作者： Yuan-Rong YAO~*,Jie WANG Department of Neurology,Neurology Institute,General Hospital,Tianjin Medical University,Tianjin 300052,China

＜正＞Objective To explore whether metabolic deficit in muscle,a key metabolic tissue and the primary target of MND disease,may contribute to the physiopathological process of MND and whether the metabolic deficit is limited in symptomatic muscles or is a generalized event occurring also in asymptomatic muscles in MND.Methods Biopsies were taken from a most affected muscle and one muscle from the limb most remote from that muscle from each patient,while only one muscle was biopsied from each control.Total RNA was isolated from muscle tissues obtained from 10 patients and 6 controls.By real-time PCR we investigated the expression levels of the transcripts encoding the cytosolic malate dehydrogenase （MDH1）,the human guanine nucleotide-binding regulatory protein Go-alpha（GNAO1）,the pyruvate dehydrogenase kinase 2（PDK2） and the hexokinase 3（HK3） using that of the gene encodingβ-actin as an endogenous control. Results Expression levels of transcripts encoding MDH1 were decreased in remote muscle（0.41-fold,vs affected muscle, P＜0.05;0.51-fold,vs controls,P＞0.05）.The levels of the transcripts from MDH1 were elevated at 1.25-fold（P＞0.05） in affected muscles in cases as compared with controls.The expression levels of the transcripts encoding PDK2 were decreased to 0.49-fold（P＜0.01） in remote muscles in cases compared with controls.The levels of transcripts encoding PDK2 were negatively correlated with age（P＜0.05） in controls,but no such correlation was observed in patients.No significant differences of the expression levels of transcripts encoding GNAO1 and HK3 were observed between groups. Conclusion The results suggest that metabolic deficitis involved in the pathogenetic process of skeletal muscle in MND and the metabolic deficit is not only limited in symptomatic muscles but also occurs in asymptomatic muscles in MND. These findings may indicate that the aberrant metabolism not only occurs in motor neurons but also in skeletal muscle. This preliminary study will contribute to the possible identification of novel targets

关键词： motor neuron disease skeletal muscle cytosolic malate dehydrogenase pyruvate dehydrogenase kinase 2

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The active role of glial cells in familial and sporadic moto...

Obstructive sleep apnea hypopnea syndrome and alveolar hypoventilation syndrome in motor neuron disease:a case report and literature review

中国神经科学学会第九届全国学术会议暨第五次会员代表大会

作者： Koji Yamanaka RIKEN Brain Science Institute

＜正＞Dominant mutations in the Cu/Zn superoxide dismutase（SOD1） gene lead to a familial form of amyotrophic lateral sclerosis（ALS）,an adult motor neuron disease.Although ubiquitous expression of mutant SOD1 provokes progressive,selective motor neuron degeneration in human and rodents due to an acquired toxic property（ies） of the mutant,the distinct roles of mutant toxicity within motor neurons and non-neuronal cells are recently established by our cell-type specific gene ablation from mutant SOD1 mice.The toxicity（ies） within astrocytes and microglia accelerates disease progression,indicating that glial cells contribute to non-cell autonomous neurodegeneration. Recent discovery of TDP-43 protein accumulation as a pathological hallmark of sporadic ALS prompted us to test whether SOD1-linked familial ALS and sporadic ALS share the common disease mechanisms in glial cells.To address this question,we have compared gene expression profile of spinal cords of SOD1 mice and sporadic ALS patients by establishing the cell-type specific transcriptome.Significant overlap of misregulated genes enriched in microglia was observed in sporadic ALS and SOD1 mouse models.The pathway analysis indicated the innate immune system,NF- kappaB signaling,and caspase-interleukin cascade that were misregulated in glial cells,suggesting these pathways may be the potential therapeutic targets of ALS.

关键词： glia motor neuron disease ALS SODl

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Obstructive sleep apnea hypopnea syndrome and alveolar hypov...

Histone deacetylase 6 delays motor neuron degeneration by ameliorating the autophagic flux defect in a transgenic mouse model of amyotrophic lateral sclerosis

2017全国睡眠呼吸障碍学术大会暨睡眠呼吸疾患新进展学...

作者：周莉欧阳若芸陈平罗红刘贵钱中南大学湘雅二医院呼吸内科

Objective:To analyze the clinical characteristics of a patient with motor neuron disease which caused obstructive sleep apnea hypopnea syndrome（OSAHS）and alveolar hypoventilation syndrome,and raise the understanding and diagnosis rate of this disease.Method:Retrospectively analyze the diagnosis and treatment process of a 52 year-old male patient who was accepted by The Second Xiangya Hospital,Central South University because of dyspnea,shortness of breath and malaise for 4 months,and eventually was diagnosed as motor neuron disease associated with OSAHS and alveolar hypoventilation syndrome,which is an intractable and significant case.Besides,we searched HowNet,WanFang and PubMed databases to review related literature.Result:The major clinical manifestation of motor neuron disease is impaired upper and lower motor neuron which appeared as proximal muscle weakness,muscle tremor,amyotrophy,bulbar symptoms and pyramidal sign.And it is a chronic,progressive disease with worse prognosis,low survival and more intractable to diagnose most of time in which electroneuromyography is an vital examination for diagnosis.What’s more,sleep disordered breathing is common in patients with motor neuron disease which is featured as decreased rapid eye movement sleep,increased awaking time and frequency,apnea and hypopnea.The main mechanism of sleep disordered breathing in motor neuron disease is disturbed central nervous system and paralysis of diaphragm and respiratory muscle.Moreover,the patient is susceptible to suffer with restrictive ventilatory dysfunction and alveolar hypoventilation and subsequent partial pressure of carbon dioxide and hypoxemia.Therefore,respiratory failure is the most frequent cause of death in patients of motor neuron disease.non-invasive positive pressure ventilation is suggested to apply in such patients who forced vital capability is less than 75 percent of predicted value.Conclusion:Sleep disordered breathing is common in patients with motor neuron disease.Hence,polysomnography is suggested as a rout

关键词： motor neuron disease sleep disordered breathing alveolar hypoventilation syndrome diagnosis and treatment clinical feature

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Neuroscience Bulletin 2015年第4期31卷 459-468页

作者： Sheng Chen Xiao-Jie Zhang Li-Xi Li Yin Wang Ru-Jia Zhong Weidong Le Department of Neurology Ruijin HospitalShanghai Jiaotong University School of Medicine Center for Translational Research on Neurological diseases First Affiliated Hospital of Dalian Medical University

Amyotrophic lateral sclerosis （ALS） is a fatal neurodegenerative disorder characterized by the selective loss of motor neurons. Abnormal protein aggregation and impaired protein degradation are believed to contribute to the pathogenesis of this disease. Our previous studies showed that an autophagic flux defect is involved in motor neuron degeneration in the SOD1G93A mouse model of ALS. Histone deacetylase 6 （HDAC6） is a class II deacetylase that promotes autophagy by inducing the fusion of autophagosomes to lysosomes. In the present study, we showed that HDAC6 expression was decreased at the onset of disease and became extremely low at the late stage in ALS mice. Using lentivirus-HDAC6 gene injection, we found that HDAC6 overexpression prolonged the lifespan and delayed the motor neuron degeneration in ALS mice. Moreover, HDAC6 induced the formation of autolysosomes and accelerated the degradation of SOD1 protein aggregates in the motor neurons of ALS mice. Collectively, our results indicate that HDAC6 has neuroprotective effects in an animal model of ALS by improving the autophagic flux in motor neurons, and autophagosome-lysosome fusion might be a therapeutic target for ALS.

关键词： motor neuron disease motor neuron neurodegenerative disease amyotrophic lateral sclerosis autophagy histone deacetylase 6