Assessment of the upper motor neuron degeneration by detailed motor homunculus cortex thickness in amyotrophic lateral sclerosis / 西安交通大学学报(医学版)

【Objective】 The involvement of upper motor neuron (UMN) degeneration is crucial to the diagnosis of amyotrophic lateral sclerosis (ALS). This study aimed to determine objective and sensitive UMN degeneration markers for an accurate and early diagnosis. 【Methods】 A total of 108 ALS patients and 90 age- and gender-matched control subjects were recruited from ALS Clinic of The First Affiliated Hospital of Xi’an Jiaotong University. The motor homunculus cortex thickness data in MRI were collected from all the participants. The clinical characteristics and UMN clinical examination of bulbar, cervical, thoracic and lumbosacral regions were collected from the ALS patients. 【Results】 Cortical thickness was significantly thinner in the ALS group than in the control group in bilateral head-face-bulbar and upper-limb areas (P<0.05). The cortical thickness of the global UMN positive group was significantly thinner than that of control groups in bilateral head-face-bulbar and upper-limb areas (P<0.05). The cortical thickness of the UMN positive group in the corresponding region was significantly thinner than that of control groups in bilateral head-face-bulbar and upper-limb areas (P<0.05). 【Conclusion】 The thinning of the motor homunculus cortex can be used as an objective marker of UMN involvement in ALS patients in clinical practice.

Neuroimaging advances in patients with amyotrophic lateral sclerosis / 西安交通大学学报(医学版)

Amyotrophic lateral sclerosis (ALS) is a multi-system neurodegenerative disease characterized with degeneration of both motor and non-motor areas. Complicated clinical manifestations and lack of objective biomarkers for upper motor neuron deficits challenged the early diagnosis of ALS. Meanwhile, heterogeneous non-motor symptoms and conflicted treatment effects exacerbated the management and therapy of the disease. The multiparametric functional MRI has the potential to address all the needs for diagnosis, management, and disease modified therapy in ALS. The present paper summarizes the research progress in both motor and non-motor impairment in ALS, as well as their potential value in visualizing disease stages and drug effect evaluation. Focusing on the heterogeneity of the disease and combining with brain and spinal cord imaging may provide direct evidence for disease diagnosis and treatment and be the priority in the future for ALS.

Bulbar involvement time in spinal-onset amyotrophic lateral sclerosis: Effect on survival / 西安交通大学学报(医学版)

Objective: To explore the effect of bulbar involvement time on survival time of patients with spinal-onset amyotrophic lateral sclerosis (ALS). Methods: We followed up 168 patients with spinal-onset ALS admitted to our hospital from January 2, 2011 to December 31, 2017 until December 31, 2018. Univariate and multivariate analyses were performed to evaluate the affecting factors of the ALS patients' survival time. Kaplan-Meier analysis was made to evaluate the effects of bulbar involvement time on survival time. Results: COX multivariate analysis showed that the risk of death in age-onset <55 y patients was 0.72 times that in age-onset ≥55 y (P=0.09), the risk of death in diagnosis delay time <10.98 m patients was 2.64 times that ≥10.98 m (P<0.001); the risk of death in bulbar involvement time ≥11.5 m and bulbar uninvolvement was 0.30 and 0.32 times respectively that bulbar involvement time <11.5 m (P<0.001). Kaplan-Meier analysis showed differences among bulbar involvement time <11.5 m, ≥11.5 m and bulbar uninvolvement groups (median survival time 20.37 m vs. 40.6 m vs. 39.60 m, Test statistic =39.96, P<0.001). The 2-year, 3-year and 5-year survival rates were 32.17%, 10.80% and 0%, respectively, in bulbar involvement time <11.5 m patients; 89.20%, 57.24% and 10.53% in bulbar involvement time ≥11.5 months patients; and 62.16%, 38.39% and 10.53% in bulbar uninvolvement patients. Conclusion: Similar to the diagnosis delay time and whether to have taken riluzole, the occurrence of bulbar involvement at 11.5 month after onset was an independent risk factor affecting survival time in spinal-onset ALS. The median survival time in patients with bulbar involvement time <11.5 months was significantly shorter than that in patients with bulbar involvement time ≥11.5 months and bulbar uninvolvement.

Features of quantitative EEG in patients with amyotrophic lateral sclerosis and their relationship with cognitive impairment / 西安交通大学学报(医学版)

Objective: To investigate the characteristics of quantitative electroencephalogram (EEG) in patients with amyotrophic lateral sclerosis (ALS) and their relationship with cognitive impairment. Methods: We recruited 38 patients with ALS and 26 healthy controls. All the patients underwent quantitative EEG examination to obtain the relative power of each frequency band and calculate the slow wave ratio (δ+θ)/(α+β) as comparison indexes. Among them, 27 patients with ALS underwent the ECAS scale examination to assess their cognitive function. At the same time, 25 healthy controls underwent the Edinburgh Cognitive and Behavioural ALS Screen (ECAS) to determine the cut-off of scale score. We compared the slow wave ratio in ALS patients with and without cognitive impairment according to the cut-off score. Results: The relative powers of δ and θ bands and slow wave ratios of quantitative EEG in ALS patients were significantly higher than those in healthy controls, and there was no significant difference in relative powers of α and β bands. In the comparison of slow wave ratios in different brain regions, the proportion of slow waves in the bilateral temporal-occipital regions and the right parietal areas was significantly higher than that in healthy controls. The slow wave ratio in the left temporal area was positively correlated with the course of ALS (correlation coefficient 0.405, P=0.05). The ECAS scale screening revealed that 33.3% of ALS patients had cognitive impairment. ALS patients with cognitive impairment had higher slow wave ratios in the frontal and temporal areas than patients without cognitive impairment. The ALS specific item score, ALS non-specific item score and the total score of ECAS were all negatively correlated with the slow wave ratios in the frontal and temporal areas. Conclusion: The changes of EEG activity in patients with ALS are mainly the increase of slow wave activity, which is significant in the temporal, parietal and occipital areas. The slow wave ratios in frontal and temporal areas of ALS patients are correlated with cognitive impairment.

Optimization of muscle selection for needle electromyography in amyotrophic lateral sclerosis / 西安交通大学学报(医学版)

Objective: To compare the diagnostic sensitivity of muscles in different regions on electromyography (EMG) to optimize and the muscle selection of needle electromyography in amyotrophic lateral sclerosis (ALS). To compare the diagnostic performance of revised El Escorial criteria (rEEC) and Awaji criteria (AwC) in ALS. Methods: Totally 198 ALS patients were recruited from ALS Clinic of The First Affiliated Hospital of Xi'an Jiaotong University and diagnosed with rEEC and AwC diagnostic criteria. Needle EMG was detected in muscles of bulbar, cervical, thoracal, and lumbosacral regions. Results: The muscle sensitivity in ALS regions (with or without clinical involvement) was consistent with that in the regions without clinical involvement. The diagnostic sensitivity of muscles were presented as follows: tongue (54.7% vs. 39.2%), trapezius (44.2% vs. 30.2%), lower orbicularis oris (33.2% vs. 20.7%), sternocleidomastoid (20% vs. 13.2%) in bulbar region, the first dorsal interosseus (93.8% vs. 77.3%), abductor pollicis brevis (92.8% vs. 72.7%), biceps (82% vs. 50%), deltoid (82% vs. 45.4%) in cervical region, thoracic paraspinal muscle 10 (86.5% vs. 85.3%) and rectus abdominis (49.5% vs. 49.3%) in thoracal region, the tibialis anterior (74.6% vs. 46.3%), and gastrocnemius (53.4% vs. 19.7%) in lumbosacral region. The diagnostic rate at AwC standard (75.3%) was significantly higher than that at rEEG standard (24.2%) (McNemar test P<0.001). Conclusion: The muscles of clinical affected region should be detected first, followed by the non-affected region in clinically suspected ALS. The tongue in bulbar region, the first dorsal interosseus in cervical region, thoracic paraspinal muscle 10 in thoracal region, tibialis anterior in lumbosacral region are recommended to detect in EMG protocol. The AwC criteria are suggested in ALS clinical diagnosis.

A platform to understand amyotrophic lateral sclerosis (ALS) and extend human motor neurons longevity / Plataforma para empezar a comprender la esclerosis lateral amiotrófica (ELA) y extender la longevidad de neuronas motoras humanas

In vitro modeling of neurodegenerative diseases is now possible by using patient-derived induced pluripotent stem cells (iPS). Through them, it is nowadays conceivable to obtain human neurons and glia, and study diseases cellular and molecular mechanisms, an attribute that was previously unavailable to any human condition. Amyotrophic lateral sclerosis (ALS) is one of the diseases that has gained a rapid advance with iPS technology. By differentiating motor neurons from iPS cells of ALS- patients, we are studying the mechanisms underlying ALS- disease onset and progression. Here, we introduce a cellular platform to help maintain longevity of ALS iPS-motor neurons, a cellular feature relevant for most late-onset human diseases. Long term cultures of patient-derived iPS cells might prove to be critical for the development of personalized-drugs.

Actualmente es posible modelar in vitro enfermedades neurodegenerativas humanas mediante el uso de células madre pluripotentes inducidas (iPS) derivadas del paciente. A través de ellas, es hoy concebible obtener neuronas y glía humanas, y estudiar mecanismos celulares y moleculares de enfermedades, un atributo que anteriormente no era posible para ninguna condición humana. La esclerosis lateral amiotrófica (ELA) es una de las enfermedades que se ha beneficiado con la tecnología de iPS. Al diferenciar neuronas motoras de células iPS obtenidas de pacientes con ELA, hemos iniciado estudios sobre los mecanismos que subyacen a la aparición y progresión de la enfermedad. Aquí, presentamos el desarrollo de una plataforma celular que permite extender la longevidad de las neuronas motoras derivadas de iPS, una característica relevante para la mayoría de las enfermedades humanas de inicio tardío. Los cultivos a largo plazo de células iPS provenientes de pacientes pueden ser determinantes en el desarrollo de terapias asociadas a la medicina de precisión.

Relación entre soporte social y TIC´s en cuidadores familiares de personas con Esclerosis Lateral Amiotrófica / Relationship between social support and ICTs in family caregivers of people with Amyotrophic Lateral Sclerosis

Introducción: La esclerosis lateral amiotrófica (ELA) es una enfermedad neurodegenerativa devastadora que se manifiesta por debilidad muscular y produce dificultades progresivas de movilización, comunicación, alimentación y, en última instancia, respiración, creando una dependencia creciente de familiares y de otros cuidadores La experiencia de cuidado demanda esfuerzo físico, emocional y social requiriendo todo tipo de apoyos, en especial aquellos que brinda la tecnología para proveer soporte social ya que algunas experiencias con TIC's han demostrado eliminar barreras en el acceso al cuidado, disminuir los costos que implican en los cuidadores el desplazamiento y el tiempo, garantizando un servicio disponible para la persona enferma en su ausencia. Objetivo: Describir cómo se relacionan la apropiación de las tecnologías de la información y comunicación y la percepción de soporte social en cuidadores familiares de personas con Esclerosis Lateral Amiotrófica que pertenecen a la Asociación Colombiana de Esclerosis Lateral Amiotrófica. Método: Estudio descriptivo, de relación, abordaje cuantitativo, de corte trasversal. Participaron 76 cuidadores familiares de personas con ELA pertenecientes a ACELA. Instrumentos utilizados: GCPC-UN-D Este instrumento se define como una encuesta de caracterización para el cuidado de una "Diada persona con enfermedad crónica- cuidador familiar" se identifican las necesidades básicas de información para cuidar a una Diada a través de 42 ítems y tres dimensiones: 1) Las condiciones y perfil socio demográfico de la Diada. 2) La percepción de carga y apoyo. 3) Los medios de información y comunicación " y el Cuestionario estudio de desenlaces médicos de apoyo social MOS (Sherbourne & Stewart, 1991) el cual contiene 4 dimensiones de apoyo social funcional o cualitativo: a) apoyo emocional/informacional; b) interacción social positiva; c) apoyo afectivo y d) apoyo instrumental de ayuda material o tangible. El análisis estadístico de relación se realizó mediante la determinación de los coeficientes de correlación de Spearman. Resultados: Las características socio demográficas de los cuidadores de personas con ELA son: mayoría mujeres, edades entre los 30 a 49 años, estado civil casados, estrato socioeconómico 5 y 6, nivel educativo bachillerato, ocupación empleados. Cuando se analiza la apropiación de todas las TIC´s surge de revisar el acceso, el conocimiento y el uso de estas TIC's. Los hallazgos señalan que la apropiación de las tecnologías es heterogénea dentro del grupo de cuidadores además que tienen una elevada apropiación de las mismas. Se evidencia que predomina una percepción alta del soporte social en cada una de las dimensiones. A pesar de no encontrar relación estadísticamente significativa entre la percepción de soporte social y la apropiación de las TIC´s, si se presenta relación fuerte y estadísticamente significativa entre las variables Uso de las TIC´s para el cuidado de la persona con ELA y el apoyo percibido para el cuidado por parte del cuidador familiar de estas personas. Conclusiones: Al establecer la relación entre el soporte social percibido y la apropiación de las TIC's en cuidadores de personas con ELA, se acepta la hipótesis nula de que no existe relación estadísticamente significativa entre las dos variables. Se requiere, a partir de estudios posteriores, qué otras variables inciden en el soporte social percibido ya que hay una relación estadísticamente significativa y fuerte entre el uso de las TIC´s para el cuidado y la percepción de soporte a través de ellas genera alternativas para mayores exploraciones del fenómeno abordado.

Introduction: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease manifested by progressive muscle weakness and produces difficulties of mobilization, communication, food and, ultimately, breathing, creating a growing dependence on family and other caregivers Experience care demands physical, emotional and social effort requiring all kinds of support, especially those offered by technology to provide social support as some experiences with ICT have proven to eliminate barriers to access to care, reduce costs involved in caregivers the displacement and time, ensuring a service available to the sick person in his absence. To describe how the appropriation of information technologies and communication and perception of social support family caregivers of people with ALS who belong to the Colombian Association of Amyotrophic Lateral Sclerosis relate. Method: Descriptive, relationship, quantitative approach to cross-cutting. They involved 76 family caregivers of people with ALS belonging to ACELA. Instruments used: GCPC-A-D This instrument is defined as a characterization survey for the care of a "National Day person familiar chronicle disease caregiver" basic information needs are identified to care for a National Day through 42 items and three dimensions: 1) The conditions and sociodemographic profile of the Day. 2) The perception of load and support. 3) The means of information and communication "and the Medical Outcomes Study Questionnaire of social support MOS (Sherbourne & Stewart, 1991) which contains 4 functional or qualitative dimensions of social support: a) emotional / informational support; b) positive social interaction; c) emotional support d) instrumental support material or tangible help. Statistical analysis was performed relationship by determining the Spearman correlation coefficients. Results: Demographic partner caregivers of people with ALS features are mostly women aged 30-49 years married marital status, socioeconomic stratum 5 and 6, high school education, occupation employees. When all the appropriation of ICTs arises to review the access, knowledge and use of these ICTs it is analyzed. The findings indicate that the appropriation of technologies is heterogeneous within the group of caregivers also having a high ownership of them. It is evident that dominates a high perception of social support in each of the dimensions. Despite not find statistically significant relationship between perceived social support and appropriation of ICTs, if strong and statistically significant relationship occurs between the variables use of ICT for the care of the person with ALS and perceived support for care of the family caregiver of these people. Conclusions: To establish the relationship between perceived social support and appropriation of ICTs in carers of people with ALS, the null hypothesis that there is no statistically significant relationship between the two variables is accepted. It requires from later studies, what other variables affect the perceived social support as there is a statistically significant and strong relationship between the use of ICT for the care and support perception through them generates alternatives further exploration of the phenomenon addressed.

Melittin Ameliorates the Inflammation of Organs in an Amyotrophic Lateral Sclerosis Animal Model

Amyotrophic lateral sclerosis (ALS) is a devastating progressive neurodegenerative disorder characterized by a selective loss of motor neurons in the spinal cord, brainstem, and motor cortex, leading to weakness of the limb and bulbar muscles. Although the immediate cause of death in ALS is the destruction of motor neurons, ALS is a multi-organ disease that also affects the lungs, spleen, and liver. Melittin is one of components of bee venom and has anti-neuroinflammatory effects in the spinal cord, as shown in an ALS animal model. To investigate the effects of melittin on inflammation in the lungs and spleen, we used hSOD1(G93A) transgenic mice that are mimic for ALS. Melittin treatment reduced the expression of inflammatory proteins, including Iba-1 and CD14 by 1.9- and 1.3-fold (p<0.05), respectively, in the lungs of symptomatic hSOD1(G93A) transgenic mice. In the spleen, the expression of CD14 and COX2 that are related to inflammation were decreased by 1.4 fold (p<0.05) and cell survival proteins such as pERK and Bcl2 were increased by 1.3- and 1.5-fold (p<0.05) in the melittin-treated hSOD1G93A transgenic mice. These findings suggest that melittin could be a candidate to regulate the immune system in organs affected by ALS.

Availability of Neurophysiological Index in Amyotrophic Lateral Sclerosis: Application of Neurophysiological Index to Median Nerve /Abductor Digiti Minimi and Posterior Tibial Nerve/Abductor Hallucis

BACKGROUND: Neurophysiological Index (NI) is derived from compound muscle action potentials, distal motor latency and F-wave frequency in the ulnar nerve/abductor digiti minimi. Recent studies suggested that NI could be used as a sensitive measure of change during the course of ALS. However, the NI has several limitations which include being derived only from the ulnar nerve territory and is less valuable when atrophic change of the abductor digiti minimi is severe. Thus, this study aimed to evaluate the correlation of NI with the functional status of ALS patients and the availability of NI obtained from median and posterior tibial nerve territory. METHODS: The subjects of the study were 25 patients with ALS. The NI, Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) and grip power were obtained during the same period and NI values were compared with ALSFRS-R and grip power. RESULTS: A significant correlation was observed between ALSFRS-R and various NI values. Moreover, NI values derived from the ulnar nerve/abductor digiti minimi and the median nerve/abductor pollicis brevis on the dominant hand were statistically correlated with fine motor function scores in ALSFRS-R, and NI values from posterior tibial nerve/abductor hallucis were significantly correlated with lower limb function scores. CONCLUSIONS: Our results support the previous findings that NI is a useful neurophysiological measurement in ALS patients. Moreover, we might suggest NI values from the median nerve/abductor pollicis brevis and the posterior tibial nerve/abductor hallucis also could be used in measuring the functional status of ALS patients.

Immunohistochemical Study on the Distribution of Glycogen Synthase Kinase (GSK) 3beta in the Central Nervous System of SOD1G93A Transgenic Mice / 체질인류학회지

In the present study, we investigated influences of glycogen synthase kinase (GSK) 3beta on the development and/or progression of amyotrophic lateral sclerosis (ALS). We used transgenic mice expressing a human Cu/Zn superoxide dismutase mutant (SOD1G93A) as an in vivo model of ALS and examined expressional changes of GSK3beta immunohistochemically in the spinal cord, brain stem and cerebellum. With these experiments we demonstrate that the neurons in these regions of symptomatic SOD1G93A transgenic mice showed increased GSK3beta immunoreactivities compared with wild-type SOD1 transgenic mice. In contrast to symptomatic SOD1G93A transgenic mice, few GSK3beta immunoreactivity changes were detected in 8w- and 13w-old presymptomatic SOD1G93A transgenic mice. These data suggest the possibility that GSK3 functions as a modulating factor of apoptosis-related alterations in ALS and that GSK3beta exert differential functions in the development and/or progression of ALS. But the exact functional significances of these changes require further elucidation.

Korean version of Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised: A Pilot Study on the Reliability and Validity

BACKGROUND: The Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) is a quantitative measure of ALS-related physical deficit with established reliability and validity in prospective clinical research. This study aimed to test the reliability and validity of the Korean version of ALSFRS-R (K-ALSFRS-R). METHODS: The subjects of the study were 51 patients with ALS diagnosed on the basis of El Escorial criteria. The patients were evaluated by one rater using K-ALSFRS-R, Norris scale, and Appel ALS rating scale on the same day. Subsequently, K-ALSFRS-R was measured by two other raters using a videotape design. Test-retest data were obtained within the time interval of 7 days. RESULTS: Internal consistency and test-retest reliability were high. Inter-rater comparisons showed significant reliability with Kappa or Kendall's tau-b value. Moreover, K-ALSFRS-R scores correlated significantly with clinical status as measured by Norris and Appel ALS rating scale. CONCLUSIONS: Our results showed that K-ALSFRS-R would be a reliable and useful instrument for the evaluation of functional status in patients with ALS.

Changes of Astrocyte in the Cultural Model of Amyotrophic Lateral Sclerosis / 中国康复理论与实践

@#Objective To establish the model of amyotrophic lateral sclerosis (ALS) with selective motor neuron disorder by organotypic spinal cord cultures, and analyze the role of astrocyte in the pathagenisis of ALS.Methods Organotypic spinal cord cultures were prepared using lumbar spinal cord slices from 8-day-old SD rat pups. The threohydroxyaspartate (THA) was applied into culture medium to establish ALS organotypic spinal cord cultures model. Motor neurons survival was evaluated by monoclonal SMI-32 immunohistochemical staining and glial fibrillary acidic protein staining to show astrocyte survival.Results Compared with the control group, there was significantly astrogliosis in the anterior horn and surrounding white matter in THA 100 μmol/L group, and the level of gliosis was increased followed the elongation of THA interference time. With the increasing of the number of astrocyte, the morphology of astrocyte was changed.Conclusion There is significantly astrogliosis in the anterior horn and the time of astrogliosis is markedly earlier than the time of motor neuron loss in the ALS model intervented with THA.

Selective Cytotoxic Mechanism of Homocysteine to Motor Neuronal Cells Expressing the Mutant Cu,Zn-superoxide Dismutase

BACKGROUND: Mutations in Cu, Zn-superoxide dismutase (SOD1) cause about 20% of familial amyotrophic lateral sclerosis (FALS) cases. The mechanism of late-onset disease manifestation despite the innate mutation has no clear explanation. The relationship between homocysteine (HC) and amyotrophic lateral sclerosis (ALS) has not been investigated fully, in spite of the similarity in their pathogenesis. METHODS: We investigated the effect of HC on the motor neuronal cell-line (VSC4.1) transfected with SOD1 of either wild-type or mutant forms (G93A and A4V) using various methods including the MTT assay for the cytotoxic assay, the immunocytochemical staining using anti-SOD1 for the aggregation of SOD1, the western blotting using anti-nitrotyrosine and anti-DNPH for the oxidative protein damage, and the measurement of the intracellular Ca2+ concentration using Fura2-AM. RESULTS: In the MTT assay, the HC induced significant cytotoxicity in the mutants, as compared with wild-type. This HC-induced cytotoxicity was inhibited by the trolox and the bathocuproinedisulfonate (BC). HC increased the carbonylation and nitrosylation of the mutant proteins. HC also increased significant SOD1-aggregation in mutants. This HC-induced SOD1-aggregation in mutants was inhibited by trolox, N-nitro-L-arginine methyl ester, BC, and z-VAD-FMK. HC did not change the intracellular concentration of Ca2+ in the mutants compared with the wild-type. CONCLUSIONS: The authors showed that the vulnerability of the SOD1 mutant motor neuronal cells to HC involves the copper-mediated oxygen radical toxicity, and that HC may be a lifelong precipitating factor in some forms of FALS, suggesting a possible treatment modality with vitamin supplements.

Neuroprotective Effect of Estrogen on Motor Neuron Cells Expressing Wild Type or Mutant Cu/Zn Superoxide Dismutase

BACKGROUND: Recently, the mechanism involved in nitric oxide (NO)-mediated motor neuron death is under extensive investigation. The role of Cu/Zn superoxide dismutase (SOD) mutation, which is found in about 2% of all ALS patients, has been implicated in selective motor neuron death and it is said to play an important role in NO-mediated motor neuron death. Estrogen is reported to have neuroprotective effect in various neurological diseases. However, neuroprotective effect on estradiol on spinal motor neuron exposed to NO has rarely been studied. METHODS: Motor neuron-neuroblastoma hybrid cell expressing wild-type or mutant (G93A or A4V) SOD gene was treated with 200 micro M Snitrosoglutathione. After 24 hours, cell viability was measured by MTT assay. To see the neuroprotective effect of estradiol, pretreatment with 5 nM or 50 nM 17 beta-estradiols was done 24 hours before S-nitrosoglutathione treatment. RESULTS: S-nitrosoglutathione showed significant neurotoxic effect in all three cell lines. Percentage of cell death was significantly different in each cell line. Both 5 nM and 50 nM estradiols showed neuroprotective effect in G93A cell line. In wild-type cell line, 50 nM estradiol showed neuroprotective effect, but 5 nM estradiol did not. In A4V cell line, estradiol did not showed neuroprotective effect. CONCLUSIONS: This study showed that NO-mediated motor neuron death could be influenced by presence or absence of mutation and type of mutation in SOD gene. Neuroprotective effect of estradiol is also influenced by SOD gene mutation. This study implies that estrogen might be beneficial to some ALS patients.

Effect of Familial Amyotrophic Lateral Sclerosis-associated Cu, Zn-superox-ide Dismutase Mutation on Neural Differentiation in Motor Neuronal Cells

BACKGROUND: Mutations in the human Cu, Zn-superoxide dismutase(SOD1) gene have been identified in some cases of familial amyotrophic lateral sclerosis(ALS). The aim of this study is to delineate the effect of the SOD1 mutation on neural differentiation, and to investigate the mechanism of neuronal death. METHODS: We studied motorneuron-neurob-lastoma hybrid cells(VSC 4.1) expressing wild type or mutant SOD1(G93A, A4V) during differentiation by dibutyryl cAMP and aphidicolin. RESULTS: Mutant cells(G93A) revealed a decreased viability compared with the control cells, mainly in the early stage ofdifferentiation. The release of cytochrome c and increased nuclear fragmentation were observed. However, cell death was not protected by nonselective caspase inhibitor(z-VAD-fmk), but by the antioxi-dant( Trolox). CONCLUSIONS: The results suggest that oxidative stress may be the main mechanism of neuronal death, particularly in the early stage of differentiation.

Impairment of Neurite Formation in Familial ALS-associated Cu, Zn-Superoxide Dismutase Mutant Cells

BACKGROUND: Mutations in the human Cu, Zn-superoxide dismutase (SOD1) gene have been identified in some cases of familial amyotrophic lateral sclerosis (ALS). Neuronal cells with mutant SOD1 gene promoted cell death during differentiation by dibutyryl cAMP and aphidicolin. The aim of this study is to delineate if there is an impairment of the neural differentiation process in mutant SOD1 cells. METHODS: We studied the motoneuron-neuroblastoma hybrid cells (VSC 4.1) expressing wild-type or mutant SOD1 (G93A) during the differentiation by dibutyryl cAMP and aphidicolin. RESULTS: Mutant SOD1 cell (G93A) showed an impairment in the neurite formation. Western blot analysis revealed that the amount of neurofilament decreased before differentiation. A decrease in the amount of MAP-2 is observed during differentiation. CONCLUSIONS: Our results suggest that the impairment in the neurite formation of mutant SOD1 cell (G93A) is a differentiation failure and is associated with neuronal cell death.

Visualization and Quantitative Analysis of Bulbar Palsy and Its Progression Using Sound Spectrography: A case report

Distortion of vowels in dysarthria associated with amyotrophic lateral sclerosis can be detected at the perceptual, physiological, and acoustical levels of analysis. Sound spectrography was used to analyse the formants of vowels which reflect position and space of articulatory organs. We analyse status and progression of dysarthria in 54 year old women with amyotrophic lateral sclerosis using sound spectrography. Target formant frequencies were measured from select words containing the vowels /a/, /e/, /i/, /o/, /u/. Results revealed that dysarthric patient exhibited smaller vowel space areas and less systematic changes in vowel spaces for pronouncing different vowels in comparison with normal control. Changes of vowel formants in sound spectrographic analysis reflected progression of dysarthric symptom in this patient. We conclude that acoustic analysis of vowels using sound spectrography is a useful tool to visualize and quantitatively analyse the severity and progression of dysarthria due to paralytic articulatory organ.

Therapeutic potential of madecassoside in transgenic mice of amyotrophic lateral sclerosis / 中草药

Objective To investigate the therapeutic potential of madecassoside in mice expressing a mutant human Cu,Zn superoxide dismutase(SOD1)-G93A linked to human amyotrophic lateral sclerosis(ALS).Methods Effects of madecassoside on onset of clinical disease,survival of mice,decline of motor function,and motor neuron(MN) degeneration were observed by behavioral analysis and histological eva-(luation.) Results Madecassoside(61.1?11.0) and(185.6?18.7) mg/(kg?d) ig administration,beginning at 70 d of age until death,prolonged survival of SOD1-G93A ALS mice by 11.4 and 9.4 d,respectively(P