The onset of amyotrophic lateral sclerosis is usually characterized by focal death of both upper and/or lower motor neurons occurring in the motor cortex,basal ganglia,brainstem,and spinal cord,and commonly involves t...The onset of amyotrophic lateral sclerosis is usually characterized by focal death of both upper and/or lower motor neurons occurring in the motor cortex,basal ganglia,brainstem,and spinal cord,and commonly involves the muscles of the upper and/or lower extremities,and the muscles of the bulbar and/or respiratory regions.However,as the disease progresses,it affects the adjacent body regions,leading to generalized muscle weakness,occasionally along with memory,cognitive,behavioral,and language impairments;respiratory dysfunction occurs at the final stage of the disease.The disease has a complicated pathophysiology and currently,only riluzole,edaravone,and phenylbutyrate/taurursodiol are licensed to treat amyotrophic lateral sclerosis in many industrialized countries.The TAR DNA-binding protein 43 inclusions are observed in 97%of those diagnosed with amyotrophic lateral sclerosis.This review provides a preliminary overview of the potential effects of TAR DNAbinding protein 43 in the pathogenesis of amyotrophic lateral sclerosis,including the abnormalities in nucleoplasmic transport,RNA function,post-translational modification,liquid-liquid phase separation,stress granules,mitochondrial dysfunction,oxidative stress,axonal transport,protein quality control system,and non-cellular autonomous functions(e.g.,glial cell functions and prion-like propagation).展开更多
Objective To study the activation changes of the brain in patients with amyotrophic lateral sclerosis （ALS） while executing sequential finger tapping movement using the method of blood oxygenation level dependent （...Objective To study the activation changes of the brain in patients with amyotrophic lateral sclerosis （ALS） while executing sequential finger tapping movement using the method of blood oxygenation level dependent （BOLD） functional magnetic resonance imaging （tMRI）. Methods Fifteen patients with definite or probable ALS and fifteen age and gender matched normal controls were enrolled. MRI was performed on a 3.0 Tesla scanner with standard headcoiL The functional images were acquired using a gradient echo single shot echo planar imaging （EPI） sequence. All patients and normal subjects executed sequential finger tapping movement at the frequency of 1-2 Hz during a block-design motor task. Structural MRI was acquired using a three-dimensional fast spoiled gradient echo （3D-FSPGR） sequence. The tMRI data were analyzed by statistical parametric mapping （SPM）. Results Bilateral primary sensorimotor cortex （ PSM）, bilateral premotor area （ PA）, bilateral supplementary motor area （SMA）, bilateral parietal region （ PAR）, contralateral inferior lateral premotor area （ ILPA）, and ipsilateral cerebellum showed activation in both ALS patients and normal controls when executing the same motor task. The activation areas in bilateral PSM, bilateral PA, bilateral SMA, and ipsilateral cerebellum were significantly larger in ALS patients than those in normal controls （ P 〈 0.05 ）. Extra activation areas including ipsilateral ILPA, bilateral posterior limb of internal capsule, and contralateral cerebellum were only detected in ALS patients. Conclusions Similar activation areas are activated in ALS patients and normal subjects while executing the same motor task. The increased activation areas in ALS patients may represent neural reorganization, while the extra activation areas in ALS patients may indicate functional compensation.展开更多
The neutrophil-to-lymphocyte ratio(NLR)is considered a robust prognostic biomarker for predicting patient survival outcomes in many diseases.However,it remains unclear whether it can be used as a biomarker for amyotro...The neutrophil-to-lymphocyte ratio(NLR)is considered a robust prognostic biomarker for predicting patient survival outcomes in many diseases.However,it remains unclear whether it can be used as a biomarker for amyotrophic lateral sclerosis(ALS).To correlate NLR with disease progression and survival in sporadic ALS,1030 patients with ALS between January 2012 and December 2018 were included in this study.These patients were assigned into three groups according to their NLR values:Group 1(NLR<2,n=544[52.8%]),Group 2(NLR=2–3,n=314[30.5%]),and Group 3(NLR>3,n=172[16.7%]).All patients were followed up until April 2020.Patients in Group 3 had a significantly older onset age,a lower score on the Revised ALS Functional Rating Scale,and rapidly progressing disease conditions.Furthermore,faster disease progression rates were associated with higher NLR values(odds ratio=1.211,95%confidence interval[CI]:1.090–1.346,P<0.001)after adjusting for other risk factors.Compared with Groups 1 and 2,the survival time in Group 3 was significantly shorter(log-rank P=0.002).The NLR value was considered an independent parameter for the prediction of survival in ALS patients after normalizing for all other potential parameters(hazard ratio[HR]=1.079,95%CI:1.016–1.146,P=0.014).The effects on ALS survival remained significant when adjusted for treatment(HR=1.074,95%CI:1.012–1.141,P_(trend)=0.019)or when considering the stratified NLR value(HR=1.115,95%CI:1.009–1.232,P_(trend)=0.033).Thus,the NLR may help to predict the rate of disease progression and survival in patients with sporadic ALS.The study was approved by the Institutional Ethics Committee of West China Hospital of Sichuan University,China(approval No.2015(236))on December 23,2015.展开更多
We describe a pre-clinical spinal cord motor neuron injury model that is minimal invasive, reproducible, focal and easily applied to small rodents.Retrograde axonal transport of a pro-apoptotic phosphatidylinosotol 3&...We describe a pre-clinical spinal cord motor neuron injury model that is minimal invasive, reproducible, focal and easily applied to small rodents.Retrograde axonal transport of a pro-apoptotic phosphatidylinosotol 3'-kinase inhibitor, wortmannin, via the sciatic nerve results in loss of ipsilateral lumbar motor neurons proportional to the level of drug administered.Motor neuron loss was detected by choline acetyltransferase(ChAT) immunostaining and with a transgenic thy1-eGFP marker.The short half-life of wortmannin generates minimal wound spread, and wortmannin does not affect axon transport, as determined by co-injection of a pseudorabies virus tracer.Using quantitative transcript analysis, we found that ChAT transcripts significantly decreased at 14 days post-delivery of 1 μg wortmannin, relative to sham controls, and remained low after 90 days.Smaller effects were observed with 200 ng and 100 ng wortmannin.Wortmannin also generated a transient and significant increase in astrocyte Gfap transcripts after 14 days with a return to control levels at 90 days.Treated mice had hind limb spasticity and a forced motor function defect that was quantified using a water exit test.Controls rapidly exit a shallow water tray, and wortmannin treated animals were up to 12-fold slower, a phenotype that persisted for at least 3 months.Thus the focal delivery of wortmannin to motor neurons generates a reproducible and scalable injury that can facilitate quantitative studies on neural regeneration and repair.The efficacy of sciatic nerve suicide transport can also explain neurotoxin-mediated selective loss of motor neurons in diseases such as amyotrophic lateral sclerosis.All procedures were performed at Rutgers under established Institutional Animal Care and Use protocols(eIACUC_TR201800022, approved on March 20, 2018).展开更多
Background： Mitochondrial dysfunction plays an important role in the pathogenesis of amyotrophic lateral sclerosis （ALS）. We aimed to demonstrate mitochondrial dysfunction in ALS using a lactate stress test and to ...Background： Mitochondrial dysfunction plays an important role in the pathogenesis of amyotrophic lateral sclerosis （ALS）. We aimed to demonstrate mitochondrial dysfunction in ALS using a lactate stress test and to examine the relationship between mitochondrial dysfunction with motor deterioration. Methods： We enrolled 116 patients and observed clinical variables, including the survival state. Results： Patients with a rapid slope of revised ALS functional rating scales （ALSFRS-r） （〉20 U/year） exhibited the slowest elimination rate （median -4.67 × 10^-3 mmol·L ^-1min ^-1, coefficient of variation, 590.15%）, the shortest duration （0.63 ± 0.28 years） and the worst ALSFRS-r （32.59±4.93）. Patients with a moderate slope ofALSFRS-r （1~20 U/year） showed a moderate elimination rate （median -11.33 × 10^-3 mmol·L ^-1min ^-1, coefficient of variation, 309.89%）, duration （1.16± 0.45 years）, and ALSFRS-r （34.83 ± 6.11）. The slower progressing （〈10 U/year group） patients exhibited a rapid elimination rate （median： - 12.00 × 10^-3 mmol·L ^-1min ^-1, coefficient of variation： 143.08%）, longer duration （median： 3 years, coefficient of variation： 193.33%）, and adequate ALSFRS-r values （39.58 ± 9.44）. Advanced-phase ALS patients also showed slower elimination rate （ER, quartiles - 17.33, -5.67, 4.00） and worse ALSFRS-r （34.88 ± 9.27）, while early-phase patients showed a more rapid ER （quartiles -25.17, -11.33, -3.50） and better ALSFRS-r （39.28 ± 7.59）. These differences were statistically significant. Multiple linear regression analysis revealed strong direct associations among ER, ALSFRS-r slope （standard beta = 0.33, P = 0.007）, and forced vital capacity （predict %） （standard beta = -0.458, P = 0.006, adjusted for ALSFRS-r, course and onset region）. However, the data obtained from 3 years of follow-up showed no statistically significant difference in the survival rates between the most rapid and slowest ER groups. Conclusion： There is a potential linear relationship between ER and motor deterioration in ALS. Slower ER might be associated with faster disease progression.展开更多
基金in part supported by the National Natural Science Foundation of China,Nos.30560042,81160161,81360198,and 82160255Education Department of Jiangxi Province,Nos.GJJ13198 and GJJ170021+1 种基金Jiangxi Provincial Department of Science and Technology,No.20192BAB205043Health and Family Planning Commission of Jiangxi Province,Nos.20181019 and 202210002(all to RX)。
文摘The onset of amyotrophic lateral sclerosis is usually characterized by focal death of both upper and/or lower motor neurons occurring in the motor cortex,basal ganglia,brainstem,and spinal cord,and commonly involves the muscles of the upper and/or lower extremities,and the muscles of the bulbar and/or respiratory regions.However,as the disease progresses,it affects the adjacent body regions,leading to generalized muscle weakness,occasionally along with memory,cognitive,behavioral,and language impairments;respiratory dysfunction occurs at the final stage of the disease.The disease has a complicated pathophysiology and currently,only riluzole,edaravone,and phenylbutyrate/taurursodiol are licensed to treat amyotrophic lateral sclerosis in many industrialized countries.The TAR DNA-binding protein 43 inclusions are observed in 97%of those diagnosed with amyotrophic lateral sclerosis.This review provides a preliminary overview of the potential effects of TAR DNAbinding protein 43 in the pathogenesis of amyotrophic lateral sclerosis,including the abnormalities in nucleoplasmic transport,RNA function,post-translational modification,liquid-liquid phase separation,stress granules,mitochondrial dysfunction,oxidative stress,axonal transport,protein quality control system,and non-cellular autonomous functions(e.g.,glial cell functions and prion-like propagation).
基金Supported by National Natural Sciences Foundation of China(30470512)
文摘Objective To study the activation changes of the brain in patients with amyotrophic lateral sclerosis （ALS） while executing sequential finger tapping movement using the method of blood oxygenation level dependent （BOLD） functional magnetic resonance imaging （tMRI）. Methods Fifteen patients with definite or probable ALS and fifteen age and gender matched normal controls were enrolled. MRI was performed on a 3.0 Tesla scanner with standard headcoiL The functional images were acquired using a gradient echo single shot echo planar imaging （EPI） sequence. All patients and normal subjects executed sequential finger tapping movement at the frequency of 1-2 Hz during a block-design motor task. Structural MRI was acquired using a three-dimensional fast spoiled gradient echo （3D-FSPGR） sequence. The tMRI data were analyzed by statistical parametric mapping （SPM）. Results Bilateral primary sensorimotor cortex （ PSM）, bilateral premotor area （ PA）, bilateral supplementary motor area （SMA）, bilateral parietal region （ PAR）, contralateral inferior lateral premotor area （ ILPA）, and ipsilateral cerebellum showed activation in both ALS patients and normal controls when executing the same motor task. The activation areas in bilateral PSM, bilateral PA, bilateral SMA, and ipsilateral cerebellum were significantly larger in ALS patients than those in normal controls （ P 〈 0.05 ）. Extra activation areas including ipsilateral ILPA, bilateral posterior limb of internal capsule, and contralateral cerebellum were only detected in ALS patients. Conclusions Similar activation areas are activated in ALS patients and normal subjects while executing the same motor task. The increased activation areas in ALS patients may represent neural reorganization, while the extra activation areas in ALS patients may indicate functional compensation.
基金supported by the Science and Technology Bureau Fund of Sichuan Province of China,No.2020YFS0220the China Postdoctoral Science Foundation,No.2019M653427+1 种基金Postdoctoral Research Project,West China Hospital,Sichuan University of China,No.2019HXBH029Health Commission of Sichuan Province of China,No.20PJ038(all to QQW)。
文摘The neutrophil-to-lymphocyte ratio(NLR)is considered a robust prognostic biomarker for predicting patient survival outcomes in many diseases.However,it remains unclear whether it can be used as a biomarker for amyotrophic lateral sclerosis(ALS).To correlate NLR with disease progression and survival in sporadic ALS,1030 patients with ALS between January 2012 and December 2018 were included in this study.These patients were assigned into three groups according to their NLR values:Group 1(NLR<2,n=544[52.8%]),Group 2(NLR=2–3,n=314[30.5%]),and Group 3(NLR>3,n=172[16.7%]).All patients were followed up until April 2020.Patients in Group 3 had a significantly older onset age,a lower score on the Revised ALS Functional Rating Scale,and rapidly progressing disease conditions.Furthermore,faster disease progression rates were associated with higher NLR values(odds ratio=1.211,95%confidence interval[CI]:1.090–1.346,P<0.001)after adjusting for other risk factors.Compared with Groups 1 and 2,the survival time in Group 3 was significantly shorter(log-rank P=0.002).The NLR value was considered an independent parameter for the prediction of survival in ALS patients after normalizing for all other potential parameters(hazard ratio[HR]=1.079,95%CI:1.016–1.146,P=0.014).The effects on ALS survival remained significant when adjusted for treatment(HR=1.074,95%CI:1.012–1.141,P_(trend)=0.019)or when considering the stratified NLR value(HR=1.115,95%CI:1.009–1.232,P_(trend)=0.033).Thus,the NLR may help to predict the rate of disease progression and survival in patients with sporadic ALS.The study was approved by the Institutional Ethics Committee of West China Hospital of Sichuan University,China(approval No.2015(236))on December 23,2015.
基金Supported by grants to Dr McKinnon (PI) from the New Jersey Commission on Spinal Cord Research (05-304711-015)。
文摘We describe a pre-clinical spinal cord motor neuron injury model that is minimal invasive, reproducible, focal and easily applied to small rodents.Retrograde axonal transport of a pro-apoptotic phosphatidylinosotol 3'-kinase inhibitor, wortmannin, via the sciatic nerve results in loss of ipsilateral lumbar motor neurons proportional to the level of drug administered.Motor neuron loss was detected by choline acetyltransferase(ChAT) immunostaining and with a transgenic thy1-eGFP marker.The short half-life of wortmannin generates minimal wound spread, and wortmannin does not affect axon transport, as determined by co-injection of a pseudorabies virus tracer.Using quantitative transcript analysis, we found that ChAT transcripts significantly decreased at 14 days post-delivery of 1 μg wortmannin, relative to sham controls, and remained low after 90 days.Smaller effects were observed with 200 ng and 100 ng wortmannin.Wortmannin also generated a transient and significant increase in astrocyte Gfap transcripts after 14 days with a return to control levels at 90 days.Treated mice had hind limb spasticity and a forced motor function defect that was quantified using a water exit test.Controls rapidly exit a shallow water tray, and wortmannin treated animals were up to 12-fold slower, a phenotype that persisted for at least 3 months.Thus the focal delivery of wortmannin to motor neurons generates a reproducible and scalable injury that can facilitate quantitative studies on neural regeneration and repair.The efficacy of sciatic nerve suicide transport can also explain neurotoxin-mediated selective loss of motor neurons in diseases such as amyotrophic lateral sclerosis.All procedures were performed at Rutgers under established Institutional Animal Care and Use protocols(eIACUC_TR201800022, approved on March 20, 2018).
文摘Background： Mitochondrial dysfunction plays an important role in the pathogenesis of amyotrophic lateral sclerosis （ALS）. We aimed to demonstrate mitochondrial dysfunction in ALS using a lactate stress test and to examine the relationship between mitochondrial dysfunction with motor deterioration. Methods： We enrolled 116 patients and observed clinical variables, including the survival state. Results： Patients with a rapid slope of revised ALS functional rating scales （ALSFRS-r） （〉20 U/year） exhibited the slowest elimination rate （median -4.67 × 10^-3 mmol·L ^-1min ^-1, coefficient of variation, 590.15%）, the shortest duration （0.63 ± 0.28 years） and the worst ALSFRS-r （32.59±4.93）. Patients with a moderate slope ofALSFRS-r （1~20 U/year） showed a moderate elimination rate （median -11.33 × 10^-3 mmol·L ^-1min ^-1, coefficient of variation, 309.89%）, duration （1.16± 0.45 years）, and ALSFRS-r （34.83 ± 6.11）. The slower progressing （〈10 U/year group） patients exhibited a rapid elimination rate （median： - 12.00 × 10^-3 mmol·L ^-1min ^-1, coefficient of variation： 143.08%）, longer duration （median： 3 years, coefficient of variation： 193.33%）, and adequate ALSFRS-r values （39.58 ± 9.44）. Advanced-phase ALS patients also showed slower elimination rate （ER, quartiles - 17.33, -5.67, 4.00） and worse ALSFRS-r （34.88 ± 9.27）, while early-phase patients showed a more rapid ER （quartiles -25.17, -11.33, -3.50） and better ALSFRS-r （39.28 ± 7.59）. These differences were statistically significant. Multiple linear regression analysis revealed strong direct associations among ER, ALSFRS-r slope （standard beta = 0.33, P = 0.007）, and forced vital capacity （predict %） （standard beta = -0.458, P = 0.006, adjusted for ALSFRS-r, course and onset region）. However, the data obtained from 3 years of follow-up showed no statistically significant difference in the survival rates between the most rapid and slowest ER groups. Conclusion： There is a potential linear relationship between ER and motor deterioration in ALS. Slower ER might be associated with faster disease progression.
