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Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration最新文献

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Sequence variations in C9orf72 downstream of the hexanucleotide repeat region and its effect on repeat-primed PCR interpretation: a large multinational screening study C9orf72下游六核苷酸重复区序列变异及其对重复引物PCR解释的影响:一项大型跨国筛选研究
IF 2.8 4区 医学 Q2 CLINICAL NEUROLOGY Pub Date : 2017-04-03 DOI: 10.1080/21678421.2016.1262423
Angelica Nordin, C. Akimoto, Anna Wuolikainen, Helena Alstermark, K. Forsberg, P. Baumann, S. Pinto, M. de Carvalho, A. Hübers, Frida Nordin, A. Ludolph, Jochen H Weishaupt, T. Meyer, T. Grehl, K. Schweikert, Markus Weber, Christian Burkhardt, C. Neuwirth, T. Holmøy, M. Morita, O. Tysnes, M. Benatar, J. Wuu, D. Lange, C. Bisgård, N. Asgari, I. Tarvainen, T. Brännström, P. Andersen
Abstract A large GGGGCC-repeat expansion mutation (HREM) in C9orf72 is the most common known cause of ALS and FTD in European populations. Sequence variations immediately downstream of the HREM region have previously been observed and have been suggested to be one reason for difficulties in interpreting RP-PCR data. Our objective was to determine the properties of these sequence variations with regard to prevalence, the range of variation, and effect on disease prognosis. We screened a multi-national cohort (n = 6981) for the HREM and samples with deviant RP-PCR curves were identified. The deviant samples were subsequently sequenced to determine sequence alteration. Our results show that in the USA and European cohorts (n = 6508) 10.7% carried the HREM and 3% had a sequence variant, while no HREM or sequence variants were observed in the Japanese cohort (n = 473). Sequence variations were more common on HREM alleles; however, certain population specific variants were associated with a non-expanded allele.In conclusion, we identified 38 different sequence variants, most located within the first 50 bp downstream of the HREM region. Furthermore, the presence of an HREM was found to be coupled to a lower age of onset and a shorter disease survival, while sequence variation did not have any correlation with these parameters.
摘要C9orf72中的一个大GGGGCC重复扩增突变(HREM)是欧洲人群中ALS和FTD最常见的已知原因。先前已经观察到HREM区域下游的序列变化,并认为这是解释RP-PCR数据困难的原因之一。我们的目的是确定这些序列变异在患病率、变异范围和对疾病预后的影响方面的特性。我们筛选了一个多国队列(n = 6981),并鉴定出具有偏差RP-PCR曲线的样品。随后对异常样本进行测序,以确定序列变化。我们的结果表明,在美国和欧洲的队列中(n = 6508)10.7%携带HREM,3%有序列变异,而在日本队列中没有观察到HREM或序列变异(n = 473)。HREM等位基因的序列变异更为常见;然而,某些群体特异性变异与非扩增等位基因相关。总之,我们确定了38个不同的序列变体,大多数位于前50个 HREM区域下游的bp。此外,发现HREM的存在与较低的发病年龄和较短的疾病生存期有关,而序列变异与这些参数没有任何相关性。
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引用次数: 16
Survival in amyotrophic lateral sclerosis patients on non-invasive ventilation. What can we do more? 肌萎缩侧索硬化症患者无创通气的生存率。我们还能做些什么?
IF 2.8 4区 医学 Q2 CLINICAL NEUROLOGY Pub Date : 2017-04-03 DOI: 10.1080/21678421.2016.1223141
A. Esquinas, G. Garuti, G. Pellegrino, G. S. Sferrazza Papa
Poor prognosis in amyotrophic lateral sclerosis (ALS) is primarily caused by the development of acute respiratory failure (ARF). Despite the recent proposal of a scoring system for early prediction of patient survival (1), this remains challenging due to the clinical heterogeneity of the disease. Non-invasive ventilation (NIV) may counterbalance the progression of ARF; however, the optimal strategies for applying NIV, including patient selection and timing, remain controversial (2). On this issue, we read with interest the article by N. Gonzalez Calzada et al., which focused on defining potential survival factors in ALS (3). In a large cohort of ALS patients, the author confirmed that the severity of bulbar involvement and the ALSFRS-R score at the time of NIV initiation strongly predict patient survival. A key topic in assessing patient survival is the definition of survival time as time to death or to tracheostomy. We think that the clinical protocol used by the authors to propose tracheostomy and invasive mechanical ventilation, and the percentage of patients in which it was performed, should be reported and discussed in the letter. We agree with the authors that a better assessment of bulbar involvement, including evaluation of the upper airways, and a careful titration of NIV are necessary to improve the efficacy of the treatment. However, we would like to point out an important unresolved issue, which is how respiratory evaluation should be performed. Respiratory symptoms may be under-perceived and arterial blood gas analysis usually begins to alter only late in the progression of the disease. Authors have considered spirometry with the generally accepted cut-off of forced vital capacity (FVC) of less than 50% of the predicted value as the threshold to start NIV. In spite of this, spirometry remains the reference test to assess overall ventilatory function; in this cohort a valid spirometry was available only for half to onethird of patients with moderate to severe bulbar dysfunction. Thus, this cohort highlights a gap in evaluating respiratory function in patients with advanced disease. If it is true that pulmonary function tests are affected by diaphragmatic dysfunction as shown by a decrease in vital capacity, due to the non-linear relationship between lung volume and muscle force, the decrease in lung volumes occurs relatively late compared to the development of muscle dysfunction. Moreover, spirometry requires patient cooperation and may not be reliable in the presence of facial weakness and mouth leaks during forced manoeuvre, which is frequently the case with ALS patients. Performing the test becomes more challenging in patients with bulbar dysfunction who tend to rapidly progress towards ARF and, thus, would require frequent monitoring. Sleep studies may help show nocturnal desaturation. However, what it is needed is a test focused on measuring respiratory muscles. Ultrasonography is a non-invasive, non-ionizing imaging technique th
肌萎缩侧索硬化症(ALS)预后不良主要是由急性呼吸衰竭(ARF)的发展引起的。尽管最近提出了一种用于早期预测患者生存率的评分系统(1),但由于疾病的临床异质性,这仍然具有挑战性。无创通气(NIV)可以抵消ARF的进展;然而,应用NIV的最佳策略,包括患者选择和时间安排,仍然存在争议(2)。关于这个问题,我们饶有兴趣地阅读了N.Gonzalez-Calzada等人的文章,该文章侧重于定义ALS的潜在生存因素(3)。在一个大型ALS患者队列中,作者证实,在NIV开始时,延髓受累的严重程度和ALSFRS-R评分可以有力地预测患者的生存率。评估患者生存率的一个关键主题是将生存时间定义为死亡或气管切开时间。我们认为,作者提出气管造口术和有创机械通气的临床方案,以及实施该方案的患者百分比,应该在信中报告和讨论。我们同意作者的观点,即更好地评估延髓受累,包括评估上呼吸道,并仔细滴定NIV,对于提高治疗效果是必要的。然而,我们想指出一个尚未解决的重要问题,即应如何进行呼吸评估。呼吸系统症状可能被低估,动脉血气分析通常只有在疾病进展的晚期才开始改变。作者认为肺活量测定法的强迫肺活量(FVC)临界值小于预测值的50%,作为开始NIV的阈值。尽管如此,肺活量测定仍然是评估整体通气功能的参考测试;在该队列中,有效的肺活量测定法仅适用于一半至三分之一的中度至重度延髓功能障碍患者。因此,这一队列突出了在评估晚期疾病患者呼吸功能方面的差距。如果肺功能测试确实受到膈肌功能障碍的影响,如肺活量下降所示,由于肺容量和肌肉力量之间的非线性关系,与肌肉功能障碍的发展相比,肺容量的下降发生得相对较晚。此外,肺活量测定需要患者的配合,在强迫操作过程中出现面部无力和口漏的情况下可能不可靠,ALS患者经常出现这种情况。在延髓功能障碍患者中进行测试变得更具挑战性,这些患者往往会迅速发展为ARF,因此需要频繁监测。睡眠研究可能有助于显示夜间的不饱和度。然而,它需要的是一项专注于测量呼吸肌肉的测试。超声检查是一种非侵入性、非电离成像技术,可直接评估
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引用次数: 3
Is firstly diagnosed ALS really ALS? Results of a population-based study with long-term follow-up 首次诊断的ALS真的是ALS吗?一项基于人群的长期随访研究结果
IF 2.8 4区 医学 Q2 CLINICAL NEUROLOGY Pub Date : 2017-04-03 DOI: 10.1080/21678421.2016.1249886
E. Pupillo, E. Bianchi, M. Poloni, E. Beghi
Abstract Objective: To revise the first diagnosis of amyotrophic lateral sclerosis (ALS) in patients from a well-defined population. Methods: Patients diagnosed with ALS in the years 1998-2002 and resident of Lombardy Region, Northern Italy were followed until death or April 30 2016 to assess long-term survival. During follow-up, the caring neurologists were asked to confirm the first diagnosis. Revised diagnoses were classified as confirmed and unconfirmed motor neuron disease (MND) with further specification where available. The two groups were compared for age, sex, disease duration at diagnosis, site of onset, and El Escorial category. Survival with predictors were also compared. Results: Included were 280 men and 203 women aged 18-93 years. During follow-up, 25 cases (5.2%) received a diagnosis different from MND. Diseases of spinal roots and peripheral nerves and vascular encephalopathy predominated. Patients with definite (OR 0.15; 95%CI 0.04-0.52) and probable (OR 0.15; 95%CI 0.04-0.62) ALS were least likely to have an unconfirmed MND diagnosis. At end of follow-up, 2.2% of patients with confirmed MND and 44.0% of patients with unconfirmed MND were reported alive (HR 0.14; 95%CI 0.08-0.25). Conclusions: At the time of a first diagnosis of ALS, the possibility still exists that another, less severe clinical condition, is present.
【摘要】目的:对明确人群中肌萎缩性侧索硬化症(ALS)的首次诊断进行修正。方法:对1998-2002年诊断为ALS的意大利北部伦巴第地区居民进行随访,直至死亡或2016年4月30日评估长期生存率。在随访期间,护理神经科医生被要求确认首次诊断。修订后的诊断分为确诊和未确诊的运动神经元疾病(MND),并提供进一步的说明。比较两组患者的年龄、性别、诊断时病程、发病部位和El Escorial分类。生存率与预测指标也进行了比较。结果:纳入男性280人,女性203人,年龄18 ~ 93岁。在随访中,25例(5.2%)的诊断与MND不同。脊髓根、周围神经疾病和血管性脑病占主导地位。明确(OR 0.15;95%CI 0.04-0.52)和probable (OR 0.15;(95%CI 0.04-0.62) ALS患者最不可能有未确诊的MND诊断。随访结束时,2.2%确诊MND患者和44.0%未确诊MND患者报告存活(HR 0.14;95%可信区间0.08 - -0.25)。结论:在首次诊断ALS时,仍然存在另一种不太严重的临床症状存在的可能性。
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引用次数: 4
Proteomic profiling of the spinal cord in ALS: decreased ATP5D levels suggest synaptic dysfunction in ALS pathogenesis ALS脊髓的蛋白质组学分析:ATP5D水平降低提示ALS发病机制中的突触功能障碍
IF 2.8 4区 医学 Q2 CLINICAL NEUROLOGY Pub Date : 2017-04-03 DOI: 10.1080/21678421.2016.1245757
Joo-Yeon Engelen-Lee, A. Blokhuis, Wim G.M. Spliet, R. Pasterkamp, E. Aronica, Jeroen A. A. Demmers, R. Broekhuizen, Giovanni Nardo, N. Bovenschen, Leonard H. van den Berg
Abstract Background: We aimed to gain new insights into the pathogenesis of sporadic ALS (sALS) through a comprehensive proteomic analysis. Methods: Protein profiles of the anterior and posterior horn in post-mortem spinal cord samples of 10 ALS patients and 10 controls were analysed using 2D-differential gel electrophoresis. The identified protein spots with statistically significant level changes and a spot ratio >2.0 were analysed by LC-MS/MS. Results: In the posterior horn only 3 proteins were differentially expressed. In the anterior horn, 16 proteins with increased levels and 2 proteins with decreased levels were identified in ALS compared to controls. The identified proteins were involved in mitochondrial metabolism, calcium homeostasis, protein metabolism, glutathione homeostasis, protein transport and snRNP assembly. The two proteins with decreased levels, ATP5D and calmodulin, were validated by Western blot and immunostaining. Immunohistochemical and immunofluorescent double staining of ATP5D and synaptophysin showed that the reduction of ATP5D was most pronounced at synapses. Conclusions: We speculate that mitochondrial dysfunction in synaptic clefts could play an important role in sALS pathogenesis. A similar approach revealed decreased calmodulin expression mainly in the neuronal body and dendrites of ALS patients. These findings contribute to a deeper understanding of the disease process underlying ALS.
摘要背景:我们旨在通过全面的蛋白质组学分析,对散发性ALS(sALS)的发病机制获得新的见解。方法:应用2D差分凝胶电泳分析10例ALS患者和10例对照者死后脊髓前角和后角的蛋白质谱。通过LC-MS/MS分析具有统计学显著水平变化且斑点比率>2.0的已鉴定蛋白质斑点。结果:在后角,只有3种蛋白质有差异表达。在前角,与对照组相比,ALS中鉴定出16种水平升高的蛋白质和2种水平降低的蛋白质。所鉴定的蛋白质参与线粒体代谢、钙稳态、蛋白质代谢、谷胱甘肽稳态、蛋白质转运和snRNP组装。通过蛋白质印迹和免疫染色验证了ATP5D和钙调蛋白这两种水平降低的蛋白质。ATP5D和突触素的免疫组织化学和免疫荧光双染色显示,ATP5D的减少在突触处最为明显。结论:我们推测突触间隙中的线粒体功能障碍可能在sALS的发病机制中发挥重要作用。类似的方法显示,钙调素的表达减少,主要发生在ALS患者的神经元体和树突中。这些发现有助于更深入地了解ALS的发病过程。
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引用次数: 17
Genetic analysis of patients with familial and sporadic amyotrophic lateral sclerosis in a Brazilian Research Center 巴西研究中心家族性和散发性肌萎缩侧索硬化症患者的基因分析
IF 2.8 4区 医学 Q2 CLINICAL NEUROLOGY Pub Date : 2017-04-03 DOI: 10.1080/21678421.2016.1254245
G. Chadi, J. R. Maximino, F. Jorge, Fabrício Castro de Borba, J. M. Gilio, D. Callegaro, C. G. Lopes, Samantha Nakamura Dos Santos, G. Rebelo
Abstract Objective: To investigate gene mutations in familial form (FALS) and sporadic form (SALS) of amyotrophic lateral sclerosis (ALS) in a highly miscegenated population. Methods: Frequencies of mutations in the C9orfF72, TARDBP, SOD1, FUS and VAPB genes were investigated in a cohort of FALS (n = 39) and SALS (n = 189) subjects from the Research Centre of the University of São Paulo School of Medicine. All patients were subjected to C9orf72 and TARDBP analyses. SOD1, FUS and VAPB were also evaluated in FALS subjects. Results: Mutations were identified in FALS (61.3%) and SALS (5.3%) patients. Mutations in C9orf72 (12.8%, >45 GGGGCC hexanucleotide repeats), VAPB (43.6%, P56S) and SOD1 (7.7%, L145S) were identified in FALS subjects. Pathogenic C9orf72 expansions (2.64%) were identified in some SALS patients. Similar changes of TARDBP were found in SALS (2.64%) but not in FALS subjects. No FUS mutations were seen in any FALS subjects. Conclusions: TARDBP and C9orf72 mutations in this cohort were similar to those found in other centres worldwide. VAPB mutation (P56S) was highly prevalent in Brazilian FALS patients.
摘要目的:探讨家族型(FALS)和散发性(SALS)肌萎缩性侧索硬化症(ALS)在高混种人群中的基因突变。方法:对来自圣保罗大学医学院研究中心的FALS (n = 39)和SALS (n = 189)患者的C9orfF72、TARDBP、SOD1、FUS和VAPB基因突变频率进行研究。所有患者均接受C9orf72和TARDBP分析。测定FALS患者的SOD1、FUS和VAPB。结果:FALS(61.3%)和SALS(5.3%)患者中存在突变。在FALS患者中发现了C9orf72 (12.8%, bbbb45 GGGGCC六核苷酸重复序列)、VAPB (43.6%, P56S)和SOD1 (7.7%, L145S)突变。部分SALS患者存在致病性C9orf72扩增(2.64%)。SALS患者TARDBP也有类似的变化(2.64%),而FALS患者则没有。在所有FALS受试者中未见FUS突变。结论:该队列中的TARDBP和C9orf72突变与全球其他中心的突变相似。VAPB突变(P56S)在巴西FALS患者中高度流行。
{"title":"Genetic analysis of patients with familial and sporadic amyotrophic lateral sclerosis in a Brazilian Research Center","authors":"G. Chadi, J. R. Maximino, F. Jorge, Fabrício Castro de Borba, J. M. Gilio, D. Callegaro, C. G. Lopes, Samantha Nakamura Dos Santos, G. Rebelo","doi":"10.1080/21678421.2016.1254245","DOIUrl":"https://doi.org/10.1080/21678421.2016.1254245","url":null,"abstract":"Abstract Objective: To investigate gene mutations in familial form (FALS) and sporadic form (SALS) of amyotrophic lateral sclerosis (ALS) in a highly miscegenated population. Methods: Frequencies of mutations in the C9orfF72, TARDBP, SOD1, FUS and VAPB genes were investigated in a cohort of FALS (n = 39) and SALS (n = 189) subjects from the Research Centre of the University of São Paulo School of Medicine. All patients were subjected to C9orf72 and TARDBP analyses. SOD1, FUS and VAPB were also evaluated in FALS subjects. Results: Mutations were identified in FALS (61.3%) and SALS (5.3%) patients. Mutations in C9orf72 (12.8%, >45 GGGGCC hexanucleotide repeats), VAPB (43.6%, P56S) and SOD1 (7.7%, L145S) were identified in FALS subjects. Pathogenic C9orf72 expansions (2.64%) were identified in some SALS patients. Similar changes of TARDBP were found in SALS (2.64%) but not in FALS subjects. No FUS mutations were seen in any FALS subjects. Conclusions: TARDBP and C9orf72 mutations in this cohort were similar to those found in other centres worldwide. VAPB mutation (P56S) was highly prevalent in Brazilian FALS patients.","PeriodicalId":7740,"journal":{"name":"Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration","volume":"18 1","pages":"249 - 255"},"PeriodicalIF":2.8,"publicationDate":"2017-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/21678421.2016.1254245","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46748939","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 30
Open label study to assess the safety of VM202 in subjects with amyotrophic lateral sclerosis 评估VM202在肌萎缩侧索硬化症患者中的安全性的开放标签研究
IF 2.8 4区 医学 Q2 CLINICAL NEUROLOGY Pub Date : 2017-02-06 DOI: 10.1080/21678421.2016.1259334
R. Sufit, S. Ajroud-Driss, Patricia Casey, J. Kessler
Abstract Objective: To assess safety and define efficacy measures of hepatocyte growth factor (HGF) DNA plasmid, VM202, administered by intramuscular injections in patients with amyotrophic lateral sclerosis (ALS). Methods: Eighteen participants were treated with VM202 administered in divided doses by injections alternating between the upper and lower limbs on d 0, 7, 14, and 21. Subjects were followed for nine months to evaluate possible adverse events. Functional outcome was assessed using the ALS Functional Rating Scale-Revised (ALSFRS-R) as well as by serially measuring muscle strength, muscle circumference, and forced vital capacity. Results: Seventeen of 18 participants completed the study. All participants tolerated 64 mg of VM202 well with no serious adverse events (SAE) related to the drug. Twelve participants reported 26 mild or moderate injection site reactions. Three participants experienced five SAEs unrelated to VM202. One subject died from respiratory insufficiency secondary to ALS progression. Conclusions: Multiple intramuscular injection of VM202 into the limbs appears safe in ALS subjects. Future trials with retreatment after three months will determine whether VM202 treatment alters the long-term course of ALS.
摘要目的:评价肌内注射肝细胞生长因子(HGF)DNA质粒VM202治疗肌萎缩侧索硬化症(ALS)的安全性并确定有效性措施。方法:18名参与者在第0天、第7天、第14天和第21天通过上肢和下肢交替注射的方式分剂量服用VM202。受试者接受了9个月的随访,以评估可能的不良事件。使用ALS功能评定量表修订版(ALSFRS-R)以及通过连续测量肌肉力量、肌肉周长和强迫肺活量来评估功能结果。结果:18名参与者中有17人完成了研究。所有参与者均耐受64 mg的VM202,没有与该药物相关的严重不良事件(SAE)。12名参与者报告了26例轻度或中度注射部位反应。三名参与者经历了五次与VM202无关的SAE。一名受试者死于ALS进展继发的呼吸功能不全。结论:四肢多次肌内注射VM202对ALS患者是安全的。未来三个月后再治疗的试验将确定VM202治疗是否会改变ALS的长期病程。
{"title":"Open label study to assess the safety of VM202 in subjects with amyotrophic lateral sclerosis","authors":"R. Sufit, S. Ajroud-Driss, Patricia Casey, J. Kessler","doi":"10.1080/21678421.2016.1259334","DOIUrl":"https://doi.org/10.1080/21678421.2016.1259334","url":null,"abstract":"Abstract Objective: To assess safety and define efficacy measures of hepatocyte growth factor (HGF) DNA plasmid, VM202, administered by intramuscular injections in patients with amyotrophic lateral sclerosis (ALS). Methods: Eighteen participants were treated with VM202 administered in divided doses by injections alternating between the upper and lower limbs on d 0, 7, 14, and 21. Subjects were followed for nine months to evaluate possible adverse events. Functional outcome was assessed using the ALS Functional Rating Scale-Revised (ALSFRS-R) as well as by serially measuring muscle strength, muscle circumference, and forced vital capacity. Results: Seventeen of 18 participants completed the study. All participants tolerated 64 mg of VM202 well with no serious adverse events (SAE) related to the drug. Twelve participants reported 26 mild or moderate injection site reactions. Three participants experienced five SAEs unrelated to VM202. One subject died from respiratory insufficiency secondary to ALS progression. Conclusions: Multiple intramuscular injection of VM202 into the limbs appears safe in ALS subjects. Future trials with retreatment after three months will determine whether VM202 treatment alters the long-term course of ALS.","PeriodicalId":7740,"journal":{"name":"Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration","volume":"18 1","pages":"269 - 278"},"PeriodicalIF":2.8,"publicationDate":"2017-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/21678421.2016.1259334","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49585000","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 31
Longitudinal assessment of the Edinburgh Cognitive and Behavioural Amyotrophic Lateral Sclerosis Screen (ECAS): lack of practice effect in ALS patients? 爱丁堡认知和行为肌萎缩侧索硬化症筛查(ECAS)的纵向评估:ALS患者缺乏实践效果?
IF 2.8 4区 医学 Q2 CLINICAL NEUROLOGY Pub Date : 2017-02-06 DOI: 10.1080/21678421.2017.1283418
Christian Burkhardt, C. Neuwirth, Markus Weber
Abstract Objective: The study objective was to assess whether controls and ALS patients show a practice effect in the Edinburgh Cognitive and Behavioural ALS Screen (ECAS) on repeated longitudinal testing and if the ECAS detects progression of cognitive or behavioural changes over time. Methods: The ECAS was administered serially to ALS patients (n = 24 after six months, n = 10 after 12–18 months) and controls (n = 21 after six months). The ECAS was fully performed by all participants. For comparison purposes the Frontal Assessment Battery (FAB) was administered to a subgroup of 14 patients and 14 controls. Results: After six months controls showed a significantly higher overall score (p < 0.001) and significantly higher scores in all subdomains of the ECAS, except for visuospatial function and fluency. ALS patients showed no significant difference in any score of the ECAS after six months and up to18 months. Behavioural changes were increasingly, but not statistically, significant, noted by patient carers. The FAB was no longer applicable due to progressive motor deficits in 20% of ALS patients. Conclusions: In conclusion, in contrast to healthy controls, ALS patients show no practice effects. This could reflect ‘pre-symptomatic’ cognitive decline and progressive behavioural symptoms.
摘要目的:本研究的目的是评估对照组和ALS患者在爱丁堡认知和行为ALS筛查(ECAS)中是否表现出重复纵向测试的实践效果,以及ECAS是否检测到认知或行为变化的进展。方法:对ALS患者(6个月后n = 24, 12-18个月后n = 10)和对照组(6个月后n = 21)连续给予ECAS。所有参与者都完成了ECAS。为了进行比较,对14名患者和14名对照组进行了正面评估组(FAB)。结果:6个月后,对照组的总分显著提高(p < 0.001),除视觉空间功能和流畅性外,ECAS的所有子域得分均显著提高。ALS患者在6个月和18个月后的ECAS评分均无显著差异。患者护理人员注意到,行为变化越来越多,但在统计上并不显著。由于20%的ALS患者出现进行性运动障碍,FAB不再适用。结论:与健康对照相比,ALS患者无实践效果。这可能反映了“症状前”认知能力下降和进行性行为症状。
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引用次数: 32
Incidence of amyotrophic lateral sclerosis in the province of Novara, Italy, and possible role of environmental pollution 意大利诺瓦拉省肌萎缩侧索硬化症的发病率和环境污染的可能作用
IF 2.8 4区 医学 Q2 CLINICAL NEUROLOGY Pub Date : 2017-02-02 DOI: 10.1080/21678421.2017.1281961
M. Tesauro, M. Consonni, T. Filippini, L. Mazzini, F. Pisano, A. Chiò, Aniello Esposito, M. Vinceti
Abstract Objective and methods: Based on nationwide death certificates, a cluster of amyotrophic lateral sclerosis (ALS) has been reported in the area of Briga (Novara province, northern Italy), known for its severe environmental contamination. We further investigated this finding, by following up with the collection of recent incidence ALS data in 2002–2012 of Novara province, also to assess the possible long-term effects of environmental pollution in that area. Results: In the whole Novara province we identified 106 ALS cases, of which 35 were from the Briga area. Incidence rates of Novara province were 3.98, 5.14 and 2.97 for the total population, males and females, respectively, compared with the Briga area where they were 4.65, 4.27 and 4.98, respectively. The ratio of observed-to-expected ALS cases in the Briga area, using incidence of the rest of Novara province as a reference, was 1.17 (95% CI 0.81–1.62), with a value of 0.83 (95% CI 0.47–1.37) in males and 1.68 (95% CI 1.03–2.60) in females. Conclusions: Overall, our study did not confirm previous findings of an excess ALS incidence in an area characterised by severe environmental heavy metal pollution, and it suggests the need to interpret with caution clusters identified through mortality data.
目的与方法:根据全国死亡证明,在意大利北部诺瓦拉省布里加地区报告了一起肌萎缩性侧索硬化症(ALS)聚集性病例,该地区以环境污染严重而闻名。我们进一步调查了这一发现,通过收集诺瓦拉省2002-2012年最近ALS发病率的数据,也评估了该地区环境污染可能产生的长期影响。结果:在整个Novara省,我们发现106例ALS病例,其中35例来自Briga地区。诺瓦拉省总人口、男性和女性发病率分别为3.98、5.14和2.97,布里加地区发病率分别为4.65、4.27和4.98。以诺瓦拉省其他地区的发病率为参考,布里加地区的ALS观察病例与预期病例之比为1.17 (95% CI 0.81-1.62),其中男性为0.83 (95% CI 0.47-1.37),女性为1.68 (95% CI 1.03-2.60)。结论:总的来说,我们的研究并没有证实之前的研究结果,即在环境重金属污染严重的地区ALS发病率过高,这表明需要谨慎解释通过死亡率数据确定的聚类。
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引用次数: 24
Further analysis of KIFAP3 gene in ALS patients from Switzerland and Sweden 瑞士和瑞典ALS患者KIFAP3基因的进一步分析
IF 2.8 4区 医学 Q2 CLINICAL NEUROLOGY Pub Date : 2017-01-31 DOI: 10.1080/21678421.2017.1280509
D. Czell, P. Sapp, C. Neuwirth, Markus Weber, P. Andersen, Robert H. Brown
Abstract A series of studies suggests that susceptibility to ALS may be influenced by variants in multiple genes. While analyses of the 10% of cases of familial origin have identified more than 33 monogenic ALS-causing genetic defects, little is known about genetic factors that influence susceptibility or phenotype in sporadic ALS (SALS). We and others conducted a genome-wide association study (GWAS) in a cohort of 1014 ALS cases from Western Europe, England and the United States, and identified an intronic single nucleotide polymorphism (SNP) rs1541160 in the KIFAP3 gene that was statistically associated with improved survival. We have now completed an additional survival analysis examining the impact of the rs1541160 genotype in a cohort of 264 ALS and progressive bulbar palsy (PBP) cases. In the combined cohort of 264 patients, the CC, CT and TT genotypes for rs1541160 were detected, respectively, in 8.3% (22), 41.7% (110) and 50.0% (132). This study does not show an influence of KIFAP3 variants on survival in the studied Swiss and Swedish cohort. There was a difference in survival between the US and English patients and the patients from the Netherlands. The effect of KIFAP3 variants may be population specific, or the rs1541160 association reported previously may have been a false-positive.
摘要一系列研究表明,ALS的易感性可能受到多个基因变异的影响。虽然对10%的家族性ALS病例的分析已经确定了超过33个单基因ALS导致遗传缺陷,但对影响散发性ALS(SALS)易感性或表型的遗传因素知之甚少。我们和其他人对来自西欧、英国和美国的1014例ALS病例进行了全基因组关联研究(GWAS),并在KIFAP3基因中发现了一个内含子单核苷酸多态性(SNP)rs1541160,该多态性在统计学上与生存率的提高相关。我们现在已经完成了一项额外的生存分析,研究了rs1541160基因型在264例ALS和进行性球麻痹(PBP)病例队列中的影响。在264名患者的联合队列中,rs1541160的CC、CT和TT基因型分别为8.3%(22)、41.7%(110)和50.0%(132)。这项研究没有显示KIFAP3变体对所研究的瑞士和瑞典队列的生存率的影响。美国和英国患者与荷兰患者的生存率存在差异。KIFAP3变体的作用可能是群体特异性的,或者之前报道的rs1541160关联可能是假阳性。
{"title":"Further analysis of KIFAP3 gene in ALS patients from Switzerland and Sweden","authors":"D. Czell, P. Sapp, C. Neuwirth, Markus Weber, P. Andersen, Robert H. Brown","doi":"10.1080/21678421.2017.1280509","DOIUrl":"https://doi.org/10.1080/21678421.2017.1280509","url":null,"abstract":"Abstract A series of studies suggests that susceptibility to ALS may be influenced by variants in multiple genes. While analyses of the 10% of cases of familial origin have identified more than 33 monogenic ALS-causing genetic defects, little is known about genetic factors that influence susceptibility or phenotype in sporadic ALS (SALS). We and others conducted a genome-wide association study (GWAS) in a cohort of 1014 ALS cases from Western Europe, England and the United States, and identified an intronic single nucleotide polymorphism (SNP) rs1541160 in the KIFAP3 gene that was statistically associated with improved survival. We have now completed an additional survival analysis examining the impact of the rs1541160 genotype in a cohort of 264 ALS and progressive bulbar palsy (PBP) cases. In the combined cohort of 264 patients, the CC, CT and TT genotypes for rs1541160 were detected, respectively, in 8.3% (22), 41.7% (110) and 50.0% (132). This study does not show an influence of KIFAP3 variants on survival in the studied Swiss and Swedish cohort. There was a difference in survival between the US and English patients and the patients from the Netherlands. The effect of KIFAP3 variants may be population specific, or the rs1541160 association reported previously may have been a false-positive.","PeriodicalId":7740,"journal":{"name":"Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration","volume":"18 1","pages":"302 - 304"},"PeriodicalIF":2.8,"publicationDate":"2017-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/21678421.2017.1280509","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44815547","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 4
Visual encoding, consolidation, and retrieval in amyotrophic lateral sclerosis: executive function as a mediator, and predictor of performance 肌萎缩性侧索硬化症的视觉编码、巩固和检索:执行功能作为中介和表现的预测因子
IF 2.8 4区 医学 Q2 CLINICAL NEUROLOGY Pub Date : 2017-01-13 DOI: 10.1080/21678421.2016.1272615
T. Burke, K. Lonergan, Marta Pinto-Grau, M. Elamin, P. Bede, Caoifa Madden, O. Hardiman, N. Pender
Abstract Objective: This study aimed to illustrate the variation of non-executive cognitive processes, i.e. visual memory, considering executive dysfunction in amyotrophic lateral sclerosis (ALS). Methods: Patients with ALS (n = 203), and matched healthy controls (n = 117) completed a battery of neuropsychological tests. Sub-stratification was based on whether cognitive assessment detected no cognitive abnormalities (NCA: n = 117), multiple executive cognitive deficits (ALS-Exec; n = 56), or a comorbid frontotemporal dementia process (ALS-FTD; n = 30). The Rey-Osterrieth Complex Figure Test (ROCFT) was the main dependent variable for visual memory in this study. Results: Patients and controls significantly differed on the Copy trial (p < 0.0001: ω2 = 0.317) immediate recall (p < 0.0001: ω2 = 0.272) and delayed recall (p < 0.0001: ω2 = 0.308) of the ROCFT. Sub-stratification based on executive dysfunction revealed an association with greater executive dysfunction and lower ROCFT performance. Regression analysis predicted that premorbid IQ, executive function, and demographics predict performance on the ROCFT delayed recall trial (R2 = 0.833). Conclusions: These findings illustrate that patients without executive dysfunction do not show visual memory impairments within this cohort; that patients with executive dysfunction have poorer performance on visual memory tasks; and that the severity of executive dysfunction, as per cognitive categorisation, is related to increased visual memory impairment as tested with the ROCFT.
摘要目的:本研究旨在说明考虑肌萎缩侧索硬化症(ALS)执行功能障碍的非执行认知过程,即视觉记忆的变化。方法:ALS患者(n = 203)和匹配的健康对照组(n = 117)完成了一系列神经心理学测试。亚分层基于认知评估是否未检测到认知异常(NCA:n = 117)、多种执行认知缺陷(ALS-Exec;n = 56)或共病额颞叶痴呆过程(ALS-FTD;n = 30)。Rey-Osterrieth复杂图形测试(ROCFT)是本研究中视觉记忆的主要因变量。结果:患者和对照组在Copy试验中存在显著差异(p < 0.0001:ω2= 0.317)立即召回(p < 0.0001:ω2= 0.272)和延迟召回(p < 0.0001:ω2= 0.308)。基于执行功能障碍的亚分层揭示了更大的执行功能障碍和更低的ROCFT表现之间的关联。回归分析预测,在ROCFT延迟召回试验中,病前智商、执行功能和人口统计学预测表现(R2 = 0.833)。结论:这些发现表明,在该队列中,没有执行功能障碍的患者没有表现出视觉记忆障碍;执行功能障碍患者在视觉记忆任务上的表现较差;根据认知分类,执行功能障碍的严重程度与ROCFT测试的视觉记忆障碍增加有关。
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引用次数: 18
期刊
Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration
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