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A speech measure for early stratification of fast and slow progressors of bulbar amyotrophic lateral sclerosis: lip movement jitter 快速和缓慢进展的球肌萎缩性侧索硬化症早期分层的言语测量:唇运动抖动
IF 2.8 4区 医学 Q2 Medicine Pub Date : 2019-11-07 DOI: 10.1080/21678421.2019.1681454
Panying Rong, Y. Yunusova, M. Eshghi, Hannah P. Rowe, Jordan R. Green
Abstract Objective: To assess the utility of novel measures derived from a rapid syllable repetition task (i.e. oral dysdiadochokinesis [DDK]) in early stratification of fast and slow progressive bulbar amyotrophic lateral sclerosis (ALS) and prediction of bulbar disease progression rate. Methods: Fifty-four individuals with ALS were tracked longitudinally on their oral DDK and global bulbar/speech performance (i.e. bulbar subscore on the ALS Functional Rating Scale-Revised [ALSFRS-R]; articulation rate during passage reading) for a four-month average duration. Based on the bulbar deterioration rate over the tracked period, the participants were stratified as 14 fast bulbar progressors and 40 slow bulbar progressors using a posteriori classification approach. To determine if oral DDK performance predicts the differential bulbar disease progression trajectories in these individuals during the early stages of the tracked period (prior to significant bulbar/speech signs), twenty-two measures of lip motor performance in an oral DDK task were derived to (1) differentiate fast and slow bulbar progressors using the Receiver Operating Characteristic analysis and (2) predict bulbar disease progression rates across all individuals using linear regressions. Results: Movement jitter, a measure of temporal variability of alternating lip movement during DDK, showed 80% sensitivity and 95% specificity in differentiating fast and slow bulbar progressors early in the disease, and outperformed the ALSFRS-R bulbar subscore and articulation rate. Movement jitter also predicted bulbar disease progression rates across participants. Conclusion: Findings provided preliminary validation of the clinical value of movement jitter during oral DDK in patient stratification and bulbar disease prognosis.
摘要目的:评估由快速音节重复任务(即口腔发音困难[DDK])衍生的新测量方法在快速和慢速进行性球肌萎缩侧索硬化症(ALS)早期分层和预测球疾病进展率中的效用。方法:对54名ALS患者的口腔DDK和整体延髓/言语表现(即ALS功能评定量表修订版[ALSFRS-R]上的延髓分量表;段落阅读期间的发音率)进行纵向跟踪,平均持续时间为4个月。根据追踪期间的延髓退化率,使用后验分类方法将参与者分为14名快速延髓进展者和40名慢速延髓进展者。为了确定口服DDK表现是否预测了这些个体在追踪期的早期阶段(在显著的延髓/言语体征之前)的不同延髓疾病进展轨迹,导出了口腔DDK任务中唇运动表现的22项指标,以(1)使用受试者操作特征分析区分快速和慢速延髓进展者,以及(2)使用线性回归预测所有个体的延髓疾病进展率。结果:运动抖动是DDK过程中嘴唇交替运动的时间变异性的一种测量方法,在疾病早期区分快速和慢速延髓进展者方面显示出80%的敏感性和95%的特异性,并且优于ALSFRS-R延髓分量表和发音率。运动抖动也预测了参与者的延髓疾病进展率。结论:研究结果为口服DDK过程中运动抖动在患者分层和延髓疾病预后中的临床价值提供了初步验证。
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引用次数: 18
Table of Contents - Poster Communications 目录-海报通讯
IF 2.8 4区 医学 Q2 Medicine Pub Date : 2019-10-31 DOI: 10.1080/21678421.2019.1647011
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引用次数: 0
Theme 2 Genetics and genomics 主题2遗传学和基因组学
IF 2.8 4区 医学 Q2 Medicine Pub Date : 2019-10-31 DOI: 10.1080/21678421.2019.1646990
J. Roggenbuck, Carly Doyle, Tara Lincoln, J. Glass
Background: A genetic basis is found in ∼70% of familial and ∼15% of sporadic ALS, in research cohorts. Clinical trials of gene-targeted therapies are underway, heralding a new era of personalized medicine in ALS treatment. However, ALS management guidelines do not include recommendations for the offer of genetic testing. Many persons with ALS who desire genetic testing are not currently offered it, and the yield of genetic testing in clinic-based ALS populations is unknown. The ALS GAP program, sponsored by the Northeast ALS (NEALS) Consortium, provides free genetic testing for patients with ALS who have a family history of ALS or dementia. We report genetic testing outcomes in the first 142 patients tested in the 
program.Objectives: 1) To create a pilot ALS genetic testing program for NEALS clinics, 2) To study the rate of ALS gene identification in a US clinic-based populationMethods: Persons with ALS and a family history of ALS (fALS) or dementia (dALS) who receive care at a US NEALS clinic are eligible for testing. Patients classified as fALS (having a positive family history of ALS in a 1st, 2nd, or 3rd degree relative) are eligible for C9orf72 testing, with the option to reflex to a 5 gene (SOD1, FUS, TARDBP, TBK1, VCP) panel. Patients classified as dALS (having a positive family history of dementia of any type in a 1st or 2nd degree relative) are eligible for C9orf72 testing only.Results: Currently, 29.5% (34/115) of US NEALS clinics have participated in the program. Of 142 patients who have completed testing to date, 78 (54.9%) were classified as fALS and 64 (45.1%) as dALS. Among fALS cases, 42/78 (53.9%) tested positive, including 32/78 (41%) with a C9orf72 repeat expansion, and 10/78 (12.8%) with other pathogenic or likely pathogenic variants in SOD, FUS, TARDP or VCP. Variants of uncertain significance (VUS) in FUS were identified in 2/78 (2.6%). Among dALS cases, 12/60 (20%) tested positive for C9orf72.Discussion and conclusions: Participation in ALS-GAP indicates significant clinician and patient interest in ALS genetic testing. This program addresses several current barriers to testing access, including cost, identifying appropriate candidates for testing, and appropriate test selection. Although 38% of patients who participated in the program have thus far received a genetic diagnosis, our testing outcome data suggests that the gene identification rate in fALS cases may be lower in clinic-based patients than in research cohorts, particularly for genes other than C9orf72. This program may serve as a model for the practice of ALS genetic testing in the clinic setting. Consistent, equitable testing policies, as well as an accurate understanding of the genetic profile of clinic-based ALS populations, are needed as gene-targeted therapies reach patient care.
背景:在研究队列中,约70%的家族性ALS和约15%的散发性ALS存在遗传基础。基因靶向治疗的临床试验正在进行中,预示着ALS治疗的个性化医学新时代的到来。然而,ALS管理指南不包括提供基因检测的建议。许多希望进行基因检测的ALS患者目前还没有得到这样的服务,而且基因检测在临床ALS人群中的效果尚不清楚。ALS GAP项目由东北ALS协会(NEALS)赞助,为有ALS或痴呆家族史的ALS患者提供免费的基因检测。我们报告了在
项目中测试的前142名患者的基因检测结果。目的:1)为NEALS诊所建立一个ALS基因检测试点项目;2)研究美国临床人群中ALS基因鉴定率。方法:在美国NEALS诊所接受治疗的ALS患者和ALS家族史(fALS)或痴呆(dALS)患者有资格进行检测。被归类为fALS的患者(有1、2或3度亲属有ALS阳性家族史)有资格进行C9orf72检测,并可选择对5个基因(SOD1、FUS、TARDBP、TBK1、VCP)进行反射。被归类为dALS的患者(在一级或二级亲属中有任何类型的阳性痴呆家族史)仅适用于C9orf72检测。结果:目前,29.5%(34/115)的美国NEALS诊所参与了该项目。迄今为止完成检测的142例患者中,78例(54.9%)被分类为fALS, 64例(45.1%)被分类为dALS。在fALS病例中,42/78(53.9%)检测呈阳性,其中32/78(41%)为C9orf72重复扩增,10/78(12.8%)为SOD、FUS、TARDP或VCP的其他致病或可能致病变异。在2/78(2.6%)中发现了FUS的不确定意义变异(VUS)。在dALS病例中,12/60(20%)的C9orf72检测呈阳性。讨论和结论:参与ALS- gap表明临床医生和患者对ALS基因检测有重要的兴趣。该计划解决了目前测试访问的几个障碍,包括成本,确定适当的测试候选人,以及适当的测试选择。虽然目前参与该项目的患者中有38%接受了基因诊断,但我们的测试结果数据表明,临床患者的fALS病例的基因识别率可能低于研究队列,特别是对于C9orf72以外的基因。本项目可作为临床ALS基因检测实践的典范。随着基因靶向治疗进入患者护理,一致、公平的检测政策以及对临床ALS人群基因谱的准确理解是必要的。
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引用次数: 0
Theme 5 Human cell biology and pathology 主题5:人类细胞生物学和病理学
IF 2.8 4区 医学 Q2 Medicine Pub Date : 2019-10-31 DOI: 10.1080/21678421.2019.1646993
Anne Gieseler, Reyk Hillert, Andreas Krusche, K. Zacher
Background: The delay from onset of the first symptoms to a definite ALS diagnosis depends also on the elusiveness of the initial clinical manifestations. The lack of disease-specific biomarkers to detect early pathology when ALS is supposed complicates the situation. This latency reduces the therapeutic time frame, in which neuron-rescuing strategies exert their greatest chance to work. Various biomarkers are currently promised, but none of them are specific enough to allow monitoring of disease progression. This, as well as the heterogeneity of the disease concerning clinical onset pattern and survival rates, makes difficult the correct stratification of patients into clinical trials, masking the potential positive outcome in some patients.Objective: Our main objective is to establish and test an early diagnostic tool based on microscopic immune cell monitoring of ALS patients' blood samples by using the Toponome Imaging System (TIS).Methods: TIS is based on automatically controlled microscopic device involving conjugated dye-tag incubation, protein-tag-dye-imaging, and tag-dye bleaching (1). This leads to the collection of at least 21 cycle images of fixated peripheral blood mononuclear cells (PBMCs) isolated from freshly drawn blood of ALS patients and healthy "control" donors. Resulting data sets contain combinatorial molecular information about the spatial protein network, called toponome. The PBMC toponome architectures are quantitatively analyzed as a threshold-binary code with 1 = protein is present and 0 = protein is absent.Results: Preliminary screening data of PBMCs from 4 ALS patients reveal a subpopulation of lymphocytes expressing a specific surface protein pattern, called "ALS toponome". These aberrant T cells could not be found in blood samples of controls. We observe that the number of these cells correlate with the ALS progression rate of patients, supporting the conclusion that these cells may be causal for the disease.Discussion and conclusion: Although these findings open up a potential strategy to detect early ALS disease and to monitor disease progression, a statistical analysis with many more patients, as well as data based differentiation to other neurodegenerative diseases, is mandatory. A clinical trial initiated by our faceALS foundation with at least 60 patients classified in three subsets (1. control, 2. ALS, and 3. Multiple Sclerosis (MS)) and in close cooperation with leading ALS centres in Germany is still in progress. The detection of specific and/or aberrant immune cells in blood samples of ALS patients may provide a key to understand disease onset and progression, could be used for the "staging" of disease, and contribute to effective therapy options.
背景:从最初症状的发作到明确的ALS诊断的延迟也取决于最初临床表现的难以捉摸。当ALS被认为是早期病理时,缺乏疾病特异性的生物标志物来检测使情况复杂化。这种潜伏期减少了治疗时间框架,在此期间,神经元拯救策略发挥其最大的工作机会。目前有多种生物标志物被承诺,但没有一种具有足够的特异性,可以监测疾病的进展。这一点,以及该疾病在临床发病模式和生存率方面的异质性,使得很难将患者正确分层到临床试验中,掩盖了一些患者的潜在阳性结果。目的:我们的主要目的是建立和测试一种基于Toponome成像系统(TIS)对ALS患者血液样本进行显微免疫细胞监测的早期诊断工具。方法:TIS是基于自动控制的显微镜设备,包括共轭染料-标签孵育、蛋白质-标签-染料成像和标签-染料漂白(1)。这使得从ALS患者和健康“对照”供者的新鲜抽血中分离的固定外周血单个核细胞(PBMCs)收集至少21个周期图像。由此产生的数据集包含有关空间蛋白质网络的组合分子信息,称为拓扑onome。对PBMC拓扑组结构进行了定量分析,认为存在1 =蛋白质而不存在0 =蛋白质的阈值二进制代码。结果:来自4例ALS患者的PBMCs的初步筛选数据显示淋巴细胞亚群表达一种特定的表面蛋白模式,称为“ALS toponome”。这些异常的T细胞在对照组的血液样本中找不到。我们观察到这些细胞的数量与患者的ALS进展率相关,支持这些细胞可能是该疾病的病因的结论。讨论和结论:尽管这些发现为发现早期ALS疾病和监测疾病进展开辟了一种潜在的策略,但对更多患者的统计分析以及基于数据的其他神经退行性疾病的区分是必要的。我们的faceALS基金会发起了一项临床试验,至少有60名患者被分为三个亚群(1;控制,2。ALS和3。多发性硬化症(MS),并与德国领先的ALS中心密切合作,仍在进行中。ALS患者血液样本中特异性和/或异常免疫细胞的检测可能为了解疾病的发生和进展提供关键,可用于疾病的“分期”,并有助于有效的治疗选择。
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引用次数: 1
Theme 6 Tissue biomarkers 主题6组织生物标志物
IF 2.8 4区 医学 Q2 Medicine Pub Date : 2019-10-31 DOI: 10.1080/21678421.2019.1646994
Karen R. Garnaas, J. Kittelsrud, M. Behnke
Background: Glutamate excitotoxicity is a longstanding hypothesis in the pathophysiology of ALS. Prior studies have demonstrated increased plasma glutamate levels in ALS patients, which suggest a systemic defect in glutamate metabolism (1). The most abundant amino acid consumed in our diet is glutamate. Studies in healthy human subjects have demonstrated efficient metabolism of dietary glutamate via metabolism by enzymes present in the liver, gut lumen and residential gut bacteria. There is increasing evidence that the gut microbiota has significant CNS effects and intestinal dysbiosis has been found in the ALS transgenic SOD1G93A mouse model (2). If intestinal dysbiosis altered the prevalence of glutamine synthetase (GS) producing bacteria, dietary glutamate homeostasis could be impaired, leading to elevated plasma glutamate levels.Objectives: This study examined the degree of fluctuation in plasma glutamate levels seen with consumption of a protein shake in a cohort of ALS patients and family members from a single ALS center.Methods: Twenty six patients (87% of total cohort followed in the ALS center) underwent measurement of plasma amino acid analysis prior to and 1 hour following consumption of a 75 gm protein shake. A subset of 16 patients went on to receive a probiotic with high GS activity and completed serial protein challenges and amino acid analysis during the study. Ten unaffected family members of ALS patients underwent a similar protein challenge. Glutamate Metabolism Dysfunction (GMD) was defined as >30 umol difference post-prandially compared to fasting, and graded as mild (>30-60), moderate (>60-90) or severe (>90).Results: At baseline, 65.4% (17/26) ALS patients screened were GMD positive, compared to 30% (3/10) of tested family members. The severity of GMD in ALS patients was 41% mild, 29% moderate, 29% severe with only mild severity identified in family members. In the six month treatment phase, 75% (6/8) of patients with stable or improving GMD status saw significant improvements in their ALSFRS-R rate of decline, while 71.4% (5/7) with worsening or remaining severe GMD status experienced worsening of their rate of progression.Discussion and conclusions: Although limited by small sample size, this study does represent an excellent sampling within a single ALS center and is the first of its kind to investigate whether impairment in dietary glutamate metabolism exists in ALS patients. If validated in a larger ALS population, detection of glutamate metabolism dysfunction (GMD) could represent a novel biomarker linked to a potential therapeutic target in ALS patients. Planned microbiome analysis will also help in validating this hypothesis.
背景:谷氨酸兴奋性毒性是ALS病理生理学中一个长期存在的假说。先前的研究表明,ALS患者的血浆谷氨酸水平升高,这表明谷氨酸代谢存在系统性缺陷(1)。我们饮食中消耗的最丰富的氨基酸是谷氨酸。对健康人类受试者的研究表明,通过肝脏、肠腔和肠道细菌中存在的酶的代谢,膳食谷氨酸的有效代谢。越来越多的证据表明,肠道微生物群具有显著的中枢神经系统影响,并且在ALS转基因SOD1G93A小鼠模型中发现了肠道微生态失调(2)。如果肠道微生态失调改变了谷氨酰胺合成酶(GS)产生细菌的流行率,那么饮食中的谷氨酸稳态可能会受损,导致血浆谷氨酸水平升高。目的:本研究检测了来自一个ALS中心的ALS患者和家庭成员队列中,随着蛋白质奶昔的摄入,血浆谷氨酸水平的波动程度。方法:26名患者(占ALS中心随访的总队列的87%)在治疗前和治疗前接受了血浆氨基酸分析的测量 消耗75 gm蛋白奶昔。16名患者的子集继续接受具有高GS活性的益生菌,并在研究期间完成了一系列蛋白质挑战和氨基酸分析。10名未受影响的ALS患者家庭成员接受了类似的蛋白质挑战。谷氨酸代谢障碍(GMD)被定义为餐后与禁食相比差异>30μmol,分为轻度(>30-60)、中度(>60-90)或重度(>90)。ALS患者的GMD严重程度为41%轻度,29%中度,29%重度,仅在家庭成员中发现轻度。在六个月的治疗阶段,75%(6/8)的GMD状态稳定或改善的患者的ALSFRS-R下降率有显著改善,而71.4%(5/7)GMD状态恶化或仍然严重的患者的进展率恶化。讨论和结论:尽管受样本量小的限制,但这项研究确实代表了一个单一ALS中心内的一个极好的样本,也是首次调查ALS患者是否存在饮食谷氨酸代谢障碍的同类研究。如果在更大的ALS人群中得到验证,谷氨酸代谢功能障碍(GMD)的检测可能代表一种与ALS患者潜在治疗靶点相关的新生物标志物。有计划的微生物组分析也将有助于验证这一假设。
{"title":"Theme 6 Tissue biomarkers","authors":"Karen R. Garnaas, J. Kittelsrud, M. Behnke","doi":"10.1080/21678421.2019.1646994","DOIUrl":"https://doi.org/10.1080/21678421.2019.1646994","url":null,"abstract":"Background: Glutamate excitotoxicity is a longstanding hypothesis in the pathophysiology of ALS. Prior studies have demonstrated increased plasma glutamate levels in ALS patients, which suggest a systemic defect in glutamate metabolism (1). The most abundant amino acid consumed in our diet is glutamate. Studies in healthy human subjects have demonstrated efficient metabolism of dietary glutamate via metabolism by enzymes present in the liver, gut lumen and residential gut bacteria. There is increasing evidence that the gut microbiota has significant CNS effects and intestinal dysbiosis has been found in the ALS transgenic SOD1G93A mouse model (2). If intestinal dysbiosis altered the prevalence of glutamine synthetase (GS) producing bacteria, dietary glutamate homeostasis could be impaired, leading to elevated plasma glutamate levels.Objectives: This study examined the degree of fluctuation in plasma glutamate levels seen with consumption of a protein shake in a cohort of ALS patients and family members from a single ALS center.Methods: Twenty six patients (87% of total cohort followed in the ALS center) underwent measurement of plasma amino acid analysis prior to and 1 hour following consumption of a 75 gm protein shake. A subset of 16 patients went on to receive a probiotic with high GS activity and completed serial protein challenges and amino acid analysis during the study. Ten unaffected family members of ALS patients underwent a similar protein challenge. Glutamate Metabolism Dysfunction (GMD) was defined as >30 umol difference post-prandially compared to fasting, and graded as mild (>30-60), moderate (>60-90) or severe (>90).Results: At baseline, 65.4% (17/26) ALS patients screened were GMD positive, compared to 30% (3/10) of tested family members. The severity of GMD in ALS patients was 41% mild, 29% moderate, 29% severe with only mild severity identified in family members. In the six month treatment phase, 75% (6/8) of patients with stable or improving GMD status saw significant improvements in their ALSFRS-R rate of decline, while 71.4% (5/7) with worsening or remaining severe GMD status experienced worsening of their rate of progression.Discussion and conclusions: Although limited by small sample size, this study does represent an excellent sampling within a single ALS center and is the first of its kind to investigate whether impairment in dietary glutamate metabolism exists in ALS patients. If validated in a larger ALS population, detection of glutamate metabolism dysfunction (GMD) could represent a novel biomarker linked to a potential therapeutic target in ALS patients. Planned microbiome analysis will also help in validating this hypothesis.","PeriodicalId":7740,"journal":{"name":"Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2019-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/21678421.2019.1646994","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46534891","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: 0
Theme 13 Clinical management and support 主题13临床管理和支持
IF 2.8 4区 医学 Q2 Medicine Pub Date : 2019-10-31 DOI: 10.1080/21678421.2019.1647002
A. Crook, A. Hogden, V. Mumford, I. Blair, K. Williams, D. Rowe
Background: Pathogenic variants in ALS genes are known to be present in up to 70% of familial and 10% of apparently sporadic ALS cases, and can be associated with risks for ALS only, or risks for other neurodegenerative diseases (eg. frontotemporal dementia). While there are no changes to medical management for patients confirmed as pathogenic variant carriers, genetic testing may be important for future drug trials. Confirmation of a pathogenic variant also provides relatives with the opportunity to consider predictive and/or reproductive genetic testing. Genetic counselling is an important aspect of testing decision-making as it enables individuals to make informed decisions about genetic testing while minimising adverse psychological, ethical and legal outcomes. Few studies have explored how individuals decide whether to pursue testing, nor the needs and experiences of familial ALS families.Objective: To identify factors that influence patient and family member decision-making about genetic testing for ALS genes, assess the impact of familial disease on the patient and their family, and identify information and support needs.Methods: In-depth, semi-structured interviews with individuals from Australian ALS families with known pathogenic gene variants explored experiences of familial ALS, and factors that influenced genetic testing decision-making. Interviews were analysed using an inductive approach.Results: Thirty-four individuals from 24 families were interviewed and included patients (n = 4), spouses (n = 4), and asymptomatic at-risk relatives (n = 26). Life stage, experience of disease, costs, research opportunities, and attitudes to familial ALS and/or reproductive options influenced decision-making. Some patients and relatives experienced difficulty gaining accurate information from their health professionals about the costs and implications of genetic counselling or testing, resulting in a reluctance to proceed.Discussion and conclusion: This study provides new insight into the Australian experience of genetic testing and counselling for familial ALS. It highlights the need to work together with other health professionals to ensure the complexities of genetic testing decision-making, and referral pathways are better understood.
背景:已知高达70%的家族性ALS病例和10%的明显散发性ALS病例中存在ALS基因的致病性变异,并且可能仅与ALS的风险相关,或与其他神经退行性疾病(如脊髓灰质炎)的风险相关。额颞叶痴呆)。虽然确诊为致病变异携带者的患者的医疗管理没有变化,但基因检测可能对未来的药物试验很重要。致病变异的确认也为亲属提供了考虑预测性和/或生殖基因检测的机会。遗传咨询是检测决策的一个重要方面,因为它使个人能够对基因检测做出明智的决定,同时最大限度地减少不利的心理、道德和法律后果。很少有研究探讨个体如何决定是否进行检测,也很少有研究探讨家族性ALS家庭的需求和经历。目的:了解影响ALS患者及家属基因检测决策的因素,评估家族性疾病对患者及家属的影响,识别信息和支持需求。方法:对来自澳大利亚已知致病基因变异的ALS家族的个体进行深入的半结构化访谈,探讨家族性ALS的经历,以及影响基因检测决策的因素。访谈采用归纳方法进行分析。结果:采访了来自24个家庭的34个人,包括患者(n = 4)、配偶(n = 4)和无症状高危亲属(n = 26)。生命阶段、疾病经历、费用、研究机会以及对家族性ALS和/或生殖选择的态度影响决策。一些病人和家属难以从他们的保健专业人员那里获得关于遗传咨询或检测的费用和影响的准确信息,因此不愿继续进行。讨论和结论:本研究为澳大利亚家族性ALS基因检测和咨询的经验提供了新的见解。它强调需要与其他卫生专业人员共同努力,以确保更好地了解基因检测决策的复杂性和转诊途径。
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引用次数: 1
Theme 4 In vivo experimental models 主题4体内实验模型
IF 2.8 4区 医学 Q2 Medicine Pub Date : 2019-10-31 DOI: 10.1080/21678421.2019.1646992
A. Chudinova, M. Rossel, A. Vergunst, Gwendal Le-Masson, W. Camu, C. Raoul, S. Lumbroso, K. Mouzat
Background: In 90% of Amyotrophic Lateral Sclerosis (ALS) cases, the disease is sporadic, the remaining 10% being familial. Many genes have been associated with the disease. The use of next generation sequencing has allowed increasing the number of genes analysed in routine diagnostics. However, this increase raises the issue of genetic variants interpretation within a growing number of ALS-associated-genes. Variant classification is based on a combinatory analysis of multiple factors. Among them, functional analyses provide strong arguments on pathogenicity interpretation.Objectives: We developed a simple animal model, the Zebrafish, for the functional analysis of candidate variants pathogenicity identified by routine genetic testing.Methods: Transient overexpression of different ALS associated genetic variants has been performed by mRNA injection in 1-cell stage zebrafish eggs. Validation of protein overexpression has been done by western blot. Embryos mortality, developmental delay and morphological abnormalities have been assessed within the first two days of development. Cellular phenotype has been investigated by the analysis of axonal length of 2-days old larvae with confocal microscopy. Motor phenotype of 5-days old larvae has been explored by touched-evoked response assay.Results: The model has been validated by the analysis of well-described ALS mutations, SOD1-Gly93Ala and OPTN Glu478Gly. Overexpression of this mutated protein was shown to provoke a shortening of axons and a premature axonal branching, as well as an impairment of motor performances as expected. We did not observe these aberrations in SOD1-WT injected fishes. Two candidate variants observed in ALS-patients have been explored with our model: SOD1 NM_000454.4:c.400_402del, p.Glu134del and OPTN NM_021980.4:c.1475T > G, p. Leu492Arg. Overexpression of both variants induced morphological abnormalities and motor impairment, suggesting a pathogenic involvement of these variants in ALS-patients.Discussion and conclusions: We developed for the first time a simple animal model, the Zebrafish, useful for the functional analysis of variant pathogenicity in order to assist ALS molecular diagnosis. Our model has been used to assess the pathogenicity of SOD1 and OPTN candidate variants, allowing to improve genetic testing interpretation.
背景:在90%的肌萎缩侧索硬化症(ALS)病例中,疾病是散发的,其余10%是家族性的。许多基因都与这种疾病有关。下一代测序的使用增加了常规诊断中分析的基因数量。然而,这种增加提出了在越来越多的als相关基因中解释遗传变异的问题。变异分类是基于多因素的组合分析。其中,功能分析为致病性解释提供了有力的论据。目的:我们开发了一种简单的动物模型,斑马鱼,用于通过常规基因检测确定的候选变异致病性的功能分析。方法:通过mRNA注射在斑马鱼1细胞期卵中短暂过表达不同的ALS相关遗传变异。western blot验证蛋白过表达。胚胎死亡率、发育迟缓和形态异常在发育的头两天内进行了评估。用共聚焦显微镜对2日龄幼虫的轴突长度进行了分析,研究了细胞表型。采用接触诱发反应法研究了5日龄幼虫的运动表型。结果:该模型通过分析已描述的ALS突变SOD1-Gly93Ala和OPTN Glu478Gly得到了验证。这种突变蛋白的过度表达引起轴突缩短和过早的轴突分支,以及预期的运动性能障碍。我们在注射SOD1-WT的鱼类中未观察到这些畸变。我们的模型探索了在als患者中观察到的两个候选变异:SOD1 NM_000454.4:c。p.Glu134del和OPTN NM_021980.4:c。[1475t>g], p. lu92arg。这两种变体的过表达引起了形态异常和运动障碍,表明这些变体在als患者中有致病作用。讨论与结论:我们首次建立了一种简单的动物模型——斑马鱼,用于变异致病性的功能分析,以协助ALS的分子诊断。我们的模型已被用于评估SOD1和OPTN候选变异的致病性,从而改进基因检测的解释。
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引用次数: 1
Theme 1 Epidemiology and informatics 主题1流行病学和信息学
IF 2.8 4区 医学 Q2 Medicine Pub Date : 2019-10-31 DOI: 10.1080/21678421.2019.1646989
C. Armon
Background: Identifying mechanisms of neurodegenerative disease causation has for long seemed to be beyond the pale of traditional epidemiological tools. Elucidating a plausible mechanism for initiation of amyotrophic lateral sclerosis (ALS) has appeared particularly elusive (1). The impression, that environmental risk factors for ALS were not providing consistent direction, meant there was no sturdy epidemiologically-based "handle" to grasp when trying to envisage a biological mechanism for triggering sporadic ALS (2). There have been challenges with interpreting the data. At times, generic concerns over potential limitations of traditional epidemiological studies have appeared to overshadow the findings in circumstances where these limitations had been overcome largely. At other times, studies with different degrees of methodological limitations have been lumped together, thereby obscuring the results of the studies with less limitations. On occasion, methodological limitations have been downplayed or ignored entirely.Emergence of Mendelian Randomization (MR) methods has offered the promise of overcoming some of the potential limitations of epidemiological studies that used traditional methods. MR methods apply concepts developed in the field of economics to infer causality in the presence of unmeasured confounding (3). The principal idea is: 1) a genetic pattern is identified that predicts a suspected risk factor - a laboratory value in patients' blood, or a particular behavior; 2) that pattern is sought in patients and controls; 3) excess presence of the pattern in patients suggests that the risk factor plays a causal role in producing the disease.However, application of MR methods requires that several underlying assumptions, specific to these methods, have been satisfied (3). Moreover, epidemiological analyses using MR methods need to adhere to core epidemiological and statistical principles. Finally, findings from MR studies need to be interpreted critically, with close attention to the context from which they arise, and with utilization of internal and external comparators (4,5).This presentation will discuss the assumptions that need to be met to apply MR methods in general and how they relate to studies in patients with ALS, drawing on recently published reports.
背景:长期以来,识别神经退行性疾病病因的机制似乎超出了传统流行病学工具的范畴。阐明肌萎缩侧索硬化症(ALS)的发病机制似乎特别难以捉摸(1)。ALS的环境风险因素没有提供一致的方向,这意味着在试图设想触发散发性ALS的生物学机制时,没有可靠的基于流行病学的“处理方法”(2)。在解释数据方面存在挑战。有时,对传统流行病学研究潜在局限性的普遍担忧似乎掩盖了这些局限性在很大程度上得到克服的情况下的发现。在其他时候,具有不同程度方法学局限性的研究被集中在一起,从而模糊了局限性较小的研究的结果。有时,方法上的局限性被淡化或完全忽视。孟德尔随机化(MR)方法的出现为克服使用传统方法的流行病学研究的一些潜在局限性提供了希望。MR方法应用经济学领域中发展起来的概念,在存在未测量的混杂因素的情况下推断因果关系(3)。主要想法是:1)确定了一种基因模式,可以预测疑似风险因素——患者血液中的实验室值,或特定行为;2) 在患者和对照组中寻求这种模式;3) 这种模式在患者中的过度存在表明,风险因素在产生这种疾病中起着因果作用。然而,MR方法的应用需要满足这些方法特有的几个基本假设(3)。此外,使用MR方法进行的流行病学分析需要遵守核心流行病学和统计原则。最后,需要对MR研究的结果进行批判性解读,密切关注其产生的背景,并使用内部和外部比较器(4,5)。本报告将根据最近发表的报告,讨论应用MR方法所需满足的假设,以及它们与ALS患者研究的关系。
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引用次数: 0
Platform Communications: Abstract Book - 30th International Symposium on ALS/MND (Complete printable file) 平台通讯:摘要书-第30届ALS/MND国际研讨会(完整可打印文件)
IF 2.8 4区 医学 Q2 Medicine Pub Date : 2019-10-31 DOI: 10.1080/21678421.2019.1646546
O. Hardiman, Sharon Abrahams, A. Al-Chalabi
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引用次数: 4
Theme 12 Respiratory and nutritional management 主题12呼吸和营养管理
IF 2.8 4区 医学 Q2 Medicine Pub Date : 2019-10-31 DOI: 10.1080/21678421.2019.1647001
Q. Wei, R. Ou, Yongping Chen, Xueping Chen, B. Cao, Yanbing Hou, Lingyu Zhang, H. Shang
Background: Previous studies explored the associations between body weight index (BMI) at diagnosis, weight change after diagnosis and survival in amyotrophic lateral sclerosis (ALS). But significance of weight stability before diagnosis remains to be established.Objective: The aim of this study is to clarify the weight loss from baseline (6 months before diagnosis) to diagnostic and the effect on disease prognosis.Methods: Total of 911 patients were enrolled from 2014 to 2018 in West China Hospital of Sichuan University. BMI is divided into four subgroups: lean, normal, overweight, and obese. The formula for calculating the rate of weight change = (weight at baseline - weight at diagnosis)/weight at baseline * 100%. Survival analysis was performed using Kaplan-Meier curves and Cox proportional hazard models.Results: The mean age of onset was 55.4 ± 11.1 years. The percentage of overweight and obesity in ALS at baseline were significantly lower than healthy controls. The median of weight loss was 2.9%. 36.9% patients had weight loss more than 5%, and 16.5% of them lose weight more than 10%. Patients with bulbar onset, bulbar impairment, lower ALS functional rating scale-revised score had more serious weight loss. The Kaplan-Meier curve showed that, compared to other patients, patients with weight loss more than 10% had a shorter survival time (30.5 months vs. 48.8 months, log-rank p < 0.001). Cox analysis showed that the weight loss was found to be an independent predictor of survival after adjusting for other survival factors (HR= 1.165, p trend <0.001). Each additional increased class of weight loss was associated with a 16.5% (95% CI: 7.3%-26.5%) increased risk of mortality and worse survival.Discussion and conclusion: Our study suggested that the weight variation is associated with survival in ALS patients. This has strong implications for management of nutritional issues in ALS, that the patient education and therapy recommendation should be earlier and standardize to promote the nutritional support and prognosis.
背景:既往研究探讨了肌萎缩性侧索硬化症(ALS)患者诊断时体重指数(BMI)、诊断后体重变化与生存之间的关系。但诊断前体重稳定性的意义仍有待确定。目的:本研究的目的是明确从基线(诊断前6个月)到诊断的体重减轻及其对疾病预后的影响。方法:选取四川大学华西医院2014 - 2018年收治的患者911例。BMI分为四个亚组:瘦、正常、超重和肥胖。体重变化率计算公式=(基线体重-诊断时体重)/基线体重* 100%。生存率分析采用Kaplan-Meier曲线和Cox比例风险模型。结果:平均发病年龄为55.4±11.1岁。肌萎缩侧索硬化症患者超重和肥胖的比例在基线时明显低于健康对照组。体重减轻的中位数为2.9%。36.9%的患者体重减轻5%以上,16.5%的患者体重减轻10%以上。有球发病、球损伤、ALS功能评定量表修订评分较低的患者体重下降更严重。Kaplan-Meier曲线显示,与其他患者相比,体重减轻超过10%的患者生存时间更短(30.5个月vs 48.8个月,log-rank p < 0.001)。Cox分析显示,在调整其他生存因素后,体重减轻是独立的生存预测因子(HR= 1.165, p趋势<0.001)。体重每增加一级,死亡风险增加16.5% (95% CI: 7.3%-26.5%),生存率降低。讨论与结论:我们的研究表明,体重变化与ALS患者的生存有关。这对肌萎缩侧索硬化症营养问题的管理具有重要意义,应尽早对患者进行教育和推荐治疗,以促进营养支持和预后。
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引用次数: 3
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Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration
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