Pub Date : 2024-08-01Epub Date: 2024-05-08DOI: 10.1080/21678421.2024.2346502
Xinyi Zhang, Ye Sun, Xinzhe Zhang, Dongchao Shen, Shi Shu, Xunzhe Yang, Mingsheng Liu, Liying Cui, Qing Liu, Xue Zhang
Background: Pathogenic variants in hnRNPA1 have been reported in amyotrophic lateral sclerosis (ALS) patients. However, studies on hnRNPA1 mutant spectrum and pathogenicity of variants were rare.
Methods: We performed whole exome sequencing of ALS-associated genes and subsequent verification of rare variants in hnRNPA1 in our ALS patients. The hnRNPA1 mutations reported in literature were reviewed and combined with our results to determine the genotype-phenotype relationship. Functional analysis of the novel variant p.G195A was performed in vitro by transfection of mutant hnRNPA1 into 293T cell.
Results: Among 207 ALS patients recruited, 3 rare hnRNPA1 variants were identified (mutant frequency 1.45%), including two recurrent mutations (p.P340S and p.G283R), and a novel rare variant p.G195A. In combination with previous reports, there are 27 ALS patients with 15 hnRNPA1 mutations identified. Disease onset age was 47.90 ± 1.52 years with predominant limb onset. The p.P340S mutation caused flail arm syndrome (FAS) in two independent families with extended life expectancy. The newly identified p.G195A mutation, lying at the start of the PrLD ("prion-like" domain)/LCD (low-complexity domain), causes local structural changes in 3D protein prediction. Upon sodium arsenite exposure, mutant hnRNPA1 retained in the nucleus but deficit of cytoplasmic G3BP1-positive stress granule clearance was observed. This is different from the p.P340S mutation which caused both cytoplasmic translocation and stress granule formation. No cytoplasmic TDP-43 translocation was observed.
Conclusion: Mutations in hnRNPA1 are overall minor in ALS patients. The p.P340S mutation is associated with manifestation of FAS. Mutations in LCD of hnRNPA1 cause stress granule misprocessing.
背景:据报道,肌萎缩侧索硬化症(ALS)患者中存在hnRNPA1致病变异。然而,有关 hnRNPA1 突变谱和变异致病性的研究却很少见:我们对 ALS 相关基因进行了全外显子组测序,并随后对 ALS 患者中的 hnRNPA1 罕见变异进行了验证。我们回顾了文献中报道的 hnRNPA1 变异,并结合我们的研究结果确定了基因型与表型之间的关系。通过将突变的 hnRNPA1 转染至 293T 细胞,对新型变异 p.G195A 进行了体外功能分析:结果:在招募的207名ALS患者中,发现了3个罕见的hnRNPA1变异体(变异频率为1.45%),包括两个复发性变异体(p.P340S和p.G283R)和一个新型罕见变异体p.G195A。结合之前的报告,共有27名ALS患者发现了15个hnRNPA1突变。发病年龄为(47.90 ± 1.52)岁,以肢体发病为主。p.P340S突变在两个独立的家庭中引起了脆臂综合征(FAS),并延长了预期寿命。新发现的p.G195A突变位于PrLD("类朊病毒 "结构域)/LCD(低复杂性结构域)的起始位置,会导致三维蛋白质预测的局部结构变化。暴露于亚砷酸钠后,突变体 hnRNPA1 保留在细胞核中,但细胞质中 G3BP1 阳性的应激颗粒清除能力不足。这与p.P340S突变不同,p.P340S突变会导致细胞质易位和应激颗粒形成。没有观察到细胞质中的 TDP-43 易位:结论:在 ALS 患者中,hnRNPA1 的突变总体上较小。p.P340S突变与FAS的表现有关。hnRNPA1的LCD突变会导致应激颗粒处理不当。
{"title":"Genotype-phenotype association and functional analysis of <i>hnRNPA1</i> mutations in amyotrophic lateral sclerosis.","authors":"Xinyi Zhang, Ye Sun, Xinzhe Zhang, Dongchao Shen, Shi Shu, Xunzhe Yang, Mingsheng Liu, Liying Cui, Qing Liu, Xue Zhang","doi":"10.1080/21678421.2024.2346502","DOIUrl":"10.1080/21678421.2024.2346502","url":null,"abstract":"<p><strong>Background: </strong>Pathogenic variants in <i>hnRNPA1</i> have been reported in amyotrophic lateral sclerosis (ALS) patients. However, studies on <i>hnRNPA1</i> mutant spectrum and pathogenicity of variants were rare.</p><p><strong>Methods: </strong>We performed whole exome sequencing of ALS-associated genes and subsequent verification of rare variants in <i>hnRNPA1</i> in our ALS patients. The <i>hnRNPA1</i> mutations reported in literature were reviewed and combined with our results to determine the genotype-phenotype relationship. Functional analysis of the novel variant p.G195A was performed in vitro by transfection of mutant <i>hnRNPA1</i> into 293T cell.</p><p><strong>Results: </strong>Among 207 ALS patients recruited, 3 rare <i>hnRNPA1</i> variants were identified (mutant frequency 1.45%), including two recurrent mutations (p.P340S and p.G283R), and a novel rare variant p.G195A. In combination with previous reports, there are 27 ALS patients with 15 <i>hnRNPA1</i> mutations identified. Disease onset age was 47.90 ± 1.52 years with predominant limb onset. The p.P340S mutation caused flail arm syndrome (FAS) in two independent families with extended life expectancy. The newly identified p.G195A mutation, lying at the start of the PrLD (\"prion-like\" domain)/LCD (low-complexity domain), causes local structural changes in 3D protein prediction. Upon sodium arsenite exposure, mutant hnRNPA1 retained in the nucleus but deficit of cytoplasmic G3BP1-positive stress granule clearance was observed. This is different from the p.P340S mutation which caused both cytoplasmic translocation and stress granule formation. No cytoplasmic TDP-43 translocation was observed.</p><p><strong>Conclusion: </strong>Mutations in <i>hnRNPA1</i> are overall minor in ALS patients. The p.P340S mutation is associated with manifestation of FAS. Mutations in LCD of <i>hnRNPA1</i> cause stress granule misprocessing.</p>","PeriodicalId":72184,"journal":{"name":"Amyotrophic lateral sclerosis & frontotemporal degeneration","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140878002","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-01Epub Date: 2024-04-01DOI: 10.1080/21678421.2024.2336127
Federico Maria Sopranzi, Andrea Faragalli, Marco Pompili, Flavia Carle, Rosaria Gesuita, Maria Gabriella Ceravolo
Background: Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disorder with a high multidimensional burden, with an obscure etiopathogenesis.
Methods: We designed a longitudinal, population-based study of people residing in Central Italy (Marche Region) who were beneficiaries of the National Health System. People with an unprecedented ALS hospitalization (335.20 ICD-9 CM) or tagged with an ALS exemption between 2014 and 2021 were considered incident cases. ALS cases residing in the region for <3 years or with an active ALS exemption or hospitalized for ALS before 2014 were excluded. We used secondary sources to identify new ALS diagnoses. The regional referral center for ALS's database was used to test the accuracy of secondary sources in detecting cases. ALS mean incidence was compared to that reported in similar studies conducted in Italy. The incidence rate trend adjusted by sex and age was evaluated using the Poisson regression model.
Results: We detected 425 new ALS cases (median age: 70y) in the 2014-2021 period, with a mean incidence of 3.5:100,000 py (95%CI: 3.2-3.8; M:F = 1.2), similar to that reported in similar studies conducted in Italy. No trend was observed during 2014-2019. After including 2020-2021 in the model, we observed a mean decrease in incidence of 5.8% (95% CI 2.0%; 9.5%, p = 0.003).
Conclusion: We show a decrease in the incidence rate of ALS in Marche, during the 2014-2021 period, as a possible outcome of a delayed neurological assessment and diagnosis during the pandemic. An ad hoc developed identification algorithm, based on healthcare utilization databases, is a valuable tool to assess the health impact of global contingencies.
背景:肌萎缩性脊髓侧索硬化症(ALS)是一种致命的神经退行性疾病,具有多方面的高负担,发病机制不明确:我们设计了一项基于人口的纵向研究,研究对象是居住在意大利中部(马尔凯大区)的国民健康系统受益者。在 2014 年至 2021 年期间发生过前所未有的 ALS 住院病例(335.20 ICD-9 CM)或贴有 ALS 豁免标签的人被视为事件病例。居住在该地区的 ALS 病例:我们在 2014-2021 年期间发现了 425 例新的 ALS 病例(中位年龄:70 岁),平均发病率为 3.5:100,000(95%CI:3.2-3.8;男:女 = 1.2),与意大利进行的类似研究中报告的发病率相似。在 2014-2019 年期间未观察到任何趋势。将 2020-2021 年纳入模型后,我们观察到发病率平均下降了 5.8%(95% CI 2.0%; 9.5%,p = 0.003):我们发现,在 2014-2021 年期间,马尔凯的 ALS 发病率有所下降,这可能是大流行期间神经系统评估和诊断延迟的结果。基于医疗保健利用率数据库开发的特殊识别算法是评估全球突发事件对健康影响的重要工具。
{"title":"Incidence of amyotrophic lateral sclerosis before and during the COVID-19 pandemic: evidence from an 8-year population-based study in Central Italy based on healthcare utilization databases.","authors":"Federico Maria Sopranzi, Andrea Faragalli, Marco Pompili, Flavia Carle, Rosaria Gesuita, Maria Gabriella Ceravolo","doi":"10.1080/21678421.2024.2336127","DOIUrl":"10.1080/21678421.2024.2336127","url":null,"abstract":"<p><strong>Background: </strong>Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disorder with a high multidimensional burden, with an obscure etiopathogenesis.</p><p><strong>Methods: </strong>We designed a longitudinal, population-based study of people residing in Central Italy (Marche Region) who were beneficiaries of the National Health System. People with an unprecedented ALS hospitalization (335.20 ICD-9 CM) or tagged with an ALS exemption between 2014 and 2021 were considered incident cases. ALS cases residing in the region for <3 years or with an active ALS exemption or hospitalized for ALS before 2014 were excluded. We used secondary sources to identify new ALS diagnoses. The regional referral center for ALS's database was used to test the accuracy of secondary sources in detecting cases. ALS mean incidence was compared to that reported in similar studies conducted in Italy. The incidence rate trend adjusted by sex and age was evaluated using the Poisson regression model.</p><p><strong>Results: </strong>We detected 425 new ALS cases (median age: 70y) in the 2014-2021 period, with a mean incidence of 3.5:100,000 py (95%CI: 3.2-3.8; M:F = 1.2), similar to that reported in similar studies conducted in Italy. No trend was observed during 2014-2019. After including 2020-2021 in the model, we observed a mean decrease in incidence of 5.8% (95% CI 2.0%; 9.5%, p = 0.003).</p><p><strong>Conclusion: </strong>We show a decrease in the incidence rate of ALS in Marche, during the 2014-2021 period, as a possible outcome of a delayed neurological assessment and diagnosis during the pandemic. An ad hoc developed identification algorithm, based on healthcare utilization databases, is a valuable tool to assess the health impact of global contingencies.</p>","PeriodicalId":72184,"journal":{"name":"Amyotrophic lateral sclerosis & frontotemporal degeneration","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140337840","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-01Epub Date: 2024-03-11DOI: 10.1080/21678421.2024.2322545
Carolyn A Young, Amina Chaouch, Christopher J Mcdermott, Ammar Al-Chalabi, Suresh K Chhetri, Kevin Talbot, Timothy Harrower, Richard W Orrell, Joe Annadale, C Oliver Hanemann, Antonio Scalfari, Alan Tennant, Roger Mills
Objective: Dyspnea, or breathlessness, is an important symptom in amyotrophic lateral sclerosis/motor neuron disease (ALS/MND). We examined the measurement properties of the Dyspnea-12.
Methods: Rasch analysis enabled conversion of raw Dyspnea-12 scores to interval level metric equivalents. Converted data were used to perform trajectory modeling; those following different trajectories were compared for demographic, clinical, symptom, and functioning characteristics. Logistic regression examined differences between distinct trajectories.
Results: In 1022 people, at baseline, mean metric Dyspnea-12 was 7.6 (SD 9.3). 49.8% had dyspnea, severe in 12.6%. Trajectory analysis over 28 months revealed three breathlessness trajectories: group 1 reported none at baseline/follow-up (42.7%); group 2 significantly increased over time (9.4%); group 3 had a much higher level at baseline which rose over follow-up (47.9%). Group 3 had worse outcomes on all symptoms, functioning and quality of life; compared to group 1, their odds of: respiratory onset sixfold greater; King's stage ≥3 2.9 greater; increased odds of being bothered by choking, head drop, fasciculations, and muscle cramps; fatigue and anxiety also elevated (p < .01).
Conclusion: Dyspnea is a cardinal symptom in ALS/MND and can be quickly measured using the Dyspnea-12. Raw scores can easily be converted to interval level measurement, for valid change scores and trajectory modeling. Dyspnea trajectories reveal different patterns, showing that clinical services must provide monitoring which is customized to individual patient need. Almost half of this large population had worsening dyspnea, confirming the importance of respiratory monitoring and interventions being integrated into routine ALS care.
{"title":"Dyspnea (breathlessness) in amyotrophic lateral sclerosis/motor neuron disease: prevalence, progression, severity, and correlates.","authors":"Carolyn A Young, Amina Chaouch, Christopher J Mcdermott, Ammar Al-Chalabi, Suresh K Chhetri, Kevin Talbot, Timothy Harrower, Richard W Orrell, Joe Annadale, C Oliver Hanemann, Antonio Scalfari, Alan Tennant, Roger Mills","doi":"10.1080/21678421.2024.2322545","DOIUrl":"10.1080/21678421.2024.2322545","url":null,"abstract":"<p><strong>Objective: </strong>Dyspnea, or breathlessness, is an important symptom in amyotrophic lateral sclerosis/motor neuron disease (ALS/MND). We examined the measurement properties of the Dyspnea-12.</p><p><strong>Methods: </strong>Rasch analysis enabled conversion of raw Dyspnea-12 scores to interval level metric equivalents. Converted data were used to perform trajectory modeling; those following different trajectories were compared for demographic, clinical, symptom, and functioning characteristics. Logistic regression examined differences between distinct trajectories.</p><p><strong>Results: </strong>In 1022 people, at baseline, mean metric Dyspnea-12 was 7.6 (SD 9.3). 49.8% had dyspnea, severe in 12.6%. Trajectory analysis over 28 months revealed three breathlessness trajectories: group 1 reported none at baseline/follow-up (42.7%); group 2 significantly increased over time (9.4%); group 3 had a much higher level at baseline which rose over follow-up (47.9%). Group 3 had worse outcomes on all symptoms, functioning and quality of life; compared to group 1, their odds of: respiratory onset sixfold greater; King's stage ≥3 2.9 greater; increased odds of being bothered by choking, head drop, fasciculations, and muscle cramps; fatigue and anxiety also elevated (<i>p</i> < .01).</p><p><strong>Conclusion: </strong>Dyspnea is a cardinal symptom in ALS/MND and can be quickly measured using the Dyspnea-12. Raw scores can easily be converted to interval level measurement, for valid change scores and trajectory modeling. Dyspnea trajectories reveal different patterns, showing that clinical services must provide monitoring which is customized to individual patient need. Almost half of this large population had worsening dyspnea, confirming the importance of respiratory monitoring and interventions being integrated into routine ALS care.</p>","PeriodicalId":72184,"journal":{"name":"Amyotrophic lateral sclerosis & frontotemporal degeneration","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11286210/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140095278","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-01Epub Date: 2024-03-07DOI: 10.1080/21678421.2024.2324896
Saileyee Roychowdhury, Deepika Joshi, Vinay Kumar Singh, Mohammed Faruq, Parimal Das
Background: Amyotrophic lateral sclerosis (ALS) is an old onset devastating neurodegenerative disorder. Young-onset ALS cases especially sporadic ones who are between 25 and 45 years are rarely affected by the disease. Despite the identification of numerous candidate genes associated with ALS, the etiology of the disease remains elusive due to extreme genetic and phenotypic variability. The advent of affordable whole exome sequencing (WES) has opened new avenues for unraveling the disease's pathophysiology better.
Methods and results: We aimed to determine the genetic basis of an Indian-origin, young onset sporadic ALS patient with very rapid deterioration of the disease course without any cognitive decline who was screened for mutations in major ALS candidate genes by WES. Variants detected were reconfirmed by Sanger sequencing. The clinicopathological features were investigated and two heterozygous missense variants were identified: R452W, not previously associated with ALS, present in one of the four conserved C terminal domains in ANXA11 and R208W in SIGMAR1, respectively. Both of these variants were predicted to be damaging by pathogenicity prediction tools and various in silico methods.
Conclusion: Our study revealed two potentially pathogenic variants in two ALS candidate genes. The genetic makeup of ALS patients from India has been the subject of a few prior studies, but none of them examined ANXA11 and SIGMAR1 genes so far. These results establish the framework for additional research into the pathogenic processes behind these variations that result in sporadic ALS disease and further our understanding of the genetic makeup of Indian ALS patients.
背景:肌萎缩性脊髓侧索硬化症(ALS肌萎缩性脊髓侧索硬化症(ALS)是一种古老的破坏性神经退行性疾病。年轻的 ALS 患者,尤其是 25 至 45 岁之间的散发性患者很少患病。尽管发现了许多与 ALS 相关的候选基因,但由于遗传和表型变异极大,该病的病因仍然难以捉摸。价格低廉的全外显子组测序(WES)的出现为更好地揭示该病的病理生理学开辟了新的途径。方法和结果:我们的目的是确定一名印度裔年轻偶发性 ALS 患者的遗传基础,该患者的病程迅速恶化,但无任何认知能力下降,我们通过 WES 对其主要 ALS 候选基因进行了突变筛查。通过桑格测序再次确认了检测到的变异。对患者的临床病理特征进行了调查,发现了两个杂合错义变异:R452W 以前与 ALS 无关,分别出现在 ANXA11 的四个保守 C 端结构域之一和 SIGMAR1 的 R208W 中。致病性预测工具和各种硅学方法都预测这两个变异具有损伤性。结论我们的研究发现了两个 ALS 候选基因中的两个潜在致病变异。印度 ALS 患者的基因构成是之前几项研究的主题,但迄今为止还没有研究 ANXA11 和 SIGMAR1 基因。这些结果为进一步研究导致散发性 ALS 疾病的这些变异背后的致病过程建立了框架,并进一步加深了我们对印度 ALS 患者基因构成的了解。
{"title":"Genetic and <i>in silico</i> analysis of Indian sporadic young onset patient with amyotrophic lateral sclerosis.","authors":"Saileyee Roychowdhury, Deepika Joshi, Vinay Kumar Singh, Mohammed Faruq, Parimal Das","doi":"10.1080/21678421.2024.2324896","DOIUrl":"10.1080/21678421.2024.2324896","url":null,"abstract":"<p><strong>Background: </strong>Amyotrophic lateral sclerosis (ALS) is an old onset devastating neurodegenerative disorder. Young-onset ALS cases especially sporadic ones who are between 25 and 45 years are rarely affected by the disease. Despite the identification of numerous candidate genes associated with ALS, the etiology of the disease remains elusive due to extreme genetic and phenotypic variability. The advent of affordable whole exome sequencing (WES) has opened new avenues for unraveling the disease's pathophysiology better.</p><p><strong>Methods and results: </strong>We aimed to determine the genetic basis of an Indian-origin, young onset sporadic ALS patient with very rapid deterioration of the disease course without any cognitive decline who was screened for mutations in major ALS candidate genes by WES. Variants detected were reconfirmed by Sanger sequencing. The clinicopathological features were investigated and two heterozygous missense variants were identified: R452W, not previously associated with ALS, present in one of the four conserved C terminal domains in <i>ANXA11 and</i> R208W in <i>SIGMAR1</i>, respectively. Both of these variants were predicted to be damaging by pathogenicity prediction tools and various <i>in silico</i> methods.</p><p><strong>Conclusion: </strong>Our study revealed two potentially pathogenic variants in two ALS candidate genes. The genetic makeup of ALS patients from India has been the subject of a few prior studies, but none of them examined <i>ANXA11</i> and <i>SIGMAR1</i> genes so far. These results establish the framework for additional research into the pathogenic processes behind these variations that result in sporadic ALS disease and further our understanding of the genetic makeup of Indian ALS patients.</p>","PeriodicalId":72184,"journal":{"name":"Amyotrophic lateral sclerosis & frontotemporal degeneration","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140051230","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-01Epub Date: 2024-03-19DOI: 10.1080/21678421.2024.2322549
M Kelley Erb, Narghes Calcagno, Roland Brown, Katherine M Burke, Zoe A Scheier, Amrita S Iyer, Alison Clark, Max P Higgins, Mackenzie Keegan, Anoopum S Gupta, Stephen A Johnson, Sheena Chew, James D Berry
Objective: Test the feasibility, adherence rates and optimal frequency of digital, remote assessments using the ALSFRS-RSE via a customized smartphone-based app.
Methods: This fully remote, longitudinal study was conducted over a 24-week period, with virtual visits every 3 months and weekly digital assessments. 19 ALS participants completed digital assessments via smartphone, including a digital version of the ALSFRS-RSE and mood survey. Interclass correlation coefficients (ICC) and Bland-Altman plots were used to assess agreement between staff-administered and self-reported ALSFRS-R pairs. Longitudinal change was evaluated using ANCOVA models and linear mixed models, including impact of mood and time of day. Impact of frequency of administration of the ALSFRS-RSE on precision of the estimate slope was tested using a mixed effects model.
Results: In our ALS cohort, digital assessments were well-accepted and adherence was robust, with completion rates of 86%. There was excellent agreement between the digital self-entry and staff-administered scores computing multiple ICCs (ICC range = 0.925-0.961), with scores on the ALSFRS-RSE slightly higher (1.304 points). Digital assessments were associated with increased precision of the slope, resulting in higher standardized response mean estimates for higher frequencies, though benefit appeared to diminish at biweekly and weekly frequency. Effects of participant mood and time of day on total ALSFRS-RSE score were evaluated but were minimal and not statistically significant.
Conclusion: Remote collection of digital patient-reported outcomes of functional status such as the ALSFRS-RSE yield more accurate estimates of change over time and provide a broader understanding of the lived experience of people with ALS.
{"title":"Longitudinal comparison of the self-administered ALSFRS-RSE and ALSFRS-R as functional outcome measures in ALS.","authors":"M Kelley Erb, Narghes Calcagno, Roland Brown, Katherine M Burke, Zoe A Scheier, Amrita S Iyer, Alison Clark, Max P Higgins, Mackenzie Keegan, Anoopum S Gupta, Stephen A Johnson, Sheena Chew, James D Berry","doi":"10.1080/21678421.2024.2322549","DOIUrl":"10.1080/21678421.2024.2322549","url":null,"abstract":"<p><strong>Objective: </strong>Test the feasibility, adherence rates and optimal frequency of digital, remote assessments using the ALSFRS-RSE via a customized smartphone-based app.</p><p><strong>Methods: </strong>This fully remote, longitudinal study was conducted over a 24-week period, with virtual visits every 3 months and weekly digital assessments. 19 ALS participants completed digital assessments via smartphone, including a digital version of the ALSFRS-RSE and mood survey. Interclass correlation coefficients (ICC) and Bland-Altman plots were used to assess agreement between staff-administered and self-reported ALSFRS-R pairs. Longitudinal change was evaluated using ANCOVA models and linear mixed models, including impact of mood and time of day. Impact of frequency of administration of the ALSFRS-RSE on precision of the estimate slope was tested using a mixed effects model.</p><p><strong>Results: </strong>In our ALS cohort, digital assessments were well-accepted and adherence was robust, with completion rates of 86%. There was excellent agreement between the digital self-entry and staff-administered scores computing multiple ICCs (ICC range = 0.925-0.961), with scores on the ALSFRS-RSE slightly higher (1.304 points). Digital assessments were associated with increased precision of the slope, resulting in higher standardized response mean estimates for higher frequencies, though benefit appeared to diminish at biweekly and weekly frequency. Effects of participant mood and time of day on total ALSFRS-RSE score were evaluated but were minimal and not statistically significant.</p><p><strong>Conclusion: </strong>Remote collection of digital patient-reported outcomes of functional status such as the ALSFRS-RSE yield more accurate estimates of change over time and provide a broader understanding of the lived experience of people with ALS.</p>","PeriodicalId":72184,"journal":{"name":"Amyotrophic lateral sclerosis & frontotemporal degeneration","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140159625","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-01Epub Date: 2024-05-14DOI: 10.1080/21678421.2024.2351177
Victoria K Shephard, Mikayla L Brown, Bryony A Thompson, Alisha Harpur, Luke McAlary
Variants of the oxygen free radical scavenging enzyme superoxide dismutase-1 (SOD1) are associated with the neurodegenerative disease amyotrophic lateral sclerosis (ALS). These variants occur in roughly 20% of familial ALS cases, and 1% of sporadic ALS cases. Here, we identified a novel SOD1 variant in a patient in their 50s who presented with movement deficiencies and neuropsychiatric features. The variant was heterozygous and resulted in the isoleucine at position 149 being substituted with a serine (I149S). In silico analysis predicted the variant to be destabilizing to the SOD1 protein structure. Expression of the SOD1I149S variant with a C-terminal EGFP tag in neuronal-like NSC-34 cells resulted in extensive inclusion formation and reduced cell viability. Immunoblotting revealed that the intramolecular disulphide between Cys57 and Cys146 was fully reduced for SOD1I149S. Furthermore, SOD1I149S was highly susceptible to proteolytic digestion, suggesting a large degree of instability to the protein fold. Finally, fluorescence correlation spectroscopy and native-PAGE of cell lysates showed that SOD1I149S was monomeric in solution in comparison to the dimeric SOD1WT. This experimental data was obtained within 3 months and resulted in the rapid re-classification of the variant from a variant of unknown significance (VUS) to a clinically actionable likely pathogenic variant.
{"title":"Rapid classification of a novel ALS-causing I149S variant in superoxide dismutase-1.","authors":"Victoria K Shephard, Mikayla L Brown, Bryony A Thompson, Alisha Harpur, Luke McAlary","doi":"10.1080/21678421.2024.2351177","DOIUrl":"10.1080/21678421.2024.2351177","url":null,"abstract":"<p><p>Variants of the oxygen free radical scavenging enzyme superoxide dismutase-1 (SOD1) are associated with the neurodegenerative disease amyotrophic lateral sclerosis (ALS). These variants occur in roughly 20% of familial ALS cases, and 1% of sporadic ALS cases. Here, we identified a novel SOD1 variant in a patient in their 50s who presented with movement deficiencies and neuropsychiatric features. The variant was heterozygous and resulted in the isoleucine at position 149 being substituted with a serine (I149S). <i>In silico</i> analysis predicted the variant to be destabilizing to the SOD1 protein structure. Expression of the SOD1<sup>I149S</sup> variant with a C-terminal EGFP tag in neuronal-like NSC-34 cells resulted in extensive inclusion formation and reduced cell viability. Immunoblotting revealed that the intramolecular disulphide between Cys57 and Cys146 was fully reduced for SOD1<sup>I149S</sup>. Furthermore, SOD1<sup>I149S</sup> was highly susceptible to proteolytic digestion, suggesting a large degree of instability to the protein fold. Finally, fluorescence correlation spectroscopy and native-PAGE of cell lysates showed that SOD1<sup>I149S</sup> was monomeric in solution in comparison to the dimeric SOD1<sup>WT</sup>. This experimental data was obtained within 3 months and resulted in the rapid re-classification of the variant from a variant of unknown significance (VUS) to a clinically actionable likely pathogenic variant.</p>","PeriodicalId":72184,"journal":{"name":"Amyotrophic lateral sclerosis & frontotemporal degeneration","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140923547","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-01Epub Date: 2024-05-15DOI: 10.1080/21678421.2024.2349924
T Katangwe-Chigamba, E Flanagan, E Mioshi
Objective: MiNDToolkit is a novel psychoeducational intervention for carers to support management of behavioral symptoms in people living with motor neuron disease (PlwMND). Implementation of MiNDToolkit involves delivery of an online intervention to carers, which is reinforced by trained healthcare professionals (HCPs).
Methods: A mixed-methods process evaluation of the MiNDToolkit feasibility trial was conducted, focusing on reinforcement of the intervention by HCPs. Quantitative data, descriptively analyzed, were included from platform analytics, questionnaire, and 10 semi-structured interviews with HCPs. Interviews were transcribed verbatim; data were inductively analyzed using Reflective Thematic Analysis.
Results: The MiNDToolkit training and platform is a beneficial and acceptable resource for HCPs with potential to increase knowledge and confidence in identifying and managing behavioral symptoms in MND. Implementation barriers included HCPs' perceptions that highlighting behavior changes would be burdensome to carers and assumptions that carers would take the initiative to ask for support from clinicians. Degree of intervention reinforcement varied, with most HCPs delegating intervention delivery solely to the online platform.
Conclusions: Implementation of the MiNDToolkit was viewed to be feasible and the platform thought to increase accessibility of support to carers. The flexible approach to delivery (online platform and optional HCP reinforcement) is acceptable as an intervention for supporting carers of PlwMND with behavioral symptoms. However, MiNDToolkit should not negate HCP involvement in providing medical and practical information to PlwMND and families. Future research should explore ways to incorporate support for carers in the management of PlwMND alongside standard care, alongside tools such as the MiNDToolkit.
{"title":"Implementation of the MiNDToolkit intervention for the management of behavioral symptoms in MND by healthcare professionals: a mixed-methods process evaluation.","authors":"T Katangwe-Chigamba, E Flanagan, E Mioshi","doi":"10.1080/21678421.2024.2349924","DOIUrl":"10.1080/21678421.2024.2349924","url":null,"abstract":"<p><strong>Objective: </strong>MiNDToolkit is a novel psychoeducational intervention for carers to support management of behavioral symptoms in people living with motor neuron disease (PlwMND). Implementation of MiNDToolkit involves delivery of an online intervention to carers, which is reinforced by trained healthcare professionals (HCPs).</p><p><strong>Methods: </strong>A mixed-methods process evaluation of the MiNDToolkit feasibility trial was conducted, focusing on reinforcement of the intervention by HCPs. Quantitative data, descriptively analyzed, were included from platform analytics, questionnaire, and 10 semi-structured interviews with HCPs. Interviews were transcribed verbatim; data were inductively analyzed using Reflective Thematic Analysis.</p><p><strong>Results: </strong>The MiNDToolkit training and platform is a beneficial and acceptable resource for HCPs with potential to increase knowledge and confidence in identifying and managing behavioral symptoms in MND. Implementation barriers included HCPs' perceptions that highlighting behavior changes would be burdensome to carers and assumptions that carers would take the initiative to ask for support from clinicians. Degree of intervention reinforcement varied, with most HCPs delegating intervention delivery solely to the online platform.</p><p><strong>Conclusions: </strong>Implementation of the MiNDToolkit was viewed to be feasible and the platform thought to increase accessibility of support to carers. The flexible approach to delivery (online platform and optional HCP reinforcement) is acceptable as an intervention for supporting carers of PlwMND with behavioral symptoms. However, MiNDToolkit should not negate HCP involvement in providing medical and practical information to PlwMND and families. Future research should explore ways to incorporate support for carers in the management of PlwMND alongside standard care, alongside tools such as the MiNDToolkit.</p>","PeriodicalId":72184,"journal":{"name":"Amyotrophic lateral sclerosis & frontotemporal degeneration","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11286209/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140923426","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. Abnormalities in the peripheral immune system in ALS have been paid attention; however, the results of changes in peripheral immune parameters were inconsistent.
Methods: A total of 1109 ALS patients were enrolled in the study. All patients received clinical evaluation and peripheral immune parameters measurement. The outcomes were analyzed by correlation analysis, multiple linear regression and cox survival analysis.
Results: We found that ALS patients had significantly higher percentage of CD4+ T cells (39.3 vs. 37.1%, p < 0.001) and CD4+/CD8+ ratio (1.88 vs. 1.72, p = 0.011), significantly lower IgG (11.73 vs.12.82, p < 0.001) and IgA (2130.70 vs. 2284.8, p = 0.013) compared with the health controls. In the multivariate linear model, we found that each increase of 1.262, 0.278, and 4.44E-4 in ALSFRS-R scores were significantly associated with each increment of lymphocyte count, IgG, and IgA, respectively. However, each decrease of 0.341, 0.068, and 0.682 in ALSFRS-R score was associated with each increment in neutrophils, CD4+ T cells, and CD4+/CD8+ ratio, respectively. Cox survival regression analysis showed that the death risk of ALS patients was related to the levels of C3 (HR 0.592, 95% CI 0.361-0.973).
Conclusion: We found that there were differences in peripheral immune parameters of ALS patients with the severity of the disease, especially neutrophil, lymphocyte, CD4+ T, and IgG; C3 is an independent predictor of survival in ALS patients. More studies are needed to elucidate the mechanisms associated with altered immune parameters in ALS.
背景:肌萎缩性脊髓侧索硬化症(ALS肌萎缩性脊髓侧索硬化症(ALS)是一种致命的神经退行性疾病。ALS 患者外周免疫系统的异常已引起人们的重视,但有关外周免疫参数变化的研究结果并不一致。研究方法共有 1109 名 ALS 患者参与研究。所有患者均接受了临床评估和外周免疫参数测量。研究结果通过相关分析、多元线性回归和 cox 生存分析进行分析。结果:我们发现,ALS 患者的 CD4+ T 细胞比例(39.3 对 37.1%,p +/CD8+ 比值(1.88 对 1.72,p = 0.011))明显较高,IgG(11.73 对 12.82,p + T 细胞)和 CD4+/CD8+ 比值(1.88 对 1.72,p = 0.011)明显较低。Cox 生存回归分析显示,ALS 患者的死亡风险与 C3 水平有关(HR 0.592,95% CI 0.361-0.973)。结论我们发现,ALS 患者的外周免疫指标随病情严重程度存在差异,尤其是中性粒细胞、淋巴细胞、CD4+ T 和 IgG;C3 是 ALS 患者生存的独立预测因子。还需要更多的研究来阐明 ALS 免疫参数改变的相关机制。
{"title":"Peripheral immunity relate to disease progression and prognosis in amyotrophic lateral sclerosis.","authors":"Qirui Jiang, Qianqian Wei, Lingyu Zhang, Tianmi Yang, Junyu Lin, Yi Xiao, Chunyu Li, Yanbing Hou, Ruwei Ou, Kuncheng Liu, Bi Zhao, Ying Wu, Xiaohui Lai, Huifang Shang","doi":"10.1080/21678421.2024.2306969","DOIUrl":"10.1080/21678421.2024.2306969","url":null,"abstract":"<p><strong>Background: </strong>Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. Abnormalities in the peripheral immune system in ALS have been paid attention; however, the results of changes in peripheral immune parameters were inconsistent.</p><p><strong>Methods: </strong>A total of 1109 ALS patients were enrolled in the study. All patients received clinical evaluation and peripheral immune parameters measurement. The outcomes were analyzed by correlation analysis, multiple linear regression and cox survival analysis.</p><p><strong>Results: </strong>We found that ALS patients had significantly higher percentage of CD4<sup>+</sup> T cells (39.3 vs. 37.1%, p < 0.001) and CD4<sup>+</sup>/CD8<sup>+</sup> ratio (1.88 vs. 1.72, p = 0.011), significantly lower IgG (11.73 vs.12.82, p < 0.001) and IgA (2130.70 vs. 2284.8, p = 0.013) compared with the health controls. In the multivariate linear model, we found that each increase of 1.262, 0.278, and 4.44E-4 in ALSFRS-R scores were significantly associated with each increment of lymphocyte count, IgG, and IgA, respectively. However, each decrease of 0.341, 0.068, and 0.682 in ALSFRS-R score was associated with each increment in neutrophils, CD4<sup>+</sup> T cells, and CD4<sup>+</sup>/CD8<sup>+</sup> ratio, respectively. Cox survival regression analysis showed that the death risk of ALS patients was related to the levels of C3 (HR 0.592, 95% CI 0.361-0.973).</p><p><strong>Conclusion: </strong>We found that there were differences in peripheral immune parameters of ALS patients with the severity of the disease, especially neutrophil, lymphocyte, CD4<sup>+</sup> T, and IgG; C3 is an independent predictor of survival in ALS patients. More studies are needed to elucidate the mechanisms associated with altered immune parameters in ALS.</p>","PeriodicalId":72184,"journal":{"name":"Amyotrophic lateral sclerosis & frontotemporal degeneration","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139545551","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-01Epub Date: 2024-05-10DOI: 10.1080/21678421.2024.2348636
Lyndal Henden, Liam G Fearnley, Dean Southwood, Andrew Smith, Dominic B Rowe, Matthew C Kiernan, Roger Pamphlett, Melanie Bahlo, Ian P Blair, Kelly L Williams
In patients of Asian ancestry, a heterozygous CGG repeat expansion of >100 units in LRP12 is the cause of oculopharyngodistal myopathy type 1 (OPDM1). Repeat lengths of between 61 and 100 units have been associated with rare amyotrophic lateral sclerosis (ALS) cases of Asian ancestry, although with unusually long disease duration and without significant upper motor neuron involvement. This study sought to determine whether LRP12 CGG repeat expansions were also present in ALS patients of European ancestry. Whole-genome sequencing data from 608 sporadic ALS patients, 35 familial ALS probands, and 4703 neurologically normal controls were screened for LRP12 CGG expansions using ExpansionHunter v4. All individuals had LRP12 CGG repeat lengths within the normal range of 3-25 units. To date, LRP12 CGG repeat expansions have not been reported in ALS patients of European ancestry and may be limited to rare ALS patients of Asian ancestry and atypical clinical presentations.
在亚洲血统的患者中,LRP12 中大于 100 个单位的杂合 CGG 重复扩增是 1 型眼咽喉肌病(OPDM1)的病因。亚洲血统的罕见肌萎缩性脊髓侧索硬化症(ALS)病例中,重复长度在 61 到 100 个单位之间,但病程异常长,且没有明显的上运动神经元受累。本研究试图确定欧洲血统的 ALS 患者中是否也存在 LRP12 CGG 重复扩增。研究人员使用 ExpansionHunter v4 对 608 名散发性 ALS 患者、35 名家族性 ALS 疑似患者和 4703 名神经正常对照者的全基因组测序数据进行了 LRP12 CGG 扩增筛选。所有个体的 LRP12 CGG 重复长度都在 3-25 个单位的正常范围内。迄今为止,在欧洲血统的 ALS 患者中还没有发现 LRP12 CGG 重复序列扩展的报道,可能仅限于罕见的亚洲血统 ALS 患者和非典型临床表现。
{"title":"Short tandem repeat expansions in <i>LRP12</i> are absent in cohorts of familial and sporadic amyotrophic lateral sclerosis patients of European ancestry.","authors":"Lyndal Henden, Liam G Fearnley, Dean Southwood, Andrew Smith, Dominic B Rowe, Matthew C Kiernan, Roger Pamphlett, Melanie Bahlo, Ian P Blair, Kelly L Williams","doi":"10.1080/21678421.2024.2348636","DOIUrl":"10.1080/21678421.2024.2348636","url":null,"abstract":"<p><p>In patients of Asian ancestry, a heterozygous CGG repeat expansion of >100 units in <i>LRP12</i> is the cause of oculopharyngodistal myopathy type 1 (OPDM1). Repeat lengths of between 61 and 100 units have been associated with rare amyotrophic lateral sclerosis (ALS) cases of Asian ancestry, although with unusually long disease duration and without significant upper motor neuron involvement. This study sought to determine whether <i>LRP12</i> CGG repeat expansions were also present in ALS patients of European ancestry. Whole-genome sequencing data from 608 sporadic ALS patients, 35 familial ALS probands, and 4703 neurologically normal controls were screened for <i>LRP12</i> CGG expansions using ExpansionHunter v4. All individuals had <i>LRP12</i> CGG repeat lengths within the normal range of 3-25 units. To date, <i>LRP12</i> CGG repeat expansions have not been reported in ALS patients of European ancestry and may be limited to rare ALS patients of Asian ancestry and atypical clinical presentations.</p>","PeriodicalId":72184,"journal":{"name":"Amyotrophic lateral sclerosis & frontotemporal degeneration","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140900590","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-01Epub Date: 2024-02-14DOI: 10.1080/21678421.2024.2315185
Alexander A Hart, Andrea Swenson, Nandakumar S Narayanan, Jacob E Simmering
Objective: We utilized national claims-based data to identify the change in odds of diagnosis of ALS following possible-ALS-symptoms-and whether the change varies in urban/rural areas.
Methods: Insurance claims were obtained from the Merative MarketScan databases, 2001-2021 in the United States. Individuals with incident ALS were identified and matched on age, sex, and enrollment period to individuals without ALS. For all individuals, claims for 8 possible-ALS-symptoms in the time before any ALS diagnosis were identified. We then used conditional logistic regression to estimate the odds of being diagnosed with ALS following these symptoms and whether the association varied by urban/rural location.
Results: 19,226 individuals with ALS were matched to 96,126 controls. Patients with ALS were more likely to live in an urban area (87.0% vs 84.5%). Of those with ALS 84% had 1+ of our 8 possible-ALS-symptom compared to 51% of controls. After adjustment for confounders, having possible-ALS-symptoms increased the odds of a future ALS diagnosis by nearly 5-fold. A dose-response pattern was present with increasing odds as the number of symptoms increased. In all models, urban areas were associated with increased odds of diagnosis with ALS while the effect of having a symptom was smaller in urban places. Urban cases of ALS are diagnosed at younger ages.
Conclusions: These results suggest symptoms may appear and be noted years before the diagnosis of ALS. Additionally, rural patients are diagnosed at later ages with a greater dependence on symptoms than urban patients. These results highlight potential improvements for screening for ALS.
目的我们利用基于索赔的全国性数据来确定在可能出现 ALS 症状后确诊 ALS 的几率变化,以及这种变化在城市/农村地区是否存在差异:保险理赔数据来自美国 Merative MarketScan 数据库(2001-2021 年)。确定了 ALS 患者,并根据年龄、性别和投保时间将其与非 ALS 患者进行匹配。对于所有患者,我们确定了他们在确诊 ALS 之前的 8 种可能的 ALS 症状。然后,我们使用条件逻辑回归法估算了出现这些症状后被诊断为 ALS 的几率,以及这种关联是否因城市/农村地区而异:19,226 名 ALS 患者与 96,126 名对照者进行了配对。ALS 患者更有可能居住在城市地区(87.0% 对 84.5%)。在 ALS 患者中,84% 的人有 8 种可能的 ALS 症状中的 1 种以上,而对照组中只有 51%。在对混杂因素进行调整后,具有可能的 ALS 症状会使将来被诊断为 ALS 的几率增加近 5 倍。随着症状数量的增加,几率也随之增加。在所有模型中,城市地区与 ALS 诊断几率增加有关,而在城市地区,有症状的影响较小。城市地区的 ALS 诊断年龄更小:这些结果表明,症状可能会在 ALS 诊断前数年出现并被注意到。此外,与城市患者相比,农村患者的诊断年龄更晚,对症状的依赖性更大。这些结果凸显了对 ALS 筛查的潜在改进。
{"title":"Rurality modifies the association between symptoms and the diagnosis of amyotrophic lateral sclerosis.","authors":"Alexander A Hart, Andrea Swenson, Nandakumar S Narayanan, Jacob E Simmering","doi":"10.1080/21678421.2024.2315185","DOIUrl":"10.1080/21678421.2024.2315185","url":null,"abstract":"<p><strong>Objective: </strong>We utilized national claims-based data to identify the change in odds of diagnosis of ALS following possible-ALS-symptoms-and whether the change varies in urban/rural areas.</p><p><strong>Methods: </strong>Insurance claims were obtained from the Merative MarketScan databases, 2001-2021 in the United States. Individuals with incident ALS were identified and matched on age, sex, and enrollment period to individuals without ALS. For all individuals, claims for 8 possible-ALS-symptoms in the time before any ALS diagnosis were identified. We then used conditional logistic regression to estimate the odds of being diagnosed with ALS following these symptoms and whether the association varied by urban/rural location.</p><p><strong>Results: </strong>19,226 individuals with ALS were matched to 96,126 controls. Patients with ALS were more likely to live in an urban area (87.0% vs 84.5%). Of those with ALS 84% had 1+ of our 8 possible-ALS-symptom compared to 51% of controls. After adjustment for confounders, having possible-ALS-symptoms increased the odds of a future ALS diagnosis by nearly 5-fold. A dose-response pattern was present with increasing odds as the number of symptoms increased. In all models, urban areas were associated with increased odds of diagnosis with ALS while the effect of having a symptom was smaller in urban places. Urban cases of ALS are diagnosed at younger ages.</p><p><strong>Conclusions: </strong>These results suggest symptoms may appear and be noted years before the diagnosis of ALS. Additionally, rural patients are diagnosed at later ages with a greater dependence on symptoms than urban patients. These results highlight potential improvements for screening for ALS.</p>","PeriodicalId":72184,"journal":{"name":"Amyotrophic lateral sclerosis & frontotemporal degeneration","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139731161","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}