Pub Date : 2024-07-08DOI: 10.1080/21678421.2024.2376732
Omer Berkman, Eitan Raveh, Eran Harpaz, Rivka Kreitman, Edmund Ben-Ami, Elisheva Nechushtan, Nurit Birman, Vivian E Drory
Objective: Saccadic Intrusions (SIs) are abnormal eye movements during gaze fixation. Studies have indicated the clinical relevance of SIs, especially of square wave jerks (SWJ) in ALS. We used a software-based platform to extract SIs as a part of an interventional drug trial. The objective was to examine SIs' change over time as a potential biomarker of ALS disease progression. Methods: 28 ALS patients (61.95 ± 8.6 years) were assessed with the revised ALS Functional Rating Scale (ALSFRS-R) and with an oculometric test. Changes of SIs over time and correlations with ALSFRS-R and its bulbar subscale were calculated. A power calculation was conducted to understand the practical implications of results. Results: A significant increase of SWJ over trial duration was observed, with an increase in frequency (mean rise of 0.14 ± 0.28, p < 0.01), amplitude (0.001 ± 0.0016 degrees, p < 0.005), overall duration of SWJ (0.13 ± 0.25, in %, p < 0.01), and in their relative part out of all intrusions (0.18 ± 0.32, in %, p < 0.005). Negative correlations were found with the bulbar subscale (R=-0.43, -0.41, -0.39 and -0.47, respectively, p < 0.001). The required sample size for observing a 40% reduction in bulbar aspects when using the oculometric test (α = 0.05 and β = 0.8), was found to be 150 patients per arm, compared with 200 patients using the bulbar subscale. Conclusions: Evaluation of saccadic intrusions during fixation was able to detect disease progression over time, correlated with ALSFRS-R bulbar subscale. Eye movements can potentially serve as an objective biomarker in ALS clinical trials and reduce the required sample size to show clinical effect of therapies.
目的眼球内斜视(SIs)是凝视固定过程中的异常眼球运动。研究表明,SIs 具有临床相关性,尤其是在 ALS 中的方波抽动(SWJ)。我们使用基于软件的平台提取 SIs,作为干预药物试验的一部分。目的是研究 SIs 随时间的变化,以此作为 ALS 疾病进展的潜在生物标志物。方法:对 28 名 ALS 患者(61.95 ± 8.6 岁)进行了 ALS 功能评定量表(ALSFRS-R)修订版和视力测试评估。计算了 SI 随时间的变化以及与 ALSFRS-R 及其球部分量表的相关性。进行了功率计算,以了解结果的实际意义。结果:观察发现,随着试验时间的延长,SWJ 明显增加,频率也有所增加(平均上升 0.14 ± 0.28,p 结论:SWJ 与 ALSFRS-R 及其球状分量表之间的相关性较低:对固定过程中的囊回侵入进行评估能够检测出疾病随时间的进展,并与 ALSFRS-R 球部分量表相关。眼球运动有可能成为 ALS 临床试验中的客观生物标记物,并减少显示疗法临床效果所需的样本量。
{"title":"Changes in saccadic intrusions over time as an objective biomarker to follow ALS disease progression.","authors":"Omer Berkman, Eitan Raveh, Eran Harpaz, Rivka Kreitman, Edmund Ben-Ami, Elisheva Nechushtan, Nurit Birman, Vivian E Drory","doi":"10.1080/21678421.2024.2376732","DOIUrl":"https://doi.org/10.1080/21678421.2024.2376732","url":null,"abstract":"<p><p><i>Objective</i>: Saccadic Intrusions (SIs) are abnormal eye movements during gaze fixation. Studies have indicated the clinical relevance of SIs, especially of square wave jerks (SWJ) in ALS. We used a software-based platform to extract SIs as a part of an interventional drug trial. The objective was to examine SIs' change over time as a potential biomarker of ALS disease progression. <i>Methods</i>: 28 ALS patients (61.95 ± 8.6 years) were assessed with the revised ALS Functional Rating Scale (ALSFRS-R) and with an oculometric test. Changes of SIs over time and correlations with ALSFRS-R and its bulbar subscale were calculated. A power calculation was conducted to understand the practical implications of results. <i>Results</i>: A significant increase of SWJ over trial duration was observed, with an increase in frequency (mean rise of 0.14 ± 0.28, p < 0.01), amplitude (0.001 ± 0.0016 degrees, p < 0.005), overall duration of SWJ (0.13 ± 0.25, in %, p < 0.01), and in their relative part out of all intrusions (0.18 ± 0.32, in %, p < 0.005). Negative correlations were found with the bulbar subscale (R=-0.43, -0.41, -0.39 and -0.47, respectively, p < 0.001). The required sample size for observing a 40% reduction in bulbar aspects when using the oculometric test (α = 0.05 and β = 0.8), was found to be 150 patients per arm, compared with 200 patients using the bulbar subscale. <i>Conclusions</i>: Evaluation of saccadic intrusions during fixation was able to detect disease progression over time, correlated with ALSFRS-R bulbar subscale. Eye movements can potentially serve as an objective biomarker in ALS clinical trials and reduce the required sample size to show clinical effect of therapies.</p>","PeriodicalId":72184,"journal":{"name":"Amyotrophic lateral sclerosis & frontotemporal degeneration","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141556075","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 : 2024-07-07DOI: 10.1080/21678421.2024.2375330
Philippe Corcia, Nathalie Guy, Pierre-François Pradat, Marie-Helene Soriani, Annie Verschueren, Philippe Couratier
Amyotrophic lateral sclerosis (ALS) is a rare multisystem neurodegenerative disease leading to death due to respiratory failure. Riluzole was the first disease modifying treatment approved in ALS. Randomized clinical trials showed a significant benefit of riluzole on survival in the months following randomization, with a good safety profile. 'Real-world' studies suggested that the survival benefit of riluzole is substantially greater, with an extended survival ranging between 6 and 19 months. The main limiting associated adverse effects of riluzole are non-severe gastrointestinal complications and an elevation of liver enzymes, observed in 10% of patients. While different classes of drugs have been approved in some countries, riluzole remains the gold standard of therapy. Dysphagia induced by ALS is a major challenge for food intake and riluzole administration. Tablet crushing is associated with a loss of drug intake and a risk of powder aspiration, which jeopardizes the benefits of riluzole. Riluzole oral suspension (ROS) and oral film (ROF) allow riluzole intake in patients with dysphagia. Both formulations are bioequivalent to riluzole tablets with a good safety profile albeit transient oral hypoaesthesia. In case of severe dysphagia, ROS can be used with percutaneous endoscopic gastrostomy. ROF, the last approved formulation, requires low swallowing capacities and may contribute to maintain the efficacy of riluzole when tablets are inadequate according to patient's status and/or preferences. To optimize treatment continuity in newly diagnosed patients, the expected psychological impact of formulation switching that may be perceived as the sign of disease progression should be anticipated.
{"title":"Treatment continuity of amyotrophic lateral sclerosis with available riluzole formulations: state of the art and current challenges in a 'real-world' setting.","authors":"Philippe Corcia, Nathalie Guy, Pierre-François Pradat, Marie-Helene Soriani, Annie Verschueren, Philippe Couratier","doi":"10.1080/21678421.2024.2375330","DOIUrl":"10.1080/21678421.2024.2375330","url":null,"abstract":"<p><p>Amyotrophic lateral sclerosis (ALS) is a rare multisystem neurodegenerative disease leading to death due to respiratory failure. Riluzole was the first disease modifying treatment approved in ALS. Randomized clinical trials showed a significant benefit of riluzole on survival in the months following randomization, with a good safety profile. 'Real-world' studies suggested that the survival benefit of riluzole is substantially greater, with an extended survival ranging between 6 and 19 months. The main limiting associated adverse effects of riluzole are non-severe gastrointestinal complications and an elevation of liver enzymes, observed in 10% of patients. While different classes of drugs have been approved in some countries, riluzole remains the gold standard of therapy. Dysphagia induced by ALS is a major challenge for food intake and riluzole administration. Tablet crushing is associated with a loss of drug intake and a risk of powder aspiration, which jeopardizes the benefits of riluzole. Riluzole oral suspension (ROS) and oral film (ROF) allow riluzole intake in patients with dysphagia. Both formulations are bioequivalent to riluzole tablets with a good safety profile albeit transient oral hypoaesthesia. In case of severe dysphagia, ROS can be used with percutaneous endoscopic gastrostomy. ROF, the last approved formulation, requires low swallowing capacities and may contribute to maintain the efficacy of riluzole when tablets are inadequate according to patient's status and/or preferences. To optimize treatment continuity in newly diagnosed patients, the expected psychological impact of formulation switching that may be perceived as the sign of disease progression should be anticipated.</p>","PeriodicalId":72184,"journal":{"name":"Amyotrophic lateral sclerosis & frontotemporal degeneration","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141556077","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 : 2024-07-04DOI: 10.1080/21678421.2024.2374372
Pedro Lucas Grangeiro de Sá Barreto Lima, Eugenia Machado Couto, Paulo Ribeiro Nóbrega
{"title":"Response letter to: a homozygous p.Val120Leu (c.358G > C) SOD1 mutation led to slowly progressive amyotrophic lateral sclerosis in a Brazilian family.","authors":"Pedro Lucas Grangeiro de Sá Barreto Lima, Eugenia Machado Couto, Paulo Ribeiro Nóbrega","doi":"10.1080/21678421.2024.2374372","DOIUrl":"https://doi.org/10.1080/21678421.2024.2374372","url":null,"abstract":"","PeriodicalId":72184,"journal":{"name":"Amyotrophic lateral sclerosis & frontotemporal degeneration","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141536123","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 : 2024-07-04DOI: 10.1080/21678421.2024.2374382
Keith Pearson, Stephanie Dobak
Objective: To assess current practices of U.S. professionals providing outpatient ALS nutrition care.
Methods: A cross-sectional survey assessing nutrition care practices was distributed in February/March 2023 through electronic mailing lists of relevant professional organizations.
Results: Of the 87 professionals completing the survey, 85.1% were registered dietitians and 50.6% had five or fewer years of experience in ALS care. Many (44.2%) professionals reported receiving no training on the nutrition care of people with ALS (PALS), and 40.2% reported having no other ALS dietitians in their close network. Methods utilized to estimate calorie and protein requirements in PALS varied widely. Although 95.4% of respondents reported that their clinic's dietitian participates in feeding tube discussions, many practitioners may be waiting until ALS symptoms negatively impact PALS' breathing, eating, swallowing, or weight to begin discussing feeding tubes. Additionally, few professionals reported institutional practices conducive for refeeding syndrome prevention or monitoring.
Conclusions: Many professionals providing outpatient nutrition care to PALS possess limited experience, received insufficient training, and are not connected to other ALS dietitians. Specific nutrition care practices, including nutrient need estimation, vary widely among health professionals. Practices surrounding feeding tube discussions and refeeding syndrome may be suboptimal at many institutions. These findings highlight the need for initiatives that educate and connect practitioners providing nutrition care to PALS.
目的评估美国提供 ALS 门诊营养护理的专业人员的当前做法:2023 年 2 月/3 月,通过相关专业组织的电子邮寄名单分发了一份评估营养护理实践的横断面调查:在完成调查的 87 名专业人员中,85.1% 是注册营养师,50.6% 在 ALS 护理方面拥有五年或五年以下的经验。许多专业人士(44.2%)表示没有接受过 ALS 患者(PALS)营养护理方面的培训,40.2%的专业人士表示在他们的密切网络中没有其他 ALS 营养师。用于估算 PALS 卡路里和蛋白质需求量的方法差别很大。尽管 95.4% 的受访者表示他们诊所的营养师参与了喂食管讨论,但许多从业人员可能要等到 ALS 症状对 PALS 的呼吸、进食、吞咽或体重造成负面影响时才开始讨论喂食管。此外,很少有专业人员报告了有利于预防或监测再喂养综合症的机构做法:结论:许多为 PALS 提供门诊营养护理的专业人员经验有限、接受的培训不足,而且没有与其他 ALS 营养师建立联系。具体的营养护理实践,包括营养需求评估,在医疗专业人员之间存在很大差异。在许多机构中,围绕喂食管讨论和再喂食综合症的做法可能并不理想。这些研究结果突出表明,有必要对提供营养护理的从业人员进行教育,并将其与 PALS 联系起来。
{"title":"Current practices in the nutrition management of people with amyotrophic lateral sclerosis (ALS): a survey of U.S. ALS care teams.","authors":"Keith Pearson, Stephanie Dobak","doi":"10.1080/21678421.2024.2374382","DOIUrl":"https://doi.org/10.1080/21678421.2024.2374382","url":null,"abstract":"<p><strong>Objective: </strong>To assess current practices of U.S. professionals providing outpatient ALS nutrition care.</p><p><strong>Methods: </strong>A cross-sectional survey assessing nutrition care practices was distributed in February/March 2023 through electronic mailing lists of relevant professional organizations.</p><p><strong>Results: </strong>Of the 87 professionals completing the survey, 85.1% were registered dietitians and 50.6% had five or fewer years of experience in ALS care. Many (44.2%) professionals reported receiving no training on the nutrition care of people with ALS (PALS), and 40.2% reported having no other ALS dietitians in their close network. Methods utilized to estimate calorie and protein requirements in PALS varied widely. Although 95.4% of respondents reported that their clinic's dietitian participates in feeding tube discussions, many practitioners may be waiting until ALS symptoms negatively impact PALS' breathing, eating, swallowing, or weight to begin discussing feeding tubes. Additionally, few professionals reported institutional practices conducive for refeeding syndrome prevention or monitoring.</p><p><strong>Conclusions: </strong>Many professionals providing outpatient nutrition care to PALS possess limited experience, received insufficient training, and are not connected to other ALS dietitians. Specific nutrition care practices, including nutrient need estimation, vary widely among health professionals. Practices surrounding feeding tube discussions and refeeding syndrome may be suboptimal at many institutions. These findings highlight the need for initiatives that educate and connect practitioners providing nutrition care to PALS.</p>","PeriodicalId":72184,"journal":{"name":"Amyotrophic lateral sclerosis & frontotemporal degeneration","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141499795","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 : 2024-07-04DOI: 10.1080/21678421.2024.2374374
Hiroya Naruse, Chifumi Iseki, Jun Mitsui, Jun Miki, Hikaru Nagasawa, Katsuro Kurokawa, Ryota Kobayashi, Hiroyasu Sato, Jun Goto, Wataru Satake, Hiroyuki Ishiura, Shoji Tsuji, Yasuyuki Ohta, Tatsushi Toda
Loss-of-function (LoF) variants in the TANK binding kinase 1 (TBK1) gene are implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. In this study, we present the first familial cases of ALS and parkinsonism associated with a novel TBK1 variant. We describe two siblings: one diagnosed with classical ALS and the other with a unique syndrome overlapping ALS and parkinsonism. Comprehensive clinical and imaging evaluations supported these diagnoses. Genetic analysis through whole-genome sequencing revealed a previously unknown heterozygous splice site variant in TBK1. Functional assessments demonstrated that this splice site variant leads to abnormal splicing and subsequent degradation of the mutated TBK1 allele by nonsense-mediated decay, confirming its pathogenic impact. Our findings suggest a broader involvement of TBK1 in neurodegenerative diseases and underscore the need for further research into TBK1's role, advocating for screening for TBK1 variants in similar familial cases.
TANK结合激酶1(TBK1)基因的功能缺失(LoF)变异与肌萎缩侧索硬化症(ALS)和额颞叶痴呆症的发病机制有关。在本研究中,我们发现了首例与新型 TBK1 基因变异有关的 ALS 和帕金森氏症家族病例。我们描述了两个兄弟姐妹:一个被诊断为典型的 ALS,另一个则患有 ALS 和帕金森病重叠的独特综合征。全面的临床和影像学评估支持这些诊断。通过全基因组测序进行的遗传分析发现,TBK1 中存在一个以前未知的杂合剪接位点变异。功能评估表明,该剪接位点变异导致剪接异常,随后变异的TBK1等位基因被无义介导的衰变降解,证实了其致病影响。我们的研究结果表明,TBK1更广泛地参与了神经退行性疾病,并强调了进一步研究TBK1作用的必要性,提倡在类似家族病例中筛查TBK1变体。
{"title":"A novel <i>TBK1</i> loss-of-function variant associated with ALS and parkinsonism phenotypes.","authors":"Hiroya Naruse, Chifumi Iseki, Jun Mitsui, Jun Miki, Hikaru Nagasawa, Katsuro Kurokawa, Ryota Kobayashi, Hiroyasu Sato, Jun Goto, Wataru Satake, Hiroyuki Ishiura, Shoji Tsuji, Yasuyuki Ohta, Tatsushi Toda","doi":"10.1080/21678421.2024.2374374","DOIUrl":"https://doi.org/10.1080/21678421.2024.2374374","url":null,"abstract":"<p><p>Loss-of-function (LoF) variants in the TANK binding kinase 1 (<i>TBK1</i>) gene are implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. In this study, we present the first familial cases of ALS and parkinsonism associated with a novel <i>TBK1</i> variant. We describe two siblings: one diagnosed with classical ALS and the other with a unique syndrome overlapping ALS and parkinsonism. Comprehensive clinical and imaging evaluations supported these diagnoses. Genetic analysis through whole-genome sequencing revealed a previously unknown heterozygous splice site variant in <i>TBK1</i>. Functional assessments demonstrated that this splice site variant leads to abnormal splicing and subsequent degradation of the mutated TBK1 allele by nonsense-mediated decay, confirming its pathogenic impact. Our findings suggest a broader involvement of TBK1 in neurodegenerative diseases and underscore the need for further research into TBK1's role, advocating for screening for <i>TBK1</i> variants in similar familial cases.</p>","PeriodicalId":72184,"journal":{"name":"Amyotrophic lateral sclerosis & frontotemporal degeneration","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141499794","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 : 2024-07-03DOI: 10.1080/21678421.2024.2372648
Sadegh Ghaderi, Farzad Fatehi, Sanjay Kalra, Sana Mohammadi, Seyed Amir Hossein Batouli
Objective: Previous studies have suggested a link between dysregulation of cortical iron levels and neuronal loss in amyotrophic lateral sclerosis (ALS) patients. However, few studies have reported differences in quantitative susceptibility mapping (QSM) values in subcortical nuclei between patients with ALS and healthy controls (HCs). Methods: MRI was performed using a 3 Tesla Prisma scanner (64-channel head coil), including 3D T1-MPRAGE and multi-echo 3D GRE for QSM reconstruction. Automated QSM segmentation was used to measure susceptibility values in the subcortical nuclei, which were compared between the groups. Correlations with clinical scales were analyzed. Group comparisons were performed using independent t-tests, with p < 0.05 considered significant. Correlations were assessed using Pearson's correlation, with p < 0.05 considered significant. Cohen's d was reported to compare the standardized mean difference (SMD) of QSM. Results: Twelve patients with limb-onset ALS (mean age 48.7 years, 75% male) and 13 age-, sex-, and handedness-matched HCs (mean age 44.6 years, 69% male) were included. Compared to HCs, ALS patients demonstrated significantly lower susceptibility in the left caudate nucleus (CN) (SMD = -0.845), right CN (SMD = -0.851), whole CN (SMD = -1.016), and left subthalamic nucleus (STN) (SMD = -1.000). Susceptibility in the left putamen (SMD = -0.857), left thalamus (SMD = -1.081), and whole thalamus (SMD = -0.968) was significantly higher in the patients. The susceptibility of the substantia nigra (SN), CN, and pulvinar was positively correlated with disease duration. Conclusions: QSM detects abnormal iron accumulation patterns in the subcortical gray matter of ALS patients, which correlates with disease characteristics, supporting its potential as a neuroimaging biomarker.
{"title":"Quantitative susceptibility mapping in amyotrophic lateral sclerosis: automatic quantification of the magnetic susceptibility in the subcortical nuclei.","authors":"Sadegh Ghaderi, Farzad Fatehi, Sanjay Kalra, Sana Mohammadi, Seyed Amir Hossein Batouli","doi":"10.1080/21678421.2024.2372648","DOIUrl":"10.1080/21678421.2024.2372648","url":null,"abstract":"<p><p><i>Objective</i>: Previous studies have suggested a link between dysregulation of cortical iron levels and neuronal loss in amyotrophic lateral sclerosis (ALS) patients. However, few studies have reported differences in quantitative susceptibility mapping (QSM) values in subcortical nuclei between patients with ALS and healthy controls (HCs). <i>Methods</i>: MRI was performed using a 3 Tesla Prisma scanner (64-channel head coil), including 3D T1-MPRAGE and multi-echo 3D GRE for QSM reconstruction. Automated QSM segmentation was used to measure susceptibility values in the subcortical nuclei, which were compared between the groups. Correlations with clinical scales were analyzed. Group comparisons were performed using independent <i>t</i>-tests, with <i>p</i> < 0.05 considered significant. Correlations were assessed using Pearson's correlation, with <i>p</i> < 0.05 considered significant. Cohen's <i>d</i> was reported to compare the standardized mean difference (SMD) of QSM. <i>Results</i>: Twelve patients with limb-onset ALS (mean age 48.7 years, 75% male) and 13 age-, sex-, and handedness-matched HCs (mean age 44.6 years, 69% male) were included. Compared to HCs, ALS patients demonstrated significantly lower susceptibility in the left caudate nucleus (CN) (SMD = -0.845), right CN (SMD = -0.851), whole CN (SMD = -1.016), and left subthalamic nucleus (STN) (SMD = -1.000). Susceptibility in the left putamen (SMD = -0.857), left thalamus (SMD = -1.081), and whole thalamus (SMD = -0.968) was significantly higher in the patients. The susceptibility of the substantia nigra (SN), CN, and pulvinar was positively correlated with disease duration. <i>Conclusions</i>: QSM detects abnormal iron accumulation patterns in the subcortical gray matter of ALS patients, which correlates with disease characteristics, supporting its potential as a neuroimaging biomarker.</p>","PeriodicalId":72184,"journal":{"name":"Amyotrophic lateral sclerosis & frontotemporal degeneration","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141494498","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 : 2024-06-26DOI: 10.1080/21678421.2024.2371986
Gabriela Stegmann, Chelsea Krantsevich, Julie Liss, Sherman Charles, Meredith Bartlett, Jeremy Shefner, Seward Rutkove, Kan Kawabata, Tanya Talkar, Visar Berisha
Objective: Although studies have shown that digital measures of speech detected ALS speech impairment and correlated with the ALSFRS-R speech item, no study has yet compared their performance in detecting speech changes. In this study, we compared the performances of the ALSFRS-R speech item and an algorithmic speech measure in detecting clinically important changes in speech. Importantly, the study was part of a FDA submission which received the breakthrough device designation for monitoring ALS; we provide this paper as a roadmap for validating other speech measures for monitoring disease progression. Methods: We obtained ALSFRS-R speech subscores and speech samples from participants with ALS. We computed the minimum detectable change (MDC) of both measures; using clinician-reported listener effort and a perceptual ratings of severity, we calculated the minimal clinically important difference (MCID) of each measure with respect to both sets of clinical ratings. Results: For articulatory precision, the MDC (.85) was lower than both MCID measures (2.74 and 2.28), and for the ALSFRS-R speech item, MDC (.86) was greater than both MCID measures (.82 and .72), indicating that while the articulatory precision measure detected minimal clinically important differences in speech, the ALSFRS-R speech item did not. Conclusion: The results demonstrate that the digital measure of articulatory precision effectively detects clinically important differences in speech ratings, outperforming the ALSFRS-R speech item. Taken together, the results herein suggest that this speech outcome is a clinically meaningful measure of speech change.
研究目的虽然有研究表明,数字语音测量方法可以检测到 ALS 言语障碍,并与 ALSFRS-R 言语项目相关,但还没有研究比较过它们在检测言语变化方面的性能。在本研究中,我们比较了 ALSFRS-R 言语项目和算法语音测量在检测临床上重要的言语变化方面的性能。重要的是,该研究是美国食品药品管理局(FDA)提交的研究报告的一部分,该报告获得了用于监测 ALS 的突破性设备称号;我们将本文作为验证用于监测疾病进展的其他语音测量方法的路线图。方法:我们从 ALS 患者那里获得了 ALSFRS-R 言语子分数和言语样本。我们计算了这两项测量的最小可检测变化 (MDC);利用临床医生报告的听者努力程度和对严重程度的感知评分,我们计算了每项测量相对于两组临床评分的最小临床重要差异 (MCID)。结果显示就发音精确度而言,MDC(.85)低于两个 MCID 测量值(2.74 和 2.28),而就 ALSFRS-R 言语项目而言,MDC(.86)高于两个 MCID 测量值(.82 和 .72),这表明发音精确度测量值能检测出言语中最小临床重要差异,而 ALSFRS-R 言语项目则不能。结论结果表明,数字发音精确度测量方法能有效检测出言语评分中的临床重要差异,其效果优于 ALSFRS-R 言语项目。总之,本文的结果表明,这种语音结果是一种对语音变化有临床意义的测量方法。
{"title":"Automated speech analytics in ALS: higher sensitivity of digital articulatory precision over the ALSFRS-R.","authors":"Gabriela Stegmann, Chelsea Krantsevich, Julie Liss, Sherman Charles, Meredith Bartlett, Jeremy Shefner, Seward Rutkove, Kan Kawabata, Tanya Talkar, Visar Berisha","doi":"10.1080/21678421.2024.2371986","DOIUrl":"10.1080/21678421.2024.2371986","url":null,"abstract":"<p><p><i>Objective</i>: Although studies have shown that digital measures of speech detected ALS speech impairment and correlated with the ALSFRS-R speech item, no study has yet compared their performance in detecting speech changes. In this study, we compared the performances of the ALSFRS-R speech item and an algorithmic speech measure in detecting clinically important changes in speech. Importantly, the study was part of a FDA submission which received the breakthrough device designation for monitoring ALS; we provide this paper as a roadmap for validating other speech measures for monitoring disease progression. <i>Methods</i>: We obtained ALSFRS-R speech subscores and speech samples from participants with ALS. We computed the minimum detectable change (MDC) of both measures; using clinician-reported listener effort and a perceptual ratings of severity, we calculated the minimal clinically important difference (MCID) of each measure with respect to both sets of clinical ratings. <i>Results</i>: For articulatory precision, the MDC (.85) was lower than both MCID measures (2.74 and 2.28), and for the ALSFRS-R speech item, MDC (.86) was greater than both MCID measures (.82 and .72), indicating that while the articulatory precision measure detected minimal clinically important differences in speech, the ALSFRS-R speech item did not. <i>Conclusion</i>: The results demonstrate that the digital measure of articulatory precision effectively detects clinically important differences in speech ratings, outperforming the ALSFRS-R speech item. Taken together, the results herein suggest that this speech outcome is a clinically meaningful measure of speech change.</p>","PeriodicalId":72184,"journal":{"name":"Amyotrophic lateral sclerosis & frontotemporal degeneration","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141461158","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 : 2024-06-26DOI: 10.1080/21678421.2024.2370808
Dean Spencer, James Polke, Joanna Campbell, Henry Houlden, Aleksandar Radunovic
Background: Despite recognition of the importance of genetic factors in the pathogenesis of MND and the increasing availability of genetic testing, testing practice remains highly variable. With the arrival of gene-targeted therapies there is a growing need to promptly identify actionable genetic results and patient death before receipt of results raises ethical dilemmas and limits access to novel therapies. Objective: To identify pathogenic mutations within a London tertiary MND center and their correlation with family history. To record waiting times for genetic results and deaths prior to receipt of results. Methods: In this series of 100 cases, genetic testing was offered to all patients with an MND diagnosis from the tertiary clinic. Data on demographics, disease progression and a detailed family history were taken. Time to receipt of genetic results and patient deaths prior to this were recorded. Results: Of the 97 patients who accepted testing a genetic cause was identified in 10%, including seven C9orf72 and two positive SOD1 cases. Only three patients with positive genetic findings had a family history of MND, although alternative neurological diagnoses and symptoms in the family were frequently reported. 14% of patients who underwent testing were deceased by the time results were received, including one actionable SOD1 case. Conclusions: Genetic testing should be made available to all patients who receive an MND diagnosis as family history alone is inadequate to identify potential familial cases. Time to receipt of results remains a significant issue due to the limited life expectancy following diagnosis.
{"title":"'Outcomes of genetic testing in the London MND Center: the importance of achieving timely results and correlations to family history'.","authors":"Dean Spencer, James Polke, Joanna Campbell, Henry Houlden, Aleksandar Radunovic","doi":"10.1080/21678421.2024.2370808","DOIUrl":"https://doi.org/10.1080/21678421.2024.2370808","url":null,"abstract":"<p><p><i>Background</i>: Despite recognition of the importance of genetic factors in the pathogenesis of MND and the increasing availability of genetic testing, testing practice remains highly variable. With the arrival of gene-targeted therapies there is a growing need to promptly identify actionable genetic results and patient death before receipt of results raises ethical dilemmas and limits access to novel therapies. <i>Objective</i>: To identify pathogenic mutations within a London tertiary MND center and their correlation with family history. To record waiting times for genetic results and deaths prior to receipt of results. <i>Methods</i>: In this series of 100 cases, genetic testing was offered to all patients with an MND diagnosis from the tertiary clinic. Data on demographics, disease progression and a detailed family history were taken. Time to receipt of genetic results and patient deaths prior to this were recorded. <i>Results</i>: Of the 97 patients who accepted testing a genetic cause was identified in 10%, including seven C9orf72 and two positive SOD1 cases. Only three patients with positive genetic findings had a family history of MND, although alternative neurological diagnoses and symptoms in the family were frequently reported. 14% of patients who underwent testing were deceased by the time results were received, including one actionable SOD1 case. <i>Conclusions</i>: Genetic testing should be made available to all patients who receive an MND diagnosis as family history alone is inadequate to identify potential familial cases. Time to receipt of results remains a significant issue due to the limited life expectancy following diagnosis.</p>","PeriodicalId":72184,"journal":{"name":"Amyotrophic lateral sclerosis & frontotemporal degeneration","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141461159","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 : 2024-06-20DOI: 10.1080/21678421.2024.2362854
Laynie Dratch, Daniel D Kinnamon, Elizabeth A Harrington, Jill Goldman, Jamie C Fong, Tara Jones, Wendy R Uhlmann, Jennifer Roggenbuck
{"title":"Response to \"assessment of risk of ALS conferred by the GGGGCC hexanucleotide expansion in C9orf72 among first-degree relatives of patients with ALS carrying the repeat expansion\".","authors":"Laynie Dratch, Daniel D Kinnamon, Elizabeth A Harrington, Jill Goldman, Jamie C Fong, Tara Jones, Wendy R Uhlmann, Jennifer Roggenbuck","doi":"10.1080/21678421.2024.2362854","DOIUrl":"https://doi.org/10.1080/21678421.2024.2362854","url":null,"abstract":"","PeriodicalId":72184,"journal":{"name":"Amyotrophic lateral sclerosis & frontotemporal degeneration","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141433479","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}