Aowei Lv, Yaofeng Fang, Xiaohong Lin, Jiaying Chen, Huanhuan Song, Ning Wang, Wan-Jin Chen, Ying Fu, Rui Li, Yi Lin
Objective
Human T-cell leukemia virus type 1-associated myelopathy (HAM) is a chronic, progressive, inflammatory disease with unclear pathogenesis and no effective treatments. We aimed to investigate a novel mechanistic theory and treat HAM patients with rituximab, which can deplete CD20+ B lymphocytes in circulation.
Methods
Single-cell RNA sequencing (scRNA-seq) data was analyzed to identify HTLV-1-associated B cells and their effect on T cells. An observational analysis of our HAM cohort was conducted to elucidate changes in the immunological microenvironment of these patients. Peripheral blood mononuclear cells (PBMC) from HAM patients were isolated to explore the efficacy of B cell depletion in vitro. To assess the effect of B-cell depletion on HAM patients, eligible participants in our cohort received rituximab therapy (NCT04004819).
Results
ScRNA-seq results suggest a significant effect of HTLV-1-associated B cells on T cells. Additionally, HTLV-1 was found to infect B cells and depletion of B cells inhibited the proliferation of T cells. Number of B cells in HAM patients had positive correlation with the proviral load and infected cell counts. Depletion of B cells led to a reduction in HTLV-1 proviral load in vitro. Furthermore, in clinical trial, 14 HAM patients were enrolled. Three patients (21.4%) who received rituximab failed to achieve remission, compared to 24 (85.7%) patients received any other therapy that failed to achieve remission. With a low level of circulating B cells, the proportion of Ki67-positive cells in CD4+ T cells fell.
Interpretation
This study provided evidence that depleting B-lymphocytes is an innovative strategy for treating patients with HAM and broadens the understanding of the role of B cells in infectious immunity.
目的：人类 T 细胞白血病病毒 1 型相关骨髓病（HAM）是一种慢性、进行性、炎症性疾病，发病机制不明，也没有有效的治疗方法。我们旨在研究一种新的机理理论，并用利妥昔单抗治疗HAM患者，因为利妥昔单抗能消耗循环中的CD20+ B淋巴细胞：我们分析了单细胞 RNA 测序（scRNA-seq）数据，以确定与 HTLV-1 相关的 B 细胞及其对 T 细胞的影响。我们对 HAM 队列进行了观察分析，以阐明这些患者免疫微环境的变化。我们分离了 HAM 患者的外周血单核细胞 (PBMC)，以探索体外 B 细胞耗竭的疗效。为了评估B细胞耗竭对HAM患者的影响，我们的队列中符合条件的参与者接受了利妥昔单抗治疗（NCT04004819）：ScRNA-seq结果表明，HTLV-1相关B细胞对T细胞有显著影响。结果：ScRNA-seq 结果表明，HTLV-1 相关 B 细胞对 T 细胞有显著影响。此外，HTLV-1 还可感染 B 细胞，而 B 细胞的耗竭可抑制 T 细胞的增殖。HAM患者的B细胞数量与病毒载量和感染细胞数量呈正相关。消耗 B 细胞可减少体外 HTLV-1 病毒载量。此外，在临床试验中，有 14 名 HAM 患者参加。接受利妥昔单抗治疗的患者中有3人（21.4%）未能获得缓解，而接受其他疗法的患者中有24人（85.7%）未能获得缓解。由于循环B细胞水平较低，CD4+T细胞中Ki67阳性细胞的比例下降：这项研究提供了证据，证明消耗B淋巴细胞是治疗HAM患者的一种创新策略，并拓宽了人们对B细胞在感染性免疫中作用的认识。
{"title":"B-cell depletion limits HTLV-1-infected T-cell expansion and ameliorate HTLV-1-associated myelopathy","authors":"Aowei Lv, Yaofeng Fang, Xiaohong Lin, Jiaying Chen, Huanhuan Song, Ning Wang, Wan-Jin Chen, Ying Fu, Rui Li, Yi Lin","doi":"10.1002/acn3.52190","DOIUrl":"10.1002/acn3.52190","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>Human T-cell leukemia virus type 1-associated myelopathy (HAM) is a chronic, progressive, inflammatory disease with unclear pathogenesis and no effective treatments. We aimed to investigate a novel mechanistic theory and treat HAM patients with rituximab, which can deplete CD20<sup>+</sup> B lymphocytes in circulation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Single-cell RNA sequencing (scRNA-seq) data was analyzed to identify HTLV-1-associated B cells and their effect on T cells. An observational analysis of our HAM cohort was conducted to elucidate changes in the immunological microenvironment of these patients. Peripheral blood mononuclear cells (PBMC) from HAM patients were isolated to explore the efficacy of B cell depletion in vitro. To assess the effect of B-cell depletion on HAM patients, eligible participants in our cohort received rituximab therapy (NCT04004819).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>ScRNA-seq results suggest a significant effect of HTLV-1-associated B cells on T cells. Additionally, HTLV-1 was found to infect B cells and depletion of B cells inhibited the proliferation of T cells. Number of B cells in HAM patients had positive correlation with the proviral load and infected cell counts. Depletion of B cells led to a reduction in HTLV-1 proviral load in vitro. Furthermore, in clinical trial, 14 HAM patients were enrolled. Three patients (21.4%) who received rituximab failed to achieve remission, compared to 24 (85.7%) patients received any other therapy that failed to achieve remission. With a low level of circulating B cells, the proportion of Ki67-positive cells in CD4<sup>+</sup> T cells fell.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>This study provided evidence that depleting B-lymphocytes is an innovative strategy for treating patients with HAM and broadens the understanding of the role of B cells in infectious immunity.</p>\u0000 </section>\u0000 </div>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/acn3.52190","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142054306","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Omid Shirvani, Stefanie Warnat-Herresthal, Ivan Savchuk, Felix J. Bode, Louisa Nitsch, Sebastian Stösser, Taraneh Ebrahimi, Niklas von Danwitz, Hannah Asperger, Julia Layer, Julius Meissner, Christian Thielscher, Franziska Dorn, Nils Lehnen, Joachim L. Schultze, Gabor C. Petzold, Johannes M. Weller, the GSR-ET Investigators
Objective
Predicting long-term functional outcomes shortly after a stroke is challenging, even for experienced neurologists. Therefore, we aimed to evaluate multiple machine learning models and the importance of clinical/radiological parameters to develop a model that balances minimal input data with reliable predictions of long-term functional independency.
Methods
Our study utilized data from the German Stroke Registry on patients with large anterior vessel occlusion who underwent endovascular treatment. We trained seven machine learning models using 30 parameters from the first day postadmission to predict a modified Ranking Scale of 0–2 at 90 days poststroke. Model performance was assessed using a 20-fold cross-validation and one-sided Wilcoxon rank-sum tests. Key features were identified through backward feature selection.
Results
We included 7485 individuals with a median age of 75 years and a median NIHSS score at admission of 14 in our analysis. Our Deep Neural Network model demonstrated the best performance among all models including data from 24 h postadmission. Backward feature selection identified the seven most important features to be NIHSS after 24 h, age, modified Ranking Scale after 24 h, premorbid modified Ranking Scale, intracranial hemorrhage within 24 h, intravenous thrombolysis, and NIHSS at admission. Narrowing the Deep Neural Network model's input data to these features preserved the high performance with an AUC of 0.9 (CI: 0.89–0.91).
Interpretation
Our Deep Neural Network model, trained on over 7000 patients, predicts 90-day functional independence using only seven clinical/radiological features from the first day postadmission, demonstrating both high accuracy and practicality for clinical implementation on stroke units.
{"title":"Machine learning models for outcome prediction in thrombectomy for large anterior vessel occlusion","authors":"Omid Shirvani, Stefanie Warnat-Herresthal, Ivan Savchuk, Felix J. Bode, Louisa Nitsch, Sebastian Stösser, Taraneh Ebrahimi, Niklas von Danwitz, Hannah Asperger, Julia Layer, Julius Meissner, Christian Thielscher, Franziska Dorn, Nils Lehnen, Joachim L. Schultze, Gabor C. Petzold, Johannes M. Weller, the GSR-ET Investigators","doi":"10.1002/acn3.52185","DOIUrl":"10.1002/acn3.52185","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>Predicting long-term functional outcomes shortly after a stroke is challenging, even for experienced neurologists. Therefore, we aimed to evaluate multiple machine learning models and the importance of clinical/radiological parameters to develop a model that balances minimal input data with reliable predictions of long-term functional independency.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Our study utilized data from the German Stroke Registry on patients with large anterior vessel occlusion who underwent endovascular treatment. We trained seven machine learning models using 30 parameters from the first day postadmission to predict a modified Ranking Scale of 0–2 at 90 days poststroke. Model performance was assessed using a 20-fold cross-validation and one-sided Wilcoxon rank-sum tests. Key features were identified through backward feature selection.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We included 7485 individuals with a median age of 75 years and a median NIHSS score at admission of 14 in our analysis. Our Deep Neural Network model demonstrated the best performance among all models including data from 24 h postadmission. Backward feature selection identified the seven most important features to be NIHSS after 24 h, age, modified Ranking Scale after 24 h, premorbid modified Ranking Scale, intracranial hemorrhage within 24 h, intravenous thrombolysis, and NIHSS at admission. Narrowing the Deep Neural Network model's input data to these features preserved the high performance with an AUC of 0.9 (CI: 0.89–0.91).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>Our Deep Neural Network model, trained on over 7000 patients, predicts 90-day functional independence using only seven clinical/radiological features from the first day postadmission, demonstrating both high accuracy and practicality for clinical implementation on stroke units.</p>\u0000 </section>\u0000 </div>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/acn3.52185","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142046017","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Julia C. M. Pottkämper, Joey P. A. J. Verdijk, Sven Stuiver, Eva Aalbregt, Freek ten Doesschate, Esmée Verwijk, Martin Schmettow, Guido A. van Wingen, Michel J. A. M. van Putten, Jeannette Hofmeijer, Jeroen A. van Waarde
Objective
The postictal state is underrecognized in epilepsy. Animal models show improvement of postictal symptoms and cerebral perfusion with acetaminophen or nimodipine. We studied the effects of acetaminophen or nimodipine on postictal electroencephalographic (EEG) recovery, clinical reorientation, and hypoperfusion in patients with ECT-induced seizures.
Methods
In this prospective clinical trial with three-condition randomized crossover design, study interventions were administered orally 2 h before ECT sessions (1000 mg acetaminophen, 60 mg nimodipine, or a placebo condition). Primary outcome measure was the speed of postictal EEG recovery. Secondary outcomes were the extent of postictal EEG recovery, clinical reorientation time, and postictal cerebral blood flow as assessed by perfusion-weighted MRI. Bayesian generalized mixed-effects models were applied for analyses.
Results
We included 300 seizures, postictal EEGs, and reorientation time values, and 76 MRI perfusion measures from 33 patients (median age 53 years, 19 female). Pretreatment with acetaminophen or nimodipine was not associated with change in speed of EEG recovery compared to placebo (1.13 [95%CI 0.92, 1.40] and 1.07 [95%CI 0.87, 1.31], respectively), nor with the secondary outcomes. No patient reached full EEG recovery at 1 h post-seizure, despite clinical recovery in 89%. Longer seizures were associated with slower EEG recovery and lower postictal perfusion. Nimodipine altered regional perfusion in the posterior cortex.
Interpretation
Pretreatment with acetaminophen or nimodipine did not alleviate symptoms and signs of the postictal state. Systematic study of the postictal state after ECT-induced seizures is feasible.
{"title":"Exploring postictal recovery with acetaminophen or nimodipine: A randomized-controlled crossover trial","authors":"Julia C. M. Pottkämper, Joey P. A. J. Verdijk, Sven Stuiver, Eva Aalbregt, Freek ten Doesschate, Esmée Verwijk, Martin Schmettow, Guido A. van Wingen, Michel J. A. M. van Putten, Jeannette Hofmeijer, Jeroen A. van Waarde","doi":"10.1002/acn3.52143","DOIUrl":"10.1002/acn3.52143","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>The postictal state is underrecognized in epilepsy. Animal models show improvement of postictal symptoms and cerebral perfusion with acetaminophen or nimodipine. We studied the effects of acetaminophen or nimodipine on postictal electroencephalographic (EEG) recovery, clinical reorientation, and hypoperfusion in patients with ECT-induced seizures.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>In this prospective clinical trial with three-condition randomized crossover design, study interventions were administered orally 2 h before ECT sessions (1000 mg acetaminophen, 60 mg nimodipine, or a placebo condition). Primary outcome measure was the speed of postictal EEG recovery. Secondary outcomes were the extent of postictal EEG recovery, clinical reorientation time, and postictal cerebral blood flow as assessed by perfusion-weighted MRI. Bayesian generalized mixed-effects models were applied for analyses.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We included 300 seizures, postictal EEGs, and reorientation time values, and 76 MRI perfusion measures from 33 patients (median age 53 years, 19 female). Pretreatment with acetaminophen or nimodipine was not associated with change in speed of EEG recovery compared to placebo (1.13 [95%CI 0.92, 1.40] and 1.07 [95%CI 0.87, 1.31], respectively), nor with the secondary outcomes. No patient reached full EEG recovery at 1 h post-seizure, despite clinical recovery in 89%. Longer seizures were associated with slower EEG recovery and lower postictal perfusion. Nimodipine altered regional perfusion in the posterior cortex.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>Pretreatment with acetaminophen or nimodipine did not alleviate symptoms and signs of the postictal state. Systematic study of the postictal state after ECT-induced seizures is feasible.</p>\u0000 </section>\u0000 </div>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/acn3.52143","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142003167","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yi Sun, Xitao Yang, Xindong Fan, Lixin Su, Ren Cai
Cobb syndrome is a rare neurocutaneous disease characterized by vascular anomalies involving the skin and spinal cord at the same metamere. The most common initial symptoms are neurological manifestations such as pain, monoparesis, headache, scoliosis, and motor damage. We present two patients with Cobb syndrome and severe disease burden harboring somatic mutations in KRAS. The two patients were subsequently treated with the MEK inhibitor trametinib, indicating the potential therapeutic benefit of this treatment for patients with life-threatening Cobb syndrome who are currently considered incurable.
{"title":"Cobb syndrome effectively treated with trametinib","authors":"Yi Sun, Xitao Yang, Xindong Fan, Lixin Su, Ren Cai","doi":"10.1002/acn3.52181","DOIUrl":"10.1002/acn3.52181","url":null,"abstract":"<p>Cobb syndrome is a rare neurocutaneous disease characterized by vascular anomalies involving the skin and spinal cord at the same metamere. The most common initial symptoms are neurological manifestations such as pain, monoparesis, headache, scoliosis, and motor damage. We present two patients with Cobb syndrome and severe disease burden harboring somatic mutations in KRAS. The two patients were subsequently treated with the MEK inhibitor trametinib, indicating the potential therapeutic benefit of this treatment for patients with life-threatening Cobb syndrome who are currently considered incurable.</p>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/acn3.52181","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141994815","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yi Ge, Cong Chen, Hong Li, Ruyi Wang, Yuyu Yang, Lingqi Ye, Chenmin He, Ruotong Chen, Zijian Wang, Xiaotong Shao, Yuting Gong, Linglin Yang, Shan Wang, Jiping Zhou, Xunyi Wu, Shuang Wang, Yao Ding
Objectives
This study aims to investigate whether alterations in white matter topological networks are associated with focal to bilateral tonic–clonic seizures (FBTCS) in temporal lobe epilepsy (TLE). Additionally, we investigated the variables contributing to memory impairment in TLE.
Methods
This cross-sectional study included 88 unilateral people with TLE (45 left/43 right), and 42 healthy controls. Graph theory analysis was employed to compare the FBTCS (+) group (n = 51) with the FBTCS (−) group (n = 37). The FBTCS (+) group was subcategorized into current-FBTCS (n = 31) and remote-FBTCS (n = 20), based on the history of FBTCS within 1 year or longer than 1 year before scanning, respectively. We evaluated the discriminatory power of topological network properties by receiver operating characteristic (ROC) analysis. Generalized linear models (GLMs) were employed to investigate variables associated with memory impairment in TLE.
Results
Global efficiency (Eg) was significantly reduced in the FBTCS (+) group, especially in the current-FBTCS subgroup. Greater disruption of regional properties in the ipsilateral occipital and temporal association cortices was observed in the FBTCS (+) group. ROC analysis revealed that Eg, normalized characteristic shortest path length, and nodal efficiency of the ipsilateral middle temporal gyrus could distinguish between FBTCS (+) and FBTCS (−) groups. Additionally, GLMs linked the occurrence of current FBTCS with poorer verbal memory outcomes in TLE.
Interpretation
Our study suggests that abnormal networks could be the structural basis of seizure propagation in FBTCS. Strategies aimed at reducing the occurrence of FBTCS could potentially improve the memory outcomes in people with TLE.
{"title":"Altered structural network in temporal lobe epilepsy with focal to bilateral tonic–clonic seizures","authors":"Yi Ge, Cong Chen, Hong Li, Ruyi Wang, Yuyu Yang, Lingqi Ye, Chenmin He, Ruotong Chen, Zijian Wang, Xiaotong Shao, Yuting Gong, Linglin Yang, Shan Wang, Jiping Zhou, Xunyi Wu, Shuang Wang, Yao Ding","doi":"10.1002/acn3.52135","DOIUrl":"10.1002/acn3.52135","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>This study aims to investigate whether alterations in white matter topological networks are associated with focal to bilateral tonic–clonic seizures (FBTCS) in temporal lobe epilepsy (TLE). Additionally, we investigated the variables contributing to memory impairment in TLE.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This cross-sectional study included 88 unilateral people with TLE (45 left/43 right), and 42 healthy controls. Graph theory analysis was employed to compare the FBTCS (+) group (<i>n</i> = 51) with the FBTCS (−) group (<i>n</i> = 37). The FBTCS (+) group was subcategorized into current-FBTCS (<i>n</i> = 31) and remote-FBTCS (<i>n</i> = 20), based on the history of FBTCS within 1 year or longer than 1 year before scanning, respectively. We evaluated the discriminatory power of topological network properties by receiver operating characteristic (ROC) analysis. Generalized linear models (GLMs) were employed to investigate variables associated with memory impairment in TLE.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Global efficiency (Eg) was significantly reduced in the FBTCS (+) group, especially in the current-FBTCS subgroup. Greater disruption of regional properties in the ipsilateral occipital and temporal association cortices was observed in the FBTCS (+) group. ROC analysis revealed that Eg, normalized characteristic shortest path length, and nodal efficiency of the ipsilateral middle temporal gyrus could distinguish between FBTCS (+) and FBTCS (−) groups. Additionally, GLMs linked the occurrence of current FBTCS with poorer verbal memory outcomes in TLE.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>Our study suggests that abnormal networks could be the structural basis of seizure propagation in FBTCS. Strategies aimed at reducing the occurrence of FBTCS could potentially improve the memory outcomes in people with TLE.</p>\u0000 </section>\u0000 </div>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/acn3.52135","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141994813","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Nai-Qing Cai, Wu-Xiang Shi, Ru-Kai Chen, Bo-Li Chen, Yu-Rong Li, Ning Wang
Objective
The objective of this study was to investigate the activity and connectivity of cerebral and cerebellar cortices underlying the sensory trick (ST) effects in patients with cervical dystonia (CD), using electroencephalography (EEG).
Methods
We recruited 15 CD patients who exhibited clinically effective ST and 15 healthy controls (HCs) who mimicked the ST maneuver. EEG signals and multiple-channel electromyography (EMG) were recorded simultaneously during resting and acting stages. EEG source analysis and functional connectivity were performed. To account for the effects of sensory processing, we calculated relative power changes as the difference in power spectral density between resting and the maneuver execution.
Results
ST induced a decrease in low gamma (30–50 Hz) spectral power in the primary sensory and cerebellar cortices, which remained lower than in HCs during the maintenance period. Compared with HCs, patients exhibited consistently strengthened connectivity within the sensorimotor network during the maintenance period, particularly in the primary sensory-sensorimotor cerebellum connection.
Interpretation
The application of ST resulted in altered cortical excitability and functional connectivity regulated by gamma oscillation in CD patients, suggesting that this effect cannot be solely attributed to motor components. The cerebellum may play important roles in mediating the ST effects.
研究目的本研究的目的是利用脑电图（EEG）研究颈性肌张力障碍（CD）患者感觉伎俩（ST）效应所依赖的大脑和小脑皮层的活动和连接性：方法：我们招募了 15 名在临床上表现出有效 ST 的 CD 患者和 15 名模仿 ST 动作的健康对照组（HCs）。我们同时记录了静息和行动阶段的脑电信号和多通道肌电图（EMG）。进行了脑电图信号源分析和功能连接分析。为了考虑感觉处理的影响，我们将相对功率变化计算为静息和动作执行时功率谱密度的差异：结果：ST导致初级感觉皮层和小脑皮层的低伽马（30-50赫兹）频谱功率下降，在维持期仍低于普通人。与普通人相比，患者在维持期的感觉运动网络中表现出持续增强的连通性，尤其是在初级感觉-感觉运动小脑连接中：ST的应用导致CD患者大脑皮层兴奋性和由伽马振荡调节的功能连接发生改变，这表明这种效应不能完全归因于运动成分。小脑可能在介导 ST 效应方面发挥了重要作用。
{"title":"Cerebral-Cerebellar Cortical Activity and Connectivity Underlying Sensory Trick in Cervical Dystonia","authors":"Nai-Qing Cai, Wu-Xiang Shi, Ru-Kai Chen, Bo-Li Chen, Yu-Rong Li, Ning Wang","doi":"10.1002/acn3.52177","DOIUrl":"10.1002/acn3.52177","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>The objective of this study was to investigate the activity and connectivity of cerebral and cerebellar cortices underlying the sensory trick (ST) effects in patients with cervical dystonia (CD), using electroencephalography (EEG).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We recruited 15 CD patients who exhibited clinically effective ST and 15 healthy controls (HCs) who mimicked the ST maneuver. EEG signals and multiple-channel electromyography (EMG) were recorded simultaneously during resting and acting stages. EEG source analysis and functional connectivity were performed. To account for the effects of sensory processing, we calculated relative power changes as the difference in power spectral density between resting and the maneuver execution.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>ST induced a decrease in low gamma (30–50 Hz) spectral power in the primary sensory and cerebellar cortices, which remained lower than in HCs during the maintenance period. Compared with HCs, patients exhibited consistently strengthened connectivity within the sensorimotor network during the maintenance period, particularly in the primary sensory-sensorimotor cerebellum connection.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>The application of ST resulted in altered cortical excitability and functional connectivity regulated by gamma oscillation in CD patients, suggesting that this effect cannot be solely attributed to motor components. The cerebellum may play important roles in mediating the ST effects.</p>\u0000 </section>\u0000 </div>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/acn3.52177","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141994814","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Rong Gao, Huan Luo, Su Yan, Li Ba, Sirui Peng, Bitao Bu, Xufang Sun, Min Zhang
Objective
To characterize the retinal microvasculature and structure in subjective cognitive decline (SCD) and identify the potential biomarker for the early stage of the Alzheimer's disease (AD) spectrum.
Methods
In this study, 35 patients with SCD, 36 with cognitive impairment, and 29 with normal cognition (NC) were enrolled. Optical coherence tomography angiography was employed to assess retinal vascular density, fovea avascular zone area, and retinal thickness. The parameters reflecting retinal perfusion and structure were compared among the three groups. In addition, the association between retinal parameters, cerebral blood flow (CBF), and peripheral blood biomarkers in the SCD stage was analyzed.
Results
The superficial vascular complex (SVC) vascular density in the macula and retinal nerve fiber layer thickness in the peripapillary were significantly reduced in individuals with SCD compared to NC. Furthermore, there was a positive correlation between macular ganglion cell complex thickness and CBF in SCD.
Interpretation
The retinal microvasculature and structure exhibit alterations in individuals with SCD. Macular ganglion cell complex thickness demonstrates correlations with cerebral perfusion. The retina holds potential as a novel biomarker for early detection of AD.
{"title":"Retina as a potential biomarker for the early stage of Alzheimer's disease spectrum","authors":"Rong Gao, Huan Luo, Su Yan, Li Ba, Sirui Peng, Bitao Bu, Xufang Sun, Min Zhang","doi":"10.1002/acn3.52172","DOIUrl":"10.1002/acn3.52172","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>To characterize the retinal microvasculature and structure in subjective cognitive decline (SCD) and identify the potential biomarker for the early stage of the Alzheimer's disease (AD) spectrum.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>In this study, 35 patients with SCD, 36 with cognitive impairment, and 29 with normal cognition (NC) were enrolled. Optical coherence tomography angiography was employed to assess retinal vascular density, fovea avascular zone area, and retinal thickness. The parameters reflecting retinal perfusion and structure were compared among the three groups. In addition, the association between retinal parameters, cerebral blood flow (CBF), and peripheral blood biomarkers in the SCD stage was analyzed.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The superficial vascular complex (SVC) vascular density in the macula and retinal nerve fiber layer thickness in the peripapillary were significantly reduced in individuals with SCD compared to NC. Furthermore, there was a positive correlation between macular ganglion cell complex thickness and CBF in SCD.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>The retinal microvasculature and structure exhibit alterations in individuals with SCD. Macular ganglion cell complex thickness demonstrates correlations with cerebral perfusion. The retina holds potential as a novel biomarker for early detection of AD.</p>\u0000 </section>\u0000 </div>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/acn3.52172","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141905157","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Julia Konrad, Ting Guo, Steven Ufkes, Thiviya Selvanathan, Min Sheng, Eiman Al-Ajmi, Helen M. Branson, Vann Chau, Linh G. Ly, Edmond N. Kelly, Ruth E. Grunau, Steven P. Miller
Objective
The hippocampus plays a critical role in cognitive networks. The anterior hippocampus is vulnerable to early-life stress and socioeconomic status (SES) with alterations persisting beyond childhood. How SES modifies the relationship between early hippocampal development and cognition remains poorly understood. This study examined associations between SES, structural and functional development of neonatal hippocampus, and 18-month cognition in very preterm neonates.
Methods
In total, 179 preterm neonates were followed prospectively. Structural and resting-state functional MRI were obtained early-in-life and at term-equivalent age (median 32.9 and 41.1 weeks post-menstrual age) to calculate anterior and posterior hippocampal volumes and hippocampal functional connectivity strength. Eighteen-month cognition was assessed via Bayley-III. Longitudinal statistical analysis using generalized estimating equations, accounting for birth gestational age, post-menstrual age at scan, sex, and motion, was performed.
Results
SES, measured as maternal education level, modified associations between anterior but not posterior hippocampal volumes and 18-month cognition (interaction term p = 0.005), and between hippocampal connectivity and cognition (interaction term p = 0.05). Greater anterior hippocampal volumes and hippocampal connectivity were associated with higher cognitive scores only in the lowest SES group. Maternal education alone did not predict neonatal hippocampal volume from early-in-life and term.
Interpretation
SES modified the relationship between neonatal hippocampal development and 18-month cognition in very preterm neonates. The lack of direct association between maternal education and neonatal hippocampal volumes indicates that socio-environmental factors beyond the neonatal period contribute to modifying the relationship between hippocampal development and cognition. These findings point toward opportunities to more equitably promote optimal neurodevelopmental outcomes in very preterm infants.
目的海马在认知网络中发挥着关键作用。海马前部容易受到早期生活压力和社会经济地位（SES）的影响，这种改变会持续到童年之后。人们对社会经济地位如何改变早期海马发育与认知之间的关系仍然知之甚少。本研究探讨了社会经济地位、新生儿海马结构和功能发育与极早产新生儿18个月认知能力之间的关系：共对179名早产新生儿进行了前瞻性随访。研究人员在新生儿早期和足月新生儿（月经后中位数分别为32.9周和41.1周）进行了结构和静息状态功能磁共振成像，以计算海马前部和后部体积以及海马功能连接强度。通过 Bayley-III 评估了 18 个月的认知能力。使用广义估计方程进行了纵向统计分析，并考虑了出生胎龄、扫描时的月经后年龄、性别和运动：以母亲教育水平衡量的社会经济地位改变了海马前部体积（而非后部体积）与 18 个月认知能力之间的关系（交互项 p = 0.005），以及海马连接性与认知能力之间的关系（交互项 p = 0.05）。只有在社会经济地位最低的组别中，海马前部体积和海马连通性越大，认知得分越高。单凭母亲的教育程度并不能预测新生儿海马体积从出生初期到足月的变化：SES改变了极早产新生儿海马体发育与18个月认知能力之间的关系。母亲教育程度与新生儿海马体积之间缺乏直接联系，这表明新生儿期以外的社会环境因素有助于改变海马发育与认知之间的关系。这些发现为更公平地促进早产儿获得最佳神经发育结果提供了机会。
{"title":"Socioeconomic status moderates associations between hippocampal development and cognition in preterms","authors":"Julia Konrad, Ting Guo, Steven Ufkes, Thiviya Selvanathan, Min Sheng, Eiman Al-Ajmi, Helen M. Branson, Vann Chau, Linh G. Ly, Edmond N. Kelly, Ruth E. Grunau, Steven P. Miller","doi":"10.1002/acn3.52168","DOIUrl":"10.1002/acn3.52168","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>The hippocampus plays a critical role in cognitive networks. The anterior hippocampus is vulnerable to early-life stress and socioeconomic status (SES) with alterations persisting beyond childhood. How SES modifies the relationship between <i>early</i> hippocampal development and cognition remains poorly understood. This study examined associations between SES, structural and functional development of neonatal hippocampus, and 18-month cognition in very preterm neonates.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>In total, 179 preterm neonates were followed prospectively. Structural and resting-state functional MRI were obtained early-in-life and at term-equivalent age (median 32.9 and 41.1 weeks post-menstrual age) to calculate anterior and posterior hippocampal volumes and hippocampal functional connectivity strength. Eighteen-month cognition was assessed via Bayley-III. Longitudinal statistical analysis using generalized estimating equations, accounting for birth gestational age, post-menstrual age at scan, sex, and motion, was performed.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>SES, measured as maternal education level, modified associations between anterior but not posterior hippocampal volumes and 18-month cognition (interaction term <i>p</i> = 0.005), and between hippocampal connectivity and cognition (interaction term <i>p</i> = 0.05). Greater anterior hippocampal volumes and hippocampal connectivity were associated with higher cognitive scores only in the lowest SES group. Maternal education alone did not predict neonatal hippocampal volume from early-in-life and term.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>SES modified the relationship between neonatal hippocampal development and 18-month cognition in very preterm neonates. The lack of direct association between maternal education and neonatal hippocampal volumes indicates that socio-environmental factors beyond the neonatal period contribute to modifying the relationship between hippocampal development and cognition. These findings point toward opportunities to more equitably promote optimal neurodevelopmental outcomes in very preterm infants.</p>\u0000 </section>\u0000 </div>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/acn3.52168","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141905158","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Philipp Klyscz, Susanna Asseyer, Ricardo Alonso, Charlotte Bereuter, Omer Bialer, Atira Bick, Sara Carta, John J. Chen, Leila Cohen, Yamit Cohen-Tayar, Edgar Carnero Contentti, Russell C. Dale, Eoin P. Flanagan, Jonathan A. Gernert, Julian Haas, Joachim Havla, Christoph Heesen, Mark Hellmann, Netta Levin, Pablo Lopez, Itay Lotan, Maria Belen Luis, Sara Mariotto, Christina Mayer, Alvaro Jose Mejia Vergara, Cassandra Ocampo, Susana Ochoa, Frederike C. Oertel, Maja Olszewska, José Luis Peralta Uribe, Jaume Sastre-Garriga, Dario Scocco, Sudarshini Ramanathan, Natthapon Rattanathamsakul, Fu-Dong Shi, Jemal Shifa, Ilya Simantov, Sasitorn Siritho, Alon Tiosano, Nanthaya Tisavipat, Isabel Torres, Adi Vaknin Dembinsky, Angela Vidal-Jordana, Adi Wilf-Yarkoni, Ti Wu, Sol Zamir, Luis Alfonso Zarco, Hanna G. Zimmermann, Axel Petzold, Friedemann Paul, Hadas Stiebel-Kalish
Objective
The first international consensus criteria for optic neuritis (ICON) were published in 2022. We applied these criteria to a prospective, global observational study of acute optic neuritis (ON).
Methods
We included 160 patients with a first-ever acute ON suggestive of a demyelinating CNS disease from the Acute Optic Neuritis Network (ACON). We applied the 2022 ICON to all participants and subsequently adjusted the ICON by replacing a missing relative afferent pupillary defect (RAPD) or dyschromatopsia if magnetic resonance imaging pathology of the optical nerve plus optical coherence tomography abnormalities or certain biomarkers are present.
Results
According to the 2022 ICON, 80 (50%) patients were classified as definite ON, 12 (7%) patients were classified as possible ON, and 68 (43%) as not ON (NON). The main reasons for classification as NON were absent RAPD (52 patients, 76%) or dyschromatopsia (49 patients, 72%). Distribution of underlying ON etiologies was as follows: 78 (49%) patients had a single isolated ON, 41 (26%) patients were diagnosed with multiple sclerosis, 25 (16%) patients with myelin oligodendrocyte glycoprotein antibody-associated disease, and 15 (9%) with neuromyelitis optica spectrum disorder. The application of the adjusted ON criteria yielded a higher proportion of patients classified as ON (126 patients, 79%).
Interpretation
According to the 2022 ICON, almost half of the included patients in ACON did not fulfill the requirements for classification of definite or possible ON, particularly due to missing RAPD and dyschromatopsia. Thorough RAPD examination and formal color vision testing are critical to the application of the 2022 ICON.
{"title":"Application of the international criteria for optic neuritis in the Acute Optic Neuritis Network","authors":"Philipp Klyscz, Susanna Asseyer, Ricardo Alonso, Charlotte Bereuter, Omer Bialer, Atira Bick, Sara Carta, John J. Chen, Leila Cohen, Yamit Cohen-Tayar, Edgar Carnero Contentti, Russell C. Dale, Eoin P. Flanagan, Jonathan A. Gernert, Julian Haas, Joachim Havla, Christoph Heesen, Mark Hellmann, Netta Levin, Pablo Lopez, Itay Lotan, Maria Belen Luis, Sara Mariotto, Christina Mayer, Alvaro Jose Mejia Vergara, Cassandra Ocampo, Susana Ochoa, Frederike C. Oertel, Maja Olszewska, José Luis Peralta Uribe, Jaume Sastre-Garriga, Dario Scocco, Sudarshini Ramanathan, Natthapon Rattanathamsakul, Fu-Dong Shi, Jemal Shifa, Ilya Simantov, Sasitorn Siritho, Alon Tiosano, Nanthaya Tisavipat, Isabel Torres, Adi Vaknin Dembinsky, Angela Vidal-Jordana, Adi Wilf-Yarkoni, Ti Wu, Sol Zamir, Luis Alfonso Zarco, Hanna G. Zimmermann, Axel Petzold, Friedemann Paul, Hadas Stiebel-Kalish","doi":"10.1002/acn3.52166","DOIUrl":"10.1002/acn3.52166","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>The first international consensus criteria for optic neuritis (ICON) were published in 2022. We applied these criteria to a prospective, global observational study of acute optic neuritis (ON).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We included 160 patients with a first-ever acute ON suggestive of a demyelinating CNS disease from the Acute Optic Neuritis Network (ACON). We applied the 2022 ICON to all participants and subsequently adjusted the ICON by replacing a missing relative afferent pupillary defect (RAPD) or dyschromatopsia if magnetic resonance imaging pathology of the optical nerve plus optical coherence tomography abnormalities or certain biomarkers are present.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>According to the 2022 ICON, 80 (50%) patients were classified as definite ON, 12 (7%) patients were classified as possible ON, and 68 (43%) as not ON (NON). The main reasons for classification as NON were absent RAPD (52 patients, 76%) or dyschromatopsia (49 patients, 72%). Distribution of underlying ON etiologies was as follows: 78 (49%) patients had a single isolated ON, 41 (26%) patients were diagnosed with multiple sclerosis, 25 (16%) patients with myelin oligodendrocyte glycoprotein antibody-associated disease, and 15 (9%) with neuromyelitis optica spectrum disorder. The application of the adjusted ON criteria yielded a higher proportion of patients classified as ON (126 patients, 79%).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>According to the 2022 ICON, almost half of the included patients in ACON did not fulfill the requirements for classification of definite or possible ON, particularly due to missing RAPD and dyschromatopsia. Thorough RAPD examination and formal color vision testing are critical to the application of the 2022 ICON.</p>\u0000 </section>\u0000 </div>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/acn3.52166","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141887651","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Hereditary transthyretin (TTR) amyloidosis (ATTRv) is frequently complicated by polyneuropathy (ATTRv-PN) and cardiomyopathy (ATTRv-CM). The long-term efficacy of diflunisal on both polyneuropathy and cardiomyopathy in ATTRv patients, especially those with non-V30M genotypes, has not been fully investigated and compared with that of tafamidis.
Methods
We compared the structural and biochemical characteristics of A97S-TTR complexed with tafamidis with those of diflunisal, and prospectively followed up and compared the progression of polyneuropathy and cardiomyopathy between ATTRv-PN patients taking diflunisal and those taking tafamidis.
Results
Both diflunisal and tafamidis effectively bind to the two thyroxine-binding sites at the A97S-TTR dimer–dimer interface and equally and almost sufficiently reduce amyloid fibril formation. Thirty-five ATTRv-PN patients receiving diflunisal and 22 patients receiving tafamidis were enrolled. Compared with no treatment, diflunisal treatment significantly delayed the transition of FAP Stage 1 to 2 and Stage 2 to 3 and decreased the deterioration in parameters of the ulnar nerve conduction study (NCS). The progression of FAP stage or NCS parameters did not differ between patients treated with diflunisal and those treated with tafamidis. Both diflunisal and tafamidis treatments significantly decreased radiotracer uptake on 99mTc-PYP SPECT and stabilized cardiac wall thickness and blood pro-B-type natriuretic peptide levels. No significant adverse events occurred during diflunisal or tafamidis treatment.
Interpretations
The binding patterns of both tafamidis and diflunisal to A97S-TTR closely resembled those observed in the wild type. Diflunisal can effectively delay the progression of polyneuropathy and cardiomyopathy with similar efficacy to tafamidis and may become a cost-effective alternative treatment for late-onset ATTRv-PN.
{"title":"Diflunisal versus tafamidis on neuropathy and cardiomyopathy in hereditary transthyretin amyloidosis","authors":"Chi-Chao Chao, Shiou-Ru Tzeng, Ming-Chang Chiang, Hsueh-Wen Hsueh, Wan-Jen Hsieh, Yuan-Chun Chao, Mei-Fang Cheng, Yen-Hung Lin, Mao-Yuan Su, Chun-Hsiang Huang, Yi-Shiang Wang, Ming-Fang Hsieh, Ping-Huei Tseng, Sung-Tsang Hsieh","doi":"10.1002/acn3.52158","DOIUrl":"10.1002/acn3.52158","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Hereditary transthyretin (TTR) amyloidosis (ATTRv) is frequently complicated by polyneuropathy (ATTRv-PN) and cardiomyopathy (ATTRv-CM). The long-term efficacy of diflunisal on both polyneuropathy and cardiomyopathy in ATTRv patients, especially those with non-V30M genotypes, has not been fully investigated and compared with that of tafamidis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We compared the structural and biochemical characteristics of A97S-TTR complexed with tafamidis with those of diflunisal, and prospectively followed up and compared the progression of polyneuropathy and cardiomyopathy between ATTRv-PN patients taking diflunisal and those taking tafamidis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Both diflunisal and tafamidis effectively bind to the two thyroxine-binding sites at the A97S-TTR dimer–dimer interface and equally and almost sufficiently reduce amyloid fibril formation. Thirty-five ATTRv-PN patients receiving diflunisal and 22 patients receiving tafamidis were enrolled. Compared with no treatment, diflunisal treatment significantly delayed the transition of FAP Stage 1 to 2 and Stage 2 to 3 and decreased the deterioration in parameters of the ulnar nerve conduction study (NCS). The progression of FAP stage or NCS parameters did not differ between patients treated with diflunisal and those treated with tafamidis. Both diflunisal and tafamidis treatments significantly decreased radiotracer uptake on <sup>99m</sup>Tc-PYP SPECT and stabilized cardiac wall thickness and blood pro-B-type natriuretic peptide levels. No significant adverse events occurred during diflunisal or tafamidis treatment.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretations</h3>\u0000 \u0000 <p>The binding patterns of both tafamidis and diflunisal to A97S-TTR closely resembled those observed in the wild type. Diflunisal can effectively delay the progression of polyneuropathy and cardiomyopathy with similar efficacy to tafamidis and may become a cost-effective alternative treatment for late-onset ATTRv-PN.</p>\u0000 </section>\u0000 </div>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/acn3.52158","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141877982","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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