Pub Date : 2024-10-01DOI: 10.1001/jamaneurol.2024.2461
Kirk R Daffner, Margaret O'Connor
{"title":"It Is Time for Medicare to Cover Driving Safety Assessments.","authors":"Kirk R Daffner, Margaret O'Connor","doi":"10.1001/jamaneurol.2024.2461","DOIUrl":"10.1001/jamaneurol.2024.2461","url":null,"abstract":"","PeriodicalId":14677,"journal":{"name":"JAMA neurology","volume":" ","pages":"1021-1022"},"PeriodicalIF":20.4,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141916693","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01DOI: 10.1001/jamaneurol.2024.2564
Lars Wessels, Stefan Wolf, Tiziana Adage, Jörg Breitenbach, Claudius Thomé, Johannes Kerschbaumer, Martin Bendszus, Matthias Gmeiner, Andreas Gruber, Dorothee Mielke, Veit Rohde, Maria Wostrack, Bernard Meyer, Jens Gempt, Gerhard Bavinzski, Dorian Hirschmann, Peter Vajkoczy, Nils Hecht
Importance: Cerebral vasospasm largely contributes to a devastating outcome after aneurysmal subarachnoid hemorrhage (aSAH), with limited therapeutic options.
Objective: To investigate the safety and efficacy of localized nicardipine release implants positioned around the basal cerebral vasculature at risk for developing proximal vasospasm after aSAH.
Design, setting, and participants: This single-masked randomized clinical trial with a 52-week follow-up was performed between April 5, 2020, and January 23, 2023, at 6 academic neurovascular centers in Germany and Austria. Consecutive patients with World Federation of Neurological Surgeons grade 3 or 4 aSAH due to a ruptured anterior circulation aneurysm requiring microsurgical aneurysm repair participated.
Intervention: During aneurysm repair, patients were randomized 1:1 to intraoperatively receive 10 implants at 4 mg of nicardipine each plus standard of care (implant group) or aneurysm repair alone plus standard of care (control group).
Main outcome and measures: The primary end point was the incidence of moderate to severe cerebral angiographic vasospasm (aVS) between days 7 and 9 after aneurysm rupture as determined by digital subtraction angiography.
Results: Of 41 patients, 20 were randomized to the control group (mean [SD] age, 54.9 [9.1] years; 17 female [85%]) and 21 to the implant group (mean [SD] age, 53.6 [11.9] years; 14 female [67%]). A total of 39 patients were included in the primary efficacy analysis. In the control group, 11 of 19 patients (58%) developed moderate or severe aVS compared with 4 of 20 patients (20%) in the implant group (P = .02). This outcome was paralleled by a lower clinical need for vasospasm rescue therapy in the implant group (2 of 20 patients [10%]) compared with the control group (11 of 19 patients [58%]; P = .002). Between days 13 and 15 after aneurysm rupture, new cerebral infarcts were noted in 6 of 19 patients (32%) in the control group and in 2 of 20 patients (10%) in the implant group (P = .13). At 52 weeks, favorable outcomes were noted in 12 of 18 patients (67%) in the control group and 16 of 19 patients (84%) in the implant group (P = .27). The adverse event rate did not differ between groups.
Conclusions and relevance: These findings show that placing nicardipine release implants during microsurgical aneurysm repair can provide safe and effective prevention of moderate to severe aVS after aSAH. A phase 3 clinical trial to investigate the effect of nicardipine implants on clinical outcome may be warranted.
{"title":"Localized Nicardipine Release Implants for Prevention of Vasospasm After Aneurysmal Subarachnoid Hemorrhage: A Randomized Clinical Trial.","authors":"Lars Wessels, Stefan Wolf, Tiziana Adage, Jörg Breitenbach, Claudius Thomé, Johannes Kerschbaumer, Martin Bendszus, Matthias Gmeiner, Andreas Gruber, Dorothee Mielke, Veit Rohde, Maria Wostrack, Bernard Meyer, Jens Gempt, Gerhard Bavinzski, Dorian Hirschmann, Peter Vajkoczy, Nils Hecht","doi":"10.1001/jamaneurol.2024.2564","DOIUrl":"10.1001/jamaneurol.2024.2564","url":null,"abstract":"<p><strong>Importance: </strong>Cerebral vasospasm largely contributes to a devastating outcome after aneurysmal subarachnoid hemorrhage (aSAH), with limited therapeutic options.</p><p><strong>Objective: </strong>To investigate the safety and efficacy of localized nicardipine release implants positioned around the basal cerebral vasculature at risk for developing proximal vasospasm after aSAH.</p><p><strong>Design, setting, and participants: </strong>This single-masked randomized clinical trial with a 52-week follow-up was performed between April 5, 2020, and January 23, 2023, at 6 academic neurovascular centers in Germany and Austria. Consecutive patients with World Federation of Neurological Surgeons grade 3 or 4 aSAH due to a ruptured anterior circulation aneurysm requiring microsurgical aneurysm repair participated.</p><p><strong>Intervention: </strong>During aneurysm repair, patients were randomized 1:1 to intraoperatively receive 10 implants at 4 mg of nicardipine each plus standard of care (implant group) or aneurysm repair alone plus standard of care (control group).</p><p><strong>Main outcome and measures: </strong>The primary end point was the incidence of moderate to severe cerebral angiographic vasospasm (aVS) between days 7 and 9 after aneurysm rupture as determined by digital subtraction angiography.</p><p><strong>Results: </strong>Of 41 patients, 20 were randomized to the control group (mean [SD] age, 54.9 [9.1] years; 17 female [85%]) and 21 to the implant group (mean [SD] age, 53.6 [11.9] years; 14 female [67%]). A total of 39 patients were included in the primary efficacy analysis. In the control group, 11 of 19 patients (58%) developed moderate or severe aVS compared with 4 of 20 patients (20%) in the implant group (P = .02). This outcome was paralleled by a lower clinical need for vasospasm rescue therapy in the implant group (2 of 20 patients [10%]) compared with the control group (11 of 19 patients [58%]; P = .002). Between days 13 and 15 after aneurysm rupture, new cerebral infarcts were noted in 6 of 19 patients (32%) in the control group and in 2 of 20 patients (10%) in the implant group (P = .13). At 52 weeks, favorable outcomes were noted in 12 of 18 patients (67%) in the control group and 16 of 19 patients (84%) in the implant group (P = .27). The adverse event rate did not differ between groups.</p><p><strong>Conclusions and relevance: </strong>These findings show that placing nicardipine release implants during microsurgical aneurysm repair can provide safe and effective prevention of moderate to severe aVS after aSAH. A phase 3 clinical trial to investigate the effect of nicardipine implants on clinical outcome may be warranted.</p><p><strong>Trial registration: </strong>ClinicalTrials.gov Identifier: NCT04269408.</p>","PeriodicalId":14677,"journal":{"name":"JAMA neurology","volume":" ","pages":"1060-1065"},"PeriodicalIF":20.4,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11334004/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141999926","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01DOI: 10.1001/jamaneurol.2024.2599
Daniela Renedo, Kevin N Sheth
{"title":"Sex Differences in Case-Fatality Rates of Stroke-Reply.","authors":"Daniela Renedo, Kevin N Sheth","doi":"10.1001/jamaneurol.2024.2599","DOIUrl":"10.1001/jamaneurol.2024.2599","url":null,"abstract":"","PeriodicalId":14677,"journal":{"name":"JAMA neurology","volume":" ","pages":"1103"},"PeriodicalIF":20.4,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141999942","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01DOI: 10.1001/jamaneurol.2024.2612
Toshiaki Komura, Yusuke Tsugawa, Elizabeth Rose Mayeda, M Maria Glymour, Kosuke Inoue
{"title":"Association of Cardiovascular Events With Spouse's Subsequent Dementia.","authors":"Toshiaki Komura, Yusuke Tsugawa, Elizabeth Rose Mayeda, M Maria Glymour, Kosuke Inoue","doi":"10.1001/jamaneurol.2024.2612","DOIUrl":"10.1001/jamaneurol.2024.2612","url":null,"abstract":"","PeriodicalId":14677,"journal":{"name":"JAMA neurology","volume":" ","pages":"1098-1099"},"PeriodicalIF":20.4,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11348081/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142055541","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01DOI: 10.1001/jamaneurol.2024.2835
Neha Aggarwal
{"title":"Behind the Brow That Furrows.","authors":"Neha Aggarwal","doi":"10.1001/jamaneurol.2024.2835","DOIUrl":"10.1001/jamaneurol.2024.2835","url":null,"abstract":"","PeriodicalId":14677,"journal":{"name":"JAMA neurology","volume":" ","pages":"1025-1026"},"PeriodicalIF":20.4,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142119819","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01DOI: 10.1001/jamaneurol.2024.2500
Huanwen Chen, Jin Soo Lee, Patrik Michel, Bernard Yan, Seemant Chaturvedi
Importance: Recently, 6 randomized clinical trials-RESCUE-Japan-LIMIT (Recovery by Endovascular Salvage for Cerebral Ultra-Acute Embolism-Japan Large Ischemic Core Trial), ANGEL-ASPECT (Trial of Endovascular Therapy for Acute Ischemic Stroke With Large Infarct), SELECT2 (Trial of Endovascular Thrombectomy for Large Ischemic Strokes), TESLA (Thrombectomy for Emergent Salvage of Large Anterior Circulation Ischemic Stroke), TENSION (Endovascular Thrombectomy for Acute Ischemic Stroke With Established Large Infarct), and LASTE (Large Stroke Therapy Evaluation)-have concluded their investigations on the efficacy and safety of endovascular thrombectomy (EVT) for the treatment of patients with ischemic stroke, anterior-circulation large vessel occlusions, and large areas of ischemic changes defined as an Alberta Stroke Program Early Computed Tomography Score (ASPECTS) of 5 or less. Overall, the results appeared to be positive, with 5 of the 6 trials meeting their primary efficacy end point, and 1 trial that was a near miss. However, questions remain regarding how these trial results should be interpreted and incorporated into routine clinical practice.
Observations: In this narrative review and analysis of published trials, important nuances of the available clinical data were identified, and important areas of lingering uncertainty were highlighted, including the efficacy and safety of EVT for patients with a low ASPECTS score in late treatment windows and those with large core volumes. Also emphasized was the possibly important role of advanced neuroimaging modalities such as perfusion and magnetic resonance imaging when making EVT treatment decisions for select patients with low ASPECTS scores.
Conclusions and relevance: Recent trial data provide strong evidence that EVT is safe and effective for patients with anterior, large vessel-occlusion stroke and low ASPECTS scores who present within 6 hours from stroke onset. However, patient outcomes often remain poor despite EVT treatment. The efficacy and safety of EVT for patients with low ASPECTS scores who present beyond 6 hours of stroke onset remain uncertain, and the current trial data seem too scarce to justify forgoing advanced stroke imaging during this extended time window. Furthermore, the efficacy and safety of EVT for patients with large core volumes (100 mL or greater) or M2 occlusions (ie, occlusions of the second segment of the middle cerebral artery) remain uncertain. Future research to better identify patients likely to meaningfully respond to EVT is needed to further optimize the stroke triage process and health care resource utilization.
重要性:最近,6 项随机临床试验--RESCUE-Japan-LIMIT(Recovery by Endovascular Salvage for Cerebral Ultra-Acute Embolism-Japan Large Ischemic Core Trial)、ANGEL-ASPECT(Trial of Endovascular Therapy for Acute Ischemic Stroke With Large Infarct)、SELECT2(大面积缺血性脑卒中血管内血栓切除术试验)、TESLA(大面积前循环缺血性脑卒中紧急抢救血栓切除术)、TENSION(大面积梗死急性缺血性卒中血管内血栓切除术)和 LASTE(大面积卒中治疗评估)--已经完成了对血管内血栓切除术(EVT)治疗缺血性卒中、前循环大血管闭塞和大面积缺血性病变(定义为阿尔伯塔卒中计划早期计算机断层扫描评分(ASPECTS)5 分或以下)患者的有效性和安全性的研究。总的来说,结果似乎是积极的,6 项试验中有 5 项达到了主要疗效终点,1 项试验几乎没有达到。然而,如何解释这些试验结果并将其纳入常规临床实践仍存在疑问:在对已发表的试验进行的叙述性回顾和分析中,发现了现有临床数据的重要细微差别,并强调了仍存在不确定性的重要领域,包括 EVT 对晚期治疗窗口期 ASPECTS 评分较低的患者和核心体积较大的患者的疗效和安全性。此外,还强调了先进的神经成像模式(如灌注成像和磁共振成像)在选择ASPECTS评分较低的患者进行EVT治疗决策时可能发挥的重要作用:最近的试验数据提供了强有力的证据,证明 EVT 对于卒中发生后 6 小时内出现的前方大血管闭塞性卒中和 ASPECTS 评分低的患者是安全有效的。然而,尽管进行了 EVT 治疗,患者的预后仍然很差。对于卒中发生 6 小时后出现的 ASPECTS 评分较低的患者,EVT 的有效性和安全性仍不确定,目前的试验数据似乎太少,不足以证明在这一延长时间窗内放弃高级卒中成像是合理的。此外,对于核心容量较大(100 mL 或以上)或 M2 闭塞(即大脑中动脉第二段闭塞)的患者,EVT 的有效性和安全性仍不确定。未来的研究需要更好地识别可能对 EVT 有意义反应的患者,以进一步优化卒中分流流程和医疗资源的利用。
{"title":"Endovascular Stroke Thrombectomy for Patients With Large Ischemic Core: A Review.","authors":"Huanwen Chen, Jin Soo Lee, Patrik Michel, Bernard Yan, Seemant Chaturvedi","doi":"10.1001/jamaneurol.2024.2500","DOIUrl":"10.1001/jamaneurol.2024.2500","url":null,"abstract":"<p><strong>Importance: </strong>Recently, 6 randomized clinical trials-RESCUE-Japan-LIMIT (Recovery by Endovascular Salvage for Cerebral Ultra-Acute Embolism-Japan Large Ischemic Core Trial), ANGEL-ASPECT (Trial of Endovascular Therapy for Acute Ischemic Stroke With Large Infarct), SELECT2 (Trial of Endovascular Thrombectomy for Large Ischemic Strokes), TESLA (Thrombectomy for Emergent Salvage of Large Anterior Circulation Ischemic Stroke), TENSION (Endovascular Thrombectomy for Acute Ischemic Stroke With Established Large Infarct), and LASTE (Large Stroke Therapy Evaluation)-have concluded their investigations on the efficacy and safety of endovascular thrombectomy (EVT) for the treatment of patients with ischemic stroke, anterior-circulation large vessel occlusions, and large areas of ischemic changes defined as an Alberta Stroke Program Early Computed Tomography Score (ASPECTS) of 5 or less. Overall, the results appeared to be positive, with 5 of the 6 trials meeting their primary efficacy end point, and 1 trial that was a near miss. However, questions remain regarding how these trial results should be interpreted and incorporated into routine clinical practice.</p><p><strong>Observations: </strong>In this narrative review and analysis of published trials, important nuances of the available clinical data were identified, and important areas of lingering uncertainty were highlighted, including the efficacy and safety of EVT for patients with a low ASPECTS score in late treatment windows and those with large core volumes. Also emphasized was the possibly important role of advanced neuroimaging modalities such as perfusion and magnetic resonance imaging when making EVT treatment decisions for select patients with low ASPECTS scores.</p><p><strong>Conclusions and relevance: </strong>Recent trial data provide strong evidence that EVT is safe and effective for patients with anterior, large vessel-occlusion stroke and low ASPECTS scores who present within 6 hours from stroke onset. However, patient outcomes often remain poor despite EVT treatment. The efficacy and safety of EVT for patients with low ASPECTS scores who present beyond 6 hours of stroke onset remain uncertain, and the current trial data seem too scarce to justify forgoing advanced stroke imaging during this extended time window. Furthermore, the efficacy and safety of EVT for patients with large core volumes (100 mL or greater) or M2 occlusions (ie, occlusions of the second segment of the middle cerebral artery) remain uncertain. Future research to better identify patients likely to meaningfully respond to EVT is needed to further optimize the stroke triage process and health care resource utilization.</p>","PeriodicalId":14677,"journal":{"name":"JAMA neurology","volume":" ","pages":"1085-1093"},"PeriodicalIF":20.4,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141916692","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01DOI: 10.1001/jamaneurol.2024.2876
Jonas Graf, Manas K Akmatov, Sven G Meuth, Helen Tremlett, Jakob Holstiege
{"title":"Updated Multiple Sclerosis Incidence, 2015-2022.","authors":"Jonas Graf, Manas K Akmatov, Sven G Meuth, Helen Tremlett, Jakob Holstiege","doi":"10.1001/jamaneurol.2024.2876","DOIUrl":"10.1001/jamaneurol.2024.2876","url":null,"abstract":"","PeriodicalId":14677,"journal":{"name":"JAMA neurology","volume":" ","pages":"1100-1102"},"PeriodicalIF":20.4,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11385316/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142154092","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01DOI: 10.1001/jamaneurol.2024.2579
Lei Liu, Adriana Saba, Jesse R Pascual, Michael B Miller, Elizabeth L Hennessey, Ira T Lott, Adam M Brickman, Donna M Wilcock, Jordan P Harp, Frederick A Schmitt, Dennis J Selkoe, Jasmeer P Chhatwal, Elizabeth Head
Importance: Anti-β-amyloid immunotherapy using lecanemab is becoming increasingly available to patients with Alzheimer disease (AD). Individuals with Down syndrome (DS) develop AD neuropathology by age 40 years, representing a significant cohort of genetically determined AD.
Objective: To investigate the binding properties of lecanemab in the brains of people with DS, in anticipation of their inclusion in clinical trials or access to antiamyloid immunotherapies.
Design, setting, participants: The study included cases of postmortem brain tissue analysis from 15 individuals with DS aged 43 to 68 years that were acquired from Alzheimer Disease research centers at the University of California, Irvine and the University of Kentucky from 2008 to 2021. Data were analyzed from August 2023 through May 2024.
Exposure: The binding properties of lecanemab were assessed in brain tissue.
Main outcome: The primary outcome was the extent of lecanemab binding to amyloid plaques and brain blood vessels.
Results: Tissue from 15 people (8 were female [53%]) with DS ranging in age from 43 to 68 (mean, 56.6) years were included in the study. Lecanemab-labeled amyloid plaques appeared in all 15 DS cases studied, indicating potential target engagement. However, extensive binding of lecanemab to brain blood vessels in DS was observed, raising significant safety concerns. These findings underscore the necessity for clinical trials of lecanemab in people with DS to evaluate both safety and efficacy, particularly in individuals older than 43 years.
Conclusions and relevance: These findings suggest significant binding of lecanemab to cerebral amyloid angiopathy in DS. Lecanemab should be rigorously tested in clinical trials for AD in the DS population to determine its safety and efficacy, especially in those older than 43 years.
{"title":"Lecanemab and Vascular-Amyloid Deposition in Brains of People With Down Syndrome.","authors":"Lei Liu, Adriana Saba, Jesse R Pascual, Michael B Miller, Elizabeth L Hennessey, Ira T Lott, Adam M Brickman, Donna M Wilcock, Jordan P Harp, Frederick A Schmitt, Dennis J Selkoe, Jasmeer P Chhatwal, Elizabeth Head","doi":"10.1001/jamaneurol.2024.2579","DOIUrl":"10.1001/jamaneurol.2024.2579","url":null,"abstract":"<p><strong>Importance: </strong>Anti-β-amyloid immunotherapy using lecanemab is becoming increasingly available to patients with Alzheimer disease (AD). Individuals with Down syndrome (DS) develop AD neuropathology by age 40 years, representing a significant cohort of genetically determined AD.</p><p><strong>Objective: </strong>To investigate the binding properties of lecanemab in the brains of people with DS, in anticipation of their inclusion in clinical trials or access to antiamyloid immunotherapies.</p><p><strong>Design, setting, participants: </strong>The study included cases of postmortem brain tissue analysis from 15 individuals with DS aged 43 to 68 years that were acquired from Alzheimer Disease research centers at the University of California, Irvine and the University of Kentucky from 2008 to 2021. Data were analyzed from August 2023 through May 2024.</p><p><strong>Exposure: </strong>The binding properties of lecanemab were assessed in brain tissue.</p><p><strong>Main outcome: </strong>The primary outcome was the extent of lecanemab binding to amyloid plaques and brain blood vessels.</p><p><strong>Results: </strong>Tissue from 15 people (8 were female [53%]) with DS ranging in age from 43 to 68 (mean, 56.6) years were included in the study. Lecanemab-labeled amyloid plaques appeared in all 15 DS cases studied, indicating potential target engagement. However, extensive binding of lecanemab to brain blood vessels in DS was observed, raising significant safety concerns. These findings underscore the necessity for clinical trials of lecanemab in people with DS to evaluate both safety and efficacy, particularly in individuals older than 43 years.</p><p><strong>Conclusions and relevance: </strong>These findings suggest significant binding of lecanemab to cerebral amyloid angiopathy in DS. Lecanemab should be rigorously tested in clinical trials for AD in the DS population to determine its safety and efficacy, especially in those older than 43 years.</p>","PeriodicalId":14677,"journal":{"name":"JAMA neurology","volume":" ","pages":"1066-1072"},"PeriodicalIF":20.4,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11334015/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141999925","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01DOI: 10.1001/jamaneurol.2024.2811
Young Nam Kwon, Boram Kim, Jun-Soon Kim, Kyung Seok Park, Da-Young Seo, Hyunjin Kim, Eun-Jae Lee, Young-Min Lim, Hyunjin Ju, Yeon Hak Chung, Ju-Hong Min, Tai-Seung Nam, Sooyoung Kim, Eunhee Sohn, Kyong Jin Shin, Jin Myoung Seok, Sunyoung Kim, Jong Seok Bae, Sukyoon Lee, Seong-Il Oh, Yu Jin Jung, Jinseok Park, Seung Hyun Kim, Ki Hoon Kim, Ho Jin Kim, Jae Ho Jung, Seong-Joon Kim, Seung Woo Kim, Myoung-Jin Jang, Jung-Joon Sung, Patrick Waters, Ha Young Shin, Sung-Min Kim
<p><strong>Importance: </strong>A proportion of people with myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) have a relapsing disease course and persistent anti-myelin oligodendrocyte glycoprotein immunoglobulin G (MOG-IgG) seropositivity. Few studies have investigated whether treatment of the first MOGAD attack is associated with the long-term disease course and/or MOG-IgG seronegative conversion.</p><p><strong>Objective: </strong>To investigate the association of time to treat the first acute MOGAD attack with relapse risk and MOG-IgG serostatus.</p><p><strong>Design, setting, and participants: </strong>This was a retrospective, nationwide, multicenter cohort study involving 14 secondary or tertiary hospitals in South Korea between November 2009 and August 2023. People with adult-onset MOGAD, who either had a relapse or were followed up for more than 12 months after disease onset and had a detailed medical record of their first attack, were included. Individuals were excluded for adolescent-onset MOGAD or short disease duration.</p><p><strong>Exposures: </strong>Patients were categorized based on the time to treat the first acute MOGAD attack: early (<5 days), intermediate (5-14 days), and late (not treated within 14 days).</p><p><strong>Main outcomes and measures: </strong>A multivariable analysis for clinical and treatment factors associated with relapsing disease course and/or MOG-IgG seronegative conversion. Further subgroup analyses were conducted among those without long-term nonsteroidal immunosuppressant (NSIS) maintenance treatment.</p><p><strong>Results: </strong>Among the 315 individuals screened, 75 were excluded. A total of 240 patients (median [IQR] age at onset, 40.4 [28.8-56.1] years; 125 female [52.1%]) with median (IQR) disease duration of 3.07 (1.95-6.15) years were included. A total of 110 of 240 patients (45.8%) relapsed after a median (IQR) of 0.45 (0.18-1.68) years, and 29 of 116 patients (25.0%) experienced a conversion to seronegative MOG-IgG. Both the time to treatment of the first MOGAD attack (late vs early: adjusted hazard ratio [aHR], 2.64; 95% CI, 1.43-4.84; P = .002; intermediate vs early: aHR, 2.02; 95% CI, 1.10-3.74; P = .02) and NSIS maintenance treatment (aHR, 0.24; 95% CI, 0.14-0.42; P < .001) were independently associated with the risk of relapse. In a subgroup without NSIS maintenance, the time to treat of the first MOGAD attack was still associated with higher risk of relapse (late vs early: aHR, 3.51; 95% CI, 1.64-7.50; P = .001; intermediate vs early: aHR, 2.68; 95% CI, 1.23-5.85; P = .01). Lastly, the time to treat of the first MOGAD attack was also associated with MOG-IgG seronegative conversion (early vs late: adjusted odds ratio, 7.04; 95% CI, 1.58-31.41; P = .01), whereas NSIS maintenance treatment was not.</p><p><strong>Conclusions and relevance: </strong>Results of this cohort study suggest that early treatment of the first acute MOGAD attack was associated with a reduction
{"title":"Time to Treat First Acute Attack of Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease.","authors":"Young Nam Kwon, Boram Kim, Jun-Soon Kim, Kyung Seok Park, Da-Young Seo, Hyunjin Kim, Eun-Jae Lee, Young-Min Lim, Hyunjin Ju, Yeon Hak Chung, Ju-Hong Min, Tai-Seung Nam, Sooyoung Kim, Eunhee Sohn, Kyong Jin Shin, Jin Myoung Seok, Sunyoung Kim, Jong Seok Bae, Sukyoon Lee, Seong-Il Oh, Yu Jin Jung, Jinseok Park, Seung Hyun Kim, Ki Hoon Kim, Ho Jin Kim, Jae Ho Jung, Seong-Joon Kim, Seung Woo Kim, Myoung-Jin Jang, Jung-Joon Sung, Patrick Waters, Ha Young Shin, Sung-Min Kim","doi":"10.1001/jamaneurol.2024.2811","DOIUrl":"10.1001/jamaneurol.2024.2811","url":null,"abstract":"<p><strong>Importance: </strong>A proportion of people with myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) have a relapsing disease course and persistent anti-myelin oligodendrocyte glycoprotein immunoglobulin G (MOG-IgG) seropositivity. Few studies have investigated whether treatment of the first MOGAD attack is associated with the long-term disease course and/or MOG-IgG seronegative conversion.</p><p><strong>Objective: </strong>To investigate the association of time to treat the first acute MOGAD attack with relapse risk and MOG-IgG serostatus.</p><p><strong>Design, setting, and participants: </strong>This was a retrospective, nationwide, multicenter cohort study involving 14 secondary or tertiary hospitals in South Korea between November 2009 and August 2023. People with adult-onset MOGAD, who either had a relapse or were followed up for more than 12 months after disease onset and had a detailed medical record of their first attack, were included. Individuals were excluded for adolescent-onset MOGAD or short disease duration.</p><p><strong>Exposures: </strong>Patients were categorized based on the time to treat the first acute MOGAD attack: early (<5 days), intermediate (5-14 days), and late (not treated within 14 days).</p><p><strong>Main outcomes and measures: </strong>A multivariable analysis for clinical and treatment factors associated with relapsing disease course and/or MOG-IgG seronegative conversion. Further subgroup analyses were conducted among those without long-term nonsteroidal immunosuppressant (NSIS) maintenance treatment.</p><p><strong>Results: </strong>Among the 315 individuals screened, 75 were excluded. A total of 240 patients (median [IQR] age at onset, 40.4 [28.8-56.1] years; 125 female [52.1%]) with median (IQR) disease duration of 3.07 (1.95-6.15) years were included. A total of 110 of 240 patients (45.8%) relapsed after a median (IQR) of 0.45 (0.18-1.68) years, and 29 of 116 patients (25.0%) experienced a conversion to seronegative MOG-IgG. Both the time to treatment of the first MOGAD attack (late vs early: adjusted hazard ratio [aHR], 2.64; 95% CI, 1.43-4.84; P = .002; intermediate vs early: aHR, 2.02; 95% CI, 1.10-3.74; P = .02) and NSIS maintenance treatment (aHR, 0.24; 95% CI, 0.14-0.42; P < .001) were independently associated with the risk of relapse. In a subgroup without NSIS maintenance, the time to treat of the first MOGAD attack was still associated with higher risk of relapse (late vs early: aHR, 3.51; 95% CI, 1.64-7.50; P = .001; intermediate vs early: aHR, 2.68; 95% CI, 1.23-5.85; P = .01). Lastly, the time to treat of the first MOGAD attack was also associated with MOG-IgG seronegative conversion (early vs late: adjusted odds ratio, 7.04; 95% CI, 1.58-31.41; P = .01), whereas NSIS maintenance treatment was not.</p><p><strong>Conclusions and relevance: </strong>Results of this cohort study suggest that early treatment of the first acute MOGAD attack was associated with a reduction","PeriodicalId":14677,"journal":{"name":"JAMA neurology","volume":" ","pages":"1073-1084"},"PeriodicalIF":20.4,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11372657/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142119820","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01DOI: 10.1001/jamaneurol.2024.2843
Michael E Belloy, Yann Le Guen, Ilaria Stewart, Kennedy Williams, Joachim Herz, Richard Sherva, Rui Zhang, Victoria Merritt, Matthew S Panizzon, Richard L Hauger, J Michael Gaziano, Mark Logue, Valerio Napolioni, Michael D Greicius
Importance: The X chromosome has remained enigmatic in Alzheimer disease (AD), yet it makes up 5% of the genome and carries a high proportion of genes expressed in the brain, making it particularly appealing as a potential source of unexplored genetic variation in AD.
Objectives: To perform the first large-scale X chromosome-wide association study (XWAS) of AD.
Design, setting, and participants: This was a meta-analysis of genetic association studies in case-control, family-based, population-based, and longitudinal AD-related cohorts from the US Alzheimer's Disease Genetics Consortium, the Alzheimer's Disease Sequencing Project, the UK Biobank, the Finnish health registry, and the US Million Veterans Program. Risk of AD was evaluated through case-control logistic regression analyses. Data were analyzed between January 2023 and March 2024. Genetic data available from high-density single-nucleotide variant microarrays and whole-genome sequencing and summary statistics for multitissue expression and protein quantitative trait loci available from published studies were included, enabling follow-up genetic colocalization analyses. A total of 1 629 863 eligible participants were selected from referred and volunteer samples, 477 596 of whom were excluded for analysis exclusion criteria. The number of participants who declined to participate in original studies was not available.
Main outcome and measures: Risk of AD, reported as odds ratios (ORs) with 95% CIs. Associations were considered at X chromosome-wide (P < 1 × 10-5) and genome-wide (P < 5 × 10-8) significance. Primary analyses are nonstratified, while secondary analyses evaluate sex-stratified effects.
Results: Analyses included 1 152 284 participants of non-Hispanic White, European ancestry (664 403 [57.7%] female and 487 881 [42.3%] male), including 138 558 individuals with AD. Six independent genetic loci passed X chromosome-wide significance, with 4 showing support for links between the genetic signal for AD and expression of nearby genes in brain and nonbrain tissues. One of these 4 loci passed conservative genome-wide significance, with its lead variant centered on an intron of SLC9A7 (OR, 1.03; 95% CI, 1.02-1.04) and colocalization analyses prioritizing both the SLC9A7 and nearby CHST7 genes. Of these 6 loci, 4 displayed evidence for escape from X chromosome inactivation with regard to AD risk.
Conclusion and relevance: This large-scale XWAS of AD identified the novel SLC9A7 locus. SLC9A7 regulates pH homeostasis in Golgi secretory compartments and is anticipated to have downstream effects on amyloid β accumulation. Overall, this study advances our knowledge of AD genetics and may provide novel biological drug targets. The results further provide initial insights into elucidating the role of the X chromosome in sex-based differences in AD.
重要性:在阿尔茨海默病(AD)中,X 染色体一直是个谜,但它占基因组的 5%,并携带着在大脑中表达的很高比例的基因,这使它成为阿尔茨海默病中未探索的遗传变异的潜在来源,因而特别具有吸引力:进行首次大规模的X染色体全基因组AD关联研究(XWAS):这是一项对病例对照、家族、人群和纵向AD相关队列中遗传关联研究的荟萃分析,这些队列来自美国阿尔茨海默病遗传学联合会、阿尔茨海默病测序项目、英国生物库、芬兰健康登记处和美国百万退伍军人计划。通过病例对照逻辑回归分析评估阿尔茨海默病风险。数据分析时间为 2023 年 1 月至 2024 年 3 月。从高密度单核苷酸变异微阵列和全基因组测序中获得的遗传数据,以及从已发表研究中获得的多组织表达和蛋白质定量性状位点的汇总统计数据都被纳入其中,以便进行后续的遗传共定位分析。从转介样本和志愿者样本中共筛选出 1 629 863 名符合条件的参与者,其中 477 596 人因分析排除标准而被排除。拒绝参与原始研究的参与者人数不详:AD风险,以几率比(ORs)和95% CIs的形式报告。在 X 染色体范围内考虑相关性(P 结果):分析包括 1 152 284 名非西班牙裔白人、欧洲血统的参与者(664 403 名女性[57.7%]和 487 881 名男性[42.3%]),其中包括 138 558 名 AD 患者。有 6 个独立的基因位点通过了 X 染色体范围内的显著性鉴定,其中 4 个位点显示出 AD 基因信号与附近基因在大脑和非大脑组织中的表达之间的联系。在这 4 个基因位点中,有一个位点通过了保守的全基因组显著性分析,其主导变异位于 SLC9A7 的一个内含子上(OR,1.03;95% CI,1.02-1.04),共定位分析优先考虑 SLC9A7 和附近的 CHST7 基因。在这 6 个基因位点中,有 4 个基因位点显示了摆脱 X 染色体失活的证据,这与 AD 风险有关:这项大规模的 AD XWAS 发现了新的 SLC9A7 基因位点。SLC9A7调节高尔基体分泌区的pH平衡,预计会对淀粉样β的积累产生下游影响。总之,这项研究增进了我们对AD遗传学的了解,并可能提供新的生物药物靶点。研究结果进一步为阐明X染色体在AD性别差异中的作用提供了初步见解。
{"title":"Role of the X Chromosome in Alzheimer Disease Genetics.","authors":"Michael E Belloy, Yann Le Guen, Ilaria Stewart, Kennedy Williams, Joachim Herz, Richard Sherva, Rui Zhang, Victoria Merritt, Matthew S Panizzon, Richard L Hauger, J Michael Gaziano, Mark Logue, Valerio Napolioni, Michael D Greicius","doi":"10.1001/jamaneurol.2024.2843","DOIUrl":"10.1001/jamaneurol.2024.2843","url":null,"abstract":"<p><strong>Importance: </strong>The X chromosome has remained enigmatic in Alzheimer disease (AD), yet it makes up 5% of the genome and carries a high proportion of genes expressed in the brain, making it particularly appealing as a potential source of unexplored genetic variation in AD.</p><p><strong>Objectives: </strong>To perform the first large-scale X chromosome-wide association study (XWAS) of AD.</p><p><strong>Design, setting, and participants: </strong>This was a meta-analysis of genetic association studies in case-control, family-based, population-based, and longitudinal AD-related cohorts from the US Alzheimer's Disease Genetics Consortium, the Alzheimer's Disease Sequencing Project, the UK Biobank, the Finnish health registry, and the US Million Veterans Program. Risk of AD was evaluated through case-control logistic regression analyses. Data were analyzed between January 2023 and March 2024. Genetic data available from high-density single-nucleotide variant microarrays and whole-genome sequencing and summary statistics for multitissue expression and protein quantitative trait loci available from published studies were included, enabling follow-up genetic colocalization analyses. A total of 1 629 863 eligible participants were selected from referred and volunteer samples, 477 596 of whom were excluded for analysis exclusion criteria. The number of participants who declined to participate in original studies was not available.</p><p><strong>Main outcome and measures: </strong>Risk of AD, reported as odds ratios (ORs) with 95% CIs. Associations were considered at X chromosome-wide (P < 1 × 10-5) and genome-wide (P < 5 × 10-8) significance. Primary analyses are nonstratified, while secondary analyses evaluate sex-stratified effects.</p><p><strong>Results: </strong>Analyses included 1 152 284 participants of non-Hispanic White, European ancestry (664 403 [57.7%] female and 487 881 [42.3%] male), including 138 558 individuals with AD. Six independent genetic loci passed X chromosome-wide significance, with 4 showing support for links between the genetic signal for AD and expression of nearby genes in brain and nonbrain tissues. One of these 4 loci passed conservative genome-wide significance, with its lead variant centered on an intron of SLC9A7 (OR, 1.03; 95% CI, 1.02-1.04) and colocalization analyses prioritizing both the SLC9A7 and nearby CHST7 genes. Of these 6 loci, 4 displayed evidence for escape from X chromosome inactivation with regard to AD risk.</p><p><strong>Conclusion and relevance: </strong>This large-scale XWAS of AD identified the novel SLC9A7 locus. SLC9A7 regulates pH homeostasis in Golgi secretory compartments and is anticipated to have downstream effects on amyloid β accumulation. Overall, this study advances our knowledge of AD genetics and may provide novel biological drug targets. The results further provide initial insights into elucidating the role of the X chromosome in sex-based differences in AD.</p>","PeriodicalId":14677,"journal":{"name":"JAMA neurology","volume":" ","pages":"1032-1042"},"PeriodicalIF":20.4,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11385320/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142154091","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}