首页 > 最新文献

Annals of Neurology最新文献

英文 中文
Association Between Early-Life and Premorbid Measurements of Body Composition and Risk of Motor Neuron Disease: A Prospective Cohort Study in the UK Biobank. 生命早期和病前身体成分测量值与运动神经元疾病风险之间的关系:英国生物库前瞻性队列研究》。
IF 8.1 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-10-25 DOI: 10.1002/ana.27109
Emily E Joyce, Shishi Xu, Caroline Ingre, Rosa Luisa Potenza, Christina Seitz, Huazhen Yang, Yu Zeng, Huan Song, Fang Fang

Objective: The objective of this study was to investigate the association between developmental and premorbid body composition measurements and the risk of motor neuron disease (MND).

Methods: We performed a cohort study in the UK Biobank to assess the association of developmental body metrics and premorbid body composition measures (using 28 measurements and 7 patterns of body composition) with the risk of MND. Among participants with longitudinal measures, we compared the changes in body composition over time between individuals who later developed MND and those who remained free of MND.

Results: Among the 412,691 individuals included in this study, 549 people received an MND diagnosis during the follow-up visit. Higher birth weight was associated with an increased risk of MND among individuals born over 4 kg (hazard ratio [HR] per kg increase = 2.21, 95% confidence interval [CI] = 1.38-3.55), and taller adult height was associated with an increased risk of MND (HR per 5 cm increase = 1.10, 95% CI = 1.03-1.17). We observed that measures of elevated fat mass were associated with a lower risk of MND more than 5 years before diagnosis. A higher "leg-dominant fat distribution" pattern was associated with an increased risk whereas higher "muscle strength" was associated with a reduced risk of MND 5 years before diagnosis. Longitudinal analyses indicated a faster decline in measures of fat mass and muscle strength, as well as a shift in fat distribution from arm to leg dominant, among individuals who later developed MND, compared with others.

Interpretation: Body composition at early and middle age may be indicative of the risk of MND development. ANN NEUROL 2024.

研究目的本研究旨在调查发育期和病前身体成分测量与运动神经元疾病(MND)风险之间的关系:我们在英国生物库中进行了一项队列研究,以评估发育期身体指标和病前身体成分测量(采用 28 种测量方法和 7 种身体成分模式)与 MND 风险之间的关系。在进行了纵向测量的参与者中,我们比较了后来患上MND的人和没有患上MND的人的身体成分随时间的变化:在这项研究的 412,691 名参与者中,有 549 人在随访期间确诊为 MND。出生时体重超过4千克的人患MND的风险较高(每增加1千克的危险比[HR]=2.21,95%置信区间[CI]=1.38-3.55),成人身高较高的人患MND的风险较高(每增加5厘米的危险比[HR]=1.10,95%置信区间[CI]=1.03-1.17)。我们观察到,脂肪量升高与确诊前5年以上罹患MND的风险降低有关。较高的 "腿部脂肪分布 "模式与风险增加有关,而较高的 "肌肉力量 "则与确诊前5年MND风险降低有关。纵向分析表明,与其他人相比,后来患上MND的人的脂肪量和肌肉力量下降得更快,脂肪分布也从以手臂为主转向以腿部为主:解释:早年和中年的身体成分可能预示着MND的发病风险。ann neurol 2024.
{"title":"Association Between Early-Life and Premorbid Measurements of Body Composition and Risk of Motor Neuron Disease: A Prospective Cohort Study in the UK Biobank.","authors":"Emily E Joyce, Shishi Xu, Caroline Ingre, Rosa Luisa Potenza, Christina Seitz, Huazhen Yang, Yu Zeng, Huan Song, Fang Fang","doi":"10.1002/ana.27109","DOIUrl":"https://doi.org/10.1002/ana.27109","url":null,"abstract":"<p><strong>Objective: </strong>The objective of this study was to investigate the association between developmental and premorbid body composition measurements and the risk of motor neuron disease (MND).</p><p><strong>Methods: </strong>We performed a cohort study in the UK Biobank to assess the association of developmental body metrics and premorbid body composition measures (using 28 measurements and 7 patterns of body composition) with the risk of MND. Among participants with longitudinal measures, we compared the changes in body composition over time between individuals who later developed MND and those who remained free of MND.</p><p><strong>Results: </strong>Among the 412,691 individuals included in this study, 549 people received an MND diagnosis during the follow-up visit. Higher birth weight was associated with an increased risk of MND among individuals born over 4 kg (hazard ratio [HR] per kg increase = 2.21, 95% confidence interval [CI] = 1.38-3.55), and taller adult height was associated with an increased risk of MND (HR per 5 cm increase = 1.10, 95% CI = 1.03-1.17). We observed that measures of elevated fat mass were associated with a lower risk of MND more than 5 years before diagnosis. A higher \"leg-dominant fat distribution\" pattern was associated with an increased risk whereas higher \"muscle strength\" was associated with a reduced risk of MND 5 years before diagnosis. Longitudinal analyses indicated a faster decline in measures of fat mass and muscle strength, as well as a shift in fat distribution from arm to leg dominant, among individuals who later developed MND, compared with others.</p><p><strong>Interpretation: </strong>Body composition at early and middle age may be indicative of the risk of MND development. ANN NEUROL 2024.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":null,"pages":null},"PeriodicalIF":8.1,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142491409","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}
引用次数: 0
Polygenic Landscape of Cryptogenic New-Onset Refractory Status Epilepticus: A Comprehensive Whole-Genome Sequencing Study. 隐源性新发难治性癫痫状态的多基因景观:全基因组测序综合研究
IF 8.1 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-10-23 DOI: 10.1002/ana.27100
Yoonhyuk Jang, Sung Eun Hong, Soo Hyun Ahn, Su Yee Mon, Ji Hye You, Kon Chu, Sang Kun Lee, Murim Choi, Soon-Tae Lee

Cryptogenic new-onset refractory status epilepticus (cNORSE) is a devastating condition with unclear pathogenesis. Here, we analyzed the genetic underprints of 31 cNORSE patients from an autoimmune encephalitis observational cohort through whole-genome sequencing. Compared to their controls, cNORSE patients exhibited elevated polygenic risk scores (PRS) for traits associated with autoimmune diseases. The individual PRS against these diseases were correlated with specific clinical phenotypes of cNORSE. The variants were enriched in genes expressed in the central nervous system and lymphocytes. These results suggest a shared genetic framework between cNORSE and other autoimmune/autoinflammatory diseases, and its involvement in the disease pathogenesis. ANN NEUROL 2024.

隐源性新发难治性癫痫(cNORSE)是一种发病机制不明的破坏性疾病。在这里,我们通过全基因组测序分析了来自自身免疫性脑炎观察队列的 31 名 cNORSE 患者的遗传特征。与对照组相比,cNORSE 患者在与自身免疫性疾病相关的特征方面表现出较高的多基因风险评分(PRS)。针对这些疾病的个体PRS与cNORSE的特定临床表型相关。变异富集在中枢神经系统和淋巴细胞中表达的基因中。这些结果表明,cNORSE 与其他自身免疫/自身炎症性疾病之间存在着共同的遗传框架,并与疾病的发病机制有关。ann neurol 2024.
{"title":"Polygenic Landscape of Cryptogenic New-Onset Refractory Status Epilepticus: A Comprehensive Whole-Genome Sequencing Study.","authors":"Yoonhyuk Jang, Sung Eun Hong, Soo Hyun Ahn, Su Yee Mon, Ji Hye You, Kon Chu, Sang Kun Lee, Murim Choi, Soon-Tae Lee","doi":"10.1002/ana.27100","DOIUrl":"https://doi.org/10.1002/ana.27100","url":null,"abstract":"<p><p>Cryptogenic new-onset refractory status epilepticus (cNORSE) is a devastating condition with unclear pathogenesis. Here, we analyzed the genetic underprints of 31 cNORSE patients from an autoimmune encephalitis observational cohort through whole-genome sequencing. Compared to their controls, cNORSE patients exhibited elevated polygenic risk scores (PRS) for traits associated with autoimmune diseases. The individual PRS against these diseases were correlated with specific clinical phenotypes of cNORSE. The variants were enriched in genes expressed in the central nervous system and lymphocytes. These results suggest a shared genetic framework between cNORSE and other autoimmune/autoinflammatory diseases, and its involvement in the disease pathogenesis. ANN NEUROL 2024.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":null,"pages":null},"PeriodicalIF":8.1,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142491411","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}
引用次数: 0
Recessive Variants in PIGG Cause a Motor Neuropathy with Variable Conduction Block, Childhood Tremor, and Febrile Seizures: Expanding the Phenotype. PIGG 的隐性变异会导致具有可变传导阻滞、儿童震颤和热性惊厥的运动神经病:扩展表型。
IF 8.1 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-10-23 DOI: 10.1002/ana.27113
Christopher J Record, Antoinette O'Connor, Nienke E Verbeek, Wouter van Rheenen, Eleni Zamba Papanicolaou, Stojan Peric, Peter C Ligthart, Mariola Skorupinska, Ellen van Binsbergen, Philippe M Campeau, Vukan Ivanovic, Brian Hennigan, John C McHugh, Julian C Blake, Yoshiko Murakami, Matilde Laura, Sinéad M Murphy, Mary M Reilly

Biallelic variants in phosphatidylinositol glycan anchor biosynthesis, class G (PIGG) cause hypotonia, intellectual disability, seizures, and cerebellar features. We present 8 patients from 6 families with a childhood-onset motor neuropathy and neurophysiology demonstrating variable motor conduction block and temporal dispersion. All individuals had a childhood onset tremor, 5 of 8 had cerebellar involvement, and 6 of 8 had childhood febrile seizures. All individuals have biallelic PIGG variants, including the previously reported pathogenic variant Trp505*, plus 6 novel variants. Null enzyme activity is demonstrated via PIGO/PIGG double knockout system for Val339Gly and Gly19Glu, and residual activity for Trp505* due to read-through. Emm negative blood group status was confirmed in 1 family. PIGG should be considered in unsolved motor neuropathy. ANN NEUROL 2024.

磷脂酰肌醇聚糖锚生物合成 G 类(PIGG)的双拷贝变体会导致肌张力低下、智力障碍、癫痫发作和小脑特征。我们介绍了来自 6 个家庭的 8 位患者,他们都患有儿童期发病的运动神经病变,神经生理学表现为不同的运动传导阻滞和颞叶弥散。所有患者均在儿童期发病,8 人中有 5 人有小脑受累,8 人中有 6 人在儿童期有发热性癫痫发作。所有患者都有双叶 PIGG 变异,包括之前报道的致病变异 Trp505*,以及 6 个新型变异。通过PIGO/PIGG双基因敲除系统,Val339Gly和Gly19Glu的酶活性被证明为无效,Trp505*的残余活性则是由于通读所致。1 个家庭的 Emm 阴性血型得到确认。未解决的运动神经病变应考虑 PIGG。ann neurol 2024.
{"title":"Recessive Variants in PIGG Cause a Motor Neuropathy with Variable Conduction Block, Childhood Tremor, and Febrile Seizures: Expanding the Phenotype.","authors":"Christopher J Record, Antoinette O'Connor, Nienke E Verbeek, Wouter van Rheenen, Eleni Zamba Papanicolaou, Stojan Peric, Peter C Ligthart, Mariola Skorupinska, Ellen van Binsbergen, Philippe M Campeau, Vukan Ivanovic, Brian Hennigan, John C McHugh, Julian C Blake, Yoshiko Murakami, Matilde Laura, Sinéad M Murphy, Mary M Reilly","doi":"10.1002/ana.27113","DOIUrl":"https://doi.org/10.1002/ana.27113","url":null,"abstract":"<p><p>Biallelic variants in phosphatidylinositol glycan anchor biosynthesis, class G (PIGG) cause hypotonia, intellectual disability, seizures, and cerebellar features. We present 8 patients from 6 families with a childhood-onset motor neuropathy and neurophysiology demonstrating variable motor conduction block and temporal dispersion. All individuals had a childhood onset tremor, 5 of 8 had cerebellar involvement, and 6 of 8 had childhood febrile seizures. All individuals have biallelic PIGG variants, including the previously reported pathogenic variant Trp505*, plus 6 novel variants. Null enzyme activity is demonstrated via PIGO/PIGG double knockout system for Val339Gly and Gly19Glu, and residual activity for Trp505* due to read-through. Emm negative blood group status was confirmed in 1 family. PIGG should be considered in unsolved motor neuropathy. ANN NEUROL 2024.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":null,"pages":null},"PeriodicalIF":8.1,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142491412","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}
引用次数: 0
Coexistence of Acute Cerebral Infarction and Reversible Posterior Encephalopathy Syndrome in a Patient with Hashimoto's Thyroiditis. 一名桥本氏甲状腺炎患者同时患有急性脑梗塞和可逆性后遗脑病综合征
IF 8.1 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-10-23 DOI: 10.1002/ana.27120
Wan Wang, Juntao Yin
{"title":"Coexistence of Acute Cerebral Infarction and Reversible Posterior Encephalopathy Syndrome in a Patient with Hashimoto's Thyroiditis.","authors":"Wan Wang, Juntao Yin","doi":"10.1002/ana.27120","DOIUrl":"https://doi.org/10.1002/ana.27120","url":null,"abstract":"","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":null,"pages":null},"PeriodicalIF":8.1,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142491410","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}
引用次数: 0
Annals of Neurology: Volume 96, Number 5, November 2024 神经病学年鉴》:第 96 卷第 5 号,2024 年 11 月
IF 8.1 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-10-22 DOI: 10.1002/ana.26706
{"title":"Annals of Neurology: Volume 96, Number 5, November 2024","authors":"","doi":"10.1002/ana.26706","DOIUrl":"https://doi.org/10.1002/ana.26706","url":null,"abstract":"","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":null,"pages":null},"PeriodicalIF":8.1,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ana.26706","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142540930","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}
引用次数: 0
Obesity and Multiple Sclerosis Severity: A Mendelian Randomization Study. 肥胖与多发性硬化症的严重程度:孟德尔随机研究
IF 8.1 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-10-21 DOI: 10.1002/ana.27112
Fatema Alzamanan, Yuan Ding, Adil Harroud

Obesity is implicated in the development of multiple sclerosis (MS), but its effect on disability is less well-established. This study examined the effects of various obesity measures on MS severity in 12,584 MS cases, using Mendelian randomization to mitigate confounding. Results showed a significant association between higher genetically-determined body mass index (N = 806,834) and increased MS severity (P = 0.02). This finding was supported by additional measures of general obesity but not adiposity distribution. The convergence of this genetic evidence with prior observational studies strengthens the association between obesity and adverse long-term disability in MS, suggesting weight management as a potential therapeutic strategy. ANN NEUROL 2024.

肥胖与多发性硬化症(MS)的发病有关,但肥胖对残疾的影响尚未得到充分证实。本研究采用孟德尔随机化方法减轻混杂因素,对 12,584 例多发性硬化症病例中各种肥胖指标对多发性硬化症严重程度的影响进行了研究。结果显示,由基因决定的体重指数越高(N = 806,834),多发性硬化症的严重程度就越高(P = 0.02)。这一发现还得到了其他一般肥胖测量指标的支持,但没有得到脂肪分布测量指标的支持。这一遗传学证据与之前的观察性研究相吻合,加强了肥胖与多发性硬化症长期残疾之间的联系,表明体重管理是一种潜在的治疗策略。ann neurol 2024.
{"title":"Obesity and Multiple Sclerosis Severity: A Mendelian Randomization Study.","authors":"Fatema Alzamanan, Yuan Ding, Adil Harroud","doi":"10.1002/ana.27112","DOIUrl":"https://doi.org/10.1002/ana.27112","url":null,"abstract":"<p><p>Obesity is implicated in the development of multiple sclerosis (MS), but its effect on disability is less well-established. This study examined the effects of various obesity measures on MS severity in 12,584 MS cases, using Mendelian randomization to mitigate confounding. Results showed a significant association between higher genetically-determined body mass index (N = 806,834) and increased MS severity (P = 0.02). This finding was supported by additional measures of general obesity but not adiposity distribution. The convergence of this genetic evidence with prior observational studies strengthens the association between obesity and adverse long-term disability in MS, suggesting weight management as a potential therapeutic strategy. ANN NEUROL 2024.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":null,"pages":null},"PeriodicalIF":8.1,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142453964","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}
引用次数: 0
Fighting Amyotrophic Lateral Sclerosis by Protecting the Liver? A Prospective Cohort Study. 通过保护肝脏对抗肌萎缩性脊髓侧索硬化症?一项前瞻性队列研究
IF 8.1 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-10-19 DOI: 10.1002/ana.27115
Luyi Zhu, Yaojia Li, Xinyue Yu, Yinuo Chen, Junwei Zhang, Chunyang Pang, Jiali Xie, Lingfei Gao, Lihuai Du, Wen Cao, Dongsheng Fan, Can Cui, Huan Yu, Binbin Deng

Background: Previous studies have observed liver abnormalities in amyotrophic lateral sclerosis (ALS) patients. This study aimed to investigate whether early signs of liver disease, measured by magnetic resonance imaging-derived iron-corrected T1-mapping (cT1), are risk factors for developing ALS.

Methods: cT1 and proton density fat fraction were measured and automatically analyzed using LiverMultiScan® software. The Fibrosis-4 index was calculated using an established formula based on age and blood markers. Cox proportional hazard models were used to examine the relationship between liver disease, liver biomarkers, and incident ALS.

Results: In a cohort of 533,707 individuals from UK Biobank, 24 ALS cases were identified among 28,328 participants with liver disease during the follow-up period. Among a total of 33,959 individuals with complete liver imaging data, 15 incident ALS cases were observed during a median follow-up period of 5.6 years. Individuals with liver disease had a higher risk of developing ALS, with an adjusted hazard ratio of 7.35 (95% CI 4.47-12.09; p < 0.001). An increase in cT1 was also associated with a higher risk of ALS. After adjusting for age, sex, Townsend deprivation index, smoking status, alcohol intake frequency, body mass index, proton density fat fraction, Fibrosis-4, and metabolic syndrome, an increase in cT1 remained significantly associated with a higher risk of ALS, with an adjusted hazard ratio of 3.15 (95% CI 1.79-5.55) per 1-SD increase. Sensitivity analyses confirmed these robust results.

Interpretation: Liver disease activity, indicated by cT1, increases the risk of developing ALS, independent of metabolic syndrome, liver fat, or fibrosis. ANN NEUROL 2024.

背景:先前的研究发现肌萎缩侧索硬化症(ALS)患者的肝脏存在异常。本研究旨在探讨通过磁共振成像衍生铁校正T1映射(cT1)测量的肝脏疾病早期症状是否是导致肌萎缩侧索硬化症的风险因素。方法:使用LiverMultiScan®软件测量并自动分析cT1和质子密度脂肪分数。纤维化-4指数是根据年龄和血液标记物的既定公式计算得出的。采用 Cox 比例危险模型研究肝脏疾病、肝脏生物标志物与 ALS 发病之间的关系:结果:在英国生物库的 533,707 人队列中,有 28,328 名参与者在随访期间患有肝病,其中发现了 24 例 ALS 病例。在中位随访期为5.6年的总共33959名有完整肝脏成像数据的参与者中,观察到15例ALS病例。肝病患者罹患 ALS 的风险较高,调整后的危险比为 7.35(95% CI 4.47-12.09;P 解释:以 cT1 为标志的肝病活动会增加 ALS 的发病风险,与代谢综合征、肝脏脂肪或纤维化无关。ann neurol 2024.
{"title":"Fighting Amyotrophic Lateral Sclerosis by Protecting the Liver? A Prospective Cohort Study.","authors":"Luyi Zhu, Yaojia Li, Xinyue Yu, Yinuo Chen, Junwei Zhang, Chunyang Pang, Jiali Xie, Lingfei Gao, Lihuai Du, Wen Cao, Dongsheng Fan, Can Cui, Huan Yu, Binbin Deng","doi":"10.1002/ana.27115","DOIUrl":"https://doi.org/10.1002/ana.27115","url":null,"abstract":"<p><strong>Background: </strong>Previous studies have observed liver abnormalities in amyotrophic lateral sclerosis (ALS) patients. This study aimed to investigate whether early signs of liver disease, measured by magnetic resonance imaging-derived iron-corrected T1-mapping (cT1), are risk factors for developing ALS.</p><p><strong>Methods: </strong>cT1 and proton density fat fraction were measured and automatically analyzed using LiverMultiScan® software. The Fibrosis-4 index was calculated using an established formula based on age and blood markers. Cox proportional hazard models were used to examine the relationship between liver disease, liver biomarkers, and incident ALS.</p><p><strong>Results: </strong>In a cohort of 533,707 individuals from UK Biobank, 24 ALS cases were identified among 28,328 participants with liver disease during the follow-up period. Among a total of 33,959 individuals with complete liver imaging data, 15 incident ALS cases were observed during a median follow-up period of 5.6 years. Individuals with liver disease had a higher risk of developing ALS, with an adjusted hazard ratio of 7.35 (95% CI 4.47-12.09; p < 0.001). An increase in cT1 was also associated with a higher risk of ALS. After adjusting for age, sex, Townsend deprivation index, smoking status, alcohol intake frequency, body mass index, proton density fat fraction, Fibrosis-4, and metabolic syndrome, an increase in cT1 remained significantly associated with a higher risk of ALS, with an adjusted hazard ratio of 3.15 (95% CI 1.79-5.55) per 1-SD increase. Sensitivity analyses confirmed these robust results.</p><p><strong>Interpretation: </strong>Liver disease activity, indicated by cT1, increases the risk of developing ALS, independent of metabolic syndrome, liver fat, or fibrosis. ANN NEUROL 2024.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":null,"pages":null},"PeriodicalIF":8.1,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142453961","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}
引用次数: 0
Comprehensive Analysis of Sex Differences in Amyotrophic Lateral Sclerosis Prognosis and Disease Progression 肌萎缩侧索硬化症预后和疾病进展的性别差异综合分析
IF 8.1 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-10-19 DOI: 10.1002/ana.27092
Liangping Zhang MSc, Xizhuo Zhou MSc, Shuqiang Cha MSc
{"title":"Comprehensive Analysis of Sex Differences in Amyotrophic Lateral Sclerosis Prognosis and Disease Progression","authors":"Liangping Zhang MSc,&nbsp;Xizhuo Zhou MSc,&nbsp;Shuqiang Cha MSc","doi":"10.1002/ana.27092","DOIUrl":"10.1002/ana.27092","url":null,"abstract":"","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":null,"pages":null},"PeriodicalIF":8.1,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142453969","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}
引用次数: 0
RNA Binding Protein Dysfunction Links Smoldering/Slowly Expanding Lesions to Neurodegeneration in Multiple Sclerosis. RNA 结合蛋白功能障碍将多发性硬化症的烟熏/缓慢扩展病变与神经退行性变联系起来。
IF 8.1 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-10-18 DOI: 10.1002/ana.27114
Miranda L Messmer, Hannah E Salapa, Bogdan F Popescu, Michael C Levin

Objective: Despite the advances in treatments for multiple sclerosis (MS), unremitting neurodegeneration continues to drive disability and disease progression. Smoldering/slowly expanding lesions (SELs) and dysfunction of the RNA binding protein (RBP) heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) are pathologic hallmarks of MS cortex and intricately tied to disability and neurodegeneration, respectively. We hypothesized that neuronal hnRNP A1 dysfunction contributes to neurodegeneration and is exacerbated by smoldering/SELs in progressive MS.

Methods: Neuronal hnRNP A1 pathology (nucleocytoplasmic mislocalization of hnRNP A1) was examined in healthy control and MS brains using immunohistochemistry. MS cases were stratified by severity of hnRNP A1 pathology to examine the link between RBP dysfunction, demyelination, and neurodegeneration.

Results: We found that smoldering/SELs were only present within a subset of MS tissues characterized by elevated neuronal hnRNP A1 pathology (MS-A1high) in adjacent cortical gray matter. In contrast to healthy controls and MS with low hnRNP A1 pathology (MS-A1low), MS-A1high showed elevated markers of neurodegeneration, including neuronal loss and injury, brain atrophy, axonal loss, and axon degeneration. Additionally, we discovered a subpopulation of morphologically intact neurons lacking expression of NeuN, a neuron-specific RBP, in cortical projection neurons in MS-A1high cases.

Interpretation: hnRNP A1 dysfunction contributes to neurodegeneration and may be exacerbated by smoldering/SELs in progressive MS. The discovery of NeuN-negative neurons suggests that some cortical neurons may only be injured and not lost. By characterizing RBP pathology in MS cortex, this study has important implications for understanding the pathogenic mechanisms driving neurodegeneration, the substrate of disability and disease progression. ANN NEUROL 2024.

目的:尽管多发性硬化症(MS)的治疗方法不断进步,但持续的神经变性仍在导致残疾和疾病进展。燃烧/缓慢扩展病变(SELs)和 RNA 结合蛋白(RBP)异质核糖核蛋白 A1(hnRNP A1)功能障碍是多发性硬化症皮质的病理特征,分别与残疾和神经变性密切相关。我们假设神经元 hnRNP A1 功能障碍会导致神经变性,并因进行性多发性硬化症中的烟熏/SELs 而加剧:方法:使用免疫组化方法检测健康对照组和多发性硬化症患者大脑中神经元 hnRNP A1 的病理变化(hnRNP A1 的核胞质错定位)。根据 hnRNP A1 病理学的严重程度对多发性硬化症病例进行分层,以研究 RBP 功能障碍、脱髓鞘和神经变性之间的联系:结果:我们发现,烟雾状/SELs仅存在于以邻近皮质灰质中神经元hnRNP A1病理学升高(MS-A1高)为特征的MS组织亚群中。与健康对照组和 hnRNP A1 病理变化较低的 MS(MS-A1-low)相比,MS-A1high 显示出神经变性标志物的升高,包括神经元丢失和损伤、脑萎缩、轴突丢失和轴突变性。此外,我们还在 MS-A1high 病例的皮质投射神经元中发现了一个形态完整的神经元亚群,该亚群缺乏神经元特异性 RBP NeuN 的表达。NeuN阴性神经元的发现表明,一些皮质神经元可能只是受伤而不是丧失。通过描述多发性硬化症皮质中 RBP 的病理特征,这项研究对了解驱动神经变性的致病机制、残疾和疾病进展的基质具有重要意义。ann neurol 2024.
{"title":"RNA Binding Protein Dysfunction Links Smoldering/Slowly Expanding Lesions to Neurodegeneration in Multiple Sclerosis.","authors":"Miranda L Messmer, Hannah E Salapa, Bogdan F Popescu, Michael C Levin","doi":"10.1002/ana.27114","DOIUrl":"https://doi.org/10.1002/ana.27114","url":null,"abstract":"<p><strong>Objective: </strong>Despite the advances in treatments for multiple sclerosis (MS), unremitting neurodegeneration continues to drive disability and disease progression. Smoldering/slowly expanding lesions (SELs) and dysfunction of the RNA binding protein (RBP) heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) are pathologic hallmarks of MS cortex and intricately tied to disability and neurodegeneration, respectively. We hypothesized that neuronal hnRNP A1 dysfunction contributes to neurodegeneration and is exacerbated by smoldering/SELs in progressive MS.</p><p><strong>Methods: </strong>Neuronal hnRNP A1 pathology (nucleocytoplasmic mislocalization of hnRNP A1) was examined in healthy control and MS brains using immunohistochemistry. MS cases were stratified by severity of hnRNP A1 pathology to examine the link between RBP dysfunction, demyelination, and neurodegeneration.</p><p><strong>Results: </strong>We found that smoldering/SELs were only present within a subset of MS tissues characterized by elevated neuronal hnRNP A1 pathology (MS-A1<sup>high</sup>) in adjacent cortical gray matter. In contrast to healthy controls and MS with low hnRNP A1 pathology (MS-A1<sup>low</sup>), MS-A1<sup>high</sup> showed elevated markers of neurodegeneration, including neuronal loss and injury, brain atrophy, axonal loss, and axon degeneration. Additionally, we discovered a subpopulation of morphologically intact neurons lacking expression of NeuN, a neuron-specific RBP, in cortical projection neurons in MS-A1<sup>high</sup> cases.</p><p><strong>Interpretation: </strong>hnRNP A1 dysfunction contributes to neurodegeneration and may be exacerbated by smoldering/SELs in progressive MS. The discovery of NeuN-negative neurons suggests that some cortical neurons may only be injured and not lost. By characterizing RBP pathology in MS cortex, this study has important implications for understanding the pathogenic mechanisms driving neurodegeneration, the substrate of disability and disease progression. ANN NEUROL 2024.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":null,"pages":null},"PeriodicalIF":8.1,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142453965","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}
引用次数: 0
Clemastine Induces Oligodendrocyte Progenitor Pool Exhaustion and Senescence in the Context of Chronic Demyelination in a Rabbit Model. 氯马斯汀诱导兔模型中慢性脱髓鞘背景下的少突胶质细胞祖细胞池耗竭和衰老
IF 8.1 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-10-18 DOI: 10.1002/ana.27098
James J M Cooper, Rupadevi Muthaiah, Jon R Frost, Gregory T Buck, Roopa Ravichandar, Farah Gadelkarim, Faye D Raymond, Fraser J Sim

Objectives: Clemastine has emerged as a promising therapy for the restoration of neurologic function in patients with multiple sclerosis (MS). However, clemastine and other agents with prodifferentiative effects on oligodendrocyte progenitor cells (OPCs) in rodent models have underperformed in clinical trials. We hypothesized that the preclinical studies showed more robust effects because of the abundance of OPCs in rodent models. To better examine the therapeutic potential of clemastine, we examined its effect on demyelinated white matter lesions in rabbits, which exhibit progenitor densities and limited remyelination more closely matching those found in tissues from patients with MS.

Methods: We used lysolecithin to induce demyelination in white matter of New Zealand rabbits and then administered oral clemastine (10mg/kg/day) for various periods before assessing the OPC and oligodendrocyte (OL) populations in these lesions.

Results: Daily administration of clemastine for the full study period (56 days) increased oligodendrogenesis in white matter lesions. However, shorter durations of treatment failed to increase overall OL density despite enhancing OPC-to-OL differentiation. This effect was due to exhaustion of the OPC pool, as the differentiating progenitors were not replaced because of reduced OPC proliferation. Notably, delayed administration of clemastine led to an accumulation of activated OPCs expressing markers of senescence.

Interpretation: Although capable of driving OL differentiation, clemastine treatment in rabbits hampered progenitor pool replenishment, induced senescence, and promoted conversion of microglia/macrophages to a proinflammatory phenotype. Whether these effects would also occur in humans or with other prodifferentiative therapies should be studied further, but our data suggest the need to carefully consider progenitor dynamics in the treatment of MS. ANN NEUROL 2024.

目的:氯马斯汀已成为恢复多发性硬化症(MS)患者神经功能的一种有前途的疗法。然而,在啮齿类动物模型中,氯马斯汀和其他对少突胶质祖细胞(OPC)具有促分化作用的药物在临床试验中表现不佳。我们假设,由于啮齿类动物模型中存在大量 OPCs,因此临床前研究显示出了更强大的效果。为了更好地研究氯马斯汀的治疗潜力,我们研究了它对兔子脱髓鞘白质病变的影响,这些病变表现出的祖细胞密度和有限的再髓鞘化更接近多发性硬化症患者组织中发现的情况:我们使用溶血卵磷脂诱导新西兰兔白质脱髓鞘,然后在不同时期口服氯马斯汀(10 毫克/千克/天),然后评估这些病变中的 OPC 和少突胶质细胞(OL)数量:结果:在整个研究期间(56 天)每天服用氯马斯汀可增加白质病变中的少突胶质细胞数量。然而,较短的治疗时间虽然能增强OPC到OL的分化,但却不能增加OL的整体密度。这种效应是由于OPC池耗竭所致,因为OPC增殖减少导致分化祖细胞无法替代。值得注意的是,延迟服用氯马斯汀会导致表达衰老标记的活化 OPC 累积:兔子体内的氯马斯汀虽然能驱动OL分化,但它阻碍了祖细胞池的补充,诱导了衰老,并促进了小胶质细胞/巨噬细胞向促炎表型的转化。这些影响是否也会发生在人类身上或其他促分化治疗中,还有待进一步研究,但我们的数据表明,在治疗多发性硬化症时需要仔细考虑祖细胞的动态变化。ann neurol 2024.
{"title":"Clemastine Induces Oligodendrocyte Progenitor Pool Exhaustion and Senescence in the Context of Chronic Demyelination in a Rabbit Model.","authors":"James J M Cooper, Rupadevi Muthaiah, Jon R Frost, Gregory T Buck, Roopa Ravichandar, Farah Gadelkarim, Faye D Raymond, Fraser J Sim","doi":"10.1002/ana.27098","DOIUrl":"https://doi.org/10.1002/ana.27098","url":null,"abstract":"<p><strong>Objectives: </strong>Clemastine has emerged as a promising therapy for the restoration of neurologic function in patients with multiple sclerosis (MS). However, clemastine and other agents with prodifferentiative effects on oligodendrocyte progenitor cells (OPCs) in rodent models have underperformed in clinical trials. We hypothesized that the preclinical studies showed more robust effects because of the abundance of OPCs in rodent models. To better examine the therapeutic potential of clemastine, we examined its effect on demyelinated white matter lesions in rabbits, which exhibit progenitor densities and limited remyelination more closely matching those found in tissues from patients with MS.</p><p><strong>Methods: </strong>We used lysolecithin to induce demyelination in white matter of New Zealand rabbits and then administered oral clemastine (10mg/kg/day) for various periods before assessing the OPC and oligodendrocyte (OL) populations in these lesions.</p><p><strong>Results: </strong>Daily administration of clemastine for the full study period (56 days) increased oligodendrogenesis in white matter lesions. However, shorter durations of treatment failed to increase overall OL density despite enhancing OPC-to-OL differentiation. This effect was due to exhaustion of the OPC pool, as the differentiating progenitors were not replaced because of reduced OPC proliferation. Notably, delayed administration of clemastine led to an accumulation of activated OPCs expressing markers of senescence.</p><p><strong>Interpretation: </strong>Although capable of driving OL differentiation, clemastine treatment in rabbits hampered progenitor pool replenishment, induced senescence, and promoted conversion of microglia/macrophages to a proinflammatory phenotype. Whether these effects would also occur in humans or with other prodifferentiative therapies should be studied further, but our data suggest the need to carefully consider progenitor dynamics in the treatment of MS. ANN NEUROL 2024.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":null,"pages":null},"PeriodicalIF":8.1,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142453943","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}
引用次数: 0
期刊
Annals of Neurology
全部 Acc. Chem. Res. ACS Applied Bio Materials ACS Appl. Electron. Mater. ACS Appl. Energy Mater. ACS Appl. Mater. Interfaces ACS Appl. Nano Mater. ACS Appl. Polym. Mater. ACS BIOMATER-SCI ENG ACS Catal. ACS Cent. Sci. ACS Chem. Biol. ACS Chemical Health & Safety ACS Chem. Neurosci. ACS Comb. Sci. ACS Earth Space Chem. ACS Energy Lett. ACS Infect. Dis. ACS Macro Lett. ACS Mater. Lett. ACS Med. Chem. Lett. ACS Nano ACS Omega ACS Photonics ACS Sens. ACS Sustainable Chem. Eng. ACS Synth. Biol. Anal. Chem. BIOCHEMISTRY-US Bioconjugate Chem. BIOMACROMOLECULES Chem. Res. Toxicol. Chem. Rev. Chem. Mater. CRYST GROWTH DES ENERG FUEL Environ. Sci. Technol. Environ. Sci. Technol. Lett. Eur. J. Inorg. Chem. IND ENG CHEM RES Inorg. Chem. J. Agric. Food. Chem. J. Chem. Eng. Data J. Chem. Educ. J. Chem. Inf. Model. J. Chem. Theory Comput. J. Med. Chem. J. Nat. Prod. J PROTEOME RES J. Am. Chem. Soc. LANGMUIR MACROMOLECULES Mol. Pharmaceutics Nano Lett. Org. Lett. ORG PROCESS RES DEV ORGANOMETALLICS J. Org. Chem. J. Phys. Chem. J. Phys. Chem. A J. Phys. Chem. B J. Phys. Chem. C J. Phys. Chem. Lett. Analyst Anal. Methods Biomater. Sci. Catal. Sci. Technol. Chem. Commun. Chem. Soc. Rev. CHEM EDUC RES PRACT CRYSTENGCOMM Dalton Trans. Energy Environ. Sci. ENVIRON SCI-NANO ENVIRON SCI-PROC IMP ENVIRON SCI-WAT RES Faraday Discuss. Food Funct. Green Chem. Inorg. Chem. Front. Integr. Biol. J. Anal. At. Spectrom. J. Mater. Chem. A J. Mater. Chem. B J. Mater. Chem. C Lab Chip Mater. Chem. Front. Mater. Horiz. MEDCHEMCOMM Metallomics Mol. Biosyst. Mol. Syst. Des. Eng. Nanoscale Nanoscale Horiz. Nat. Prod. Rep. New J. Chem. Org. Biomol. Chem. Org. Chem. Front. PHOTOCH PHOTOBIO SCI PCCP Polym. Chem.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1