Bachmann D, Wybitul M, Studer S, et al. Protective effects of socioeconomic status and lifestyle on amyloid- and white matter hyperintensity-related longitudinal brain atrophy and cognitive decline. Ann Neurol 2025. 10.1002/ana.70022.
In the caption of Figure 4, high SES was incorrectly reported and should be replaced with low SES. The corrected sentence reads: “The mediating effect of gray matter (GM) atrophy is more pronounced in individuals with low socioeconomic status (SES) because of faster amyloid-beta (Aβ)-related GM atrophy rates.”
In the Statistical Analysis section and the caption of Figure 4, the description of voxel-wise analyses was inaccurate. The correct criteria are: voxel-level p < 0.001; cluster-level p < 0.001, rather than the originally reported voxel-level p < 0.001; cluster-level p < 0.05.
These corrections do not affect the data, interpretation, or conclusions of the study.
The authors apologize for these errors in the originally published article.
{"title":"Correction to “Protective Effects of Socioeconomic Status and Lifestyle on Amyloid- and White Matter Hyperintensity-Related Longitudinal Brain Atrophy and Cognitive Decline”","authors":"Dario Bachmann PhD, Valerie Treyer PhD","doi":"10.1002/ana.78058","DOIUrl":"10.1002/ana.78058","url":null,"abstract":"<p>Bachmann D, Wybitul M, Studer S, et al. Protective effects of socioeconomic status and lifestyle on amyloid- and white matter hyperintensity-related longitudinal brain atrophy and cognitive decline. Ann Neurol 2025. 10.1002/ana.70022.</p><p>In the caption of Figure 4, <i>high SES</i> was incorrectly reported and should be replaced with <i>low SES</i>. The corrected sentence reads: “The mediating effect of gray matter (GM) atrophy is more pronounced in individuals with low socioeconomic status (SES) because of faster amyloid-beta (Aβ)-related GM atrophy rates.”</p><p>In the Statistical Analysis section and the caption of Figure 4, the description of voxel-wise analyses was inaccurate. The correct criteria are: voxel-level <i>p</i> < 0.001; cluster-level <i>p</i> < 0.001, rather than the originally reported voxel-level <i>p</i> < 0.001; cluster-level <i>p</i> < 0.05.</p><p>These corrections do not affect the data, interpretation, or conclusions of the study.</p><p>The authors apologize for these errors in the originally published article.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":"98 6","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ana.78058","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145249095","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}
Yun-Xiang Zhou MSc, Zheng-Yang Peng MSc, Wen-Bo Wang MD
{"title":"Clarifying the Moderating Role of Socioeconomic Status on Amyloid-Related Gray Matter Atrophy","authors":"Yun-Xiang Zhou MSc, Zheng-Yang Peng MSc, Wen-Bo Wang MD","doi":"10.1002/ana.78059","DOIUrl":"10.1002/ana.78059","url":null,"abstract":"","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":"98 6","pages":"1397-1398"},"PeriodicalIF":7.7,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145237611","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}
<p>To the Editor,</p><p>We thank Drs. Zhou, Peng, and Wang for their interest and thoughtful comments on our recent article, “Protective Effects of Socioeconomic Status and Lifestyle on Amyloid- and White Matter Hyperintensity-Related Longitudinal Brain Atrophy and Cognitive Decline.”<span><sup>1</sup></span> We appreciate the opportunity to clarify and expand on several points raised in their letter.</p><p>First, we acknowledge the inconsistency between the caption of figure 4 and the main text. The caption incorrectly states that “The mediating effect of gray matter (GM) atrophy is more pronounced in individuals with <i>high</i> socioeconomic status (SES)…” However, as indicated in figure 4 and correctly described in the text, the association between amyloid (Aβ) positron emission tomography (PET) burden and Aβ-related GM atrophy is more pronounced in individuals with <i>low</i> SES. Importantly, all other references to this effect are accurate, and this error does not alter our interpretation or conclusions. We apologize for the oversight, and we thank the authors of the letter for their careful reading of our study. A correction is published with this reply.</p><p>Second, in our original analysis we applied a median split for the moderated mediation analysis to simplify both the analysis and visualization of our results. We consider it unlikely that this approach biased our findings, as the initial models predicting cognitive performance treated SES as a continuous variable and similar patterns also emerged when we repeated the analysis separately in men and women using gender-specific medians (see Fig S4 in the Supplementary Materials in our original article). To further clarify, we now conducted a Johnson–Neyman analysis (Fig 1A), which produced results consistent with our initial median split approach, while providing additional information by identifying that the interaction between Aβ standardized uptake value ratio and education was no longer significant above 18 years of education. The low- and high-SES group-specific coefficients and confidence intervals are already provided in the mediation models (Figures 4C and 4E in our original article).</p><p>Third, in our study we modeled SES as a latent variable to capture its multi-dimensional nature and reduce multiple comparisons. We agree that examining individual SES indicators is informative, particularly because years of education had a very high factor loading. In response to the letter, we, therefore, ran separate linear regression models (adjusted for age, sex, and APOE4 status) testing interactions between Aβ PET burden and years of education, occupation, and net income. Educational complexity was not included separately because of its strong correlation with years of education (Spearman's ρ = 0.81, Fig 1C in our original article). These analyses (Fig 1B–D) suggest that both years of education and net income, but not occupation, moderate Aβ-related GM atrophy. When including both in
我们感谢编辑。周、彭和王对我们最近的文章“社会经济地位和生活方式对淀粉样蛋白和白质高强度相关的纵向脑萎缩和认知能力下降的保护作用”感兴趣并发表了深思熟虑的评论。“我们感谢有机会澄清和阐述他们信中提出的几点。首先，我们承认图4的标题与正文不一致。标题错误地指出“灰质（GM）萎缩的中介作用在高社会经济地位（SES）的个体中更为明显……”然而，如图4所示，并在文本中正确描述，淀粉样蛋白（Aβ）正电子发射断层扫描（PET）负担与Aβ相关的GM萎缩之间的关联在低社会经济地位的个体中更为明显。重要的是，所有其他关于这个效应的参考都是准确的，这个错误不会改变我们的解释或结论。我们为疏忽道歉，并感谢这封信的作者仔细阅读了我们的研究。在此回复中发表了更正。其次，在我们的原始分析中，我们对有调节的中介分析应用了中位数分割，以简化分析和结果的可视化。我们认为这种方法不太可能使我们的研究结果产生偏差，因为预测认知表现的初始模型将SES视为连续变量，当我们使用特定性别的中位数分别在男性和女性中重复分析时，也出现了类似的模式（见原始文章补充材料中的图S4）。为了进一步澄清，我们现在进行了Johnson-Neyman分析（图1A），其结果与我们最初的中位数分裂方法一致，同时通过确定a β标准化摄取值比与受教育程度之间的相互作用在18年以上不再显著提供了额外的信息。中介模型中已经提供了特定于低ses和高ses群体的系数和置信区间（原始文章中的图4C和图4E）。第三，在我们的研究中，我们将社会经济地位建模为一个潜在变量，以捕捉其多维性并减少多重比较。我们同意，检查个人社会经济地位指标是有益的，特别是因为教育年限具有非常高的因素负荷。因此，在回复这封信时，我们运行了单独的线性回归模型（调整了年龄、性别和APOE4状态）来测试Aβ PET负担与受教育年限、职业和净收入之间的相互作用。教育复杂性没有单独包括，因为它与受教育年限有很强的相关性（Spearman的ρ = 0.81，在我们的原始文章中见图1C）。这些分析（图1B-D）表明，受教育年限和净收入，而不是职业，都可以调节a β相关的GM萎缩。当在同一模型中包含这两种相互作用时，Aβ ×净收入仍然显著（β = 0.0026, p = 0.016），而Aβ ×受教育年限是边际的（β = 0.002, p = 0.052）。总之，这些互补分析支持了我们研究结果的稳健性，并提供了初步证据，证明教育和净收入独立影响a β相关的GM萎缩率。要证实这些结果，更大规模的研究将非常重要。达里奥·巴赫曼：可视化；写作——原稿；正式的分析。瓦莱丽·特雷耶：写作-评论和编辑。
{"title":"Reply to “Clarifying the Moderating Role of Socioeconomic Status on Amyloid-Related Gray Matter Atrophy”","authors":"Dario Bachmann PhD, Valerie Treyer PhD","doi":"10.1002/ana.78057","DOIUrl":"10.1002/ana.78057","url":null,"abstract":"<p>To the Editor,</p><p>We thank Drs. Zhou, Peng, and Wang for their interest and thoughtful comments on our recent article, “Protective Effects of Socioeconomic Status and Lifestyle on Amyloid- and White Matter Hyperintensity-Related Longitudinal Brain Atrophy and Cognitive Decline.”<span><sup>1</sup></span> We appreciate the opportunity to clarify and expand on several points raised in their letter.</p><p>First, we acknowledge the inconsistency between the caption of figure 4 and the main text. The caption incorrectly states that “The mediating effect of gray matter (GM) atrophy is more pronounced in individuals with <i>high</i> socioeconomic status (SES)…” However, as indicated in figure 4 and correctly described in the text, the association between amyloid (Aβ) positron emission tomography (PET) burden and Aβ-related GM atrophy is more pronounced in individuals with <i>low</i> SES. Importantly, all other references to this effect are accurate, and this error does not alter our interpretation or conclusions. We apologize for the oversight, and we thank the authors of the letter for their careful reading of our study. A correction is published with this reply.</p><p>Second, in our original analysis we applied a median split for the moderated mediation analysis to simplify both the analysis and visualization of our results. We consider it unlikely that this approach biased our findings, as the initial models predicting cognitive performance treated SES as a continuous variable and similar patterns also emerged when we repeated the analysis separately in men and women using gender-specific medians (see Fig S4 in the Supplementary Materials in our original article). To further clarify, we now conducted a Johnson–Neyman analysis (Fig 1A), which produced results consistent with our initial median split approach, while providing additional information by identifying that the interaction between Aβ standardized uptake value ratio and education was no longer significant above 18 years of education. The low- and high-SES group-specific coefficients and confidence intervals are already provided in the mediation models (Figures 4C and 4E in our original article).</p><p>Third, in our study we modeled SES as a latent variable to capture its multi-dimensional nature and reduce multiple comparisons. We agree that examining individual SES indicators is informative, particularly because years of education had a very high factor loading. In response to the letter, we, therefore, ran separate linear regression models (adjusted for age, sex, and APOE4 status) testing interactions between Aβ PET burden and years of education, occupation, and net income. Educational complexity was not included separately because of its strong correlation with years of education (Spearman's ρ = 0.81, Fig 1C in our original article). These analyses (Fig 1B–D) suggest that both years of education and net income, but not occupation, moderate Aβ-related GM atrophy. When including both in","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":"98 6","pages":"1398-1399"},"PeriodicalIF":7.7,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ana.78057","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145237528","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}
Hormos Salimi Dafsari MD, Celine Deneubourg PhD, Kritarth Singh PhD, Reza Maroofian PhD, Zita Suprenant MD, MPH, Ay Lin Kho PhD, Neil J Ingham PhD, Karen P Steel PhD, Preethi Sheshadri PhD, Franciska Baur MD, Lea Hentrich, Birgit Gerisch PhD, Mina Zamani PhD, Cesar Alves MD, PhD, Ata Siddiqui MD, Haidar S Dafsari MD, Mehri Salari MD, Anthony E. Lang MD, Michael Harris MA, Alice Abdelaleem MD, Saeid Sadeghian MD, Reza Azizimalamiri MD, Hamid Galehdari PhD, Gholamreza Shariati PhD, Alireza Sedaghat MD, Jawaher Zeighami MD, Daniel Calame MD, PhD, Dana Marafi MD, MSc, Ruizhi Duan PhD, Adrian Boehnke BS, Gary D. Clark MD, Jill A. Rosenfeld MS, Carrie A. Mohila MD, PhD, Dora Steel MD, Saurabh Chopra MD, Suvasini Sharma MD, Nicolai Kohlschmidt MD, Steffi Patzer MD, Afshin Saffari MD, Darius Ebrahimi-Fakhari MD, PhD, Büşra Eser Çavdartepe MD, Irene J Chang MD, Erika Beckman MS, CGC, Renate Peters MD, Andrew Paul Fennell MD, Bernice Lo PhD, Luisa Averdunk MD, Felix Distelmaier MD, Martina Baethmann MD, Frances Elmslie MD(res), Kairit Joost MD, PhD, Sheela Nampoothiri MNAMS, MSc, Dhanya Yesodharan MD, Hanna Mandel MD, Amy Kimball MS, Antonie D. Kline MD, Cyril Mignot MD, PhD, Boris Keren MD, Vincent Laugel MD, PhD, Katrin Õunap MD, PhD, Kalpana Devadathan MD, Frederique M.C. van Berkestijn MD, Arpana Silwal MD, MSc, Saskia Koene MD, PhD, Sumit Verma MD, Mohammed Yousuf Karim MBBChir, Chahynez Boubidi MD, PhD, Majid Aziz MD, Gehad ElGhazali MD, PhD, Lauren Mattas MS, CGC, Mohammad Miryounesi MD, PhD, Farzad Hashemi-Gorji MSc, Shahryar Alavi MSc, Nayereh Nouri MSc, Mehrdad Noruzinia MD, Saeideh Kavousi PhD, Arveen Kamath MD, Sandeep Jayawant MD, Russell Saneto PhD, Nourelhoda A. Haridy MD, Pinar Ozkan Kart MD, Ali Cansu MD, Madeleine Joubert MD, Claire Beneteau MD, Kyra E. Stuurman MD, Martina Wilke PhD, Tahsin Stefan Barakat MD, PhD, Homa Tajsharghi PhD, Annarita Scardamaglia BSc, Sadeq Vallian MSc, PhD, Semra Hız MD, Ali Shoeibi MD, Reza Boostani MD, Narges Hashemi MD, Meisam Babaei MD, Norah Saleh Alsaleh MD, Julie Porter MD, PhD, Tania Attié-Bitach MD, PhD, Pauline Marzin MD, Dorota Wicher MD, PhD, Jessica I. Gold MD, PhD, Elisabeth Schuler MD, Amna Kashgari MD, Rakan F. Alanazi MD, Wafaa Eyaid MD, Marc Engelen MD, PhD, Mirjam Langeveld MD, Burkhard Stüve MD, Yun Li, Gökhan Yigit PhD, Bernd Wollnik MD, Mariana H.G Monje MD, PhD, Dimitri Krainc MD, PhD, Niccolò E. Mencacci MD, PhD, Somayeh Bakhtiari PhD, Michael Kruer MD, Emanuela Argilli PhD, Elliott Sherr MD, PhD, Yalda Jamshidi PhD, Ehsan Ghayoor Karimiani MD, MRes, PhD, Yiu Wing Sunny Cheung PhD, Ivan Karin MD, Giovanni Zifarelli PhD, Peter Bauer MD, Wendy K Chung MD, PhD, James R. Lupski MD, PhD, Manju A. Kurian PhD, Jörg Dötsch MD, Jürgen-Christoph von Kleist-Retzow MD, Thomas Klopstock MD, Matias Wagner MD, Calvin Yip PhD, Andreas Roos PhD, Rita Carsetti MD, Carlo Dionisi-Vici MD, Mathias Gautel MD, PhD, Michael R Duchen PhD, Adam Antebi PhD, Henry Houlden MD, PhD, Manolis Fanto PhD, Heinz Jungbluth MD, PhD
Objective
Autophagy is a fundamental biological pathway with vital roles in intracellular homeostasis. During autophagy, defective cargoes including mitochondria are targeted to lysosomes for clearance and recycling. Recessive truncating variants in the autophagy gene EPG5 have been associated with Vici syndrome, a severe early-onset neurodevelopmental disorder with extensive multisystem involvement. Here, we aimed to delineate the extended, age-dependent EPG5-related disease spectrum.
Methods
We investigated clinical, radiological, and molecular features from the largest cohort of EPG5-related patients identified to date, complemented by experimental investigation of cellular and animal models of EPG5 defects.
Results
Through worldwide collaboration, we identified 211 patients, 97 of them previously unpublished, with recessive EPG5 variants. The phenotypic spectrum ranged from antenatally lethal presentations to milder isolated neurodevelopmental disorders. A novel Epg5 knock-in mouse model of a recurrent EPG5 missense variant featured motor impairments and defective autophagy in brain areas particularly relevant for the neurological disorders in milder presentations. Novel age-dependent neurodegenerative manifestations in our cohort included adolescent-onset parkinsonism and dystonia with cognitive decline, and myoclonus. Radiological features suggested an emerging continuum with brain iron accumulation disorders. Patient fibroblasts showed defects in PINK1-Parkin-dependent mitophagic clearance and α-synuclein overexpression, indicating a cellular basis for the observed neurodegenerative phenotypes. In Caenorhabditis elegans, EPG5 knockdown caused motor impairments, defective mitophagic clearance, and changes in mitochondrial respiration comparable to observations in C. elegans knockdown of parkinsonism-related genes.
Interpretation
Our findings illustrate a lifetime neurological disease continuum associated with pathogenic EPG5 variants, linking neurodevelopmental and neurodegenerative disorders through the common denominator of defective autophagy. ANN NEUROL 2025;98:932–950
Samuel S. Bruce MD, MA, Hooman Kamel MD, MS, Santosh B. Murthy MD, MPH
{"title":"Reply to “Methodological Considerations in the Nationwide Cohort Study of Cerebral Amyloid Angiopathy”","authors":"Samuel S. Bruce MD, MA, Hooman Kamel MD, MS, Santosh B. Murthy MD, MPH","doi":"10.1002/ana.78019","DOIUrl":"10.1002/ana.78019","url":null,"abstract":"","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":"98 5","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145211112","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}
Laura Ghezzi, Peter Kosa, Mark Greenwood, Enrique Alvarez, C L Freedman, Anne H Cross, Francesca Pace, Mark S Freedman, Joanna Kocot, Laura Piccio, Bibiana Bielekova
Objective: The growing demand for personalized treatment in multiple sclerosis (MS) highlights the need for more precise biomarkers that can outperform magnetic resonance imaging and clinical assessment in patient stratification. Advances in multiplex proteomic technologies suggest that cerebrospinal fluid (CSF) analysis at MS onset may not only improve diagnostic accuracy, but also offer prognostic and staging information, as well as insight into molecular therapeutic targets.
Methods: This multicenter study retrospectively analyzed cryopreserved CSF samples from 160 individuals undergoing diagnostic evaluation for possible neuroimmunological disorder, and among these, followed a cohort of 96 people with confirmed MS for at least 3 years. The goal was to externally validate previously published CSF-based diagnostic and prognostic classifiers.
Results: Upon unblinding, the CSF-based molecular diagnostic test distinguished 96 people with confirmed MS from 30 individuals with other inflammatory neurological diseases, and 34 individuals with non-inflammatory neurological diseases, achieving an area under the receiver operating characteristic curve of 0.94 (p = 4.7 × 10-21). The test also differentiated 65 individuals with relapsing-remitting MS from 31 individuals with progressive MS, with an area under the receiver operating characteristic curve of 0.76 (p = 1.4 × 10-5). The prognostic classifier predicted prospectively measured Expanded Disability Status Scale scores at follow up (rho = 0.43, p = 2.54 × 10-5).
Interpretation: This multicenter external validation study demonstrates that CSF-based molecular tests can robustly distinguish MS from other neurological conditions, stratify MS subtypes, and predict future disability progression in real-world settings. These results lay the groundwork for development of next-generation molecular tools to personalize care in MS. ANN NEUROL 2025.
{"title":"From Diagnosis to Disease Staging: Multisite Validation of Cerebrospinal Fluid Molecular Tests in Multiple Sclerosis.","authors":"Laura Ghezzi, Peter Kosa, Mark Greenwood, Enrique Alvarez, C L Freedman, Anne H Cross, Francesca Pace, Mark S Freedman, Joanna Kocot, Laura Piccio, Bibiana Bielekova","doi":"10.1002/ana.78047","DOIUrl":"https://doi.org/10.1002/ana.78047","url":null,"abstract":"<p><strong>Objective: </strong>The growing demand for personalized treatment in multiple sclerosis (MS) highlights the need for more precise biomarkers that can outperform magnetic resonance imaging and clinical assessment in patient stratification. Advances in multiplex proteomic technologies suggest that cerebrospinal fluid (CSF) analysis at MS onset may not only improve diagnostic accuracy, but also offer prognostic and staging information, as well as insight into molecular therapeutic targets.</p><p><strong>Methods: </strong>This multicenter study retrospectively analyzed cryopreserved CSF samples from 160 individuals undergoing diagnostic evaluation for possible neuroimmunological disorder, and among these, followed a cohort of 96 people with confirmed MS for at least 3 years. The goal was to externally validate previously published CSF-based diagnostic and prognostic classifiers.</p><p><strong>Results: </strong>Upon unblinding, the CSF-based molecular diagnostic test distinguished 96 people with confirmed MS from 30 individuals with other inflammatory neurological diseases, and 34 individuals with non-inflammatory neurological diseases, achieving an area under the receiver operating characteristic curve of 0.94 (p = 4.7 × 10<sup>-21</sup>). The test also differentiated 65 individuals with relapsing-remitting MS from 31 individuals with progressive MS, with an area under the receiver operating characteristic curve of 0.76 (p = 1.4 × 10<sup>-5</sup>). The prognostic classifier predicted prospectively measured Expanded Disability Status Scale scores at follow up (rho = 0.43, p = 2.54 × 10<sup>-5</sup>).</p><p><strong>Interpretation: </strong>This multicenter external validation study demonstrates that CSF-based molecular tests can robustly distinguish MS from other neurological conditions, stratify MS subtypes, and predict future disability progression in real-world settings. These results lay the groundwork for development of next-generation molecular tools to personalize care in MS. ANN NEUROL 2025.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145211162","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}
{"title":"Neurosyphilis with Abnormal in the Bilateral Pons and Multifocal Cranial Nerve Enhancement.","authors":"Yu Zhang, Peng Chao, Ling Liu","doi":"10.1002/ana.78055","DOIUrl":"https://doi.org/10.1002/ana.78055","url":null,"abstract":"","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145197576","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}
Oleksandr Dergai, Joanne Wuu, Magdalena Koziczak-Holbro, Andrea Malaspina, Volkan Granit, Jessica P Hernandez, Anne Cooley, Ruchika Sachdev, Lili Yu, Michael Bidinosti, Ludivine Flotte, Mark Nash, Lori L Jennings, James D Berry, Lucie I Bruijn, Sophie Brachat, Michael Benatar
Objective: Biomarkers with clear contexts of use are important tools for amyotrophic lateral sclerosis (ALS) therapy development. Understanding their longitudinal trajectory in the untreated state is key to their use as potential markers of pharmacodynamic response. To this end, we undertook a large-scale proteomic study in well-phenotyped cohorts to identify biomarker candidates of ALS disease state and disease progression.
Methods: Clinical phenotypic data and biofluid samples, collected from patients with ALS and healthy controls through multiple longitudinal natural history studies, were used to identify biomarker candidates. Slow off-rate modified aptamer (SOMAmer)-based relatively quantitative measurement of ~7,000 proteins was performed in plasma and cerebrospinal fluid (CSF), with immunoassay validation of candidates of interest.
Results: We identified 329 plasma proteins significantly differentially regulated between ALS and controls (adjusted p-value <0.05), with 25 showing >40% relative abundance. PDLIM3, TNNT2, and MYL11 had the greatest log-fold elevation, whereas ANTXR2 and ART3 had the greatest log-fold reduction. A similar set of plasma proteins was found to increase (eg, PDLIM3, TNNT2, and MYL11) or decrease (eg, ANTXR2, ART3, and MSTN) with disease progression. CSF proteins with the greatest log-fold elevation included NEFL, NEFH, CHIT1, CA3, MYL11, and GPNMB. These results were confirmed in an independent replication cohort. Moreover, tissue-specific signature enrichment suggests a significant contribution of muscle as a source of these biomarkers. Plasma KCNIP3 was elevated by ~60% in those on riluzole. Immunoassays provided orthogonal validation of plasma TNNT2 and CSF GPNMB.
Interpretation: We identified an array of novel biomarkers with the potential to serve as response biomarkers to aid therapy development, as well as to shed light on the underlying biology of disease. ANN NEUROL 2025.
{"title":"Skeletal Muscle Biomarkers of Amyotrophic Lateral Sclerosis: A Large-Scale, Multi-Cohort Proteomic Study.","authors":"Oleksandr Dergai, Joanne Wuu, Magdalena Koziczak-Holbro, Andrea Malaspina, Volkan Granit, Jessica P Hernandez, Anne Cooley, Ruchika Sachdev, Lili Yu, Michael Bidinosti, Ludivine Flotte, Mark Nash, Lori L Jennings, James D Berry, Lucie I Bruijn, Sophie Brachat, Michael Benatar","doi":"10.1002/ana.78046","DOIUrl":"10.1002/ana.78046","url":null,"abstract":"<p><strong>Objective: </strong>Biomarkers with clear contexts of use are important tools for amyotrophic lateral sclerosis (ALS) therapy development. Understanding their longitudinal trajectory in the untreated state is key to their use as potential markers of pharmacodynamic response. To this end, we undertook a large-scale proteomic study in well-phenotyped cohorts to identify biomarker candidates of ALS disease state and disease progression.</p><p><strong>Methods: </strong>Clinical phenotypic data and biofluid samples, collected from patients with ALS and healthy controls through multiple longitudinal natural history studies, were used to identify biomarker candidates. Slow off-rate modified aptamer (SOMAmer)-based relatively quantitative measurement of ~7,000 proteins was performed in plasma and cerebrospinal fluid (CSF), with immunoassay validation of candidates of interest.</p><p><strong>Results: </strong>We identified 329 plasma proteins significantly differentially regulated between ALS and controls (adjusted p-value <0.05), with 25 showing >40% relative abundance. PDLIM3, TNNT2, and MYL11 had the greatest log-fold elevation, whereas ANTXR2 and ART3 had the greatest log-fold reduction. A similar set of plasma proteins was found to increase (eg, PDLIM3, TNNT2, and MYL11) or decrease (eg, ANTXR2, ART3, and MSTN) with disease progression. CSF proteins with the greatest log-fold elevation included NEFL, NEFH, CHIT1, CA3, MYL11, and GPNMB. These results were confirmed in an independent replication cohort. Moreover, tissue-specific signature enrichment suggests a significant contribution of muscle as a source of these biomarkers. Plasma KCNIP3 was elevated by ~60% in those on riluzole. Immunoassays provided orthogonal validation of plasma TNNT2 and CSF GPNMB.</p><p><strong>Interpretation: </strong>We identified an array of novel biomarkers with the potential to serve as response biomarkers to aid therapy development, as well as to shed light on the underlying biology of disease. ANN NEUROL 2025.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145184303","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}
Ikjae Lee, Grace Jang, Ying Kuen Ken Cheung, Alexander V Sherman, Wendy S Johnston, Frank Diaz, J Americo M Fernandes, Ali A Habib, Nicholas J Maragakis, Sabrina Paganoni, Katherine Burke, Bjorn Oskarsson, Jaimin Shah, Lorne Zinman, Mary Kay Floeter, Senda Ajroud-Driss, Kelly Gwathmey, Terry Heiman-Patterson, Omar Jawdat, Edward J Kasarskis, Yaz Y Kisanuki, James Wymer, Christina Fournier, Ghazala Hayat, Daragh Heitzman, Catherine Lomen-Hoerth, Michael T Pulley, Stephen N Scelsa, David Walk, Stephen A Goutman, Christen Shoesmith, Zachary Simmons, Eric Sorenson, Lauren Elman, Matthew B Harms, Benjamin N Hoover, Rebecca Y Yun, Regina M Santella, Hiroshi Mitsumoto
Objective: The primary lateral sclerosis (PLS) consensus diagnostic criteria and functional rating scale (PLSFRS) were recently established to facilitate and optimize future PLS clinical trials. We examined the trajectory of the PLSFRS and other functional outcome measures and biomarkers in the PLS Natural History Study (PLS NHS) to understand their performance in this prospective cohort.
Methods: The PLS NHS is a prospective, longitudinal, multicenter study of people living with PLS in different diagnostic categories: early (disease duration <2 years); probable (2-4 years); and definite PLS (4-15 years). PLSFRS scores and other functional outcome measures were collected at baseline, 3-, 6-, 9-, and 12-month follow-up visits. Baseline characteristics were compared between the groups. The slopes of the PLSFRS and other functional outcome measures over 12 months were examined in the overall cohort and subgroups using linear mixed-effect models. The associations between baseline characteristics and the rate of PLSFRS decline were analyzed with linear regression models.
Results: A total of 76 participants were included: early (n = 6); probable (n = 26); and definite (n = 44) PLS. Baseline PLSFRS total scores were highest in the early PLS group, followed by the probable and definite PLS groups. In the overall cohort, the PLSFRS total score declined by 0.33 points/month (95% confidence interval [0.27-0.39], adjusted p < 0.05). The rate of decline was steepest in the early PLS group, followed by the probable and definite PLS groups. Baseline neurofilament light chain level was associated with the rate of PLSFRS decline over 1 year (p = 0.001).
Interpretation: In PLS, the rate of functional decline, as measured by the PLSFRS total score, is faster during the early phase of the disease. Neurofilament light might serve as a prognostic biomarker in PLS. ANN NEUROL 2025.
目的：最近建立了原发性侧索硬化（PLS）共识诊断标准和功能评定量表（PLSFRS），以促进和优化未来的PLS临床试验。我们在PLS自然历史研究（PLS NHS）中检查了PLSFRS和其他功能结果测量和生物标志物的轨迹，以了解它们在这一前瞻性队列中的表现。方法：PLS NHS是一项针对不同诊断类别PLS患者的前瞻性、纵向、多中心研究：早期（疾病持续时间）结果：共纳入76名参与者：早期（n = 6）；可能（n = 26）；早期PLS组的基线PLSFRS总分最高，其次是可能PLS组和明确PLS组。在整个队列中，PLSFRS总分下降了0.33分/月（95%置信区间[0.27-0.39]，校正p）。解释：在PLS中，由PLSFRS总分测量的功能下降速度在疾病早期更快。神经丝光可能作为PLS. ANN NEUROL 2025的预后生物标志物。
{"title":"Primary Lateral Sclerosis Natural History Study: Primary Lateral Sclerosis Functional Rating Scale and Other Outcomes Assessment.","authors":"Ikjae Lee, Grace Jang, Ying Kuen Ken Cheung, Alexander V Sherman, Wendy S Johnston, Frank Diaz, J Americo M Fernandes, Ali A Habib, Nicholas J Maragakis, Sabrina Paganoni, Katherine Burke, Bjorn Oskarsson, Jaimin Shah, Lorne Zinman, Mary Kay Floeter, Senda Ajroud-Driss, Kelly Gwathmey, Terry Heiman-Patterson, Omar Jawdat, Edward J Kasarskis, Yaz Y Kisanuki, James Wymer, Christina Fournier, Ghazala Hayat, Daragh Heitzman, Catherine Lomen-Hoerth, Michael T Pulley, Stephen N Scelsa, David Walk, Stephen A Goutman, Christen Shoesmith, Zachary Simmons, Eric Sorenson, Lauren Elman, Matthew B Harms, Benjamin N Hoover, Rebecca Y Yun, Regina M Santella, Hiroshi Mitsumoto","doi":"10.1002/ana.78056","DOIUrl":"https://doi.org/10.1002/ana.78056","url":null,"abstract":"<p><strong>Objective: </strong>The primary lateral sclerosis (PLS) consensus diagnostic criteria and functional rating scale (PLSFRS) were recently established to facilitate and optimize future PLS clinical trials. We examined the trajectory of the PLSFRS and other functional outcome measures and biomarkers in the PLS Natural History Study (PLS NHS) to understand their performance in this prospective cohort.</p><p><strong>Methods: </strong>The PLS NHS is a prospective, longitudinal, multicenter study of people living with PLS in different diagnostic categories: early (disease duration <2 years); probable (2-4 years); and definite PLS (4-15 years). PLSFRS scores and other functional outcome measures were collected at baseline, 3-, 6-, 9-, and 12-month follow-up visits. Baseline characteristics were compared between the groups. The slopes of the PLSFRS and other functional outcome measures over 12 months were examined in the overall cohort and subgroups using linear mixed-effect models. The associations between baseline characteristics and the rate of PLSFRS decline were analyzed with linear regression models.</p><p><strong>Results: </strong>A total of 76 participants were included: early (n = 6); probable (n = 26); and definite (n = 44) PLS. Baseline PLSFRS total scores were highest in the early PLS group, followed by the probable and definite PLS groups. In the overall cohort, the PLSFRS total score declined by 0.33 points/month (95% confidence interval [0.27-0.39], adjusted p < 0.05). The rate of decline was steepest in the early PLS group, followed by the probable and definite PLS groups. Baseline neurofilament light chain level was associated with the rate of PLSFRS decline over 1 year (p = 0.001).</p><p><strong>Interpretation: </strong>In PLS, the rate of functional decline, as measured by the PLSFRS total score, is faster during the early phase of the disease. Neurofilament light might serve as a prognostic biomarker in PLS. ANN NEUROL 2025.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145184230","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}
In multiple disease areas, neurology has failed to translate promising treatments from positive preclinical studies to successful clinical trial results. Despite this history, we persist in testing new, putative neuroprotectants using the same concepts, approaches, and methods without much modification. Recent novel data and new concepts offer an opportunity to break with past doctrine decisively, and open a new era of different approaches, methods, and strategies for studying future protections for brain injury. Cerebroprotection is a fresh framework for designing neurological therapy that targets glia and vascular cells, in addition to neurons. ANN NEUROL 2025.
{"title":"Back Again to the Future: A New Era for Cerebroprotection.","authors":"Patrick Lyden","doi":"10.1002/ana.78041","DOIUrl":"https://doi.org/10.1002/ana.78041","url":null,"abstract":"<p><p>In multiple disease areas, neurology has failed to translate promising treatments from positive preclinical studies to successful clinical trial results. Despite this history, we persist in testing new, putative neuroprotectants using the same concepts, approaches, and methods without much modification. Recent novel data and new concepts offer an opportunity to break with past doctrine decisively, and open a new era of different approaches, methods, and strategies for studying future protections for brain injury. Cerebroprotection is a fresh framework for designing neurological therapy that targets glia and vascular cells, in addition to neurons. ANN NEUROL 2025.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145147148","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}
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