Gbambele Kone MD, Nino Kvantaliani MD, Brett Cucchiara MD
A 52-year-old man with atrial fibrillation not on anticoagulation presented with 3 days of mild left hemiparesis. He reported taking aspirin 325 mg prior to presentation. Head computed tomography (CT) showed subacute right subcortical infarction (Fig 1A). Several hours later, he developed right gaze deviation and worsened left hemiparesis. Repeat CT showed confluent hemorrhage in the prior infarct; CT angiography performed at the same time showed a spot sign within the hemorrhage (Fig 1B,C). Follow-up imaging demonstrated stable hemorrhage. Hemorrhagic transformation after ischemic stroke is often ascribed to reperfusion of necrotic infarcted tissue with associated blood—brain barrier disruption; ischemia has also been proposed to cause direct vessel injury causing vessel rupture and hemorrhage, though with limited supportive evidence.1, 2 The spot sign, as seen here, represents direct evidence of vessel injury with associated contrast extravasation,3 supporting the latter as the mechanism in this case. Prior studies have demonstrated that the presence of a spot sign is associated with more than double the risk of both early hematoma expansion and worse functional outcome and mortality in non-traumatic intracerebral hemorrhage.4
G.K., B.C., and N.K. contributed to the conception and design of the study; G.K., B.C., and N.K. contributed to the acquisition and analysis of data; G.K. and B.C. contributed to drafting the manuscript and preparing the figures.
{"title":"Spot Sign in Hemorrhagic Transformation of Ischemic Stroke","authors":"Gbambele Kone MD, Nino Kvantaliani MD, Brett Cucchiara MD","doi":"10.1002/ana.26969","DOIUrl":"10.1002/ana.26969","url":null,"abstract":"<p>A 52-year-old man with atrial fibrillation not on anticoagulation presented with 3 days of mild left hemiparesis. He reported taking aspirin 325 mg prior to presentation. Head computed tomography (CT) showed subacute right subcortical infarction (Fig 1A). Several hours later, he developed right gaze deviation and worsened left hemiparesis. Repeat CT showed confluent hemorrhage in the prior infarct; CT angiography performed at the same time showed a spot sign within the hemorrhage (Fig 1B,C). Follow-up imaging demonstrated stable hemorrhage. Hemorrhagic transformation after ischemic stroke is often ascribed to reperfusion of necrotic infarcted tissue with associated blood—brain barrier disruption; ischemia has also been proposed to cause direct vessel injury causing vessel rupture and hemorrhage, though with limited supportive evidence.<span><sup>1, 2</sup></span> The spot sign, as seen here, represents direct evidence of vessel injury with associated contrast extravasation,<span><sup>3</sup></span> supporting the latter as the mechanism in this case. Prior studies have demonstrated that the presence of a spot sign is associated with more than double the risk of both early hematoma expansion and worse functional outcome and mortality in non-traumatic intracerebral hemorrhage.<span><sup>4</sup></span></p><p>G.K., B.C., and N.K. contributed to the conception and design of the study; G.K., B.C., and N.K. contributed to the acquisition and analysis of data; G.K. and B.C. contributed to drafting the manuscript and preparing the figures.</p><p>Nothing to report.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":null,"pages":null},"PeriodicalIF":8.1,"publicationDate":"2024-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ana.26969","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140954834","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}
{"title":"Annals of Neurology: Volume 95, Number 6, June 2024","authors":"","doi":"10.1002/ana.26696","DOIUrl":"https://doi.org/10.1002/ana.26696","url":null,"abstract":"","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":null,"pages":null},"PeriodicalIF":11.2,"publicationDate":"2024-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ana.26696","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140953190","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}
Ikjae Lee MD MSc, Hiroshi Mitsumoto MD, Seonjoo Lee PhD, Edward Kasarskis MD, PhD, Michael Rosenbaum MD, Pam Factor-Litvak PhD, Jeri W. Nieves PhD
{"title":"Reply to Glycemic Index/Load Effect on ALS Progression: Potential Interaction with Riluzole","authors":"Ikjae Lee MD MSc, Hiroshi Mitsumoto MD, Seonjoo Lee PhD, Edward Kasarskis MD, PhD, Michael Rosenbaum MD, Pam Factor-Litvak PhD, Jeri W. Nieves PhD","doi":"10.1002/ana.26971","DOIUrl":"10.1002/ana.26971","url":null,"abstract":"","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":null,"pages":null},"PeriodicalIF":11.2,"publicationDate":"2024-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140954796","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}
Chen Chen MPH, Mathew J. Reeves PhD, Kevin He PhD, Lewis B. Morgenstern MD, Lynda D. Lisabeth PhD
Objective
This study was undertaken to delineate 21-year sex-specific trends in recurrence and postrecurrence mortality.
Methods
Between 2000 and 2020, first-ever ischemic stroke (IS) patients, ascertained from the population-based BASIC (Brain Attack Surveillance in Corpus Christi) project in South Texas, were followed for recurrent stroke and all-cause mortality until December 31, 2020. Multivariable regression models with an interaction between calendar year and sex were used to estimate sex-specific trends and sex differences in recurrence and postrecurrence mortality.
Results
Of the 6,057 IS patients (median age = 69 years, 49.8% women), 654 (10.8%) had a recurrence and 399 (47.7%) had postrecurrence mortality during 5 years of follow-up. In 2000, women had 2.5% higher albeit non-statistically significant 5-year risk of recurrence than men in absolute scale. With the trend declining in women by 7.6% (95% confidence interval [CI] = −10.8 to −4.5%) and in men by 3.6% (95% CI = −6.5% to −0.7%), the risk at the end of the study period was 1.5% (95% CI = −0.3% to 3.6%) lower among women than men. For postrecurrence mortality, the risk was 10.2% lower among women in 2000, but the sex difference was 3.3% by the end of the period, which was due to a larger overall increase in the risk among women than men over the entire time period.
Interpretation
The declines in recurrent stroke suggest successful secondary stroke prevention, especially in women. However, the continued high postrecurrence mortality among both sexes at the end of study period emphasizes the need for ongoing interventions to improve prognosis in those who have had recurrent cerebrovascular events. ANN NEUROL 2024;96:332–342
{"title":"Sex Differences in Trends in Stroke Recurrence and Postrecurrence Mortality 2000–2020: Population-Based Brain Attack Surveillance in Corpus Christi Project","authors":"Chen Chen MPH, Mathew J. Reeves PhD, Kevin He PhD, Lewis B. Morgenstern MD, Lynda D. Lisabeth PhD","doi":"10.1002/ana.26955","DOIUrl":"10.1002/ana.26955","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>This study was undertaken to delineate 21-year sex-specific trends in recurrence and postrecurrence mortality.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Between 2000 and 2020, first-ever ischemic stroke (IS) patients, ascertained from the population-based BASIC (Brain Attack Surveillance in Corpus Christi) project in South Texas, were followed for recurrent stroke and all-cause mortality until December 31, 2020. Multivariable regression models with an interaction between calendar year and sex were used to estimate sex-specific trends and sex differences in recurrence and postrecurrence mortality.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Of the 6,057 IS patients (median age = 69 years, 49.8% women), 654 (10.8%) had a recurrence and 399 (47.7%) had postrecurrence mortality during 5 years of follow-up. In 2000, women had 2.5% higher albeit non-statistically significant 5-year risk of recurrence than men in absolute scale. With the trend declining in women by 7.6% (95% confidence interval [CI] = −10.8 to −4.5%) and in men by 3.6% (95% CI = −6.5% to −0.7%), the risk at the end of the study period was 1.5% (95% CI = −0.3% to 3.6%) lower among women than men. For postrecurrence mortality, the risk was 10.2% lower among women in 2000, but the sex difference was 3.3% by the end of the period, which was due to a larger overall increase in the risk among women than men over the entire time period.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>The declines in recurrent stroke suggest successful secondary stroke prevention, especially in women. However, the continued high postrecurrence mortality among both sexes at the end of study period emphasizes the need for ongoing interventions to improve prognosis in those who have had recurrent cerebrovascular events. ANN NEUROL 2024;96:332–342</p>\u0000 </section>\u0000 </div>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":null,"pages":null},"PeriodicalIF":8.1,"publicationDate":"2024-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11236512/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140954802","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}
Aaron Rodriguez-Calienes MD, Fazeel M. Siddiqui MD, Milagros Galecio-Castillo MD, Mahmoud H. Mohammaden MD, Jaydevsinh N. Dolia MD, Jonathan A. Grossberg MD, Aqueel Pabaney MD, Ameer E. Hassan MD, Wondwossen G. Tekle MD, Hamzah Saei MD, Samantha Miller MD, Shahram Majidi MD, Johana T. Fifi MD, Gabrielle Valestin MD, James E. Siegler MD, Mary Penckofer MD, Linda Zhang MD, Sunil A. Sheth MD, Sergio Salazar-Marioni MD, Ananya Iyyangar MD, Thanh N. Nguyen MD, Mohamad Abdalkader MD, Italo Linfante MD, Guilherme Dabus MD, Brijesh P. Mehta MD, Joy Sessa MD, Mouhammad A. Jumma MD, Rebecca M. Sugg MD, Guillermo Linares MD, Raul G. Nogueira MD, David S. Liebeskind MD, Diogo C. Haussen MD, Santiago Ortega-Gutierrez MD, MSc
Objective
We aimed to evaluate the association between rescue therapy (RT) and functional outcomes compared to medical management (MM) in patients presenting after failed mechanical thrombectomy (MT).
Methods
This cross-sectional study utilized prospectively collected and maintained data from the Society of Vascular and Interventional Neurology Registry, spanning from 2011 to 2021. The cohort comprised patients with large vessel occlusions (LVOs) with failed MT. The primary outcome was the shift in the degree of disability, as gauged by the modified Rankin Scale (mRS) at 90 days. Additional outcomes included functional independence (90-day mRS score of 0–2), symptomatic intracranial hemorrhage (sICH), and 90-day mortality.
Results
Of a total of 7,018 patients, 958 presented failed MT and were included in the analysis. The RT group comprised 407 (42.4%) patients, and the MM group consisted of 551 (57.5%) patients. After adjusting for confounders, the RT group showed a favorable shift in the overall 90-day mRS distribution (adjusted common odds ratio = 1.79, 95% confidence interval [CI] = 1.32–2.45, p < 0.001) and higher rates of functional independence (RT: 28.8% vs MM: 15.7%, adjusted odds ratio [aOR] = 1.93, 95% CI = 1.21–3.07, p = 0.005) compared to the MM group. RT also showed lower rates of sICH (RT: 3.8% vs MM: 9.1%, aOR = 0.52, 95% CI = 0.28–0.97, p = 0.039) and 90-day mortality (RT: 33.4% vs MM: 45.5%, aOR = 0.61, 95% CI = 0.42–0.89, p = 0.009).
Interpretation
Our findings advocate for the utilization of RT as a potential treatment strategy for cases of LVO resistant to first-line MT techniques. Prospective studies are warranted to validate these observations and optimize the endovascular approach for failed MT patients. ANN NEUROL 2024;96:343–355
{"title":"Rescue Therapy for Failed Mechanical Thrombectomy in Acute Ischemic Stroke: A Pooled Analysis of the Society of Vascular and Interventional Neurology Registry","authors":"Aaron Rodriguez-Calienes MD, Fazeel M. Siddiqui MD, Milagros Galecio-Castillo MD, Mahmoud H. Mohammaden MD, Jaydevsinh N. Dolia MD, Jonathan A. Grossberg MD, Aqueel Pabaney MD, Ameer E. Hassan MD, Wondwossen G. Tekle MD, Hamzah Saei MD, Samantha Miller MD, Shahram Majidi MD, Johana T. Fifi MD, Gabrielle Valestin MD, James E. Siegler MD, Mary Penckofer MD, Linda Zhang MD, Sunil A. Sheth MD, Sergio Salazar-Marioni MD, Ananya Iyyangar MD, Thanh N. Nguyen MD, Mohamad Abdalkader MD, Italo Linfante MD, Guilherme Dabus MD, Brijesh P. Mehta MD, Joy Sessa MD, Mouhammad A. Jumma MD, Rebecca M. Sugg MD, Guillermo Linares MD, Raul G. Nogueira MD, David S. Liebeskind MD, Diogo C. Haussen MD, Santiago Ortega-Gutierrez MD, MSc","doi":"10.1002/ana.26967","DOIUrl":"10.1002/ana.26967","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>We aimed to evaluate the association between rescue therapy (RT) and functional outcomes compared to medical management (MM) in patients presenting after failed mechanical thrombectomy (MT).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This cross-sectional study utilized prospectively collected and maintained data from the Society of Vascular and Interventional Neurology Registry, spanning from 2011 to 2021. The cohort comprised patients with large vessel occlusions (LVOs) with failed MT. The primary outcome was the shift in the degree of disability, as gauged by the modified Rankin Scale (mRS) at 90 days. Additional outcomes included functional independence (90-day mRS score of 0–2), symptomatic intracranial hemorrhage (sICH), and 90-day mortality.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Of a total of 7,018 patients, 958 presented failed MT and were included in the analysis. The RT group comprised 407 (42.4%) patients, and the MM group consisted of 551 (57.5%) patients. After adjusting for confounders, the RT group showed a favorable shift in the overall 90-day mRS distribution (adjusted common odds ratio = 1.79, 95% confidence interval [CI] = 1.32–2.45, <i>p</i> < 0.001) and higher rates of functional independence (RT: 28.8% vs MM: 15.7%, adjusted odds ratio [aOR] = 1.93, 95% CI = 1.21–3.07, <i>p</i> = 0.005) compared to the MM group. RT also showed lower rates of sICH (RT: 3.8% vs MM: 9.1%, aOR = 0.52, 95% CI = 0.28–0.97, <i>p</i> = 0.039) and 90-day mortality (RT: 33.4% vs MM: 45.5%, aOR = 0.61, 95% CI = 0.42–0.89, <i>p</i> = 0.009).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>Our findings advocate for the utilization of RT as a potential treatment strategy for cases of LVO resistant to first-line MT techniques. Prospective studies are warranted to validate these observations and optimize the endovascular approach for failed MT patients. ANN NEUROL 2024;96:343–355</p>\u0000 </section>\u0000 </div>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":null,"pages":null},"PeriodicalIF":8.1,"publicationDate":"2024-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ana.26967","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140943455","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}
Although accumulating evidence implicating altered gut microbiota in human immunodeficiency virus (HIV) infection and neurodegenerative disorders; however, the association between dysbiosis of the gut microbiota and metabolites in the pathogenesis of HIV-associated neurocognitive disorder (HAND) remains unclear.
Methods
Fecal and plasma samples were obtained from 3 cohorts (HAND, HIV–non-HAND, and healthy controls), metagenomic analysis and metabolomic profiling were performed to investigate alterations in the gut microbial composition and circulating metabolites in HAND.
Results
The gut microbiota of people living with HIV (PLWH) had an increased relative abundance of Prevotella and a decreased relative abundance of Bacteroides. In contrast, Prevotella and Megamonas were substantially decreased, and Bacteroides and Phocaeicola were increased in HAND patients. Moreover, untargeted metabolomics identified several neurotransmitters and certain amino acids associated with neuromodulation, and the differential metabolic pathways of amino acids associated with neurocognition were depleted in HAND patients. Notably, most neuromodulatory metabolites are associated with an altered abundance of specific gut bacteria.
Interpretation
Our findings provide new insights into the intricate interplay between the gut and microbiome-brain axis in the pathogenesis of HAND, highlighting the potential for developing novel therapeutic strategies that specifically target the gut microbiota. ANN NEUROL 2024;96:306–320
目的：尽管有越来越多的证据表明肠道微生物群的改变与人类免疫缺陷病毒（HIV）感染和神经退行性疾病有关，但肠道微生物群失调与代谢物在HIV相关神经认知障碍（HAND）发病机制中的关联仍不清楚：方法：从3个队列（HAND、HIV-非HAND和健康对照组）中获取粪便和血浆样本，进行元基因组分析和代谢组分析，研究HAND患者肠道微生物组成和循环代谢物的改变：结果：HIV 感染者（PLWH）的肠道微生物群中，普雷沃特氏菌（Prevotella）的相对丰度增加，乳杆菌（Bacteroides）的相对丰度降低。相比之下，HAND 患者的普雷沃特氏菌和 Megamonas 大量减少，而 Bacteroides 和 Phocaeicola 增加。此外，非靶向代谢组学发现了几种神经递质和某些与神经调节相关的氨基酸，而与神经认知相关的氨基酸的不同代谢途径在 HAND 患者中被耗尽。值得注意的是，大多数神经调节代谢物与特定肠道细菌丰度的改变有关：我们的研究结果为了解肠道和微生物脑轴在 HAND 发病机制中错综复杂的相互作用提供了新的视角，凸显了开发专门针对肠道微生物群的新型治疗策略的潜力。ann neurol 2024.
{"title":"Dysregulation of Gut Microbiota-Derived Neuromodulatory Amino Acid Metabolism in Human Immunodeficiency Virus-Associated Neurocognitive Disorder: An Integrative Metagenomic and Metabolomic Analysis","authors":"Xue Chen, Jiaqi Wei, Zhen Li, Yang Zhang, Xin Zhang, Ling Zhang, Xia Wang, Yulin Zhang, Tong Zhang","doi":"10.1002/ana.26963","DOIUrl":"10.1002/ana.26963","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>Although accumulating evidence implicating altered gut microbiota in human immunodeficiency virus (HIV) infection and neurodegenerative disorders; however, the association between dysbiosis of the gut microbiota and metabolites in the pathogenesis of HIV-associated neurocognitive disorder (HAND) remains unclear.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Fecal and plasma samples were obtained from 3 cohorts (HAND, HIV–non-HAND, and healthy controls), metagenomic analysis and metabolomic profiling were performed to investigate alterations in the gut microbial composition and circulating metabolites in HAND.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The gut microbiota of people living with HIV (PLWH) had an increased relative abundance of <i>Prevotella</i> and a decreased relative abundance of <i>Bacteroides</i>. In contrast, <i>Prevotella</i> and <i>Megamonas</i> were substantially decreased, and <i>Bacteroides</i> and <i>Phocaeicola</i> were increased in HAND patients. Moreover, untargeted metabolomics identified several neurotransmitters and certain amino acids associated with neuromodulation, and the differential metabolic pathways of amino acids associated with neurocognition were depleted in HAND patients. Notably, most neuromodulatory metabolites are associated with an altered abundance of specific gut bacteria.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>Our findings provide new insights into the intricate interplay between the gut and microbiome-brain axis in the pathogenesis of HAND, highlighting the potential for developing novel therapeutic strategies that specifically target the gut microbiota. ANN NEUROL 2024;96:306–320</p>\u0000 </section>\u0000 </div>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":null,"pages":null},"PeriodicalIF":8.1,"publicationDate":"2024-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140943454","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}
Theresa M. Harrison PhD, Trevor Chadwick BS, Stefania Pezzoli PhD, JiaQie Lee BS, Susan M. Landau PhD, William J. Jagust MD, for the Alzheimer's Disease Neuroimaging Initiative
Objective
Cross-sectional definitions of successful cognitive aging have been widely utilized, but longitudinal measurements can identify people who do not decline. We performed this study to contrast maintenance with declining trajectories, including clinical conversion.
Methods
We included baseline cognitively unimpaired Alzheimer's Disease Neuroimaging Initiative participants with 3 or more cognitive testing sessions (n = 539, follow-up 6.1 ± 3.5 years) and calculated slopes of an episodic memory composite (MEM) to classify them into two groups: maintainers (slope ≥ 0) and decliners (slope < 0). Within decliners, we examined a subgroup of individuals who became clinically impaired during follow-up. These groups were compared on baseline characteristics and cognitive performance, as well as both cross-sectional and longitudinal Alzheimer disease (AD) biomarker measures (beta-amyloid [Aβ], tau, and hippocampal volume).
Results
Forty-one percent (n = 221) of the cohort were MEM maintainers, and 33% (n = 105) of decliners converted to clinical impairment during follow-up. Compared to those with superior baseline scores, maintainers had lower education and were more likely to be male. Maintainers and decliners did not differ on baseline MEM scores, but maintainers did have higher non-MEM cognitive scores. Maintainers had lower baseline global Aβ, lower tau pathology, and larger hippocampal volumes than decliners, even after removing converters. There were no differences in rates of change of any AD biomarkers between any cognitive trajectory groups except for a higher rate of hippocampal atrophy in clinical converters compared to maintainers.
Interpretation
Using longitudinal data to define cognitive trajectory groups reduces education and sex bias and reveals the prognostic importance of early onset of accumulation of AD pathology. ANN NEUROL 2024;96:378–389
{"title":"Cognitive Trajectories and Alzheimer Disease Biomarkers: From Successful Cognitive Aging to Clinical Impairment","authors":"Theresa M. Harrison PhD, Trevor Chadwick BS, Stefania Pezzoli PhD, JiaQie Lee BS, Susan M. Landau PhD, William J. Jagust MD, for the Alzheimer's Disease Neuroimaging Initiative","doi":"10.1002/ana.26964","DOIUrl":"10.1002/ana.26964","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>Cross-sectional definitions of successful cognitive aging have been widely utilized, but longitudinal measurements can identify people who do not decline. We performed this study to contrast maintenance with declining trajectories, including clinical conversion.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We included baseline cognitively unimpaired Alzheimer's Disease Neuroimaging Initiative participants with 3 or more cognitive testing sessions (n = 539, follow-up 6.1 ± 3.5 years) and calculated slopes of an episodic memory composite (MEM) to classify them into two groups: maintainers (slope ≥ 0) and decliners (slope < 0). Within decliners, we examined a subgroup of individuals who became clinically impaired during follow-up. These groups were compared on baseline characteristics and cognitive performance, as well as both cross-sectional and longitudinal Alzheimer disease (AD) biomarker measures (beta-amyloid [Aβ], tau, and hippocampal volume).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Forty-one percent (n = 221) of the cohort were MEM maintainers, and 33% (n = 105) of decliners converted to clinical impairment during follow-up. Compared to those with superior baseline scores, maintainers had lower education and were more likely to be male. Maintainers and decliners did not differ on baseline MEM scores, but maintainers did have higher non-MEM cognitive scores. Maintainers had lower baseline global Aβ, lower tau pathology, and larger hippocampal volumes than decliners, even after removing converters. There were no differences in rates of change of any AD biomarkers between any cognitive trajectory groups except for a higher rate of hippocampal atrophy in clinical converters compared to maintainers.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>Using longitudinal data to define cognitive trajectory groups reduces education and sex bias and reveals the prognostic importance of early onset of accumulation of AD pathology. ANN NEUROL 2024;96:378–389</p>\u0000 </section>\u0000 </div>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":null,"pages":null},"PeriodicalIF":8.1,"publicationDate":"2024-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11236492/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140920449","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}
Xu-Qiao Chen PhD, Ann Becker BA, Ricardo Albay PhD, Phuong D. Nguyen PhD, Dmitry Karachentsev PhD, Amanda J. Roberts PhD, Kevin D. Rynearson PhD, Rudolph E. Tanzi PhD, William C. Mobley MD, PhD
Objectives
Due to increased gene dose for the amyloid precursor protein (APP), elderly adults with Down syndrome (DS) are at a markedly increased risk of Alzheimer's disease (AD), known as DS-AD. How the increased APP gene dose acts and which APP products are responsible for DS-AD is not well understood, thus limiting strategies to target pathogenesis. As one approach to address this question, we used a novel class of γ-secretase modulators that promote γ-site cleavages by the γ-secretase complex, resulting in lower levels of the Aβ42 and Aβ40 peptides.
Methods
Ts65Dn mice, which serve as a model of DS, were treated via oral gavage with 10 mg/kg/weekday of BPN15606 (a potent and novel pyridazine-containing γ-secretase modulators). Treatment started at 3 months-of-age and lasted for 4 months.
Results
Demonstrating successful target engagement, treatment with BPN15606 significantly decreased levels of Aβ40 and Aβ42 in the cortex and hippocampus; it had no effect on full-length APP or its C-terminal fragments in either 2 N or Ts65Dn mice. Importantly, the levels of total amyloid-β were not impacted, pointing to BPN15606-mediated enhancement of processivity of γ-secretase. Additionally, BPN15606 rescued hyperactivation of Rab5, a protein responsible for regulating endosome function, and normalized neurotrophin signaling deficits. BPN15606 treatment also normalized the levels of synaptic proteins and tau phosphorylation, while reducing astrocytosis and microgliosis, and countering cognitive deficits.
Interpretation
Our findings point to the involvement of increased levels of Aβ42 and/or Aβ40 in contributing to several molecular and cognitive traits associated with DS-AD. They speak to increased dosage of the APP gene acting through heightened levels of Aβ42 and/or Aβ40 as supporting pathogenesis. These findings further the interest in the potential use of γ-secretase modulators for treating and possibly preventing AD in individuals with DS. ANN NEUROL 2024;96:390–404
{"title":"γ-Secretase Modulator BPN15606 Reduced Aβ42 and Aβ40 and Countered Alzheimer-Related Pathologies in a Mouse Model of Down Syndrome","authors":"Xu-Qiao Chen PhD, Ann Becker BA, Ricardo Albay PhD, Phuong D. Nguyen PhD, Dmitry Karachentsev PhD, Amanda J. Roberts PhD, Kevin D. Rynearson PhD, Rudolph E. Tanzi PhD, William C. Mobley MD, PhD","doi":"10.1002/ana.26958","DOIUrl":"10.1002/ana.26958","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Due to increased gene dose for the amyloid precursor protein (APP), elderly adults with Down syndrome (DS) are at a markedly increased risk of Alzheimer's disease (AD), known as DS-AD. How the increased APP gene dose acts and which APP products are responsible for DS-AD is not well understood, thus limiting strategies to target pathogenesis. As one approach to address this question, we used a novel class of γ-secretase modulators that promote γ-site cleavages by the γ-secretase complex, resulting in lower levels of the Aβ42 and Aβ40 peptides.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Ts65Dn mice, which serve as a model of DS, were treated via oral gavage with 10 mg/kg/weekday of BPN15606 (a potent and novel pyridazine-containing γ-secretase modulators). Treatment started at 3 months-of-age and lasted for 4 months.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Demonstrating successful target engagement, treatment with BPN15606 significantly decreased levels of Aβ40 and Aβ42 in the cortex and hippocampus; it had no effect on full-length APP or its C-terminal fragments in either 2 N or Ts65Dn mice. Importantly, the levels of total amyloid-β were not impacted, pointing to BPN15606-mediated enhancement of processivity of γ-secretase. Additionally, BPN15606 rescued hyperactivation of Rab5, a protein responsible for regulating endosome function, and normalized neurotrophin signaling deficits. BPN15606 treatment also normalized the levels of synaptic proteins and tau phosphorylation, while reducing astrocytosis and microgliosis, and countering cognitive deficits.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>Our findings point to the involvement of increased levels of Aβ42 and/or Aβ40 in contributing to several molecular and cognitive traits associated with DS-AD. They speak to increased dosage of the <i>APP</i> gene acting through heightened levels of Aβ42 and/or Aβ40 as supporting pathogenesis. These findings further the interest in the potential use of γ-secretase modulators for treating and possibly preventing AD in individuals with DS. ANN NEUROL 2024;96:390–404</p>\u0000 </section>\u0000 </div>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":null,"pages":null},"PeriodicalIF":8.1,"publicationDate":"2024-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11236496/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140920456","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}
Multiple sclerosis (MS) has a complex pathobiology, with genetic and environmental factors being crucial players. Understanding the mechanisms underlying heterogeneity in disease activity is crucial for tailored treatment. We explored the impact of DNA methylation, a key mechanism in the genetics-environment interplay, on disease activity in MS.
Methods
Peripheral immune methylome profiling using Illumina Infinium MethylationEPIC BeadChips was conducted on 249 untreated relapsing–remitting MS patients, sampled at the start of disease-modifying treatment (DMT). A differential methylation analysis compared patients with evidence of disease activity (EDA) to those with no evidence of disease activity (NEDA) over 2 years from DMT start. Utilizing causal inference testing (CIT) and Mendelian randomization (MR), we sought to elucidate the relationships between DNA methylation, gene expression, genetic variation, and disease activity.
Results
Four differentially methylated regions (DMRs) were identified between EDA and NEDA. Examining the influence of single nucleotide polymorphisms (SNPs), 923 variants were found to account for the observed differences in the 4 DMRs. Importantly, 3 out of the 923 SNPs, affecting DNA methylation in a DMR linked to the anti-Mullerian hormone (AMH) gene, were associated with disease activity risk in an independent cohort of 1,408 MS patients. CIT and MR demonstrated that DNA methylation in AMH acts as a mediator for the genetic risk of disease activity.
Interpretation
This study uncovered a novel molecular pathway implicating the interaction between DNA methylation and genetic variation in the risk of disease activity in MS, emphasizing the role of sex hormones, particularly the AMH, in MS pathobiology. ANN NEUROL 2024;96:289–301
{"title":"DNA Methylation in the Anti-Mullerian Hormone Gene and the Risk of Disease Activity in Multiple Sclerosis","authors":"Antonino Giordano MD, PhD, Béatrice Pignolet PhD, Elisabetta Mascia PhD, Ferdinando Clarelli MSc, Melissa Sorosina PhD, Kaalindi Misra PhD, Florence Bucciarelli MSc, Laura Ferrè MD, PhD, Lucia Moiola MD, Roland Liblau MD, PhD, Massimo Filippi MD, Federica Esposito MD, PhD","doi":"10.1002/ana.26959","DOIUrl":"10.1002/ana.26959","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>Multiple sclerosis (MS) has a complex pathobiology, with genetic and environmental factors being crucial players. Understanding the mechanisms underlying heterogeneity in disease activity is crucial for tailored treatment. We explored the impact of DNA methylation, a key mechanism in the genetics-environment interplay, on disease activity in MS.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Peripheral immune methylome profiling using Illumina Infinium MethylationEPIC BeadChips was conducted on 249 untreated relapsing–remitting MS patients, sampled at the start of disease-modifying treatment (DMT). A differential methylation analysis compared patients with evidence of disease activity (EDA) to those with no evidence of disease activity (NEDA) over 2 years from DMT start. Utilizing causal inference testing (CIT) and Mendelian randomization (MR), we sought to elucidate the relationships between DNA methylation, gene expression, genetic variation, and disease activity.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Four differentially methylated regions (DMRs) were identified between EDA and NEDA. Examining the influence of single nucleotide polymorphisms (SNPs), 923 variants were found to account for the observed differences in the 4 DMRs. Importantly, 3 out of the 923 SNPs, affecting DNA methylation in a DMR linked to the anti-Mullerian hormone (AMH) gene, were associated with disease activity risk in an independent cohort of 1,408 MS patients. CIT and MR demonstrated that DNA methylation in AMH acts as a mediator for the genetic risk of disease activity.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>This study uncovered a novel molecular pathway implicating the interaction between DNA methylation and genetic variation in the risk of disease activity in MS, emphasizing the role of sex hormones, particularly the AMH, in MS pathobiology. ANN NEUROL 2024;96:289–301</p>\u0000 </section>\u0000 </div>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":null,"pages":null},"PeriodicalIF":8.1,"publicationDate":"2024-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ana.26959","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140920452","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}
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