Alexander Rau, Gabriel Gonzalez-Escamilla, Nils Schroeter, Ahmed Othman, Andrea Dressing, Cornelius Weiller, Horst Urbach, Marco Reisert, Sergiu Groppa, Jonas A. Hosp
Objective
To investigate whether choroid plexus volumes in subacute coronavirus disease 2019 (COVID-19) patients with neurological symptoms could indicate inflammatory activation or barrier dysfunction and assess their association with clinical data.
Methods
Choroid plexus volumes were measured in 28 subacute COVID-19 patients via cerebral magnetic resonance imaging (MRI), compared with those in infection-triggered non-COVID-19 encephalopathy patients (n = 25), asymptomatic individuals after COVID-19 (n = 21), and healthy controls (n = 21). Associations with inflammatory serum markers (peak counts of leukocytes, C-reactive protein [CRP], interleukin 6), an MRI-based marker of barrier dysfunction (CSF volume fraction [V-CSF]), and clinical parameters like olfactory performance and cognitive scores (Montreal Cognitive Assessment) were investigated.
Results
COVID-19 patients showed significantly larger choroid plexus volumes than control groups (p < 0.001, η2 = 0.172). These volumes correlated significantly with peak leukocyte levels (p = 0.001, Pearson's r = 0.621) and V-CSF (p = 0.009, Spearman's rho = 0.534), but neither with CRP nor interleukin 6. No significant correlations were found with clinical parameters.
Interpretation
In patients with subacute COVID-19, choroid plexus volume is a marker of central nervous system inflammation and barrier dysfunction in the presence of neurologic symptoms. The absence of plexus enlargement in infection-triggered non-COVID-19 encephalopathy suggests a specific severe acute respiratory syndrome coronavirus 2 effect. This study also documents an increase in choroid plexus volume for the first time as a parainfectious event. ANN NEUROL 2024;96:715–725
{"title":"Inflammation-Triggered Enlargement of Choroid Plexus in Subacute COVID-19 Patients with Neurological Symptoms","authors":"Alexander Rau, Gabriel Gonzalez-Escamilla, Nils Schroeter, Ahmed Othman, Andrea Dressing, Cornelius Weiller, Horst Urbach, Marco Reisert, Sergiu Groppa, Jonas A. Hosp","doi":"10.1002/ana.27016","DOIUrl":"10.1002/ana.27016","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>To investigate whether choroid plexus volumes in subacute coronavirus disease 2019 (COVID-19) patients with neurological symptoms could indicate inflammatory activation or barrier dysfunction and assess their association with clinical data.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Choroid plexus volumes were measured in 28 subacute COVID-19 patients via cerebral magnetic resonance imaging (MRI), compared with those in infection-triggered non-COVID-19 encephalopathy patients (n = 25), asymptomatic individuals after COVID-19 (n = 21), and healthy controls (n = 21). Associations with inflammatory serum markers (peak counts of leukocytes, C-reactive protein [CRP], interleukin 6), an MRI-based marker of barrier dysfunction (CSF volume fraction [V-CSF]), and clinical parameters like olfactory performance and cognitive scores (Montreal Cognitive Assessment) were investigated.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>COVID-19 patients showed significantly larger choroid plexus volumes than control groups (<i>p</i> < 0.001, η<sup>2</sup> = 0.172). These volumes correlated significantly with peak leukocyte levels (<i>p</i> = 0.001, Pearson's r = 0.621) and V-CSF (<i>p</i> = 0.009, Spearman's rho = 0.534), but neither with CRP nor interleukin 6. No significant correlations were found with clinical parameters.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>In patients with subacute COVID-19, choroid plexus volume is a marker of central nervous system inflammation and barrier dysfunction in the presence of neurologic symptoms. The absence of plexus enlargement in infection-triggered non-COVID-19 encephalopathy suggests a specific severe acute respiratory syndrome coronavirus 2 effect. This study also documents an increase in choroid plexus volume for the first time as a parainfectious event. ANN NEUROL 2024;96:715–725</p>\u0000 </section>\u0000 </div>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":null,"pages":null},"PeriodicalIF":8.1,"publicationDate":"2024-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ana.27016","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141453976","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}
Fahad S. Al-Ajlan MD, Ahmed Alkhiri MBBS, Aser F. Alamri MBBS, Basil A. Alghamdi MBBS, Ahmed A. Almaghrabi MBBS, Abdullah R. Alharbi MBBS, Nayef Alansari MBBS, Ahmed Z. Almilibari MBBS, M. Shazam Hussain MD, Heinrich J. Audebert MD, James C. Grotta MD, Ashfaq Shuaib MD, Jeffrey L. Saver MD, Adel Alhazzani MD
Objectives
The benefits of intravenous thrombolysis are time-dependent, with maximum efficacy when administered within the first “golden” hour after onset. Nevertheless, the impact of golden hour thrombolysis has not been well quantified.
Methods
Medline, Embase, and Web of Science databases were systematically searched from inception to August 27, 2023. We included studies that reported safety and efficacy outcomes of ischemic stroke patients treated with intravenous thrombolysis in the golden hour versus later treatment window. The primary outcome was an excellent functional outcome, defined as a modified Rankin Scale score of 0–1 at 90 days. The secondary efficacy outcome was a good functional outcome (defined as modified Rankin Scale score of 0–2). The main safety outcome was symptomatic intracerebral hemorrhage.
Results
Seven studies involving 78,826 patients met the selection criteria. Golden hour thrombolysis was associated with higher odds of 90-day excellent functional outcomes (OR 1.40, 95% CI 1.16–1.67) and 90-day good functional outcomes (OR 1.38, 95% CI 1.13–1.69) compared with thrombolysis outside the golden hour. The number needed to treat to benefit for golden hour thrombolysis to reduce disability by at least 1 level on the modified Rankin Scale per patient was 2.6. Rates of symptomatic intracerebral hemorrhage and mortality were similar between groups.
Interpretation
Golden hour thrombolysis significantly improved acute ischemic stroke outcomes. The findings provide rationale for intensive efforts aimed at expediting thrombolytic therapy within the golden hour window following the onset of acute ischemic stroke. ANN NEUROL 2024;96:582–590
目的：静脉溶栓的疗效与时间有关，在发病后的第一个 "黄金 "小时内进行溶栓疗效最佳。然而，"黄金 "一小时溶栓的影响尚未得到很好的量化：我们对 Medline、Embase 和 Web of Science 数据库进行了系统检索，检索时间从开始到 2023 年 8 月 27 日。我们纳入了报告缺血性脑卒中患者在黄金时间内接受静脉溶栓治疗的安全性和有效性结果的研究。主要疗效结果是极佳的功能预后，即 90 天时修正的 Rankin 量表评分为 0-1。次要疗效结果是良好的功能结果（定义为修改后的 Rankin 量表评分为 0-2）。主要安全性结果为无症状性脑出血：有7项研究符合筛选标准，涉及78826名患者。与黄金时间外的溶栓相比，黄金时间内的溶栓与更高的90天卓越功能预后（OR 1.40，95% CI 1.16-1.67）和90天良好功能预后（OR 1.38，95% CI 1.13-1.69）相关。黄金时间内溶栓治疗使每名患者的残疾程度在改良Rankin量表上至少降低一级所需的治疗人数为2.6人。两组患者的无症状脑出血率和死亡率相似：黄金一小时溶栓治疗可明显改善急性缺血性中风的预后。这些研究结果为在急性缺血性中风发病后的黄金一小时内加快溶栓治疗提供了理论依据。ann neurol 2024.
{"title":"Golden Hour Intravenous Thrombolysis for Acute Ischemic Stroke: A Systematic Review and Meta-Analysis","authors":"Fahad S. Al-Ajlan MD, Ahmed Alkhiri MBBS, Aser F. Alamri MBBS, Basil A. Alghamdi MBBS, Ahmed A. Almaghrabi MBBS, Abdullah R. Alharbi MBBS, Nayef Alansari MBBS, Ahmed Z. Almilibari MBBS, M. Shazam Hussain MD, Heinrich J. Audebert MD, James C. Grotta MD, Ashfaq Shuaib MD, Jeffrey L. Saver MD, Adel Alhazzani MD","doi":"10.1002/ana.27007","DOIUrl":"10.1002/ana.27007","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>The benefits of intravenous thrombolysis are time-dependent, with maximum efficacy when administered within the first “golden” hour after onset. Nevertheless, the impact of golden hour thrombolysis has not been well quantified.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Medline, Embase, and Web of Science databases were systematically searched from inception to August 27, 2023. We included studies that reported safety and efficacy outcomes of ischemic stroke patients treated with intravenous thrombolysis in the golden hour versus later treatment window. The primary outcome was an excellent functional outcome, defined as a modified Rankin Scale score of 0–1 at 90 days. The secondary efficacy outcome was a good functional outcome (defined as modified Rankin Scale score of 0–2). The main safety outcome was symptomatic intracerebral hemorrhage.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Seven studies involving 78,826 patients met the selection criteria. Golden hour thrombolysis was associated with higher odds of 90-day excellent functional outcomes (OR 1.40, 95% CI 1.16–1.67) and 90-day good functional outcomes (OR 1.38, 95% CI 1.13–1.69) compared with thrombolysis outside the golden hour. The number needed to treat to benefit for golden hour thrombolysis to reduce disability by at least 1 level on the modified Rankin Scale per patient was 2.6. Rates of symptomatic intracerebral hemorrhage and mortality were similar between groups.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>Golden hour thrombolysis significantly improved acute ischemic stroke outcomes. The findings provide rationale for intensive efforts aimed at expediting thrombolytic therapy within the golden hour window following the onset of acute ischemic stroke. ANN NEUROL 2024;96:582–590</p>\u0000 </section>\u0000 </div>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":null,"pages":null},"PeriodicalIF":8.1,"publicationDate":"2024-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141453975","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}
Fredrik Piehl MD, PhD, Peter Alping MD, PhD, Suvi Virtanen MSc, Simon Englund MSc, Joachim Burman MD, PhD, Katharina Fink MD, PhD, Anna Fogdell-Hahn PhD, Martin Gunnarsson MD, PhD, Jan Hillert MD, PhD, Annette Langer-Gould MD, PhD, Jan Lycke MD, PhD, Johan Mellergård MD, PhD, Petra Nilsson MD, PhD, Tomas Olsson MD, PhD, Jonatan Salzer MD, PhD, Anders Svenningsson MD, PhD, Thomas Frisell PhD
Objective
To assess comparative effectiveness, safety, and tolerability of off-label rituximab, compared with frequently used therapies approved for multiple sclerosis (MS).
Methods
A Swedish cohort study of persons with relapsing–remitting MS, age 18 to 75 years at inclusion and with a first therapy start or a first therapy switch between 2011 and 2018. Low-dose rituximab was compared with MS-approved therapies. Primary outcomes were proportions with 12 months confirmed disability worsening and change in MS Impact Scale-29 (MSIS-29) scores, respectively. Secondary endpoints included relapses, therapy discontinuation, and serious adverse events. Analyses used an intention-to-treat approach and were adjusted for demographics, MS features, and health characteristics.
Results
We included 2,449 participants as first therapy start and 2,463 as first therapy switch. Proportions with disability worsening at 3 years were 9.1% for rituximab as first therapy and 5.1% after therapy switch, with no differences to MS-approved comparators. Worsening on rituximab was mostly independent of relapses. MSIS-29 with rituximab at 3 years improved by 1.3/8.4 points (physical/psychological) for first disease-modifying therapy (DMT) and 0.4/3.6 for DMT switch, and was mostly similar across therapies. Rituximab had lower relapse rates and higher therapy persistence in both groups. The rate of hospital-treated infections was higher with rituximab after a therapy switch, but not as a first therapy.
Interpretation
This population-based real-world cohort study found low rates of disability progression, mostly independent of relapses, and without significant differences between rituximab and MS-approved comparators. Rituximab led to lower rates of inflammatory activity and higher treatment persistence, but was associated with an increased rate of serious infections. ANN NEUROL 2024;96:678–693
{"title":"COMBAT-MS: A Population-Based Observational Cohort Study Addressing the Benefit–Risk Balance of Multiple Sclerosis Therapies Compared with Rituximab","authors":"Fredrik Piehl MD, PhD, Peter Alping MD, PhD, Suvi Virtanen MSc, Simon Englund MSc, Joachim Burman MD, PhD, Katharina Fink MD, PhD, Anna Fogdell-Hahn PhD, Martin Gunnarsson MD, PhD, Jan Hillert MD, PhD, Annette Langer-Gould MD, PhD, Jan Lycke MD, PhD, Johan Mellergård MD, PhD, Petra Nilsson MD, PhD, Tomas Olsson MD, PhD, Jonatan Salzer MD, PhD, Anders Svenningsson MD, PhD, Thomas Frisell PhD","doi":"10.1002/ana.27012","DOIUrl":"10.1002/ana.27012","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>To assess comparative effectiveness, safety, and tolerability of off-label rituximab, compared with frequently used therapies approved for multiple sclerosis (MS).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A Swedish cohort study of persons with relapsing–remitting MS, age 18 to 75 years at inclusion and with a first therapy start or a first therapy switch between 2011 and 2018. Low-dose rituximab was compared with MS-approved therapies. Primary outcomes were proportions with 12 months confirmed disability worsening and change in MS Impact Scale-29 (MSIS-29) scores, respectively. Secondary endpoints included relapses, therapy discontinuation, and serious adverse events. Analyses used an intention-to-treat approach and were adjusted for demographics, MS features, and health characteristics.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We included 2,449 participants as first therapy start and 2,463 as first therapy switch. Proportions with disability worsening at 3 years were 9.1% for rituximab as first therapy and 5.1% after therapy switch, with no differences to MS-approved comparators. Worsening on rituximab was mostly independent of relapses. MSIS-29 with rituximab at 3 years improved by 1.3/8.4 points (physical/psychological) for first disease-modifying therapy (DMT) and 0.4/3.6 for DMT switch, and was mostly similar across therapies. Rituximab had lower relapse rates and higher therapy persistence in both groups. The rate of hospital-treated infections was higher with rituximab after a therapy switch, but not as a first therapy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>This population-based real-world cohort study found low rates of disability progression, mostly independent of relapses, and without significant differences between rituximab and MS-approved comparators. Rituximab led to lower rates of inflammatory activity and higher treatment persistence, but was associated with an increased rate of serious infections. ANN NEUROL 2024;96:678–693</p>\u0000 </section>\u0000 </div>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":null,"pages":null},"PeriodicalIF":8.1,"publicationDate":"2024-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ana.27012","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141453974","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}
James J. Lah MD, PhD, Ganzhong Tian PhD, Benjamin B. Risk PhD, John J. Hanfelt PhD, Liangkang Wang BS, Liping Zhao MS, Chadwick M. Hales MD, PhD, Erik C.B. Johnson MD, PhD, Morgan B. Elmor BS, Sarah J. Malakauskas MS, Craig Heilman BS, Thomas S. Wingo MD, Cornelya D. Dorbin MPA, Crystal P. Davis MPH, Tiffany I. Thomas MPH, Ihab M. Hajjar MD, Allan I. Levey MD, PhD, Monica W. Parker MD
Objective
Alzheimer's disease (AD) is believed to be more common in African Americans (AA), but biomarker studies in AA populations are limited. This report represents the largest study to date examining cerebrospinal fluid AD biomarkers in AA individuals.
Methods
We analyzed 3,006 cerebrospinal fluid samples from controls, AD cases, and non-AD cases, including 495 (16.5%) self-identified black/AA and 2,456 (81.7%) white/European individuals using cutoffs derived from the Alzheimer's Disease Neuroimaging Initiative, and using a data-driven multivariate Gaussian mixture of regressions.
Results
Distinct effects of race were found in different groups. Total Tauand phospho181-Tau were lower among AA individuals in all groups (p < 0.0001), and Aβ42 was markedly lower in AA controls compared with white controls (p < 0.0001). Gaussian mixture of regressions modeling of cerebrospinal fluid distributions incorporating adjustments for covariates revealed coefficient estimates for AA race comparable with 2-decade change in age. Using Alzheimer's Disease Neuroimaging Initiative cutoffs, fewer AA controls were classified as biomarker-positive asymptomatic AD (8.0% vs 13.4%). After adjusting for covariates, our Gaussian mixture of regressions model reduced this difference, but continued to predict lower prevalence of asymptomatic AD among AA controls (9.3% vs 13.5%).
Interpretation
Although the risk of dementia is higher, data-driven modeling indicates lower frequency of asymptomatic AD in AA controls, suggesting that dementia among AA populations may not be driven by higher rates of AD. ANN NEUROL 2024;96:463–475
目的：阿尔茨海默病（AD）被认为在非裔美国人（AA）中更为常见，但针对AA人群的生物标志物研究却很有限。本报告是迄今为止对非裔美国人脑脊液中阿兹海默症生物标志物进行的最大规模研究：我们分析了来自对照组、AD 病例和非 AD 病例的 3,006 份脑脊液样本，其中包括 495 名（16.5%）自我认同的黑人/AA 人和 2,456 名（81.7%）白人/欧洲人，我们使用了从阿尔茨海默病神经影像学倡议中得出的分界线，并使用了数据驱动的多元高斯混合回归：结果：在不同群体中发现了不同的种族影响。在所有组别中，AA 人的总 Tau 和磷酸化 181-Tau 均较低（p 42）：虽然痴呆症的风险较高，但数据驱动的模型显示，AA 对照组中无症状 AD 的发生率较低，这表明 AA 人口中的痴呆症可能并非由 AD 发生率较高所致。ann neurol 2024.
{"title":"Lower Prevalence of Asymptomatic Alzheimer's Disease Among Healthy African Americans","authors":"James J. Lah MD, PhD, Ganzhong Tian PhD, Benjamin B. Risk PhD, John J. Hanfelt PhD, Liangkang Wang BS, Liping Zhao MS, Chadwick M. Hales MD, PhD, Erik C.B. Johnson MD, PhD, Morgan B. Elmor BS, Sarah J. Malakauskas MS, Craig Heilman BS, Thomas S. Wingo MD, Cornelya D. Dorbin MPA, Crystal P. Davis MPH, Tiffany I. Thomas MPH, Ihab M. Hajjar MD, Allan I. Levey MD, PhD, Monica W. Parker MD","doi":"10.1002/ana.26960","DOIUrl":"10.1002/ana.26960","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>Alzheimer's disease (AD) is believed to be more common in African Americans (AA), but biomarker studies in AA populations are limited. This report represents the largest study to date examining cerebrospinal fluid AD biomarkers in AA individuals.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We analyzed 3,006 cerebrospinal fluid samples from controls, AD cases, and non-AD cases, including 495 (16.5%) self-identified black/AA and 2,456 (81.7%) white/European individuals using cutoffs derived from the Alzheimer's Disease Neuroimaging Initiative, and using a data-driven multivariate Gaussian mixture of regressions.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Distinct effects of race were found in different groups. Total Tauand phospho181-Tau were lower among AA individuals in all groups (<i>p</i> < 0.0001), and Aβ<sub>42</sub> was markedly lower in AA controls compared with white controls (<i>p</i> < 0.0001). Gaussian mixture of regressions modeling of cerebrospinal fluid distributions incorporating adjustments for covariates revealed coefficient estimates for AA race comparable with 2-decade change in age. Using Alzheimer's Disease Neuroimaging Initiative cutoffs, fewer AA controls were classified as biomarker-positive asymptomatic AD (8.0% vs 13.4%). After adjusting for covariates, our Gaussian mixture of regressions model reduced this difference, but continued to predict lower prevalence of asymptomatic AD among AA controls (9.3% vs 13.5%).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>Although the risk of dementia is higher, data-driven modeling indicates lower frequency of asymptomatic AD in AA controls, suggesting that dementia among AA populations may not be driven by higher rates of AD. ANN NEUROL 2024;96:463–475</p>\u0000 </section>\u0000 </div>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":null,"pages":null},"PeriodicalIF":8.1,"publicationDate":"2024-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ana.26960","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141453977","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}
Pitcha Chompoopong MD, Michelle L. Mauermann MD, Hasan Siddiqi MD, Amanda Peltier MD
Amyloid neuropathy is caused by deposition of insoluble β-pleated amyloid sheets in the peripheral nervous system. It is most common in: (1) light-chain amyloidosis, a clonal non-proliferative plasma cell disorder in which fragments of immunoglobulin, light or heavy chain, deposit in tissues, and (2) hereditary transthyretin (ATTRv) amyloidosis, a disorder caused by autosomal dominant mutations in the TTR gene resulting in mutated protein that has a higher tendency to misfold. Amyloid fibrils deposit in the endoneurium of peripheral nerves, often extensive in the dorsal root ganglia and sympathetic ganglia, leading to atrophy of Schwann cells in proximity to amyloid fibrils and blood–nerve barrier disruption. Clinically, amyloid neuropathy is manifested as a length-dependent sensory predominant neuropathy associated with generalized autonomic failure. Small unmyelinated nerves are involved early and prominently in early-onset Val30Met ATTRv, whereas other ATTRv and light-chain amyloidosis often present with large- and small-fiber involvement. Nerve conduction studies, quantitative sudomotor axon testing, and intraepidermal nerve fiber density are useful tools to evaluate denervation. Amyloid deposition can be demonstrated by tissue biopsy of the affected organ or surrogate site, as well as bone-avid radiotracer cardiac imaging. Treatment of light-chain amyloidosis has been revolutionized by monoclonal antibodies and stem cell transplantation with improved 5-year survival up to 77%. Novel gene therapy and transthyretin stabilizers have revolutionized treatment of ATTRv, improving the course of neuropathy (less change in the modified Neuropathy Impairment Score + 7 from baseline) and quality of life. With great progress in amyloidosis therapies, early diagnosis and presymptomatic testing for ATTRv family members has become paramount. ANN NEUROL 2024;96:423–440
{"title":"Amyloid Neuropathy: From Pathophysiology to Treatment in Light-Chain Amyloidosis and Hereditary Transthyretin Amyloidosis","authors":"Pitcha Chompoopong MD, Michelle L. Mauermann MD, Hasan Siddiqi MD, Amanda Peltier MD","doi":"10.1002/ana.26965","DOIUrl":"10.1002/ana.26965","url":null,"abstract":"<p>Amyloid neuropathy is caused by deposition of insoluble β-pleated amyloid sheets in the peripheral nervous system. It is most common in: (1) light-chain amyloidosis, a clonal non-proliferative plasma cell disorder in which fragments of immunoglobulin, light or heavy chain, deposit in tissues, and (2) hereditary transthyretin (ATTRv) amyloidosis, a disorder caused by autosomal dominant mutations in the <i>TTR</i> gene resulting in mutated protein that has a higher tendency to misfold. Amyloid fibrils deposit in the endoneurium of peripheral nerves, often extensive in the dorsal root ganglia and sympathetic ganglia, leading to atrophy of Schwann cells in proximity to amyloid fibrils and blood–nerve barrier disruption. Clinically, amyloid neuropathy is manifested as a length-dependent sensory predominant neuropathy associated with generalized autonomic failure. Small unmyelinated nerves are involved early and prominently in early-onset Val30Met ATTRv, whereas other ATTRv and light-chain amyloidosis often present with large- and small-fiber involvement. Nerve conduction studies, quantitative sudomotor axon testing, and intraepidermal nerve fiber density are useful tools to evaluate denervation. Amyloid deposition can be demonstrated by tissue biopsy of the affected organ or surrogate site, as well as bone-avid radiotracer cardiac imaging. Treatment of light-chain amyloidosis has been revolutionized by monoclonal antibodies and stem cell transplantation with improved 5-year survival up to 77%. Novel gene therapy and transthyretin stabilizers have revolutionized treatment of ATTRv, improving the course of neuropathy (less change in the modified Neuropathy Impairment Score + 7 from baseline) and quality of life. With great progress in amyloidosis therapies, early diagnosis and presymptomatic testing for ATTRv family members has become paramount. ANN NEUROL 2024;96:423–440</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":null,"pages":null},"PeriodicalIF":8.1,"publicationDate":"2024-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ana.26965","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141453973","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}
Michael P. H Stanley MD, Clifford B. Saper MD, PhD
{"title":"Self Portrait – Artist as Patient: An Illustration of Left-Sided Neglect","authors":"Michael P. H Stanley MD, Clifford B. Saper MD, PhD","doi":"10.1002/ana.27011","DOIUrl":"10.1002/ana.27011","url":null,"abstract":"","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":null,"pages":null},"PeriodicalIF":8.1,"publicationDate":"2024-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141453979","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}
Johanne Juhl Korsbæk, Rigmor Højland Jensen, Dagmar Beier, Elisabeth Arnberg Wibroe, Snorre Malm Hagen, Laleh Dehghani Molander, Matthew Paul Gillum, Katrine Svart, Thomas Folkmann Hansen, Lisette J.A. Kogelman, Connar Stanley James Westgate
Objective
Idiopathic intracranial hypertension (IIH) is a neurometabolic disease with an increasing incidence. The pathophysiology is unknown, but improvement of diagnosis and management requires discovery of novel biomarkers. Our objective was to identify such candidate biomarkers in IIH, and secondarily, test for associations between identified metabolites and disease severity.
Methods
This is a prospective case–control study with collection of cerebrospinal fluid (CSF), serum, and clinical data from new-onset, treatment-naïve patients with IIH (n = 60). Patients were included consecutively from 2 tertiary headache centers in Denmark, and age, sex, and body mass index (BMI) -matched healthy controls (n = 35) were recruited. Clinical data were retrieved at ocular remission (n = 55). Samples were analyzed using non-targeted mass spectrometry.
Results
Serum sphingosine 1-phosphate (S1P), adenosine, and glutamate were 0.46-fold (q < 0.0001), 0.25-fold (q = 0.0048), and 0.44-fold (q < 0.0001) lower, respectively, in IIH. CSF stearoyl-lysophosphatidylcholine (LysoPC-18) and 2-palmitoyl-lysophosphatidylcholine (LysoPC-16) were 0.42 (q = 0.0025) and 0.37 (q < 0.001) -fold lower. LysoPC-18 was higher in patients with moderate–severe versus mild papilledema (p = 0.022). LysoPC-18 correlated positively with retinal nerve fiber layer thickness (p = 0.0012, r = 0.42) and inversely with mean deviation on automated perimetry (p = 0.01, r = −0.35). Higher baseline serum S1P (p = 0.018) and lower CSF LysoPC-16 (p = 0.003) were associated with optic nerve atrophy at ocular remission. Pathway analysis suggests dysregulated lipid metabolism and redox disturbances in new-onset IIH.
Interpretation
We identify perturbed metabolism in new-onset IIH. S1P and LysoPC-16 demonstrate potential prognostic value due to association with subsequent optic nerve atrophy. This association between specific, differential metabolites and outcome provides substantial evidence for novel biomarkers of clinical significance that should be the focus of further targeted studies. ANN NEUROL 2024;96:595–607
{"title":"Metabolic Dysfunction in New-Onset Idiopathic Intracranial Hypertension: Identification of Novel Biomarkers","authors":"Johanne Juhl Korsbæk, Rigmor Højland Jensen, Dagmar Beier, Elisabeth Arnberg Wibroe, Snorre Malm Hagen, Laleh Dehghani Molander, Matthew Paul Gillum, Katrine Svart, Thomas Folkmann Hansen, Lisette J.A. Kogelman, Connar Stanley James Westgate","doi":"10.1002/ana.27010","DOIUrl":"10.1002/ana.27010","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>Idiopathic intracranial hypertension (IIH) is a neurometabolic disease with an increasing incidence. The pathophysiology is unknown, but improvement of diagnosis and management requires discovery of novel biomarkers. Our objective was to identify such candidate biomarkers in IIH, and secondarily, test for associations between identified metabolites and disease severity.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This is a prospective case–control study with collection of cerebrospinal fluid (CSF), serum, and clinical data from new-onset, treatment-naïve patients with IIH (n = 60). Patients were included consecutively from 2 tertiary headache centers in Denmark, and age, sex, and body mass index (BMI) -matched healthy controls (n = 35) were recruited. Clinical data were retrieved at ocular remission (n = 55). Samples were analyzed using non-targeted mass spectrometry.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Serum sphingosine 1-phosphate (S1P), adenosine, and glutamate were 0.46-fold (q < 0.0001), 0.25-fold (q = 0.0048), and 0.44-fold (q < 0.0001) lower, respectively, in IIH. CSF stearoyl-lysophosphatidylcholine (LysoPC-18) and 2-palmitoyl-lysophosphatidylcholine (LysoPC-16) were 0.42 (q = 0.0025) and 0.37 (q < 0.001) -fold lower. LysoPC-18 was higher in patients with moderate–severe versus mild papilledema (<i>p</i> = 0.022). LysoPC-18 correlated positively with retinal nerve fiber layer thickness (<i>p</i> = 0.0012, r = 0.42) and inversely with mean deviation on automated perimetry (<i>p</i> = 0.01, r = −0.35). Higher baseline serum S1P (<i>p</i> = 0.018) and lower CSF LysoPC-16 (<i>p</i> = 0.003) were associated with optic nerve atrophy at ocular remission. Pathway analysis suggests dysregulated lipid metabolism and redox disturbances in new-onset IIH.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>We identify perturbed metabolism in new-onset IIH. S1P and LysoPC-16 demonstrate potential prognostic value due to association with subsequent optic nerve atrophy. This association between specific, differential metabolites and outcome provides substantial evidence for novel biomarkers of clinical significance that should be the focus of further targeted studies. ANN NEUROL 2024;96:595–607</p>\u0000 </section>\u0000 </div>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":null,"pages":null},"PeriodicalIF":8.1,"publicationDate":"2024-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ana.27010","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141519631","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 96, Number 1, July 2024","authors":"","doi":"10.1002/ana.26698","DOIUrl":"https://doi.org/10.1002/ana.26698","url":null,"abstract":"","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":null,"pages":null},"PeriodicalIF":11.2,"publicationDate":"2024-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ana.26698","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141430284","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}
Carla Abdelnour MD, PhD, Christina B. Young PhD, Marian Shahid-Besanti MSc, Alena Smith, Edward N. Wilson PhD, Javier Ramos Benitez, Hillary Vossler, Melanie J. Plastini PhD, Joseph R. Winer PhD, Geoffrey A. Kerchner MD, PhD, Brenna Cholerton PhD, Katrin I. Andreasson MD, Victor W. Henderson MD, MS, Maya Yutsis PhD, Thomas J. Montine MD, PhD, Lu Tian PhD, Elizabeth C. Mormino PhD, Kathleen L. Poston MD, MS
Objective
To determine whether plasma phosphorylated-Tau181 (pTau181) could be used as a diagnostic biomarker of concurrent Alzheimer's disease neuropathologic change (ADNC) or amyloidosis alone, as well as a prognostic, monitoring, and susceptibility/risk biomarker for clinical outcomes in Lewy body disease (LBD).
Methods
We studied 565 participants: 94 LBD with normal cognition, 83 LBD with abnormal cognition, 114 with Alzheimer's disease, and 274 cognitively normal. Plasma pTau181 levels were measured with the Lumipulse G platform. Diagnostic accuracy for concurrent ADNC and amyloidosis was assessed with Receiver Operating Characteristic curves in a subset of participants with CSF pTau181/Aβ42, and CSF Aβ42/Aβ40 or amyloid-β PET, respectively. Linear mixed effects models were used to examine the associations between baseline and longitudinal plasma pTau181 levels and clinical outcomes.
Results
Plasma pTau181 predicted concurrent ADNC and amyloidosis in LBD with abnormal cognition with 87% and 72% accuracy, respectively. In LBD patients with abnormal cognition, higher baseline plasma pTau181 was associated with worse baseline MoCA and CDR-SB, as well as accelerated decline in CDR-SB. Additionally, in this group, rapid increases in plasma pTau181 over 3 years predicted a faster decline in CDR-SB and memory. In LBD patients with normal cognition, there was no association between baseline or longitudinal plasma pTau181 levels and clinical outcomes; however, elevated pTau181 at baseline increased the risk of conversion to cognitive impairment.
Interpretation
Our findings suggest that plasma pTau181 is a promising biomarker for concurrent ADNC and amyloidosis in LBD. Furthermore, plasma pTau181 holds potential as a prognostic, monitoring, and susceptibility/risk biomarker, predicting disease progression in LBD. ANN NEUROL 2024;96:526–538
{"title":"Plasma pTau181 Reveals a Pathological Signature that Predicts Cognitive Outcomes in Lewy Body Disease","authors":"Carla Abdelnour MD, PhD, Christina B. Young PhD, Marian Shahid-Besanti MSc, Alena Smith, Edward N. Wilson PhD, Javier Ramos Benitez, Hillary Vossler, Melanie J. Plastini PhD, Joseph R. Winer PhD, Geoffrey A. Kerchner MD, PhD, Brenna Cholerton PhD, Katrin I. Andreasson MD, Victor W. Henderson MD, MS, Maya Yutsis PhD, Thomas J. Montine MD, PhD, Lu Tian PhD, Elizabeth C. Mormino PhD, Kathleen L. Poston MD, MS","doi":"10.1002/ana.27003","DOIUrl":"10.1002/ana.27003","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>To determine whether plasma phosphorylated-Tau181 (pTau181) could be used as a diagnostic biomarker of concurrent Alzheimer's disease neuropathologic change (ADNC) or amyloidosis alone, as well as a prognostic, monitoring, and susceptibility/risk biomarker for clinical outcomes in Lewy body disease (LBD).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We studied 565 participants: 94 LBD with normal cognition, 83 LBD with abnormal cognition, 114 with Alzheimer's disease, and 274 cognitively normal. Plasma pTau181 levels were measured with the Lumipulse <i>G</i> platform. Diagnostic accuracy for concurrent ADNC and amyloidosis was assessed with Receiver Operating Characteristic curves in a subset of participants with CSF pTau181/Aβ42, and CSF Aβ42/Aβ40 or amyloid-β PET, respectively. Linear mixed effects models were used to examine the associations between baseline and longitudinal plasma pTau181 levels and clinical outcomes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Plasma pTau181 predicted concurrent ADNC and amyloidosis in LBD with abnormal cognition with 87% and 72% accuracy, respectively. In LBD patients with abnormal cognition, higher baseline plasma pTau181 was associated with worse baseline MoCA and CDR-SB, as well as accelerated decline in CDR-SB. Additionally, in this group, rapid increases in plasma pTau181 over 3 years predicted a faster decline in CDR-SB and memory. In LBD patients with normal cognition, there was no association between baseline or longitudinal plasma pTau181 levels and clinical outcomes; however, elevated pTau181 at baseline increased the risk of conversion to cognitive impairment.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>Our findings suggest that plasma pTau181 is a promising biomarker for concurrent ADNC and amyloidosis in LBD. Furthermore, plasma pTau181 holds potential as a prognostic, monitoring, and susceptibility/risk biomarker, predicting disease progression in LBD. ANN NEUROL 2024;96:526–538</p>\u0000 </section>\u0000 </div>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":null,"pages":null},"PeriodicalIF":8.1,"publicationDate":"2024-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ana.27003","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141416891","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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