Frank Jessen, M. G. Kramberger, D. Angioni, D. Aarsland, M. Balasa, K. Bennys, M. Boada, M. Boban, A. Chincarini, L. Exalto, A. Felbecker, K. Fliessbach, G. B. Frisoni, A. J. Garza-Martínez, T. Grimmer, B. Hanseeuw, J. Hort, A. Ivanoiu, S. Klöppel, L. Krajcovicova, B. McGuinness, P. Mecocci, A. de Mendonca, A. Nous, P.-J. Ousset, C. Paquet, R. Perneczky, O. Peters, M. Tabuas-Pereira, F. Piazza, D. Plantone, M. Riverol, A. Ruiz, G. Sacco, I. Santana, N. Scarmeas, E. Solje, E. Stefanova, S. Sutovsky, W. van der Flier, T. Welsh, A. Wimo, B. Winblad, L. Frölich, S. Engelborghs
β-amyloid-targeting antibodies represent the first generation of effective causal treatment of Alzheimer’s disease (AD) and can be considered historical research milestones. Their effect sizes, side effects, implementation challenges and costs, however, have stimulated debates about their overall value. In this position statement academic clinicians of the European Alzheimer’s Disease Consortium (EADC) discuss the critical relevance of introducing these new treatments in clinical care now. Given the complexity of AD it is unlikely that molecular single-target treatments will achieve substantially larger effects than those seen with current β-amyloid-targeting antibodies. Larger effects will most likely only be achieved incrementally by continuous optimization of molecular approaches, patient selection and combinations therapies. To be successful in this regard, drug development must be informed by the use of innovative treatments in real world practice, because full understanding of all facets of novel treatments requires experience and data of real-world care beyond those of clinical trials. Regarding the antibodies under discussion we consider their effects meaningful and potential side effects manageable. We assume that the number of eventually treated patient will only be a fraction of all early AD patients due to narrow eligibility criteria and barriers of access. We strongly endorse the use of these new compound in clinical practice in selected patients with treatment documentation in registries. We understand this as a critical step in advancing the field of AD treatment, and in shaping the health care systems for the new area of molecular-targeted treatment of neurodegenerative diseases.
β-淀粉样蛋白靶向抗体代表了第一代有效的阿尔茨海默病(AD)因果治疗方法,可以说是历史性的研究里程碑。然而,其效果大小、副作用、实施挑战和成本引发了对其整体价值的争论。在这份立场声明中,欧洲阿尔茨海默病联盟(EADC)的临床医生们讨论了现在将这些新疗法引入临床治疗的重要意义。鉴于阿尔茨海默病的复杂性,分子单靶点治疗不太可能取得比目前的β-淀粉样蛋白靶向抗体更大的疗效。更大的疗效很可能只能通过不断优化分子方法、患者选择和组合疗法来逐步实现。要想在这方面取得成功,药物开发必须参考创新疗法在现实世界中的使用情况,因为要充分了解新型疗法的方方面面,除了临床试验之外,还需要现实世界中的治疗经验和数据。关于正在讨论的抗体,我们认为其效果是有意义的,潜在的副作用是可控的。我们假定,由于资格标准狭窄和获得治疗的障碍,最终接受治疗的患者人数仅占所有早期AD患者的一小部分。我们强烈支持在临床实践中对选定的患者使用这些新化合物,并在登记册中记录治疗情况。我们认为这是推进 AD 治疗领域的关键一步,也是为神经退行性疾病分子靶向治疗这一新领域建立医疗保健系统的关键一步。
{"title":"Progress in the Treatment of Alzheimer’s Disease Is Needed – Position Statement of European Alzheimer’s Disease Consortium (EADC) Investigators","authors":"Frank Jessen, M. G. Kramberger, D. Angioni, D. Aarsland, M. Balasa, K. Bennys, M. Boada, M. Boban, A. Chincarini, L. Exalto, A. Felbecker, K. Fliessbach, G. B. Frisoni, A. J. Garza-Martínez, T. Grimmer, B. Hanseeuw, J. Hort, A. Ivanoiu, S. Klöppel, L. Krajcovicova, B. McGuinness, P. Mecocci, A. de Mendonca, A. Nous, P.-J. Ousset, C. Paquet, R. Perneczky, O. Peters, M. Tabuas-Pereira, F. Piazza, D. Plantone, M. Riverol, A. Ruiz, G. Sacco, I. Santana, N. Scarmeas, E. Solje, E. Stefanova, S. Sutovsky, W. van der Flier, T. Welsh, A. Wimo, B. Winblad, L. Frölich, S. Engelborghs","doi":"10.14283/jpad.2024.153","DOIUrl":"https://doi.org/10.14283/jpad.2024.153","url":null,"abstract":"<p>β-amyloid-targeting antibodies represent the first generation of effective causal treatment of Alzheimer’s disease (AD) and can be considered historical research milestones. Their effect sizes, side effects, implementation challenges and costs, however, have stimulated debates about their overall value. In this position statement academic clinicians of the European Alzheimer’s Disease Consortium (EADC) discuss the critical relevance of introducing these new treatments in clinical care now. Given the complexity of AD it is unlikely that molecular single-target treatments will achieve substantially larger effects than those seen with current β-amyloid-targeting antibodies. Larger effects will most likely only be achieved incrementally by continuous optimization of molecular approaches, patient selection and combinations therapies. To be successful in this regard, drug development must be informed by the use of innovative treatments in real world practice, because full understanding of all facets of novel treatments requires experience and data of real-world care beyond those of clinical trials. Regarding the antibodies under discussion we consider their effects meaningful and potential side effects manageable. We assume that the number of eventually treated patient will only be a fraction of all early AD patients due to narrow eligibility criteria and barriers of access. We strongly endorse the use of these new compound in clinical practice in selected patients with treatment documentation in registries. We understand this as a critical step in advancing the field of AD treatment, and in shaping the health care systems for the new area of molecular-targeted treatment of neurodegenerative diseases.</p>","PeriodicalId":22711,"journal":{"name":"The Journal of Prevention of Alzheimer's Disease","volume":"11 1","pages":""},"PeriodicalIF":6.4,"publicationDate":"2024-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142197471","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
H. Zhang, J. Liu, N. Zhang, A. Jeromin, Zhongping John Lin
Background
Both blood (plasma and serum) and CSF tau phosphorylated at Threonine 217 (pTau217) have been shown to be able to discriminate early to mild Alzheimer’s disease (AD) from non-AD neurodegenerative disorders and healthy controls with high sensitivity and specificity.
Objectives
We report the full validation of the ALZpath ultra-sensitive pTau217 research-use only (RUO) assays for human EDTA plasma, serum, and CSF using the Quanterix Simoa HD-X platform, in support of clinical trials and early diagnosis of Alzheimer’s disease.
Methods
The ALZpath pTau217 Simoa Advantage v2 kit from ALZpath/Quanterix was used for method development and validation of pTau217 in human plasma, serum, and CSF. All three method validations have followed the 2018 FDA BMV and 2022 ICH M10 guidelines.
Results
Validation of pTau217 quantitation in human plasma, serum, and CSF demonstrated that the validated pTau217 assay has an analytical LLOQ of 0.00977 pg/mL. It is one of the most sensitive assays with a minimal required sample volume of 33.3 µl for plasma and serum, and 5 µl for CSF, and is relatively cost-effective, compared to the currently published data. The minimum required dilution (MRD) for plasma, serum, and CSF were determined. The analyte passed short-term stability tests. It was also tolerant of moderate hemolytic, and lipemic interferences in plasma and serum. pTau217 was detected in 100% of tested healthy control plasma, 90.0% of healthy control serum, 92.3% of healthy control CSF samples, and 100% of AD plasma and CSF samples. The validated assay was successfully applied in the analysis of AD samples, with data showing dramatic differences in the pTau217 levels between healthy control subjects and AD patients in both plasma and CSF.
Conclusion
Validation of the ALZpath pTau217 Simoa assay in human plasma, serum, and CSF demonstrates ultra sensitivity, high accuracy, and assay robustness. Together with other established and sensitive assays for pTau181, GFAP, and NfL, these assays have immediate utility for application in clinical trials and can play a role in the early diagnosis of neurodegenerative diseases.
{"title":"Validation of an Ultra-Sensitive Method for Quantitation of Phospho-Tau 217 (pTau217) in Human Plasma, Serum, and CSF using the ALZpath pTau217 Assay on the Quanterix HD-X Platform","authors":"H. Zhang, J. Liu, N. Zhang, A. Jeromin, Zhongping John Lin","doi":"10.14283/jpad.2024.155","DOIUrl":"https://doi.org/10.14283/jpad.2024.155","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Background</h3><p>Both blood (plasma and serum) and CSF tau phosphorylated at Threonine 217 (pTau217) have been shown to be able to discriminate early to mild Alzheimer’s disease (AD) from non-AD neurodegenerative disorders and healthy controls with high sensitivity and specificity.</p><h3 data-test=\"abstract-sub-heading\">Objectives</h3><p>We report the full validation of the ALZpath ultra-sensitive pTau217 research-use only (RUO) assays for human EDTA plasma, serum, and CSF using the Quanterix Simoa HD-X platform, in support of clinical trials and early diagnosis of Alzheimer’s disease.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>The ALZpath pTau217 Simoa Advantage v2 kit from ALZpath/Quanterix was used for method development and validation of pTau217 in human plasma, serum, and CSF. All three method validations have followed the 2018 FDA BMV and 2022 ICH M10 guidelines.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>Validation of pTau217 quantitation in human plasma, serum, and CSF demonstrated that the validated pTau217 assay has an analytical LLOQ of 0.00977 pg/mL. It is one of the most sensitive assays with a minimal required sample volume of 33.3 µl for plasma and serum, and 5 µl for CSF, and is relatively cost-effective, compared to the currently published data. The minimum required dilution (MRD) for plasma, serum, and CSF were determined. The analyte passed short-term stability tests. It was also tolerant of moderate hemolytic, and lipemic interferences in plasma and serum. pTau217 was detected in 100% of tested healthy control plasma, 90.0% of healthy control serum, 92.3% of healthy control CSF samples, and 100% of AD plasma and CSF samples. The validated assay was successfully applied in the analysis of AD samples, with data showing dramatic differences in the pTau217 levels between healthy control subjects and AD patients in both plasma and CSF.</p><h3 data-test=\"abstract-sub-heading\">Conclusion</h3><p>Validation of the ALZpath pTau217 Simoa assay in human plasma, serum, and CSF demonstrates ultra sensitivity, high accuracy, and assay robustness. Together with other established and sensitive assays for pTau181, GFAP, and NfL, these assays have immediate utility for application in clinical trials and can play a role in the early diagnosis of neurodegenerative diseases.</p>","PeriodicalId":22711,"journal":{"name":"The Journal of Prevention of Alzheimer's Disease","volume":"6 1","pages":""},"PeriodicalIF":6.4,"publicationDate":"2024-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141929869","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
M. T. Hoang, P. G. Jurado, T. Abzhandadze, S. Mostafaei, M. Mo, M. Åkerman, K. Vestling, C. Chen, H. Xu, M. Eriksdotter, Sara Garcia-Ptacek
Background
Care trajectories were disrupted during the COVID-19 pandemic. However, how COVID-19 influenced the number of new dementia diagnoses, and the quality of dementia work-ups, and treatment is understudied.
Objective
To investigate the change in new dementia registrations, diagnostics, and treatment in the pre-, COVID-19 and post-COVID-19 pandemic periods.
Design
A nationwide cohort study.
Setting
This population-based study used data from the Swedish Registry for Cognitive/Dementia disorders - SveDem, and other nationwide registries in Sweden.
Participants
Persons with dementia diagnosed between 2019 and 2021 were divided into three groups based on the date of diagnosis
the pre-COVID-19 period (01 January 2019 – 29 February 2020), the COVID-19 period (01 March 2020 – 31 December 2020), and the post-COVID-19 period (01 January 2021 – 31 August 2021).
Measurements
Outcomes included dementia diagnostics and treatments.
Results
The monthly average number of new dementia cases registered in SveDem was 595, 415 and 470, respectively in the pre-COVID-19, COVID-19 and post-COVID-19 period. Compared to the pre-COVID-19 period, the monthly number of registrations decreased, but provision of the basic diagnostic work-up, its individual tests, and the use of cholinesterase inhibitors, memantine and antipsychotics were not significantly different in the COVID-19 period. Compared to the pre-COVID-19 period, new dementia diagnoses continued to be low in the post-COVID-19 period, but diagnosed individuals were more likely to receive the complete basic diagnostic work-up (OR 1.14, 95% CI 1.00–1.29), blood analysis (OR 1.88, 95% CI 1.44–2.49), computed tomography and magnetic resonance imaging (OR 1.22, 95% CI 1.01–1.48), occupational therapy assessment (OR 1.13, 95% CI 1.04–1.22), and memantine (OR 1.19, 95% CI 1.07–1.31).
Conclusion
The quantity of new dementia registrations in SveDem decreased in the COVID-19 period and has not returned to pre-COVID-19 levels, but the quality of the work-ups which were conducted and registered in SveDem was similar or higher than in the pre-COVID-19 period. It is imperative to implement policies to increase SveDem registration with the aim of matching or exceeding pre-COVID-19 levels.
{"title":"Effects of the COVID-19 Pandemic on the Number of New Dementia Diagnoses and the Quality of Dementia Diagnostics and Treatment","authors":"M. T. Hoang, P. G. Jurado, T. Abzhandadze, S. Mostafaei, M. Mo, M. Åkerman, K. Vestling, C. Chen, H. Xu, M. Eriksdotter, Sara Garcia-Ptacek","doi":"10.14283/jpad.2024.150","DOIUrl":"https://doi.org/10.14283/jpad.2024.150","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Background</h3><p>Care trajectories were disrupted during the COVID-19 pandemic. However, how COVID-19 influenced the number of new dementia diagnoses, and the quality of dementia work-ups, and treatment is understudied.</p><h3 data-test=\"abstract-sub-heading\">Objective</h3><p>To investigate the change in new dementia registrations, diagnostics, and treatment in the pre-, COVID-19 and post-COVID-19 pandemic periods.</p><h3 data-test=\"abstract-sub-heading\">Design</h3><p>A nationwide cohort study.</p><h3 data-test=\"abstract-sub-heading\">Setting</h3><p>This population-based study used data from the Swedish Registry for Cognitive/Dementia disorders - SveDem, and other nationwide registries in Sweden.</p><h3 data-test=\"abstract-sub-heading\">Participants</h3><p>Persons with dementia diagnosed between 2019 and 2021 were divided into three groups based on the date of diagnosis</p><p>the pre-COVID-19 period (01 January 2019 – 29 February 2020), the COVID-19 period (01 March 2020 – 31 December 2020), and the post-COVID-19 period (01 January 2021 – 31 August 2021).</p><h3 data-test=\"abstract-sub-heading\">Measurements</h3><p>Outcomes included dementia diagnostics and treatments.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>The monthly average number of new dementia cases registered in SveDem was 595, 415 and 470, respectively in the pre-COVID-19, COVID-19 and post-COVID-19 period. Compared to the pre-COVID-19 period, the monthly number of registrations decreased, but provision of the basic diagnostic work-up, its individual tests, and the use of cholinesterase inhibitors, memantine and antipsychotics were not significantly different in the COVID-19 period. Compared to the pre-COVID-19 period, new dementia diagnoses continued to be low in the post-COVID-19 period, but diagnosed individuals were more likely to receive the complete basic diagnostic work-up (OR 1.14, 95% CI 1.00–1.29), blood analysis (OR 1.88, 95% CI 1.44–2.49), computed tomography and magnetic resonance imaging (OR 1.22, 95% CI 1.01–1.48), occupational therapy assessment (OR 1.13, 95% CI 1.04–1.22), and memantine (OR 1.19, 95% CI 1.07–1.31).</p><h3 data-test=\"abstract-sub-heading\">Conclusion</h3><p>The quantity of new dementia registrations in SveDem decreased in the COVID-19 period and has not returned to pre-COVID-19 levels, but the quality of the work-ups which were conducted and registered in SveDem was similar or higher than in the pre-COVID-19 period. It is imperative to implement policies to increase SveDem registration with the aim of matching or exceeding pre-COVID-19 levels.</p>","PeriodicalId":22711,"journal":{"name":"The Journal of Prevention of Alzheimer's Disease","volume":"75 1","pages":""},"PeriodicalIF":6.4,"publicationDate":"2024-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141929868","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sanaz Dabiri, R. Raman, J. Grooms, D. Molina-Henry
Background
Despite higher dementia prevalence in racial and ethnic minoritized communities, they are underrepresented in Alzheimer’s disease clinical trials. Community-based recruitment strategies are believed to yield positive outcomes in various fields, such as cancer and cardiovascular clinical trials, but their outcomes in Alzheimer’s disease and Related Dementias (AD/ADRD) require further study. In this systematic rapid review, we synthesized the available evidence on community-engaged recruitment strategies in enhancing participation in AD/ADRD clinical trials and observational study participation.
Methods
We searched and identified studies describing a community-based recruitment approach for racial and ethnic minoritized communities across seven databases (Pubmed, OVID MEDLINE, Cochrane Central Register of Controlled Trials, CINAHL, PsychINFO, Web of Science, and EMBASE).
Results
Out of 1915 screened studies, 49 met the inclusion criteria. Most studies employed multiple community-based recruitment approaches, including educational presentations, collaborations with community-based faith organizations, community advisory boards, and engagement with local clinics or health professionals. 52% of studies targeted more than one racial and ethnic minoritized population, primarily African Americans and then Hispanic/Latino. Gaps in knowledge about AD/ADRD, its increased risk among minoritized populations, distrust, and stigma were noted as barriers to research participation. Approximately 50% of the studies specified whether they evaluated their recruitment approaches, and in studies where approaches were evaluated, there was substantial heterogeneity in methods utilized.
Conclusion
The quality of available evidence on the use of community-based recruitment approaches to include racial and ethnic minoritized populations in AD/ADRD research, particularly in clinical trials, is limited. Systematic assessment of recruitment strategies is urgently needed to increase the evidence base around community-engaged recruitment approaches.
背景尽管少数种族和族裔社区的痴呆症发病率较高,但他们在阿尔茨海默病临床试验中的代表性却不足。以社区为基础的招募策略被认为在癌症和心血管临床试验等多个领域产生了积极的效果,但其在阿尔茨海默病及相关痴呆症(AD/ADRD)中的效果还需要进一步研究。在这篇系统性的快速综述中,我们综合了社区参与招募策略在提高 AD/ADRD 临床试验参与度和观察性研究参与度方面的现有证据。方法我们在 7 个数据库(Pubmed、OVID MEDLINE、Cochrane Central Register of Controlled Trials、CINAHL、PsychINFO、Web of Science 和 EMBASE)中搜索并确定了针对少数种族和族裔社区的社区招募方法的研究。大多数研究采用了多种基于社区的招募方法,包括教育演讲、与社区信仰组织合作、社区咨询委员会以及与当地诊所或医疗专业人员合作。52% 的研究针对一个以上的少数种族和族裔人群,主要是非裔美国人,然后是西班牙裔/拉丁美洲人。人们注意到,对注意力缺失症/注意力缺失性痴呆症的认识不足、其在少数民族人群中的风险增加、不信任和耻辱感是参与研究的障碍。约50%的研究明确说明了他们是否对招募方法进行了评估,而在对招募方法进行评估的研究中,所使用的方法存在很大的不一致性。迫切需要对招募策略进行系统评估,以增加社区参与招募方法的证据基础。
{"title":"Examining the Role of Community Engagement in Enhancing the Participation of Racial and Ethnic Minoritized Communities in Alzheimer’s Disease Clinical Trials; A Rapid Review","authors":"Sanaz Dabiri, R. Raman, J. Grooms, D. Molina-Henry","doi":"10.14283/jpad.2024.149","DOIUrl":"https://doi.org/10.14283/jpad.2024.149","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Background</h3><p>Despite higher dementia prevalence in racial and ethnic minoritized communities, they are underrepresented in Alzheimer’s disease clinical trials. Community-based recruitment strategies are believed to yield positive outcomes in various fields, such as cancer and cardiovascular clinical trials, but their outcomes in Alzheimer’s disease and Related Dementias (AD/ADRD) require further study. In this systematic rapid review, we synthesized the available evidence on community-engaged recruitment strategies in enhancing participation in AD/ADRD clinical trials and observational study participation.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>We searched and identified studies describing a community-based recruitment approach for racial and ethnic minoritized communities across seven databases (Pubmed, OVID MEDLINE, Cochrane Central Register of Controlled Trials, CINAHL, PsychINFO, Web of Science, and EMBASE).</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>Out of 1915 screened studies, 49 met the inclusion criteria. Most studies employed multiple community-based recruitment approaches, including educational presentations, collaborations with community-based faith organizations, community advisory boards, and engagement with local clinics or health professionals. 52% of studies targeted more than one racial and ethnic minoritized population, primarily African Americans and then Hispanic/Latino. Gaps in knowledge about AD/ADRD, its increased risk among minoritized populations, distrust, and stigma were noted as barriers to research participation. Approximately 50% of the studies specified whether they evaluated their recruitment approaches, and in studies where approaches were evaluated, there was substantial heterogeneity in methods utilized.</p><h3 data-test=\"abstract-sub-heading\">Conclusion</h3><p>The quality of available evidence on the use of community-based recruitment approaches to include racial and ethnic minoritized populations in AD/ADRD research, particularly in clinical trials, is limited. Systematic assessment of recruitment strategies is urgently needed to increase the evidence base around community-engaged recruitment approaches.</p>","PeriodicalId":22711,"journal":{"name":"The Journal of Prevention of Alzheimer's Disease","volume":"16 1","pages":""},"PeriodicalIF":6.4,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141929867","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Francisco Martínez-Dubarbie, A. Guerra-Ruiz, S. López-García, C. Lage, M. Fernández-Matarrubia, J. Infante, A. Pozueta-Cantudo, M. García-Martínez, A. Corrales-Pardo, M. Bravo, M. López-Hoyos, J. Irure-Ventura, E. Valeriano-Lorenzo, M. T. García-Unzueta, P. Sánchez-Juan, E. Rodríguez-Rodríguez
Background
Plasma biomarkers of Alzheimer’s disease (AD), especially p-tau217, are promising tools to identify subjects with amyloid deposition in the brain, determined either by cerebrospinal fluid (CSF) or positron emission tomography. However, it is essential to measure them in an accurate and fully automated way in order to apply them in clinical practice.
Objectives
To evaluate the diagnostic performance of the fully-automated Lumipulse plasma p-tau217 assay in preclinical AD.
Design
Cross-sectional analyses from a prospective cohort.
Setting
A population-based study.
Participants
Volunteers over 55 years without cognitive impairment or contraindications for complementary tests.
Measurements
Plasma p-tau217 was measured with the fully-automated Lumipulse assay, as well as CSF Aβ40, Aβ42, p-taul81, and t-tau levels. We correlated plasma p-tau217 with CSF Aβ40, Aβ42 and p-tau181, and assessed the differences in plasma p-tau217 according to CSF amyloid status (A−/+), AD status (AD+ being those subjects A+T+ and AD- the rest) and ATN group. We performed ROC curves and measured the areas under the curve (AUC) using CSF amyloid as result, and both p-tau217 and ApoE4 status as predictor.
Results
We screened 209 cognitively unimpaired volunteers with a mean age 64 years (60–69) and 30.2% of ApoE4 carriers. Plasma p-tau217 correlated significantly with CSF Aβ42/Aβ40 (Rho=−0.51; p-value<0.001) and p-tau181 (r=0.59; p-value<0.001). Its levels were significantly higher in A+ subjects (0.26 pg/ml) compared with A- (0.12 pg/ml; p-value<0.001); and along ATN groups. It predicts CSF amyloid pathology with an AUC of 0.85.
Conclusions
Plasma p-tau217 measured using the Lumipulse platform shows promise as an accurate biomarker of preclinical AD pathology.
{"title":"Diagnostic Accuracy of Plasma p-tau217 for Detecting Pathological Cerebrospinal Fluid Changes in Cognitively Unimpaired Subjects Using the Lumipulse Platform","authors":"Francisco Martínez-Dubarbie, A. Guerra-Ruiz, S. López-García, C. Lage, M. Fernández-Matarrubia, J. Infante, A. Pozueta-Cantudo, M. García-Martínez, A. Corrales-Pardo, M. Bravo, M. López-Hoyos, J. Irure-Ventura, E. Valeriano-Lorenzo, M. T. García-Unzueta, P. Sánchez-Juan, E. Rodríguez-Rodríguez","doi":"10.14283/jpad.2024.152","DOIUrl":"https://doi.org/10.14283/jpad.2024.152","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Background</h3><p>Plasma biomarkers of Alzheimer’s disease (AD), especially p-tau217, are promising tools to identify subjects with amyloid deposition in the brain, determined either by cerebrospinal fluid (CSF) or positron emission tomography. However, it is essential to measure them in an accurate and fully automated way in order to apply them in clinical practice.</p><h3 data-test=\"abstract-sub-heading\">Objectives</h3><p>To evaluate the diagnostic performance of the fully-automated Lumipulse plasma p-tau217 assay in preclinical AD.</p><h3 data-test=\"abstract-sub-heading\">Design</h3><p>Cross-sectional analyses from a prospective cohort.</p><h3 data-test=\"abstract-sub-heading\">Setting</h3><p>A population-based study.</p><h3 data-test=\"abstract-sub-heading\">Participants</h3><p>Volunteers over 55 years without cognitive impairment or contraindications for complementary tests.</p><h3 data-test=\"abstract-sub-heading\">Measurements</h3><p>Plasma p-tau217 was measured with the fully-automated Lumipulse assay, as well as CSF Aβ40, Aβ42, p-taul81, and t-tau levels. We correlated plasma p-tau217 with CSF Aβ40, Aβ42 and p-tau181, and assessed the differences in plasma p-tau217 according to CSF amyloid status (A−/+), AD status (AD+ being those subjects A+T+ and AD- the rest) and ATN group. We performed ROC curves and measured the areas under the curve (AUC) using CSF amyloid as result, and both p-tau217 and ApoE4 status as predictor.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>We screened 209 cognitively unimpaired volunteers with a mean age 64 years (60–69) and 30.2% of ApoE4 carriers. Plasma p-tau217 correlated significantly with CSF Aβ42/Aβ40 (Rho=−0.51; p-value<0.001) and p-tau181 (r=0.59; p-value<0.001). Its levels were significantly higher in A+ subjects (0.26 pg/ml) compared with A- (0.12 pg/ml; p-value<0.001); and along ATN groups. It predicts CSF amyloid pathology with an AUC of 0.85.</p><h3 data-test=\"abstract-sub-heading\">Conclusions</h3><p>Plasma p-tau217 measured using the Lumipulse platform shows promise as an accurate biomarker of preclinical AD pathology.</p>","PeriodicalId":22711,"journal":{"name":"The Journal of Prevention of Alzheimer's Disease","volume":"79 1","pages":""},"PeriodicalIF":6.4,"publicationDate":"2024-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141929877","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
E. Vijverberg, W. de Haan, E. Scheijbeler, M. E. Hamby, S. Catalano, P. Scheltens, M. Grundman, Anthony O. Caggiano
Background
CT1812 is a first-in-class, sigma-2 receptor ligand, that prevents and displaces binding of amyloid beta (Aβ) oligomers. Normalization of quantitative electroencephalography (qEEG) markers suggests that CT1812 protects synapses from Aβ oligomer toxicity.
Objectives
Evaluate CT1812 impact on synaptic function using qEEG measurements.
VU University Medical Center and Brain Research Center Amsterdam, The Netherlands.
Participants
Adults with mild or moderate Alzheimer’s disease (AD).
Intervention
A daily 300 mg dose of CT1812 or placebo for 4 weeks.
Measurements
A resting-state, eyes closed qEEG assessment occurred on Day 1 and on Day 29 of Treatment Periods 1 and 2, and at follow-up. The primary endpoint was global relative theta power (4–8 Hz), along with secondary EEG measures including global alpha corrected Amplitude Envelope Correlation (AEC-c). Cognitive and functional assessments, fluid biomarkers, and safety and tolerability were assessed.
Results
16 patients were randomized, and 15 completed. A non-significant (p=0.123) but consistent reduction occurred in global relative theta power and in relative theta power in frontal, temporal, parietal, occipital and central (p<0.006) brain regions with CT1812. A nominally significant (p=0.034) improvement was observed in global alpha AEC-c. Adverse events occurred in 11 patients with CT1812 and 6 with placebo -most commonly nausea, diarrhea, and procedural headache. No severe or serious AEs, deaths or discontinuations were reported.
Conclusion
CT1812 improved established EEG markers of spontaneous brain activity (spectral power, functional connectivity) in patients with mild-to-moderate AD, suggesting improved neuronal/synaptic function within a 4-week timespan.
{"title":"A Pilot Electroencephalography Study of the Effect of CT1812 Treatment on Synaptic Activity in Patients with Mild to Moderate Alzheimer’s Disease","authors":"E. Vijverberg, W. de Haan, E. Scheijbeler, M. E. Hamby, S. Catalano, P. Scheltens, M. Grundman, Anthony O. Caggiano","doi":"10.14283/jpad.2024.154","DOIUrl":"https://doi.org/10.14283/jpad.2024.154","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Background</h3><p>CT1812 is a first-in-class, sigma-2 receptor ligand, that prevents and displaces binding of amyloid beta (Aβ) oligomers. Normalization of quantitative electroencephalography (qEEG) markers suggests that CT1812 protects synapses from Aβ oligomer toxicity.</p><h3 data-test=\"abstract-sub-heading\">Objectives</h3><p>Evaluate CT1812 impact on synaptic function using qEEG measurements.</p><h3 data-test=\"abstract-sub-heading\">Design</h3><p>Phase 2, randomized, double-blind, placebo-controlled, 4-week crossover study.</p><h3 data-test=\"abstract-sub-heading\">Setting</h3><p>VU University Medical Center and Brain Research Center Amsterdam, The Netherlands.</p><h3 data-test=\"abstract-sub-heading\">Participants</h3><p>Adults with mild or moderate Alzheimer’s disease (AD).</p><h3 data-test=\"abstract-sub-heading\">Intervention</h3><p>A daily 300 mg dose of CT1812 or placebo for 4 weeks.</p><h3 data-test=\"abstract-sub-heading\">Measurements</h3><p>A resting-state, eyes closed qEEG assessment occurred on Day 1 and on Day 29 of Treatment Periods 1 and 2, and at follow-up. The primary endpoint was global relative theta power (4–8 Hz), along with secondary EEG measures including global alpha corrected Amplitude Envelope Correlation (AEC-c). Cognitive and functional assessments, fluid biomarkers, and safety and tolerability were assessed.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>16 patients were randomized, and 15 completed. A non-significant (p=0.123) but consistent reduction occurred in global relative theta power and in relative theta power in frontal, temporal, parietal, occipital and central (p<0.006) brain regions with CT1812. A nominally significant (p=0.034) improvement was observed in global alpha AEC-c. Adverse events occurred in 11 patients with CT1812 and 6 with placebo -most commonly nausea, diarrhea, and procedural headache. No severe or serious AEs, deaths or discontinuations were reported.</p><h3 data-test=\"abstract-sub-heading\">Conclusion</h3><p>CT1812 improved established EEG markers of spontaneous brain activity (spectral power, functional connectivity) in patients with mild-to-moderate AD, suggesting improved neuronal/synaptic function within a 4-week timespan.</p>","PeriodicalId":22711,"journal":{"name":"The Journal of Prevention of Alzheimer's Disease","volume":"100 1","pages":""},"PeriodicalIF":6.4,"publicationDate":"2024-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141929870","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Fred B. Ketchum, C. M. Erickson, K. E. Basche, N. A. Chin, M. L. Eveler, C. E. Conway, D. M. Coughlin, L. R. Clark
Background
Biomarker results are increasingly disclosed in research and clinical settings, but less is known about how individuals interpret their results or concerns raised during the disclosure visit that may need to be addressed by clinicians to ensure appropriate disclosure.
Methods
Fifty-two cognitively unimpaired older adults aged 65 to 89 years old from the Wisconsin Registry for Alzheimer’s Prevention, who had undergone an amyloid PET scan in the previous 18 months, were enrolled in the disclosure substudy. After ensuring psychological readiness, trained study clinicians disclosed amyloid PET results using a structured protocol. We assessed participants’ level of understanding, concerns, and the perceived personal significance of their biomarker results during the disclosure visit through a series of question prompts in real-time.
Results
Thirty-four received a non-elevated amyloid result and 18 received an elevated result. The average age was 72.2 years (range 65–81); most were women (64%) and non-Hispanic White (92%). Participants understood their results (98%), and both non-elevated and elevated groups provided similar responses around topics of sharing with others, privacy, accuracy of testing, and risk. Participants with elevated results were significantly more likely than those with non-elevated results to want to change their lifestyle (78% vs 12%, p=<0.01) and have questions about their results (61% vs 30%, p=0.05). Participants interpreted the personal significance of results in terms of several themes relating to individual risk status, emotional impact, whether the result was expected, and prevention/planning.
Conclusion
Results show that participants understand their biomarker results, and have a number of concerns during the disclosure process that clinical and research protocols could address. en These findings could be important considerations as effective processes are developed for widespread biomarker disclosure in clinical and research settings.
背景生物标记物结果越来越多地在研究和临床环境中披露,但人们对个人如何解释他们的结果或在披露访问期间提出的顾虑却知之甚少,而这些顾虑可能需要临床医生来解决,以确保适当的披露。方法威斯康星州阿尔茨海默氏症预防登记处的 52 名认知功能未受损的 65-89 岁老年人参加了披露子研究,他们在过去 18 个月中接受了淀粉样蛋白 PET 扫描。在确保做好心理准备后,经过培训的研究临床医生采用结构化协议披露淀粉样蛋白 PET 结果。在披露过程中,我们通过一系列实时问题提示来评估参与者对其生物标志物结果的理解程度、担忧和感知到的个人意义。结果34人的淀粉样蛋白结果未升高,18人的结果升高。参与者的平均年龄为 72.2 岁(65-81 岁不等);大多数为女性(64%)和非西班牙裔白人(92%)。参与者了解自己的结果(98%),未升高组和升高组对与他人分享、隐私、检测的准确性和风险等话题的回答相似。结果升高的参与者希望改变生活方式(78% 对 12%,p=0.01)和对结果有疑问(61% 对 30%,p=0.05)的可能性明显高于结果未升高的参与者。结果表明,参与者了解他们的生物标记物结果,并在披露过程中提出了一些临床和研究方案可以解决的问题。 这些发现可能是在临床和研究环境中为广泛披露生物标记物而开发有效流程时的重要考虑因素。
{"title":"Informing Alzheimer’s Biomarker Communication: Concerns and Understanding of Cognitively Unimpaired Adults During Amyloid Results Disclosure","authors":"Fred B. Ketchum, C. M. Erickson, K. E. Basche, N. A. Chin, M. L. Eveler, C. E. Conway, D. M. Coughlin, L. R. Clark","doi":"10.14283/jpad.2024.151","DOIUrl":"https://doi.org/10.14283/jpad.2024.151","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Background</h3><p>Biomarker results are increasingly disclosed in research and clinical settings, but less is known about how individuals interpret their results or concerns raised during the disclosure visit that may need to be addressed by clinicians to ensure appropriate disclosure.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>Fifty-two cognitively unimpaired older adults aged 65 to 89 years old from the Wisconsin Registry for Alzheimer’s Prevention, who had undergone an amyloid PET scan in the previous 18 months, were enrolled in the disclosure substudy. After ensuring psychological readiness, trained study clinicians disclosed amyloid PET results using a structured protocol. We assessed participants’ level of understanding, concerns, and the perceived personal significance of their biomarker results during the disclosure visit through a series of question prompts in real-time.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>Thirty-four received a non-elevated amyloid result and 18 received an elevated result. The average age was 72.2 years (range 65–81); most were women (64%) and non-Hispanic White (92%). Participants understood their results (98%), and both non-elevated and elevated groups provided similar responses around topics of sharing with others, privacy, accuracy of testing, and risk. Participants with elevated results were significantly more likely than those with non-elevated results to want to change their lifestyle (78% vs 12%, p=<0.01) and have questions about their results (61% vs 30%, p=0.05). Participants interpreted the personal significance of results in terms of several themes relating to individual risk status, emotional impact, whether the result was expected, and prevention/planning.</p><h3 data-test=\"abstract-sub-heading\">Conclusion</h3><p>Results show that participants understand their biomarker results, and have a number of concerns during the disclosure process that clinical and research protocols could address. en These findings could be important considerations as effective processes are developed for widespread biomarker disclosure in clinical and research settings.</p>","PeriodicalId":22711,"journal":{"name":"The Journal of Prevention of Alzheimer's Disease","volume":"45 1","pages":""},"PeriodicalIF":6.4,"publicationDate":"2024-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141929871","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Alzheimer’s disease (AD) has a high comorbidity with type 2 diabetes (T2D). However, there is still some controversy over whether T2D has a causal impact on AD at present.
Objectives
We aimed to reveal whether T2D has a causal effect on AD using large-scale genetic data.
Methods
Firstly, we performed a primary two-sample Mendelian randomization (MR) analysis to assess the potential causal effects of T2D on AD. For this analysis, we used the largest available genome-wide association studies (GWAS) T2D (T2D1, including 80,154 cases and 853,816 controls) and AD (AD1, including 111,326 cases and 677,663 controls) datasets. Additionally, we performed a validation MR analysis using two largely overlapping-sample datasets from FinnGen, including T2D (T2D2, including 57,698 cases and 308,252 controls) and AD (AD2, including 13,393 cases and 363,884 controls). In all MR analyses, the inverse variance-weighted method was used as the primary analysis method, supplemented by the weighted-median and MR-Egger techniques.
Results
In the primary analysis, we found that T2D was not associated with the risk of AD (OR: 0.98, CI: 0.95–1.01, P=0.241). Similarly, no significant association was detected in the validation MR analysis (OR: 0.97, CI: 0.64–1.47, P=0.884).
Conclusion
Our findings provide robust evidence that T2D does not have a causal impact on AD. Future studies need to further explore the effect of T2D on the non-AD components of the dementia phenotype.
{"title":"Evaluating the Causal Effect of Type 2 Diabetes on Alzheimer’s Disease Using Large-Scale Genetic Data","authors":"D. Liu, A. Baranova, Fuquan Zhang","doi":"10.14283/jpad.2024.148","DOIUrl":"https://doi.org/10.14283/jpad.2024.148","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Background</h3><p>Alzheimer’s disease (AD) has a high comorbidity with type 2 diabetes (T2D). However, there is still some controversy over whether T2D has a causal impact on AD at present.</p><h3 data-test=\"abstract-sub-heading\">Objectives</h3><p>We aimed to reveal whether T2D has a causal effect on AD using large-scale genetic data.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>Firstly, we performed a primary two-sample Mendelian randomization (MR) analysis to assess the potential causal effects of T2D on AD. For this analysis, we used the largest available genome-wide association studies (GWAS) T2D (T2D1, including 80,154 cases and 853,816 controls) and AD (AD1, including 111,326 cases and 677,663 controls) datasets. Additionally, we performed a validation MR analysis using two largely overlapping-sample datasets from FinnGen, including T2D (T2D2, including 57,698 cases and 308,252 controls) and AD (AD2, including 13,393 cases and 363,884 controls). In all MR analyses, the inverse variance-weighted method was used as the primary analysis method, supplemented by the weighted-median and MR-Egger techniques.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>In the primary analysis, we found that T2D was not associated with the risk of AD (OR: 0.98, CI: 0.95–1.01, P=0.241). Similarly, no significant association was detected in the validation MR analysis (OR: 0.97, CI: 0.64–1.47, P=0.884).</p><h3 data-test=\"abstract-sub-heading\">Conclusion</h3><p>Our findings provide robust evidence that T2D does not have a causal impact on AD. Future studies need to further explore the effect of T2D on the non-AD components of the dementia phenotype.</p>","PeriodicalId":22711,"journal":{"name":"The Journal of Prevention of Alzheimer's Disease","volume":"63 1","pages":""},"PeriodicalIF":6.4,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141783223","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yasuo Toda, T. Iwatsubo, Y. Nakamura, N. Matsuda, M. Miyata, M. Jin, T. Chen, K. Kuribayashi, Y. Tian, R. Hughes, J. Yamamoto, K. K. Muralidharan, C. Rubel, R. M. Hutchison, S. Budd Haeberlein
<h3 data-test="abstract-sub-heading">Background</h3><p>Global prevalence and incidence of dementia continue to rise at a rapid rate. There is a need for new Alzheimer’s disease (AD) treatments globally. Aducanumab is a human monoclonal antibody that selectively targets aggregated soluble amyloid beta oligomers and insoluble amyloid beta fibrils. In June 2021, aducanumab was approved by the US Food and Drug Administration for the treatment of AD under the accelerated approval pathway.</p><h3 data-test="abstract-sub-heading">Objectives</h3><p>We evaluated the efficacy, safety, biomarker and pharmacokinetics (PK) of aducanumab in Japanese subgroups in EMERGE and ENGAGE studies.</p><h3 data-test="abstract-sub-heading">Design</h3><p>EMERGE and ENGAGE were two randomized, double-blind, placebo-controlled, global, phase 3 studies of aducanumab in patients with early AD (mild cognitive impairment due to AD or mild AD dementia).</p><h3 data-test="abstract-sub-heading">Setting</h3><p>These studies involved 348 sites in 20 countries. PARTICIPANTS: Participants enrolled in Japan included 121 (7.4% of total 1638 in EMERGE) and 100 (6.1% of total 1647 in ENGAGE) patients (aged 50–85 years with confirmed amyloid pathology) who met clinical criteria for mild cognitive impairment due to AD or mild AD dementia.</p><h3 data-test="abstract-sub-heading">Intervention</h3><p>Participants were randomly assigned 1:1:1 to receive aducanumab low dose (3 or 6 mg/kg target dose), high dose (6 or 10 mg/kg target dose) or placebo via IV infusion once every 4 weeks over 76 weeks.</p><h3 data-test="abstract-sub-heading">Measurements</h3><p>The primary outcome measure was change from baseline to Week 78 on the Clinical Dementia Rating Sum of Boxes (CDR-SB), an integrated scale that assesses both function and cognition. Other measures included safety assessments; secondary and tertiary clinical outcomes that assessed cognition, function, and behavior; biomarker endpoints (amyloid PET and plasma p-tau181); serum PK profiles and immunogenicity.</p><h3 data-test="abstract-sub-heading">Results</h3><p>Results from the Japanese subgroup analyses were generally consistent with those of the overall study population across endpoints, while a lower mean body weight (kg) and a smaller proportion of ApoE ε4 carriers were observed in the Japanese subgroup population. A treatment effect was observed in favor of aducanumab on the primary and secondary efficacy endpoints at Week 78 in EMERGE, but not ENGAGE. The incidence and type of adverse events in the Japanese subgroups were generally comparable to those observed in the overall study population; amyloid related imaging abnormalities (ARIA) were common treatment-related adverse events that appeared to be related to the aducanumab dose. ARIA incidence was generally lower in the Japanese subgroup compared with the overall population. Consistent with the overall data set, a robust dose-dependent decrease in amyloid beta levels as assessed with am
{"title":"Japanese Subgroup Analyses from EMERGE and ENGAGE, Phase 3 Clinical Trials of Aducanumab in Patients with Early Alzheimer’s Disease","authors":"Yasuo Toda, T. Iwatsubo, Y. Nakamura, N. Matsuda, M. Miyata, M. Jin, T. Chen, K. Kuribayashi, Y. Tian, R. Hughes, J. Yamamoto, K. K. Muralidharan, C. Rubel, R. M. Hutchison, S. Budd Haeberlein","doi":"10.14283/jpad.2024.106","DOIUrl":"https://doi.org/10.14283/jpad.2024.106","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Background</h3><p>Global prevalence and incidence of dementia continue to rise at a rapid rate. There is a need for new Alzheimer’s disease (AD) treatments globally. Aducanumab is a human monoclonal antibody that selectively targets aggregated soluble amyloid beta oligomers and insoluble amyloid beta fibrils. In June 2021, aducanumab was approved by the US Food and Drug Administration for the treatment of AD under the accelerated approval pathway.</p><h3 data-test=\"abstract-sub-heading\">Objectives</h3><p>We evaluated the efficacy, safety, biomarker and pharmacokinetics (PK) of aducanumab in Japanese subgroups in EMERGE and ENGAGE studies.</p><h3 data-test=\"abstract-sub-heading\">Design</h3><p>EMERGE and ENGAGE were two randomized, double-blind, placebo-controlled, global, phase 3 studies of aducanumab in patients with early AD (mild cognitive impairment due to AD or mild AD dementia).</p><h3 data-test=\"abstract-sub-heading\">Setting</h3><p>These studies involved 348 sites in 20 countries. PARTICIPANTS: Participants enrolled in Japan included 121 (7.4% of total 1638 in EMERGE) and 100 (6.1% of total 1647 in ENGAGE) patients (aged 50–85 years with confirmed amyloid pathology) who met clinical criteria for mild cognitive impairment due to AD or mild AD dementia.</p><h3 data-test=\"abstract-sub-heading\">Intervention</h3><p>Participants were randomly assigned 1:1:1 to receive aducanumab low dose (3 or 6 mg/kg target dose), high dose (6 or 10 mg/kg target dose) or placebo via IV infusion once every 4 weeks over 76 weeks.</p><h3 data-test=\"abstract-sub-heading\">Measurements</h3><p>The primary outcome measure was change from baseline to Week 78 on the Clinical Dementia Rating Sum of Boxes (CDR-SB), an integrated scale that assesses both function and cognition. Other measures included safety assessments; secondary and tertiary clinical outcomes that assessed cognition, function, and behavior; biomarker endpoints (amyloid PET and plasma p-tau181); serum PK profiles and immunogenicity.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>Results from the Japanese subgroup analyses were generally consistent with those of the overall study population across endpoints, while a lower mean body weight (kg) and a smaller proportion of ApoE ε4 carriers were observed in the Japanese subgroup population. A treatment effect was observed in favor of aducanumab on the primary and secondary efficacy endpoints at Week 78 in EMERGE, but not ENGAGE. The incidence and type of adverse events in the Japanese subgroups were generally comparable to those observed in the overall study population; amyloid related imaging abnormalities (ARIA) were common treatment-related adverse events that appeared to be related to the aducanumab dose. ARIA incidence was generally lower in the Japanese subgroup compared with the overall population. Consistent with the overall data set, a robust dose-dependent decrease in amyloid beta levels as assessed with am","PeriodicalId":22711,"journal":{"name":"The Journal of Prevention of Alzheimer's Disease","volume":"83 1","pages":""},"PeriodicalIF":6.4,"publicationDate":"2024-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141783224","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Charlotte Sørensen, I. Kåreholt, G. Kalpouzos, C. T. Udeh-Momoh, J. Holleman, M. Aspö, G. Hagman, G. Spulber, M. Kivipelto, A. Solomon, S. Sindi
Background
Sleep disturbances as well as cortisol hypersecretion are increasingly acknowledged as risk factors for Alzheimer’s disease (AD). However, the mechanisms underlying the association, and the interplay with cortisol abnormalities, remain unclear.
Objectives
This study aims to identify how self-reported sleep disturbances are associated with structural brain measures and diurnal cortisol dysregulation among memory clinic patients.
Design
A cross-sectional study performed at Karolinska University Hospital Memory Clinic, Sweden.
Participants
The study was based on 146 memory clinic patients diagnosed with either subjective cognitive impairment or mild cognitive impairment.
Measurements
Self-reported sleep was measured using the Karolinska Sleep Questionnaire. MRI or CT was used to quantify structural brain measures using four visual rating scales (Scheltens, Pasquier, Koedam, and Fazekas scales), and salivary cortisol was sampled to measure diurnal cortisol patterns through measures of cortisol immediately after awakening, cortisol awakening response, bedtime cortisol, total cortisol from awakening to bedtime, and the AM/PM cortisol ratio.
Results
Increased sleep apnea index (OR=1.20, 95% CI=1.04:1.39, p=0.015) was associated with greater odds of posterior brain atrophy, measured by the Koedam visual rating scale, and reduced awakening Cortisol (β=−0.03, 95% CI=− 0.07:0.00, p=0.045). Increased daytime sleepiness was associated with both reduced awakening cortisol (β=−0.03, 95% CI=−0.06:0.00, p=0.025) and a reduced AM/PM cortisol ratio (β=−0.04, CI=−0.08:−0.01, p= 0.021).
Conclusion
In a memory clinic cohort self-reported sleep disturbances are associated with both worse structural brain tissue integrity and altered diurnal cortisol profiles. These findings may add insights into possible mechanisms behind sleep disturbances in aging with subjective and cognitive impairment.
{"title":"Daytime Sleepiness, Apnea, Neuroimaging Correlates and Cortisol Dysregulation in a Memory Clinic Cohort","authors":"Charlotte Sørensen, I. Kåreholt, G. Kalpouzos, C. T. Udeh-Momoh, J. Holleman, M. Aspö, G. Hagman, G. Spulber, M. Kivipelto, A. Solomon, S. Sindi","doi":"10.14283/jpad.2024.145","DOIUrl":"https://doi.org/10.14283/jpad.2024.145","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Background</h3><p>Sleep disturbances as well as cortisol hypersecretion are increasingly acknowledged as risk factors for Alzheimer’s disease (AD). However, the mechanisms underlying the association, and the interplay with cortisol abnormalities, remain unclear.</p><h3 data-test=\"abstract-sub-heading\">Objectives</h3><p>This study aims to identify how self-reported sleep disturbances are associated with structural brain measures and diurnal cortisol dysregulation among memory clinic patients.</p><h3 data-test=\"abstract-sub-heading\">Design</h3><p>A cross-sectional study performed at Karolinska University Hospital Memory Clinic, Sweden.</p><h3 data-test=\"abstract-sub-heading\">Participants</h3><p>The study was based on 146 memory clinic patients diagnosed with either subjective cognitive impairment or mild cognitive impairment.</p><h3 data-test=\"abstract-sub-heading\">Measurements</h3><p>Self-reported sleep was measured using the Karolinska Sleep Questionnaire. MRI or CT was used to quantify structural brain measures using four visual rating scales (Scheltens, Pasquier, Koedam, and Fazekas scales), and salivary cortisol was sampled to measure diurnal cortisol patterns through measures of cortisol immediately after awakening, cortisol awakening response, bedtime cortisol, total cortisol from awakening to bedtime, and the AM/PM cortisol ratio.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>Increased sleep apnea index (OR=1.20, 95% CI=1.04:1.39, p=0.015) was associated with greater odds of posterior brain atrophy, measured by the Koedam visual rating scale, and reduced awakening Cortisol (β=−0.03, 95% CI=− 0.07:0.00, p=0.045). Increased daytime sleepiness was associated with both reduced awakening cortisol (β=−0.03, 95% CI=−0.06:0.00, p=0.025) and a reduced AM/PM cortisol ratio (β=−0.04, CI=−0.08:−0.01, p= 0.021).</p><h3 data-test=\"abstract-sub-heading\">Conclusion</h3><p>In a memory clinic cohort self-reported sleep disturbances are associated with both worse structural brain tissue integrity and altered diurnal cortisol profiles. These findings may add insights into possible mechanisms behind sleep disturbances in aging with subjective and cognitive impairment.</p>","PeriodicalId":22711,"journal":{"name":"The Journal of Prevention of Alzheimer's Disease","volume":"30 1","pages":""},"PeriodicalIF":6.4,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141745597","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}