首页 > 最新文献

Alzheimer''s and Dementia: Translational Research and Clinical Interventions最新文献

英文 中文
Statin use and dementia risk: A systematic review and updated meta-analysis 他汀类药物使用与痴呆风险:一项系统综述和最新荟萃分析。
IF 4.9 Q1 CLINICAL NEUROLOGY Pub Date : 2025-01-16 DOI: 10.1002/trc2.70039
Fernando Luiz Westphal Filho, Paulo Roberto Moss Lopes, Artur Menegaz de Almeida, Vitor Kendi Tsuchiya Sano, Fernanda Moraes Tamashiro, Ocílio Ribeiro Gonçalves, Francisco Cezar Aquino de Moraes, Michele Kreuz, Francinny Alves Kelly, Pablo Vinícius Silveira Feitoza

Dementia affects 55 million people globally, with the number projected to triple by 2050. Statins, widely prescribed for cardiovascular benefits, may also have neuroprotective effects, although studies on their impact on dementia risk have shown contradictory results. In this systematic review and meta-analysis, we searched PubMed, Embase, and Cochrane following Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. We assessed the risk of dementia, Alzheimer's disease (AD), and vascular dementia (VaD), with subgroup analyses by gender, statin type, and diabetes status. Fifty-five observational studies including over 7 million patients were analyzed. Statin use significantly reduced the risk of dementia compared to nonusers (hazard ratio [HR] 0.86; 95% confidence interval [CI]: 0.82 to 0.91; p < 0.001). It was also associated with reduced risks of AD (HR 0.82; 95% CI: 0.74 to 0.90; p < 0.001) and VaD (HR 0.89; 95% CI: 0.77 to 1.02; p = 0.093). Subgroup analyses revealed significant dementia risk reductions among patients with type 2 diabetes mellitus (HR 0.87; 95% CI: 0.85 to 0.89; p < 0.001), those with exposure to statins for more than 3 years (HR 0.37; 95% CI: 0.30 to 0.46; p < 0.001), and populations from Asia, where the greatest protective effect was observed (HR 0.84; 95% CI: 0.80 to 0.88). Additionally, rosuvastatin demonstrated the most pronounced protective effect for all-cause dementia among specific statins (HR 0.72; 95% CI: 0.60 to 0.88). Our findings underscore the neuroprotective potential of statins in dementia prevention. Despite the inherent limitations of observational studies, the large dataset and detailed subgroup analyses enhance the reliability of our results. Future randomized clinical trials are necessary to confirm these findings and enlighten clinical guidelines.

Highlights

  • Largest meta-analysis to date on statins and dementia risk, including 55 studies and more than 7 million patients.
  • Statin use linked to lower risks of all-dementia, AD, and VaD.
  • Numerous significant subgroup results highlight statins' diverse neuroprotective effects.
  • Findings support statins as a public health tool, especially in low-income countries.
  • Future research should explore the impact of statins across diverse patient populations.
全球有5500万人患有痴呆症,预计到2050年这一数字将增加两倍。他汀类药物广泛用于治疗心血管疾病,也可能具有神经保护作用,尽管有关其对痴呆风险影响的研究显示出相互矛盾的结果。在本系统评价和荟萃分析中,我们按照系统评价和荟萃分析(PRISMA)指南的首选报告项目检索了PubMed、Embase和Cochrane。我们评估了痴呆、阿尔茨海默病(AD)和血管性痴呆(VaD)的风险,并根据性别、他汀类药物类型和糖尿病状况进行了亚组分析。共分析了55项观察性研究,包括700多万患者。与未使用他汀类药物的患者相比,使用他汀类药物可显著降低痴呆风险(风险比[HR] 0.86;95%置信区间[CI]: 0.82 ~ 0.91;p p p = 0.093)。亚组分析显示,2型糖尿病患者痴呆风险显著降低(HR 0.87;95% CI: 0.85 ~ 0.89;亮点:迄今为止最大的关于他汀类药物与痴呆风险的荟萃分析,包括55项研究和700多万患者。他汀类药物的使用与全痴呆、AD和VaD的风险降低有关。许多重要的亚组结果突出了他汀类药物不同的神经保护作用。研究结果支持他汀类药物作为公共卫生工具,特别是在低收入国家。未来的研究应该探索他汀类药物对不同患者群体的影响。
{"title":"Statin use and dementia risk: A systematic review and updated meta-analysis","authors":"Fernando Luiz Westphal Filho,&nbsp;Paulo Roberto Moss Lopes,&nbsp;Artur Menegaz de Almeida,&nbsp;Vitor Kendi Tsuchiya Sano,&nbsp;Fernanda Moraes Tamashiro,&nbsp;Ocílio Ribeiro Gonçalves,&nbsp;Francisco Cezar Aquino de Moraes,&nbsp;Michele Kreuz,&nbsp;Francinny Alves Kelly,&nbsp;Pablo Vinícius Silveira Feitoza","doi":"10.1002/trc2.70039","DOIUrl":"10.1002/trc2.70039","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>Dementia affects 55 million people globally, with the number projected to triple by 2050. Statins, widely prescribed for cardiovascular benefits, may also have neuroprotective effects, although studies on their impact on dementia risk have shown contradictory results. In this systematic review and meta-analysis, we searched PubMed, Embase, and Cochrane following Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. We assessed the risk of dementia, Alzheimer's disease (AD), and vascular dementia (VaD), with subgroup analyses by gender, statin type, and diabetes status. Fifty-five observational studies including over 7 million patients were analyzed. Statin use significantly reduced the risk of dementia compared to nonusers (hazard ratio [HR] 0.86; 95% confidence interval [CI]: 0.82 to 0.91; <i>p</i> &lt; 0.001). It was also associated with reduced risks of AD (HR 0.82; 95% CI: 0.74 to 0.90; <i>p</i> &lt; 0.001) and VaD (HR 0.89; 95% CI: 0.77 to 1.02; <i>p</i> = 0.093). Subgroup analyses revealed significant dementia risk reductions among patients with type 2 diabetes mellitus (HR 0.87; 95% CI: 0.85 to 0.89; <i>p</i> &lt; 0.001), those with exposure to statins for more than 3 years (HR 0.37; 95% CI: 0.30 to 0.46; <i>p</i> &lt; 0.001), and populations from Asia, where the greatest protective effect was observed (HR 0.84; 95% CI: 0.80 to 0.88). Additionally, rosuvastatin demonstrated the most pronounced protective effect for all-cause dementia among specific statins (HR 0.72; 95% CI: 0.60 to 0.88). Our findings underscore the neuroprotective potential of statins in dementia prevention. Despite the inherent limitations of observational studies, the large dataset and detailed subgroup analyses enhance the reliability of our results. Future randomized clinical trials are necessary to confirm these findings and enlighten clinical guidelines.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Largest meta-analysis to date on statins and dementia risk, including 55 studies and more than 7 million patients.</li>\u0000 \u0000 <li>Statin use linked to lower risks of all-dementia, AD, and VaD.</li>\u0000 \u0000 <li>Numerous significant subgroup results highlight statins' diverse neuroprotective effects.</li>\u0000 \u0000 <li>Findings support statins as a public health tool, especially in low-income countries.</li>\u0000 \u0000 <li>Future research should explore the impact of statins across diverse patient populations.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"11 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11736423/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143016006","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
LD-informed deep learning for Alzheimer's gene loci detection using WGS data 基于ld的深度学习用于WGS数据的阿尔茨海默病基因位点检测。
IF 4.9 Q1 CLINICAL NEUROLOGY Pub Date : 2025-01-16 DOI: 10.1002/trc2.70041
Taeho Jo, Paula Bice, Kwangsik Nho, Andrew J. Saykin, Alzheimer's Disease Sequencing Project
<div> <section> <h3> INTRODUCTION</h3> <p>The exponential growth of genomic datasets necessitates advanced analytical tools to effectively identify genetic loci from large-scale high throughput sequencing data. This study presents Deep-Block, a multi-stage deep learning framework that incorporates biological knowledge into its AI architecture to identify genetic regions as significantly associated with Alzheimer's disease (AD). The framework employs a three-stage approach: (1) genome segmentation based on linkage disequilibrium (LD) patterns, (2) selection of relevant LD blocks using sparse attention mechanisms, and (3) application of TabNet and Random Forest algorithms to quantify single nucleotide polymorphism (SNP) feature importance, thereby identifying genetic factors contributing to AD risk.</p> </section> <section> <h3> METHODS</h3> <p>The Deep-Block was applied to a large-scale whole genome sequencing (WGS) dataset from the Alzheimer's Disease Sequencing Project (ADSP), comprising 7416 non-Hispanic white (NHW) participants (3150 cognitively normal older adults (CN), 4266 AD).</p> </section> <section> <h3> RESULTS</h3> <p>30,218 LD blocks were identified and then ranked based on their relevance with Alzheimer's disease. Subsequently, the Deep-Block identified novel SNPs within the top 1500 LD blocks and confirmed previously known variants, including <i>APOE</i> rs429358 and rs769449. Expression Quantitative Trait Loci (eQTL) analysis across 13 brain regions provided functional evidence for the identified variants. The results were cross-validated against established AD-associated loci from the European Alzheimer's and Dementia Biobank (EADB) and the GWAS catalog.</p> </section> <section> <h3> DISCUSSION</h3> <p>The Deep-Block framework effectively processes large-scale high throughput sequencing data while preserving SNP interactions during dimensionality reduction, minimizing bias and information loss. The framework's findings are supported by tissue-specific eQTL evidence across brain regions, indicating the functional relevance of the identified variants. Additionally, the Deep-Block approach has identified both known and novel genetic variants, enhancing our understanding of the genetic architecture and demonstrating its potential for application in large-scale sequencing studies.</p> </section> <section> <h3> Highlights</h3> <div> <ul> <li>Growing genomic datasets require adva
基因组数据集的指数级增长需要先进的分析工具来有效地从大规模高通量测序数据中识别遗传位点。本研究提出了deep - block,这是一个多阶段深度学习框架,将生物学知识纳入其人工智能架构,以识别与阿尔茨海默病(AD)显著相关的遗传区域。该框架采用三阶段方法:(1)基于连锁不平衡(LD)模式的基因组分割,(2)利用稀疏注意机制选择相关LD块,以及(3)应用TabNet和Random Forest算法量化单核苷酸多态性(SNP)特征重要性,从而确定导致AD风险的遗传因素。方法:Deep-Block应用于来自阿尔茨海默病测序项目(ADSP)的大规模全基因组测序(WGS)数据集,包括7416名非西班牙裔白人(NHW)参与者(3150名认知正常的老年人(CN), 4266名AD)。结果:30,218个LD块被确定,然后根据它们与阿尔茨海默病的相关性进行排名。随后,Deep-Block在前1500个LD块中发现了新的snp,并确认了以前已知的变体,包括APOE rs429358和rs769449。跨13个脑区的表达数量性状位点(eQTL)分析为鉴定的变异提供了功能证据。将结果与欧洲阿尔茨海默病和痴呆症生物银行(EADB)和GWAS目录中已建立的ad相关基因座进行交叉验证。讨论:Deep-Block框架有效地处理大规模高通量测序数据,同时在降维过程中保留SNP相互作用,最大限度地减少偏差和信息损失。该框架的发现得到了跨大脑区域的组织特异性eQTL证据的支持,表明了已识别变体的功能相关性。此外,Deep-Block方法已经确定了已知和新的遗传变异,增强了我们对遗传结构的理解,并展示了其在大规模测序研究中的应用潜力。亮点:不断增长的基因组数据集需要先进的工具来识别测序中的遗传位点。采用一种新的人工智能框架Deep-Block对大规模ADSP WGS数据进行处理。Deep-Block发现了已知的和新的ad相关基因位点。rs429358 (APOE)是关键;rs11556505 (TOMM40)、rs34342646 (NECTIN2)具有显著性。人工智能框架利用生物学知识来加强对阿尔茨海默氏症基因位点的检测。
{"title":"LD-informed deep learning for Alzheimer's gene loci detection using WGS data","authors":"Taeho Jo,&nbsp;Paula Bice,&nbsp;Kwangsik Nho,&nbsp;Andrew J. Saykin,&nbsp;Alzheimer's Disease Sequencing Project","doi":"10.1002/trc2.70041","DOIUrl":"10.1002/trc2.70041","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; INTRODUCTION&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;The exponential growth of genomic datasets necessitates advanced analytical tools to effectively identify genetic loci from large-scale high throughput sequencing data. This study presents Deep-Block, a multi-stage deep learning framework that incorporates biological knowledge into its AI architecture to identify genetic regions as significantly associated with Alzheimer's disease (AD). The framework employs a three-stage approach: (1) genome segmentation based on linkage disequilibrium (LD) patterns, (2) selection of relevant LD blocks using sparse attention mechanisms, and (3) application of TabNet and Random Forest algorithms to quantify single nucleotide polymorphism (SNP) feature importance, thereby identifying genetic factors contributing to AD risk.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; METHODS&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;The Deep-Block was applied to a large-scale whole genome sequencing (WGS) dataset from the Alzheimer's Disease Sequencing Project (ADSP), comprising 7416 non-Hispanic white (NHW) participants (3150 cognitively normal older adults (CN), 4266 AD).&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; RESULTS&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;30,218 LD blocks were identified and then ranked based on their relevance with Alzheimer's disease. Subsequently, the Deep-Block identified novel SNPs within the top 1500 LD blocks and confirmed previously known variants, including &lt;i&gt;APOE&lt;/i&gt; rs429358 and rs769449. Expression Quantitative Trait Loci (eQTL) analysis across 13 brain regions provided functional evidence for the identified variants. The results were cross-validated against established AD-associated loci from the European Alzheimer's and Dementia Biobank (EADB) and the GWAS catalog.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; DISCUSSION&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;The Deep-Block framework effectively processes large-scale high throughput sequencing data while preserving SNP interactions during dimensionality reduction, minimizing bias and information loss. The framework's findings are supported by tissue-specific eQTL evidence across brain regions, indicating the functional relevance of the identified variants. Additionally, the Deep-Block approach has identified both known and novel genetic variants, enhancing our understanding of the genetic architecture and demonstrating its potential for application in large-scale sequencing studies.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Highlights&lt;/h3&gt;\u0000 \u0000 &lt;div&gt;\u0000 &lt;ul&gt;\u0000 \u0000 &lt;li&gt;Growing genomic datasets require adva","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"11 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11736638/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143015954","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Cognitive and Alzheimer's disease biomarker effects of oral nicotinamide riboside (NR) supplementation in older adults with subjective cognitive decline and mild cognitive impairment 口服烟酰胺核苷(NR)补充剂对主观认知能力下降和轻度认知障碍的老年人的认知和阿尔茨海默病生物标志物的影响
IF 4.9 Q1 CLINICAL NEUROLOGY Pub Date : 2025-01-15 DOI: 10.1002/trc2.70023
Chao-Yi Wu, Ashley C. Kupferschmid, Liu Chen, Alison J. McManus, Pia Kivisäkk, Jake A. Galler, Nadine A. Schwab, Libby A. DesRuisseaux, Victoria J. Williams, Jessica Gerber, Misha Riley, Cathrine Young, Edmarie Guzmán-Vélez, Hiroko H. Dodge, Rudolph E. Tanzi, Clifford M. Singer, Steven E. Arnold
<div> <section> <h3> INTRODUCTION</h3> <p>Age-associated depletion in nicotinamide adenine dinucleotide (NAD+) concentrations has been implicated in metabolic, cardiovascular, and neurodegenerative disorders. Supplementation with NAD+ precursors, such as nicotinamide riboside (NR), offers a potential therapeutic avenue against neurodegenerative pathologies in aging, Alzheimer's disease, and related dementias. A crossover, double-blind, randomized placebo (PBO) controlled trial was conducted to test the safety and efficacy of 8 weeks' active treatment with NR (1 g/day) on cognition and plasma AD biomarkers in older adults with subjective cognitive decline and mild cognitive impairment.</p> </section> <section> <h3> METHODS</h3> <p>The primary efficacy outcome was the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Secondary outcomes included plasma phosphorylated tau 217 (pTau<sup>217</sup>), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL). Exploratory outcomes included Lumosity gameplay (<i>z</i>-scores) for cognition and step counts from wearables. Mixed model for repeated measures was used for between-group comparisons; paired <i>t</i>-tests were used for within-individual comparisons.</p> </section> <section> <h3> RESULTS</h3> <p>Forty-six participants aged over 55 were randomized to NR-PBO or PBO-NR groups; 41 completed baseline visits, and 37 completed the trial. NR supplementation was safe and well tolerated with no differences in adverse events reported between NR and PBO treatment phases. For the between-group comparison, there was a 7% reduction in pTau<sup>217</sup> concentrations after taking NR, while an 18% increase with PBO (<i>p</i> = 0.02). No significant between-group differences were observed for RBANS, other plasma biomarkers(GFAP and NfL), Lumosity gameplay scores or step counts. For the within-individual comparison, pTau<sup>217</sup> concentrations significantly decreased during the NR phase compared to the PBO (<i>p</i> = 0.02), while step counts significantly increased during the NR phase than PBO (<i>p</i> = 0.04).</p> </section> <section> <h3> DISCUSSION</h3> <p>Eight weeks NR supplementation is safe and lowered pTau<sup>217</sup> concentrations but did not alter cognition as measured by conventional or novel digital assessments. Further research is warranted to validate NR's efficacy in altering pathological brain aging processes.</p> </section> <section> <h3> Highlights</h3>
年龄相关的烟酰胺腺嘌呤二核苷酸(NAD+)浓度的减少与代谢、心血管和神经退行性疾病有关。补充NAD+前体,如烟酰胺核苷(NR),为对抗衰老、阿尔茨海默病和相关痴呆的神经退行性病变提供了一种潜在的治疗途径。本研究进行了一项交叉、双盲、随机安慰剂(PBO)对照试验,以检验NR (1 g/天)积极治疗8周对主观认知能力下降和轻度认知障碍的老年人认知和血浆AD生物标志物的安全性和有效性。方法:主要疗效指标为神经心理状态评估可重复测试(RBANS)。次要结局包括血浆磷酸化tau 217 (pTau217)、胶质纤维酸性蛋白(GFAP)和神经丝轻链(NfL)。探索性结果包括Lumosity游戏玩法(z分数)的认知和可穿戴设备的步数。组间比较采用重复测量混合模型;配对t检验用于个体内比较。结果:46名55岁以上的参与者随机分为NR-PBO组或PBO-NR组;41人完成基线访问,37人完成试验。NR补充是安全且耐受性良好的,在NR和PBO治疗阶段之间报告的不良事件没有差异。在组间比较中,服用NR后pTau217浓度降低7%,而服用PBO后pTau217浓度升高18% (p = 0.02)。rban、其他血浆生物标志物(GFAP和NfL)、Lumosity游戏得分或步数在组间无显著差异。在个体内比较中,pTau217浓度在NR期显著低于PBO (p = 0.02),步数在NR期显著高于PBO (p = 0.04)。讨论:8周NR补充是安全的,并且降低了pTau217浓度,但通过传统或新型数字评估测量没有改变认知。需要进一步的研究来验证NR在改变病理性脑老化过程中的功效。重点:综合研究设计结合了双臂平行试验和交叉阶段,为个体内分析和评估结转效应提供了增加样本量的机会。在SCD/MCI的多模式评估中,NR是安全的,但不会改变认知。在8周的随访中,pTau217水平随NR降低,随PBO升高。在个体内比较中,NR后步数增加,PBO后步数减少。需要更大规模、更长期的药效学和病理生理生物标志物研究来评估NR的疾病改善作用。
{"title":"Cognitive and Alzheimer's disease biomarker effects of oral nicotinamide riboside (NR) supplementation in older adults with subjective cognitive decline and mild cognitive impairment","authors":"Chao-Yi Wu,&nbsp;Ashley C. Kupferschmid,&nbsp;Liu Chen,&nbsp;Alison J. McManus,&nbsp;Pia Kivisäkk,&nbsp;Jake A. Galler,&nbsp;Nadine A. Schwab,&nbsp;Libby A. DesRuisseaux,&nbsp;Victoria J. Williams,&nbsp;Jessica Gerber,&nbsp;Misha Riley,&nbsp;Cathrine Young,&nbsp;Edmarie Guzmán-Vélez,&nbsp;Hiroko H. Dodge,&nbsp;Rudolph E. Tanzi,&nbsp;Clifford M. Singer,&nbsp;Steven E. Arnold","doi":"10.1002/trc2.70023","DOIUrl":"10.1002/trc2.70023","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; INTRODUCTION&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Age-associated depletion in nicotinamide adenine dinucleotide (NAD+) concentrations has been implicated in metabolic, cardiovascular, and neurodegenerative disorders. Supplementation with NAD+ precursors, such as nicotinamide riboside (NR), offers a potential therapeutic avenue against neurodegenerative pathologies in aging, Alzheimer's disease, and related dementias. A crossover, double-blind, randomized placebo (PBO) controlled trial was conducted to test the safety and efficacy of 8 weeks' active treatment with NR (1 g/day) on cognition and plasma AD biomarkers in older adults with subjective cognitive decline and mild cognitive impairment.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; METHODS&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;The primary efficacy outcome was the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Secondary outcomes included plasma phosphorylated tau 217 (pTau&lt;sup&gt;217&lt;/sup&gt;), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL). Exploratory outcomes included Lumosity gameplay (&lt;i&gt;z&lt;/i&gt;-scores) for cognition and step counts from wearables. Mixed model for repeated measures was used for between-group comparisons; paired &lt;i&gt;t&lt;/i&gt;-tests were used for within-individual comparisons.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; RESULTS&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Forty-six participants aged over 55 were randomized to NR-PBO or PBO-NR groups; 41 completed baseline visits, and 37 completed the trial. NR supplementation was safe and well tolerated with no differences in adverse events reported between NR and PBO treatment phases. For the between-group comparison, there was a 7% reduction in pTau&lt;sup&gt;217&lt;/sup&gt; concentrations after taking NR, while an 18% increase with PBO (&lt;i&gt;p&lt;/i&gt; = 0.02). No significant between-group differences were observed for RBANS, other plasma biomarkers(GFAP and NfL), Lumosity gameplay scores or step counts. For the within-individual comparison, pTau&lt;sup&gt;217&lt;/sup&gt; concentrations significantly decreased during the NR phase compared to the PBO (&lt;i&gt;p&lt;/i&gt; = 0.02), while step counts significantly increased during the NR phase than PBO (&lt;i&gt;p&lt;/i&gt; = 0.04).&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; DISCUSSION&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Eight weeks NR supplementation is safe and lowered pTau&lt;sup&gt;217&lt;/sup&gt; concentrations but did not alter cognition as measured by conventional or novel digital assessments. Further research is warranted to validate NR's efficacy in altering pathological brain aging processes.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Highlights&lt;/h3&gt;\u0000 \u0000 ","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"11 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11733434/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143016144","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Evaluation of efficiency and effectiveness of different recruitment strategies for the FINGER-NL multidomain lifestyle intervention trial via the Dutch Brain Research Registry 通过荷兰脑研究注册中心评估FINGER-NL多域生活方式干预试验的不同招募策略的效率和有效性。
IF 4.9 Q1 CLINICAL NEUROLOGY Pub Date : 2025-01-09 DOI: 10.1002/trc2.70017
Lisa Waterink, Sietske A. M. Sikkes, Lion M. Soons, Sonja Beers, Yvonne Meijer-Krommenhoek, Ondine van de Rest, Smidt Nynke, Joukje M. Oosterman, Erik Scherder, Kay Deckers, Yannick Vermeiren, Rianne A. A. de Heus, Sebastian Köhler, Wiesje M. van der Flier, MOCIA consortium, FINGER-NL consortium, Marissa D. Zwan
<div> <section> <h3> INTRODUCTION</h3> <p>Recruitment of participants for intervention studies is challenging. We evaluated the effectiveness and efficiency of a participant recruitment campaign through an online registry for the FINGER-NL study, a multi-domain lifestyle intervention trial targeting cognitively healthy individuals aged 60–79 with dementia prevention potential. Additionally, we explored which recruitment strategy successfully reached individuals from underrepresented groups in research.</p> </section> <section> <h3> METHODS</h3> <p>The campaign entailed seven recruitment strategies referring to The Dutch Brain Research Registry (DBRR): (1) Facebook advertisements, (2) appearance on national television, (3) newspaper articles, (4) researcher outreach, (5) patient organizations, (6) search engines, and (7) other. For each strategy, we describe the number of individuals (a) registered, (b) potentially eligible, and (c) included in FINGER-NL. Subsequently, the efficiency, defined by the eligibility ratio (eligible/registered), and effectiveness, defined by the inclusion ratio (included/registered) were calculated. Associations between recruitment strategies and sociodemographic factors of underrepresented groups were tested with binomial logistic regressions.</p> </section> <section> <h3> RESULTS</h3> <p>The campaign resulted in 13,795 new DBRR registrants, of which <i>n</i> = 3475 were eligible (eligibility ratio = 0.25) and <i>n</i> = 1008 were included (inclusion ratio = 0.07). The Facebook advertisements and television appearance resulted in the highest numbers of registrants (<i>n</i> = 4678 and <i>n</i> = 2182) which translated to the highest number of inclusions (<i>n</i> = 288 and <i>n</i> = 262). The appearance on national television (eligibility ratio = 0.35), newspaper articles (0.26), and Facebook campaigns (0.26) were the most efficient strategies. The national television appearance (inclusion ratio = 0.13) was the most effective strategy. The Facebook campaign and appearance on national television performed relatively better in recruiting individuals from underrepresented groups.</p> </section> <section> <h3> DISCUSSION</h3> <p>A multipronged recruitment campaign via a national online recruitment registry is efficient and effective in recruiting and prescreening an adequate number of individuals aged 60–79 years with prevention potential for a multi-site intervention trial within a limited time frame of 15 months. Social media advertisements and television are preferred strategies to recruit individuals from underrepresent
引言:干预研究的参与者招募是具有挑战性的。我们通过FINGER-NL研究的在线注册评估了参与者招募活动的有效性和效率,FINGER-NL研究是一项多领域生活方式干预试验,针对60-79岁具有痴呆症预防潜力的认知健康个体。此外,我们探索了哪种招聘策略能成功地吸引到研究中代表性不足的群体的个人。方法:该活动涉及荷兰脑研究登记处(DBRR)的七种招募策略:(1)Facebook广告,(2)在国家电视上露面,(3)报纸文章,(4)研究人员外展,(5)患者组织,(6)搜索引擎,以及(7)其他。对于每个策略,我们描述了(a)已注册的个体数量,(b)潜在合格的个体数量,以及(c)包括在FINGER-NL中的个体数量。随后,计算以合格比(合格/注册)定义的效率和以纳入比(纳入/注册)定义的有效性。用二项logistic回归检验了代表性不足群体的招聘策略与社会人口学因素之间的关系。结果:本次活动共获得13795名DBRR新注册人,其中n = 3475名(合格比= 0.25),n = 1008名(纳入比= 0.07)。Facebook广告和电视露面导致注册人数最多(n = 4678和n = 2182),这转化为最多的包含数(n = 288和n = 262)。在全国电视上露面(合格率为0.35)、在报纸上发表文章(合格率为0.26)、在Facebook上进行宣传(合格率为0.26)是最有效的策略。全国电视亮相(纳入比= 0.13)是最有效的策略。Facebook的竞选活动和在全国电视上的露面在从代表性不足的群体中招募个人方面表现相对较好。讨论:在15个月的有限时间框架内,通过国家在线招募注册进行多管齐下的招募活动,在招募和预筛选足够数量的60-79岁具有预防潜力的个体进行多站点干预试验方面是高效和有效的。社交媒体广告和电视是从代表性不足的群体中招募个人的首选策略。亮点:一个在线脑研究注册成功招募了合格的参与者。大众媒体的招聘策略对于接触到大量的人是有效的。通过研究人员和患者组织直接招募似乎更有效。在线注册提供自动预筛选和屏幕故障的替代方案。需要有针对性的战略来接触代表性不足的群体,以改善多样性。
{"title":"Evaluation of efficiency and effectiveness of different recruitment strategies for the FINGER-NL multidomain lifestyle intervention trial via the Dutch Brain Research Registry","authors":"Lisa Waterink,&nbsp;Sietske A. M. Sikkes,&nbsp;Lion M. Soons,&nbsp;Sonja Beers,&nbsp;Yvonne Meijer-Krommenhoek,&nbsp;Ondine van de Rest,&nbsp;Smidt Nynke,&nbsp;Joukje M. Oosterman,&nbsp;Erik Scherder,&nbsp;Kay Deckers,&nbsp;Yannick Vermeiren,&nbsp;Rianne A. A. de Heus,&nbsp;Sebastian Köhler,&nbsp;Wiesje M. van der Flier,&nbsp;MOCIA consortium, FINGER-NL consortium,&nbsp;Marissa D. Zwan","doi":"10.1002/trc2.70017","DOIUrl":"10.1002/trc2.70017","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; INTRODUCTION&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Recruitment of participants for intervention studies is challenging. We evaluated the effectiveness and efficiency of a participant recruitment campaign through an online registry for the FINGER-NL study, a multi-domain lifestyle intervention trial targeting cognitively healthy individuals aged 60–79 with dementia prevention potential. Additionally, we explored which recruitment strategy successfully reached individuals from underrepresented groups in research.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; METHODS&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;The campaign entailed seven recruitment strategies referring to The Dutch Brain Research Registry (DBRR): (1) Facebook advertisements, (2) appearance on national television, (3) newspaper articles, (4) researcher outreach, (5) patient organizations, (6) search engines, and (7) other. For each strategy, we describe the number of individuals (a) registered, (b) potentially eligible, and (c) included in FINGER-NL. Subsequently, the efficiency, defined by the eligibility ratio (eligible/registered), and effectiveness, defined by the inclusion ratio (included/registered) were calculated. Associations between recruitment strategies and sociodemographic factors of underrepresented groups were tested with binomial logistic regressions.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; RESULTS&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;The campaign resulted in 13,795 new DBRR registrants, of which &lt;i&gt;n&lt;/i&gt; = 3475 were eligible (eligibility ratio = 0.25) and &lt;i&gt;n&lt;/i&gt; = 1008 were included (inclusion ratio = 0.07). The Facebook advertisements and television appearance resulted in the highest numbers of registrants (&lt;i&gt;n&lt;/i&gt; = 4678 and &lt;i&gt;n&lt;/i&gt; = 2182) which translated to the highest number of inclusions (&lt;i&gt;n&lt;/i&gt; = 288 and &lt;i&gt;n&lt;/i&gt; = 262). The appearance on national television (eligibility ratio = 0.35), newspaper articles (0.26), and Facebook campaigns (0.26) were the most efficient strategies. The national television appearance (inclusion ratio = 0.13) was the most effective strategy. The Facebook campaign and appearance on national television performed relatively better in recruiting individuals from underrepresented groups.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; DISCUSSION&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;A multipronged recruitment campaign via a national online recruitment registry is efficient and effective in recruiting and prescreening an adequate number of individuals aged 60–79 years with prevention potential for a multi-site intervention trial within a limited time frame of 15 months. Social media advertisements and television are preferred strategies to recruit individuals from underrepresent","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"11 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11712179/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142958835","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Cost-effectiveness of a multicomponent intervention against cognitive decline 多组分干预对抗认知衰退的成本效益。
IF 4.9 Q1 CLINICAL NEUROLOGY Pub Date : 2025-01-03 DOI: 10.1002/trc2.70028
Christian Brettschneider, Elżbieta Buczak-Stec, Melanie Luppa, Andrea Zülke, Bernhard Michalowsky, Anika Rädke, Alexander Bauer, Christine Brütting, Robert P. Kosilek, Isabel Zöllinger, Juliane Döhring, Martin Williamson, Birgitt Wiese, Wolfgang Hoffmann, Thomas Frese, Jochen Gensichen, Hanna Kaduszkiewicz, Jochen René Thyrian, Steffi G. Riedel-Heller, Hans-Helmut König, the AGEWELL.DE study group
<div> <section> <h3> INTRODUCTION</h3> <p>The societal costs of dementia and cognitive decline are substantial and likely to increase during the next decades due to the increasing number of people in older age groups. The aim of this multicenter cluster-randomized controlled trial was to assess the cost-effectiveness of a multi-domain intervention to prevent cognitive decline in older people who are at risk for dementia.</p> </section> <section> <h3> METHODS</h3> <p>We used data from a multi-centric, two-armed, cluster-randomized controlled trial (<i>AgeWell.de</i> trial, ID: DRKS00013555). Eligible participants with increased dementia risk at baseline (Cardiovascular Risk Factors, Aging, and Incidence of Dementia/CAIDE Dementia Risk Score ≥ 9), 60–77 years of age, were recruited by their general practitioners, and assigned randomly to a multi-domain lifestyle intervention or general health advice. We performed a cost-effectiveness analysis from the societal perspective. The time horizon was 2 years. Health care utilization was measured using the “Questionnaire for Health-Related Resource Use in Older Populations.” As effect measure, we used quality-adjusted life-years (QALYs) based on the 5-level EQ-5D version (EQ-5D-5L). We calculated the incremental cost-effectiveness ratios (ICER) and cost-effectiveness acceptability curves (CEAC) using the net-benefit approach. Exploratory analyses considering women and the EQ visual analogue scale (EQ VAS) were conducted.</p> </section> <section> <h3> RESULTS</h3> <p>Data were available for 819 participants (mean age 69.0 [standard deviation (SD)5-level EQ-5D version 4.9]); 378 were treated in the intervention group and 441 in the control group. The participants in the intervention group caused higher costs (+€445.88 [SD: €1,244.52]) and gained additional effects (+0.026 QALY [SD: 0.020]) compared to the participants in the control group (the difference was statistically significant). The ICER was €17,149.23/QALY. The CEAC showed that the probability of the intervention being cost-effective was moderate, reaching 59% at a willingness-to-pay (WTP) of €50,000/QALY. The exploratory analyses showed promising results, especially in the female subsample.</p> </section> <section> <h3> DISCUSSION</h3> <p>Considering aspects like the WTP and the limited time horizon, the multi-domain intervention was cost-effective compared to general health advice.</p> </section> <section> <h3> Highlights</h3> <div>
导言:由于老年群体人数的增加,痴呆症和认知能力下降的社会成本是巨大的,并且在未来几十年可能会增加。这项多中心集群随机对照试验的目的是评估多领域干预预防有痴呆风险的老年人认知能力下降的成本效益。方法:我们使用的数据来自一项多中心、双臂、集群随机对照试验(AgeWell.de试验,ID: DRKS00013555)。基线时痴呆风险增加(心血管危险因素、年龄和痴呆发病率/CAIDE痴呆风险评分≥9)、60-77岁的符合条件的参与者由全科医生招募,并随机分配到多领域生活方式干预或一般健康建议组。我们从社会的角度进行了成本效益分析。时间范围是2年。使用“老年人健康相关资源使用问卷”测量医疗保健利用情况。作为效果测量,我们使用基于5级EQ-5D版本(EQ-5D- 5l)的质量调整生命年(QALYs)。我们使用净效益方法计算了增量成本-效果比(ICER)和成本-效果可接受曲线(CEAC)。对女性和EQ视觉模拟量表(EQ VAS)进行探索性分析。结果:819名参与者获得数据(平均年龄69.0岁[标准差(SD)5级EQ-5D版本4.9]);干预组378例,对照组441例。与对照组相比,干预组参与者的成本更高(+€445.88 [SD:€1244.52]),获得的额外效果(+0.026 QALY [SD: 0.020])(差异有统计学意义)。ICER为17,149.23欧元/QALY。CEAC表明,干预措施具有成本效益的可能性是中等的,在支付意愿(WTP)为50,000欧元/QALY时达到59%。探索性分析显示了有希望的结果,特别是在女性子样本中。讨论:考虑到WTP和有限的时间范围等方面,与一般健康建议相比,多领域干预具有成本效益。亮点:第一个德国随机对照试验(RCT)评估多成分方法对抗认知能力下降。我们发现了一个有利的增量成本效益比。成本-效果概率达到78.6%。女性可能是一个重要的目标群体。需要更长的时间范围。
{"title":"Cost-effectiveness of a multicomponent intervention against cognitive decline","authors":"Christian Brettschneider,&nbsp;Elżbieta Buczak-Stec,&nbsp;Melanie Luppa,&nbsp;Andrea Zülke,&nbsp;Bernhard Michalowsky,&nbsp;Anika Rädke,&nbsp;Alexander Bauer,&nbsp;Christine Brütting,&nbsp;Robert P. Kosilek,&nbsp;Isabel Zöllinger,&nbsp;Juliane Döhring,&nbsp;Martin Williamson,&nbsp;Birgitt Wiese,&nbsp;Wolfgang Hoffmann,&nbsp;Thomas Frese,&nbsp;Jochen Gensichen,&nbsp;Hanna Kaduszkiewicz,&nbsp;Jochen René Thyrian,&nbsp;Steffi G. Riedel-Heller,&nbsp;Hans-Helmut König,&nbsp;the AGEWELL.DE study group","doi":"10.1002/trc2.70028","DOIUrl":"10.1002/trc2.70028","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; INTRODUCTION&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;The societal costs of dementia and cognitive decline are substantial and likely to increase during the next decades due to the increasing number of people in older age groups. The aim of this multicenter cluster-randomized controlled trial was to assess the cost-effectiveness of a multi-domain intervention to prevent cognitive decline in older people who are at risk for dementia.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; METHODS&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;We used data from a multi-centric, two-armed, cluster-randomized controlled trial (&lt;i&gt;AgeWell.de&lt;/i&gt; trial, ID: DRKS00013555). Eligible participants with increased dementia risk at baseline (Cardiovascular Risk Factors, Aging, and Incidence of Dementia/CAIDE Dementia Risk Score ≥ 9), 60–77 years of age, were recruited by their general practitioners, and assigned randomly to a multi-domain lifestyle intervention or general health advice. We performed a cost-effectiveness analysis from the societal perspective. The time horizon was 2 years. Health care utilization was measured using the “Questionnaire for Health-Related Resource Use in Older Populations.” As effect measure, we used quality-adjusted life-years (QALYs) based on the 5-level EQ-5D version (EQ-5D-5L). We calculated the incremental cost-effectiveness ratios (ICER) and cost-effectiveness acceptability curves (CEAC) using the net-benefit approach. Exploratory analyses considering women and the EQ visual analogue scale (EQ VAS) were conducted.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; RESULTS&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Data were available for 819 participants (mean age 69.0 [standard deviation (SD)5-level EQ-5D version 4.9]); 378 were treated in the intervention group and 441 in the control group. The participants in the intervention group caused higher costs (+€445.88 [SD: €1,244.52]) and gained additional effects (+0.026 QALY [SD: 0.020]) compared to the participants in the control group (the difference was statistically significant). The ICER was €17,149.23/QALY. The CEAC showed that the probability of the intervention being cost-effective was moderate, reaching 59% at a willingness-to-pay (WTP) of €50,000/QALY. The exploratory analyses showed promising results, especially in the female subsample.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; DISCUSSION&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Considering aspects like the WTP and the limited time horizon, the multi-domain intervention was cost-effective compared to general health advice.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Highlights&lt;/h3&gt;\u0000 \u0000 &lt;div&gt;\u0000 ","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"11 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11696024/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142933501","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Association of corneal endothelial cell morphology with neurodegeneration in mild cognitive impairment and dementia 轻度认知障碍和痴呆患者角膜内皮细胞形态与神经退行性变的关系。
IF 4.9 Q1 CLINICAL NEUROLOGY Pub Date : 2025-01-03 DOI: 10.1002/trc2.70025
Georgios Ponirakis, Hanadi Al Hamad, Alaa S. Al-Waisy, Ioannis N. Petropoulos, Adnan Khan, Hoda Gad, Mani Chandran, Masharig Gadelseed, Salah Mahmoud, Ahmed Elsotouhy, Marwan Ramadan, Shafi Khan, Rustu E. Akcan, Priya V. Gawhale, Noushad Thodi, Tala Nakouzi, Moayad Homssi, Nebras Hadid, Aisha Al Obaidan, Rawan Hussein, Ahmed Own, Ashfaq Shuaib, Rayaz A. Malik
<div> <section> <h3> INTRODUCTION</h3> <p>Corneal confocal microscopy (CCM) detects neurodegeneration in mild cognitive impairment (MCI) and dementia and identifies subjects with MCI who develop dementia. This study assessed whether abnormalities in corneal endothelial cell (CEC) morphology are related to corneal nerve morphology, brain volumetry, cerebral ischemia, and cognitive impairment in MCI and dementia.</p> </section> <section> <h3> METHODS</h3> <p>Participants with no cognitive impairment (NCI), MCI, and dementia underwent CCM to quantify corneal endothelial cell density (CECD) and area (CECA), corneal nerve fiber morphology, magnetic resonance imaging (MRI) brain volumetry, and severity of brain ischemia.</p> </section> <section> <h3> RESULTS</h3> <p>Of the 114 participants, 14 had NCI, 77 had MCI, and 23 had dementia. CECD (1971.3 ± 594.6 vs 2316.1 ± 499.5 cells/mm<sup>2</sup>, <i>p</i> < 0.05) was significantly lower in the dementia compared to the NCI group. CECD and CECA were comparable between the MCI and NCI groups (<i>p</i> = 0.13–0.65). Corneal nerve fiber density (CNFD) (31.7 ± 5.6 vs 24.5 ± 9.2 and 17.3 ± 5.3 fibers/mm<sup>2</sup>, <i>p</i> < 0.01), corneal nerve branch density (CNBD) (111.8 ± 58.1 vs 50.4 ± 36.4 and 52.7 ± 21.3 branches/mm<sup>2</sup>, <i>p</i> < 0.0001), and corneal nerve fiber length (CNFL) (24.6 ± 6.6 vs 16.5 ± 6.8 and 16.2 ± 5.0 mm/mm<sup>2</sup>, <i>p</i> < 0.0001) were lower in the MCI and dementia groups compared to the NCI group. Lower CECD partially mediated the impact of age and diabetes on CNFL reduction (<i>p</i> < 0.05), whereas CECA lost its significance after adjustment (<i>p</i> = 0.20). CEC morphology does not affect the association between corneal nerve fiber loss and MCI/dementia. CECD and CECA had no significant association with cerebral ischemic lesions (<i>p</i> = 0.21–0.47), dementia (<i>p</i> = 0.11–0.35), or cognitive decline (<i>p</i> = 0.37–0.38). However, lower CECD and higher CECA were associated with decreased cortical gray matter volume (<i>p</i> < 0.05–0.01).</p> </section> <section> <h3> DISCUSSION</h3> <p>CEC loss occurs in patients with dementia, and both endothelial cell loss and hypertrophy are associated with cortical gray matter atrophy. CNF loss occurs in individuals with MCI and dementia. Corneal nerve and endothelial cell abnormalities could act as biomarkers for neurovascular pathology in dementia.</p> </section> <section> <h3> Highlights</h3> <div>
角膜共聚焦显微镜(CCM)检测轻度认知障碍(MCI)和痴呆的神经退行性变,并识别MCI患者发展为痴呆。本研究评估了MCI和痴呆患者角膜内皮细胞(CEC)形态异常是否与角膜神经形态、脑容量、脑缺血和认知障碍有关。方法:无认知障碍(NCI)、轻度认知障碍(MCI)和痴呆的参与者采用CCM量化角膜内皮细胞密度(CECD)和面积(CECA)、角膜神经纤维形态、磁共振成像(MRI)脑容量和脑缺血严重程度。结果:114名参与者中,14人患有NCI, 77人患有MCI, 23人患有痴呆。痴呆患者的ced(1971.3±594.6 vs 2316.1±499.5 cells/mm2, p < 0.05)明显低于NCI组。ccd和CECA在MCI组和NCI组之间具有可比性(p = 0.13-0.65)。MCI组和痴呆组的角膜神经纤维密度(CNFD)(31.7±5.6 vs 24.5±9.2和17.3±5.3纤维/mm2, p < 0.01)、角膜神经分支密度(CNBD)(111.8±58.1 vs 50.4±36.4和52.7±21.3支/mm2, p < 0.0001)和角膜神经纤维长度(CNFL)(24.6±6.6 vs 16.5±6.8和16.2±5.0 mm/mm2, p < 0.0001)均低于NCI组。CECA降低部分介导了年龄和糖尿病对CNFL降低的影响(p < 0.05),而CECA调整后失去了其显著性(p = 0.20)。CEC形态学不影响角膜神经纤维丢失与MCI/痴呆之间的关系。CECD和CECA与脑缺血病变(p = 0.21-0.47)、痴呆(p = 0.11-0.35)、认知能力下降(p = 0.37-0.38)无显著相关性。然而,较低的CECD和较高的CECA与皮质灰质体积减少相关(p < 0.05-0.01)。讨论:CEC丢失发生在痴呆患者中,内皮细胞丢失和肥大都与皮质灰质萎缩有关。CNF丢失发生在轻度认知损伤和痴呆患者中。角膜神经和内皮细胞异常可作为痴呆患者神经血管病理的生物标志物。重点:痴呆患者角膜内皮细胞密度显著降低。轻度认知障碍(MCI)和痴呆患者的角膜神经纤维密度、分支密度和长度较低。角膜内皮细胞的丢失和肥大与皮质灰质萎缩有关。角膜神经和内皮细胞异常可作为痴呆患者神经血管病理的生物标志物。角膜内皮细胞密度降低在一定程度上介导了年龄和糖尿病对角膜神经纤维丧失的影响。
{"title":"Association of corneal endothelial cell morphology with neurodegeneration in mild cognitive impairment and dementia","authors":"Georgios Ponirakis,&nbsp;Hanadi Al Hamad,&nbsp;Alaa S. Al-Waisy,&nbsp;Ioannis N. Petropoulos,&nbsp;Adnan Khan,&nbsp;Hoda Gad,&nbsp;Mani Chandran,&nbsp;Masharig Gadelseed,&nbsp;Salah Mahmoud,&nbsp;Ahmed Elsotouhy,&nbsp;Marwan Ramadan,&nbsp;Shafi Khan,&nbsp;Rustu E. Akcan,&nbsp;Priya V. Gawhale,&nbsp;Noushad Thodi,&nbsp;Tala Nakouzi,&nbsp;Moayad Homssi,&nbsp;Nebras Hadid,&nbsp;Aisha Al Obaidan,&nbsp;Rawan Hussein,&nbsp;Ahmed Own,&nbsp;Ashfaq Shuaib,&nbsp;Rayaz A. Malik","doi":"10.1002/trc2.70025","DOIUrl":"10.1002/trc2.70025","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; INTRODUCTION&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Corneal confocal microscopy (CCM) detects neurodegeneration in mild cognitive impairment (MCI) and dementia and identifies subjects with MCI who develop dementia. This study assessed whether abnormalities in corneal endothelial cell (CEC) morphology are related to corneal nerve morphology, brain volumetry, cerebral ischemia, and cognitive impairment in MCI and dementia.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; METHODS&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Participants with no cognitive impairment (NCI), MCI, and dementia underwent CCM to quantify corneal endothelial cell density (CECD) and area (CECA), corneal nerve fiber morphology, magnetic resonance imaging (MRI) brain volumetry, and severity of brain ischemia.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; RESULTS&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Of the 114 participants, 14 had NCI, 77 had MCI, and 23 had dementia. CECD (1971.3 ± 594.6 vs 2316.1 ± 499.5 cells/mm&lt;sup&gt;2&lt;/sup&gt;, &lt;i&gt;p&lt;/i&gt; &lt; 0.05) was significantly lower in the dementia compared to the NCI group. CECD and CECA were comparable between the MCI and NCI groups (&lt;i&gt;p&lt;/i&gt; = 0.13–0.65). Corneal nerve fiber density (CNFD) (31.7 ± 5.6 vs 24.5 ± 9.2 and 17.3 ± 5.3 fibers/mm&lt;sup&gt;2&lt;/sup&gt;, &lt;i&gt;p&lt;/i&gt; &lt; 0.01), corneal nerve branch density (CNBD) (111.8 ± 58.1 vs 50.4 ± 36.4 and 52.7 ± 21.3 branches/mm&lt;sup&gt;2&lt;/sup&gt;, &lt;i&gt;p&lt;/i&gt; &lt; 0.0001), and corneal nerve fiber length (CNFL) (24.6 ± 6.6 vs 16.5 ± 6.8 and 16.2 ± 5.0 mm/mm&lt;sup&gt;2&lt;/sup&gt;, &lt;i&gt;p&lt;/i&gt; &lt; 0.0001) were lower in the MCI and dementia groups compared to the NCI group. Lower CECD partially mediated the impact of age and diabetes on CNFL reduction (&lt;i&gt;p&lt;/i&gt; &lt; 0.05), whereas CECA lost its significance after adjustment (&lt;i&gt;p&lt;/i&gt; = 0.20). CEC morphology does not affect the association between corneal nerve fiber loss and MCI/dementia. CECD and CECA had no significant association with cerebral ischemic lesions (&lt;i&gt;p&lt;/i&gt; = 0.21–0.47), dementia (&lt;i&gt;p&lt;/i&gt; = 0.11–0.35), or cognitive decline (&lt;i&gt;p&lt;/i&gt; = 0.37–0.38). However, lower CECD and higher CECA were associated with decreased cortical gray matter volume (&lt;i&gt;p&lt;/i&gt; &lt; 0.05–0.01).&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; DISCUSSION&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;CEC loss occurs in patients with dementia, and both endothelial cell loss and hypertrophy are associated with cortical gray matter atrophy. CNF loss occurs in individuals with MCI and dementia. Corneal nerve and endothelial cell abnormalities could act as biomarkers for neurovascular pathology in dementia.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Highlights&lt;/h3&gt;\u0000 \u0000 &lt;div&gt;\u0000 ","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"11 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11696023/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142933500","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
The problem of multiple adjustments in the assessment of minimal clinically important differences 多重调整的问题在评估最小的临床重要差异。
IF 4.9 Q1 CLINICAL NEUROLOGY Pub Date : 2025-01-03 DOI: 10.1002/trc2.70032
Fabricio Ferreira de Oliveira

INTRODUCTION

Anthropometric, demographic, genetic, and clinical features may affect cognitive, behavioral, and functional decline, while clinical trials seldom consider minimal clinically important differences (MCIDs) in their analyses.

METHODS

MCIDs were reviewed taking into account features that may affect cognitive, behavioral, or functional decline in clinical trials of new disease-modifying therapies.

RESULTS

The higher the number of comparisons of different confounders in statistical analyses, the lower P values will be significant. Proper selection of confounders is crucial to accurately assess MCIDs without compromising statistical significance.

DISCUSSION

Statistical adjustment of the significance of MCIDs according to multiple comparisons is essential for the generalizability of research results. Wider inclusion of confounding variables in the statistics may help bring trial results closer to real-world conditions and improve the prediction of the efficacy of new disease-modifying therapies, though such factors must be carefully selected not to compromise the statistical significance of the analyses.

Highlights

  • Anthropometric, demographic, and clinical features may affect cognitive, behavioral, and functional decline.
  • Clinical trials seldom take minimal clinically important differences (MCIDs) or their confounders into account.
  • Generalizability of research results requires the assessment of multiple confounding factors.
  • The higher the number of comparisons involved, the lower P values will be considered significant.
  • Use of MCIDs adjusted for confounding factors should be implemented when outcomes are not susceptible to translation into absolute benefits.
人体测量学、人口统计学、遗传和临床特征可能影响认知、行为和功能衰退,而临床试验在分析中很少考虑最小临床重要差异(MCIDs)。方法:在新的疾病改善疗法的临床试验中,考虑到可能影响认知、行为或功能下降的特征,对MCIDs进行了回顾。结果:统计分析中不同混杂因素的比较次数越多,P值越低。正确选择混杂因素对于在不影响统计显著性的情况下准确评估mcd至关重要。讨论:根据多重比较对MCIDs的显著性进行统计调整是研究结果的可推广性的必要条件。在统计数据中更广泛地纳入混杂变量可能有助于使试验结果更接近现实情况,并改善对新的疾病改善疗法疗效的预测,尽管必须仔细选择这些因素,以免损害分析的统计意义。重点:人体测量学、人口统计学和临床特征可能影响认知、行为和功能衰退。临床试验很少考虑最小临床重要差异(MCIDs)或其混杂因素。研究结果的概括性需要对多个混杂因素进行评估。涉及的比较次数越多,P值越低就被认为是显著的。当结果不容易转化为绝对收益时,应使用经混杂因素调整的mcd。
{"title":"The problem of multiple adjustments in the assessment of minimal clinically important differences","authors":"Fabricio Ferreira de Oliveira","doi":"10.1002/trc2.70032","DOIUrl":"10.1002/trc2.70032","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> INTRODUCTION</h3>\u0000 \u0000 <p>Anthropometric, demographic, genetic, and clinical features may affect cognitive, behavioral, and functional decline, while clinical trials seldom consider minimal clinically important differences (MCIDs) in their analyses.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>MCIDs were reviewed taking into account features that may affect cognitive, behavioral, or functional decline in clinical trials of new disease-modifying therapies.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>The higher the number of comparisons of different confounders in statistical analyses, the lower <i>P</i> values will be significant. Proper selection of confounders is crucial to accurately assess MCIDs without compromising statistical significance.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> DISCUSSION</h3>\u0000 \u0000 <p>Statistical adjustment of the significance of MCIDs according to multiple comparisons is essential for the generalizability of research results. Wider inclusion of confounding variables in the statistics may help bring trial results closer to real-world conditions and improve the prediction of the efficacy of new disease-modifying therapies, though such factors must be carefully selected not to compromise the statistical significance of the analyses.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Anthropometric, demographic, and clinical features may affect cognitive, behavioral, and functional decline.</li>\u0000 \u0000 <li>Clinical trials seldom take minimal clinically important differences (MCIDs) or their confounders into account.</li>\u0000 \u0000 <li>Generalizability of research results requires the assessment of multiple confounding factors.</li>\u0000 \u0000 <li>The higher the number of comparisons involved, the lower <i>P</i> values will be considered significant.</li>\u0000 \u0000 <li>Use of MCIDs adjusted for confounding factors should be implemented when outcomes are not susceptible to translation into absolute benefits.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"11 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11696022/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142933529","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
The association of cholesterol levels with memory and memory change over a 14-year period in a US national cohort 在美国国家队列中,胆固醇水平与14年期间记忆和记忆变化的关系。
IF 4.9 Q1 CLINICAL NEUROLOGY Pub Date : 2025-01-03 DOI: 10.1002/trc2.70021
Silvia Miramontes, Umair Khan, Erin L. Ferguson, Marina Sirota, M. Maria Glymour

INTRODUCTION

The impact of cholesterol on late-life cognition remains controversial. We investigated the association of high-density lipoprotein cholesterol (HDL-C) and non–HDL-C with memory in a nationally representative cohort.

METHODS

Health and Retirement Study (HRS) participants (N = 13,258) aged 50+ (mean age: 67.2 years) followed from 2006 to 2020 provided cholesterol measures every 4 years and cognitive assessments biennially. Linear mixed models predicted memory scores using both baseline and time-updated cholesterol values.

RESULTS

Higher baseline HDL-C (mean: 53.9 mg/dL) predicted better memory scores (β: 0.05, 95% confidence interval [CI]: 0.03 to 0.08), but not memory change. Baseline non–HDL-C (mean: 143 mg/dL) predicted poorer memory scores (β: −0.01, 95% CI: −0.02 to 0.00), but not memory change. Time-updated HDL-C predicted better memory (β: 0.02, 95% CI: 0.00 to 0.04), but non–HDL-C showed no such associations.

DISCUSSION

While higher peripheral HDL-C is linked to better memory, the small effect sizes and absence of associations of HDL-C and non–HD-CL with memory change suggests that peripheral cholesterol has a small effect on the variation of memory scores.

Highlights

  • Higher HDL-C levels predict better memory scores but not memory change across 14 years of follow-up.
  • Baseline higher LDL-C levels predict poorer memory scores across time, but not memory change.
  • The small effects and absence of consistent association between cholesterol levels and memory change suggest that cholesterol plays a minor role in cognitive decline.
导读:胆固醇对老年认知的影响仍有争议。我们在一个具有全国代表性的队列中研究了高密度脂蛋白胆固醇(HDL-C)和非HDL-C与记忆的关系。方法:健康与退休研究(HRS)参与者(N = 13,258),年龄50岁以上(平均年龄:67.2岁),从2006年到2020年,每4年进行一次胆固醇检测,每两年进行一次认知评估。线性混合模型使用基线和时间更新的胆固醇值预测记忆分数。结果:较高的基线HDL-C(平均值:53.9 mg/dL)预测较好的记忆评分(β: 0.05, 95%可信区间[CI]: 0.03 ~ 0.08),但对记忆变化没有影响。基线非hdl - c(平均值:143 mg/dL)预测较差的记忆评分(β: -0.01, 95% CI: -0.02至0.00),但不预测记忆变化。时间更新的HDL-C预测更好的记忆(β: 0.02, 95% CI: 0.00至0.04),但非HDL-C没有这种关联。讨论:虽然较高的外周HDL-C与更好的记忆有关,但小的效应大小以及HDL-C和非hd - cl与记忆变化的相关性的缺失表明外周胆固醇对记忆评分的变化影响很小。重点:高HDL-C水平预示着更好的记忆得分,但在14年的随访中并不能预测记忆变化。基线LDL-C水平越高,随着时间的推移,记忆力得分越低,但记忆变化不会改变。胆固醇水平和记忆变化之间的小影响和缺乏一致的联系表明,胆固醇在认知能力下降中起着次要作用。
{"title":"The association of cholesterol levels with memory and memory change over a 14-year period in a US national cohort","authors":"Silvia Miramontes,&nbsp;Umair Khan,&nbsp;Erin L. Ferguson,&nbsp;Marina Sirota,&nbsp;M. Maria Glymour","doi":"10.1002/trc2.70021","DOIUrl":"10.1002/trc2.70021","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> INTRODUCTION</h3>\u0000 \u0000 <p>The impact of cholesterol on late-life cognition remains controversial. We investigated the association of high-density lipoprotein cholesterol (HDL-C) and non–HDL-C with memory in a nationally representative cohort.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>Health and Retirement Study (HRS) participants (<i>N</i> = 13,258) aged 50+ (mean age: 67.2 years) followed from 2006 to 2020 provided cholesterol measures every 4 years and cognitive assessments biennially. Linear mixed models predicted memory scores using both baseline and time-updated cholesterol values.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>Higher baseline HDL-C (mean: 53.9 mg/dL) predicted better memory scores (<i>β</i>: 0.05, 95% confidence interval [CI]: 0.03 to 0.08), but not memory change. Baseline non–HDL-C (mean: 143 mg/dL) predicted poorer memory scores (<i>β</i>: −0.01, 95% CI: −0.02 to 0.00), but not memory change. Time-updated HDL-C predicted better memory (<i>β</i>: 0.02, 95% CI: 0.00 to 0.04), but non–HDL-C showed no such associations.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> DISCUSSION</h3>\u0000 \u0000 <p>While higher peripheral HDL-C is linked to better memory, the small effect sizes and absence of associations of HDL-C and non–HD-CL with memory change suggests that peripheral cholesterol has a small effect on the variation of memory scores.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Higher HDL-C levels predict better memory scores but not memory change across 14 years of follow-up.</li>\u0000 \u0000 <li>Baseline higher LDL-C levels predict poorer memory scores across time, but not memory change.</li>\u0000 \u0000 <li>The small effects and absence of consistent association between cholesterol levels and memory change suggest that cholesterol plays a minor role in cognitive decline.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"11 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11696025/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142933527","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Emerging Alzheimer's disease treatment paradigms: A late-stage clinical trial review 新出现的阿尔茨海默病治疗范例:一项晚期临床试验回顾。
IF 4.9 Q1 CLINICAL NEUROLOGY Pub Date : 2024-12-27 DOI: 10.1002/trc2.70022
Jakub P. Hlávka, Andrew T. Kinoshita, Divya Jeyasingh, Cheng Huang, Leila Mirsafian, Mireille Jacobson
<div> <section> <h3> INTRODUCTION</h3> <p>Without disease-modifying interventions, Medicare and Medicaid spending on Alzheimer's disease (AD) management is expected to reach 637 billion USD annually by 2050. The recent advent of promising AD therapies after decades of a near-total failure rate in clinical trials suggests that more disease-modifying therapies are on the horizon. In this review, we assess the late-stage pipeline of disease-modifying candidates for AD and offer a novel classification of intervention candidates by treatment paradigms—groups of candidates that share an underlying biological mechanism of action and general disease target.</p> </section> <section> <h3> METHODS</h3> <p>We extracted data from the National Library of Medicine clinical trials database regarding Phase 2 and 3 trials of disease-modifying AD therapies. We categorized trials into eight unique treatment paradigms, which we defined by combinations of therapy (biologic, small molecule, cell and gene therapy, other) and target (amyloid, tau, other). We analyzed primary endpoints, eligibility criteria including clinical ratings of cognition, trial phase and length, and funding sources.</p> </section> <section> <h3> RESULTS</h3> <p>We identified 123 unique disease-modifying intervention candidates in 175 late-stage clinical trials. Biologic and small molecule drugs comprised 30% and 54% of trials, respectively. Eligibility criteria favored patients between the ages of 60 and 80 years with mild cognitive impairment. Including multi-phase trials, 81% of studies were engaged in Phase 2 and 27% in Phase 3. Notably, within the Biologic–Amyloid paradigm, 64% of trials were engaged in Phase 3.</p> </section> <section> <h3> DISCUSSION</h3> <p>Current studies of disease-modifying therapies for AD comprise a diverse set of approaches to treating the disease. However, effort is largely concentrated in a few treatment paradigms and a narrow patient population, causing varying rates of progress among treatment paradigms in the late-stage clinical trial pipeline. Strategies may be warranted to accelerate successes in the most promising therapeutical paradigms and nurture growth within nascent areas lacking resources but not potential.</p> </section> <section> <h3> Highlights</h3> <div> <ul> <li>An analysis of Alzheimer's disease trial treatment paradigms was conducted.</li> <li>Fr
导言:如果没有疾病改善干预措施,到2050年,医疗保险和医疗补助用于阿尔茨海默病(AD)管理的支出预计将达到每年6370亿美元。在数十年的临床试验几乎完全失败之后,最近出现了有希望的阿尔茨海默病治疗方法,这表明更多的疾病改善疗法即将出现。在这篇综述中,我们评估了阿尔茨海默病的晚期疾病修饰候选药物,并根据治疗模式提供了一种新的干预候选药物分类-具有潜在生物学作用机制和一般疾病靶点的候选药物组。方法:我们从美国国家医学图书馆临床试验数据库中提取有关疾病改善性AD治疗的2期和3期试验的数据。我们将试验分为八种独特的治疗模式,我们通过治疗(生物,小分子,细胞和基因治疗,其他)和靶标(淀粉样蛋白,tau蛋白,其他)的组合来定义。我们分析了主要终点、资格标准(包括临床认知评分、试验阶段和长度)和资金来源。结果:我们在175项晚期临床试验中确定了123项独特的疾病改善干预候选措施。生物和小分子药物分别占试验的30%和54%。入选标准为60 - 80岁轻度认知障碍患者。包括多期试验在内,81%的研究处于第二阶段,27%的研究处于第三阶段。值得注意的是,在生物淀粉样蛋白范式中,64%的试验处于3期。讨论:目前对阿尔茨海默病的疾病修饰疗法的研究包括多种治疗该疾病的方法。然而,努力主要集中在少数治疗模式和狭窄的患者群体上,导致在后期临床试验管道中治疗模式的进展速度不一。有必要制定战略,以加速最有希望的治疗范例的成功,并在缺乏资源但没有潜力的新兴领域培育增长。重点:对阿尔茨海默病的试验治疗模式进行了分析。从2021年4月到2023年3月,共审查了175项试验,123项独特的候选药物。生物和小分子药物分别占试验的30%和54%。年龄在60到80岁之间,有轻度认知障碍。
{"title":"Emerging Alzheimer's disease treatment paradigms: A late-stage clinical trial review","authors":"Jakub P. Hlávka,&nbsp;Andrew T. Kinoshita,&nbsp;Divya Jeyasingh,&nbsp;Cheng Huang,&nbsp;Leila Mirsafian,&nbsp;Mireille Jacobson","doi":"10.1002/trc2.70022","DOIUrl":"10.1002/trc2.70022","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; INTRODUCTION&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Without disease-modifying interventions, Medicare and Medicaid spending on Alzheimer's disease (AD) management is expected to reach 637 billion USD annually by 2050. The recent advent of promising AD therapies after decades of a near-total failure rate in clinical trials suggests that more disease-modifying therapies are on the horizon. In this review, we assess the late-stage pipeline of disease-modifying candidates for AD and offer a novel classification of intervention candidates by treatment paradigms—groups of candidates that share an underlying biological mechanism of action and general disease target.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; METHODS&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;We extracted data from the National Library of Medicine clinical trials database regarding Phase 2 and 3 trials of disease-modifying AD therapies. We categorized trials into eight unique treatment paradigms, which we defined by combinations of therapy (biologic, small molecule, cell and gene therapy, other) and target (amyloid, tau, other). We analyzed primary endpoints, eligibility criteria including clinical ratings of cognition, trial phase and length, and funding sources.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; RESULTS&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;We identified 123 unique disease-modifying intervention candidates in 175 late-stage clinical trials. Biologic and small molecule drugs comprised 30% and 54% of trials, respectively. Eligibility criteria favored patients between the ages of 60 and 80 years with mild cognitive impairment. Including multi-phase trials, 81% of studies were engaged in Phase 2 and 27% in Phase 3. Notably, within the Biologic–Amyloid paradigm, 64% of trials were engaged in Phase 3.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; DISCUSSION&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Current studies of disease-modifying therapies for AD comprise a diverse set of approaches to treating the disease. However, effort is largely concentrated in a few treatment paradigms and a narrow patient population, causing varying rates of progress among treatment paradigms in the late-stage clinical trial pipeline. Strategies may be warranted to accelerate successes in the most promising therapeutical paradigms and nurture growth within nascent areas lacking resources but not potential.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Highlights&lt;/h3&gt;\u0000 \u0000 &lt;div&gt;\u0000 &lt;ul&gt;\u0000 \u0000 &lt;li&gt;An analysis of Alzheimer's disease trial treatment paradigms was conducted.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;Fr","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"10 4","pages":""},"PeriodicalIF":4.9,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11694526/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142923944","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Discovery and clinical translation of ceperognastat, an O-GlcNAcase (OGA) inhibitor, for the treatment of Alzheimer's disease 发现并临床转化用于治疗阿尔茨海默病的 O-GlcNA 酶(OGA)抑制剂 ceperognastat。
IF 4.9 Q1 CLINICAL NEUROLOGY Pub Date : 2024-12-26 DOI: 10.1002/trc2.70020
William Kielbasa, Paul Goldsmith, Kevin B. Donnelly, Hugh N. Nuthall, Sergey Shcherbinin, Adam S. Fleisher, Jörg Hendle, Susan L. DuBois, Stephen L. Lowe, Feiyu Fred Zhang, Eric M. Woerly, Nicolas J.-F. Dreyfus, David Evans, Jeremy Gilmore, Michele Mancini, Cristian C. Constantinescu, Roger N. Gunn, David S. Russell, Emily C. Collins, Miroslaw Brys, Michael L. Hutton, Dustin J. Mergott
<div> <section> <h3> INTRODUCTION</h3> <p>The aggregation and spread of hyperphosphorylated, pathological tau in the human brain is hypothesized to play a key role in Alzheimer's disease (AD) as well as other neurogenerative tauopathies. O-GlcNAcylation, an important post-translational modification of tau and many other proteins, is significantly decreased in brain tissue of AD patients relative to healthy controls. Increased tau O-GlcNAcylation has been shown to reduce tau pathology in mouse in vivo tauopathy models. O-GlcNAcase (OGA) catalyzes the removal of O-GlcNAc from tau thereby driving interest in OGA inhibition as a potential therapeutic approach to reduce tau pathology and slow the progression of AD.</p> </section> <section> <h3> METHODS</h3> <p>A multidisciplinary approach was used to identify ceperognastat (LY3372689) as a potent OGA inhibitor, including an extensive discovery effort with synthetic chemistry, structure-based drug design, and in vivo OGA enzyme occupancy studies. Preclinical studies assessed the target engagement, inhibition of OGA enzyme activity, OGA enzyme occupancy, and changes in tau O-GlcNAc. Four clinical Phase 1 studies of ceperognastat in healthy participants were performed to assess clinical safety and tolerability, pharmacokinetics (PK), and enzyme occupancy.</p> </section> <section> <h3> RESULTS</h3> <p>Ceperognastat is a potent, central nervous system (CNS)-penetrant, low-dose inhibitor of OGA, which can achieve > 95% OGA enzyme occupancy in animal and human brain. Overall, ceperognastat had an acceptable safety profile in Phase 1 clinical studies with no serious adverse events reported following single and multiple dosing. The PK, enzyme occupancy, and safety profile supported Phase 2 development of ceperognastat.</p> </section> <section> <h3> DISCUSSION</h3> <p>Ceperognastat is an orally available, highly potent, CNS-penetrant OGA inhibitor that achieved high (> 80%) OGA enzyme occupancy and increased brain O-GlcNAc-tau preclinically. Ceperognastat demonstrated > 95% OGA enzyme occupancy in Phase 1 trials. These occupancy data informed the dose selection for the Phase 2 clinical program.</p> </section> <section> <h3> Highlights</h3> <div> <ul> <li>Ceperognastat is a highly potent, CNS-penetrant OGA inhibitor.</li> <li>Ceperognastat is both orally available and CNS-penetrant even when given at lo
导读:过度磷酸化的病理性tau蛋白在人脑中的聚集和扩散被认为在阿尔茨海默病(AD)以及其他神经变性tau蛋白病中发挥关键作用。o - glcn酰化是tau和许多其他蛋白质的重要翻译后修饰,与健康对照组相比,AD患者脑组织中的o - glcn酰化显著降低。在小鼠体内tau病变模型中,增加的tauo - glcn酰化已被证明可以减少tau病理。O-GlcNAcase (OGA)催化O-GlcNAc从tau蛋白中去除,从而推动了对OGA抑制作为减少tau蛋白病理和减缓AD进展的潜在治疗方法的兴趣。方法:采用多学科方法确定ceperognastat (LY3372689)是一种有效的OGA抑制剂,包括合成化学、基于结构的药物设计和体内OGA酶占用研究。临床前研究评估了靶标结合、OGA酶活性抑制、OGA酶占用和tau O-GlcNAc的变化。在健康参与者中进行了四项临床一期研究,以评估临床安全性和耐受性、药代动力学(PK)和酶占用。结果:头孢那司他是一种有效的中枢神经系统(CNS)渗透性低剂量的OGA抑制剂,可在动物和人脑中达到95%以上的OGA酶占用率。总体而言,在1期临床研究中,ceperognastat具有可接受的安全性,单次和多次给药后未报告严重不良事件。PK、酶占用率和安全性支持了ceperognastat的二期开发。讨论:Ceperognastat是一种口服有效、高效、cns渗透的OGA抑制剂,可实现高(bbb80 %) OGA酶占用和临床前脑O-GlcNAc-tau增加。在i期试验中,Ceperognastat显示出95%的OGA酶占用率。这些占用数据为二期临床项目的剂量选择提供了依据。Ceperognastat是一种高效、cns渗透的OGA抑制剂。头孢那司他既可口服,即使在低剂量下也能渗透中枢神经系统。头孢那司他能在动物和人脑中达到95%的OGA酶占用率。Ceperognastat在1期临床研究中具有可接受的安全性。
{"title":"Discovery and clinical translation of ceperognastat, an O-GlcNAcase (OGA) inhibitor, for the treatment of Alzheimer's disease","authors":"William Kielbasa,&nbsp;Paul Goldsmith,&nbsp;Kevin B. Donnelly,&nbsp;Hugh N. Nuthall,&nbsp;Sergey Shcherbinin,&nbsp;Adam S. Fleisher,&nbsp;Jörg Hendle,&nbsp;Susan L. DuBois,&nbsp;Stephen L. Lowe,&nbsp;Feiyu Fred Zhang,&nbsp;Eric M. Woerly,&nbsp;Nicolas J.-F. Dreyfus,&nbsp;David Evans,&nbsp;Jeremy Gilmore,&nbsp;Michele Mancini,&nbsp;Cristian C. Constantinescu,&nbsp;Roger N. Gunn,&nbsp;David S. Russell,&nbsp;Emily C. Collins,&nbsp;Miroslaw Brys,&nbsp;Michael L. Hutton,&nbsp;Dustin J. Mergott","doi":"10.1002/trc2.70020","DOIUrl":"10.1002/trc2.70020","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; INTRODUCTION&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;The aggregation and spread of hyperphosphorylated, pathological tau in the human brain is hypothesized to play a key role in Alzheimer's disease (AD) as well as other neurogenerative tauopathies. O-GlcNAcylation, an important post-translational modification of tau and many other proteins, is significantly decreased in brain tissue of AD patients relative to healthy controls. Increased tau O-GlcNAcylation has been shown to reduce tau pathology in mouse in vivo tauopathy models. O-GlcNAcase (OGA) catalyzes the removal of O-GlcNAc from tau thereby driving interest in OGA inhibition as a potential therapeutic approach to reduce tau pathology and slow the progression of AD.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; METHODS&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;A multidisciplinary approach was used to identify ceperognastat (LY3372689) as a potent OGA inhibitor, including an extensive discovery effort with synthetic chemistry, structure-based drug design, and in vivo OGA enzyme occupancy studies. Preclinical studies assessed the target engagement, inhibition of OGA enzyme activity, OGA enzyme occupancy, and changes in tau O-GlcNAc. Four clinical Phase 1 studies of ceperognastat in healthy participants were performed to assess clinical safety and tolerability, pharmacokinetics (PK), and enzyme occupancy.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; RESULTS&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Ceperognastat is a potent, central nervous system (CNS)-penetrant, low-dose inhibitor of OGA, which can achieve &gt; 95% OGA enzyme occupancy in animal and human brain. Overall, ceperognastat had an acceptable safety profile in Phase 1 clinical studies with no serious adverse events reported following single and multiple dosing. The PK, enzyme occupancy, and safety profile supported Phase 2 development of ceperognastat.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; DISCUSSION&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Ceperognastat is an orally available, highly potent, CNS-penetrant OGA inhibitor that achieved high (&gt; 80%) OGA enzyme occupancy and increased brain O-GlcNAc-tau preclinically. Ceperognastat demonstrated &gt; 95% OGA enzyme occupancy in Phase 1 trials. These occupancy data informed the dose selection for the Phase 2 clinical program.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Highlights&lt;/h3&gt;\u0000 \u0000 &lt;div&gt;\u0000 &lt;ul&gt;\u0000 \u0000 &lt;li&gt;Ceperognastat is a highly potent, CNS-penetrant OGA inhibitor.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;Ceperognastat is both orally available and CNS-penetrant even when given at lo","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"10 4","pages":""},"PeriodicalIF":4.9,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11694536/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142923935","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
期刊
Alzheimer''s and Dementia: Translational Research and Clinical Interventions
全部 Acc. Chem. Res. ACS Applied Bio Materials ACS Appl. Electron. Mater. ACS Appl. Energy Mater. ACS Appl. Mater. Interfaces ACS Appl. Nano Mater. ACS Appl. Polym. Mater. ACS BIOMATER-SCI ENG ACS Catal. ACS Cent. Sci. ACS Chem. Biol. ACS Chemical Health & Safety ACS Chem. Neurosci. ACS Comb. Sci. ACS Earth Space Chem. ACS Energy Lett. ACS Infect. Dis. ACS Macro Lett. ACS Mater. Lett. ACS Med. Chem. Lett. ACS Nano ACS Omega ACS Photonics ACS Sens. ACS Sustainable Chem. Eng. ACS Synth. Biol. Anal. Chem. BIOCHEMISTRY-US Bioconjugate Chem. BIOMACROMOLECULES Chem. Res. Toxicol. Chem. Rev. Chem. Mater. CRYST GROWTH DES ENERG FUEL Environ. Sci. Technol. Environ. Sci. Technol. Lett. Eur. J. Inorg. Chem. IND ENG CHEM RES Inorg. Chem. J. Agric. Food. Chem. J. Chem. Eng. Data J. Chem. Educ. J. Chem. Inf. Model. J. Chem. Theory Comput. J. Med. Chem. J. Nat. Prod. J PROTEOME RES J. Am. Chem. Soc. LANGMUIR MACROMOLECULES Mol. Pharmaceutics Nano Lett. Org. Lett. ORG PROCESS RES DEV ORGANOMETALLICS J. Org. Chem. J. Phys. Chem. J. Phys. Chem. A J. Phys. Chem. B J. Phys. Chem. C J. Phys. Chem. Lett. Analyst Anal. Methods Biomater. Sci. Catal. Sci. Technol. Chem. Commun. Chem. Soc. Rev. CHEM EDUC RES PRACT CRYSTENGCOMM Dalton Trans. Energy Environ. Sci. ENVIRON SCI-NANO ENVIRON SCI-PROC IMP ENVIRON SCI-WAT RES Faraday Discuss. Food Funct. Green Chem. Inorg. Chem. Front. Integr. Biol. J. Anal. At. Spectrom. J. Mater. Chem. A J. Mater. Chem. B J. Mater. Chem. C Lab Chip Mater. Chem. Front. Mater. Horiz. MEDCHEMCOMM Metallomics Mol. Biosyst. Mol. Syst. Des. Eng. Nanoscale Nanoscale Horiz. Nat. Prod. Rep. New J. Chem. Org. Biomol. Chem. Org. Chem. Front. PHOTOCH PHOTOBIO SCI PCCP Polym. Chem.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1