D. Michelson, M. Grundman, K. Magnuson, R. Fisher, Jonathan M. Levenson, Paul S. Aisen, K. Marek, Martha Gray, Franz Hefti
The engineered fusion protein NPT088 targets amyloid in vitro and in animal models of Alzheimer’s disease. Previous studies showed that NPT088 treatment reduced β-amyloid plaque and tau aggregate loads in mouse disease models. Here, we present the results from an initial clinical study of NPT088 in patients with mild to moderate Alzheimer’s disease. Patients were treated with 4 dose levels of NPT088 for 6 months to evaluate its safety and tolerability. Exploratory measurements included measurement of change in β-amyloid plaque and tau burden utilizing Positron Emission Tomography imaging as well as measures of Alzheimer’s disease symptoms. At endpoint NPT088 was generally safe and well-tolerated with the most prominent finding being infusion reactions in a minority of patients. No effect of NPT088 on brain plaques, tau aggregates or Alzheimer’s disease symptoms was observed.
{"title":"Randomized, Placebo Controlled Trial of NPT088, A Phage-Derived, Amyloid-Targeted Treatment for Alzheimer’s Disease","authors":"D. Michelson, M. Grundman, K. Magnuson, R. Fisher, Jonathan M. Levenson, Paul S. Aisen, K. Marek, Martha Gray, Franz Hefti","doi":"10.14283/jpad.2019.37","DOIUrl":"https://doi.org/10.14283/jpad.2019.37","url":null,"abstract":"The engineered fusion protein NPT088 targets amyloid in vitro and in animal models of Alzheimer’s disease. Previous studies showed that NPT088 treatment reduced β-amyloid plaque and tau aggregate loads in mouse disease models. Here, we present the results from an initial clinical study of NPT088 in patients with mild to moderate Alzheimer’s disease. Patients were treated with 4 dose levels of NPT088 for 6 months to evaluate its safety and tolerability. Exploratory measurements included measurement of change in β-amyloid plaque and tau burden utilizing Positron Emission Tomography imaging as well as measures of Alzheimer’s disease symptoms. At endpoint NPT088 was generally safe and well-tolerated with the most prominent finding being infusion reactions in a minority of patients. No effect of NPT088 on brain plaques, tau aggregates or Alzheimer’s disease symptoms was observed.","PeriodicalId":48606,"journal":{"name":"Jpad-Journal of Prevention of Alzheimers Disease","volume":"109 1","pages":"228 - 231"},"PeriodicalIF":6.4,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.14283/jpad.2019.37","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"66893456","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
S. Burnham, Preciosa M. Coloma, Qiao-Xin Li, Steven J. Collins, G. Savage, Simon M. Laws, Simon M. Laws, J. Doecke, P. Maruff, R. Martins, R. Martins, D. Ames, Christopher Rowe, Colin L. Masters, V. Villemagne
BackgroundThe National Institute on Aging and Alzheimer’s Association (NIA-AA) have proposed a new Research Framework: Towards a biological definition of Alzheimer’s disease, which uses a three-biomarker construct: Aß-amyloid, tau and neurodegeneration AT(N), to generate a biomarker based definition of Alzheimer’s disease.ObjectivesTo stratify AIBL participants using the new NIA-AA Research Framework using cerebrospinal fluid (CSF) biomarkers. To evaluate the clinical and cognitive profiles of the different groups resultant from the AT(N) stratification. To compare the findings to those that result from stratification using two-biomarker construct criteria (AT and/or A(N)).DesignIndividuals were classified as being positive or negative for each of the A, T, and (N) categories and then assigned to the appropriate AT(N) combinatorial group: A−T−(N)−; A+T-(N)−; A+T+(N)−; A+T−(N)+; A+T+(N)+; A−T+(N)−; A−T−(N)+; A−T+(N)+. In line with the NIA-AA research framework, these eight AT(N) groups were then collapsed into four main groups of interest (normal AD biomarkers, AD pathologic change, AD and non-AD pathologic change) and the respective clinical and cognitive trajectories over 4.5 years for each group were assessed. In two sensitivity analyses the methods were replicated after assigning individuals to four groups based on being positive or negative for AT biomarkers as well as A(N) biomarkers.SettingTwo study centers in Melbourne (Victoria) and Perth (Western Australia), Australia recruited MCI individuals and individuals with AD from primary care physicians or tertiary memory disorder clinics. Cognitively healthy, elderly NCs were recruited through advertisement or via spouses of participants in the study.ParticipantsOne-hundred and forty NC, 33 MCI participants, and 27 participants with AD from the AIBL study who had undergone CSF evaluation using Elecsys® assays.Intervention (if any)Not applicable.MeasurementsThree CSF biomarkers, namely amyloid β1–42, phosphorylated tau181, and total tau, were measured to provide the AT(N) classifications. Clinical and cognitive trajectories were evaluated using the AIBL Preclinical Alzheimer Cognitive Composite (AIBL-PACC), a verbal episodic memory composite, an executive function composite, California Verbal Learning Test–Second Edition; Long-Delay Free Recall, Mini-Mental State Examination, and Clinical Dementia Rating Sum of Boxes scores.ResultsThirty-eight percent of the elderly NCs had no evidence of abnormal AD biomarkers, whereas 33% had biomarker levels consistent with AD or AD pathologic change, and 29% had evidence of non-AD biomarker change. Among NC participants, those with biomarker evidence of AD pathology tended to perform worse on cognitive outcome assessments than other biomarker groups. Approximately three in four participants with MCI or AD had biomarker levels consistent with the research framework’s definition of AD or AD pathologic change. For MCI participants, a decrease in AIBL-PACC score
美国国家衰老和阿尔茨海默病协会(NIA-AA)提出了一个新的研究框架:迈向阿尔茨海默病的生物学定义，该框架使用三种生物标志物构建:a ß-淀粉样蛋白，tau和神经变性AT(N)，以产生基于生物标志物的阿尔茨海默病定义。目的采用新的NIA-AA研究框架，利用脑脊液(CSF)生物标志物对AIBL患者进行分层。目的:评价AT(N)分层引起的不同组的临床和认知特征。将结果与使用双生物标志物构建标准(AT和/或A(N))分层的结果进行比较。设计将个体分为A、T、(N)类阳性或阴性，然后分配到适当的AT(N)组合组:A−T−(N)−;A + T - (N)−;A + T + (N)−;A + T−(N) +;+ T + (N) +;−−T + (N);−−T (N) +;−T + (N) +。根据NIA-AA研究框架，这8个AT(N)组随后被分解为4个主要的感兴趣组(正常AD生物标志物、AD病理改变、AD和非AD病理改变)，并评估每组4.5年的临床和认知轨迹。在两个敏感性分析中，根据AT生物标志物和A(N)生物标志物的阳性或阴性将个体分为四组后，重复了这些方法。背景:澳大利亚墨尔本(维多利亚)和珀斯(西澳大利亚)的两个研究中心从初级保健医生或三级记忆障碍诊所招募MCI患者和AD患者。认知健康的老年nc是通过广告或通过研究参与者的配偶招募的。参与者:来自AIBL研究的140名NC、33名MCI和27名AD患者使用Elecsys®检测方法进行了CSF评估。干预(如有)不适用。测量三种脑脊液生物标志物，即淀粉样蛋白β1-42、磷酸化tau181和总tau，以提供AT(N)分类。临床和认知轨迹评估使用AIBL临床前阿尔茨海默氏认知复合(AIBL- pacc)，言语情景记忆复合，执行功能复合，加州言语学习测试第二版;长延迟自由回忆，迷你精神状态检查，和临床痴呆评定盒子得分总和。结果:38%的老年nc没有AD生物标志物异常的证据，33%的生物标志物水平与AD或AD病理改变一致，29%的生物标志物有非AD生物标志物变化的证据。在NC参与者中，那些有AD病理生物标志物证据的人在认知结果评估中的表现往往比其他生物标志物组更差。大约四分之三的MCI或AD参与者的生物标志物水平与研究框架对AD或AD病理改变的定义一致。对于MCI参与者，随着异常生物标志物的增加，AIBL-PACC评分下降;在一些认知测量中，异常生物标志物的增加也与下降率的增加有关。结论生物标志物异常的增加与认知轨迹的恶化有关。生物标志物分类的实施有助于在临床实践中更好地描述预后，并识别那些更有可能在临床进展的高危个体，以便将其纳入未来的治疗试验。
{"title":"Application of the NIA-AA Research Framework: Towards a Biological Definition of Alzheimer’s Disease using Cerebrospinal Fluid Biomarkers in the AIBL Study","authors":"S. Burnham, Preciosa M. Coloma, Qiao-Xin Li, Steven J. Collins, G. Savage, Simon M. Laws, Simon M. Laws, J. Doecke, P. Maruff, R. Martins, R. Martins, D. Ames, Christopher Rowe, Colin L. Masters, V. Villemagne","doi":"10.14283/jpad.2019.25","DOIUrl":"https://doi.org/10.14283/jpad.2019.25","url":null,"abstract":"BackgroundThe National Institute on Aging and Alzheimer’s Association (NIA-AA) have proposed a new Research Framework: Towards a biological definition of Alzheimer’s disease, which uses a three-biomarker construct: Aß-amyloid, tau and neurodegeneration AT(N), to generate a biomarker based definition of Alzheimer’s disease.ObjectivesTo stratify AIBL participants using the new NIA-AA Research Framework using cerebrospinal fluid (CSF) biomarkers. To evaluate the clinical and cognitive profiles of the different groups resultant from the AT(N) stratification. To compare the findings to those that result from stratification using two-biomarker construct criteria (AT and/or A(N)).DesignIndividuals were classified as being positive or negative for each of the A, T, and (N) categories and then assigned to the appropriate AT(N) combinatorial group: A−T−(N)−; A+T-(N)−; A+T+(N)−; A+T−(N)+; A+T+(N)+; A−T+(N)−; A−T−(N)+; A−T+(N)+. In line with the NIA-AA research framework, these eight AT(N) groups were then collapsed into four main groups of interest (normal AD biomarkers, AD pathologic change, AD and non-AD pathologic change) and the respective clinical and cognitive trajectories over 4.5 years for each group were assessed. In two sensitivity analyses the methods were replicated after assigning individuals to four groups based on being positive or negative for AT biomarkers as well as A(N) biomarkers.SettingTwo study centers in Melbourne (Victoria) and Perth (Western Australia), Australia recruited MCI individuals and individuals with AD from primary care physicians or tertiary memory disorder clinics. Cognitively healthy, elderly NCs were recruited through advertisement or via spouses of participants in the study.ParticipantsOne-hundred and forty NC, 33 MCI participants, and 27 participants with AD from the AIBL study who had undergone CSF evaluation using Elecsys® assays.Intervention (if any)Not applicable.MeasurementsThree CSF biomarkers, namely amyloid β1–42, phosphorylated tau181, and total tau, were measured to provide the AT(N) classifications. Clinical and cognitive trajectories were evaluated using the AIBL Preclinical Alzheimer Cognitive Composite (AIBL-PACC), a verbal episodic memory composite, an executive function composite, California Verbal Learning Test–Second Edition; Long-Delay Free Recall, Mini-Mental State Examination, and Clinical Dementia Rating Sum of Boxes scores.ResultsThirty-eight percent of the elderly NCs had no evidence of abnormal AD biomarkers, whereas 33% had biomarker levels consistent with AD or AD pathologic change, and 29% had evidence of non-AD biomarker change. Among NC participants, those with biomarker evidence of AD pathology tended to perform worse on cognitive outcome assessments than other biomarker groups. Approximately three in four participants with MCI or AD had biomarker levels consistent with the research framework’s definition of AD or AD pathologic change. For MCI participants, a decrease in AIBL-PACC score","PeriodicalId":48606,"journal":{"name":"Jpad-Journal of Prevention of Alzheimers Disease","volume":"1 1","pages":"1-8"},"PeriodicalIF":6.4,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.14283/jpad.2019.25","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"66893085","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
L Cherian, Y Wang, K Fakuda, S Leurgans, N Aggarwal, M Morris
Objective: This study sought to determine if the MIND diet (a hybrid of the Mediterranean and Dash diets, with modifications based on the science of nutrition and the brain), is effective in preventing cognitive decline after stroke.
Design: We analyzed 106 participants of a community cohort study who had completed a diet assessment and two or more annual cognitive assessments and who also had a clinical history of stroke. Cognition in five cognitive domains was assessed using structured clinical evaluations that included a battery of 19 cognitive tests. MIND diet scores were computed using a valid food frequency questionnaire (FFQ). Dietary components of the MIND diet included whole grains, leafy greens and other vegetables, berries, beans, nuts, lean meats, fish, poultry, and olive oil and reduced consumption of cheese, butter, fried foods, and sweets. MIND diet scores were modeled in tertiles. The influence of baseline MIND score on change in a global cognitive function measure and in the five cognitive domains was assessed using linear mixed models adjusted for age and other potential confounders.
Results: With adjustment for age, sex, education, APOE-ε4, caloric intake, smoking, and participation in cognitive and physical activities, the top vs lowest tertiles of MIND diet scores had a slower rate of global cognitive decline (β = .08; CI = 0.0074, 0.156) over an average of 5.9 years of follow-up.
Conclusions: High adherence to the MIND diet was associated with a slower rate of cognitive decline after stroke.
目的：本研究旨在确定 MIND 饮食（地中海饮食和 Dash 饮食的混合，并根据营养和大脑科学进行了修改）是否能有效预防中风后认知能力下降：我们对一项社区队列研究的 106 名参与者进行了分析，这些参与者完成了饮食评估和两次或两次以上的年度认知评估，并且有中风的临床病史。通过结构化临床评估（包括 19 项认知测试）对五个认知领域的认知能力进行了评估。MIND 饮食评分通过有效的食物频率问卷 (FFQ) 计算得出。MIND饮食的饮食成分包括全谷物、绿叶蔬菜和其他蔬菜、浆果、豆类、坚果、瘦肉、鱼、家禽和橄榄油，并减少奶酪、黄油、油炸食品和甜食的摄入。MIND饮食得分按三等分建模。使用线性混合模型评估了基线 MIND 分数对全球认知功能测量和五个认知领域变化的影响，并对年龄和其他潜在混杂因素进行了调整：在对年龄、性别、教育程度、APOE-ε4、热量摄入、吸烟以及参与认知活动和体育活动等因素进行调整后，在平均5.9年的随访中，MIND饮食得分最高与最低三等分组的总体认知功能下降速度较慢（β = .08; CI = 0.0074, 0.156）：结论：高度坚持 MIND 饮食与中风后认知能力下降速度减慢有关。
{"title":"Mediterranean-Dash Intervention for Neurodegenerative Delay (MIND) Diet Slows Cognitive Decline After Stroke.","authors":"L Cherian, Y Wang, K Fakuda, S Leurgans, N Aggarwal, M Morris","doi":"10.14283/jpad.2019.28","DOIUrl":"10.14283/jpad.2019.28","url":null,"abstract":"<p><strong>Objective: </strong>This study sought to determine if the MIND diet (a hybrid of the Mediterranean and Dash diets, with modifications based on the science of nutrition and the brain), is effective in preventing cognitive decline after stroke.</p><p><strong>Design: </strong>We analyzed 106 participants of a community cohort study who had completed a diet assessment and two or more annual cognitive assessments and who also had a clinical history of stroke. Cognition in five cognitive domains was assessed using structured clinical evaluations that included a battery of 19 cognitive tests. MIND diet scores were computed using a valid food frequency questionnaire (FFQ). Dietary components of the MIND diet included whole grains, leafy greens and other vegetables, berries, beans, nuts, lean meats, fish, poultry, and olive oil and reduced consumption of cheese, butter, fried foods, and sweets. MIND diet scores were modeled in tertiles. The influence of baseline MIND score on change in a global cognitive function measure and in the five cognitive domains was assessed using linear mixed models adjusted for age and other potential confounders.</p><p><strong>Results: </strong>With adjustment for age, sex, education, APOE-ε4, caloric intake, smoking, and participation in cognitive and physical activities, the top vs lowest tertiles of MIND diet scores had a slower rate of global cognitive decline (β = .08; CI = 0.0074, 0.156) over an average of 5.9 years of follow-up.</p><p><strong>Conclusions: </strong>High adherence to the MIND diet was associated with a slower rate of cognitive decline after stroke.</p>","PeriodicalId":48606,"journal":{"name":"Jpad-Journal of Prevention of Alzheimers Disease","volume":"1 1","pages":"267-273"},"PeriodicalIF":6.4,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7199507/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"66893394","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The report explores the potential digital technology has to generate novel endpoints and digital biomarkers for Alzheimer’s disease drug development studies. Drawing from literature and novel pilots, we explore the value of innovative digital technology to digitize physiological behaviours such as sleep disturbance and gait changes. Technology now exists to monitor and quantify our use and interaction with electronics in the home, the use of social platforms and smart-phones, geolocation, sleep and activity patterns. These multimodal digital data are a feasible alternative to capturing the more complex activities of daily living that require higher cognitive processes and are a sensitive predictor of disease. The combination of biosensors and the internet of things (IoT), offers the potential to collect highly relevant, objective data in a continuous, passive and low burden manner. Digital endpoints and biomarkers could have value in the diagnosis, monitoring and development of therapies for patients living with Alzheimer’s disease.
{"title":"Can Digital Technology Advance the Development of Treatments for Alzheimer’s Disease?","authors":"M. Mc Carthy, P. Schueler","doi":"10.14283/jpad.2019.32","DOIUrl":"https://doi.org/10.14283/jpad.2019.32","url":null,"abstract":"The report explores the potential digital technology has to generate novel endpoints and digital biomarkers for Alzheimer’s disease drug development studies. Drawing from literature and novel pilots, we explore the value of innovative digital technology to digitize physiological behaviours such as sleep disturbance and gait changes. Technology now exists to monitor and quantify our use and interaction with electronics in the home, the use of social platforms and smart-phones, geolocation, sleep and activity patterns. These multimodal digital data are a feasible alternative to capturing the more complex activities of daily living that require higher cognitive processes and are a sensitive predictor of disease. The combination of biosensors and the internet of things (IoT), offers the potential to collect highly relevant, objective data in a continuous, passive and low burden manner. Digital endpoints and biomarkers could have value in the diagnosis, monitoring and development of therapies for patients living with Alzheimer’s disease.","PeriodicalId":48606,"journal":{"name":"Jpad-Journal of Prevention of Alzheimers Disease","volume":"6 1","pages":"217 - 220"},"PeriodicalIF":6.4,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"66893242","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sierra Tolbert, Sierra Tolbert, Y. Liu, C. Hellegers, J. Petrella, Michael W. Weiner, T. Wong, P. Doraiswamy
BackgroundThere is a need to more fully characterize financial capacity losses in the preclinical and prodromal stages of Alzheimer’s disease (AD) and their pathological substrates.ObjectivesTo test the association between financial skills and cortical β-amyloid deposition in aging and subjects at risk for AD.DesignCross-sectional analyses of data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI-3) study conducted across 50 plus sites in the US and Canada.SettingMulticenter biomarker study.Participants243 subjects (144 cognitively normal, 79 mild cognitive impairment [MCI], 20 mild AD).Measurements18F-Florbetapir brain PET scans to measure global cortical β-amyloid deposition (SUVr) and the Financial Capacity Instrument Short Form (FCI-SF) to evaluate an individual’s financial skills in monetary calculation, financial concepts, checkbook/register usage, and bank statement usage. There are five sub scores and a total score (range of 0–74) with higher scores indicating better financial skill.ResultsFCI-SF total score was significantly worse in MCI [Cohen’s d= 0.9 (95%CI: 0.6–1.2)] and AD subjects [Cohen’s d=3.1(CI: 2.5–3.7)] compared to normals. Domain scores and completion times also showed significant difference. Across all subjects, higher cortical β-amyloid SUVr was significantly associated with worse FCI-SF total score after co-varying for age, education, and cognitive score [Cohen’s f2=0.751(CI: 0.5–1.1)]. In cognitively normal subjects, after covarying for age, gender, and education, higher β -amyloid PET SUVr was associated with longer task completion time [Cohen’s f2=0.198(CI: 0.06–0.37)].ConclusionUsing a multicenter study sample, we document that financial capacity is impaired in the prodromal and mild stages of AD and that such impairments are, in part, associated with the extent of cortical β-amyloid deposition. In normal aging, β-amyloid deposition is associated with slowing of financial tasks. These data confirm and extend prior research highlighting the utility of financial capacity assessments in at risk samples.
{"title":"Financial Management Skills in Aging, MCI and Dementia: Cross Sectional Relationship to 18F-Florbetapir PET Cortical β-amyloid Deposition","authors":"Sierra Tolbert, Sierra Tolbert, Y. Liu, C. Hellegers, J. Petrella, Michael W. Weiner, T. Wong, P. Doraiswamy","doi":"10.14283/jpad.2019.26","DOIUrl":"https://doi.org/10.14283/jpad.2019.26","url":null,"abstract":"BackgroundThere is a need to more fully characterize financial capacity losses in the preclinical and prodromal stages of Alzheimer’s disease (AD) and their pathological substrates.ObjectivesTo test the association between financial skills and cortical β-amyloid deposition in aging and subjects at risk for AD.DesignCross-sectional analyses of data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI-3) study conducted across 50 plus sites in the US and Canada.SettingMulticenter biomarker study.Participants243 subjects (144 cognitively normal, 79 mild cognitive impairment [MCI], 20 mild AD).Measurements18F-Florbetapir brain PET scans to measure global cortical β-amyloid deposition (SUVr) and the Financial Capacity Instrument Short Form (FCI-SF) to evaluate an individual’s financial skills in monetary calculation, financial concepts, checkbook/register usage, and bank statement usage. There are five sub scores and a total score (range of 0–74) with higher scores indicating better financial skill.ResultsFCI-SF total score was significantly worse in MCI [Cohen’s d= 0.9 (95%CI: 0.6–1.2)] and AD subjects [Cohen’s d=3.1(CI: 2.5–3.7)] compared to normals. Domain scores and completion times also showed significant difference. Across all subjects, higher cortical β-amyloid SUVr was significantly associated with worse FCI-SF total score after co-varying for age, education, and cognitive score [Cohen’s f2=0.751(CI: 0.5–1.1)]. In cognitively normal subjects, after covarying for age, gender, and education, higher β -amyloid PET SUVr was associated with longer task completion time [Cohen’s f2=0.198(CI: 0.06–0.37)].ConclusionUsing a multicenter study sample, we document that financial capacity is impaired in the prodromal and mild stages of AD and that such impairments are, in part, associated with the extent of cortical β-amyloid deposition. In normal aging, β-amyloid deposition is associated with slowing of financial tasks. These data confirm and extend prior research highlighting the utility of financial capacity assessments in at risk samples.","PeriodicalId":48606,"journal":{"name":"Jpad-Journal of Prevention of Alzheimers Disease","volume":"1 1","pages":"1-9"},"PeriodicalIF":6.4,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.14283/jpad.2019.26","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"66893162","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Todd M. Solomon, J. Barbone, H. T. Feaster, David S. Miller, Guy B. deBros, Cynthia A. Murphy, D. Michalczuk
The Alzheimer’s Disease Assessment Scale (ADAS-Cog) has become the de facto gold-standard for assessing the efficacy of putative anti-dementia treatments. There has been an increasing interest in providing greater standardization, automation, and administration consistency to the scale. Recently, electronic versions of the ADAS-Cog (eADAS-Cog) have been utilized in clinical trials and demonstrated significant reductions in frequency of rater error as compared to paper. In order to establish validity of the electronic version (eADAS-Cog), 20 subjects who had received a diagnosis of probable Alzheimer’s disease (AD) at a private US Memory Clinic completed a single-center, randomized, counterbalanced, prospective trial comparing a version of the eADAS-Cog to the standard paper scale. Interclass Correlation Coefficient on total scores and Kappa analysis on domain scores yielded high agreement (0.88–0.99). Effects of order and mode of administration on ADAS-Cog total scores did not demonstrate a significant main effect. Overall, this study establishes adequate concurrent validity between the ADAS-Cog and eADAS-Cog among an adult population with diagnosed AD.
{"title":"Comparing the Standard and Electronic Versions of the Alzheimer’s Disease Assessment Scale — Cognitive Subscale: A Validation Study","authors":"Todd M. Solomon, J. Barbone, H. T. Feaster, David S. Miller, Guy B. deBros, Cynthia A. Murphy, D. Michalczuk","doi":"10.14283/jpad.2019.27","DOIUrl":"https://doi.org/10.14283/jpad.2019.27","url":null,"abstract":"The Alzheimer’s Disease Assessment Scale (ADAS-Cog) has become the de facto gold-standard for assessing the efficacy of putative anti-dementia treatments. There has been an increasing interest in providing greater standardization, automation, and administration consistency to the scale. Recently, electronic versions of the ADAS-Cog (eADAS-Cog) have been utilized in clinical trials and demonstrated significant reductions in frequency of rater error as compared to paper. In order to establish validity of the electronic version (eADAS-Cog), 20 subjects who had received a diagnosis of probable Alzheimer’s disease (AD) at a private US Memory Clinic completed a single-center, randomized, counterbalanced, prospective trial comparing a version of the eADAS-Cog to the standard paper scale. Interclass Correlation Coefficient on total scores and Kappa analysis on domain scores yielded high agreement (0.88–0.99). Effects of order and mode of administration on ADAS-Cog total scores did not demonstrate a significant main effect. Overall, this study establishes adequate concurrent validity between the ADAS-Cog and eADAS-Cog among an adult population with diagnosed AD.","PeriodicalId":48606,"journal":{"name":"Jpad-Journal of Prevention of Alzheimers Disease","volume":"43 1","pages":"1-5"},"PeriodicalIF":6.4,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.14283/jpad.2019.27","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"66893284","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
D. Hammers, Norman L. Foster, J. Hoffman, T. Greene, Kevin Duff
Screen failure rates in Alzheimer’s disease (AD) clinical trial research are unsustainable, with participant recruitment being a top barrier to AD research progress. The purpose of this project was to understand the neuropsychological, psychiatric, and functional features of individuals who failed screening measures for AD trials. Previously collected clinical data from 38 patients (aged 50–83) screened for a specific industry-sponsored clinical trial of MCI/early AD (Biogen 221AD302, [EMERGE]) were analyzed to identify predictors of AD trial screen pass/fail status. Worse performance on non-memory cognitive domains like crystalized knowledge, executive functioning, and attention, and higher self-reported anxiety, was associated with failing the screening visit for the EMERGE AD clinical trial, whereas we were not able to detect a relationship between screening status and memory performance, self-reported depression, or self-reported daily functioning. By identifying predictors of AD trial screen passing/failure, this research may influence decision-making about which patients are most likely to successfully enroll in a trial, thereby potentially lowering participant burden, maximizing study resources, and reducing costs.
{"title":"Neuropsychological, Psychiatric, and Functional Correlates of Clinical Trial Enrollment","authors":"D. Hammers, Norman L. Foster, J. Hoffman, T. Greene, Kevin Duff","doi":"10.14283/jpad.2019.38","DOIUrl":"https://doi.org/10.14283/jpad.2019.38","url":null,"abstract":"Screen failure rates in Alzheimer’s disease (AD) clinical trial research are unsustainable, with participant recruitment being a top barrier to AD research progress. The purpose of this project was to understand the neuropsychological, psychiatric, and functional features of individuals who failed screening measures for AD trials. Previously collected clinical data from 38 patients (aged 50–83) screened for a specific industry-sponsored clinical trial of MCI/early AD (Biogen 221AD302, [EMERGE]) were analyzed to identify predictors of AD trial screen pass/fail status. Worse performance on non-memory cognitive domains like crystalized knowledge, executive functioning, and attention, and higher self-reported anxiety, was associated with failing the screening visit for the EMERGE AD clinical trial, whereas we were not able to detect a relationship between screening status and memory performance, self-reported depression, or self-reported daily functioning. By identifying predictors of AD trial screen passing/failure, this research may influence decision-making about which patients are most likely to successfully enroll in a trial, thereby potentially lowering participant burden, maximizing study resources, and reducing costs.","PeriodicalId":48606,"journal":{"name":"Jpad-Journal of Prevention of Alzheimers Disease","volume":"6 1","pages":"242 - 247"},"PeriodicalIF":6.4,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.14283/jpad.2019.38","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"66893480","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
C. Udeh-Momoh, G. Price, M. Ropacki, N. Ketter, T. Andrews, H. Arrighi, H. Brashear, Catherine E. Robb, Darina T Bassil, M. Cohn, L. Curry, B. Su, D. Perera, P. Giannakopoulou, J. Car, Heather A. Ward, R. Perneczky, R. Perneczky, R. Perneczky, G. Novak, L. Middleton
BackgroundThe CHARIOT PRO Main study is a prospective, non-interventional study evaluating cognitive trajectories in participants at the preclinical stage of Alzheimer’s disease (AD) classified by risk levels for developing mild cognitive impairment due to AD (MCI-AD).ObjectivesThe study aimed to characterize factors and markers influencing cognitive and functional progression among individuals at-risk for developing MCI-AD, and examine data for more precise predictors of cognitive change, particularly in relation to APOE ε4 subgroup.DesignThis single-site study was conducted at the Imperial College London (ICL) in the United Kingdom. Participants 60 to 85 years of age were classified as high, medium (amnestic or non-amnestic) or low risk for developing MCI-AD based on RBANS z-scores. A series of clinical outcome assessments (COAs) on factors influencing baseline cognitive changes were collected in each of the instrument categories of cognition, lifestyle exposure, mood, and sleep. Data collection was planned to occur every 6 months for 48 months, however the median follow-up time was 18.1 months due to early termination of study by the sponsor.Results987 participants were screened, among them 690 participants were actively followed-up post baseline, of whom 165 (23.9%) were APOE ε4 carriers; with at least one copy of the allele. The mean age was 68.73 years, 94.6% were white, 57.4% were female, and 34.8% had a Family History of Dementia with a somewhat larger percentage in the APOE ε4 carrier group (42.4%) compared to the non-carrier group (32.4%). Over half of the participants were married and 53% had a Bachelor’s or higher degree. Most frequently, safety events typical for this population consisted of upper respiratory tract infection (10.4%), falls (5.2%), hypertension (3.5%) and back pain (3.0%).Conclusion (clinical relevance)AD-related measures collected during the CHARIOT PRO Main study will allow identification and evaluation of AD risk factors and markers associated with cognitive performance from the pre-clinical stage. Evaluating the psycho-biological characteristics of these pre-symptomatic individuals in relation to their natural neurocognitive trajectories will enhance current understanding on determinants of the initial signs of cognitive changes linked to AD.
{"title":"Prospective Evaluation of Cognitive Health and Related Factors in Elderly at Risk for Developing Alzheimer’s Dementia: A Longitudinal Cohort Study","authors":"C. Udeh-Momoh, G. Price, M. Ropacki, N. Ketter, T. Andrews, H. Arrighi, H. Brashear, Catherine E. Robb, Darina T Bassil, M. Cohn, L. Curry, B. Su, D. Perera, P. Giannakopoulou, J. Car, Heather A. Ward, R. Perneczky, R. Perneczky, R. Perneczky, G. Novak, L. Middleton","doi":"10.14283/jpad.2019.31","DOIUrl":"https://doi.org/10.14283/jpad.2019.31","url":null,"abstract":"BackgroundThe CHARIOT PRO Main study is a prospective, non-interventional study evaluating cognitive trajectories in participants at the preclinical stage of Alzheimer’s disease (AD) classified by risk levels for developing mild cognitive impairment due to AD (MCI-AD).ObjectivesThe study aimed to characterize factors and markers influencing cognitive and functional progression among individuals at-risk for developing MCI-AD, and examine data for more precise predictors of cognitive change, particularly in relation to APOE ε4 subgroup.DesignThis single-site study was conducted at the Imperial College London (ICL) in the United Kingdom. Participants 60 to 85 years of age were classified as high, medium (amnestic or non-amnestic) or low risk for developing MCI-AD based on RBANS z-scores. A series of clinical outcome assessments (COAs) on factors influencing baseline cognitive changes were collected in each of the instrument categories of cognition, lifestyle exposure, mood, and sleep. Data collection was planned to occur every 6 months for 48 months, however the median follow-up time was 18.1 months due to early termination of study by the sponsor.Results987 participants were screened, among them 690 participants were actively followed-up post baseline, of whom 165 (23.9%) were APOE ε4 carriers; with at least one copy of the allele. The mean age was 68.73 years, 94.6% were white, 57.4% were female, and 34.8% had a Family History of Dementia with a somewhat larger percentage in the APOE ε4 carrier group (42.4%) compared to the non-carrier group (32.4%). Over half of the participants were married and 53% had a Bachelor’s or higher degree. Most frequently, safety events typical for this population consisted of upper respiratory tract infection (10.4%), falls (5.2%), hypertension (3.5%) and back pain (3.0%).Conclusion (clinical relevance)AD-related measures collected during the CHARIOT PRO Main study will allow identification and evaluation of AD risk factors and markers associated with cognitive performance from the pre-clinical stage. Evaluating the psycho-biological characteristics of these pre-symptomatic individuals in relation to their natural neurocognitive trajectories will enhance current understanding on determinants of the initial signs of cognitive changes linked to AD.","PeriodicalId":48606,"journal":{"name":"Jpad-Journal of Prevention of Alzheimers Disease","volume":"1 1","pages":"1-11"},"PeriodicalIF":6.4,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.14283/jpad.2019.31","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"66893113","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
A. Lo, C. D. Evans, Michele Mancini, Qun-Fu Lin, Hong Wang, Peng Liu, Sergey, Shcherbinin, Ming Lu, Arnaud Charil, B. A. Willis, Michael, Irizarry, Robert Alexander, Daniel K. Burns, K. Welsh-Bohmer, Carl Chiang, Meredith Culp, J. O’neil, B.L. Plassman, Craig, Metz, Deborah Yarbrough, Jingtao Wu, R. Evans, Kumar Budur, Stephen K. Brannan, Ann M. Saunders, Emiliangelo Ratti
Introduction: The amyloid hypothesis proposes that Aβ peptides are intimately involved in the etiology of Alzheimer’s disease (AD) via their aggregation to form toxic complexes that lead to neurodegeneration. Aβ is produced via sequential proteolytic cleavage of the parent molecule, amyloid precursor protein, by β-secretase (BACE1) followed by γ-secretase. Inhibition of BACE1 is a potential novel therapeutic strategy for slowing or halting progression of AD by reducing Aβ production. This approach differs from previous anti-amyloid approaches using monoclonal antibodies to clear Aβ. In the first large-scale clinical trial (EPOCH) of a BACE1 inhibitor, verubecestat doses of 12 mg and 40 mg were ineffective at slowing the rate of cognitive or functional decline over 78 weeks in participants with clinically diagnosed mild-to-moderate AD, despite reducing cerebrospinal fluid (CSF) Aβ levels by 63-81% (Egan et al. NEJM 2018;378:1691-1703). One interpretation of these findings is that treatment at the AD dementia stage is too late in the disease process. A second large trial (APECS; clinicaltrials.gov NCT01953601) was initiated in 2013 to evaluate verubecestat in participants with prodromal AD. Eligible participants had subjective memory decline with objective memory impairment and were amyloid positive (determined by amyloid imaging PET scan or CSF tau: Aβ42 ratio) but did not meet criteria for dementia. A decision to terminate the APECS trial was made in February 2018 following a recommendation by the external Data Monitoring Committee, which concluded that it was unlikely that positive benefit/risk could be established if the trial continued to its scheduled completion in 2019. Objectives: The objectives of this symposium are to present key efficacy and safety findings from the APECS trial and to have a panel of experts discuss the findings and implications for future development of BACE1 inhibitors. Results will be unveiled at CTAD. Discussion: The findings from the APECS trial suggest that blocking Aβ production at the prodromal AD stage does not slow clinical progression. Because the deposition of Aβ takes place years before the prodromal stage, it is possible that administration of an antiamyloid agent like verubecestat may be effective if given even earlier in the disease process. An alternative possibility is that the production of Aβ peptides may not play a major causal role in the pathophysiology of AD. Conclusions: Verubecestat was not effective in slowing clinical progression in participants with prodromal AD.
淀粉样蛋白假说提出，Aβ肽通过聚集形成毒性复合物导致神经退行性变，与阿尔茨海默病(AD)的病因密切相关。Aβ是通过β-分泌酶(BACE1)和γ-分泌酶对淀粉样蛋白前体亲本分子的连续蛋白水解裂解产生的。抑制BACE1是一种潜在的新的治疗策略，通过减少a β的产生来减缓或停止AD的进展。这种方法不同于以往使用单克隆抗体清除Aβ的抗淀粉样蛋白方法。在BACE1抑制剂的第一次大规模临床试验(EPOCH)中，verubecestat剂量为12 mg和40 mg对临床诊断为轻度至中度AD的参与者在78周内减缓认知或功能下降的速度无效，尽管脑脊液(CSF) a β水平降低了63-81% (Egan等)。NEJM 378:1691 2018; 1703)。对这些发现的一种解释是，在阿尔茨海默病痴呆阶段的治疗在疾病过程中太晚了。第二次大型试验(APECS;clinicaltrials.gov (NCT01953601)于2013年启动，旨在评估verubecestat对前驱AD患者的治疗效果。符合条件的参与者有主观记忆衰退和客观记忆障碍，淀粉样蛋白阳性(通过淀粉样蛋白成像PET扫描或脑脊液tau: a - β42比值确定)，但不符合痴呆标准。根据外部数据监测委员会的建议，终止APECS试验的决定于2018年2月做出，该委员会的结论是，如果试验继续进行到2019年按计划完成，则不太可能确定积极的收益/风险。目的:本次研讨会的目的是介绍APECS试验的关键疗效和安全性发现，并由专家小组讨论这些发现和对BACE1抑制剂未来发展的影响。结果将在贸发会议上公布。讨论:APECS试验的结果表明，在AD前驱期阻断Aβ的产生并不会减缓临床进展。由于Aβ的沉积发生在前驱期前几年，因此在疾病早期给予抗淀粉样蛋白药物如verubecestat可能有效。另一种可能性是，β肽的产生可能在阿尔茨海默病的病理生理中不起主要的因果作用。结论:Verubecestat对减缓前驱AD患者的临床进展没有效果。
{"title":"Symposia","authors":"A. Lo, C. D. Evans, Michele Mancini, Qun-Fu Lin, Hong Wang, Peng Liu, Sergey, Shcherbinin, Ming Lu, Arnaud Charil, B. A. Willis, Michael, Irizarry, Robert Alexander, Daniel K. Burns, K. Welsh-Bohmer, Carl Chiang, Meredith Culp, J. O’neil, B.L. Plassman, Craig, Metz, Deborah Yarbrough, Jingtao Wu, R. Evans, Kumar Budur, Stephen K. Brannan, Ann M. Saunders, Emiliangelo Ratti","doi":"10.14283/jpad.2018.39","DOIUrl":"https://doi.org/10.14283/jpad.2018.39","url":null,"abstract":"Introduction: The amyloid hypothesis proposes that Aβ peptides are intimately involved in the etiology of Alzheimer’s disease (AD) via their aggregation to form toxic complexes that lead to neurodegeneration. Aβ is produced via sequential proteolytic cleavage of the parent molecule, amyloid precursor protein, by β-secretase (BACE1) followed by γ-secretase. Inhibition of BACE1 is a potential novel therapeutic strategy for slowing or halting progression of AD by reducing Aβ production. This approach differs from previous anti-amyloid approaches using monoclonal antibodies to clear Aβ. In the first large-scale clinical trial (EPOCH) of a BACE1 inhibitor, verubecestat doses of 12 mg and 40 mg were ineffective at slowing the rate of cognitive or functional decline over 78 weeks in participants with clinically diagnosed mild-to-moderate AD, despite reducing cerebrospinal fluid (CSF) Aβ levels by 63-81% (Egan et al. NEJM 2018;378:1691-1703). One interpretation of these findings is that treatment at the AD dementia stage is too late in the disease process. A second large trial (APECS; clinicaltrials.gov NCT01953601) was initiated in 2013 to evaluate verubecestat in participants with prodromal AD. Eligible participants had subjective memory decline with objective memory impairment and were amyloid positive (determined by amyloid imaging PET scan or CSF tau: Aβ42 ratio) but did not meet criteria for dementia. A decision to terminate the APECS trial was made in February 2018 following a recommendation by the external Data Monitoring Committee, which concluded that it was unlikely that positive benefit/risk could be established if the trial continued to its scheduled completion in 2019. Objectives: The objectives of this symposium are to present key efficacy and safety findings from the APECS trial and to have a panel of experts discuss the findings and implications for future development of BACE1 inhibitors. Results will be unveiled at CTAD. Discussion: The findings from the APECS trial suggest that blocking Aβ production at the prodromal AD stage does not slow clinical progression. Because the deposition of Aβ takes place years before the prodromal stage, it is possible that administration of an antiamyloid agent like verubecestat may be effective if given even earlier in the disease process. An alternative possibility is that the production of Aβ peptides may not play a major causal role in the pathophysiology of AD. Conclusions: Verubecestat was not effective in slowing clinical progression in participants with prodromal AD.","PeriodicalId":48606,"journal":{"name":"Jpad-Journal of Prevention of Alzheimers Disease","volume":"5 1","pages":"1-45"},"PeriodicalIF":6.4,"publicationDate":"2018-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.14283/jpad.2018.39","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"66893385","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mary Sano, M. Soto, M. Carrillo, J. Cummings, S. Hendrix, J. Mintzer, A. Porsteinsson, P. Rosenberg, L. Schneider, J. Touchon, P. Aisen, B. Vellas, C. Lyketsos, Euusctad Task Force members
For the second time in the past 3 years, the EU-US CTAD Task Force addressed challenges related to designing clinical trials for agitation in dementia, which is one of the most disruptive aspects of the condition for both patients and caregivers. Six recommendations emerged from the Task Force meeting: 1 – Operationalizing agitation criteria established by the IPA; 2 – Combining clinician- and caregiver-derived outcomes as primary outcome measures; 3 – Using global ratings to define clinically meaningful effects and power studies; 4 – Improving the accuracy of caregiver reports by better training and education of caregivers; 5 – Employing emerging technologies to collect near real-time behavioral data; and 6 – Utilizing innovative trial designs and increasing the use of biomarkers to maximize the productivity of clinical trials for neuropsychiatric symptoms.
{"title":"Identifying Better Outcome Measures to Improve Treatment of Agitation in Dementia: A Report from the EU/US/CTAD Task Force","authors":"Mary Sano, M. Soto, M. Carrillo, J. Cummings, S. Hendrix, J. Mintzer, A. Porsteinsson, P. Rosenberg, L. Schneider, J. Touchon, P. Aisen, B. Vellas, C. Lyketsos, Euusctad Task Force members","doi":"10.14283/jpad.2018.15","DOIUrl":"https://doi.org/10.14283/jpad.2018.15","url":null,"abstract":"For the second time in the past 3 years, the EU-US CTAD Task Force addressed challenges related to designing clinical trials for agitation in dementia, which is one of the most disruptive aspects of the condition for both patients and caregivers. Six recommendations emerged from the Task Force meeting: 1 – Operationalizing agitation criteria established by the IPA; 2 – Combining clinician- and caregiver-derived outcomes as primary outcome measures; 3 – Using global ratings to define clinically meaningful effects and power studies; 4 – Improving the accuracy of caregiver reports by better training and education of caregivers; 5 – Employing emerging technologies to collect near real-time behavioral data; and 6 – Utilizing innovative trial designs and increasing the use of biomarkers to maximize the productivity of clinical trials for neuropsychiatric symptoms.","PeriodicalId":48606,"journal":{"name":"Jpad-Journal of Prevention of Alzheimers Disease","volume":"5 1","pages":"98-102"},"PeriodicalIF":6.4,"publicationDate":"2018-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.14283/jpad.2018.15","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"66893315","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：