Pub Date : 2024-08-14DOI: 10.1186/s13195-024-01511-x
Tian-Shin Yeh, Gary C Curhan, Barbara P Yawn, Walter C Willett, Sharon G Curhan
Background: Herpes zoster (HZ), commonly known as "shingles," may contribute to cognitive decline through mechanisms such as neuroinflammation or direct neuronal injury. However, evidence on the longitudinal association between HZ and cognitive decline is conflicting and whether the risk differs by APOE ε4-carrier status has not been studied; prospective cohort studies on the association between HZ vaccination and cognitive decline are also lacking.
Methods: We included 149,327 participants from three large cohorts-the Nurses' Health Study (NHS), NHSII, and Health Professionals Follow-Up Study (HPFS)-to prospectively examine the association between HZ and subsequent subjective cognitive decline (SCD). Poisson regression was used to estimate the multivariable-adjusted relative risk (MVRR) of a 3-unit increment in SCD score according to years since HZ compared with participants with no history of HZ.
Results: Compared with individuals with no history of HZ, the MVRR (95% CI) of a 3-unit increment in SCD score was significantly and independently higher among individuals with a history of HZ, but the duration of time since HZ when the elevated risk of SCD was statistically significant differed among the cohorts. In NHS, HZ was associated with higher long-term risk of SCD; compared with individuals with no history of HZ, the MVRR (95% CI) of a 3-unit increment in SCD score was 1.14 (1.01, 1.32) for ≥ 13 years since HZ. In NHS II, HZ was associated with higher risk of SCD in both the short-term [MVRR 1.34 (1.18, 1.53) for 1-4 years] and long-term [MVRR 1.20 (1.08, 1.34) for ≥ 13 years since HZ]. In HPFS, an elevated risk of SCD was suggested across all time points. Among the subset of participants with information on APOE ε4, there was a suggestion that the association differed by APOE ε4 carrier status, but the results were not consistent between women and men. Among the subset of women with information on HZ vaccination, there was a suggestion that the long-term risk of SCD may be greater among women who were not vaccinated against HZ.
Conclusions: Data from three large independent cohorts of women and men showed that HZ was associated with higher long-term risk of SCD, and the risk may differ by APOE ε4-carrier status.
{"title":"Herpes zoster and long-term risk of subjective cognitive decline.","authors":"Tian-Shin Yeh, Gary C Curhan, Barbara P Yawn, Walter C Willett, Sharon G Curhan","doi":"10.1186/s13195-024-01511-x","DOIUrl":"10.1186/s13195-024-01511-x","url":null,"abstract":"<p><strong>Background: </strong>Herpes zoster (HZ), commonly known as \"shingles,\" may contribute to cognitive decline through mechanisms such as neuroinflammation or direct neuronal injury. However, evidence on the longitudinal association between HZ and cognitive decline is conflicting and whether the risk differs by APOE ε4-carrier status has not been studied; prospective cohort studies on the association between HZ vaccination and cognitive decline are also lacking.</p><p><strong>Methods: </strong>We included 149,327 participants from three large cohorts-the Nurses' Health Study (NHS), NHSII, and Health Professionals Follow-Up Study (HPFS)-to prospectively examine the association between HZ and subsequent subjective cognitive decline (SCD). Poisson regression was used to estimate the multivariable-adjusted relative risk (MVRR) of a 3-unit increment in SCD score according to years since HZ compared with participants with no history of HZ.</p><p><strong>Results: </strong>Compared with individuals with no history of HZ, the MVRR (95% CI) of a 3-unit increment in SCD score was significantly and independently higher among individuals with a history of HZ, but the duration of time since HZ when the elevated risk of SCD was statistically significant differed among the cohorts. In NHS, HZ was associated with higher long-term risk of SCD; compared with individuals with no history of HZ, the MVRR (95% CI) of a 3-unit increment in SCD score was 1.14 (1.01, 1.32) for ≥ 13 years since HZ. In NHS II, HZ was associated with higher risk of SCD in both the short-term [MVRR 1.34 (1.18, 1.53) for 1-4 years] and long-term [MVRR 1.20 (1.08, 1.34) for ≥ 13 years since HZ]. In HPFS, an elevated risk of SCD was suggested across all time points. Among the subset of participants with information on APOE ε4, there was a suggestion that the association differed by APOE ε4 carrier status, but the results were not consistent between women and men. Among the subset of women with information on HZ vaccination, there was a suggestion that the long-term risk of SCD may be greater among women who were not vaccinated against HZ.</p><p><strong>Conclusions: </strong>Data from three large independent cohorts of women and men showed that HZ was associated with higher long-term risk of SCD, and the risk may differ by APOE ε4-carrier status.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":null,"pages":null},"PeriodicalIF":7.9,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11323373/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141974837","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-14DOI: 10.1186/s13195-024-01549-x
Laura Ferré-González, Ángel Balaguer, Marta Roca, Artemis Ftara, Ana Lloret, Consuelo Cháfer-Pericás
Background: Alzheimer's disease (AD) is the most prevalent dementia, showing higher incidence in women. Besides, lipids play an essential role in brain, and they could be dysregulated in neurodegeneration. Specifically, impaired plasma lipid levels could predict early AD diagnosis. This work aims to identify the main plasma lipids altered in early AD female mouse model and evaluate their relationship with brain lipidome. Also, the possible involvement of the estrous cycle in lipid metabolism has been evaluated.
Methods: Plasma samples of wild-type (n = 10) and APP/PS1 (n = 10) female mice of 5 months of age were collected, processed, and analysed using a lipidomic mass spectrometry-based method. A statistical analysis involving univariate and multivariate approaches was performed to identify significant lipid differences related to AD between groups. Also, cytology tests were conducted to confirm estrous cycle phases.
Results: Three hundred thirty lipids were detected in plasma, 18 of them showed significant differences between groups; specifically, some triacylglycerols, cholesteryl esters, lysophosphatidylcholines, phosphatidylcholines, and ether-linked phosphatidylcholines, increased in early AD; while other phosphatidylcholines, phosphatidylethanolamines, ceramides, and ether-linked phosphatidylethanolamines decreased in early AD. A multivariate approach was developed from some lipid variables, showing high diagnostic indexes (70% sensitivity, 90% specificity, 80% accuracy). From brain and plasma lipidome, some significant correlations were observed, mainly in the glycerophospholipid family. Also, some differences were found in both plasma and brain lipids, according to the estrous cycle phase.
Conclusions: Therefore, lipid alterations can be identified in plasma at early AD stages in mice females, with a relationship with brain lipid metabolism for most of the lipid subfamilies, suggesting some lipids as potential AD biomarkers. In addition, the estrous cycle monitoring could be relevant in female studies.
背景:阿尔茨海默病(AD)是最常见的痴呆症,女性发病率较高。此外,血脂在大脑中扮演着重要角色,在神经退行性病变中可能出现失调。具体来说,血浆脂质水平受损可预测早期老年痴呆症的诊断。本研究旨在确定早期AD雌性小鼠模型中发生改变的主要血浆脂质,并评估它们与脑脂质组的关系。此外,还对发情周期可能参与脂质代谢进行了评估:方法:收集、处理和分析5月龄野生型(n = 10)和APP/PS1(n = 10)雌性小鼠的血浆样本,采用基于脂质体质谱的方法进行分析。采用单变量和多变量方法进行统计分析,以确定各组间与AD相关的显著脂质差异。此外,还进行了细胞学检测以确认发情周期阶段:结果:血浆中检测出 3300 种脂质,其中 18 种脂质在组间存在显著差异;具体而言,一些三酰甘油、胆固醇酯、溶血磷脂酰胆碱、磷脂酰胆碱和醚键磷脂酰胆碱在 AD 早期升高;而其他磷脂酰胆碱、磷脂酰乙醇胺、神经酰胺和醚键磷脂酰乙醇胺在 AD 早期降低。根据一些脂质变量开发的多变量方法显示出较高的诊断指数(灵敏度 70%、特异度 90%、准确度 80%)。从大脑和血浆脂质组中观察到了一些显著的相关性,主要是在甘油磷脂家族中。此外,根据发情周期阶段的不同,血浆和大脑脂质也存在一些差异:因此,在小鼠雌性AD的早期阶段,可以发现血浆中的脂质发生了改变,大多数脂质亚族与脑脂质代谢有关,这表明一些脂质可能是AD的生物标志物。此外,发情周期监测可能与雌性研究相关。
{"title":"Plasma lipidomics in early APP/PS1 female mouse model and its relationship with brain: Is it affected by the estrous cycle?","authors":"Laura Ferré-González, Ángel Balaguer, Marta Roca, Artemis Ftara, Ana Lloret, Consuelo Cháfer-Pericás","doi":"10.1186/s13195-024-01549-x","DOIUrl":"10.1186/s13195-024-01549-x","url":null,"abstract":"<p><strong>Background: </strong>Alzheimer's disease (AD) is the most prevalent dementia, showing higher incidence in women. Besides, lipids play an essential role in brain, and they could be dysregulated in neurodegeneration. Specifically, impaired plasma lipid levels could predict early AD diagnosis. This work aims to identify the main plasma lipids altered in early AD female mouse model and evaluate their relationship with brain lipidome. Also, the possible involvement of the estrous cycle in lipid metabolism has been evaluated.</p><p><strong>Methods: </strong>Plasma samples of wild-type (n = 10) and APP/PS1 (n = 10) female mice of 5 months of age were collected, processed, and analysed using a lipidomic mass spectrometry-based method. A statistical analysis involving univariate and multivariate approaches was performed to identify significant lipid differences related to AD between groups. Also, cytology tests were conducted to confirm estrous cycle phases.</p><p><strong>Results: </strong>Three hundred thirty lipids were detected in plasma, 18 of them showed significant differences between groups; specifically, some triacylglycerols, cholesteryl esters, lysophosphatidylcholines, phosphatidylcholines, and ether-linked phosphatidylcholines, increased in early AD; while other phosphatidylcholines, phosphatidylethanolamines, ceramides, and ether-linked phosphatidylethanolamines decreased in early AD. A multivariate approach was developed from some lipid variables, showing high diagnostic indexes (70% sensitivity, 90% specificity, 80% accuracy). From brain and plasma lipidome, some significant correlations were observed, mainly in the glycerophospholipid family. Also, some differences were found in both plasma and brain lipids, according to the estrous cycle phase.</p><p><strong>Conclusions: </strong>Therefore, lipid alterations can be identified in plasma at early AD stages in mice females, with a relationship with brain lipid metabolism for most of the lipid subfamilies, suggesting some lipids as potential AD biomarkers. In addition, the estrous cycle monitoring could be relevant in female studies.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":null,"pages":null},"PeriodicalIF":7.9,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11323474/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141981516","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-13DOI: 10.1186/s13195-024-01535-3
Sébastien Heyer, Maïa Simon, Matthieu Doyen, Ali Mortada, Véronique Roch, Elodie Jeanbert, Nathalie Thilly, Catherine Malaplate, Anna Kearney-Schwartz, Thérèse Jonveaux, Aurélie Bannay, Antoine Verger
Background: Precisely defining the delay in onset of dementia is a particular challenge for early diagnosis. Brain [18F] fluoro-2-deoxy-2-D-glucose (18F-FDG) Positron Emission Tomography (PET) is a particularly interesting tool for the early diagnosis of neurodegenerative diseases, through the measurement of the cerebral glucose metabolic rate. There is currently a lack of longitudinal studies under real-life conditions, with sufficient patients, to accurately evaluate the predictive values of brain 18F-FDG PET scans. Here, we aimed to estimate the value of brain 18F-FDG PET for predicting the risk of dementia conversion and the risk of occurrence of a neurodegenerative pathology.
Methods: Longitudinal data for a cohort of patients with no diagnosis of dementia at the time of recruitment referred by a tertiary memory clinic for brain 18F-FDG PET were matched with (Prince M, Wimo A, Guerchet Maëlenn, Ali G-C, Wu Y-T et al. World Alzheimer Report 2015. The Global Impact of Dementia: An analysis of prevalence, incidence, cost and trends. [Research Report] Alzheimer's Disease International. 2015. 2015.) data from the French National Health Data System (NHDS), (Jack CR, Bennett DA, Blennow K, Carrillo MC, Dunn B, Haeberlein SB, et al. NIA-AA Research Framework: Toward a biological definition of Alzheimer's disease. Alzheimers Dement. 2018;14(4):535-62.) data from the National Alzheimer Bank (NAB), and (Davis M, O`Connell T, Johnson S, Cline S, Merikle E, Martenyi F, et al. Estimating Alzheimer's Disease Progression Rates from Normal Cognition Through Mild Cognitive Impairment and Stages of Dementia. CAR. 2018;15(8):777-88.) lumbar puncture (LP) biomarker data. The criteria for dementia conversion were the designation, within the three years after the brain 18F-FDG PET scan, of a long-term condition for dementia in the NHDS and a dementia stage of cognitive impairment in the NAB. The criterion for the identification of a neurodegenerative disease in the medical records was the determination of LP biomarker levels.
Results: Among the 403 patients (69.9 ± 11.4 years old, 177 women) from the initial cohort with data matched with the NHDS data, 137 were matched with the NAB data, and 61 were matched with LP biomarker data. Within three years of the scan, a 18F-FDG PET had negative predictive values of 85% for dementia conversion (according to the NHDS and NAB datasets) and 95% for the presence of LP neurodegeneration biomarkers.
Conclusion: A normal brain 18F-FDG PET scan can help rule out the risk of dementia conversion and the presence of cerebrospinal fluid (CSF) biomarker of neurodegeneration early with high certainty, allowing modifications to patient management regimens in the short term.
Trial registration: Clinical Trials database (NCT04804722). March
背景:准确界定痴呆症发病的延迟时间是早期诊断的一项特殊挑战。脑[18F]氟-2-脱氧-2-D-葡萄糖(18F-FDG)正电子发射断层扫描(PET)通过测量脑葡萄糖代谢率,是早期诊断神经退行性疾病的一种特别有趣的工具。目前,还缺乏在真实条件下对足够多的患者进行纵向研究,以准确评估脑 18F-FDG PET 扫描的预测价值。在此,我们旨在估算脑 18F-FDG PET 对预测痴呆转化风险和神经退行性病变发生风险的价值:将招募时未确诊痴呆症的患者队列的纵向数据与一家三级记忆诊所转诊的脑18F-FDG PET数据进行比对(Prince M、Wimo A、Guerchet Maëlenn、Ali G-C、Wu Y-T et al.痴呆症的全球影响:对患病率、发病率、成本和趋势的分析。[研究报告] 阿尔茨海默病国际。2015.2015.) 数据来自法国国家健康数据系统 (NHDS),(Jack CR, Bennett DA, Blennow K, Carrillo MC, Dunn B, Haeberlein SB, et al. NIA-AA Research Framework:NIA-AA Research Framework: Toward a biological definition of Alzheimer's disease.Alzheimers Dement.2018;14(4):535-62.) 数据来自国家阿尔茨海默病库(NAB),以及(Davis M, O`Connell T, Johnson S, Cline S, Merikle E, Martenyi F, et al. Estimating Alzheimer's Disease Progression Rates from Normal Cognition Through Mild Cognitive Impairment and Stages of Dementia.CAR.2018;15(8):777-88。)腰椎穿刺(LP)生物标志物数据。痴呆转换的标准是,在脑18F-FDG PET扫描后的三年内,在NHDS中被指定为痴呆长期病症,在NAB中被指定为痴呆认知障碍阶段。病历中确定神经退行性疾病的标准是确定 LP 生物标志物水平:在与 NHDS 数据相匹配的初始队列中的 403 名患者(69.9 ± 11.4 岁,177 名女性)中,137 人与 NAB 数据相匹配,61 人与 LP 生物标记物数据相匹配。扫描后三年内,18F-FDG PET 对痴呆症转化的阴性预测值为 85%(根据 NHDS 和 NAB 数据集),对 LP 神经变性生物标记物存在的阴性预测值为 95%:结论:正常的脑18F-FDG正电子发射计算机断层扫描可帮助早期排除痴呆转化的风险和存在脑脊液(CSF)神经变性生物标志物的高度确定性,从而在短期内修改患者管理方案:临床试验数据库(NCT04804722)。2021年3月18日。回顾性注册。
{"title":"<sup>18</sup>F-FDG PET can effectively rule out conversion to dementia and the presence of CSF biomarker of neurodegeneration: a real-world data analysis.","authors":"Sébastien Heyer, Maïa Simon, Matthieu Doyen, Ali Mortada, Véronique Roch, Elodie Jeanbert, Nathalie Thilly, Catherine Malaplate, Anna Kearney-Schwartz, Thérèse Jonveaux, Aurélie Bannay, Antoine Verger","doi":"10.1186/s13195-024-01535-3","DOIUrl":"10.1186/s13195-024-01535-3","url":null,"abstract":"<p><strong>Background: </strong>Precisely defining the delay in onset of dementia is a particular challenge for early diagnosis. Brain [<sup>18</sup>F] fluoro-2-deoxy-2-D-glucose (<sup>18</sup>F-FDG) Positron Emission Tomography (PET) is a particularly interesting tool for the early diagnosis of neurodegenerative diseases, through the measurement of the cerebral glucose metabolic rate. There is currently a lack of longitudinal studies under real-life conditions, with sufficient patients, to accurately evaluate the predictive values of brain <sup>18</sup>F-FDG PET scans. Here, we aimed to estimate the value of brain <sup>18</sup>F-FDG PET for predicting the risk of dementia conversion and the risk of occurrence of a neurodegenerative pathology.</p><p><strong>Methods: </strong>Longitudinal data for a cohort of patients with no diagnosis of dementia at the time of recruitment referred by a tertiary memory clinic for brain <sup>18</sup>F-FDG PET were matched with (Prince M, Wimo A, Guerchet Maëlenn, Ali G-C, Wu Y-T et al. World Alzheimer Report 2015. The Global Impact of Dementia: An analysis of prevalence, incidence, cost and trends. [Research Report] Alzheimer's Disease International. 2015. 2015.) data from the French National Health Data System (NHDS), (Jack CR, Bennett DA, Blennow K, Carrillo MC, Dunn B, Haeberlein SB, et al. NIA-AA Research Framework: Toward a biological definition of Alzheimer's disease. Alzheimers Dement. 2018;14(4):535-62.) data from the National Alzheimer Bank (NAB), and (Davis M, O`Connell T, Johnson S, Cline S, Merikle E, Martenyi F, et al. Estimating Alzheimer's Disease Progression Rates from Normal Cognition Through Mild Cognitive Impairment and Stages of Dementia. CAR. 2018;15(8):777-88.) lumbar puncture (LP) biomarker data. The criteria for dementia conversion were the designation, within the three years after the brain <sup>18</sup>F-FDG PET scan, of a long-term condition for dementia in the NHDS and a dementia stage of cognitive impairment in the NAB. The criterion for the identification of a neurodegenerative disease in the medical records was the determination of LP biomarker levels.</p><p><strong>Results: </strong>Among the 403 patients (69.9 ± 11.4 years old, 177 women) from the initial cohort with data matched with the NHDS data, 137 were matched with the NAB data, and 61 were matched with LP biomarker data. Within three years of the scan, a <sup>18</sup>F-FDG PET had negative predictive values of 85% for dementia conversion (according to the NHDS and NAB datasets) and 95% for the presence of LP neurodegeneration biomarkers.</p><p><strong>Conclusion: </strong>A normal brain <sup>18</sup>F-FDG PET scan can help rule out the risk of dementia conversion and the presence of cerebrospinal fluid (CSF) biomarker of neurodegeneration early with high certainty, allowing modifications to patient management regimens in the short term.</p><p><strong>Trial registration: </strong>Clinical Trials database (NCT04804722). March ","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":null,"pages":null},"PeriodicalIF":7.9,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11320856/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141970411","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-12DOI: 10.1186/s13195-024-01546-0
Musung Keum, Boung Chul Lee, Young Min Choe, Guk-Hee Suh, Shin Gyeom Kim, Hyun Soo Kim, Jaeuk Hwang, Dahyun Yi, Jee Wook Kim
This study investigated the correlation between protein intake and Alzheimer’s disease (AD)-related cognitive decline, particularly in episodic memory, among older adults without dementia. Furthermore, we assessed the moderating effect of apolipoprotein ε4 (APOE4) on this association and analyzed its influence on other cognitive functions beyond memory. The study involved 196 participants who underwent assessments for protein intake, cognitive performance, APOE4 genotyping, and nutritional biomarkers. Protein intake was categorized into low, medium, and high based on the consumption of dairy, legumes, eggs, meat, and fish. High protein intake was significantly associated with better episodic memory and overall cognition. Moreover, a significant interaction was found between high protein intake and APOE4, indicating that APOE4 moderates the association between high protein intake level and episodic memory. Sensitivity analysis confirmed these results among participants with stable food intake. Our study results demonstrated that high protein intake is associated with better episodic memory among older adults without dementia. Furthermore, the findings highlight the significant role of APOE4 status in moderating the relationship between protein consumption and episodic memory. These results suggest that dietary interventions focusing on protein intake could be beneficial for cognitive health, particularly in individuals with a genetic predisposition to AD.
{"title":"Protein intake and episodic memory: the moderating role of the apolipoprotein E ε4 status","authors":"Musung Keum, Boung Chul Lee, Young Min Choe, Guk-Hee Suh, Shin Gyeom Kim, Hyun Soo Kim, Jaeuk Hwang, Dahyun Yi, Jee Wook Kim","doi":"10.1186/s13195-024-01546-0","DOIUrl":"https://doi.org/10.1186/s13195-024-01546-0","url":null,"abstract":"This study investigated the correlation between protein intake and Alzheimer’s disease (AD)-related cognitive decline, particularly in episodic memory, among older adults without dementia. Furthermore, we assessed the moderating effect of apolipoprotein ε4 (APOE4) on this association and analyzed its influence on other cognitive functions beyond memory. The study involved 196 participants who underwent assessments for protein intake, cognitive performance, APOE4 genotyping, and nutritional biomarkers. Protein intake was categorized into low, medium, and high based on the consumption of dairy, legumes, eggs, meat, and fish. High protein intake was significantly associated with better episodic memory and overall cognition. Moreover, a significant interaction was found between high protein intake and APOE4, indicating that APOE4 moderates the association between high protein intake level and episodic memory. Sensitivity analysis confirmed these results among participants with stable food intake. Our study results demonstrated that high protein intake is associated with better episodic memory among older adults without dementia. Furthermore, the findings highlight the significant role of APOE4 status in moderating the relationship between protein consumption and episodic memory. These results suggest that dietary interventions focusing on protein intake could be beneficial for cognitive health, particularly in individuals with a genetic predisposition to AD.","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":null,"pages":null},"PeriodicalIF":9.0,"publicationDate":"2024-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141942644","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-10DOI: 10.1186/s13195-024-01550-4
Xue Liu, Guang-Xiang Yu, Mei Xue, Liang-Yu Huang, Yan Fu, Zuo-Teng Wang, Lan Tan, Ya-Nan Ou
Background: Microglial activation has been suggested to be involved in the pathogenesis of depression and Alzheimer's disease (AD). Soluble triggering receptor expressed on myeloid cells 2 (sTREM2) is a marker of microglial activation. The purpose of this study was to investigate the interrelationships of cerebrospinal fluid (CSF) sTREM2, AD pathology, as well as minimal depressive symptoms (MDSs), and cognition.
Methods: A total of 545 non-demented individuals from the Alzheimer's Disease Neuroimaging Initiative cohort were included in our study. The average age of the total population was 72.6 years and the percentage of females was 42.6%. Linear regression models were conducted to investigate the linear relationships of MDSs with CSF sTREM2, AD pathology, cognition, and brain structure. Mediation models and structural equation models (SEM) were conducted to examine whether CSF sTREM2 mediated the relationships of MDSs with AD pathology and cognition.
Results: Results revealed that individuals with MDSs had lower CSF sTREM2 levels than normal controls. Linear regression showed that MDSs were linearly associated with CSF sTREM2 (PFDR = 0.012) and amyloid biomarkers (PFDR < 0.05), as well as cognitive scores (PFDR < 0.05) and hippocampal volume (PFDR = 0.003). Mediation analyses revealed that CSF sTREM2 mediated the association between MDSs and amyloid pathology, with the mediating proportions ranging from 6.030 to 18.894%. However, SEM failed to reveal that MDS affected cognition through CSF amyloid pathology and CSF sTREM2.
Conclusions: MDSs are associated with amyloid pathology and cognition. CSF sTREM2 may potentially be an intervenable target between depression and AD pathology.
{"title":"The interrelationships of CSF sTREM2, AD pathology, minimal depressive symptoms, and cognition in non-demented adults.","authors":"Xue Liu, Guang-Xiang Yu, Mei Xue, Liang-Yu Huang, Yan Fu, Zuo-Teng Wang, Lan Tan, Ya-Nan Ou","doi":"10.1186/s13195-024-01550-4","DOIUrl":"10.1186/s13195-024-01550-4","url":null,"abstract":"<p><strong>Background: </strong>Microglial activation has been suggested to be involved in the pathogenesis of depression and Alzheimer's disease (AD). Soluble triggering receptor expressed on myeloid cells 2 (sTREM2) is a marker of microglial activation. The purpose of this study was to investigate the interrelationships of cerebrospinal fluid (CSF) sTREM2, AD pathology, as well as minimal depressive symptoms (MDSs), and cognition.</p><p><strong>Methods: </strong>A total of 545 non-demented individuals from the Alzheimer's Disease Neuroimaging Initiative cohort were included in our study. The average age of the total population was 72.6 years and the percentage of females was 42.6%. Linear regression models were conducted to investigate the linear relationships of MDSs with CSF sTREM2, AD pathology, cognition, and brain structure. Mediation models and structural equation models (SEM) were conducted to examine whether CSF sTREM2 mediated the relationships of MDSs with AD pathology and cognition.</p><p><strong>Results: </strong>Results revealed that individuals with MDSs had lower CSF sTREM2 levels than normal controls. Linear regression showed that MDSs were linearly associated with CSF sTREM2 (P<sub>FDR</sub> = 0.012) and amyloid biomarkers (P<sub>FDR</sub> < 0.05), as well as cognitive scores (P<sub>FDR</sub> < 0.05) and hippocampal volume (P<sub>FDR</sub> = 0.003). Mediation analyses revealed that CSF sTREM2 mediated the association between MDSs and amyloid pathology, with the mediating proportions ranging from 6.030 to 18.894%. However, SEM failed to reveal that MDS affected cognition through CSF amyloid pathology and CSF sTREM2.</p><p><strong>Conclusions: </strong>MDSs are associated with amyloid pathology and cognition. CSF sTREM2 may potentially be an intervenable target between depression and AD pathology.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":null,"pages":null},"PeriodicalIF":7.9,"publicationDate":"2024-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11316296/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141911298","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-05DOI: 10.1186/s13195-024-01548-y
Charlotte Havreng-Théry, Bruno Oquendo, Victoria Zolnowski-Kolp, Pierre Krolak-Salmon, François Bertin-Hugault, Carmelo Lafuente-Lafuente, Joël Belmin
{"title":"Correction: Cholinesterase inhibitors and memantine are associated with a reduced mortality in nursing home residents with dementia: a longitudinal observational study.","authors":"Charlotte Havreng-Théry, Bruno Oquendo, Victoria Zolnowski-Kolp, Pierre Krolak-Salmon, François Bertin-Hugault, Carmelo Lafuente-Lafuente, Joël Belmin","doi":"10.1186/s13195-024-01548-y","DOIUrl":"10.1186/s13195-024-01548-y","url":null,"abstract":"","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":null,"pages":null},"PeriodicalIF":7.9,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11302329/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141892652","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-01DOI: 10.1186/s13195-024-01540-6
Yihan Wang, Shu Liu, Alanna G Spiteri, Andrew Liem Hieu Huynh, Chenyin Chu, Colin L Masters, Benjamin Goudey, Yijun Pan, Liang Jin
Several (inter)national longitudinal dementia observational datasets encompassing demographic information, neuroimaging, biomarkers, neuropsychological evaluations, and muti-omics data, have ushered in a new era of potential for integrating machine learning (ML) into dementia research and clinical practice. ML, with its proficiency in handling multi-modal and high-dimensional data, has emerged as an innovative technique to facilitate early diagnosis, differential diagnosis, and to predict onset and progression of mild cognitive impairment and dementia. In this review, we evaluate current and potential applications of ML, including its history in dementia research, how it compares to traditional statistics, the types of datasets it uses and the general workflow. Moreover, we identify the technical barriers and challenges of ML implementations in clinical practice. Overall, this review provides a comprehensive understanding of ML with non-technical explanations for broader accessibility to biomedical scientists and clinicians.
一些(国家间)纵向痴呆症观察数据集涵盖了人口统计学信息、神经影像学、生物标记物、神经心理学评估和突变组学数据,为将机器学习(ML)融入痴呆症研究和临床实践开创了一个新时代。机器学习能熟练处理多模态和高维数据,已成为促进早期诊断、鉴别诊断以及预测轻度认知障碍和痴呆症发病和进展的创新技术。在这篇综述中,我们将评估 ML 的当前和潜在应用,包括其在痴呆症研究中的历史、与传统统计学的比较、使用的数据集类型以及一般工作流程。此外,我们还指出了在临床实践中实施 ML 的技术障碍和挑战。总之,这篇综述提供了对 ML 的全面了解,并提供了非技术性的解释,使生物医学科学家和临床医生更容易理解。
{"title":"Understanding machine learning applications in dementia research and clinical practice: a review for biomedical scientists and clinicians.","authors":"Yihan Wang, Shu Liu, Alanna G Spiteri, Andrew Liem Hieu Huynh, Chenyin Chu, Colin L Masters, Benjamin Goudey, Yijun Pan, Liang Jin","doi":"10.1186/s13195-024-01540-6","DOIUrl":"10.1186/s13195-024-01540-6","url":null,"abstract":"<p><p>Several (inter)national longitudinal dementia observational datasets encompassing demographic information, neuroimaging, biomarkers, neuropsychological evaluations, and muti-omics data, have ushered in a new era of potential for integrating machine learning (ML) into dementia research and clinical practice. ML, with its proficiency in handling multi-modal and high-dimensional data, has emerged as an innovative technique to facilitate early diagnosis, differential diagnosis, and to predict onset and progression of mild cognitive impairment and dementia. In this review, we evaluate current and potential applications of ML, including its history in dementia research, how it compares to traditional statistics, the types of datasets it uses and the general workflow. Moreover, we identify the technical barriers and challenges of ML implementations in clinical practice. Overall, this review provides a comprehensive understanding of ML with non-technical explanations for broader accessibility to biomedical scientists and clinicians.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":null,"pages":null},"PeriodicalIF":7.9,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11293066/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141858766","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-01DOI: 10.1186/s13195-024-01547-z
Antoine Garnier-Crussard
Since 2014, sacubitril/valsartan (Entresto®) is widely prescribed for heart failure. Despite neprilysin inhibition’s benefits in heart failure, concerns about potential amyloid-beta (Aβ) accumulation and Alzheimer’s disease (AD) risk have persisted. This narrative review, a decade post-approval, evaluates the risk of amyloid pathology and neurocognitive disorders in long-term sacubitril/valsartan use. Clinical trials, real-world studies, and pharmacovigilance data do not indicate an increased risk of cognitive decline. In patients treated with sacubitril/valsartan blood-based amyloid biomarkers show perturbations, while neuroimaging biomarkers reveal no significant increase in amyloid load. Despite a theoretical risk of amyloid accumulation and AD under treatment with sacubitril/valsartan, current clinical data appears reassuring, and there is no signal indicating an increased risk of cognitive decline, but a perturbation of amyloid blood-based biomarkers, which implies great caution when interpreting biomarkers in this context.
{"title":"Association between treatment with sacubitril/valsartan and the risk of Alzheimer’s disease: a clinical update","authors":"Antoine Garnier-Crussard","doi":"10.1186/s13195-024-01547-z","DOIUrl":"https://doi.org/10.1186/s13195-024-01547-z","url":null,"abstract":"Since 2014, sacubitril/valsartan (Entresto®) is widely prescribed for heart failure. Despite neprilysin inhibition’s benefits in heart failure, concerns about potential amyloid-beta (Aβ) accumulation and Alzheimer’s disease (AD) risk have persisted. This narrative review, a decade post-approval, evaluates the risk of amyloid pathology and neurocognitive disorders in long-term sacubitril/valsartan use. Clinical trials, real-world studies, and pharmacovigilance data do not indicate an increased risk of cognitive decline. In patients treated with sacubitril/valsartan blood-based amyloid biomarkers show perturbations, while neuroimaging biomarkers reveal no significant increase in amyloid load. Despite a theoretical risk of amyloid accumulation and AD under treatment with sacubitril/valsartan, current clinical data appears reassuring, and there is no signal indicating an increased risk of cognitive decline, but a perturbation of amyloid blood-based biomarkers, which implies great caution when interpreting biomarkers in this context.","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":null,"pages":null},"PeriodicalIF":9.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141873025","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-01DOI: 10.1186/s13195-024-01543-3
Rosanne L. van den Berg, Casper de Boer, Marissa D. Zwan, Roos J. Jutten, Mariska van Liere, Marie-Christine A.B.J. van de Glind, Mark A. Dubbelman, Lisa Marie Schlüter, Argonde C. van Harten, Charlotte E. Teunissen, Elsmarieke van de Giessen, Frederik Barkhof, Lyduine E. Collij, Jessica Robin, William Simpson, John E Harrison, Wiesje M. van der Flier, Sietske A.M. Sikkes
Digital speech assessment has potential relevance in the earliest, preclinical stages of Alzheimer’s disease (AD). We evaluated the feasibility, test-retest reliability, and association with AD-related amyloid-beta (Aβ) pathology of speech acoustics measured over multiple assessments in a remote setting. Fifty cognitively unimpaired adults (Age 68 ± 6.2 years, 58% female, 46% Aβ-positive) completed remote, tablet-based speech assessments (i.e., picture description, journal-prompt storytelling, verbal fluency tasks) for five days. The testing paradigm was repeated after 2–3 weeks. Acoustic speech features were automatically extracted from the voice recordings, and mean scores were calculated over the 5-day period. We assessed feasibility by adherence rates and usability ratings on the System Usability Scale (SUS) questionnaire. Test-retest reliability was examined with intraclass correlation coefficients (ICCs). We investigated the associations between acoustic features and Aβ-pathology, using linear regression models, adjusted for age, sex and education. The speech assessment was feasible, indicated by 91.6% adherence and usability scores of 86.0 ± 9.9. High reliability (ICC ≥ 0.75) was found across averaged speech samples. Aβ-positive individuals displayed a higher pause-to-word ratio in picture description (B = -0.05, p = 0.040) and journal-prompt storytelling (B = -0.07, p = 0.032) than Aβ-negative individuals, although this effect lost significance after correction for multiple testing. Our findings support the feasibility and reliability of multi-day remote assessment of speech acoustics in cognitively unimpaired individuals with and without Aβ-pathology, which lays the foundation for the use of speech biomarkers in the context of early AD.
{"title":"Digital remote assessment of speech acoustics in cognitively unimpaired adults: feasibility, reliability and associations with amyloid pathology","authors":"Rosanne L. van den Berg, Casper de Boer, Marissa D. Zwan, Roos J. Jutten, Mariska van Liere, Marie-Christine A.B.J. van de Glind, Mark A. Dubbelman, Lisa Marie Schlüter, Argonde C. van Harten, Charlotte E. Teunissen, Elsmarieke van de Giessen, Frederik Barkhof, Lyduine E. Collij, Jessica Robin, William Simpson, John E Harrison, Wiesje M. van der Flier, Sietske A.M. Sikkes","doi":"10.1186/s13195-024-01543-3","DOIUrl":"https://doi.org/10.1186/s13195-024-01543-3","url":null,"abstract":"Digital speech assessment has potential relevance in the earliest, preclinical stages of Alzheimer’s disease (AD). We evaluated the feasibility, test-retest reliability, and association with AD-related amyloid-beta (Aβ) pathology of speech acoustics measured over multiple assessments in a remote setting. Fifty cognitively unimpaired adults (Age 68 ± 6.2 years, 58% female, 46% Aβ-positive) completed remote, tablet-based speech assessments (i.e., picture description, journal-prompt storytelling, verbal fluency tasks) for five days. The testing paradigm was repeated after 2–3 weeks. Acoustic speech features were automatically extracted from the voice recordings, and mean scores were calculated over the 5-day period. We assessed feasibility by adherence rates and usability ratings on the System Usability Scale (SUS) questionnaire. Test-retest reliability was examined with intraclass correlation coefficients (ICCs). We investigated the associations between acoustic features and Aβ-pathology, using linear regression models, adjusted for age, sex and education. The speech assessment was feasible, indicated by 91.6% adherence and usability scores of 86.0 ± 9.9. High reliability (ICC ≥ 0.75) was found across averaged speech samples. Aβ-positive individuals displayed a higher pause-to-word ratio in picture description (B = -0.05, p = 0.040) and journal-prompt storytelling (B = -0.07, p = 0.032) than Aβ-negative individuals, although this effect lost significance after correction for multiple testing. Our findings support the feasibility and reliability of multi-day remote assessment of speech acoustics in cognitively unimpaired individuals with and without Aβ-pathology, which lays the foundation for the use of speech biomarkers in the context of early AD.","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":null,"pages":null},"PeriodicalIF":9.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141863789","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-01DOI: 10.1186/s13195-024-01537-1
Noor Abdulhameed, Alice Babin, Kim Hansen, Riley Weaver, William A Banks, Konrad Talbot, Elizabeth M Rhea
Targeting brain insulin resistance (BIR) has become an attractive alternative to traditional therapeutic treatments for Alzheimer's disease (AD). Incretin receptor agonists (IRAs), targeting either or both of the glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors, have proven to reverse BIR and improve cognition in mouse models of AD. We previously showed that many, but not all, IRAs can cross the blood-brain barrier (BBB) after intravenous (IV) delivery. Here we determined if widespread brain uptake of IRAs could be achieved by circumventing the BBB using intranasal (IN) delivery, which has the added advantage of minimizing adverse gastrointestinal effects of systemically delivered IRAs. Of the 5 radiolabeled IRAs tested (exenatide, dulaglutide, semaglutide, DA4-JC, and DA5-CH) in CD-1 mice, exenatide, dulaglutide, and DA4-JC were successfully distributed throughout the brain following IN delivery. We observed significant sex differences in uptake for DA4-JC. Dulaglutide and DA4-JC exhibited high uptake by the hippocampus and multiple neocortical areas. We further tested and found the presence of AD-associated Aβ pathology minimally affected uptake of dulaglutide and DA4-JC. Of the 5 tested IRAs, dulaglutide and DA4-JC are best capable of accessing brain regions most vulnerable in AD (neocortex and hippocampus) after IN administration. Future studies will need to be performed to determine if IN IRA delivery can reduce BIR in AD or animal models of that disorder.
针对脑胰岛素抵抗(BIR)的治疗已成为阿尔茨海默病(AD)传统疗法的一种有吸引力的替代疗法。事实证明,以胰高血糖素样肽 1(GLP-1)和葡萄糖依赖性促胰岛素多肽(GIP)受体中的一种或两种受体为靶点的胰岛素受体激动剂(IRAs)可以逆转胰岛素抵抗并改善 AD 小鼠模型的认知能力。我们以前的研究表明,静脉注射后,许多(但不是所有)IRA 可以穿过血脑屏障(BBB)。在这里,我们确定了是否可以通过鼻内给药绕过血脑屏障来实现脑部对 IRAs 的广泛吸收,鼻内给药的另一个优点是可以最大程度地减少全身给药对胃肠道的不良影响。在CD-1小鼠体内测试的5种放射性标记IRA(艾塞那肽、度拉鲁肽、赛马鲁肽、DA4-JC和DA5-CH)中,艾塞那肽、度拉鲁肽和DA4-JC在IN给药后成功分布于整个大脑。我们观察到 DA4-JC 的摄取存在明显的性别差异。杜拉鲁肽和 DA4-JC 在海马和多个新皮质区域表现出较高的摄取率。我们进一步测试发现,AD 相关 Aβ 病理学的存在对度拉鲁肽和 DA4-JC 的摄取影响很小。在测试的5种IRA中,杜拉鲁肽和DA4-JC在IN给药后最能进入AD最脆弱的脑区(新皮质和海马)。未来还需要进行研究,以确定 IN IRA 给药是否能减少注意力缺失症或该疾病动物模型的 BIR。
{"title":"Comparing regional brain uptake of incretin receptor agonists after intranasal delivery in CD-1 mice and the APP/PS1 mouse model of Alzheimer's disease.","authors":"Noor Abdulhameed, Alice Babin, Kim Hansen, Riley Weaver, William A Banks, Konrad Talbot, Elizabeth M Rhea","doi":"10.1186/s13195-024-01537-1","DOIUrl":"10.1186/s13195-024-01537-1","url":null,"abstract":"<p><p>Targeting brain insulin resistance (BIR) has become an attractive alternative to traditional therapeutic treatments for Alzheimer's disease (AD). Incretin receptor agonists (IRAs), targeting either or both of the glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors, have proven to reverse BIR and improve cognition in mouse models of AD. We previously showed that many, but not all, IRAs can cross the blood-brain barrier (BBB) after intravenous (IV) delivery. Here we determined if widespread brain uptake of IRAs could be achieved by circumventing the BBB using intranasal (IN) delivery, which has the added advantage of minimizing adverse gastrointestinal effects of systemically delivered IRAs. Of the 5 radiolabeled IRAs tested (exenatide, dulaglutide, semaglutide, DA4-JC, and DA5-CH) in CD-1 mice, exenatide, dulaglutide, and DA4-JC were successfully distributed throughout the brain following IN delivery. We observed significant sex differences in uptake for DA4-JC. Dulaglutide and DA4-JC exhibited high uptake by the hippocampus and multiple neocortical areas. We further tested and found the presence of AD-associated Aβ pathology minimally affected uptake of dulaglutide and DA4-JC. Of the 5 tested IRAs, dulaglutide and DA4-JC are best capable of accessing brain regions most vulnerable in AD (neocortex and hippocampus) after IN administration. Future studies will need to be performed to determine if IN IRA delivery can reduce BIR in AD or animal models of that disorder.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":null,"pages":null},"PeriodicalIF":7.9,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11293113/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141858764","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}