Aging and Dementia in Adults with Down Syndrome

唐氏综合症成人的衰老和痴呆

• 批准号: 8678955
• 负责人: WAYNE P. SILVERMAN
• 金额: $ 165.25万
• 依托单位: HUGO W. MOSER RES INST KENNEDY KRIEGER
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-02-05 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8678955
• 关键词: Academic Medical Centers; Activities of Daily Living; Address; Adult; Advisory Committees; Affect; Age; Age of Onset; Aging; Aging-Related Process; Alzheimer' s Disease; Alzheimer' s disease risk; Anemia; Area; Attention; Autoimmunity; Basic Science; Biological; Biological Markers; Biometry; Blood Cells; Blood specimen; Brain; Candidate Disease Gene; Characteristics; Chromosomes; Chromosomes, Human, Pair 21; Classification; Clinical; Cognition; Cognitive; Collaborations; Collection; Consensus; DNA Methylation; Data; Data Collection; Data Set; Dementia; Development; Developmental Disabilities; Diagnostic; Discipline; Disease; Disease Progression; Down Syndrome; Early Diagnosis; Elderly; Epigenetic Process; Funding; General Population; Genetic; Genetic Markers; Genotype; Goals; Hand; Health; Health Status; Impaired cognition; Individual; Individual Differences; Infection; Institutes; Insulin Resistance; Intellectual functioning disability; Laboratories; Leadership; Leukocytes; Life Expectancy; Longevity; Measures; Metabolic syndrome; Methods; Monitor; Nature; New York; Older Population; Participant; Pathogenesis; Pattern; Phenotype; Population; Populations at Risk; Procedures; Process; Productivity; Progress Reports; Property; Psychometrics; Recurrence; Reporting; Research; Research Personnel; Research Project Grants; Risk; Risk Factors; Role; Sample Size; Sampling; Sensitivity and Specificity; Single Nucleotide Polymorphism; Staging; Symptoms; Target Populations; Tissue Banking; Tissue Banks; Universities; Validation; Variant; Work; age effect; base; cognitive change; effective intervention; experience; functional status; genetic epidemiology; genetic risk factor; insight; interest; medical schools; mild cognitive impairment; multidisciplinary; neuropathology; normal aging; programs; tool

The program of research focusing on adults with Down syndrome (DS), ongoing since 1987, will be continued, now consisting of four projects supported by three cores. While all of the projects have clear origins in the program's current activities, several new initiatives are included. The investigators will: (a) determine if individual differences in risk for Alzheimer's disease (AD) within the elderly population with DS is associated with insulin resistance and other features of metabolic syndrome; (b) develop empirically validated methods for identifying the presence of mild cognitive impairment (MCI) in adults with DS, differentiating this condition from cognitive changes associated with developmentally appropriate aging, per se; (c) determine the role of altered patterns of DNA methylation in DS pathogenesis and variation in phenotypic expression within this population, including selected aging-related processes; and (d) use independent datasets to evaluate the relations between age at onset of AD (as well as related phenotypic characteristics) and single nucleotide polymorphisms (SNPs) of approximately 60 candidate genes located on chromosome 21 as well as other chromosomes. As in the past, goals will be achieved through extensive collaborations among investigators representing multiple disciplines. Common assessment procedures, repeated at intervals of approximately 18 months, will be employed to characterize in detail the health, cognitive, and functional status of each of the 300 adults with DS actively participating in the program. Findings and biological samples from previous studies will also be available for the genetic and epigenetic studies now being proposed, bringing the total projected sample size to 788 adults with DS. Cognitive and functional changes will be related to selected biomarkers as well as genetic and epigenetic findings, providing a far richer description of this population than could occur in the context of any single research project. Findings should provide clear insights into: (a) mechanisms underlying important features of the DS phenotype, (b) individual differences in those features, (c) factors modifying risk for dementia, and (d) assessment methods that can inform diagnostic decisions relatively early in disease progression. Further, some findings may have direct implications for promoting more successful aging for adults with DS.

自 1987 年以来一直持续进行的针对成人唐氏综合症 (DS) 的研究计划将继续下去，目前由三个核心支持的四个项目组成。 虽然所有项目都有明确的起源于该计划当前的活动，但其中还包括一些新举措。 研究人员将：(a) 确定患有 DS 的老年人群中阿尔茨海默病 (AD) 风险的个体差异是否与胰岛素抵抗和代谢综合征的其他特征相关； (b) 开发经经验验证的方法来识别患有 DS 的成人是否存在轻度认知障碍（MCI），将这种情况与与发育适当的衰老相关的认知变化本身区分开来； (c) 确定 DNA 甲基化模式改变在 DS 发病机制中的作用以及该群体内表型表达的变化，包括选定的衰老相关过程； (d) 使用独立数据集评估 AD 发病年龄（以及相关表型特征）与位于 21 号染色体以及其他染色体上约 60 个候选基因的单核苷酸多态性 (SNP) 之间的关系。 与过去一样，目标将通过代表多个学科的研究人员之间的广泛合作来实现。 每隔大约 18 个月重复一次的通用评估程序将用于详细描述积极参与该计划的 300 名 DS 成人的健康、认知和功能状态。 先前研究的结果和生物样本也将可用于目前提议的遗传和表观遗传研究，使预计样本总数达到 788 名患有 DS 的成年人。 认知和功能变化将与选定的生物标志物以及遗传和表观遗传发现相关，从而为该人群提供比任何单一研究项目更丰富的描述。 研究结果应提供对以下方面的清晰见解：(a) DS 表型重要特征的机制，(b) 这些特征的个体差异，(c) 改变痴呆风险的因素，以及 (d) 可以在疾病进展相对早期为诊断决策提供信息的评估方法。 此外，一些研究结果可能对促进患有 DS 的成年人更成功地老龄化有直接影响。

项目成果

Cell type-specific over-expression of chromosome 21 genes in fibroblasts and fetal hearts with trisomy 21.

• DOI: 10.1186/1471-2350-7-24
• 发表时间: 2006-03-15
• 期刊: BMC MEDICAL GENETICS
• 作者: Li, CM;Guo, MR;Salas, M;Schupf, N;Silverman, W;Zigman, WB;Husain, S;Warburton, D;Thaker, H;Tycko, B
• 通讯作者: Tycko, B

Faithful tissue-specific expression of the human chromosome 21-linked COL6A1 gene in BAC-transgenic mice.

人类 21 号染色体连接的 COL6A1 基因在 BAC 转基因小鼠中忠实地组织特异性表达。

• DOI: 10.1007/s00335-006-0082-y
• 发表时间: 2007
• 期刊: Mammalian genome : official journal of the International Mammalian Genome Society
• 作者: Xing,Luzhou;Salas,Martha;Lin,Chyuan-Sheng;Zigman,Warren;Silverman,Wayne;Subramaniyam,Shivakumar;Murty,VundavalliV;Tycko,Benjamin
• 通讯作者: Tycko,Benjamin

Creation and characterization of BAC-transgenic mice with physiological overexpression of epitope-tagged RCAN1 (DSCR1).

• DOI: 10.1007/s00335-012-9436-9
• 发表时间: 2013-02
• 期刊: MAMMALIAN GENOME
• 影响因子: 2.5
• 作者: Xing, Luzhou;Salas, Martha;Zhang, Hong;Gittler, Julia;Ludwig, Thomas;Lin, Chyuan-Sheng;Murty, Vundavalli V.;Silverman, Wayne;Arancio, Ottavio;Tycko, Benjamin
• 通讯作者: Tycko, Benjamin

Trans effects of chromosome aneuploidies on DNA methylation patterns in human Down syndrome and mouse models.

• DOI: 10.1186/s13059-015-0827-6
• 发表时间: 2015-11-25
• 期刊: Genome biology
• 影响因子: 12.3
• 作者: Mendioroz M;Do C;Jiang X;Liu C;Darbary HK;Lang CF;Lin J;Thomas A;Abu-Amero S;Stanier P;Temkin A;Yale A;Liu MM;Li Y;Salas M;Kerkel K;Capone G;Silverman W;Yu YE;Moore G;Wegiel J;Tycko B
• 通讯作者: Tycko B

Plasma beta-amyloid and duration of Alzheimer's disease in adults with Down syndrome.

• DOI: 10.1002/gps.2321
• 发表时间: 2010-02
• 期刊: INTERNATIONAL JOURNAL OF GERIATRIC PSYCHIATRY
• 影响因子: 4
• 作者: Prasher, V. P.;Sajith, S. G.;Mehta, P.;Zigman, W. B.;Schupf, N.
• 通讯作者: Schupf, N.