Comparison of CSF biomarkers in Down syndrome and autosomal dominant Alzheimer's disease: a cross-sectional study,The Lancet Neurology

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Comparison of CSF biomarkers in Down syndrome and autosomal dominant Alzheimer's disease: a cross-sectional study
The Lancet Neurology ( IF 48.0 ) Pub Date : 2021-07-21 , DOI: 10.1016/s1474-4422(21)00139-3
Anne M Fagan ₁ , Rachel L Henson ₁ , Yan Li ₁ , Anna H Boerwinkle ₁ , Chengjie Xiong ₂ , Randall J Bateman ₁ , Alison Goate ₃ , Beau M Ances ₁ , Eric Doran ₄ , Bradley T Christian ₅ , Florence Lai ₆ , H Diana Rosas ₆ , Nicole Schupf ₇ , Sharon Krinsky-McHale ₈ , Wayne Silverman ₄ , Joseph H Lee ₇ , William E Klunk ₉ , Benjamin L Handen ₉ , Ricardo F Allegri ₁₀ , Jasmeer P Chhatwal ₆ , Gregory S Day ₁₁ , Neill R Graff-Radford ₁₁ , Mathias Jucker ₁₂ , Johannes Levin ₁₃ , Ralph N Martins ₁₄ , Colin L Masters ₁₅ , Hiroshi Mori ₁₆ , Catherine J Mummery ₁₇ , Yoshiki Niimi ₁₈ , John M Ringman ₁₉ , Stephen Salloway ₂₀ , Peter R Schofield ₂₁ , Mikio Shoji ₂₂ , Ira T Lott ₄ , ,

Affiliation

Department of Neurology, Washington University School of Medicine, St Louis, MO, USA.
Division of Biostatistics, Washington University School of Medicine, St Louis, MO, USA.
Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Department of Pediatrics, UC Irvine School of Medicine, Irvine, CA, USA.
Department of Medical Physics, Waisman Center, University of Wisconsin-Madison, Madison, WI, USA; Department of Psychiatry, Waisman Center, University of Wisconsin-Madison, Madison, WI, USA.
Department of Neurology, Harvard Medical School, Massachusetts General Hospital, Boston, MA, USA.
Department of Epidemiology, Columbia University Irving Medical Center, New York, NY, USA; Department of Neurology, Columbia University Irving Medical Center, New York, NY, USA.
New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY, USA.
Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA.
Department of Cognitive Neurology, Instituto Neurologico Fleni, Buenos Aires, Argentina.
Department of Neurology, Mayo Clinic Florida, Jacksonville, FL, USA.
Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany; German Center for Neurodegenerative Diseases, Tübingen, Germany.
Department of Neurology, Ludwig-Maximilians-Universität München, German Center for Neurodegenerative Diseases, Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
School of Medical Health and Sciences, Edith Cowan University, Joondalup, WA, Australia.
Florey Institute, Melbourne, VIC, Australia; University of Melbourne, Melbourne, VIC, Australia.
Department of Clinical Neuroscience, Osaka City University Medical School, Abenoku, Osaka, Japan.
Dementia Research Centre, Institute of Neurology, University College London, London, UK.
Unit for Early and Exploratory Clinical Development, University of Tokyo, Tokyo, Japan.
Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
Memory and Aging Program, Brown University, Butler Hospital, Providence, RI, USA.
Neuroscience Research Australia, School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia.
Geriatrics Research Institute and Hospital, Maebashi, Gunma, Japan.

Background

Due to trisomy of chromosome 21 and the resultant extra copy of the amyloid precursor protein gene, nearly all adults with Down syndrome develop Alzheimer's disease pathology by the age of 40 years and are at high risk for dementia given their increased life expectancy compared with adults with Down syndrome in the past. We aimed to compare CSF biomarker patterns in Down syndrome with those of carriers of autosomal dominant Alzheimer's disease mutations to enhance our understanding of disease mechanisms in these two genetic groups at high risk for Alzheimer's disease.

Methods

We did a cross-sectional study using data from adults enrolled in the Alzheimer's Biomarker Consortium-Down Syndrome (ABC-DS) study, a multisite longitudinal study of Alzheimer's disease in Down syndrome, as well as a cohort of carriers of autosomal dominant Alzheimer's disease mutations and non-carrier sibling controls enrolled in the Dominantly Inherited Alzheimer Network (DIAN) study. For ABC-DS, participants with baseline CSF, available clinical diagnosis, and apolipoprotein E genotype as of Jan 31, 2019, were included in the analysis. DIAN participants with baseline CSF, available clinical diagnosis, and apolipoprotein E genotype as of June 30, 2018, were evaluated as comparator groups. CSF samples obtained from adults with Down syndrome, similarly aged carriers of autosomal dominant Alzheimer's disease mutations, and non-carrier siblings (aged 30–61 years) were analysed for markers of amyloid β (Aβ_1–40, Aβ_1–42); tau phosphorylated at threonine 181-related processes; neuronal, axonal, or synaptic injury (total tau, visinin-like protein 1, neurofilament light chain [NfL], synaptosomal-associated protein 25); and astrogliosis and neuroinflammation (chitinase-3-like protein 1 [YKL-40]) via immunoassay. Biomarker concentrations were compared as a function of dementia status (asymptomatic or symptomatic), and linear regression was used to evaluate and compare the relationship between biomarker concentrations and age among groups.

Findings

We assessed CSF samples from 341 individuals (178 [52%] women, 163 [48%] men, aged 30–61 years). Participants were adults with Down syndrome (n=41), similarly aged carriers of autosomal dominant Alzheimer's disease mutations (n=192), and non-carrier siblings (n=108). Individuals with Down syndrome had patterns of Alzheimer's disease-related CSF biomarkers remarkably similar to carriers of autosomal dominant Alzheimer's disease mutations, including reductions (all p<0·0080) in Aβ_1–42 to Aβ_1–40 ratio and increases in markers of phosphorylated tau-related processes; neuronal, axonal, and synaptic injury (p<0·080); and astrogliosis and neuroinflammation, with greater degrees of abnormality in individuals with dementia. Differences included overall higher concentrations of Aβ and YKL-40 (both p<0·0008) in Down syndrome and potential elevations in CSF tau (p<0·010) and NfL (p<0·0001) in the asymptomatic stage (ie, no dementia symptoms).

Funding

National Institute on Aging, Eunice Kennedy Shriver National Institute of Child Health and Human Development, German Center for Neurodegenerative Diseases, and Japan Agency for Medical Research and Development.

中文翻译：

唐氏综合征和常染色体显性阿尔茨海默病中脑脊液生物标志物的比较：一项横断面研究

背景

由于 21 号染色体的三体性和由此产生的淀粉样前体蛋白基因的额外拷贝，几乎所有患有唐氏综合症的成年人都会在 40 岁时患上阿尔茨海默病，并且与患有痴呆症的成年人相比，他们的预期寿命更长，因此患痴呆症的风险很高。过去的唐氏综合症。我们的目的是比较唐氏综合症和常染色体显性阿尔茨海默病突变携带者的脑脊液生物标志物模式，以增强我们对这两个阿尔茨海默病高风险基因组疾病机制的理解。

方法

我们使用来自参加阿尔茨海默氏症生物标志物联盟-唐氏综合症 (ABC-DS) 研究的成年人的数据进行了一项横断面研究，该研究是一项针对唐氏综合症中阿尔茨海默病的多中心纵向研究，以及一组常染色体显性遗传的阿尔茨海默病携带者突变和非携带者兄弟姐妹对照参加了显性遗传的阿尔茨海默病网络 (DIAN) 研究。对于 ABC-DS，分析包括截至 2019 年 1 月 31 日具有基线 CSF、可用临床诊断和载脂蛋白 E 基因型的参与者。截至 2018 年 6 月 30 日，具有基线 CSF、可用临床诊断和载脂蛋白 E 基因型的 DIAN 参与者被评估为比较组。从患有唐氏综合症的成年人获得的脑脊液样本，同样年龄的常染色体显性阿尔茨海默病突变携带者，_1-40 , Aβ _1-42 ); tau 在苏氨酸 181 相关过程中被磷酸化；神经元、轴突或突触损伤（总 tau、visinin 样蛋白 1、神经丝轻链 [NfL]、突触体相关蛋白 25）；通过免疫分析发现星形胶质细胞增生和神经炎症（几丁质酶 3 样蛋白 1 [YKL-40]）。将生物标志物浓度作为痴呆状态（无症状或有症状）的函数进行比较，并使用线性回归来评估和比较生物标志物浓度与组间年龄之间的关系。

发现

我们评估了 341 名个体（178 名 [52%] 女性，163 名 [48%] 男性，年龄 30-61 岁）的 CSF 样本。参与者是患有唐氏综合症的成年人（n = 41）、年龄相近的常染色体显性阿尔茨海默病突变携带者（n = 192）和非携带者兄弟姐妹（n = 108）。患有唐氏综合症的个体与阿尔茨海默病相关的脑脊液生物标志物的模式与常染色体显性阿尔茨海默病突变的携带者非常相似，包括 Aβ _1-42到 Aβ _{1-40的减少（所有 p<0·0080）}磷酸化 tau 相关过程的标志物的比率和增加；神经元、轴突和突触损伤 (p<0·080)；和星形胶质细胞增生和神经炎症，痴呆患者的异常程度更大。差异包括唐氏综合征中 Aβ 和 YKL-40 的总体浓度较高（均 p<0·0008）以及无症状阶段（即，没有痴呆症状）。