散发性早发性阿尔茨海默病的异质性临床表型:一种神经心理学数据驱动的方法。

IF 7.9 1区 医学 Q1 CLINICAL NEUROLOGY
Deepti Putcha, Yuta Katsumi, Alexandra Touroutoglou, Ani Eloyan, Alexander Taurone, Maryanne Thangarajah, Paul Aisen, Jeffrey L Dage, Tatiana Foroud, Clifford R Jack, Joel H Kramer, Kelly N H Nudelman, Rema Raman, Prashanthi Vemuri, Alireza Atri, Gregory S Day, Ranjan Duara, Neill R Graff-Radford, Ian M Grant, Lawrence S Honig, Erik C B Johnson, David T Jones, Joseph C Masdeu, Mario F Mendez, Erik Musiek, Chiadi U Onyike, Meghan Riddle, Emily Rogalski, Stephen Salloway, Sharon Sha, R Scott Turner, Thomas S Wingo, David A Wolk, Kyle Womack, Maria C Carrillo, Gil D Rabinovici, Bradford C Dickerson, Liana G Apostolova, Dustin B Hammers
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引用次数: 0

摘要

背景:早发性阿尔茨海默病(EOAD)和晚发性阿尔茨海默病的临床表现不同,EOAD的病程更具侵袭性,异质性更大。最近来自纵向早发性阿尔茨海默病研究(LEADS)的出版物将EOAD描述为主要的健忘症,尽管这种表型描述仅基于临床判断。为了更好地了解EOAD表现的表型范围,我们应用神经心理学数据驱动方法对LEADS队列进行亚型分析。方法:分析169例淀粉样蛋白阳性EOAD参与者的神经心理测试表现。使用98名认知正常参与者的样本进行教育校正的规范比较。比较每个认知领域之间的相对损伤水平,我们采用比所有其他领域得分低1 SD的截止值来表示给定认知领域的“显性”损伤表型。个体被认为有多域损伤。将皮质萎缩的全皮质一般线性模型应用于基于mri的这些不同临床表型的验证。结果:我们确定了EOAD的6种表型亚型:执行障碍显性(占样本的22%)、遗忘显性(11%)、语言显性(11%)、视觉空间显性(15%)、混合性遗忘/执行障碍显性(11%)和多域(30%)。这些表型不受年龄、性别或受教育年限的影响。APOE / 4基因型在遗忘显性组中富集,也被评为受损程度最低的组。皮质厚度分析证实了这些临床表型,在执行障碍和遗忘优势组之间观察到的萎缩模式分离。与我们的神经心理学数据驱动方法观察到的异质性相反,同一样本的诊断分类仅基于临床判断表明82%的个体为遗忘为主,9%为非遗忘,4%符合后皮质萎缩标准,5%符合原发性进行性失语症标准。结论:与单独的临床判断相比,对EOAD个体进行表型分析的神经心理学数据驱动方法揭示了对该非典型AD样本中呈现的异质性的更详细的了解。临床医生和患者可能会以牺牲非记忆症状为代价而过度报告记忆功能障碍。这些发现对诊断准确性和治疗考虑具有重要意义。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Heterogeneous clinical phenotypes of sporadic early-onset Alzheimer's disease: a neuropsychological data-driven approach.

Background: The clinical presentations of early-onset Alzheimer's disease (EOAD) and late-onset Alzheimer's disease are distinct, with EOAD having a more aggressive disease course with greater heterogeneity. Recent publications from the Longitudinal Early-Onset Alzheimer's Disease Study (LEADS) described EOAD as predominantly amnestic, though this phenotypic description was based solely on clinical judgment. To better understand the phenotypic range of EOAD presentation, we applied a neuropsychological data-driven method to subtype the LEADS cohort.

Methods: Neuropsychological test performance from 169 amyloid-positive EOAD participants were analyzed. Education-corrected normative comparisons were made using a sample of 98 cognitively normal participants. Comparing the relative levels of impairment between each cognitive domain, we applied a cut-off of 1 SD below all other domain scores to indicate a phenotype of "predominant" impairment in a given cognitive domain. Individuals were otherwise considered to have multidomain impairment. Whole-cortex general linear modeling of cortical atrophy was applied as an MRI-based validation of these distinct clinical phenotypes.

Results: We identified 6 phenotypic subtypes of EOAD: Dysexecutive Predominant (22% of sample), Amnestic Predominant (11%), Language Predominant (11%), Visuospatial Predominant (15%), Mixed Amnestic/Dysexecutive Predominant (11%), and Multidomain (30%). These phenotypes did not differ by age, sex, or years of education. The APOE ɛ4 genotype was enriched in the Amnestic Predominant group, who were also rated as least impaired. Cortical thickness analysis validated these clinical phenotypes with dissociations in atrophy patterns observed between the Dysexecutive and Amnestic Predominant groups. In contrast to the heterogeneity observed from our neuropsychological data-driven approach, diagnostic classifications for this same sample based solely on clinical judgment indicated that 82% of individuals were amnestic-predominant, 9% were non-amnestic, 4% met criteria for Posterior Cortical Atrophy, and 5% met criteria for Primary Progressive Aphasia.

Conclusion: A neuropsychological data-driven method to phenotype EOAD individuals uncovered a more detailed understanding of the presenting heterogeneity in this atypical AD sample compared to clinical judgment alone. Clinicians and patients may over-report memory dysfunction at the expense of non-memory symptoms. These findings have important implications for diagnostic accuracy and treatment considerations.

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来源期刊
Alzheimer's Research & Therapy
Alzheimer's Research & Therapy 医学-神经病学
CiteScore
13.10
自引率
3.30%
发文量
172
审稿时长
>12 weeks
期刊介绍: Alzheimer's Research & Therapy is an international peer-reviewed journal that focuses on translational research into Alzheimer's disease and other neurodegenerative diseases. It publishes open-access basic research, clinical trials, drug discovery and development studies, and epidemiologic studies. The journal also includes reviews, viewpoints, commentaries, debates, and reports. All articles published in Alzheimer's Research & Therapy are included in several reputable databases such as CAS, Current contents, DOAJ, Embase, Journal Citation Reports/Science Edition, MEDLINE, PubMed, PubMed Central, Science Citation Index Expanded (Web of Science) and Scopus.
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