多系统萎缩的边缘阿尔茨海默病共病理与认知障碍和诊断不准确有关

IF 9.3 1区 医学 Q1 CLINICAL NEUROLOGY
Janna van Wetering, Natasja A. C. Deshayes, Joëlle Boone, Inês Rodrigues Fernandes, Dagmar H. Hepp, Henk W. Berendse, Laura E. Jonkman, Annemieke J. M. Rozemuller, Wilma D. J. van de Berg
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引用次数: 0

摘要

多系统萎缩(MSA)的临床异质性可能与α-突触核蛋白(α-syn)的原发性聚集在一起,部分由淀粉样蛋白- β (Aβ)、磷酸化(p)-tau和pTDP-43等共病理形成,尽管它们的相关性尚不清楚。在这里,我们的目的是在一个特征明确的MSA尸检队列中描述患病率、形态、区域模式和共同病理的临床相关性。我们对来自荷兰脑库的70例MSA供体的边缘区α-syn (KM51)、a - β (6F/3D)、p-tau (AT8)和pTDP-43 (pSer409)病理进行了区域负荷(%area)和形态学表征。收集该队列患者APOE-ε4基因分型及临床参数。使用ANCOVA和混合线性模型分析与临床特征的关联,并根据年龄和性别进行调整。在所有MSA病例中,分别有31%、91%和11%的患者检测到Aβ、p-tau和pTDP-43的病理变化,其中内嗅皮层和杏仁核的负荷最高。与单纯MSA相比,MSA + AD混合病例的死亡年龄更高(75±7比64±7,p < 0.001), APOE-ε4等位基因频率更高(p < 0.001)。认知障碍(CDR评分)与所有区域的弥漫性和致密性β斑块(r≥0.24,p≤0.015)、CA1和CA3 + 4的p-tau病理(r≥0.32,p≤0.020)和杏仁核的神经元α-syn包涵体(r = 0.54, p < 0.001)相关。α-syn总负荷与α β或p-tau之间无显著相关性。误诊率随着共同病理负担(Aβ: p = 0.040; p-tau: p = 0.020)和发病年龄(发病≥75岁者占80%)的增加而增加。我们的研究结果表明,边缘a β、p-tau和神经元α-syn病变发生在相当大比例的MSA供体中,并且与认知能力下降和诊断不准确独立相关,特别是在发病年龄较大的患者中。通过对MSA边缘区域的共同病理进行系统的定量和形态学评估,我们的研究超越了之前的患病率报告,并强调了它们的直接临床相关性。这些发现强调了对MSA的精确诊断标准和共同病理信息的生物标志物策略的需求。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Limbic Alzheimer’s co-pathology in multiple system atrophy is associated with cognitive impairment and diagnostic inaccuracy

The clinical heterogeneity of multiple system atrophy (MSA) may, along with the primary aggregation of alpha-synuclein (α-syn), partly be shaped by co-pathologies, such as amyloid-beta (Aβ), phosphorylated (p)-tau, and pTDP-43, though their relevance remains unclear. Here, we aimed to characterize the prevalence, morphology, regional patterns, and clinical relevance of co-pathologies in a well-characterized MSA autopsy cohort. Regional load (%area) and morphological characterization of α-syn (KM51), Aβ (6F/3D), p-tau (AT8), and pTDP-43 (pSer409) pathology were assessed in limbic regions of MSA (n = 70) donors from the Netherlands Brain Bank. APOE-ε4 genotyping and clinical parameters of the cohort were collected. Associations with clinical features were analyzed using ANCOVA and mixed linear models, adjusted for age and sex. Aβ, p-tau, and pTDP-43 pathology were detected in 31%, 91%, and 11% of all MSA cases, respectively, with the highest burdens in the entorhinal cortex and amygdala. Mixed MSA + AD cases had a higher age at death (75 ± 7 vs. 64 ± 7, p < 0.001), and more frequently APOE-ε4 alleles (p < 0.001) than pure MSA. Cognitive impairment (CDR scores) was associated with diffuse and compact Aβ plaques across all regions (r ≥ 0.24, p ≤ 0.015), p-tau pathology in CA1 and CA3 + 4 (r ≥ 0.32, p ≤ 0.020), and neuronal α-syn inclusions in the amygdala (r = 0.54, p < 0.001). No robust correlations were found between total α-syn burden and Aβ or p-tau. Misdiagnoses increased with co-pathology burden (Aβ: p = 0.040; p-tau: p = 0.020) and age at onset (80% in those with onset > 75 years). Our results demonstrate that limbic Aβ, p-tau, and neuronal α-syn pathologies occur in a substantial proportion of MSA donors and are independently associated with cognitive decline and diagnostic inaccuracy, particularly among those with older age at onset. By providing a systematic quantitative and morphological assessment of co-pathologies in limbic regions of MSA, our study advances beyond prior prevalence reports and highlights their direct clinical relevance. These findings highlight the need for refined diagnostic criteria and co-pathology-informed biomarker strategies for MSA.

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来源期刊
Acta Neuropathologica
Acta Neuropathologica 医学-病理学
CiteScore
23.70
自引率
3.90%
发文量
118
审稿时长
4-8 weeks
期刊介绍: Acta Neuropathologica publishes top-quality papers on the pathology of neurological diseases and experimental studies on molecular and cellular mechanisms using in vitro and in vivo models, ideally validated by analysis of human tissues. The journal accepts Original Papers, Review Articles, Case Reports, and Scientific Correspondence (Letters). Manuscripts must adhere to ethical standards, including review by appropriate ethics committees for human studies and compliance with principles of laboratory animal care for animal experiments. Failure to comply may result in rejection of the manuscript, and authors are responsible for ensuring accuracy and adherence to these requirements.
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