Neuropathological and genetic correlates of survival and dementia onset in synucleinopathies: a retrospective analysis.
Neuropathological and genetic correlates of survival and dementia onset in synucleinopathies: a retrospective analysis.
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DOI：
10.1016/s1474-4422(16)30291-5
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发表时间：
2017-01
期刊：
影响因子：
48
通讯作者：
Trojanowski, John Q.
中科院分区：
文献类型：
--
作者：
Irwin, David;Grossman, Murray;Weintraub, Daniel;Hurtig, Howard I.;Duda, John E.;Xie, Sharon X.;Lee, Edward B.;Van Deerlin, Vivianna M.;Lopez, Oscar L.;Kofler, Julia K.;Nelson, Peter T.;Jicha, Gregory A.;Woltjer, Randy;Quinn, Joseph F.;Kaye, Jeffery;Leverenz, James B.;Tsuang, Debby;Longfellow, Katelan;Yearout, Dora;Kukull, Walter;Keene, C. Dirk;Montine, Thomas J.;Zabetian, Cyrus P.;Trojanowski, John Q.
路易体谱系障碍（Lewy body spectrum disorders，LBSD）患者的生存率和从运动症状到痴呆发作的时间间隔存在很大的异质性。本研究的目的是确定与LBSD临床异质性特征相关性最强的遗传学和病理学发现。在这项回顾性研究中，我们检查了从美国5个城市的5个临床研究中心招募的尸检证实为α-突触核蛋白病（截至2015年10月1日）的LBSD患者队列的症状发作、遗传和神经病理学数据。使用组织病理学技术和标记物，我们评估了tau神经元缠结、神经炎性斑块、α-突触核蛋白包涵体和皮质区域其他病理变化的负担，使用平均序数评分和与LBSD相关的变异的基因分型病例。我们评估了从运动症状发作到痴呆（MDI）的时间间隔和不同水平的共病阿尔茨海默病病理学（AD）组的总生存率，根据目前的国家老龄化研究所阿尔茨海默病协会神经病理学标准，并使用多变量回归控制死亡年龄和性别。本研究纳入了213例尸检后随访的患者，这些患者符合尸检证实的α-synculein病的临床LBSD入选标准。患者组的特征为无（n= 49，23%）、低水平（n= 56，26%）、中等水平（n= 45，21%）和高水平（n= 63，30%）AD神经病理学。在AD神经病理学水平升高的组中，大脑α-突触核蛋白评分较高，MDI较短，病程较短（均p<0.0001）。多变量回归发现大脑tau评分与MDI独立负相关（β= −4·0，95% CI −5·5至−2·6; p<0·0001）（R2=0·22，p<0·0001），且生存期（β=−2·0，95%CI −3·2至−0·8; p<0.0001）（R2=0·15，p<0·0001），包括死亡年龄、性别、脑神经炎斑块评分、脑α-突触核蛋白、脑血管疾病、MAPT单倍型，和APOE基因型作为协变量。AD神经病理学在LBSD中很常见，并且神经病理学变化的每一个增加水平都赋予更差的预后。脑神经元tau蛋白缠结负荷、α-突触核蛋白病理学和淀粉样斑块病理学是LBSD患者MDI较短和生存率最强的病理学预测因子。在未来，使用LBSD中AD神经病理学的可靠生物标志物的临床诊断标准应有助于确定最适合用于靶向tau、淀粉样蛋白-β或α-突触核蛋白的新兴疗法的临床试验的患者，并按AD神经病理学水平对其进行分层。NIH（NIA/NINDS）。
There exists great heterogeneity in patient survival and the time interval between motor symptom and dementia onset (MDI) across Lewy body spectrum disorders (LBSD). The goal of this study is to identify genetic and pathological findings that have the strongest association with these features of clinical heterogeneity in LBSD. In this retrospective study, we examined symptom onset, and genetic and neuropathological data from a cohort of LBSD patients with autopsy-confirmed α-synucleinopathy (as of Oct 1, 2015) recruited from 5 clinical research centres in 5 cities in the USA. Using histopathology techniques and markers, we assessed the burden of tau neurofibrillary tangles, neuritic plaques, α-synuclein inclusions, and other pathologic changes in cortical regions using averaged ordinal scores and genotyped cases for variants associated with LBSD. We evaluated the time interval from onset of motor symptoms to dementia (MDI) and overall survival in groups with varying levels of co-morbid Alzheimer’s disease pathology (AD) according to current National Institute on Aging–Alzheimer’s Association neuropathological criteria and used multivariate regression to control for age at death and gender. This study included 213 patients who had been followed to autopsy and met inclusion criteria of clinical LBSD with autopsy-confirmed α-synculeinopathy. Patient groups were characterized by no (n=49,23%), low-level (n=56,26%), intermediate-level (n=45,21%) or high-level (n=63,30%) AD neuropathology. Across groups of increasing levels of AD neuropathology, there were higher cerebral α-synuclein scores, shorter MDI, and shorter disease duration (p<0·0001 all). Multivariate regression found independent negative associations of cerebral tau score with MDI (β= −4·0, 95% CI −5·5 to −2·6; p<0·0001) (R2=0·22, p<0·0001) and with survival (β=−2·0, 95% CI −3·2 to −0·8; p<0·0001) (R2=0·15, p<0·0001) in models including age at death, gender, cerebral neuritic plaque scores, cerebral α-synuclein, presence of cerebrovascular disease, MAPT haplotype, and APOE genotype as covariates. AD neuropathology is common in LBSD and confers a worse prognosis for each increasing level of neuropathological change. Cerebral neurofibrillary tau tangle burden, α-synuclein pathology, and amyloid plaque pathology are the strongest pathological predictors of a shorter MDI and survival in LBSD. In the future, clinical diagnostic criteria which use reliable biomarkers for AD neuropathology in LBSD should help identify the most appropriate patients for clinical trials of emerging therapies targeting tau, amyloid-beta or α-synuclein, and stratify them by level of AD neuropathology. NIH (NIA/NINDS).