Pathological α-synuclein distribution in subjects with coincident Alzheimer's and Lewy body pathology
Pathological α-synuclein distribution in subjects with coincident Alzheimer's and Lewy body pathology
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DOI：
10.1007/s00401-015-1526-9
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发表时间：
2016-03-01
影响因子：
12.7
通讯作者：
Trojanowski, John Q.
中科院分区：
文献类型：
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作者：
Toledo, Jon B.;Gopal, Pallavi;Trojanowski, John Q.
我们使用数据驱动的聚类方法研究了路易体相关病理学（LRP）的分布模式和同时阿尔茨海默病（AD）病理学的影响，该方法在两个队列中识别具有不同LRP病理学分布的组，而无需任何诊断或研究人员的输入，包括：帕金森病患者无AD患者（PD，n = 141）和AD患者（PD-AD，n = 80）、无AD的路易体痴呆受试者（DLB，n = 13）和有AD和LRP病理的痴呆受试者（Dem-AD-LB，n = 308）。Dem-AD-LB组表现出两种LRP模式，嗅觉-杏仁核和边缘LRP，脑干病理可忽略不计，这在PD组中不存在，目前不包括在DLB分期系统中，并且与PD组相比缺乏颅外LRP。Dem-AD-LB个体表现出黑质细胞和壳核中多巴胺活性转运蛋白的相对保留。患有AD病理的PD病例显示LRP增加。在Dem-AD-LB组中，枕叶LRP簇与非AD型痴呆临床诊断相关，在PD组中与更快进展为痴呆相关。我们发现（1）Dem-AD-LB中的LRP病理显示出与PD不同的分布，在初始阶段没有显著的脑干或颅外LRP;（2）同时的AD病理与PD中的LRP增加相关，表明相互作用;（3）LRP和并发AD病理独立预测PD进展为痴呆，和（4）LRP的评估需要承认不同的LRP扩散模式，并在神经病理学评估中评估黑质的完整性，并考虑神经病理学异质性对临床和生物标志物表征的影响。
We investigated the distribution patterns of Lewy body-related pathology (LRP) and the effect of coincident Alzheimer disease (AD) pathology using a data-driven clustering approach that identified groups with different LRP pathology distributions without any diagnostic or researcher's input in two cohorts including: Parkinson disease patients without (PD, n = 141) and with AD (PD-AD, n = 80), dementia with Lewy bodies subjects without AD (DLB, n = 13) and demented subjects with AD and LRP pathology (Dem-AD-LB, n = 308). The Dem-AD-LB group presented two LRP patterns, olfactory-amygdala and limbic LRP with negligible brainstem pathology, that were absent in the PD groups, which are not currently included in the DLB staging system and lacked extracranial LRP as opposed to the PD group. The Dem-AD-LB individuals showed relative preservation of substantia nigra cells and dopamine active transporter in putamen. PD cases with AD pathology showed increased LRP. The cluster with occipital LRP was associated with non-AD type dementia clinical diagnosis in the Dem-AD-LB group and a faster progression to dementia in the PD groups. We found that (1) LRP pathology in Dem-AD-LB shows a distribution that differs from PD, without significant brainstem or extracranial LRP in initial phases; (2) coincident AD pathology is associated with increased LRP in PD indicating an interaction; (3) LRP and coincident AD pathology independently predict progression to dementia in PD, and (4) evaluation of LRP needs to acknowledge different LRP spreading patterns and evaluate substantia nigra integrity in the neuropathological assessment and consider the implications of neuropathological heterogeneity for clinical and biomarker characterization.