Yu Lei, Dawe Robert J, Boyle Patricia A, Gaiteri Chris, Yang Jingyun, Buchman Aron S, Schneider Julie A, Arfanakis Konstantinos, De Jager Philip L, Bennett David A
Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois.
Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois.
JAMA Neurol. 2017 Dec 1;74(12):1473-1480. doi: 10.1001/jamaneurol.2017.2807.
Alteration of ex vivo magnetic resonance imaging transverse relaxation is associated with late-life cognitive decline even after controlling for common neuropathologic conditions. However, the underlying neurobiology of this association is unknown.
To investigate the association between brain gene expression, DNA methylation, and alteration of magnetic resonance imaging transverse relaxation in late-life cognitive decline.
DESIGN, SETTING, AND PARTICIPANTS: Data came from 2 community-based longitudinal cohort studies of aging and dementia, the Religious Orders Study, which began in 1993, and the Rush Memory and Aging Project, which began in 1997. All participants agreed to undergo annual clinical evaluations and to donate their brains after death. By October 24, 2016, a total of 1358 individuals had died and had brain autopsies that were approved by board-certified neuropathologists. Of those, 552 had undergone ex vivo imaging. The gene expression analysis was limited to 174 individuals with both imaging and brain RNA sequencing data. The DNA methylation analysis was limited to 225 individuals with both imaging and brain methylation data.
Maps of ex vivo magnetic resonance imaging transverse relaxation were generated using fast spin echo imaging. The target was a composite measure of the transverse relaxation rate (R2) that was associated with cognitive decline after controlling for common neuropathologic conditions. Next-generation RNA sequencing and DNA methylation data were generated using frozen tissue from the dorsolateral prefrontal cortex. Genome-wide association analysis was used to investigate gene expression and, separately, DNA methylation for signals associated with the R2 measure.
Of the 552 individuals with ex vivo imaging data, 394 were women and 158 were men, and the mean (SD) age at death was 90.4 (6.0) years. Four co-expressed genes (PADI2 [Ensembl ENSG00000117115], ZNF385A [Ensembl ENSG00000161642], PSD2 [Ensembl ENSG00000146005], and A2ML1 [Ensembl ENSG00000166535]) were identified, of which higher expressions were associated with slower R2. The association of R2 with cognitive decline was attenuated when the gene expression signals were added to the model, such that the mean (SE) coefficient of association was reduced from 0.028 (0.008) (P < .001) to 0.019 (0.009) (P = .03). The DNA methylation scan did not detect a genome-wide significant signal, but it revealed an anticorrelation between R2 and DNA methylation in many of the cytosine-guanine dinucleotides.
Brain gene expression and DNA methylation dysregulations are implicated in the alteration of brain tissue properties associated with late-life cognitive decline above and beyond the influence of common neuropathologic conditions.
即使在控制了常见神经病理状况之后，离体磁共振成像横向弛豫的改变仍与晚年认知衰退相关。然而，这种关联背后的神经生物学机制尚不清楚。
研究晚年认知衰退中脑基因表达、DNA甲基化与磁共振成像横向弛豫改变之间的关联。
设计、设置和参与者：数据来自两项基于社区的衰老与痴呆纵向队列研究，即始于1993年的宗教团体研究和始于1997年的拉什记忆与衰老项目。所有参与者均同意接受年度临床评估并在死后捐献大脑。截至2016年10月24日，共有1358人死亡并接受了经委员会认证的神经病理学家批准的脑尸检。其中，552人接受了离体成像。基因表达分析仅限于174名同时具有成像和脑RNA测序数据的个体。DNA甲基化分析仅限于225名同时具有成像和脑甲基化数据的个体。
使用快速自旋回波成像生成离体磁共振成像横向弛豫图谱。目标是横向弛豫率（R2）的综合测量指标，该指标在控制了常见神经病理状况后与认知衰退相关。使用来自背外侧前额叶皮质的冷冻组织生成下一代RNA测序和DNA甲基化数据。全基因组关联分析用于研究基因表达，并分别研究与R2测量指标相关的DNA甲基化信号。
在552名有离体成像数据的个体中，394名是女性，158名是男性，死亡时的平均（标准差）年龄为90.4（6.0）岁。鉴定出四个共表达基因（PADI2 [Ensembl ENSG00000117115]、ZNF385A [Ensembl ENSG00000161642]、PSD2 [Ensembl ENSG00000146005] 和A2ML1 [Ensembl ENSG00000166535]），其中较高的表达与较慢的R2相关。当将基因表达信号添加到模型中时，R2与认知衰退的关联减弱，使得平均（标准误）关联系数从0.028（0.008）（P <.001）降至0.019（0.009）（P =.03）。DNA甲基化扫描未检测到全基因组显著信号，但在许多胞嘧啶 - 鸟嘌呤二核苷酸中揭示了R2与DNA甲基化之间的负相关。
除常见神经病理状况的影响外，脑基因表达和DNA甲基化失调与晚年认知衰退相关的脑组织特性改变有关。
