Transcriptomic Profiling Reveals Discrete Poststroke Dementia Neuronal and Gliovascular Signatures. Transcriptomic Profiling Reveals Discrete Poststroke Dementia Neuronal and Gliovascular Signatures

Around 25% of stroke survivors over 65 years old develop progressive cognitive decline more than 3 months post-stroke, with features of vascular dementia. Poststroke dementia (PSD) is associated with pathology in frontal brain regions, in particular dorsal lateral prefrontal cortex (DLPFC) neurons and white matter, remote from the infarct, implicating damage to anterior cognitive circuits (ACC) involved in impaired executive function. We hypothesised that PSD results from progressive neuronal damage in the DLPFC and that this is associated with alterations in the gliovascular unit (GVU) of frontal white matter. We aimed to identify the cellular and molecular basis of PSD by investigating the transcriptomic profile of the neurons and white matter GVU cells previously implicated in pathology. Laser capture microdissected neurons, astrocytes and endothelial cells were obtained from the Cognitive Function After Stroke (COGFAST) cohort. Gene expression was assessed using microarrays and pathways analysis to compare changes in PSD with controls and with poststroke non-dementia (PSND). Laser captured microdissected neurons were obtained from the bilateral carotid artery stenosis (BCAS) model and equivalent SHAM animals Overall design: Control (n=10), PSD (n=10) and Post-stroke non dementia (PSND) (n=10) human subjects. Sham Group (n=5) and Bilateral carotid artery stenosis (BCAS) gorup (n=5)

65岁以上的脑卒中幸存者中，约25%会在卒中后3个月以上出现进行性认知功能下降，且表现出血管性痴呆的特征。卒中后痴呆（Poststroke dementia, PSD）与额叶脑区的病理改变相关，尤其是远离梗死灶的背外侧前额叶皮层（dorsal lateral prefrontal cortex, DLPFC）神经元与白质，这提示负责执行功能受损的前认知环路（anterior cognitive circuits, ACC）受到了损伤。我们提出假说：卒中后痴呆源于背外侧前额叶皮层的进行性神经元损伤，且该过程与额叶白质的神经血管单元（gliovascular unit, GVU）的改变相关。本研究旨在通过分析此前被发现与病理相关的神经元及白质神经血管单元细胞的转录组特征，揭示卒中后痴呆的细胞与分子机制。研究从卒中后认知功能队列（Cognitive Function After Stroke, COGFAST）中获取了经激光捕获显微切割得到的神经元、星形胶质细胞与内皮细胞。通过微阵列技术与通路分析评估基因表达水平，对比卒中后痴呆组、对照组与卒中后无痴呆组（Post-stroke non dementia, PSND）的基因表达差异。研究还从双侧颈动脉狭窄（bilateral carotid artery stenosis, BCAS）模型动物及对应的假手术（SHAM）动物中获取了经激光捕获显微切割得到的神经元。实验整体设计：人类受试者分为对照组（n=10）、卒中后痴呆组（n=10）与卒中后无痴呆组（n=10）；动物实验分为假手术组（n=5）与双侧颈动脉狭窄组（n=5）。