Pathophysiology of Hypoperfusion of the Precuneus in Early Alzheimer's Disease.
Pathophysiology of Hypoperfusion of the Precuneus in Early Alzheimer's Disease.
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DOI：
10.1111/bpa.12331
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发表时间：
2016-07
期刊：
影响因子：
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通讯作者：
Love S
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文献类型：
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作者：
Miners JS;Palmer JC;Love S
阿尔茨海默病 (AD) 中脑灌注最早下降的是内侧顶叶皮层（楔前叶）。我们分析了 70 AD 和 37 个对照大脑的死后组织中的楔前叶，以探讨低灌注的病理生理学：小动脉硬化性小血管疾病 (SVD) 和脑淀粉样血管病 (CAA)、血管收缩剂内皮素-1 (EDN1) 和血管紧张素 II (Ang II) 的作用，以及与 Aβ 的关系。髓磷脂相关糖蛋白：蛋白脂质蛋白-1 比率（MAG：PLP1）被用作死亡前楔前叶氧合的指标。 MAG:PLP1 在 AD 早期（Braak III-IV 期）减少约 50%。尽管 MAG:PLP1 在晚期 AD（V-VI 期）中仍然较低，但降低幅度不太明显，可能反映出需氧量下降。皮质 MAG:PLP1 的减少与血管内皮生长因子 (VEGF) 的升高相关，血管内皮生长因子 (VEGF) 是灌注不足的另一个标志。皮质 MAG:PLP1 随着 SVD 和 CAA 的增加而无显着下降，但随着 EDN1 浓度的增加而显着下降，EDN1 在 AD 中升高约 75%。相反，随着皮质 MAG:PLP1 的减少，Ang II 水平和血管紧张素转换酶 (ACE) 活性下降，显示出对低灌注的正常生理反应。 AD 患者顶叶白质 (WM) 中的 MAG:PLP1 减少，但这种下降与 WM EDN1 呈正相关（即生理上）。然而，WM 中 MAG:PLP1 的下降与皮质 EDN1 的增加有关，可能反映了穿过皮质以灌注 WM 的穿支小动脉的血管收缩。皮质中的 EDN1 与可溶性和不溶性 Aβ42 高度显着相关，先前显示其上调神经元内皮素转换酶 2 (ECE2)，但与 Aβ40 无关。我们的研究结果表明，早期 AD 中楔前叶的氧合减少，并表明 Aβ42 介导的 ECE2 上调导致的 EDN1 升高是一个促成因素。
The earliest decline in cerebral perfusion in Alzheimer's disease (AD) is in the medial parietal cortex (precuneus). We have analyzed precuneus in post‐mortem tissue from 70 AD and 37 control brains to explore the pathophysiology of the hypoperfusion: the contribution of arteriolosclerotic small vessel disease (SVD) and cerebral amyloid angiopathy (CAA), and of the vasoconstrictors endothelin‐1 (EDN1) and angiotensin II (Ang II), and the association with Aβ. The myelin‐associated glycoprotein:proteolipid protein‐1 ratio (MAG:PLP1) was used as an indicator of oxygenation of the precuneus prior to death. MAG:PLP1 was reduced ∼50% in early AD (Braak stage III–IV). Although MAG:PLP1 remained low in advanced AD (stage V–VI), the reduction was less pronounced, possibly reflecting falling oxygen demand. Reduction in cortical MAG:PLP1 correlated with elevation in vascular endothelial growth factor (VEGF), another marker of hypoperfusion. Cortical MAG:PLP1 declined nonsignificantly with increasing SVD and CAA, but significantly with the concentration of EDN1, which was elevated approximately 75% in AD. In contrast, with reduction in cortical MAG:PLP1, Ang II level and angiotensin‐converting enzyme (ACE) activity declined, showing a normal physiological response to hypoperfusion. MAG:PLP1 was reduced in the parietal white matter (WM) in AD but here the decline correlated positively (ie, physiologically) with WM EDN1. However, the decline of MAG:PLP1 in the WM was associated with increasing cortical EDN1 and perhaps reflected vasoconstriction of perforating arterioles, which traverse the cortex to perfuse the WM. EDN1 in the cortex correlated highly significantly with both soluble and insoluble Aβ42, shown previously to upregulate neuronal endothelin‐converting enzyme‐2 (ECE2), but not with Aβ40. Our findings demonstrate reduced oxygenation of the precuneus in early AD and suggest that elevated EDN1, resulting from Aβ42‐mediated upregulation of ECE2, is a contributor.