Neurology:CADASIL患者小纤维病理改变与认知功能障碍的临床相关性

2022-06-30 Naomi MedSci原创

常染色体显性遗传性脑动脉病伴皮质下梗塞和白质脑病(CADASIL)是最常见的单基因脑小血管病(SVD)。近日,有研究发现皮肤小纤维病变与CADASIL患者认知功能障碍和中枢神经系统退行性变相关。

常染色体显性遗传性脑动脉病伴皮质下梗塞和白质脑病(CADASIL)是最常见的单基因脑小血管病(SVD),可导致早期腔隙性脑梗塞和血管痴呆。CADASIL是由NOTCH3基因突变引起的,NOTCH3基因编码一种大的跨膜蛋白,在平滑肌细胞上表达受限。CADASIL脑的病理特征是血管平滑肌细胞周围细胞外颗粒嗜奥斯粒物质(GOM)沉积,这是由于从突变的NOTCH3受体切割的NOTCH3胞外区(NOTCH3ECD)的沉积。NOTCH3ECD的沉积不仅在脑血管中可检测到,而且在全身血管包括真皮血管也可检测到。因此,在对致病的NOTCH3变异进行遗传确认之前,皮肤活检证实NOTCH3ECD沉积可作为替代标记。 

近日,一项发表在Neurology上的研究试图探讨常染色体显性遗传性脑动脉病伴皮质下梗塞和白质脑病(CADASIL)的皮肤小纤维病理改变及其临床意义,即NOTCH3在皮肤血管中的沉积和以认知损害为重点的中枢神经系统变性。

对37例CADASIL患者和59例年龄匹配的健康对照进行了表皮内神经纤维密度、汗腺神经支配和血管神经支配的定量测量,以评价皮肤小纤维的病理改变。CADASIL患者的认知功能通过综合神经心理学评估进行评估,并通过调整年龄和糖尿病的多变量线性回归分析来检验其与小纤维病变的关系。进一步评估了IENF密度与皮肤血管NOTCH3胞外区(NOTCH3ECD)沉积和神经退变生物标志物的关系,包括脑部结构MRI测量、血清神经丝轻链(NFL)、胶质纤维酸性蛋白(GFAP)、tau和泛素羧基末端水解酶L1(UCHL1)。

  • 与年龄匹配的对照组相比,CADASIL患者的纤维密度降低(5.22±2.42vs.7.88±2.89纤维/mm,P=0.0001),汗腺(P<0.0001)和血管神经支配(P<0.0001)减少。
  • 简易智力状态检查法测量的整体认知功能受损与IENF值降低相关(B=1.062,95%CI=0.370~1.753,P=0.004),在调整了年龄和糖尿病因素后,这种关联仍然存在(P=0.043)。
  • 此外,CADASIL患者的IENF值与平均皮质厚度相关(Pearson‘s r=0.565,P=0.0023),而与白质高信号体积、总腔隙数或总微出血数无关。
  • IENF密度降低与皮肤存在外显子11致病变异的患者血管NOTCH3ECD沉积量(主要为p.R544C)(B=-0.092,95%CI=-0.175~-0.009,P=0.031)。

与认知正常者相比,CADASIL伴认知功能障碍患者无论并发小纤维神经支配与否,其血浆NFL水平均显著升高,而只有同时存在认知损害和小纤维神经支配的CADASIL患者血浆GFAP水平显著升高。

皮肤小纤维病变与CADASIL患者认知功能障碍和中枢神经系统退行性变相关,提示与NOTCH3ECD聚集相关的外周神经退行性变过程。

文献来源:Cheng YW, Chao CC, Chen CH, et al. Small Fiber Pathology in CADASIL: Clinical Correlation With Cognitive Impairment [published online ahead of print, 2022 May 18]. Neurology. 2022;10.1212/WNL.0000000000200672. doi:10.1212/WNL.0000000000200672

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    2022-10-10 yinhl1978
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    2022-06-30 般若傻瓜
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