目的:本研究探讨常染色体显性遗传性脑动脉病伴皮质下梗死和白质脑病(CADASIL)的皮肤小纤维病变及其临床意义。即皮肤血管中的NOTCH3沉积和集中于认知障碍的CNS神经变性。
方法:37例CADASIL患者和59例年龄匹配的健康对照,通过表皮内神经纤维(IENF)密度的定量测量评估皮肤小纤维病理学,汗腺神经支配,和血管神经支配。CADASIL患者的认知表现通过全面的神经心理学评估,使用校正了年龄和糖尿病的多变量线性回归分析检验了其与小纤维病理学的相关性。我们进一步评估了IENF密度与皮肤血管NOTCH3胞外域(NOTCH3ECD)沉积和神经变性生物标志物(包括结构性脑MRI测量)的关系,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)。
结果:CADASIL患者显示IENF密度降低(5.22±2.42vs.7.88±2.89光纤/mm,P=0.0001),与年龄匹配的对照组相比,汗腺(P<0.0001)和血管(P<0.0001)神经支配减少。IENF密度降低与通过简易精神状态检查测量的整体认知功能受损相关(B=1.062,95%CI=0.370~1.753,P=0.004),在校正了年龄和糖尿病后,这种关联仍然存在(p=0.043).此外,CADASIL患者的IENF密度与平均皮质厚度(Pearsonr=0.565,P=0.0023)相关,但与白质高强度体积无关。总lacune计数,或总的微出血计数。在第11外显子有致病性变异的患者中,IENF密度降低与皮肤血管NOTCH3ECD沉积量相关(主要是p.R544C)(B=-0.092,95%CI=-0.175~-0.009,p=0.031)。与那些认知正常的人相比,CADASIL认知障碍患者的血浆NfL水平升高,无论并发小纤维去神经支配,而只有同时患有认知障碍和小纤维神经支配的患者显示血浆GFAP水平升高。
结论:CADASIL患者的皮肤小纤维病理学与认知障碍和中枢神经系统神经变性相关,表明与NOTCH3ECD聚集相关的周围神经退行性过程。
This study investigated the cutaneous small fiber pathology of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and its clinical significance, that is, the NOTCH3 deposition in cutaneous vasculatures and CNS neurodegeneration focusing on cognitive impairment.
Thirty-seven patients with CADASIL and 59 age-matched healthy controls were enrolled to evaluate cutaneous small fiber pathology by quantitative measures of intraepidermal nerve fiber density (IENFD), sweat gland innervation, and vascular innervation. Cognitive performance of patients with CADASIL was evaluated by a comprehensive neuropsychological assessment, and its association with small fiber pathology was tested using multivariable linear regression analysis adjusted for age and diabetes mellitus. We further assessed the relationships of IENFD with cutaneous vascular NOTCH3 ectodomain (NOTCH3ECD) deposition and biomarkers of neurodegeneration including structural brain MRI measures, serum neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), tau, and ubiquitin carboxy-terminal hydrolase L1.
Patients with CADASIL showed reduced IENFD (5.22 ± 2.42 vs 7.88 ± 2.89 fibers/mm, p = 0.0001) and reduced sweat gland (p < 0.0001) and vascular (p < 0.0001) innervations compared with age-matched controls. Reduced IENFD was associated with impaired global cognition measured by Mini-Mental State Examination (B = 1.062, 95% CI = 0.370-1.753, p = 0.004), and this association remained after adjustment for age and diabetes mellitus (p = 0.043). In addition, IENFD in patients with CADASIL was associated with mean cortical thickness (Pearson r = 0.565, p = 0.0023) but not white matter hyperintensity volume, total lacune count, or total microbleed count. Reduced IENFD was associated with cutaneous vascular NOTCH3ECD deposition amount among patients harboring pathogenic variants in exon 11 (mainly p.R544C) (B = -0.092, 95% CI = -0.175 to -0.009, p = 0.031). Compared with those with normal cognition, patients with CADASIL with cognitive impairment had an elevated plasma NfL level regardless of concurrent small fiber denervation, whereas only patients with both cognitive impairment and small fiber denervation showed an elevated plasma GFAP level.
Cutaneous small fiber pathology correlates with cognitive impairment and CNS neurodegeneration in patients with CADASIL, indicating a peripheral neurodegenerative process related to NOTCH3ECD aggregation.