Ryan Natalie S, Biessels Geert-Jan, Kim Lois, Nicholas Jennifer M, Barber Philip A, Walsh Phoebe, Gami Priya, Morris Huw R, Bastos-Leite António J, Schott Jonathan M, Beck Jon, Mead Simon, Chavez-Gutierrez Lucia, de Strooper Bart, Rossor Martin N, Revesz Tamas, Lashley Tammaryn, Fox Nick C
Dementia Research Centre, Department of Neurodegenerative Diseases, UCL Institute of Neurology, London, UK.
Department of Neurology, Brain Center Rudolf Magnus, University Medical Centre, Utrecht, The Netherlands.
Neurobiol Aging. 2015 Dec;36(12):3140-3151. doi: 10.1016/j.neurobiolaging.2015.08.026. Epub 2015 Sep 4.
Familial Alzheimer's disease (FAD) treatment trials raise interest in the variable occurrence of cerebral amyloid angiopathy (CAA); an emerging important factor in amyloid-modifying therapy. Previous pathological studies reported particularly severe CAA with postcodon 200 PSEN1 mutations and amyloid beta coding domain APP mutations. As CAA may manifest as white matter hyperintensities (WMH) on magnetic resonance imaging, particularly posteriorly, we investigated WMH in 52 symptomatic FAD patients for associations with mutation position. WMH were visually rated in 39 PSEN1 (18 precodon 200); 13 APP mutation carriers and 25 healthy controls. Ten PSEN1 mutation carriers (5 precodon 200) had postmortem examination. Increased WMH were observed in the PSEN1 postcodon 200 group and in the single APP patient with an amyloid beta coding domain (p.Ala692Gly, Flemish) mutation. WMH burden on MRI correlated with severity of CAA and cotton wool plaques in several areas. The precodon 200 group had younger ages at onset, decreased axonal density and/or integrity, and a greater T-lymphocytic response in occipital deep white matter. Mutation site contributes to the phenotypic and pathological heterogeneity witnessed in FAD.
家族性阿尔茨海默病（FAD）治疗试验引发了人们对脑淀粉样血管病（CAA）可变发生率的关注；CAA是淀粉样蛋白修饰治疗中一个新出现的重要因素。先前的病理学研究报告称，密码子200后的PSEN1突变和淀粉样β编码域APP突变会导致特别严重的CAA。由于CAA在磁共振成像上可能表现为白质高信号（WMH），尤其是在后部，我们对52例有症状的FAD患者的WMH进行了研究，以探讨其与突变位置的关联。对39例PSEN1突变携带者（18例密码子200前）、13例APP突变携带者和25例健康对照者的WMH进行了视觉评分。10例PSEN1突变携带者（5例密码子200前）进行了尸检。在PSEN1密码子200后组以及1例具有淀粉样β编码域（p.Ala692Gly，佛兰芒）突变的APP患者中观察到WMH增加。MRI上的WMH负担与几个区域的CAA严重程度和棉絮斑相关。密码子200前组发病年龄较轻，轴突密度和/或完整性降低，枕叶深部白质中的T淋巴细胞反应更强。突变位点导致了FAD中所见的表型和病理异质性。
