Lee Seonjoo, Viqar Fawad, Zimmerman Molly E, Narkhede Atul, Tosto Giuseppe, Benzinger Tammie L S, Marcus Daniel S, Fagan Anne M, Goate Alison, Fox Nick C, Cairns Nigel J, Holtzman David M, Buckles Virginia, Ghetti Bernardino, McDade Eric, Martins Ralph N, Saykin Andrew J, Masters Colin L, Ringman John M, Ryan Natalie S, Förster Stefan, Laske Christoph, Schofield Peter R, Sperling Reisa A, Salloway Stephen, Correia Stephen, Jack Clifford, Weiner Michael, Bateman Randall J, Morris John C, Mayeux Richard, Brickman Adam M
Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, NY.
Division of Biostatistics, New York State Psychiatric Institute, New York, NY.
Ann Neurol. 2016 Jun;79(6):929-39. doi: 10.1002/ana.24647. Epub 2016 Apr 27.
White matter hyperintensities (WMHs) are areas of increased signal on T2-weighted magnetic resonance imaging (MRI) scans that most commonly reflect small vessel cerebrovascular disease. Increased WMH volume is associated with risk and progression of Alzheimer's disease (AD). These observations are typically interpreted as evidence that vascular abnormalities play an additive, independent role contributing to symptom presentation, but not core features of AD. We examined the severity and distribution of WMH in presymptomatic PSEN1, PSEN2, and APP mutation carriers to determine the extent to which WMH manifest in individuals genetically determined to develop AD.
The study comprised participants (n = 299; age = 39.03 ± 10.13) from the Dominantly Inherited Alzheimer Network, including 184 (61.5%) with a mutation that results in AD and 115 (38.5%) first-degree relatives who were noncarrier controls. We calculated the estimated years from expected symptom onset (EYO) by subtracting the affected parent's symptom onset age from the participant's age. Baseline MRI data were analyzed for total and regional WMH. Mixed-effects piece-wise linear regression was used to examine WMH differences between carriers and noncarriers with respect to EYO.
Mutation carriers had greater total WMH volumes, which appeared to increase approximately 6 years before expected symptom onset. Effects were most prominent for the parietal and occipital lobe, which showed divergent effects as early as 22 years before estimated onset.
Autosomal-dominant AD is associated with increased WMH well before expected symptom onset. The findings suggest the possibility that WMHs are a core feature of AD, a potential therapeutic target, and a factor that should be integrated into pathogenic models of the disease. Ann Neurol 2016;79:929-939.
脑白质高信号（WMHs）是T2加权磁共振成像（MRI）扫描上信号增强的区域，最常见于反映小血管性脑血管疾病。WMH体积增加与阿尔茨海默病（AD）的风险及进展相关。这些观察结果通常被解释为血管异常在导致症状表现方面起累加、独立作用的证据，但并非AD的核心特征。我们研究了症状前PSEN1、PSEN2和APP突变携带者中WMH的严重程度和分布情况，以确定在基因上注定会患AD的个体中WMH出现的程度。
该研究纳入了来自显性遗传阿尔茨海默病网络的参与者（n = 299；年龄 = 39.03 ± 10.13），其中184名（61.5%）携带导致AD的突变，115名（38.5%）一级亲属作为非携带者对照。我们通过用参与者的年龄减去受影响父母的症状发作年龄来计算预期症状发作的估计年数（EYO）。对基线MRI数据进行全脑和区域WMH分析。采用混合效应分段线性回归来研究携带者和非携带者在EYO方面的WMH差异。
突变携带者的全脑WMH体积更大，在预期症状发作前约6年似乎就开始增加。顶叶和枕叶的影响最为显著，早在估计发作前22年就表现出不同的影响。
常染色体显性AD在预期症状发作前很久就与WMH增加相关。这些发现提示WMH可能是AD的核心特征、潜在治疗靶点以及应纳入该疾病致病模型的一个因素。《神经病学纪事》2016年；79:929 - 939。
