Instituto Neurológico de Colombia, Medellín, Antioquia, Colombia.
Child Study Center, Departments of Child and Adolescent Psychiatry, Radiology, and Physiology and Neuroscience, New York University, New York, NY, USA.
Alzheimers Dement. 2014 Sep;10(5):552-61. doi: 10.1016/j.jalz.2013.08.282. Epub 2013 Nov 13.
Alzheimer's disease (AD) is the most common cause of dementia; the main risk factors are age and several recently identified genes. A major challenge for AD research is the early detection of subjects at risk. The aim of this study is to develop a predictive model using proton magnetic resonance spectroscopy (1H-MRS), a noninvasive technique that evaluates brain chemistry in vivo, for monitoring the clinical outcome of carriers of a fully penetrant mutation that causes AD.
We studied 75 subjects from the largest multigenerational pedigree in the world (∼5000 people) that segregates a unique form of early-onset Alzheimer's disease (EOAD) caused by a fully penetrant mutation in the Presenilin-1 gene (PSEN1 p.Glu280Ala [E280 A]). Forty-four subjects were carriers of the mutation, and 31 were noncarriers. Seventeen carriers had either mild cognitive impairment (MCI) or early-stage AD (collectively MCI-AD). In right and left parietal white mater and parasagittal parietal gray matter (RPPGM and LPPGM) of the posterior cingulate gyrus and precuneus, we measured levels of the brain metabolites N-acetylaspartate (NAA), inositol (Ins), choline (Cho), and glutamate-glutamine complex (Glx) relative to creatine (Cr) levels (NAA/Cr, Ins/Cr, Cho/Cr, and Glx/Cr, respectively) with two-dimensional 1H-MRS. Using advanced recursive partition analysis and random forest analysis, we built classificatory decision trees for both mutation carrier status and the presence of MCI-AD symptoms, fitting them to 1H-MRS data while controlling for age, educational level, and sex.
We found that (1) the combination of LPPGM Cho/Cr<0.165 and RPPGM Glx/Cr>1.54 fully excluded carriers; (2) LPPGM Cho/Cr>0.165, RPPGM Glx/Cr<1.54, and left parietal white mater NAA/Cr>1.16 identified asymptomatic carriers with sensitivity of 97.7% and specificity of 77.4%; and (3) RPPGM NAA/Cr>1.05 defined asymptomatic subjects (independent of carrier status) with sensitivity of 100% and a specificity of 96.6%.
Brain metabolites measured by 1H-MRS in the posterior cingulate gyrus and precuneus are optimally sensitive and specific potential noninvasive biomarkers of subclinical emergence of AD caused by the PSEN1 p.Glu280Ala (E280 A) mutation.
阿尔茨海默病（AD）是痴呆症最常见的病因；主要的风险因素是年龄和最近发现的几个基因。AD 研究的一个主要挑战是早期发现有风险的患者。本研究旨在开发一种预测模型，使用质子磁共振波谱（1H-MRS），一种评估体内大脑化学的非侵入性技术，用于监测携带完全外显突变导致 AD 的个体的临床结局。
我们研究了来自世界上最大的多代家族（约 5000 人）的 75 名患者，该家族携带一种独特的早发性阿尔茨海默病（EOAD），由早老素-1 基因（PSEN1 p.Glu280Ala [E280 A]）的完全外显突变引起。44 名患者为突变携带者，31 名患者为非携带者。17 名携带者患有轻度认知障碍（MCI）或早期 AD（统称为 MCI-AD）。我们在右和左顶叶白质和后扣带回和楔前叶的矢状旁顶叶灰质（RPPGM 和 LPPGM）中，测量了相对于肌酸（Cr）水平的脑代谢物 N-乙酰天冬氨酸（NAA）、肌醇（Ins）、胆碱（Cho）和谷氨酸-谷氨酰胺复合物（Glx）的水平（NAA/Cr、Ins/Cr、Cho/Cr 和 Glx/Cr，分别），采用二维 1H-MRS。我们使用高级递归分区分析和随机森林分析，为突变携带者状态和 MCI-AD 症状的存在建立了分类决策树，在控制年龄、教育程度和性别的同时，将其拟合到 1H-MRS 数据中。
我们发现，（1）LPPGM Cho/Cr<0.165 和 RPPGM Glx/Cr>1.54 的组合完全排除了携带者；（2）LPPGM Cho/Cr>0.165、RPPGM Glx/Cr<1.54 和左顶叶白质 NAA/Cr>1.16 确定了无症状携带者，敏感性为 97.7%，特异性为 77.4%；（3）RPPGM NAA/Cr>1.05 定义了无症状受试者（独立于携带者状态），敏感性为 100%，特异性为 96.6%。
在后扣带回和楔前叶中通过 1H-MRS 测量的脑代谢物是 PSEN1 p.Glu280Ala（E280 A）突变引起的亚临床 AD 出现的最佳敏感和特异的潜在非侵入性生物标志物。
