An H-1-MRS framework predicts the onset of Alzheimer's disease symptoms in PSEN1 mutation carriers

作者：Londono Ana C; Castellanos Francisco X; Arbelaez Andres; Ruiz Adriana; Aguirre Acevedo Daniel C; Richardson Alice M; Easteal Simon; Lidbury Brett A; Arcos Burgos Mauricio^*; Lopera Francisco

来源：Alzheimer's and Dementia, 2014, 10(5): 552-561.

DOI：10.1016/j.jalz.2013.08.282

• Alzheimer's disease
• PSEN1
• Prediction
• H-1-MRS
• Familial Alzheimer's

Background: 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 (H-1-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.
Methods: We studied 75 subjects from the largest multigenerational pedigree in the world (similar to 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.G1u280Ala [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 H-1-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 H-1-MRS data while controlling for age, educational level, and sex.
Results: 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%.
Conclusions: Brain metabolites measured by H-1-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.G1u280Ala (E280 A) mutation.

• 出版日期2014-9