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

Alzheimers Dement. 2014 Sep;10(5):552-61. doi: 10.1016/j.jalz.2013.08.282. Epub 2013 Nov 13.


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 (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.

Methods: 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.

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 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.

Keywords: (1)H-MRS; Alzheimer's disease; Familial Alzheimer's; PSEN1; Prediction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / diagnosis*
  • Alzheimer Disease / metabolism
  • Brain / metabolism*
  • Cognitive Dysfunction / genetics
  • Cognitive Dysfunction / metabolism
  • Early Diagnosis
  • Female
  • Heterozygote*
  • Humans
  • Male
  • Models, Neurological
  • Mutation*
  • Presenilin-1 / genetics*
  • Proton Magnetic Resonance Spectroscopy / methods*
  • ROC Curve
  • Sensitivity and Specificity
  • Signal Processing, Computer-Assisted


  • PSEN1 protein, human
  • Presenilin-1