Frontal Metabolites and Alzheimer's Disease Biomarkers in Healthy Older Women and Women Diagnosed with Mild Cognitive Impairment

Abstract

Background: Women account for two thirds of the prevalence and incidence of Alzheimer's disease (AD) and mild cognitive impairment (MCI). Evidence suggest that sex may differently influence the expression of proteins amyloid-beta (Aβ1-42) and tau, for which early detection is crucial in prevention of the disease.

Objective: We investigated the effect of aging and cerebrospinal fluid (CSF) levels of Aβ1-42 and tau on frontal metabolites measured with proton magnetic resonance spectroscopy (MRS) in a cohort of cognitively normal older women and women with MCI.

Methods: 3T single-voxel MRS was performed on the medial frontal cortex, using Point Resolved Spectroscopy (PRESS) and Mescher-Garwood Point Resolved Spectroscopy (MEGA-PRESS) in 120 women (age range 50-85). CSF samples of Aβ1-42 and tau and scores of general cognition were also obtained.

Results: Levels of frontal gamma aminobutyric acid (GABA+) were predicted by age, independently of disease and CSF biomarkers. Importantly, levels of GABA+ were reduced in MCI patients. Additionally, we found that levels of N-acetylaspartate relative to myo-inositol (tNAA/mI) predicted cognition in MCI patients only and were not related to CSF biomarkers.

Conclusion: This study is the first to demonstrate a strong association between frontal GABA+ levels and neurological aging in a sample consisting exclusively of healthy older women with various levels of CSF tau and Aβ1-42 and women with MCI. Importantly, our results show no correlation between CSF biomarkers and MRS metabolites in this sample.

Keywords: Aging; cerebrospinal fluid biomarkers; frontal cortex; general cognition; magnetic resonance spectroscopy; mild cognitive impairment; women’s health.

Fig. 1.

MRS voxel position over the medial frontal cortex (MFC) in the A) axial, B) sagittal, and C) coronal planes.

Fig. 2.

Sample MRS spectra for A) PRESS and B) MEGAPRESS acquisitions.

Fig. 3.

Boxplots presenting groups comparisons of CSF biomarkers A) Aβ_1–42, B) p-tau, C) t-tau, and D) MoCA scores. Values for CSF biomarkers are given in pg/mL (*p < 0.05; ***p < 0.001).

Fig. 4.

Boxplots presenting groups comparisons of MRS metabolites A) GABA+, B) mI/tCr, C) Glx (Glu + Gln), D) tNAA/tCr, E) tCr, and F) tNAA/mI. Values are given in arbitrary units (A.U.) (*p < 0.05 ***p < 0.001).

Fig. 5.

Scatterplots presenting the relationship between levels of frontal GABA+ and Age in A) BM− subjects, B) BM+ subjects, and C) MCI patients. Levels of GABA+ are given in arbitrary units (A.U.) and age in years. Confidence interval is 95% for the regression lines.

Fig. 6.

Scatterplots presenting the relationship between MoCA score and tNAA/mI ratio in A) BM− subjects, B) BM+ subjects, and C) MCI patients. Confidence interval is 95% for the regression lines.