Posterior Cingulate Lactate as a Metabolic Biomarker in Amnestic Mild Cognitive Impairment

Abstract

Mitochondrial dysfunction represents a central factor within the pathogenesis of the Alzheimer's disease (AD) spectrum. We hypothesized that in vivo measurements of lactate (lac), a by-product of glycolysis, would correlate with functional impairment and measures of brain health in a cohort of 15 amnestic mild cognitive impairment (aMCI) individuals. Lac was quantified from the precuneus/posterior cingulate (PPC) using 2-dimensional J-resolved magnetic resonance spectroscopy (MRS). Additionally, standard behavioral and imaging markers of aMCI disease progression were acquired. PPC lac was negatively correlated with performance on the Wechsler logical memory tests and on the minimental state examination even after accounting for gray matter, cerebral spinal fluid volume, and age. No such relationships were observed between lac and performance on nonmemory tests. Significant negative relationships were also noted between PPC lac and hippocampal volume and PPC functional connectivity. Together, these results reveal that aMCI individuals with a greater disease progression have increased concentrations of PPC lac. Because lac is upregulated as a compensatory response to mitochondrial impairment, we propose that J-resolved MRS of lac is a noninvasive, surrogate biomarker of impaired metabolic function and would provide a useful means of tracking mitochondrial function during therapeutic trials targeting brain metabolism.

Figure 1

1H J-resolved MRS lac imaging and analyses. (a) 3D-plot of averaged, phased proton spectra (filtered for viewing from 2 to 0.8 ppm) for 6 selected echo times (A: 72 ms, B: 92 ms, C: 112 ms, D: 232 ms, E: 252 ms, and F: 272 ms) reveals the inversion of the lac doublet located at 1.3 ppm. The full 1H spectrum at echo time of 32 ms (inset) was used to fit the classic 1H short echo NAA metabolite for absolute quantification using LCmodel. (b) Fourier transformation of the standard acquisition dimension (i.e., chemical shift) converts each FID to a frequency spectrum (F1). The NAA signal for each echo time for each individual was used for quality control purposes and for phase stabilization. No tilt correction was applied in order to inspect possible corruption by T2 noise. (c) A second Fourier transform was applied to the data along the incremented echo time (spectral dimension or F2), converting the oscillating phases of each of the coupled metabolite peaks to their respective frequency components. This contour plot of the 2D spectra, along with projections on the F1 and F2 axes over the chemical shift frequency range was used to localize, isolate, and quantify lactate at the chemical shift frequency of 1.33 ppm at J-resolved frequency of 7.5 Hz.

Figure 2

Posterior cingulate and precuneus (PPC) MRS voxel and lac specific associations. (a) During scanning, a 4 × 4 × 4 cm voxel (shown in red) was placed bilaterally, centered on medial parietal lobe, covering the posterior cingulate, the precuneus, in most individuals the retrosplenial cortex and in a few individuals the isthmus. A large voxel size is required to provide high lac signal to noise. To ensure consistent placement across subjects, the voxel was centered along the midline, placed just anterior to the parietoccipital fissure and angled in-line with cerebellar tentorium. The voxel was toggled left-to-right to avoid as much ventricular CSF as possible. PPC lac concentrations (y-axes) were correlated with performance on various neuropsychological tests including (b) memory based tasks and (c) non-memory specific tasks.  ^*Correlations were significant at P < 0.05 (partial correlations) after correcting for age, GM, and CSF. No correlations on non-memory tasks were statistically significant.

Figure 3

PPC lac correlations and brain pathology in aMCI. (a) PPC lac negatively correlates with ICV adjusted L (left) and R (right) hippocampal volumes. (b) Regions of posterior cingulate resting state fMRI functional connectivity that negatively correlate with PPC lac concentrations across aMCI. The PPC seed point (upper left inset) was selected with reference to the site of maximum FDG-PET impairment in a group of preclinical probable AD patients [26] and was contained within MRS voxel locations in all subjects (red transparent box). Z-statistics were calculated utilizing a Gaussian random field theory, thresholded using clusters determined by Z > 2.3 and a (corrected) cluster significance threshold of P = 0.05. Blue voxels showing significant negative correlations between the strength of functional connectivity and PPC lac concentrations, displayed on the MNI152 template brain and in radiological convention, were generally located within the temporal lobe including medial temporal loci (e.g., left hippocampus in upper left green crosshairs) and various subcortical structures (see Table 2). Coordinates (X, Y, and Z) are in millimeters in MNI space. MTG: middle temporal gyrus. pHG: parahippocampal gyrus. STS: superior temporal sulcus. HG: hippocampal gyrus. STG: superior temporal gyrus. POG: posterior orbital gyrus. Put: putamen.