Understanding Proton Magnetic Resonance Spectroscopy Neurochemical Changes Using Alzheimer's Disease Biofluid, PET, Postmortem Pathology Biomarkers, and APOE Genotype

Abstract

In vivo proton (¹H) magnetic resonance spectroscopy (MRS) is a powerful non-invasive method that can measure Alzheimer's disease (AD)-related neuropathological alterations at the molecular level. AD biomarkers include amyloid-beta (Aβ) plaques and hyperphosphorylated tau neurofibrillary tangles. These biomarkers can be detected via postmortem analysis but also in living individuals through positron emission tomography (PET) or biofluid biomarkers of Aβ and tau. This review offers an overview of biochemical abnormalities detected by ¹H MRS within the biologically defined AD spectrum. It includes a summary of earlier studies that explored the association of ¹H MRS metabolites with biofluid, PET, and postmortem AD biomarkers and examined how apolipoprotein e4 allele carrier status influences brain biochemistry. Studying these associations is crucial for understanding how AD pathology affects brain homeostasis throughout the AD continuum and may eventually facilitate the development of potential novel therapeutic approaches.

Keywords: Alzheimer’s disease; amyloid; apolipoprotein e4; biofluid biomarkers; magnetic resonance spectroscopy; mild cognitive impairment; tau.

Figure 1

¹H MR spectroscopic metabolite ratios plotted according to Braak NFT stage (horizontal axis). For each Braak NFT stage diagnosis, individual values (circles), a box plot of the distribution, and the estimated mean and 95% CI (darker lines) for the mean are shown. The mean and CI were derived from ANCOVA models and are assumed for a 78-year-old woman in whom the interval from ¹H MR spectroscopy to death is 2 years. With permission from Radiology [78].

Figure 2

Sagittal (A), coronal (B), and transverse (C) T1-weighted magnetic resonance images with superimposed posterior cingulate gyrus magnetic resonance spectroscopy volume of interest (20 × 20 × 20 mm³) (white square). Representative 1H MRS spectra, AV-1451-PET, and PiB-PET of a clinically normal individual. The thick red curve on the representative MRS spectra is the LCModel fit to the data. The thin curve under the spectra is the baseline. The residual (data minus the fit to the data) is shown on the top of the spectra. (D) Single-voxel proton (¹H) magnetic resonance (MR) spectrum acquired from the posterior cingulate gyrus of a cognitively unimpaired participant (age = 81) at 3 T with sLASER sequence. The thick red curve on the representative MR spectrum is the LCModel fit to the data. The thin curve under the spectrum is the fitted baseline. The residual (data minus the fit to the data) is shown at the top of the spectrum. The chemical shift axis is labeled in parts per million (ppm) unit. The Y axis is an intensity scale of each spectral line with no unit. (E) The representative cortical flortaucipir PET and PiB PET scans were acquired from the same participant. The participant had low NAA/tCr = 1.20 and Glu/tCr = 0.99, a high PCG flortaucipir standard value uptake unit ratio of 1.22, and a high PCG PiB standard value uptake unit ratio of 3.06. The PET scans were registered to the T1-weighted MR image and displayed together. We observed flortaucipir uptake in the skull of this participant. The meningeal and bone uptake of flortaucipir is a known manifestation of off-target binding. The cause is unknown. In contrast, such off-target uptake in PiB is not seen except with rare cases of bone uptake in diseases with high rates of bone remodeling (e.g., hyperostosis frontalis interna). The representative color scale shows the standardized uptake value ratios. Abbreviations: Glu, glutamate; Lip, lipid signal; NAA, N-acetylaspartate; PET, positron emission tomography; PiB, Pittsburgh compound-B; tCr, phosphocreatine + creatine; tCho, phosphocholine + glycerophosphocholine; mIns, myo-inositol; A, anterior;P, posterior; L, left; R, right. (For the interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.) This figure, originally appearing as Figure 1 and Figure 2, is reprinted from “1H MR spectroscopy biomarkers of neuronal and synaptic function are associated with tau deposition in cognitively unimpaired older adults”, Neurobiology of Aging, Volume 112, April 2022, Pages 16–26, with permission from Elsevier [63].