Alzheimer disease: postmortem neuropathologic correlates of antemortem 1H MR spectroscopy metabolite measurements

Abstract

Purpose: To determine the neuropathologic correlates of antemortem hydrogen 1 ((1)H) magnetic resonance (MR) spectroscopy metabolite measurements in subjects with Alzheimer disease (AD)-type pathology.

Materials and methods: This study was approved by the institutional review board and was compliant with HIPAA regulations. Informed consent was obtained from each subject. The authors identified 54 subjects who underwent antemortem (1)H MR spectroscopy and were clinically healthy or had AD-type pathology with low to high likelihood of AD according to National Institute on Aging-Reagan neuropathologic criteria at autopsy. They investigated the associations between (1)H MR spectroscopy metabolite measurements and Braak neurofibrillary tangle stage (Braak stage), neuritic plaque score, and AD likelihood, with adjustments for subject age, subject sex, and time between (1)H MR spectroscopy and death.

Results: Decreases in N-acetylaspartate-to-creatine ratio, an index of neuronal integrity, and increases in myo-inositol-to-creatine ratio were associated with higher Braak stage, higher neuritic plaque score, and greater likelihood of AD. The N-acetylaspartate-to-myo-inositol ratio proved to be the strongest predictor of the pathologic likelihood of AD. The strongest association observed was that between N-acetylaspartate-to-myo-inositol ratio and Braak stage (R(N)(2) = 0.47, P < .001).

Conclusion: Antemortem (1)H MR spectroscopy metabolite changes correlated with AD-type pathology seen at autopsy. The study findings validated (1)H MR spectroscopy metabolite measurements against the neuropathologic criteria for AD, and when combined with prior longitudinal (1)H MR spectroscopy findings, indicate that these measurements could be used as biomarkers for disease progression in clinical trials.

Figure 1:

Location of ¹H MR spectroscopy voxel. The ¹H MR spectroscopy voxel was placed on a midsagittal T1-weighted localizer image (700/14). The anterior border of the splenium, superior border of the corpus callosum, and cingulate sulcus were the anatomic landmarks used to define the anteroinferior and anterosuperior borders of the 8-cm³ voxel. This voxel partially included the right and left posterior cingulate gyri and the inferior precuneate gyri (portions of Brodmann areas 23 and 31) in both hemispheres.

Figure 2:

¹H MR spectroscopic metabolite ratios plotted according to pathologic diagnosis of AD likelihood (horizontal axis) based on NIA-Reagan criteria. For each AD likelihood diagnosis, individual values, a box plot of the distribution, and the estimated mean and 95% confidence interval (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.

Figure 3:

¹H MR spectroscopic metabolite ratios plotted according to Braak NFT stage (horizontal axis). For each Braak NFT stage diagnosis, individual values, 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.

Figure 4:

¹H MR spectroscopic metabolite ratios plotted according to CERAD-based neuritic plaque score (horizontal axis). For each neuritic plaque score diagnosis, individual values, 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.