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7T MRS of neurometabolites and associations with cognitive deficits in mild cognitive impairment

Georg Oeltzschner^1,2, S. Andrea Wijtenburg³, Mark Mikkelsen^1,2, Richard A. E. Edden^1,2, Peter B. Barker^1,2, Jin Hui Joo⁴, Jeannie-Marie S. Leoutsakos⁴, Laura M. Rowland³, Clifford I. Workman⁴, and Gwenn S. Smith^1,4

¹Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD, United States, ²F. M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, MD, United States, ³Neuroimaging Research Program, Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, United States, ⁴Department of Psychiatry and Behavioral Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD, United States

Synopsis

Mild cognitive impairment (MCI) is associated with increased risk of developing Alzheimer’s Disease (AD). Here, levels of multiple brain metabolites in healthy controls and MCI patients using 7T magnetic resonance spectroscopy in the anterior (ACC) and posterior (PCC) cingulate cortex were studied. MCI patients showed decreased GABA/tCr (ACC, PCC), Glu/tCr (PCC), NAA/tCr (PCC), and increased mI/tCr (ACC). Worse episodic verbal memory performance correlated with lower Glu/tCr (PCC), lower NAA/tCr (PCC), and higher mI/tCr (ACC, PCC). Worse verbal fluency performance correlated with lower GSH/tCr (PCC). In summary, MCI is associated with decreased GABA and glutamate, most consistently in the PCC.

Introduction

Alzheimer’s disease (AD) is the most common neurodegenerative disease, with potentially devastating consequences for healthcare systems and societies^1–3. The pathophysiology of AD and its early stages such as mild cognitive impairment (MCI) is not fully understood, but is thought to involve protein deposition, oxidative stress and mitochondrial dysfunction, which may lead to disruptions in neurotransmitter systems causing cognitive decline. Magnetic resonance spectroscopy (MRS) at 7T permits the assessment of biochemically important molecules, including the neurotransmitters GABA and glutamate (Glu), the antioxidant glutathione (GSH), the neuromodulator N-acetylaspartylglutamate (NAAG), the neuronal marker N-acetylaspartate (NAA) and the osmolyte and glial marker myo-inositol (mI).

Methods

13 healthy controls (HC, 7F, 63.6 ± 7.8 y) and 13 MCI patients (3F; 69.6 ± 7.7 y) were enrolled. All participants underwent a structured clinical interview by a clinical psychologist (SCID)⁴, Clinical Dementia Rating (CDR)⁵, Mini-Mental State Examination (MMSE)⁶, the letter fluency test included in the Delis-Kaplan Executive Function System (D-KEFS) test⁷, and the California Verbal Learning Test (CVLT)⁸.

All MR data were acquired on a 7T Philips Achieva scanner with a 32-channel head coil. MRS voxels (28 × 16 × 20 mm³) were prescribed in a T₁-weighted MP-RAGE image (0.96 mm isotropic) in the anterior (ACC) and posterior cingulate cortex (PCC, Fig. 1) to acquire STEAM data (TE ~14 ms (ACC/PCC); TR 3000 ms; 96 averages; VAPOR⁹ water suppression; 4 water reference averages). MRS data were analyzed with LCModel^10,11. Metabolite levels (estimated relative to total creatine, tCr) of GABA, Glu, GSH, NAA, NAAG, and mI were included in statistical analyses. Voxels were co-registered to the structural images to determine tissue composition (GM/WM/CSF), based on SPM12 segmentation.

For each metabolite, a two-way ANCOVA was performed with metabolite levels as dependent variables, and subject group and brain region as independent variables. Post-hoc pairwise Tukey-adjusted comparisons between HC and MCI groups were performed to investigate effects of group. Relationships between metabolite levels and cognitive scores were assessed with linear regression analyses. For all tests, age was included as a covariate, and the single-test α-level was 0.05.

Results

Representative spectra and LCModel fits for ACC and PCC are shown in Fig. 2, indicating good SNR and low linewidth.

Group comparisons between the HC and MCI groups revealed significant differences in metabolite-to-tCr ratios (Table 1). MCI patients had significantly lower levels of GABA/tCr (ACC and PCC, p < 0.01 each), Glu/tCr (PCC, p < 0.05) and NAA/tCr (PCC, p < 0.05), and significantly higher levels of mI/tCr (ACC, p < 0.01).

MMSE scores were negatively correlated with mI/tCr in the ACC (p < 0.01) and the PCC (p < 0.05). D-KEFS scores were positively correlated with GSH/tCr in the PCC (p < 0.01). CVLT scores were positively correlated with Glu/tCr (PCC, p < 0.05) and NAA/tCr (PCC, p < 0.05), and negatively correlated with mI/tCr (ACC and PCC, p < 0.05 each) (Table 2).

Discussion

A key finding of this study is a reduction of ~16% in both ACC and PCC GABA/tCr levels in MCI patients. Decreased posterior GABA levels are in line with previous studies of MCI and AD patients^12,13. Our finding of decreased GABA in ACC suggests that disturbed GABA homeostasis in MCI may also occur more extensively, with potential impact on cognitive function.

Reduced PCC Glu levels and their correlation with CVLT scores may suggest that disturbed Glu neurotransmission is at least partly contributing to memory impairment in MCI. The results are in line with reports of reduced PCC Glu/Glx levels in MCI^14,15 and AD¹⁶.

Links between decreased prefrontal GSH and cognitive scores¹⁷, and associations between decreased temporal and parietal GSH levels and local PiB uptake measures have previously been found¹⁸. Together with these findings, our results may indicate links between oxidative stress, amyloidosis, and cognitive decline.

Decreased NAA and increased mI in MCI/AD have been long established^19,20. It is notable that mI was the only metabolite to be associated with the MMSE score in this study, suggesting that it may serve as a functionally unspecific indicator of disease severity.

Conclusion

Results of this 7T MRS study revealed several region-specific effects of MCI on brain metabolite levels. Interactions between metabolite levels and cognitive scores were observed for specific brain regions. This suggests that key mechanisms in MCI/AD pathophysiology, such as oxidative stress and disturbed neurotransmission, may contribute to cognitive deficits in a region- and function-specific manner.

Acknowledgements

This work was supported by National Institute of Health grants 2P50AG005146, AG038893, AG041633, UL1 TR 001079, and P41EB015909. RAEE and GO received salary support from R01EB016089, R01EB023963, R01MH106564, and R21MH098228.

References

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Figures

Figure 1. Voxel placement in the ACC (upper panel) and PCC (lower panel). For both voxels, dimensions were 28 mm (anterior-posterior) × 16 mm (left-right) × 20 mm (caudal-cranial).

Figure 2. Representative spectra (black) and LCModel fits (red) for STEAM data from ACC (left panel) and PCC (right panel). Fit residuals are shown at the top of the respective panel.

Table 1. Quantitative results of post-hoc group comparisons after two-way ANCOVA analysis, with metabolite levels as dependent variable, group and region as independent variables, and age, as covariate. Results were tested for statistical significance at a single-test alpha level of 0.05. The table shows the group mean with the standard error of the mean (SEM) in parentheses.

Table 2. Results of linear regression analysis for relationships between metabolite levels and cognitive test measures for the combined group (both control and MCI subjects). P values represent partial correlations between metabolite levels (or age) and cognitive test measures. R² is the adjusted value for the complete linear regression model including age as covariate. Partial correlations between metabolite levels and cognitive test measures were considered significant at a single-test alpha level of 0.05.

Proc. Intl. Soc. Mag. Reson. Med. 27 (2019)

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