Original ContributionsA 1H MRS study of probable Alzheimer’s disease and normal aging: implications for longitudinal monitoring of dementia progression
Introduction
In addition to structural and volumetric MRI measures, single voxel proton magnetic resonance spectroscopy (1H MRS) is currently being investigated as an additional non-invasive tool to monitor neurodegenerative diseases. Localized 1H MRS can detect N-acetyl containing compounds (NA), consisting primarily of N-acetylaspartate (NAA) and, to a lesser extent, N-acetylaspartylglutamate (NAAG). Although difficult to resolve in vivo, these compounds are important putative markers for neuronal viability.1, 2, 3 Membrane biosynthesis and metabolism can be investigated by monitoring creatine, phosphocreatine (Cr) and choline containing compounds (Chol), namely free choline, phosphocholine and glycerophosphocholine.2, 3 The organic osmolyte myo-inositol (mI) is a possible glial cell marker4 and has been postulated as a breakdown product of abnormal cerebral inositol polyphosphate–inositol phosphatide metabolism.5
With respect to Alzheimer’s disease (AD), the majority of 1H MRS studies have reported a reduction in the concentration of NA relative to age-matched normal control subjects. The reduction in the NA levels have been reported either as an absolute measurement or as a decrease in the metabolite ratios of NA/Cr and NA/Cho.6, 7, 8, 9, 10, 11, 12, 13, 14, 15 In addition, an increase in the concentration of mI has been observed.8, 9, 10, 14 No significant differences in the levels of Chol or Chol/Cr have been reported between the two groups.6, 7, 8, 9, 10, 11, 12, 14 The majority of studies using absolute metabolite measures have found no change in the concentration of Cr in the brains of AD patients,6, 8, 9, 15 although one investigation has reported a significant reduction compared with normal controls.10
Despite the increasing number of 1H MRS investigations of neurodegenerative diseases, there is a paucity of data demonstrating the reproducibility and temporal stability of the metabolite measures in normal populations. Of the few studies that have been published, all have reported data acquired from younger subjects. Marshall et al.16 reported coefficients of variation (CV) for “between days” measurements of NA/Cr and Chol/Cr of between 10.1 and 22.6 percent. Simmons et al.17 reported CV values for these ratios of 4.61 and 7.12%, respectively. Both of these studies employed long echo time (TE of 135 ms) spectroscopy protocols. Two reproducibility studies have been reported using short TE MRS (TE < 30 ms). Narayana et al.18 presented grouped data with little information regarding intrasubject reproducibility, while those reported by Kreis et al.19 were presented as a “systematic trend” of variability of approximately 5%. To the best of our knowledge, no study has yet investigated the reproducibility and stability of single voxel 1H MRS measurements in a cohort of normal older adults.
A coherent approach to the analysis of repeated 1H MRS measurements is yet to be proposed and implemented. In this paper, we utilize the coefficient of variation (CV) to assess measurement precision, and the Pearson product moment correlation coefficient20 (r) to quantify the relationship between metabolite data from two longitudinal spectral acquisitions in normal subjects.22 Since spectra are acquired from the same subject on two or more occasions, it is often assumed that differences between spectral measurements are solely due to measurement error. However, the length of time between acquisitions may also be a significant contributing variable. For example, Marshall et al.16 acquired spectra over four days, whereas Narayana et al.18 acquired data over a six-month period. Determining the consistency of spectra obtained over long intervals involves an assumption that the neuronal compounds of interest themselves do not change, i.e., that they are stable. This assumption may or may not be valid. In this paper, we use the term reproducibility to refer to data obtained within the same day and conversely, use the term stability to refer to data obtained over intervals greater than 24 h.
The relationship between relative or absolute cerebral metabolite measures and cognitive dysfunction in AD patients has only recently been addressed. Significant correlations between NA/Chol, NA, and Mini Mental State Exam (MMSE)21 scores have been reported.14, 10, 22 In the present study, we report reproducibility and stability data for both relative and absolute measures of NA, mI, Cr, and Chol in a cohort of normal older adults. In addition, we report differences in these neuronal compounds between patients with probable AD and control subjects. To further establish the efficacy of 1H MRS in monitoring AD progression, relative and absolute metabolite measures were correlated with MMSE scores and indices of atrophy (as measured by CSF and GM composition) in the localized voxel.
Section snippets
Materials and methods
Thirty-three normal older adults (18 male, 15 female) and thirteen subjects with probable Alzheimer’s disease who volunteered for a longitudinal study of Alzheimer’s disease and normal aging conducted at the Center for Magnetic Resonance, University of Queensland participated in the study. A subgroup of twenty-seven of the normal subjects (16 male, 11 female, mean age 73.6 ± 3.7 years) were involved in the reproducibility and stability study of relative metabolite measures. From this group
Results
Spectra from a representative subject are shown in Fig. 2. Spectra A and B, representing the first and second time points, respectively, were acquired within the same day. Spectrum C represents a longitudinal acquisition obtained 180 days after the initial same day scans. The means and standard deviations for the metabolite measures NA, mI, Cr, Chol, NA/Cr, mI/Cr, Chol/Cr and NA/mI for each time point are presented in Table 1. There was no significant difference between the mean values of
Discussion
The absolute metabolite concentrations and ratios reported in this study are comparable with those reported by Moats et al.8 and Provencher27 from gray matter voxels in the parietal cortex. In addition, the coefficient of variation analysis of the spectroscopic data reveals a level of reproducibility equal to, or better than those reported in the literature to date.16, 17, 18 However, this interpretation is based on the calculation of mean metabolite ratios and standard deviations over all time
Acknowledgements
This study was supported by a grant from SmithKline Beecham Pharmaceuticals, UK. We would like to thank all subjects who participated in this study and RN Jenny Whitehead and RN Anne Maree Elliott for their assistance.
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