Naa In Normal Aging

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Considerable evidence suggests that normal aging is associated with gradual impairment of memory functioning [1]. The medial temporal lobe, especially the hippocampus, plays a central role in declarative memory processing [2]. However, magnetic resonance imaging (MRI) studies have produced controversial results concerning the age-related hippocampal volume loss, which could be due in part to the non-specificity of volume shrinkage as an indicator for neuron loss. In contrast to volume, NAA is generally considered a marker for viable neurons, because NAA reaches detectable concentrations only in neuronal tissue but not in other brain tissues, including glial cells. Using proton magnetic resonance spectroscopic imaging (1H MRSI) and MRI together, we studied hippocampal metabolites and volumes in 24 healthy adults from 36 to 85 years of age. Our goals were to test whether NAA levels vary in the hippocampus as a function of normal aging and 2) to determine the relationship between hippocampal NAA and volume changes. We found NAA/Cho ratios decreased by 24% (r = -0.53, p = 0.01) and NAA/Cr ratios decreased by 26% (r = -0.61, p < 0.005) over the age range studied, while Cho/Cr remained stable, implying diminished NAA levels. In the same population, hippocampal volume shrank by 20% (r = -0.64, p < 0.05). The relationships of these measures with aging are depicted in Figure 1. Since NAA is considered a marker

Magnetic Resonance Unit VA Medical Center, Department of Radiology, University of California, San Francisco, CA 94121 USA. Email: [email protected].

of neurons, these results provide stronger support for neuron loss in the aging hippocampus than volume measurements by MRI alone.

NAA/Cho NAA/Cr Volume [mm3]

NAA/Cho NAA/Cr Volume [mm3]

Canavan Disease

Figure 1. Age-related changes in metabolite concentrations and volume in hippocampus.

Figure 1. Age-related changes in metabolite concentrations and volume in hippocampus.

Since contributions to the NAA signal may arise from both gray and white matter tissue, it is critical to differentiate between metabolite changes of gray and white matter, and other tissue types. One approach for differentiation is the use of linear regressions to predict the relationship between metabolite intensity changes and gray/white matter variations in MRSI voxels (4,8-12). However, most previous MRSI studies that used linear regression averaged metabolite concentrations over different lobes of the brain, ignoring regional variations. In addition, tissues other than gray and white matter were ignored or not determined, such as white matter lesions, which occur frequently in the aged brain. We developed an approach for obtaining metabolite concentrations of gray, white matter, as well as of white matter lesions in different lobes of the brain using linear regression. We applied the new technique to measure NAA concentrations in the frontal and the parietal lobe in 40 normal elderly subjects (56 to 89 years, mean age 74 ± 8, 22 female, 18 male). NAA was about 15% lower in cortical gray matter and 23% lower in white matter lesions when compared to normal white matter. Cr was 11% higher in cortical gray than in white matter, and also about 15% higher in the parietal cortex compared to the frontal cortex. Cho was 28% lower in cortical gray matter than in white matter. Furthermore, NAA and Cr changes correlated with age. The results suggest that in addition to the hippocampus, age-related neuronal changes can also occur in cortical regions, while white matter regions seem to be spared.

2. NAA IN DEMENTIA 2.1 Alzheimer's Disease

The first 1H MRSI study on AD from this laboratory [8] showed abnormalities of metabolite ratios of NAA, and choline (Cho) and creatine (Cr) containing compounds in white and gray matter of the centrum semiovale. Decreased levels of NAA in white matter suggest diffuse axonal loss or damage. Decreased NAA in gray matter suggests loss of neurons, while increased Cho may result from membrane breakdown products.

The second study from this laboratory [9] using similar 1H MRSI methods extended the observation of metabolic abnormalities in the centrum semiovale to a larger population of AD patients and controls, and in addition, included a group of patients with subcortical ischemic vascular dementia (SIVD). While the findings from the AD and control groups were similar to the first study, different metabolite changes were noted in SIVD patients, supporting the possibility that 1H MRSI may provide information to differentiate AD from SIVD. Finally, the third report from this laboratory [10] investigated the extent to which these metabolic differences between patients and controls were independent of variations in the tissue composition of the MRSI voxels (e.g. enclosed amounts of gray matter, white matter, and WM signal hyperintensities). This analysis was made possible by using information from MRI tissue segmentation coregistered with the 1H MRSI data. Although the analysis revealed significant variations of the tissue composition in the regions of interest, these changes did not contribute significantly to the metabolite differences, indicating that reduced NAA/Cho and increased Cho/Cr in posterior mesial gray matter of AD were not simply an artifact of these structural variations. However, limitations of these previous studies were a relatively small number of subjects and an early MRI technology with relatively (compared to today's standards) thick slices (5 mm) and interslice gaps (0.5 mm), which compromised accuracy of tissue segmentation. Furthermore, acquisition of the 1H MRSI data was performed at a relatively long spinecho time (TE) of 272ms and further metabolite ratios rather than concentrations were reported. Subsequent MRSI studies from this lab tried to overcome these limitations.

We subsequently studied 28 AD patients and 22 healthy elderly using 1H MRSI and MRI for image segmentation. 1H MRSI data were aligned with MRI segmentation data to obtain volume-corrected metabolite concentrations. The results were: NAA levels were significantly reduced in frontal and posterior mesial cortex of AD, consistent with previous results from NAA ratios. Furthermore, the NAA reductions were independent from structural variations as measured by MRI, and in parietal mesial cortex correlated mildly with dementia severity. But NAA combined with MRI measures did not improve discrimination power for AD over that of MRI alone. While these results from frontoparietal brain showed reduced NAA in AD is not an artifact of underlying structural variations, and thus may provide useful information in addition to MRI, these NAA reductions were of limited use for diagnosis of AD.

Since the hippocampus is thought to be earlier involved in AD pathology than cortical regions, we tested in another MRSI study the hypothesis that hippocampal NAA and volume used together provide greater discrimination between AD and normal elderly than does either measure alone. We used proton magnetic resonance spectroscopic imaging (1H MRSI) and tissue segmented and volumetric MR images to measure atrophy corrected hippocampal NAA and volumes in 12 AD patients (mild to moderate severity) and 17 control subjects of comparable age. In AD, atrophy corrected NAA from the hippocampal region was reduced by 15.5% on the right and 16.2% on the left (both p<0.003), and hippocampal volumes were smaller by 20.1% (p < 0.003) on the right and 21.8% (p < 0.001) on the left when compared to control subjects. The NAA reductions and volume losses made independent contributions to the discrimination of AD from control subjects. When used separately, neither hippocampal NAA nor volume achieved to correctly classify AD patients better than 80%. When used together, however, the two measures correctly classified 90% of AD and 94% of control subjects. The separation between AD and controls using NAA and volume of the hippocampus together is depicted in Figure 2. In conclusion, hippocampal NAA measured by 1H MRSI combined with quantitative measurements of hippocampal atrophy by MRI may improve diagnosis of AD.

Canavan Naa Metabolism
Figure 2. Comparison of hippocampal volume and NAA levels in Alzheimer's patients (filled circles) and control subjects (open circles).

2.2. Subcortial Ischemic Vascular Dementia

The contribution of subcortical ischemic vascular disease (SIVD) to cognitive impairment and dementia is poorly understood. Disruption of subcortical-cortical connections by strategically located infarctions are considered one important mechanism for cognitive impairment in SIVD.(1) MRI studies from our group found that cognitive deficits in patients with SIVD were strongly correlated with brain atrophy, while subcortical infarctions made little contributions.(2' 3) Aside from greater numbers of ischemic lesions and more extensive white matter hyperintensities (WMH), other MRI studies comparing SIVD and AD have shown atrophy in the hippocampus and entorhinal cortex in both dementias, though less prominent in SIVD than in AD.(4, 5) Furthermore, some SIVD patients without AD pathology confirmed by autopsy had reduced hippocampal and cortical gray matter volumes.'(2) Therefore, MRI has limited ability to differentiate between SIVD and AD. Although we found a stereotypical regional pattern of NAA losses in AD that involved the hippocampus and parietal gray matter, but not frontal gray matter and white matter, regional differences in NAA reductions between SIVD and AD have not thoroughly been investigated before. Therefore, in a new MRSI study that included 13 SIVD patients (71 ± 8 years old), 43 AD patients of comparable age and dementia severity to SIVD, and 52 cognitively normal subjects with and without lacunes, we sought to determine the regional pattern of NAA in gray matter, white matter, and WMH in SIVD. We found that compared to controls, SIVD patients had lower NAA by 18% ( p < 0.001) in frontal cortex and by 27% (p < 0.003) in parietal cortex, but no significant NAA reduction in white matter and medial temporal lobe. Compared to AD, SIVD patients had lower NAA by 13% (p < 0.02) in frontal cortex and by 20% (p < 0.002) in left parietal cortex. Cortical NAA decreased in SIVD with increasing white matter lesions (r = 0.54, p < 0.02) and number of lacunes (r=0.59, p < 0.02). In particular, thalamic lacunes were associated with greater NAA reduction in frontal cortex than lacunes outside the thalamus (p < 0.02) across groups, after adjusting for cognitive impairments, as shown in Figure 3.

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