These findings reaffirm the importance of an MRI measure of the entorhinal cortex as a predictor of progression from MCI to a diagnosis of AD. In every analysis that was performed, the volume of the entorhinal cortex was a better predictor of progression from MCI to AD than any of the other 15 temporoparietal MRI measures. These data are in agreement with a number of previous reports that have concluded that the volume of entorhinal cortex is better at predicting likelihood of progression from MCI to AD than the hippocampus. 46–48
These results also emphasize the value of a volumetric measure of the inferior parietal lobule. This measure, when used in combination with the entorhinal cortex, was the best predictor of time to progress from MCI to AD. Moreover, it remained statistically significant even when the volume of the hippocampus was forced into the model. Prior studies using fluid-registration, cortical thickness and voxel-based morphometry have implicated areas within the lateral parietal cortex to be involved in the earliest stages of AD and as a predictor of progression12–18
but this is the first volumetric study, to our knowledge, to demonstrate the relative importance specifically of the inferior parietal lobule in predicting progression in comparison to the many other brain regions within the temporal and parietal lobes.
This finding is consistent with pathological studies of AD showing that specific laminae in the inferior parietal lobule are preferentially affected in the early stages of the disease. 49–50
Moreover, projections from the inferior parietal lobule target several subfields within the medial temporal lobe 51–53
, suggesting that atrophy in the inferior parietal lobule likely reflects the spread of AD pathology from the temporal lobe to an interconnected region in the parietal lobe.
The analyses presented here also demonstrate that MRI volumetric measures may be useful in identifying the subset of MCI subjects who are at a particularly high risk of progression to AD. Those MCI subjects whose entorhinal and inferior parietal lobule volumes were 1 SD below the mean for the group as a whole at baseline had markedly increased risk of progression to AD than those whose volumetric measures did not fall 1 or more SD below the mean. It is increasingly recognized that MCI subjects from a community volunteer-based cohort generally include a broad range of severity. The present findings suggest that it should be possible to use MRI measures, independent of clinical and neuropsychological measures, to identify the subset of MCI subjects at greatest risk for progression.
These findings also suggest that MRI volumetric data provide information concerning time to progress from MCI to AD that is independent of neuropsychological measures that have previously been shown to be significant predictors of progression. A number of temporoparietal regions, including the entorhinal cortex and inferior parietal lobule, continued to significantly predict time to progression, even after the addition of the neuropsychological variables to the bivariate models. Moreover, the entorhinal cortex was retained as one of the best predictors of conversion in the multivariable model that also included a neuropsychological variable, suggesting that MRI and neuropsychological data may provide complimentary information in relation to prediction of progression from MCI to AD. This finding differs somewhat from a recent report suggesting that once neuropsychological measures are considered, the added value of MRI measures is small.47
The difference between the findings reported here and the previous study may be related to the fact that the earlier study examined subjects that were more mildly impaired than those examined in the present study and additionally did not include a test of executive function, such as that included here.
Correlations between tests of episodic memory function (CVLT and SRT) and volumes of the parahippocampal gyrus, temporal pole, and hippocampus are consistent with the fact that these temporal lobe regions are critical for normal memory function (for a discussion of this topic see reference 41
). Of interest, Trails B, a test of executive function, did not demonstrate any significant correlations with any of the temporoparietal regions but was one of the best predictors in the multivariable model when combined with the MRI volumes. This suggests that regions beyond the temporal and parietal lobes are potentially responsible for executive function and may additionally be significant predictors of progression.
A concern in this study pertains to the difference in APOE-ε4 between the two groups. Since more MCI-Converters were APOE-ε4 positive than the MCI-Nonconverters and the ε4 allele of this gene is overrepresented in AD patients compared with the general population54
, one possibility is that the presence of APOE-ε4 alone can best account for the time to progress from MCI to AD. Prior work from our research group has demonstrated the influence of the ε4 allele on the time to progress from MCI to AD is largely accounted for by neuropsychological measures and assessments of clinical severity41
thus disputing the notion that the presence of this allele can solely account for the time to progress from MCI to AD.
The present study has several strengths. The subjects were followed prospectively and then categorized after their symptoms had evolved by clinicians with no access to the MRI data. The image analysis methods presented here permit a comparison of the relative strengths of prediction for each anatomic region within the temporal and parietal lobe and can be combined with survival analyses to determine which individual or combination of ROIs best predict time to progress from MCI to AD.
One limitation of this study is that only brain regions within the temporal and parietal cortices were examined. It is therefore possible that regions elsewhere in the brain may also be significantly related to time to progression from MCI to AD. In addition, a longer follow-up interval may have resulted in a larger number of subjects progressing to AD; as a result other ROIs, in addition to the ones presented here, may have been identified as significant predictors of time to progress from MCI to AD.