This study shows that aMCI subjects that progress to a diagnosis of AD within 18 months have a greater degree of grey matter loss at baseline than aMCI subjects that do not progress to AD within three years. In fact, the aMCI-S subjects showed no significant regions of grey matter loss on VBM when compared to a group of controls. These results suggest that patterns of atrophy on MRI could be useful to predict subsequent progression to AD in subjects with aMCI if an image analysis method that provided single-subject classification were employed36, 37
The patterns of atrophy identified in the aMCI-P versus control comparison were typical of those observed in AD33, 38–40
. Grey matter loss was observed throughout the medial and inferior temporal lobes, the temporoparietal association neocortex and the frontal lobes on VBM, and hippocampal atrophy was observed using volumetric measurements. These structures have been previously identified in subjects with MCI using both VBM15, 16, 41–44
and ROI techniques5, 45, 46
, and are involved pathologically in AD47
. The superior temporal gyrus was relatively spared however, suggesting that atrophy of this structure would not help predict progression to AD in subjects with MCI and also perhaps that atrophy of this structure may occur later in the disease course than the other temporal regions. Previous studies have similarly shown less severe involvement of the superior temporal gyrus compared to the medial and inferior temporal lobes in subjects with MCI and AD48, 49
. In addition, a previous longitudinal study has shown that atrophy of the superior temporal gyrus does not occur until moderate stages of AD50
. The patterns of loss were more widespread than those observed in some previous VBM studies51
of aMCI, most likely because the subjects in this study were all within 18 months of progression to AD. The aMCI-P group also had a greater WMH burden and had a larger proportion of subjects with lacunar infarcts on MRI than the control group. This is consistent with previous studies that have shown that subjects are more likely to be demented if they have a combination of vascular and AD pathology at autopsy52
. White matter hyperintensity burden has also been shown to be higher in subjects with AD than those with MCI, and higher in subjects with MCI than controls53
Interestingly, no significant regions of grey matter loss were identified on VBM in the aMCI-S subjects when compared to controls. These subjects were selected based on the fact that they did not progress to AD during a minimum required follow-up of three years, but also that they did not progress to AD during their subsequent clinical follow-up if this was longer than three years. The median follow-up time was actually three years and eight months. The aim of these inclusion criteria were to try to select subjects that are truly clinically stable, and exclude subjects that progress shortly after the follow-up cut-off point. Indeed, the aMCI-S subjects did not decline cognitively over the three years from the MRI scan. The fact that we observed no significant grey matter loss in this group on VBM raises the possibility that a number of these subjects do indeed not have a progressive neurodegenerative disorder. These subjects may instead be presenting with non-progressive memory impairment. In line with this theory is the fact that the frequency of the AD risk factor APOE e4 was slightly lower (44%) than the aMCI-P group (65%) and the frequency typically observed in AD54
. However, the frequency in the aMCI-S group was higher than that observed in the control group (18%) which suggests that a number of these subjects may still have prodromal AD, but of a less rapidly progressive nature. The fact that the volumetric measurements demonstrated hippocampal atrophy in the aMCI-S subjects also fits with this suggestion and reflects the fact that these subjects did have memory impairments. The curious observation that no hippocampal atrophy was observed in the aMCI-S to control VBM comparison may be due to the fact that the aMCI-S subjects were anatomically heterogeneous with some having hippocampal atrophy and others not. It is possible that subjects that have shown memory impairment for so long but still show normal activities of daily living, and therefore do not fulfill criteria for AD, are in some way protected against cognitive decline. Recent studies have shown that high levels of education and occupational attainment help retain cognitive function in old age55
. Indeed the aMCI-S subjects had slightly more years of education than the aMCI-P group and performed better on the CDR-SOB and MMSE. Only one previous VBM study has reported patterns of grey matter loss in aMCI-S subjects compared to controls16
. In contrast to our study they identified widespread regions of grey matter loss in the frontal lobes, fusiform gyrus and inferior temporal gyri, suggesting that a high proportion of their subjects would ultimately progress to AD. The average clinical follow-up time in that study was however only 28 months compared to the 44 months of follow-up in our study.
A direct VBM comparison was performed between the two aMCI groups and we found significantly greater grey matter loss in the aMCI-P group compared to the aMCI-S group. Regions that showed greater loss were found in the medial and inferior temporal lobes, the temporoparietal association neocortex, frontal lobes and in the posterior cingulate and precuneus. A number of studies have similarly shown greater atrophy of temporal lobe structures, including the hippocampus5, 56, 57
, entorhinal cortex56, 57
, and parahippocampal gyrus6
, in MCI-P compared to aMCI-S subjects, but no previous studies have shown greater involvement of the temporoparietal cortex and the posterior cingulate. It is notable however that less medial and inferior temporal loss was observed in the aMCI-P group when compared to aMCI-S, than when they were compared to the control group. This fits with the fact that the aMCI-S subjects did show hippocampal atrophy on volumetric measurements, and again supports the earlier suggestion that some of the aMCI-S subjects may ultimately progress to AD. Previous VBM studies that have compared aMCI progressors to stables found very few grey matter differences between the groups15, 16
. One previous study identified differences in the hippocampus, parahippocampal gyrus, and lingual and fusiform gyri, whereas another found differences in the frontal lobes, left supramarginal gyrus and the right hippocampus. The reason these studies found fewer differences between the groups was likely because they had smaller numbers of subjects and the clinical follow-up was less than in our study. Therefore a proportion of their “stables” may actually have progressed relatively soon after the follow-up cut-off, but this event was not detected because of short follow up times.
There was however an unusual finding in the patterns of loss across the different group-wise comparisons performed. Greater grey matter loss was observed in the frontal lobes, parietal lobes, posterior cingulate and precuneus, in the comparison between aMCI-P and aMCI-S than in the comparison between aMCI-P and controls. This is counter-intuitive since one would expect the control group to show less atrophy and be more homogeneous than the aMCI-S subjects. Whereas these results suggest the opposite, that the aMCI-S subjects had greater grey matter volumes at baseline than the control subjects. The direct VBM comparison did not show any regions of greater grey matter loss in controls than aMCI-S subjects but this may have due to the harsh statistical threshold applied. It is possible therefore that aMCI subjects that remain stable may have started with a greater grey matter reserve than those that progress to AD, however we can not prove this.
The strengths of this study were the fact that that we had a relatively large number of well matched aMCI-P and aMCI-S subjects with a long period of clinical follow-up. In addition, we had longitudinal cognitive data that showed that the aMCI-S subjects remained stable on tests of cognitive function for at least three years after the MRI, whereas the aMCI-P subjects showed increasing CDR-SOB and decreasing MMSE over time. The fact that the aMCI-P subjects showed a stable performance on the AVLT suggests that this test may not be a good marker of disease progression, although it appears to provide good discrimination between the groups at baseline. However, a limitation to the clinical utility of this study is that although VBM is a useful tool to identify patterns of loss in groups of subjects it does not provide valuable information on a single subject basis. In order for these patterns to be prognostic they will need to be identified in individual subjects36, 37