The data from this longitudinal MR study in MCI indicate that small hippocampal volumes, decreased neuronal marker NAA/Cr, and the presence of cortical infarctions additively increase the risk of progression to dementia in patients with MCI. Hippocampal volume is one of the most investigated imaging markers for early diagnosis of AD and has been a strong predictor of the risk of progression to AD in aMCI.30
In the current study, hippocampal atrophy increased the risk of future progression to dementia in a broadly defined MCI cohort of both aMCI and naMCI subjects. Furthermore, decreased posterior cingulate gyrus NAA/Cr increased the risk of progression to dementia in MCI patients with hippocampal atrophy. This is consistent with cross-sectional studies showing the added value of 1
H MRS and hippocampal volumes for discriminating cognitively impaired individuals without dementia from cognitively normal subjects.31
Hippocampal volumes and NAA/Cr levels have also been shown to be independent and complementary predictors of verbal memory on neuropsychometric testing in older adults without dementia, demonstrating that verbal memory depends on both structural and metabolic integrity of the hippocampus.32
NAA is synthesized in the neuronal mitochondria, and NAA levels are thought to reflect the integrity of neuronal mitochondrial metabolism.33
The volume of the hippocampus, on the other hand, is closely associated with hippocampal neuronal density.34
Our data suggest that the risk of progression to dementia in MCI increases when neuronal loss in the hippocampus is accompanied by impairment in neuronal metabolic integrity in the posterior cingulate gyrus. These MR findings from two different regions of the brain may be related to a common pathologic mechanism reflecting incremental involvement with the neurodegenerative pathology from hippocampus to the posterior cingulate gyrus as patients with MCI progress to AD. Another possible explanation, however, is the association between the neuronal changes in these regions and different pathologic mechanisms that are somewhat related but collectively increase the risk of dementia in MCI. For example, decreased glucose metabolism in the posterior cingulate gyrus on PET, which is thought to reflect decreased synaptic activity in this region, is a predictor of future progression to AD in MCI.35,36
Decreased neuronal metabolic integrity measured with NAA/Cr in the posterior cingulate gyrus may be related to a similar pathologic mechanism such as loss of synaptic integrity that increases the risk of dementia in MCI patients with hippocampal atrophy.
Presence of a cortical infarction increased the risk of progression to dementia in MCI when considered together with decreased hippocampal volumes and NAA/Cr levels. Autopsy studies indicate that people with infarctions are more likely to have dementia and can develop dementia with fewer plaques and tangles than those without infarctions.37,38
Furthermore, in a recent community-based autopsy cohort, older persons with multiple brain pathologies such as AD, infarctions, and Lewy body disease were more likely to have dementia than those who had only one of these pathologies.39
In the current study, hippocampal atrophy was a strong predictor of future dementia in MCI by itself. However, the presence of cortical infarctions increased the risk of dementia in those patients with hippocampal atrophy, demonstrating that patients with MCI progress to dementia faster if they have cortical infarctions along with findings associated with AD on MRI.40
This is in agreement with clinical–pathologic studies indicating that individuals with multiple brain pathologies have increased odds of dementia compared with individuals with a single pathology.39
Conversely, in our study subcortical infarctions did not predict progression to dementia in MCI, consistent with a previous longitudinal study in MCI,11
but not with other clinical–pathologic studies.38
WMH volume did not have an effect on the risk of dementia in patients with MCI in the multivariable model. WMH has been implicated as an important surrogate for subcortical ischemic disease in the CNS, influencing cognitive function. WMH is associated with an increased risk of cognitive decline in cognitively normal elderly.7–10
However, several studies have found no relationship between WMH and future cognitive decline in patients with MCI and AD,11–14
and our findings are consistent with this. A way to synthesize our findings in WMH and risk of progression from MCI to dementia in a manner that is consistent with the literature is the following: We speculate that the presence of WMHs is associated with a mild disturbance in cognitive function, but it is not a progressive pathology that by itself will lead to dementia. Therefore, the presence of WMHs may increase the odds of an individual receiving a diagnosis of MCI but does not increase the likelihood of progressing from MCI to dementia. That is, WMHs tend to drive people into the diagnostic category of MCI but does not drive them out of MCI to dementia. In contrast, AD pathology (manifested as hippocampal atrophy and decreased NAA/Cr) increases both the likelihood of receiving a diagnosis of MCI and of progressing from MCI to dementia. This set of circumstances leads to the result we found here that higher WMH does not increase the risk of progression from MCI to AD in a cohort of subjects with both WMHs and neurodegenerative pathology.
This study was designed to identify MRI and 1
H MRS predictors of progression to dementia in MCI. Although there are well-known genetic and clinical features that increase the risk of progression to dementia in MCI, they were not included in this study because of the large number of imaging variables we investigated. Larger cohorts are required to determine the complementary role of genetic, clinical, and imaging variables on the risk of progression to dementia.27
We also note that the subjects of this study were consecutive patients with MCI recruited from community and dementia clinics, and on average had less cognitive impairment and were more educated than the patients with MCI who did not participate in the current study. Therefore, these findings should be confirmed in a population-based cohort. Based on the multivariate modeling, we estimated that in 3 years, three times as many (78% vs 26%) MCI patients with hippocampal atrophy, low posterior cingulate gyrus NAA/Cr, and at least one cortical infarction will progress to dementia, compared with MCI patients with preserved hippocampal volumes, higher-than-average posterior cingulate NAA/Cr levels, and no infarctions. Each one of the three MR predictors contributed to the risk of dementia independently as the risk of dementia increased with the number of MR abnormalities.