There were distinct groupwise differences in MRI and 1
H MRS findings between single-domain aMCI and naMCI subtypes. Patients with single-domain aMCI tended to have smaller hippocampal volumes and elevated mI:Cr ratios compared with patients with naMCI and cognitively normal subjects. On the other hand, patients with naMCI had normal hippocampal volumes and normal mI:Cr ratios, but a greater proportion of these patients in our sample had cortical infarctions compared with the patients with single-domain aMCI. Both hippocampal atrophy and elevated mI:Cr ratios are sensitive markers of early AD pathological changes, and the severity of these abnormalities correlate with pathological severity of AD.14–20
For this reason, hippocampal atrophy and elevated mI:Cr ratios most likely represent a high frequency of early AD pathological changes in the patients with single-domain aMCI. On average, hippocampal volumes and mI:Cr ratios in the naMCI subtype suggest that underlying pathological substrates may include abnormalities other than AD in some patients with naMCI. Mixed brain abnormalities, including AD cerebrovascular and Lewy body disease, underlie most cases of dementia in the community.50
It appears likely from the higher prevalence of cortical infarctions in patients with naMCI that large-vessel cerebrovascular disease was one of the pathological contributors to naMCI, in agreement with a previous study showing that a greater proportion of patients with naMCI experienced transient ischemic attacks and stroke compared with patients with aMCI32
MRI and 1H MRS Characteristics of MCI Subtypes and the Pattern of Imaging Abnormalities That Relate to AD or CVD
On the other hand, we found a similar apolipoprotein Eε4 frequency in the naMCI and aMCI groups, yet we demonstrate that patients with naMCI on average do not have the magnetic resonance features of AD, and by definition they present with an early AD phenotype (ie, predominantly memory impairment). One possible way to reconcile these seemingly contradictory findings, although speculative, is that some patients with naMCI have AD pathological features but in an atypical anatomical distribution, thus accounting for the non–AD-like magnetic resonance findings and clinical presentation. In support of this, autopsy studies have documented the presence of AD pathological characteristics in an atypical distribution in subjects who present with a non–AD-like clinical profile.51,52
However, this will require follow-up, preferably to autopsy.
Multinomial modeling demonstrated that elevated mI:Cr and Cho:Cr ratios and increased WMH volumes were complementary to smaller hippocampal volumes in distinguishing the clinical groups. This is in agreement with a previous finding that 1
H MRS metabolites improve discrimination of cognitively impaired nondemented individuals from their cognitively normal peers, when considered together with hippocampal volumes.25
H MRS findings and hippocampal volume are independent and complementary predictors of verbal memory on neuropsychometric testing in nondemented older adults.53
The added value of 1
H MRS metabolites, hippocampal volumes, and WMH volumes in characterizing the MCI subtypes suggests that 1
H MRS scans may complement structural MRI findings as a prognostic marker in MCI; however, this will require longitudinal studies for verification.
The magnetic resonance findings in patients with multiple-domain aMCI showed some similarities to those of patients with single-domain aMCI and naMCI. These patients had some hippocampal atrophy, but this was less than the hippocampal atrophy observed in patients with single-domain aMCI. Furthermore, they typically had normal mI:Cr ratios on 1H MRS findings, suggesting that if these patients had pathological AD, it would be on average less severe than in patients with single-domain aMCI. On the other hand, in our sample, the proportion of patients with multiple-domain aMCI and cortical infarctions was more than twice as high as that for patients with single-domain aMCI. For this reason, our data suggest that AD and cerebrovascular disease, in variable amounts, are some of the underlying abnormalities in the patients with multiple-domain aMCI in this study.
Contrary to the evidence of varying prevalence rates of cortical infarctions, we did not observe any difference in the proportion of patients with subcortical infarctions among cognitively normal subjects and the 3 MCI subtypes. The possibility that cortical and subcortical infarctions have a differential effect on future progression to dementia is currently unclear. One study found that subcortical infarctions did not increase the risk of progression to dementia in MCI.54
Others have shown that silent infarctions, most of which were presumably subcortical, increase the risk of future dementia in cognitively normal elderly individuals.55
The patients with single-domain aMCI had a greater WMH volume compared with cognitively normal elderly subjects. On the other hand, we did not identify a difference in the estimated WMH volume among the MCI subtypes. Because the frequency of subcortical infarctions was also similar across the MCI subtypes, our data suggest that subcortical vascular disease is a common but not a differentiating feature of the MCI subtypes. This is consistent with the previous reports that WMH is associated with an increased risk of MCI and that there is no association between subcortical hyperintensity load and different MCI subtypes.30,56,57
This study has several limitations. First, we classified infarctions as cortical and subcortical and did not further investigate the effects of the location, number, and size of the infarctions on cognitive function in MCI. This was a deliberate choice because the small number of subjects with infarctions prevented any coherent grouping of infarctions by detailed anatomical criteria for group-wise analysis. Second, cognitively normal subjects were neurologically healthy individuals who did not have a clinical history of stroke or cortical infarctions. They were included in this study to test for the abnormalities in quantitative magnetic resonance markers in MCI subtypes without the confounding effects of overt known neurological diseases. It is possible, although not common, for cognitively normal subjects to have cortical infarctions. Therefore, the absence of cortical infarctions in the cognitively normal subjects of this study cannot be generalized to the population. Third, although it is expected, based on pathological series, that DLB is one of the underlying abnormalities in MCI subtypes,50,58
the presence of DLB-related imaging changes was not evaluated in this study because there are no established magnetic resonance markers for prodromal DLB. Normal hippocampal volumes and 1
H MRS in naMCI do not rule out the presence of Lewy body disease because patients with DLB on average have normal hippocampal volumes and normal posterior cingulate gyrus NAA:Cr and mI:Cr ratios.21,59
Although patients with DLB have elevated Cho:Cr ratios on 1
H MRS findings, it is not clear whether the Cho:Cr ratio elevation in the posterior cingulate gyrus is a feature of prodromal DLB. For these reasons, DLB may be one of the underlying pathological findings in MCI subtypes.
Our data indicate that specific constellations of magnetic resonance findings are complementary in characterizing MCI subtypes and cognitively normal individuals. The MRI and 1H MRS findings in patients with single-domain aMCI are characterized by an AD-like pattern of elevated mI:Cr ratios in the posterior cingulate gyrus and hippocampal atrophy. On the other hand, patients with naMCI do not have the magnetic resonance features of AD and are more likely to have cortical infarctions. Magnetic resonance findings in patients with multiple-domain aMCI show similarities to those in patients with single-domain aMCI and naMCI. Clinical follow-up will demonstrate the combinations of MRI and 1H MRS findings that are useful in determining which MCI patients will experience progression to specific dementia syndromes in the future.