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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Arch Neurol. Author manuscript; available in PMC Aug 31, 2009.
Published in final edited form as:
PMCID: PMC2735186
NIHMSID: NIHMS137268

Patterns of Atrophy differ among Specific Subtypes of Mild Cognitive Impairment

Abstract

Objective

To investigate patterns of cerebral atrophy associated with specific subtypes of mild cognitive impairment (MCI).

Design

Case-control study

Setting

Community-based sample at a tertiary referral center

Patients

One hundred and forty-five subjects with MCI subjects and 145 age and gender-matched cognitively normal controls. MCI subjects were classified as amnestic single cognitive domain, amnestic multi-domain, non-amnestic single-domain and non-amnestic multi-domain MCI. The non-amnestic single-domain subjects were also divided into language, attention/executive, and visuospatial groups based on the specific cognitive impairment.

Main Outcome Measure

Patterns of grey matter loss in the MCI groups compared to controls assessed using voxel-based morphometry

Results

The amnestic single and multi-domain groups both showed loss in the medial and inferior temporal lobes compared to controls, while the multi-domain group also showed involvement of the posterior temporal lobe, parietal association cortex and posterior cingulate. The non-amnestic single-domain subjects with language impairment showed loss in the left anterior inferior temporal lobe. The group with attention/executive deficits showed loss in the basal forebrain and hypothalamus. No coherent patterns of loss were observed in the other subgroups.

Conclusions

The pattern of atrophy in the amnestic groups is consistent with the concept that MCI in most of these subjects represents prodromal AD. However, the different patterns in the language and attention/executive groups suggest that these subjects may have a different underlying disorder.

INTRODUCTION

Mild cognitive impairment (MCI) is considered as a transitional stage between normal aging and a diagnosis of clinically probable Alzheimer’s disease (AD). The original description of amnestic MCI noted, but did not explicitly distinguish, two variants: one in which only memory was impaired; the second in which impairments in non-memory domains could be present but memory was the predominant domain impaired. The critical distinction between MCI and AD in subjects with predominant memory impairment plus less pronounced impairment in non-memory domains was preservation of normal activities of daily living. At a consensus conference in Stockholm in 20031, the classification of MCI was expanded to formally recognize that in patients with predominantly memory impairment, other non-memory cognitive domains can be affected including language, attention, and visuospatial skills. It was also recognized that different clinical subtypes of MCI should be defined, based on the specific cognitive domains affected2, 3. In this report amnestic single-domain MCI (aMCI-SD) refers to subjects in which memory is the only impairment; amnestic multi-domain MCI (aMCI-MD) refers to subjects that show impairment in memory and one or more other neuropsychological domain; non-amnestic single-domain MCI (naMCI-SD) refers to subjects that show impairment in one non-memory domain; and non-amnestic multi-domain MCI (naMCI-MD) refers to subjects that show impairment in two or more non-memory domains. This four-group classification scheme proposed in 20031 has been adopted by the National Institute on Aging (NIA) Alzheimer’s Disease Centers Program for the Uniform Data Set. It is also being used to classify subjects for the Alzheimers Disease Neuroimaging Initiative (ADNI). While ADNI uses the 4-group scheme for MCI classification (http://www.adni-info.org/images/stories/Documentation/adni_protocol_03.02.2005_ss.pdf), only amnestic subjects are enrolled in the study. In all previous imaging studies published from the Mayo Clinic, only subjects with amnestic MCI were included in the study analysis. In the present study however, we analyze patterns of grey matter atrophy in subjects from all four possible MCI groups.

The analysis was conducted at two levels: the subjects were first split into the four different subtypes of MCI (i.e. aMCI-SD, aMCI-MD, naMCI-SD, and naMCI-MD), and then the naMCI-SD subjects were further subdivided according to whether the cognitive impairment was language, attention/executive or visuospatial. While all, or nearly all, prior imaging publications have focused on amnestic MCI, early estimates indicate that up to 25% of MCI may be of the non-amnestic variety4. By providing clinical-imaging correlations for each MCI subtype, we hope to help clarify the overall conceptual construct of MCI.

METHODS

Subjects

The Mayo Clinic Alzheimer’s Disease Research Center (ADRC) and Alzheimer’s Disease Patient Registry (ADPR) databases were used to identify all subjects that had a clinical diagnosis of mild cognitive impairment (MCI) and a volumetric MRI within four months of the diagnosis. All cases fulfilled clinical criteria for cognitive impairment2 and were examined and diagnosed by an experienced behavioral neurologist. In all cases the diagnosis was made on clinical grounds without reference to MRI. For this study, in order to assess the anatomic correlations of different subtypes of MCI, a subset of our previous clinical cohorts were defined a priori based on the neuropsychological criteria described below. Written informed consent was obtained from all subjects. The clinical history and MRI scans were reviewed in all cases. Subjects with structural abnormalities that could produce cognitive impairment, or who had treatments or concurrent illnesses interfering with cognitive function either at baseline or during follow-up were not included in this study. MRI scans were rejected for poor quality. The first MRI with a clinical diagnosis of MCI was selected for analysis.

All subjects with MCI that were included in the analysis were age and gender-matched to a control subject. The date/year that the scans were performed were also matched in an attempt to control for any temporal fluctuations associated with different scanner platform versions. All the control subjects were prospectively recruited into the Mayo Clinic ADRC, or the ADPR, and were identified from the ADRC/ADPR database.

Follow-up information was available for a proportion of subjects. The numbers of subjects in each group that have since progressed to a clinical diagnosis of dementia were recorded, along with the specific dementia diagnosis, and the duration of follow-up.

Neuropsychological data

Neuropsychological data were available in all cases within 4 months of the scan date. Neuropsychological tests were classified into memory, language, attention/executive and visuospatial domains as was validated and implemented in a recent large MCI treatment trial5. The memory tests included in this study were the Wechsler Memory Scale – Revised (WMS-R), Logical Memory subtest (LM)6, WMS-R Visual Reproduction (VR), the Rey Auditory Verbal Learning Test (AVLT)7, and the Free and Cued Selective Reminding Tests (FCSRT) total recall score8. The language tests included the Boston Naming Test (BNT)9, Category/Semantic Fluency (CF)10 and the Controlled Oral Word Association Test (COWAT)11. The attention/executive tests included Trail Making Test (TMT) A and B12, and the Digit Symbol and Digit Span subtests of the Wechsler Adult Intelligence Scale (WAIS) – Revised or Third Edition (WAIS-R/WAIS-III)13, 14. The visuospatial tests included the Picture Completion, Block Design and Object Assembly subtests of the WAIS-R/WAIS-III. All tests were administered by experienced psychometrists and supervised by clinical neuropsychologists. Mayo Older American Normative (MOANS) age-adjusted scaled scores15 were used for all neuropsychological variables, except those derived from the WAIS-III. MOANS scores are constructed to have a mean of 10 and standard deviation of 3 among cognitively healthy participants. Early participants in this study had received the WAIS-R and latter subjects the WAIS-III.

Subject classification

A mean MOANS score was created for each domain. This involved taking the mean MOANS scores of all tests in the language, attention/executive and visuospatial domains. In the memory domain a mean was calculated using the percent retention score from the Logical Memory, Visual Reproduction, and short term and long term AVLT, and the Free and Cued total learning score. To be classified as impaired in a domain the mean MOANS score had to be 6 or lower, reflecting a score of 1.3 standard deviations below the control mean of 10, and below the 10th percentile. If the mean MOANS score was 7 or greater the domain was classified as unimpaired.

Subjects were first classified into one of four MCI categories: aMCI-SD (only memory domain impaired), aMCI-MD (memory plus one or more other domains impaired), naMCI-SD (one non-memory domain impaired) or naMCI-MD (more than one non-memory domain impaired). As mentioned above for this study we used a subset of all clinically defined MCI subjects as follows. Of 145 MCI subjects that had usable MRI scans; 88 subjects were classified as aMCI-SD, 25 as aMCI-MD, 25 as naMCI-SD, and 7 as naMCI-MD. The 25 subjects with naMCI-SD were then subdivided into groups based on the domain in which impairment was observed: 10 subjects had language impairment, 9 had attention/executive impairment, and 6 had visuospatial impairment.

Image analysis

All subjects had a T1-weighted volumetric MRI scan acquired at 1.5T (22×16.5cm FOV, 25° flip angle, 124 contiguous 1.6mm thick coronal slices). An optimized method of VBM was applied, implemented using SPM2 (http://www.fil.ion.ucl.ac.uk/spm)16, 17. In order to reduce any potential normalization bias across the disease groups’ customized templates and prior probability maps were created from all MCI subjects and controls in the study. To create the customized template and priors all images were registered to the MNI template using a 12 degrees of freedom (dof) affine transformation and segmented into grey matter (GM), white matter (WM) and CSF using MNI priors. GM images were normalized to the MNI GM prior using a nonlinear discrete cosine transformation (DCT). The normalization parameters were applied to the original whole head and the images were segmented using the MNI priors. Average images were created of whole head, GM, WM and CSF, and smoothed using 8mm full-width at half-maximum (FWHM) smoothing kernel. All images were then registered to the customized whole brain template using a 12dof affine transformation and segmented using the customized priors. The GM images were normalized to the custom GM prior using a nonlinear DCT. The normalization parameters were then applied to the original whole head and the images were segmented once again using the customized priors. All images were modulated and smoothed with an 8mm FWHM smoothing kernel. In addition, a re-initialization routine was implemented as previously described17.

Grey matter differences between each MCI subgroup and the entire control group (n=145) were assessed at an uncorrected statistical threshold (p<0.001), and after correction for multiple comparisons using the false discovery rate (FDR) (p<0.01).

Mean GM images were also created for each MCI subgroup and visually reviewed to assess whether the GM segmentations had been affected by the presence of white matter hyperintensities (WMH). There was no evidence that WMH disproportionately affected the grey matter segmentations in any of the groups, nor was there any evidence of white matter disease incorrectly classified as GM in the group maps.

Clinical data analysis

Subject demographics were compared among the controls, aMCI-SD, aMCI-MD, naMCI-SD and naMCI-MD groups, and separately among the naMCI-SD subgroups (i.e. attention/executive, language and visuospatial). ANOVA was used to compare age and education across groups. Post-hoc pair-wise comparisons were then performed using t-tests. Dichotomised data (i.e. gender and APOE ε4 carrier frequency) was analyzed using the Fisher exact test due to some sparse cell counts. Non-parametric Kruskal-Wallis tests were used to compare Mini-Mental State Examination (MMSE)18 and Mattis Dementia Rating Scale (DRS)19 scores among the MCI groups, with post-hoc pair-wise comparisons performed using the Wilcoxon rank-sum tests. The control group was excluded from the MMSE and DRS analyses because controls by definition were cognitively normal. Within-domain composite MOANS scores were compared across the naMCI-SD subgroups using the Kruskal-Wallis test; with post-hoc pair-wise comparisons performed using the Wilcoxon rank-sum tests. All analyses were performed using the statistical software environment R.2.2.1 (http://www.R-project.org).

RESULTS

Subject demographics

The demographics for the control and MCI subjects are shown in Table 1. There was no statistical difference in age or gender ratio across the control and MCI subgroups. However, both the aMCI-MD and naMCI-MD groups had fewer years of education than any of the other groups (p<0.005). There were also differences in the frequency of APOE ε4 carriers across the MCI subgroups (p=0.05) with rates ranging from 14% in the naMCI-MD group to 60% in the aMCI-SD group. There was no difference in MMSE across the MCI subgroups (p=0.19). There were highly significant differences in average DRS score across the MCI groups (p<0.001); using pairwise comparisons the aMCI-MD and naMCI-MD groups had a lower DRS score than the aMCI-SD and naMCI-SD groups (p<0.03 for all). The follow-up information for all groups is shown in Table 2 and Table 3. Of the aMCI-SD subjects that converted to dementia, the majority converted to a diagnosis of AD, whereas a lower proportion of the naMCI-SD, naMCI-MD and aMCI-MD subjects converted to AD. While a number of subjects with single-domain impairments in attention and language converted to AD, some converted to other dementias. For example, two of the naMCI-SD subjects with attention impairment converted to DLB, while one of those with language impairment converted to FTD.

Table 1
Clinical characteristics of all MCI subgroups
Table 2
Follow-up diagnostic information for each MCI group and controls
Table 3
Follow-up diagnostic information for each of the single-domain MCI groups

Image analysis

aMCI-SD

The pattern of grey matter loss in the aMCI-SD group focused on the medial and inferior temporal lobes, including the hippocampus, amygdala, entorhinal cortex and parahippocampal gyrus, compared to controls (p<0.001, uncorrected for multiple comparisons, Figure 1A). Loss was bilateral although slightly greater on the left. The parietal association neocortex, posterior corpus callosum, and midbrain were also involved to a lesser extent (Figure 1A and and2).2). After correction for multiple comparisons the medial and inferior temporal lobe and a small area in the midbrain, remained involved (p<0.01).

Figure 1
Patterns of grey matter atrophy identified by voxel-based morphometry in amnestic single-domain (A), amnestic multi-domain (B), non-amnestic single-domain (C), and non-amnestic multi-domain (D) MCI subgroups compared to controls (p<0.001, uncorrected ...
Figure 2
Surface rendering showing patterns of grey matter atrophy (shown in red) in A) amnestic single-domain, and B) amnestic multi-domain MCI subjects compared to controls (uncorrected, p<0.001). L = left, R = right.

aMCI-MD

The aMCI-MD group also showed a pattern of grey matter loss predominantly affecting the medial and inferior temporal lobes compared to controls (p<0.001, uncorrected, Figure 1B). However, loss extended back into the midbrain, posterior lateral and basal temporal lobe, the posterior cingulate, and the parietal association cortex, and forwards into the anterior insula and medial frontal lobe (p<0.001, uncorrected). Loss was bilateral although slightly greater on the left. Loss in all these regions remained after correction for multiple comparisons (p<0.01). Figure 2 shows a surface rendering of the patterns of loss in both the aMCI-SD and aMCI-MD groups compared to controls and clearly demonstrates the more widespread pattern of loss in the aMCI-MD group.

naMCI-SD

The naMCI-SD group showed a widespread pattern of grey matter loss involving the temporal lobes, including the amygdala, hippocampus and entorhinal cortex, the basal forebrain, the left hypothalamus, the lateral superior frontal lobes, the parietal lobes and the occipital lobes, compared to controls (p<0.001, uncorrected, Figure 1C). No regions remained after the correction for multiple comparisons (p<0.01).

naMCI-MD

The only regions of grey matter loss to reach significance in the naMCI-MD group compared to controls were found in the lateral anterior parietal lobes (p<0.001, uncorrected, Figure 1D). No regions remained after the correction for multiple comparisons (p<0.01).

Individual naMCI domains

The subgroup of naMCI-SD subjects with language impairment showed a pattern of grey matter loss affecting the left anterior inferior and medial temporal lobe compared to controls (p<0.001, uncorrected, Figure 3). There was also some minor involvement of the right temporal lobe and the left parietal lobe. The attention/executive impaired naMCI-SD subgroup showed grey matter loss in the basal forebrain, particularly the nucleus basalis of Meynert and the diagonal band of Broca (Figure 4A and B), and the medial septum of the hypothalamus compared to controls (p<0.001, uncorrected, Figure 4A). Some other scattered regions of loss were identified although the significance of these regions is uncertain. The subgroup of naMCI-SD subjects with impaired visuospatial skills showed a scattered pattern of grey matter loss predominantly affecting the lateral frontal lobes and the floor of the occipital horn of the lateral ventricle bilaterally compared to controls (p<0.001, uncorrected, Figure 5). Loss was also found in the posterior right hippocampus and the lateral posterior temporal lobe. No regions in any of these comparisons remained after the correction for multiple comparisons (p<0.01).

Figure 3
Patterns of grey matter atrophy identified in the non-amnestic single-domain MCI subjects with a language impairment compared to controls (p<0.001, uncorrected). Results have been overlaid on two coronal slices and two sagittal slices through ...
Figure 4
Patterns of grey matter atrophy identified in the non-amnestic single-domain MCI subjects with an attention/executive impairment compared to controls (p<0.001, uncorrected). Results have been overlaid on a coronal and axial slice from a control ...
Figure 5
Patterns of grey matter atrophy identified in the non-amnestic single-domain MCI subjects with a visuospatial impairment compared to controls (p<0.001, uncorrected). Results have been overlaid on a coronal, axial, and sagittal (through the left ...

COMMENT

In this study we divided patients with MCI into different subgroups based on deficit patterns present in specific cognitive domains. This method of MCI sub classification has been previously described1, 3 , and is currently employed in both the ADNI study as well as the Uniform Data Set of the NIA Alzheimer’s Disease Centers Program. All prior Mayo imaging studies of MCI analyzed only subjects with amnestic (SD and MD) MCI. The present study has shown that different MCI groups have different patterns of atrophy on MRI, and these patterns may provide clues as to future course and etiology of MCI subtypes.

Grey matter loss in both the single and multi-domain amnestic MCI groups focused on the medial temporal lobes. The multi-domain group also showed loss spreading into the posterior lateral and basal temporal lobe, the posterior cingulate, anterior insula and the medial frontal lobe. These regions of atrophy are typical of subjects with AD20, 21, and fit nicely with the proposed scheme of pathological progression of disease in AD in which neurofibrillary pathology starts in the entorhinal cortex and hippocampus before spreading into the isocortical association areas22. These imaging results therefore suggest that both single and multi-domain amnestic subjects are likely to progress to AD. Indeed, the follow-up data shows that a high proportion of these subjects ultimately did convert to a diagnosis of AD. The atrophy was more widespread in the aMCI-MD group, most likely reflecting the more widespread cognitive impairment and perhaps suggesting that these subjects are further along the path to AD than the amnestic single-domain group. This suggestion is supported by the lower DRS score observed in the aMCI-MD group, and by a recent study that showed increased mortality in multi-domain compared to single-domain amnestic MCI subjects23. The frequency of APOE e4 carriers was also high in both the amnestic single and multi-domain groups providing further evidence that these subjects are highly likely to progress to AD. APOE ε4 is associated with an increased risk of AD24, and has been shown to be able to help predict conversion to MCI and dementia25. A minority of the aMCI-MD subjects have however converted to non-AD dementias. This is not unexpected given the heterogeneity in cognitive deficits and the fact that the amnestic deficit was not necessarily the most prominent feature. Note that while subjects with amnestic MCI are likely to progress to AD all subjects in this study had normal activities of daily living and thus by definition could not be classified as AD. This is a particularly important distinction for MD amnestic MCI subjects who had impairments in both memory and one or more non-memory domains.

Previous studies in amnestic MCI and preclinical AD have similarly shown that the focus of loss is in the medial temporal lobes, particularly involving the hippocampus2628. Isocortical association areas, including the parietal, temporal and frontal lobes, and the posterior cingulate have also been implicated, although to a lesser degree27, 29, 30. However, to our knowledge only one other study has been published that has explicitly divided MCI subjects into single and multi-domain sub-types28. They also showed relatively restricted loss in the medial temporal lobe in the SD amnestic group, and a more diffuse and extensive pattern of loss in the MD MCI subjects. However, the number of subjects in the SD group was small (n=9), and the MD group seems to have been composed of a mixture of amnestic and non-amnestic subjects.

In contrast to the well defined patterns of grey matter loss in the amnestic MCI subjects in our study, the non-amnestic (single and multi-domain) subjects showed scattered patterns of loss without any particular focus. The hippocampus and medial temporal lobes were not the main focus of loss, consistent with the lack of significant memory impairment in these subjects. The follow-up data also showed that these subjects were less likely to progress to AD than the aMCI-SD subjects. The non-amnestic groups are however highly heterogeneous with subjects showing impairment in various different cognitive domains. The subjects in the naMCI-SD group were therefore subdivided into those with a language, attention/executive or visuospatial deficit. The naMCI-SD subjects with language impairment showed a pattern of loss predominantly affecting the left anterior inferior and medial temporal lobe – i.e. the imaging pattern was highly consistent with the observed clinical deficit. This pattern is similar to that reported in subjects with a language variant of frontotemporal dementia (FTD)3133. However, the APOE ε4 frequency in this group (50%) was higher34, and the age was older35, than one might expect in FTD. The high APOE ε4 in this subgroup may instead be indicative of AD pathology36. Subjects that present with language impairments can have AD on pathology and show a left sided pattern of atrophy37. The majority of these subjects did indeed progress to a clinical diagnosis of AD, although a couple of subjects progressed to a non-AD dementia, including FTD. The naMCI-SD subjects with attention/executive impairments showed grey matter loss in the basal nucleus of Meynert, the diagonal band of Broca, and in the hypothalamus. These regions are key nuclei of the cholinergic system which is an essential component of neuronal systems mediating attentional function38, 39. Deficits in the cholinergic system have been associated with AD, but also with Dementia with Lewy Bodies (DLB). In fact, cholinergic dysfunction occurs earlier in the disease course in DLB than AD40. Indeed, these subjects had a relatively low APOE ε4 frequency (33%) suggesting that a number of these subjects may not show AD pathology. Follow-up data showed that while three cases progressed to a clinical diagnosis of AD, two subjects did progress to DLB. The group of naMCI-SD patients with a visuospatial deficit showed no coherent pattern of atrophy although again they showed a very low APOE ε4 frequency.

While, the number of subjects in the non-amnestic groups was relatively small, many VBM studies have been published with similar numbers per subject group both with and without corrections for multiple comparisons. The power of VBM to detect significant differences depends critically on the interaction between biological effect size and the N in the sample. The more robust pattern of loss observed in the amnestic subjects could be because of the large number of subjects in these groups as well as the strong medial temporal lobe biologic signal and its coherence across subjects within the amnestic groups. The preponderance of amnestic MCI in our cohort likely reflects the recruitment mechanism at our centre which until recently has emphasized memory impairment. The prevalence proportions of the MCI subtypes in a population are unknown at this time, although this is an area of active research41. While follow-up data was available in these MCI subjects it should be regarded as preliminary since the follow-up time was too short to allow thorough characterization. In addition, pathological confirmation was not available. There are also a number of limitations inherent to the technique of VBM. In particular, misclassification of tissue due to variable degrees of ventricular enlargement among subjects is likely to have contributed to the artifactual grey matter loss observed around the lateral ventricles in the amnestic groups (Figures 1A and B). VBM may also not be equally sensitive to volume loss in all areas of the brain. The power to detect a difference is limited in regions that show greater normative variability. It is also important to stress that VBM looks at group data, and therefore the results should be interpreted at the group/concept level rather than the single subject level.

The patterns of grey matter loss observed in this study are therefore consistent with the well established fact that amnestic MCI for the most part progresses to AD and the anatomic signature of prodromal AD is medial temporal atrophy. The more widespread pattern of loss in the multi-domain amnestic subjects suggests that these subjects are further along the clinical path to AD than the single-domain subjects. Given that AD has a prodromal syndrome, i.e. amnestic MCI, it is almost certain that other neurodegenerative dementias do as well and each should have its own imaging signature. Although the results in the non-amnestic groups did not survive correction for multiple comparisons they suggest that some of these MCI subjects may progress to neurodegenerative dementias other than AD. Longitudinal follow-up studies are currently in progress to validate this hypothesis.

ACKNOWLEDGEMENTS

This study was supported by grants P50 AG16574, U01 AG06786, R01 AG11378 and R01 AG15866 from the National Institute on Aging, Bethesda MD, and the generous support of the Robert H. and Clarice Smith and Abigail Van Buren Alzheimer′s Disease Research Program of the Mayo Foundation, U.S.A. The authors would like to thank Kejal Kantarci, and Eduardo Benarroch for their help and advice.

Footnotes

Disclosure: The authors have reported no conflicts of interest

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