Summary

Mild cognitive impairment (MCI), particularly the amnestic subtype (aMCI), is considered as a transitional stage between normal aging and a diagnosis of clinically probable Alzheimer's disease (AD). The aMCI construct is particularly useful as it provides an opportunity to assess a clinical stage which in most subjects represents prodromal AD. The aim of this study was to assess the progression of cerebral atrophy over multiple serial MRI during the period from aMCI to conversion to AD. Thirty-three subjects were selected that fulfilled clinical criteria for aMCI and had three serial MRI scans: the first scan approximately three years before conversion to AD, the second scan approximately one year before conversion, and the third scan at the time of conversion from aMCI to AD. A group of 33 healthy controls were age and gender-matched to the study cohort. Voxel-based morphometry (VBM) was used to assess patterns of grey matter atrophy in the aMCI subjects at each time-point compared to the control group. Customized templates and prior probability maps were used to avoid normalization and segmentation bias. The pattern of grey matter loss in the aMCI subject scans that were three years before conversion was focused primarily on the medial temporal lobes, including the amygdala, anterior hippocampus and entorhinal cortex, with some additional involvement of the fusiform gyrus, compared to controls. The extent and magnitude of the cerebral atrophy further progressed by the time the subjects were one year before conversion. At this point atrophy in the temporal lobes spread to include the middle temporal gyrus, and extended into more posterior regions of the temporal lobe to include the entire extent of the hippocampus. The parietal lobe also started to become involved. By the time the subjects had converted to a clinical diagnosis of AD the pattern of grey matter atrophy had become still more widespread with more severe involvement of the medial temporal lobes and the temporoparietal association cortices and, for the first time, substantial involvement of the frontal lobes. This pattern of progression fits well with the Braak and Braak neurofibrillary pathological staging scheme in AD. It suggests that the earliest changes occur in the anterior medial temporal lobe and fusiform gyrus, and that these changes occur at least three years before conversion to AD. These results also suggest that 3-dimensional patterns of grey matter atrophy may help to predict the time to conversion in subjects with aMCI.

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.

Objective

To compare the patterns of grey matter loss in subjects with amnestic Mild Cognitive Impairment (aMCI) who progress to Alzheimer's disease within a fixed clinical follow-up time versus those who remain stable.

Methods

Twenty-one aMCI subjects were identified from the Mayo Clinic Alzheimer's research program that remained clinically stable for their entire observed clinical course (aMCI-S), where the minimum required follow-up time from MRI to last follow-up assessment was three years. These subjects were age and gender-matched to 42 aMCI subjects who progressed to AD within 18 months of the MRI (aMCI-P). Each subject was then age and gender-matched to a control subject. Voxel-based morphometry (VBM) was used to assess patterns of grey matter atrophy in the aMCI-P and aMCI-S groups compared to the control group, and compared to each other.

Results

The aMCI-P group showed bilateral loss affecting the medial and inferior temporal lobe, temporoparietal association neocortex and frontal lobes, compared to controls. The aMCI-S group showed no regions of grey matter loss when compared to controls. When the aMCI-P and aMCI-S groups were compared directly, the aMCI-P group showed greater loss in the medial and inferior temporal lobes, the temporoparietal neocortex, posterior cingulate, precuneus, anterior cingulate, and frontal lobes than the aMCI-S group.

Conclusions

The regions of loss observed in aMCI-P are typical of subjects with AD. The lack of grey matter loss in the aMCI-S subjects is consistent with the notion that patterns of atrophy on MRI at baseline map well onto the subsequent clinical course.

SUMMARY

Dementia with Lewy Bodies (DLB) is the second most common cause of degenerative dementia after Alzheimer's disease (AD). However, unlike in AD the patterns of cerebral atrophy associated with DLB have not been well established. The aim of this study was to identify a signature pattern of cerebral atrophy in DLB and to compare it to the pattern found in AD. Seventy-two patients that fulfilled clinical criteria for probable DLB were age and gender-matched to 72 patients with probable AD and 72 controls. Voxel-based morphometry (VBM) was used to assess patterns of grey matter atrophy in the DLB and AD groups, relative to controls, after correction for multiple comparisons (p<0.05). Study specific templates and prior probability maps were used to avoid normalization and segmentation bias. Region-of-interest (ROI) analyses were also performed comparing loss of the midbrain, substantia innominata (SI), temporoparietal cortex and hippocampus between the groups. The DLB group showed very little cortical involvement on VBM with regional grey matter loss observed primarily in the dorsal midbrain, SI and hypothalamus. In comparison, the AD group showed a widespread pattern of grey matter loss involving the temporoparietal association cortices and the medial temporal lobes. The SI and dorsal midbrain were involved in AD however they were not identified as a cluster of loss discrete from uninvolved surrounding areas, as observed in the DLB group. On direct comparison between the two groups, the AD group showed greater loss in the medial temporal lobe and inferior temporal regions than the DLB group. The ROI analysis showed reduced SI and midbrain grey matter in both the AD and DLB groups. The SI grey matter was reduced more in AD than DLB, yet the midbrain was reduced more in DLB than AD. The hippocampus and temporoparietal cortex showed significantly greater loss in the AD group compared to the DLB group. A pattern of relatively focused atrophy of the midbrain, hypothalamus and SI, with a relative sparing of the hippocampus and temporoparietal cortex, is therefore suggestive of DLB and may aid in the differentiation of DLB from AD. These findings support recent pathological studies showing an ascending pattern of Lewy Body progression from brainstem to basal areas of the brain. Damage to this network of structures in DLB may affect a number of different neurotransmitter systems which in turn may contribute to a number of the core clinical features of DLB.