Mapping progressive brain structural changes in early Alzheimer's disease and mild cognitive impairment

Abstract

Alzheimer's disease (AD), the most common neurodegenerative disorder of the elderly, ranks third in health care cost after heart disease and cancer. Given the disproportionate aging of the population in all developed countries, the socio-economic impact of AD will continue to rise. Mild cognitive impairment (MCI), a transitional state between normal aging and dementia, carries a four- to sixfold increased risk of future diagnosis of dementia. As complete drug-induced reversal of AD symptoms seems unlikely, researchers are now focusing on the earliest stages of AD where a therapeutic intervention is likely to realize the greatest impact. Recently neuroimaging has received significant scientific consideration as a promising in vivo disease-tracking modality that can also provide potential surrogate biomarkers for therapeutic trials. While several volumetric techniques laid the foundation of the neuroimaging research in AD and MCI, more precise computational anatomy techniques have recently become available. This new technology detects and visualizes discrete changes in cortical and hippocampal integrity and tracks the spread of AD pathology throughout the living brain. Related methods can visualize regionally specific correlations between brain atrophy and important proxy measures of disease such as neuropsychological tests, age of onset or factors that may influence disease progression. We describe extensively validated cortical and hippocampal mapping techniques that are sensitive to clinically relevant changes even in the single individual, and can identify group differences in epidemiological studies or clinical treatment trials. We give an overview of some recent neuroimaging advances in AD and MCI and discuss strengths and weaknesses of the various analytic approaches.

Figure 1

Tensor based morphometry analysis showing the progression of brain atrophy in posterior cortical atrophy patient scanned at 6-month intervals. The images show progressive tissue loss (purple) in the right temporal and parietal and left frontal lobes and ventricular expansion red, yellow, green).

Figure 2

Optimized voxel-based morphometry analysis of gray matter atrophy progression in MCI who converted to AD (converters) and MCI who remained stable (non-converters). The color-coded maps represent the percent annual volume loss projected on the 3D hemispheric brain customized average template (top) and on coronal sections of the template (bottom). (Reproduced with permission from Chetelat et al., 2005(87))

Figure 3

The hippocampal radial atrophy technique was applied to identify regions of hippocampal atrophy that predict future decline from amnestic MCI to AD.(95) Illustrated are the statistical and percent difference surface map comparisons between the three MCI groups – converters vs. nonconverters (left panel), converters vs. MCI patients who improved cognitively (middle panel) and non-converters vs. MCI patients who improved (right panel). In each case, red and white colors (in the top row) denote regions where those with poorer outcomes showed greater atrophy at their baseline scan. In some regions, the baseline level of atrophy is locally10–20% greater in MCI subjects who later convert to AD.

Figure 4

Using the hippocampal radial atrophy mapping technique Apostolova et al. revealed the stage wise spread of hippocampal atrophy through the hippocampus in amnestic MCI and AD. MCI converters show significantly more atrophy in the subiculum and CA1 areas of the hippocampus relative to MCI subjects who either remained stable or improved (middle row).(95) AD subjects show in addition significantly more atrophy in the CA2/3 area on the left relative to amnestic MCI. (94)

Figure 5

Cortical atrophy differences between amnestic MCI and mild AD subjects can be visualized using the cortical pattern matching technique. (51) The 3D maps on the left demonstrate significantly greater atrophy in mild AD relative to MCI in most cortical areas (red colors) with relative preservation of the primary sensory and motor regions (blue colors). The anatomical pattern resembles stages A and B from the Braak and Braak amyloid staging maps (right panels). Clearly, amyloid accumulation and cortical atrophy may not occur at exact the same times in all patients, but the anatomical sequence of cortical thinning closely matches the typical trajectory of plaque and tangle accumulation (from medial temporal, to frontal, sparing primary cortices until later).

Figure 6

The ventricular mapping technique was used to study the effects of AD and of ApoE4 genotype on ventricular expansion. AD subjects when compared to age-matched controls demonstrated posterior and anterior ventricular horn expansion (left panel). When the analysis is restricted to healthy control subjects only, ApoE4 carriers demonstrated predominantly anterior ventricular horn expansion relative to ApoE4 non-carriers (right panel).

Figure 7

Using a single surface template and an optical flow registration approach for ventricular segmentation, Carmichael et al. (102) compared the ventricular shape differences between MCI, AD and cognitively normal subjects. The figure shows the average thickness, percent deficit and significance maps of the three comparisons – cognitively normal subjects vs. MCI (top row), cognitively normal subjects vs. AD (bottom row) and MCI vs. AD (middle row). As expected, progressive ventricular expansion was evident - MCI subjects had intermediate and AD subjects largest ventricles.

Figure 8

Using the cortical pattern matching technique Apostolova et al. (113) studied the association between the performance on Boston Naming Test (BNT) and the Animal Fluency test and cortical atrophy in 19 subjects with AD and 5 MCI who later converted to AD. Declining performance on both measures associated with left more than right perisylvian and frontal atrophy.