Absolute Diffusivities Define the Landscape of White Matter Degeneration in Alzheimer's Disease

Recent imaging evidence in Alzheimer's disease suggests that neural involvement in early-stage disease is more complex than is encapsulated in the commonly held position of predominant mesial temporal lobe degeneration-there is also early posterior cingulate cortex and diencephalic damage. These findings suggest that early clinical Alzheimer's disease is underpinned by damage to an inter-connected network. If correct, this hypothesis would predict degeneration of the white matter pathways that connect this network. This prediction can be tested in vivo by diffusion magnetic resonance imaging. Most diffusion tensor imaging studies of white matter in neurodegenerative disorders such as Alzheimer's disease have concentrated on fractional anisotropy reductions and increased 'apparent' diffusivity; however, there is a lack of empirical biological evidence to assume that fractional anisotropy changes will necessarily capture the full extent of white matter changes in Alzheimer's disease. In this study, therefore, we undertook a comprehensive investigation of diffusion behaviour in Alzheimer's disease by analysing each of the component eigenvalues of the diffusion tensor in isolation to test the hypothesis that early Alzheimer's disease is associated with degeneration of a specific neural network. Using tract-based spatial statistics, we performed voxel-wise analyses of fractional anisotropy, axial, radial and mean diffusivities in 25 Alzheimer's disease patients compared with 13 elderly controls. We found that increased absolute (axial, radial and mean) diffusivities in Alzheimer's disease were concordant in a distribution consistent with the network hypothesis, highly statistically significant and far more sensitive than fractional anisotropy reductions. The former three measures identified confluent white matter abnormalities in parahippocampal gyrus and posterior cingulum, extending laterally into adjacent temporo-parietal regions as well as splenium and fornix. The caudal occipital lobe, temporal pole, genu and prefrontal white matter were relatively preserved. This distribution is highly consistent with expected predictions of tract degeneration from grey matter lesions identified by fluorodeoxyglucose positron emission tomography and structural magnetic resonance imaging. Concordant with results from these other imaging modalities, this pattern predominantly involves degeneration of the tracts connecting the circuit of Papez. These findings also highlight that early neuropathological processes are associated with changes of the diffusion ellipsoid that are predominantly proportional along all semi-principal axes.