Cerebral grey and white matter changes in mild cognitive impairment and Alzheimer’s disease

A detailed understanding of stage-specific disease mechanisms of Alzheimer s disease (AD) is an essential pre-condition for the development and refinement of early diagnosis, prognosis and treatment strategies. Neuroimaging of cerebral grey and white matter is particularly useful as a largely non-invasive, repeatable in vivo study approach to cerebral structures and tissue components that are the prime substrate of the neuropathological process of AD. Earlier cranial CT studies gave evidence of brain volume loss in AD mostly by indirect measures of enlarged sulci and ventricles. Meanwhile, total and regional brain volume losses are the core structural MRI finding in AD, as evidenced in cross-sectional group comparisons to normal controls and in longitudinal follow-up studies of subjects with mild cognitive impairment (MCI) converting to AD [1]. These changes have been largely attributed to grey matter atrophy. Medial temporal lobe (MTL) structures, including entorhinal cortex, hippocampi and amygdale, are primarily affected by the neuropathological AD process [2] and have major functions in memory processing, typically severely compromised in AD. MTL structures have, therefore, been a major focus of MR-volumetric studies employing hypothesis-driven region-of-interest based image analysis. Particularly the hippocampal formation, as it is relatively amenable to manual or semiautomated MR-volumetry, and, to a lesser extent, the entorhinal cortex and amygdale have been studied in MCI and AD with consistent results of progressive volume losses in these conditions on a group-statistical level [1]. Hippocampal atrophy rates have also been used to predict conversion from MCI to AD [3] and have been related to declining declarative memory function [4]. For multicenter assessment of hippocampal volumes in AD patients, high interrater-reliabilities with coefficients of variation below 5% have been reached [5]. Correlations of post-mortem histopathology with anteor post-mortem hippocampal MRvolumes substantiate earlier evidence that in MCI or AD hippocampal volume loss corresponds to neuronal atrophy [6]. Hippocampal MR-volumetry is, therefore, regarded as the currently best biomarker of grey matter atrophy in AD based on structural neuroimaging [7]. Whole brain voxel based morphometry (VBM), based on statistical parametric mapping of structural MRI data, has revealed more complex spatial patterns of brain atrophy in MCI and early AD encompassing multiple MTL grey matter structures and lateral cortical association areas of the temporal and parietal lobes [7], whilst there are methodological concerns of imperfect normalization procedures with VBM, possibly, leading to false positive atrophy findings [8]. Recently, VBM has been used in conjunction with algorithmic brain segmentation to study white matter as well, revealing early white matter volume losses in MCI and AD affecting MTL structures including perihippocampal and cingular white matter [9,10]. These findings meet a growing body of literature on diffusion tensor imaging (DTI) used to quantify biophysical parameters related to white matter fiber integrity. In MCI and AD subjects, declines of fractional anisotropy are reported for fiber tracts connected to MTL structures, such as posterior corpus callosum, fasciculus longitudinalis superior and cingulum [7], probably to give rise to hippocampal disconnection. Still open questions concern the exact temporal, spatial and causal relationships of white and grey matter changes in incipient and early AD. Wallerian degeneration has been suggested to account for secondary demyelination of fiber tracts connected to those MTL structures that are primarily affected by the neurodegenerative process [11]. It is, however, unclear, how the long standing evidence of white matter hyperintensities in AD, attributed to a microvascular disease component [12], fits into the scenario. Direct evidence from neuroimaging data on temporal and spatial relationships of grey and white matter changes in early AD is still sparse. In the present issue of the European Journal of Neurology, Balthasar et al. [13] make a positive contribution to this field by directly comparing atrophy patterns of grey and white matter derived from tissue type adjusted VBM in MCI and AD. They find evidence for a sequential pattern of regional grey and white matter loss in early AD and discuss possible causations. Future questions may also concern the intraindividual follow-up of grey and white matter changes in MCI and AD and the linkage of structural data with functional neuroimaging modalities and genetic data.