Episodic memory is a core feature of Alzheimer's disease (AD) and mild cognitive impairment (MCI). Impaired episodic memory in AD results from the dysfunction of an integrated network and involves both gray and white matter pathologies. We explored the neural correlates of episodic memory in AD, MCI and healthy aging by correlating a measure of episodic memory with hippocampal volume and fractional anisotropy (FA) and mean diffusivity (MD) of the cingulum and fornix. Episodic memory was associated with hippocampal volume and MD of the cingulum and fornix. In contrast, there were fewer significant associations between episodic memory and FA. These findings support a relationship between episodic memory and hippocampal circuitry, and suggest that MD is a more sensitive marker of decreased white matter integrity in the study of AD and MCI than FA. Furthermore, MD was significantly associated with hippocampal volume, indicating that white matter pathology is not completely independent of gray matter pathology. However, the pattern of diffusivity differences in AD and MCI implies a more complex pathology than simply Wallerian degeneration.
mpaired episodic memory is a core feature of both Alzheimer's disease (AD) and mild cognitive impairment (MCI) (Dubois et al., 2007), although the continuous nature of decline results in an overlap between diagnostic groups (Petersen, 2004). It is hypothesised that impaired episodic memory in AD results from the dysfunction of an integrated network that includes the medial temporal lobe, mamillary bodies, dorsomesial thalamus, posterior cingulate, and the connecting white matter tracts (Nestor et al., 2006). Correlations between episodic memory and elements of this limbic–diencephalic network have been detected across the spectrum of healthy aging, MCI and AD. For example, impaired verbal episodic memory has been associated with reduced hippocampal volume, measured using structural magnetic resonance imaging (MRI) (Choo et al., 2010 and Leube et al., 2008), and also impaired integrity of the cingulum and fornix, measured with diffusion tensor imaging (DTI) (Choo et al., 2010, Fellgiebel et al., 2005 and Mielke et al., 2009).
DTI characterises the orientation and integrity of white matter tracts by measuring the diffusion of water molecules in living neural tissue (Le Bihan, 2003). The three-dimensional water diffusivity obtained from the diffusion tensor can be modelled as an ellipsoid whose orientation is defined by the three eigenvectors (ε1, ε2, and ε3), which represent the major, medium, and minor principal axes and whose shape is defined by the three eigenvalues (λ1, λ2, and λ3), which represent the diffusivities in the three eigenvector directions. As the major eigenvector reflects the direction of maximum diffusivity, it is assumed to reflect the orientation of the white matter tract. The degree of diffusion anisotropy and the overall displacement of water molecules can be examined using fractional anisotropy (FA) and mean diffusivity (MD) values, respectively. In addition, diffusivity can be studied in greater detail using axial diffusivity (DA, λ1, diffusivity parallel to the white matter tract) and radial diffusivity (DR, (λ2 + λ3) / 2, diffusivity perpendicular to the white matter tract). Although FA is the most commonly used DTI metric, it lacks sensitivity when diffusivity in all three directions displays similar changes. This may be particularly relevant in AD, where several degenerative processes may be at play. For example, white matter degradation may result from myelin breakdown in line with the retrogenesis hypothesis, Wallerian degeneration occurring secondary to gray matter pathology, and also local microvascular changes. Indeed, MD has been found to be more sensitive than FA in detecting group differences between AD and control participants (Acosta-Cabronero et al., 2010) and in reflecting Mini-Mental State Examination (MMSE) decline within AD (Nakata et al., 2009 and Yoshiura et al., 2002).
Tract-based spatial statistics (TBSS) is a DTI analysis technique that projects all subjects' FA data onto a tract skeleton which represents the centres of all tracts common to the group. The TBSS protocol minimises the effects of misregistration, which is especially important when studying patient groups that can display significant atrophy. In the present work we use neuroimaging measures obtained from structural MRI and DTI in order to thoroughly examine the neural correlates of episodic memory. With regard to structural MRI, we use an automatic segmentation tool to examine the volume and shape of hippocampus. With DTI, we utilise the TBSS processing strategy to determine a white matter skeleton, then create cingulum and fornix regions of interest (ROIs) overlaid on the skeleton. Due to the complex pathology of AD, we hypothesised that MD would be a more sensitive marker of episodic memory than FA.
