Diffusion tensor metrics as biomarkers in Alzheimer's disease

Abstract

Background: Although diffusion tensor imaging has been a major research focus for Alzheimer's disease in recent years, it remains unclear whether it has sufficient stability to have biomarker potential. To date, frequently inconsistent results have been reported, though lack of standardisation in acquisition and analysis make such discrepancies difficult to interpret. There is also, at present, little knowledge of how the biometric properties of diffusion tensor imaging might evolve in the course of Alzheimer's disease.

Methods: The biomarker question was addressed in this study by adopting a standardised protocol both for the whole brain (tract-based spatial statistics), and for a region of interest: the midline corpus callosum. In order to study the evolution of tensor changes, cross-sectional data from very mild (N = 21) and mild (N = 22) Alzheimer's disease patients were examined as well as a longitudinal cohort (N = 16) that had been rescanned at 12 months.

Findings and significance: The results revealed that increased axial and mean diffusivity are the first abnormalities to occur and that the first region to develop such significant differences was mesial parietal/splenial white matter; these metrics, however, remained relatively static with advancing disease indicating they are suitable as 'state-specific' markers. In contrast, increased radial diffusivity, and therefore decreased fractional anisotropy-though less detectable early-became increasingly abnormal with disease progression, and, in the splenium of the corpus callosum, correlated significantly with dementia severity; these metrics therefore appear 'stage-specific' and would be ideal for monitoring disease progression. In addition, the cross-sectional and longitudinal analyses showed that the progressive abnormalities in radial diffusivity and fractional anisotropy always occurred in areas that had first shown an increase in axial and mean diffusivity. Given that the former two metrics correlate with dementia severity, but the latter two did not, it would appear that increased axial diffusivity represents an upstream event that precedes neuronal loss.

Figure 1. Cognitive status.

Depiction of average cognitive profiles for all subject cohorts assessed in this study.

Figure 2. Corpus callosum subdivision.

Depiction of the semi-automated callosal subdivision into splenium, truncus and genu (top), and their intersection with the mean FA skeleton inferred from N = 69 subjects–N = 43 Alzheimer’s disease patients and N = 26 matched controls (bottom).

Figure 3. Cross-sectional study of very mild Alzheimer’s disease.

TBSS results for the very mild Alzheimer’s disease group compared to controls. Statistical maps (thresholded at TFCE-P<0.05) for increased axial/radial diffusivity and reduced FA overlaid onto the mean FA skeleton and the MNI152 template. Coronal depths are given in millimetres.

Figure 4. Cross-sectional study of mild Alzheimer’s disease.

TBSS results for the mild-stage Alzheimer’s disease group compared to controls. Thresholded (TFCE-P<0.05) statistical maps for increased axial/radial diffusivity and reduced FA were overlaid onto the mean FA skeleton and the MNI152 template. Coronal depths are given in millimetres.

Figure 5. Cross-sectional results in the mid-sagittal corpus callosum.

TBSS results across the sagittal midline for very mild and mild Alzheimer’s disease groups compared to controls.

Figure 6. Cross-sectional diffusion tensor behaviour in the splenial region.

Mean subject values for skeletonised DTI parameters in the splenium as a function of cognitive status (ACE-R scores) for controls (green), very mild Alzheimer’s disease (blue) and mild Alzheimer’s disease patients (red). The error bars represent ± one group standard deviation. The vertical axes were scaled to 10 control standard deviations. The vertical lines delimit the control exclusion criteria (ACE-R<88/100) and the median split (ACE-R = 74). A least-square linear fit was displayed if Pearson’s correlation coefficient was deemed statistically significant (Table 4).

Figure 7. Longitudinal study of Alzheimer’s disease.

Whole-brain TBSS contrast on 12-month follow-up versus baseline in the longitudinal Alzheimer’s disease cohort (TFCE-P<0.05) for increased radial diffusivity and reduced FA n.b. no significant results for λ₁ or MD were found.

Figure 8. Longitudinal results in the mid-sagittal corpus callosum.

Longitudinal TBSS results for radial diffusivity and fractional anisotropy across the midline.

Figure 9. Longitudinal tensor behaviour in the splenium.

Longitudinal pairs of mean subject skeletonised DTI parameters as a function of cognitive status (ACE-R) for Alzheimer’s disease subjects at baseline (blue) and 12 months (red).