Free-water diffusion tensor imaging improves the accuracy and sensitivity of white matter analysis in Alzheimer's disease

Maurizio Bergamino, Ryan R Walsh, Ashley M Stokes, Maurizio Bergamino, Ryan R Walsh, Ashley M Stokes

Abstract

Magnetic resonance imaging (MRI) based diffusion tensor imaging (DTI) can assess white matter (WM) integrity through several metrics, such as fractional anisotropy (FA), axial/radial diffusivities (AxD/RD), and mode of anisotropy (MA). Standard DTI is susceptible to the effects of extracellular free water (FW), which can be removed using an advanced free-water DTI (FW-DTI) model. The purpose of this study was to compare standard and FW-DTI metrics in the context of Alzheimer's disease (AD). Data were obtained from the Open Access Series of Imaging Studies (OASIS-3) database and included both healthy controls (HC) and mild-to-moderate AD. With both standard and FW-DTI, decreased FA was found in AD, mainly in the corpus callosum and fornix, consistent with neurodegenerative mechanisms. Widespread higher AxD and RD were observed with standard DTI; however, the FW index, indicative of AD-associated neurodegeneration, was significantly elevated in these regions in AD, highlighting the potential impact of free water contributions on standard DTI in neurodegenerative pathologies. Using FW-DTI, improved consistency was observed in FA, AxD, and RD, and the complementary FW index was higher in the AD group as expected. With both standard and FW-DTI, higher values of MA coupled with higher values of FA in AD were found in the anterior thalamic radiation and cortico-spinal tract, most likely arising from a loss of crossing fibers. In conclusion, FW-DTI better reflects the underlying pathology of AD and improves the accuracy of DTI metrics related to WM integrity in Alzheimer's disease.

Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
Coronal view of ANCOVA analysis between HC and AD subjects for standard DTI metrics. Clusters are reported at a significance threshold of p-value < 0.01 corrected for FWE. (a) FA, (b) AxD, and (c) RD analysis. The color bars indicate values that are lower in AD than HC (red-to-yellow) and higher in AD than HC (blue-to-cyan). For axial and radial diffusivities, only clusters with higher values in AD than HC were found. The corresponding violin plots represent the DTI metrics inside the significant clusters for each group.
Figure 2
Figure 2
Coronal view of ANCOVA analysis between HC and AD subjects for the FW-DTI metrics. Clusters are reported at a significance threshold of p-value < 0.01 corrected for FWE, except for RDt (HC) < RDt (AD), which is reported at p-value < 0.05 FWE- corrected (c) and is indicated by the *. (a) FAt, (b) AxDt, and (c) RDt analysis. The color bars indicate values that are lower in AD than HC (red-to-yellow) and higher in AD than HC (blue-to-cyan). The corresponding violin plots represent the FW-DTI metrics inside the significant clusters for each group.
Figure 3
Figure 3
Coronal view of ANCOVA analysis between HC and AD subjects for FW index. Clusters are reported at a significance threshold of p-value < 0.01 corrected for FWE. Higher FW in AD compared to HC was observed widespread across cerebral WM. No significant clusters were found with FW (HC) > FW (AD). The corresponding violin plots represent the FW metrics inside the significant clusters for each group.
Figure 4
Figure 4
Coronal view of ANCOVA analysis between HC and AD subjects for MA index from (a) standard DTI and (b) FW-DTI. Left: MA in HC < MA in AD; right: MA in HC > MA in AD. Clusters are reported at a significance threshold of p-value < 0.01 corrected for FWE.

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