Free water: A marker of age-related modifications of the cingulum white matter and its association with cognitive decline.

Diffusion MRI is extensively used to investigate changes in white matter microstructure. However, diffusion measures within white matter tissue can be affected by partial volume effects due to cerebrospinal fluid and white matter hyperintensities, especially in the aging brain. In previous aging studies, the cingulum bundle that plays a central role in the architecture of the brain networks supporting cognitive functions has been associated with cognitive deficits. However, most of these studies did not consider the partial volume effects on diffusion measures. The aim of this study was to evaluate the effect of free water elimination on diffusion measures of the cingulum in a group of 68 healthy elderly individuals. We first determined the effect of free water elimination on conventional DTI measures and then examined the effect of free water elimination on verbal fluency performance over 12 years. The cingulum bundle was reconstructed with a tractography pipeline including a white matter hyperintensities mask to limit the negative impact of hyperintensities on fiber tracking algorithms. We observed that free water elimination increased the ability of conventional DTI measures to detect associations between tissue diffusion measures of the cingulum and changes in verbal fluency in older individuals. Moreover, free water content and mean diffusivity measured along the cingulum were independently associated with changes in verbal fluency. This suggests that both tissue modifications and an increase in interstitial isotropic water would contribute to cognitive decline. These observations reinforce the importance of using free water elimination when studying brain aging and indicate that free water itself could be a relevant marker for age-related cingulum white matter modifications and cognitive decline.