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

PLoS One. 2020 Nov 20;15(11):e0242696. doi: 10.1371/journal.pone.0242696. eCollection 2020.


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.

Publication types

  • Clinical Trial
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged, 80 and over
  • Aging / metabolism*
  • Cognition*
  • Cognitive Dysfunction* / diagnostic imaging
  • Cognitive Dysfunction* / metabolism
  • Diffusion Tensor Imaging*
  • Female
  • Humans
  • Male
  • Water / metabolism*
  • White Matter* / diagnostic imaging
  • White Matter* / metabolism


  • Water

Grants and funding

This research was funded by the FONDATION VAINCRE ALZHEIMER (#14733, This study was considered an emerging project and therefore partly funded as part of the laboratory of Excellence TRAIL ANR-10-LABX-57 ( The Three-City study is conducted under a partnership agreement between the Institut National de la Santé et de la Recherche Médicale (INSERM,, the University Bordeaux 2 Victor Segalen ( and Sanofi-Aventis (, who funded the collection of initial data for the 3C cohort (from 1999 to 2005). The Fondation pour la Recherche Médicale funded the planning and initiation of the study ( The Three-City study is also supported by the Caisse Nationale Maladie des Travailleurs Salariés (, Direction Générale de la Santé MGEN (, Institut de la Longévité (, Conseils Régionaux d’Aquitaine et Bourgogne, Fondation de France (, Ministry of Research-INSERM Programme “Cohortes et collections de données biologiques”, Agence Nationale de la Recherche ANR PNRA 2006 and LongVie 2007 (, the "Fondation Plan Alzheimer" (FCS 2009-2012) and the Caisse Nationale de Solidarité pour l'Autonomie (CNSA, Part of this research was also supported by the Fonds de recherche du Québec – Nature et technologies (FRQNT,, the NSERC Discovery grant (, the Université de Sherbrooke institutional chair in neuroinformatics from Pr Descoteaux ( and the Mitacs Accelerate program ( The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.