High levels of free water and white matter hyperintensity may be predictive of higher dementia severity and accelerated declines in episodic memory (EM) and executive function (EF) in older individuals, according to study results published in Neurology.

A subgroup of older patients (mean age, 77±8) from the University of California, Davis, Alzheimer’s Disease Center cohort were included in the study (n=536). Patients had received annual clinical assessments and a baseline magnetic resonance imaging (MRI) examination. Executive function and EM were included as the primary cognitive outcome measure, whereas the second outcome measure was the Clinical Dementia Rating (CDR) scale. Follow-up MRI data were available for 224 patients. For each patient, the researchers computed white matter microstructural measures (eg, free water, fractional anisotropy, and mean diffusivity) corrected for free water and white matter hyperintensity burden within white matter voxels.

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Patients with higher free water and white matter hyperintensity at baseline had lower baseline EM (β = −0.16; P =.0014 and β = −0.14; P =.0012, respectively) and EF (β = −0.29; P <.001 and β = −0.17; P <.001, respectively). In addition, higher baseline free water and white matter hyperintensity were associated with higher baseline CDR severity (χ = 20.22; P <.001 and χ = 6.98; P =.03, respectively). An increase of 1 standard deviation in baseline free water was associated with an almost doubled risk for a CDR ≥1 vs 0.5 (odds ratio [OR] 1.87; 95% CI, 1.3-2.72; P <.001) whereas a 1-standard deviation increase in baseline white matter hyperintensity increased the risk for a CDR of ≥1 vs 0 by 61% (OR 1.61; 95% CI, 1.04-2.56; P =.035). Higher free water and white matter hyperintensity at baseline was also associated with accelerated decline in EF (β = −0.33; P <.001 and β = −0.21; P <.001, respectively) and EM (β = −0.17; P =.0012 and β = −0.18; P <.001, respectively).

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Study limitations included the focus on global associations between functional and cognitive outcomes with MRI measures, as well as the lack of identification of free water components that may be associated with cognitive- and functional-related degeneration.

“Our work supports the need for diffusion tensor imaging (DTI) studies to correct DTI metrics for extracellular content and investigate the pathophysiologic process that manifests through increased free water within the white matter,” the researchers wrote, “potentially leading to more severe [white matter] injury and possibly resulting in subsequent accelerated cognitive and functional decline.”


Maillard P, Fletcher E, Singh B, et al. Cerebral white matter free water: a sensitive biomarker of cognition and function. Neurology. 2019;92(19):e2221-e2231.