Free-water imaging of the hippocampus is a sensitive marker of Alzheimer's disease

Neuroimage Clin. 2019;24:101985. doi: 10.1016/j.nicl.2019.101985. Epub 2019 Aug 22.


Validating sensitive markers of hippocampal degeneration is fundamental for understanding neurodegenerative conditions such as Alzheimer's disease. In this paper, we test the hypothesis that free-water in the hippocampus will be more sensitive to early stages of cognitive decline than hippocampal volume, and that free-water in hippocampus will increase across distinct clinical stages of Alzheimer's disease. We examined two separate cohorts (N = 126; N = 112) of cognitively normal controls, early and late mild cognitive impairment (MCI), and Alzheimer's disease. Demographic, clinical, diffusion-weighted and T1-weighted imaging, and positron emission tomography (PET) imaging were assessed. Results indicated elevated hippocampal free-water in early MCI individuals compared to controls across both cohorts. In contrast, there was no difference in volume of these regions between controls and early MCI. ADNI free-water values in the hippocampus was associated with low CSF AB1-42 levels and high global amyloid PET values. Free-water imaging of the hippocampus can serve as an early stage marker for AD and provides a complementary measure of AD neurodegeneration using non-invasive imaging.

Keywords: Free-water imaging; Hippocampus; Mild cognitive impairment; Neurodegeneration.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aged
  • Aged, 80 and over
  • Aging*
  • Alzheimer Disease / diagnostic imaging*
  • Biomarkers
  • Body Water / diagnostic imaging*
  • Cognitive Dysfunction / diagnostic imaging*
  • Female
  • Hippocampus / diagnostic imaging*
  • Humans
  • Magnetic Resonance Imaging / standards
  • Male
  • Neuroimaging / standards*
  • Positron-Emission Tomography / standards
  • Reproducibility of Results
  • Sensitivity and Specificity


  • Biomarkers