Amyloid-PET of the white matter: Relationship to free water, fiber integrity, and cognition in patients with dementia and small vessel disease

J Cereb Blood Flow Metab. 2023 Jun;43(6):921-936. doi: 10.1177/0271678X231152001. Epub 2023 Jan 25.

Abstract

White matter (WM) injury is frequently observed along with dementia. Positron emission tomography with amyloid-ligands (Aβ-PET) recently gained interest for detecting WM injury. Yet, little is understood about the origin of the altered Aβ-PET signal in WM regions. Here, we investigated the relative contributions of diffusion MRI-based microstructural alterations, including free water and tissue-specific properties, to Aβ-PET in WM and to cognition. We included a unique cohort of 115 participants covering the spectrum of low-to-severe white matter hyperintensity (WMH) burden and cognitively normal to dementia. We applied a bi-tensor diffusion-MRI model that differentiates between (i) the extracellular WM compartment (represented via free water), and (ii) the fiber-specific compartment (via free water-adjusted fractional anisotropy [FA]). We observed that, in regions of WMH, a decrease in Aβ-PET related most closely to higher free water and higher WMH volume. In contrast, in normal-appearing WM, an increase in Aβ-PET related more closely to higher cortical Aβ (together with lower free water-adjusted FA). In relation to cognitive impairment, we observed a closer relationship with higher free water than with either free water-adjusted FA or WM PET. Our findings support free water and Aβ-PET as markers of WM abnormalities in patients with mixed dementia, and contribute to a better understanding of processes giving rise to the WM PET signal.

Trial registration: ClinicalTrials.gov NCT02330510.

Keywords: Alzheimer’s disease; amyloid-PET; diffusion MRI; free water; white matter.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, N.I.H., Extramural

MeSH terms

  • Alzheimer Disease* / diagnostic imaging
  • Alzheimer Disease* / metabolism
  • Cognition / physiology
  • Dementia* / diagnostic imaging
  • Diffusion Tensor Imaging / methods
  • Humans
  • Vascular Diseases*
  • Water / metabolism
  • White Matter* / diagnostic imaging
  • White Matter* / metabolism

Substances

  • Water

Associated data

  • ClinicalTrials.gov/NCT02330510