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

Julie Ottoy; Miracle Ozzoude; Katherine Zukotynski; Min Su Kang; Sabrina Adamo; Christopher Scott; Joel Ramirez; Walter Swardfager; Benjamin Lam; Aparna Bhan; Parisa Mojiri; Alex Kiss; Stephen Strother; Christian Bocti; Michael Borrie; Howard Chertkow; Richard Frayne; Robin Hsiung; Robert Jr Laforce; Michael D Noseworthy; Frank S Prato; Demetrios J Sahlas; Eric E Smith; Phillip H Kuo; Jordan A Chad; Ofer Pasternak; Vesna Sossi; Alexander Thiel; Jean-Paul Soucy; Jean-Claude Tardif; Sandra E Black; Maged Goubran; Medical Imaging Trials Network of Canada (MITNEC) and Alzheimer’s Disease Neuroimaging Initiative (ADNI)

doi:10.1177/0271678X231152001

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.

Authors

Julie Ottoy¹, Miracle Ozzoude¹, Katherine Zukotynski^{1

2

3

4}, Min Su Kang^{1

5}, Sabrina Adamo¹, Christopher Scott¹, Joel Ramirez¹, Walter Swardfager⁶, Benjamin Lam⁷, Aparna Bhan¹, Parisa Mojiri¹, Alex Kiss⁸, Stephen Strother^{9

10}, Christian Bocti¹¹, Michael Borrie¹², Howard Chertkow¹³, Richard Frayne¹⁴, Robin Hsiung¹⁵, Robert Jr Laforce¹⁶, Michael D Noseworthy^{2

17}, Frank S Prato¹², Demetrios J Sahlas¹⁸, Eric E Smith¹⁹, Phillip H Kuo²⁰, Jordan A Chad^{9

10}, Ofer Pasternak²¹, Vesna Sossi¹⁵, Alexander Thiel¹³, Jean-Paul Soucy⁵, Jean-Claude Tardif²², Sandra E Black^{1

7}, Maged Goubran^{1

9

23}; Medical Imaging Trials Network of Canada (MITNEC) and Alzheimer’s Disease Neuroimaging Initiative (ADNI)

Affiliations

¹ LC Campbell Cognitive Neurology Unit, Hurvitz Brain Sciences Program, Sunnybrook Research Institute, University of Toronto, Toronto, ON, Canada.
² Departments of Medicine and Radiology, McMaster University, Hamilton, ON, Canada.
³ Department of Medical Imaging, Schulich School of Medicine & Dentistry, Western University, London, ON, Canada.
⁴ Department of Radiology, University of British Columbia, Vancouver, BC, Canada.
⁵ Montreal Neurological Institute, McGill University, Montreal, QC, Canada.
⁶ Department of Pharmacology & Toxicology, University of Toronto, Toronto, ON, Canada.
⁷ Department of Medicine (Division of Neurology), Dr. Sandra Black Centre for Brain Resilience and Recovery, Hurvitz Brain Sciences Research Program, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada.
⁸ Department of Research Design and Biostatistics, Sunnybrook Research Institute, University of Toronto, Toronto, ON, Canada.
⁹ Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
¹⁰ The Rotman Research Institute Baycrest, University of Toronto, Toronto, ON, Canada.
¹¹ Service de Neurologie, Département de Medicine, Université de Sherbrooke, Sherbrooke, QC, Canada.
¹² Lawson Health Research Institute, Western University, London, ON, Canada.
¹³ Jewish General Hospital and Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada.
¹⁴ Departments of Radiology and Clinical Neuroscience, Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada.
¹⁵ Physics and Astronomy Department and DM Center for Brain Health, University of British Columbia, Vancouver, BC, Canada.
¹⁶ Clinique Interdisciplinaire de Mémoire, Département des Sciences Neurologiques, Université Laval, Québec, QC, Canada.
¹⁷ Department of Electrical and Computer Engineering, McMaster University, Hamilton, ON, Canada.
¹⁸ Department of Medicine, McMaster University, Hamilton, ON, Canada.
¹⁹ Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada.
²⁰ Department of Medical Imaging, Medicine, and Biomedical Engineering, University of Arizona, Tucson, AZ, USA.
²¹ Departments of Psychiatry and Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, USA.
²² Montreal Heart Institute, Université de Montréal, Montreal, QC, Canada.
²³ Physical Sciences Platform, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, ON, Canada.

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

Grants and funding

U01 AG024904/AG/NIA NIH HHS/United States