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

Author:

Ottoy Julie1,Ozzoude Miracle1,Zukotynski Katherine1234,Kang Min Su15ORCID,Adamo Sabrina1,Scott Christopher1,Ramirez Joel1ORCID,Swardfager Walter6ORCID,Lam Benjamin7,Bhan Aparna1,Mojiri Parisa1,Kiss Alex8,Strother Stephen910,Bocti Christian11,Borrie Michael12,Chertkow Howard13,Frayne Richard14,Hsiung Robin15,Laforce Robert Jr16,Noseworthy Michael D217ORCID,Prato Frank S12,Sahlas Demetrios J18,Smith Eric E19,Kuo Phillip H20,Chad Jordan A910,Pasternak Ofer21,Sossi Vesna15,Thiel Alexander13,Soucy Jean-Paul5,Tardif Jean-Claude22,Black Sandra E17ORCID,Goubran Maged1923ORCID,

Affiliation:

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.

Publisher

SAGE Publications

Subject

Cardiology and Cardiovascular Medicine,Neurology (clinical),Neurology

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