Vascular burden and cognition: Mediating roles of neurodegeneration and amyloid PET

Julie Ottoy; Miracle Ozzoude; Katherine Zukotynski; Sabrina Adamo; Christopher Scott; Vincent Gaudet; Joel Ramirez; Walter Swardfager; Hugo Cogo-Moreira; Benjamin Lam; Aparna Bhan; Parisa Mojiri; Min Su Kang; Jennifer S Rabin; 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; Vesna Sossi; Alexander Thiel; Jean-Paul Soucy; Jean-Claude Tardif; Sandra E Black; Maged Goubran; Medical Imaging Trial Network of Canada (MITNEC) and Alzheimer's Disease Neuroimaging Initiative (ADNI)

doi:10.1002/alz.12750

Vascular burden and cognition: Mediating roles of neurodegeneration and amyloid PET

Alzheimers Dement. 2023 Apr;19(4):1503-1517. doi: 10.1002/alz.12750. Epub 2022 Sep 1.

Authors

Julie Ottoy¹, Miracle Ozzoude¹, Katherine Zukotynski^{1

2

3

4}, Sabrina Adamo¹, Christopher Scott¹, Vincent Gaudet⁵, Joel Ramirez¹, Walter Swardfager⁶, Hugo Cogo-Moreira^{1

7}, Benjamin Lam⁸, Aparna Bhan¹, Parisa Mojiri¹, Min Su Kang^{1

9

10}, Jennifer S Rabin^{11

12

13

14}, Alex Kiss¹⁵, Stephen Strother^{16

17}, Christian Bocti¹⁸, Michael Borrie¹⁹, Howard Chertkow²⁰, Richard Frayne²¹, Robin Hsiung²², Robert Jr Laforce²³, Michael D Noseworthy²⁴, Frank S Prato¹⁹, Demetrios J Sahlas²⁵, Eric E Smith²⁶, Phillip H Kuo²⁷, Vesna Sossi²², Alexander Thiel²⁰, Jean-Paul Soucy⁹, Jean-Claude Tardif²⁸, Sandra E Black^{1

8

29}, Maged Goubran^{1

10

16}; Medical Imaging Trial 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, Ontario, Canada.
² Departments of Medicine and Radiology, McMaster University, Hamilton, Ontario, Canada.
³ Department of Medical Imaging, Schulich School of Medicine & Dentistry, Western University, London, Ontario, Canada.
⁴ Department of Radiology, University of British Columbia, Vancouver, British Columbia, Canada.
⁵ Department of Electrical and Computer Engineering, University of Waterloo, Waterloo, Ontario, Canada.
⁶ Department of Pharmacology & Toxicology, University of Toronto, Toronto, Ontario, Canada.
⁷ Department of Education, ICT and Learning, Østfold University College, Halden, Norway.
⁸ Department of Medicine (Division of Neurology), University of Toronto, Toronto, Ontario, Canada.
⁹ Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada.
¹⁰ Physical Sciences Platform, Sunnybrook Research Institute, University of Toronto, Toronto, Ontario, Canada.
¹¹ Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Toronto, Ontario, Canada.
¹² Harquail Centre for Neuromodulation, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.
¹³ Division of Neurology, Department of Medicine, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada.
¹⁴ Rehabilitation Sciences Institute, University of Toronto, Toronto, Ontario, Canada.
¹⁵ Department of Research Design and Biostatistics, Sunnybrook Research Institute, University of Toronto, Toronto, Ontario, Canada.
¹⁶ Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
¹⁷ The Rotman Research Institute Baycrest, University of Toronto, Toronto, Ontario, Canada.
¹⁸ Département de Médecine, Université de Sherbrooke, Sherbrooke, Quebec, Canada.
¹⁹ Lawson Health Research Institute, Western University, London, Ontario, Canada.
²⁰ Jewish General Hospital and Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.
²¹ Departments of Radiology and Clinical Neuroscience, Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.
²² Physics and Astronomy Department and DM Center for Brain Health, University of British Columbia, Vancouver, British Columbia, Canada.
²³ Clinique Interdisciplinaire de Mémoire, Département des Sciences Neurologiques, Université Laval, Quebec City, Quebec, Canada.
²⁴ Department of Electrical and Computer Engineering, McMaster University, Hamilton, Ontario, Canada.
²⁵ Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
²⁶ Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.
²⁷ Department of Medical Imaging, Medicine, and Biomedical Engineering, University of Arizona, Tucson, Arizona, USA.
²⁸ Montreal Heart Institute, Université de Montréal, Montreal, Quebec, Canada.
²⁹ Dr. Sandra Black Centre for Brain Resilience and Recovery, Hurvitz Brain Sciences Research Program, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada.

PMID: 36047604
DOI: 10.1002/alz.12750

Abstract

It remains unclear to what extent cerebrovascular burden relates to amyloid beta (Aβ) deposition, neurodegeneration, and cognitive dysfunction in mixed disease populations with small vessel disease and Alzheimer's disease (AD) pathology. In 120 subjects, we investigated the association of vascular burden (white matter hyperintensity [WMH] volumes) with cognition. Using mediation analyses, we tested the indirect effects of WMH on cognition via Aβ deposition (¹⁸ F-AV45 positron emission tomography [PET]) and neurodegeneration (cortical thickness or ¹⁸ F fluorodeoxyglucose PET) in AD signature regions. We observed that increased total WMH volume was associated with poorer performance in all tested cognitive domains, with the strongest effects observed for semantic fluency. These relationships were mediated mainly via cortical thinning, particularly of the temporal lobe, and to a lesser extent serially mediated via Aβ and cortical thinning of AD signature regions. WMH volumes differentially impacted cognition depending on lobar location and Aβ status. In summary, our study suggests mainly an amyloid-independent pathway in which vascular burden affects cognitive function via localized neurodegeneration. HIGHLIGHTS: Alzheimer's disease often co-exists with vascular pathology. We studied a unique cohort enriched for high white matter hyperintensities (WMH). High WMH related to cognitive impairment of semantic fluency and executive function. This relationship was mediated via temporo-parietal atrophy rather than metabolism. This relationship was, to lesser extent, serially mediated via amyloid beta and atrophy.

Trial registration: ClinicalTrials.gov NCT02330510.

Keywords: Alzheimer's disease; amyloid; biomarker; cognition; cortical atrophy; glucose metabolism; neurodegeneration; small vessel disease; vascular; white matter disease; white matter hyperintensities.

Publication types

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

MeSH terms

Alzheimer Disease* / pathology
Amyloid / metabolism
Amyloid beta-Peptides / metabolism
Atrophy / pathology
Cerebral Cortical Thinning / pathology
Cognition
Cognitive Dysfunction* / metabolism
Humans
Magnetic Resonance Imaging
Positron-Emission Tomography
White Matter* / pathology

Substances

Amyloid beta-Peptides
Amyloid

Associated data

ClinicalTrials.gov/NCT02330510

Grants and funding

U01 AG024904/AG/NIA NIH HHS/United States