Perivascular spaces mediate a relationship between diabetes and other cerebral small vessel disease markers in cerebrovascular and neurodegenerative diseases

Julia Zebarth; Radia Kamal; George Perlman; Michael Ouk; Lisa Y Xiong; Di Yu; William Z Lin; Joel Ramirez; Mario Masellis; Maged Goubran; Bradley J MacIntosh; Sandra E Black; Hugo Cogo-Moreira; Christopher J M Scott; Robert Bartha; Sean Symons; Seyyed M H Haddad; Miracle Ozzoude; Nuwan Nanayakkara; Derek Beaton; Stephen Arnott; Dariush Dowlatshahi; Richard H Swartz; Gustavo Saposnik; David Grimes; Anthony Lang; Corinne E Fischer; Andrew Frank; Sanjeev Kumar; Bruce G Pollock; David Tang-Wai; Elizabeth Finger; Jennifer S Rabin; Walter Swardfager

doi:10.1016/j.jstrokecerebrovasdis.2023.107273

Perivascular spaces mediate a relationship between diabetes and other cerebral small vessel disease markers in cerebrovascular and neurodegenerative diseases

J Stroke Cerebrovasc Dis. 2023 Sep;32(9):107273. doi: 10.1016/j.jstrokecerebrovasdis.2023.107273. Epub 2023 Aug 3.

Authors

Julia Zebarth¹, Radia Kamal¹, George Perlman¹, Michael Ouk¹, Lisa Y Xiong¹, Di Yu¹, William Z Lin¹, Joel Ramirez², Mario Masellis², Maged Goubran³, Bradley J MacIntosh³, Sandra E Black², Hugo Cogo-Moreira⁴, Christopher J M Scott², Robert Bartha⁵, Sean Symons², Seyyed M H Haddad⁶, Miracle Ozzoude², Nuwan Nanayakkara⁷, Derek Beaton⁸, Stephen Arnott⁹, Dariush Dowlatshahi¹⁰, Richard H Swartz², Gustavo Saposnik¹¹, David Grimes¹⁰, Anthony Lang¹², Corinne E Fischer¹³, Andrew Frank¹⁴, Sanjeev Kumar¹⁵, Bruce G Pollock¹⁶, David Tang-Wai¹⁷, Elizabeth Finger¹⁸, Jennifer S Rabin¹⁹, Walter Swardfager²⁰

Affiliations

¹ Dr. Sandra Black Center for Brain Resilience and Recovery, LC Campbell Cognitive Neurology, Hurvitz Brain Sciences Program, Sunnybrook Research Institute 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada; Department of Pharmacology and Toxicology, University of Toronto, Medical Sciences building 1 Kings College Circle Room 4207, Toronto, Ontario M5S 1A8, Canada.
² Dr. Sandra Black Center for Brain Resilience and Recovery, LC Campbell Cognitive Neurology, Hurvitz Brain Sciences Program, Sunnybrook Research Institute 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada.
³ Dr. Sandra Black Center for Brain Resilience and Recovery, LC Campbell Cognitive Neurology, Hurvitz Brain Sciences Program, Sunnybrook Research Institute 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada; Department of Medical Biophysics, Temerty Faculty of Medicine, University of Toronto, Princess Margret Cancer Research Tower 101 College Street Room 15-701, Toronto M5G 1L7, Canada.
⁴ Department of Education, Østfold University College, 1757 B R A Veien 4, Halden 1757, Norway.
⁵ Department of Medical Biophysics, Western University, Medical Sciences building Room M407, London, Ontario N6A 5C1, Canada.
⁶ Center for Functional and Metabolic Mapping, Robarts Research Institute, Western University, 1151 Richmond Street, London, Ontario N6A 3K7, Canada.
⁷ Robarts Research Institute, University of Western Ontario, 100 Perth Drive, London, Ontario N6A 5K8, Canada.
⁸ Data Science and Advanced Analytics (DSAA), St. Michael's Hospital, Unity Health Toronto, 36 Queen Street East, Toronto, Ontario M5B 1W8, Canada.
⁹ Rotman Research Institute, Baycrest Centre, 3560 Bathurst Street, Toronto, Ontario M6A 2E1, Canada.
¹⁰ Division of Neurology, Department of Medicine, Ottawa Hospital Research Institute, University of Ottawa, 725 Parkdale Ave, Ottawa, Ontario K1Y 4E9, Canada.
¹¹ Stroke Outcomes and Decision Neuroscience Research Unit, Division of Neurology, St. Michael's Hospital, University of Toronto, 30 Bond Street, Toronto, Ontario M5B 1W8, Canada.
¹² Krembil Research Institute, University Health Network, 60 Leonard Ave, Toronto, Ontario M5T 0S8, Canada; Division of Neurology, Temerty Faculty of Medicine, University of Toronto, Medical Sciences building 1 Kings College Circle Room 4207, Toronto, Ontario M5S 1A8, Canada; Edmond J. Safra Program in Parkinson's Disease, Toronto Western Hospital, University Health Network, 399 Bathurst St, Toronto, Ontario M5T 2S8, Canada.
¹³ Keenan Research Centre for Biomedical Science, Unity Health, 209 Victoria Street, Toronto, Ontario M5B 1T8, Canada.
¹⁴ Bruyère Research Institute, University of Ottawa, 85 Primrose Avenue, Ottawa, Ontario K1R 6M1, Canada.
¹⁵ Adult Neurodevelopmental and Geriatric Psychiatry Division, Centre for Addiction and Mental Health, 1001 Queen Street West, Toronto, Ontario M6J 1H4, Canada; Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, 250 College Street, Toronto M5T 1R8, Canada.
¹⁶ Department of Pharmacology and Toxicology, University of Toronto, Medical Sciences building 1 Kings College Circle Room 4207, Toronto, Ontario M5S 1A8, Canada; Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health 475 Spadina Avenue, Toronto, Ontario M5S 2S1, Canada; Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, 250 College Street, Toronto M5T 1R8, Canada.
¹⁷ Krembil Research Institute, University Health Network, 60 Leonard Ave, Toronto, Ontario M5T 0S8, Canada; Division of Neurology, Temerty Faculty of Medicine, University of Toronto, Medical Sciences building 1 Kings College Circle Room 4207, Toronto, Ontario M5S 1A8, Canada; Toronto Western Hospital, University Health Network Memory Clinic, 399 Bathurst Street, Toronto M5T 2S8, Canada.
¹⁸ Department of Clinical Neurological Sciences, Western University, 550 Wellington Road, London, Ontario N6C 0A7, Canada.
¹⁹ Dr. Sandra Black Center for Brain Resilience and Recovery, LC Campbell Cognitive Neurology, Hurvitz Brain Sciences Program, Sunnybrook Research Institute 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada; Harquail Centre for Neuromodulation, Sunnybrook Research Institute, 2075 Bayview Avenue, Toronto M4N 3M5, Canada; Division of Neurology, Department of Medicine, Sunnybrook Health Sciences Centre, University of Toronto, 2075 Bayview Avenue, Toronto M4N 3M5, Canada; Rehabilitation Sciences Institute, Temerty Faculty of Medicine, University of Toronto, 1 King's College Circle, Medical Sciences Building, Room 2109, Toronto, Ontario M5S 1A8, Canada.
²⁰ Dr. Sandra Black Center for Brain Resilience and Recovery, LC Campbell Cognitive Neurology, Hurvitz Brain Sciences Program, Sunnybrook Research Institute 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada; Department of Pharmacology and Toxicology, University of Toronto, Medical Sciences building 1 Kings College Circle Room 4207, Toronto, Ontario M5S 1A8, Canada; Thunder Bay Regional Health Research Institute, 1040 Oliver Road, Thunder Bay, Ontario P7B 7A5, Canada. Electronic address: [email protected].

PMID: 37542762
DOI: 10.1016/j.jstrokecerebrovasdis.2023.107273

Abstract

Type 2 diabetes mellitus (T2DM) and hypertension are risk factors for cerebral small vessel disease (SVD); however, few studies have characterised their relationships with MRI-visible perivascular spaces (PVS). MRI was used to quantify deep (d) and periventricular (p) white matter hyperintensities (WMH), lacunes, PVS in the white matter (wmPVS) or basal ganglia (bgPVS), and diffusion metrics in white matter. Patients with T2DM had greater wmPVS volume and there were greater wmPVS volumes in patients with T2DM and hypertension together. Counterfactual moderated mediation models found indirect effects of T2DM on volumes of other SVD and diffusion markers that were mediated by wmPVS: pWMH, dWMH, periventricular lacunes, and deep lacunes, and progression of deep lacunes over 1 year, in patients with hypertension, but not in patients without hypertension. Studying the regulation of cortical perivascular fluid dynamics may reveal mechanisms that mediate the impact of T2DM on cerebral small vessels.

Keywords: Cerebrovascular disease; Diabetes mellitus; Hypertension; Neurodegeneration; Perivascular spaces; Small vessel disease.