Perivascular spaces, plasma GFAP, and speeded executive function in neurodegenerative diseases

Daniela Andriuta^{1

2

3}, Julie Ottoy³, Myuri Ruthirakuhan³, Ginelle Feliciano³, Allison A Dilliott⁴, Robert A Hegele⁵, Fuqiang Gao³, Paula M McLaughlin⁶, Jennifer S Rabin^{3

7

8

9}, Madeline Wood Alexander^{3

8}, Christopher J M Scott³, Vanessa Yhap³, Courtney Berezuk³, Miracle Ozzoude³, Walter Swardfager³, Julia Zebarth³, M Carmela Tartaglia¹⁰, Ekaterina Rogaeva¹¹, David F Tang-Wai¹⁰, Leanne Casaubon¹⁰, Sanjeev Kumar¹², Dar Dowlatshahi¹³, Jennifer Mandzia⁵, Demetrios Sahlas¹⁴, Gustavo Saposnik¹⁵, Corinne E Fischer^{15

16}, Michael Borrie⁵, Ayman Hassan^{14

17}, Malcolm A Binns^{18

19}, Morris Freedman¹⁸, Howard Chertkow^{9

18}, Elizabeth Finger⁵, Andrew Frank^{13

20}, Robert Bartha⁵, Sean Symons²¹, Henrik Zetterberg^{22

23

24}, Richard H Swartz^{3

9

25}, Mario Masellis^{3

9

25}, Sandra E Black^{3

9

25}, Joel Ramirez^{3

26}; ONDRI Investigators

Affiliations

¹ Department of Neurology, Amiens University Medical Center, Amiens, France.
² Laboratoire de Neurosciences Fonctionnelles et Pathologies (UR UPJV 4559), Jules Verne University of Picardy, Amiens, France.
³ Dr. Sandra Black Centre for Brain Resilience and Recovery, LC Campbell Cognitive Neurology, Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Toronto, Ontario, Canada.
⁴ Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University, Montréal, Quebec, Canada.
⁵ Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, Toronto, Ontario, Canada.
⁶ Nova Scotia Health, Halifax, Nova Scotia, Canada.
⁷ Harquail Centre for Neuromodulation, Sunnybrook Research Institute, Toronto, Ontario, Canada.
⁸ Rehabilitation Sciences Institute, University of Toronto, Toronto, Ontario, Canada.
⁹ Division of Neurology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
¹⁰ Division of Neurology, Toronto Western Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada.
¹¹ Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada.
¹² Department of Psychiatry, Adult Neurodevelopment and Geriatric Psychiatry, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
¹³ University of Ottawa Brain and Mind Research Institute and Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
¹⁴ Division of Neurology, Department of Medicine, Hamilton Health Sciences, McMaster University, Hamilton, Ontario, Canada.
¹⁵ Li Ka Shing Knowledge Institute, and Division of Neurology, Department of Medicine, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada.
¹⁶ Keenan Research Centre for Biomedical Science, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada.
¹⁷ Thunder Bay Regional Health Research Institute, Thunder Bay, Ontario, Canada.
¹⁸ Rotman Research Institute, Baycrest Health Sciences, Toronto, Ontario, Canada.
¹⁹ Division of Biostatistics, Dalla Lana School of Public Health, Toronto, Ontario, Canada.
²⁰ Bruyère Research Institute, Ottawa, Ontario, Canada.
²¹ Department of Medical Imaging, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.
²² Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
²³ Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
²⁴ Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, UK Dementia Research Institute at UCL, London, UK.
²⁵ Department of Medicine, Neurology, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.
²⁶ Graduate Department of Psychological Clinical Science, University of Toronto Scarborough, Toronto, Ontario, Canada.

PMID: 38961774
PMCID: PMC11350014
DOI: 10.1002/alz.14081

Perivascular spaces, plasma GFAP, and speeded executive function in neurodegenerative diseases

Daniela Andriuta et al. Alzheimers Dement. 2024 Aug.

. 2024 Aug;20(8):5800-5808.

doi: 10.1002/alz.14081. Epub 2024 Jul 4.

Authors

Affiliations

¹ Department of Neurology, Amiens University Medical Center, Amiens, France.
² Laboratoire de Neurosciences Fonctionnelles et Pathologies (UR UPJV 4559), Jules Verne University of Picardy, Amiens, France.
³ Dr. Sandra Black Centre for Brain Resilience and Recovery, LC Campbell Cognitive Neurology, Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Toronto, Ontario, Canada.
⁴ Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University, Montréal, Quebec, Canada.
⁵ Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, Toronto, Ontario, Canada.
⁶ Nova Scotia Health, Halifax, Nova Scotia, Canada.
⁷ Harquail Centre for Neuromodulation, Sunnybrook Research Institute, Toronto, Ontario, Canada.
⁸ Rehabilitation Sciences Institute, University of Toronto, Toronto, Ontario, Canada.
⁹ Division of Neurology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
¹⁰ Division of Neurology, Toronto Western Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada.
¹¹ Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada.
¹² Department of Psychiatry, Adult Neurodevelopment and Geriatric Psychiatry, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
¹³ University of Ottawa Brain and Mind Research Institute and Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
¹⁴ Division of Neurology, Department of Medicine, Hamilton Health Sciences, McMaster University, Hamilton, Ontario, Canada.
¹⁵ Li Ka Shing Knowledge Institute, and Division of Neurology, Department of Medicine, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada.
¹⁶ Keenan Research Centre for Biomedical Science, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada.
¹⁷ Thunder Bay Regional Health Research Institute, Thunder Bay, Ontario, Canada.
¹⁸ Rotman Research Institute, Baycrest Health Sciences, Toronto, Ontario, Canada.
¹⁹ Division of Biostatistics, Dalla Lana School of Public Health, Toronto, Ontario, Canada.
²⁰ Bruyère Research Institute, Ottawa, Ontario, Canada.
²¹ Department of Medical Imaging, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.
²² Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
²³ Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
²⁴ Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, UK Dementia Research Institute at UCL, London, UK.
²⁵ Department of Medicine, Neurology, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.
²⁶ Graduate Department of Psychological Clinical Science, University of Toronto Scarborough, Toronto, Ontario, Canada.

PMID: 38961774
PMCID: PMC11350014
DOI: 10.1002/alz.14081

Abstract

Introduction: We investigated the effect of perivascular spaces (PVS) volume on speeded executive function (sEF), as mediated by white matter hyperintensities (WMH) volume and plasma glial fibrillary acidic protein (GFAP) in neurodegenerative diseases.

Methods: A mediation analysis was performed to assess the relationship between neuroimaging markers and plasma biomarkers on sEF in 333 participants clinically diagnosed with Alzheimer's disease/mild cognitive impairment, frontotemporal dementia, or cerebrovascular disease from the Ontario Neurodegenerative Disease Research Initiative.

Results: PVS was significantly associated with sEF (c = -0.125 ± 0.054, 95% bootstrap confidence interval [CI] [-0.2309, -0.0189], p = 0.021). This effect was mediated by both GFAP and WMH.

Discussion: In this unique clinical cohort of neurodegenerative diseases, we demonstrated that the effect of PVS on sEF was mediated by the presence of elevated plasma GFAP and white matter disease. These findings highlight the potential utility of imaging and plasma biomarkers in the current landscape of therapeutics targeting dementia.

Highlights: Perivascular spaces (PVS) and white matter hyperintensities (WMH) are imaging markers of small vessel disease. Plasma glial fibrillary protein acidic protein (GFAP) is a biomarker of astroglial injury. PVS, WMH, and GFAP are relevant in executive dysfunction from neurodegeneration. PVS's effect on executive function was mediated by GFAP and white matter disease.

Keywords: cerebrovascular diseases; executive function; neurodegenerative diseases; perivascular spaces; plasma glial fibrillary acidic protein; white matter hyperintensities.

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Conflict of interest statement

D.A. reports no disclosures relevant to the manuscript. J.O. reports no disclosures relevant to the manuscript. M.R. reports no disclosures relevant to the manuscript. G.F. reports no disclosures relevant to the manuscript. A.A.D. reports no disclosures relevant to the manuscript. R.A.H. reports no disclosures relevant to the manuscript. F.G. reports no disclosures relevant to the manuscript. P.M.M. reports no disclosures relevant to the manuscript. J.S.R. reports no disclosures relevant to the manuscript. M.W.A. reports no disclosures relevant to the manuscript. C.J.M.S. reports no disclosures relevant to the manuscript. V.Y. reports no disclosures relevant to the manuscript. C.B. reports no disclosures relevant to the manuscript. M.O. reports no disclosures relevant to the manuscript. W.S. reports no disclosures relevant to the manuscript. J.Z. reports no disclosures relevant to the manuscript. M.C.T. reports no disclosures relevant to the manuscript. E.R. reports no disclosures relevant to the manuscript. D.F.T.‐W. reports no disclosures relevant to the manuscript. L.C. reports no disclosures relevant to the manuscript. S.K. reports no disclosures relevant to the manuscript. D.D. reports no disclosures relevant to the manuscript. J.M. reports no disclosures relevant to the manuscript. D.S. reports no disclosures relevant to the manuscript. G.S. reports no disclosures relevant to the manuscript. C.E.F. reports no disclosures relevant to the manuscript. M.B. reports no disclosures relevant to the manuscript. A.H. reports no disclosures relevant to the manuscript. M.A.B. reports no disclosures relevant to the manuscript. M.F. reports no disclosures relevant to the manuscript. H.C. reports no disclosures relevant to the manuscript. E.F. reports no disclosures relevant to the manuscript. A.F. reports no disclosures relevant to the manuscript. R.B. reports no disclosures relevant to the manuscript. S.S. reports no disclosures relevant to the manuscript. H.Z. reports no disclosures relevant to the manuscript. R.H.S. reports no disclosures relevant to the manuscript. M.M. reports no disclosures relevant to the manuscript. S.E.B. reports no disclosures relevant to the manuscript. J.R. reports no disclosures relevant to the manuscript. D.A. reports funding (travel and meetings) from Biogen, Roche, Teva, Novartis, Bristol‐Myers Squibb, Genzyme, and Sanofi outside the submitted work. H.Z. has served at scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZPath, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, Merry Life, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures in symposia sponsored by Alzecure, Biogen, Cellectricon, Fujirebio, Lilly, and Roche, and is a co‐founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). C.E.F. receives grant funding from NIA, NIH, CCNA, CIHR, ADDF, TDRA, Mito2i, the Hilary and Galen Weston Foundation, and Novo Nordisk. Author disclosures are available in the supporting information.

Figures

**FIGURE 1**
Plasma GFAP and WMH volume mediate the effect of PVS on sEF. Mediation Model showing plasma glial fibrillary acidic protein and white matter hyperintensity volumes are significantly mediating the associations of perivascular space volumes with speeded executive function. GFAP, glial fibrillary acidic protein; PVS, perivascular spaces; SDMT, Digit Symbol Modalities Test; sEF, speeded executive function; TMTb, Trail Making Test Part B; WMH, white matter hyperintensities (created with BioRender.com)

See this image and copyright information in PMC

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Perivascular spaces, plasma GFAP, and speeded executive function in neurodegenerative diseases

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Perivascular spaces, plasma GFAP, and speeded executive function in neurodegenerative diseases

Authors

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Abstract

Conflict of interest statement

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