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. 2024 Aug;20(8):5800-5808.
doi: 10.1002/alz.14081. Epub 2024 Jul 4.

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

Daniela Andriuta  1   2   3 , Julie Ottoy  3 , Myuri Ruthirakuhan  3 , Ginelle Feliciano  3 , Allison A Dilliott  4 , Robert A Hegele  5 , Fuqiang Gao  3 , Paula M McLaughlin  6 , Jennifer S Rabin  3   7   8   9 , Madeline Wood Alexander  3   8 , Christopher J M Scott  3 , Vanessa Yhap  3 , Courtney Berezuk  3 , Miracle Ozzoude  3 , Walter Swardfager  3 , Julia Zebarth  3 , M Carmela Tartaglia  10 , Ekaterina Rogaeva  11 , David F Tang-Wai  10 , Leanne Casaubon  10 , Sanjeev Kumar  12 , Dar Dowlatshahi  13 , Jennifer Mandzia  5 , Demetrios Sahlas  14 , Gustavo Saposnik  15 , Corinne E Fischer  15   16 , Michael Borrie  5 , Ayman Hassan  14   17 , Malcolm A Binns  18   19 , Morris Freedman  18 , Howard Chertkow  9   18 , Elizabeth Finger  5 , Andrew Frank  13   20 , Robert Bartha  5 , Sean Symons  21 , 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

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

Daniela Andriuta et al. Alzheimers Dement. 2024 Aug.

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
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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