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Association of cerebral microvascular dysfunction and white matter injury in Alzheimer’s disease

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Abstract

Patients with Alzheimer’s disease (AD) often have cerebral white matter (WM) hyperintensities on MRI and microinfarcts of presumed microvascular origin pathologically. Here, we determined if vasodilator dysfunction of WM-penetrating arterioles is associated with pathologically defined WM injury and disturbances in quantitative MRI-defined WM integrity in patients with mixed microvascular and AD pathology. We analyzed tissues from 28 serially collected human brains from research donors diagnosed with varying degrees of AD neuropathologic change (ADNC) with or without cerebral microinfarcts (mVBI). WM-penetrating and pial surface arteriolar responses to the endothelium-dependent agonist bradykinin were quantified ex vivo with videomicroscopy. Vascular endothelial nitric oxide synthase (eNOS) and NAD(P)H-oxidase (Nox1, 2 and 4 isoforms) expression were measured with quantitative PCR. Glial fibrillary acidic protein (GFAP)-labeled astrocytes were quantified by unbiased stereological approaches in regions adjacent to the sites of WM-penetrating vessel collection. Post-mortem diffusion tensor imaging (DTI) was used to measure mean apparent diffusion coefficient (ADC) and fractional anisotropy (FA), quantitative indices of WM integrity. In contrast to pial surface arterioles, white matter-penetrating arterioles from donors diagnosed with high ADNC and mVBI exhibited a significantly reduced dilation in response to bradykinin when compared to the other groups. Expression of eNOS was reduced, whereas Nox1 expression was increased in WM arterioles in AD and mVBI cases. WM astrocyte density was increased in AD and mVBI, which correlated with a reduced vasodilation in WM arterioles. Moreover, in cases with low ADNC, bradykinin-induced WM arteriole dilation correlated with lower ADC and higher FA values. Comorbid ADNC and mVBI appear to synergistically interact to selectively impair bradykinin-induced vasodilation in WM-penetrating arterioles, which may be related to reduced nitric oxide- and excess reactive oxygen species-mediated vascular endothelial dysfunction. WM arteriole vasodilator dysfunction is associated with WM injury, as supported by reactive astrogliosis and MRI-defined disrupted WM microstructural integrity.

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Data availability

We declare that the data supporting the findings of this study are available within the article and its Supplementary Information files and from the corresponding authors upon request.

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Acknowledgements

We thank Allison Beller and Aimee Schantz for superb administrative support, and Marta Balogh, Kim Howard, Lisa Keene, and Amanda Keen for outstanding technical support. We are very grateful to all the ACT participants and families without whose dedication to supporting critical human research this work would be impossible.

Funding

Supported by grants from the National Institute on Aging (AG054651 to ZB, AG065406 to SAB, AG031892, U01 AG006781 and U19 AG066567 which supports the ACT study, p50 AG005136 and p30AG066509, which support the UW Alzheimer’s disease Research Center), the National Institute of Neurological Disorders and Stroke (NS105984 to SAB and NS054044 to C.D.K), and by the Nancy and Buster Alvord Endowment (to C.D.K). L.S.S was supported by NIH P51 OD011092. K.A.F was supported by NIH T32HL155011.

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Authors and Affiliations

  1. Department of Physiology, Medical College of Georgia, Augusta University, 1120 15th Street, Augusta, GA, 30912, USA

    Zsolt Bagi, Katie Anne Fopiano, Yanna Tian & Jessica A. Filosa

  2. Advanced Imaging Research Center, Oregon Health & Science University, Portland, OR, USA

    Christopher D. Kroenke

  3. Division of Neuroscience, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR, USA

    Christopher D. Kroenke & Larry S. Sherman

  4. Department of Cell, Developmental and Cancer Biology, Oregon Health and Science University, Portland, OR, USA

    Larry S. Sherman

  5. Kaiser Permanente Health Research Institute, Seattle, WA, USA

    Eric B. Larson

  6. Department of Medicine, University of Washington, Seattle, WA, USA

    Eric B. Larson

  7. Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, WA, USA

    C. Dirk Keene

  8. Department of Pediatrics, Oregon Health & Science University, Portland, OR, USA

    Kiera Degener O’Brien, Philip A. Adeniyi & Stephen A. Back

  9. Department of Neurology, Oregon Health & Science University, Mail-Code L481, 3181 S.W. Sam Jackson Park Rd, Portland, OR, 97239-3098, USA

    Stephen A. Back

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  1. Zsolt Bagi
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Contributions

Z.B., L.S.S., C.D.K., E.B.L., and S.A.B. conceptualized the project and were responsible for study design. Z.B., C.D.Kr., J.A.F., L.S.S., C.D.K., and S.A.B. wrote, edited, and finalized the manuscript. C.D.K. supervised all human pathology studies. Z.B., K.A.F., and Y.T. conducted vascular reactivity studies. K.D.O. and P.A. conducted astrocyte studies. C.D.Kr. conducted MRI/DTI studies.

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Correspondence to Zsolt Bagi or Stephen A. Back.

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Bagi, Z., Kroenke, C.D., Fopiano, K.A. et al. Association of cerebral microvascular dysfunction and white matter injury in Alzheimer’s disease. GeroScience 44, 1–14 (2022). https://doi.org/10.1007/s11357-022-00585-5

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