White matter microstructure disruption in early stage amyloid pathology

L.E. Collij; S. Ingala; H. Top; V. Wottschel; K.E. Stickney; J. Tomassen; E. Konijnenberg; M.T. Kate; C. Sudre; I.L. Alves; M.M. Yaqub; A.M. Wink; D. Van ‘t Ent; P. Scheltens; B.N.M. van Berckel; P.J. Visser; F. Barkhof; A. Den Braber

doi:10.1002/dad2.12124

White matter microstructure disruption in early stage amyloid pathology

L.E. Collij, S. Ingala, H. Top, V. Wottschel, K.E. Stickney, J. Tomassen, E. Konijnenberg, M.T. Kate, C. Sudre, I.L. Alves, M.M. Yaqub, A.M. Wink, D. Van ‘t Ent, P. Scheltens, B.N.M. van Berckel, P.J. Visser, F. Barkhof, A. Den Braber

Biological Psychology

Research output: Contribution to Journal › Article › Academic › peer-review

Abstract

© 2021 The Authors. Alzheimer.Introduction: Amyloid beta (Aβ) accumulation is the first pathological hallmark of Alzheimer’s disease (AD), and it is associated with altered white matter (WM) microstructure. We aimed to investigate this relationship at a regional level in a cog-nitively unimpaired cohort. Methods: We included 179 individuals from the European Medical Information Framework for AD (EMIF-AD) preclinAD study, who underwent diffusion magnetic resonance (MR) to determine tract-level fractional anisotropy (FA); mean, radial, and axial diffusivity (MD/RD/AxD); and dynamic [18F]flutemetamol) positron emission tomogra-phy (PET) imaging to assess amyloid burden. Results: Regression analyses showed a non-linear relationship between regional amyloid burden and WM microstructure. Low amyloid burden was associated with increased FA and decreased MD/RD/AxD, followed by decreased FA and increased MD/RD/AxD upon higher amyloid burden. The strongest association was observed between amyloid burden in the precuneus and body of the corpus callosum (CC) FA and diffusivity (MD/RD) measures. In addition, amyloid burden in the anterior cingu-late cortex strongly related to AxD and RD measures in the genu CC. Discussion: Early amyloid deposition is associated with changes in WM microstruc-ture. The non-linear relationship might reflect multiple stages of axonal damage.

Original language	English
Article number	e12124
Journal	Alzheimer's and Dementia: Diagnosis, Assessment and Disease Monitoring
Volume	13
Issue number	1
DOIs	https://doi.org/10.1002/dad2.12124
Publication status	Published - 2021

Funding

The authors want to thank all PreclinAD participants for their efforts to join and complete this demanding study and our colleagues of The Netherlands Twin Register for referring participants. The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under European Medical Information Framework (EMIF) grant agreement No. 115372, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-2013) and European Federation of Pharmaceutical Industries and Associations (EFPIA) companies in-kind contribution. The project leading to this paper has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under Amyloid Imaging to Prevent Alzheimer’s Disease (AMYPAD) grant agreement No. 115952 and European Prevention of Alzheimer’s Dementia (EPAD) grant No. 115736. This Joint Undertaking receives the support from the European Union’s Horizon 2020 Research and Innovation Programme and EFPIA. Frederik Barkhof is supported by the National Institute for Health Research University College London Hospitals (NIHR UCLH) Biomedical Research Centre. This work also received in-kind sponsoring of the PET-tracer from General Electric (GE) Healthcare. This communication reflects the views of the authors and neither IMI nor the European Union and EFPIA are liable for any use that may be made of the information contained herein. The authors want to thank all PreclinAD participants for their efforts to join and complete this demanding study and our colleagues of The Netherlands Twin Register for referring participants. The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under European Medical Information Framework (EMIF) grant agreement No. 115372, resources of which are composed of financial contribution from the European Union?s Seventh Framework Programme (FP7/2007-2013) and European Federation of Pharmaceutical Industries and Associations (EFPIA) companies in-kind contribution. The project leading to this paper has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under Amyloid Imaging to Prevent Alzheimer?s Disease (AMYPAD) grant agreement No. 115952 and European Prevention of Alzheimer?s Dementia (EPAD) grant No. 115736. This Joint Undertaking receives the support from the European Union?s Horizon 2020 Research and Innovation Programme and EFPIA. Frederik Barkhof is supported by the National Institute for Health Research University College London Hospitals (NIHR UCLH) Biomedical Research Centre. This work also received in-kind sponsoring of the PET-tracer from General Electric (GE) Healthcare. This communication reflects the views of the authors and neither IMI nor the European Union and EFPIA are liable for any use that may be made of the information contained herein.Additional supporting information may be found online in the Supporting Information section at the end of the article.

Funders	Funder number
Amyloid Imaging to Prevent Alzheimer’s Disease
European Medical Information Framework
European Prevention of Alzheimer?s Dementia
European Prevention of Alzheimer’s Dementia
National Institute for Health Research University College London Hospitals
General Electric
GE Healthcare
Horizon 2020 Framework Programme
Seventh Framework Programme	115372, 115952, 115736
European Federation of Pharmaceutical Industries and Associations
European Commission
Innovative Medicines Initiative

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Collij, L. E., Ingala, S., Top, H., Wottschel, V., Stickney, K. E., Tomassen, J., Konijnenberg, E., Kate, M. T., Sudre, C., Alves, I. L., Yaqub, M. M., Wink, A. M., Van ‘t Ent, D., Scheltens, P., van Berckel, B. N. M., Visser, P. J., Barkhof, F., & Den Braber, A. (2021). White matter microstructure disruption in early stage amyloid pathology. Alzheimer's and Dementia: Diagnosis, Assessment and Disease Monitoring, 13(1), Article e12124. https://doi.org/10.1002/dad2.12124

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title = "White matter microstructure disruption in early stage amyloid pathology",

abstract = "{\textcopyright} 2021 The Authors. Alzheimer.Introduction: Amyloid beta (Aβ) accumulation is the first pathological hallmark of Alzheimer{\textquoteright}s disease (AD), and it is associated with altered white matter (WM) microstructure. We aimed to investigate this relationship at a regional level in a cog-nitively unimpaired cohort. Methods: We included 179 individuals from the European Medical Information Framework for AD (EMIF-AD) preclinAD study, who underwent diffusion magnetic resonance (MR) to determine tract-level fractional anisotropy (FA); mean, radial, and axial diffusivity (MD/RD/AxD); and dynamic [18F]flutemetamol) positron emission tomogra-phy (PET) imaging to assess amyloid burden. Results: Regression analyses showed a non-linear relationship between regional amyloid burden and WM microstructure. Low amyloid burden was associated with increased FA and decreased MD/RD/AxD, followed by decreased FA and increased MD/RD/AxD upon higher amyloid burden. The strongest association was observed between amyloid burden in the precuneus and body of the corpus callosum (CC) FA and diffusivity (MD/RD) measures. In addition, amyloid burden in the anterior cingu-late cortex strongly related to AxD and RD measures in the genu CC. Discussion: Early amyloid deposition is associated with changes in WM microstruc-ture. The non-linear relationship might reflect multiple stages of axonal damage.",

author = "L.E. Collij and S. Ingala and H. Top and V. Wottschel and K.E. Stickney and J. Tomassen and E. Konijnenberg and M.T. Kate and C. Sudre and I.L. Alves and M.M. Yaqub and A.M. Wink and {Van {\textquoteleft}t Ent}, D. and P. Scheltens and {van Berckel}, B.N.M. and P.J. Visser and F. Barkhof and {Den Braber}, A.",

year = "2021",

doi = "10.1002/dad2.12124",

language = "English",

volume = "13",

journal = "Alzheimer's and Dementia: Diagnosis, Assessment and Disease Monitoring",

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Collij, LE, Ingala, S, Top, H, Wottschel, V, Stickney, KE, Tomassen, J, Konijnenberg, E, Kate, MT, Sudre, C, Alves, IL, Yaqub, MM, Wink, AM, Van ‘t Ent, D, Scheltens, P, van Berckel, BNM, Visser, PJ, Barkhof, F & Den Braber, A 2021, 'White matter microstructure disruption in early stage amyloid pathology', Alzheimer's and Dementia: Diagnosis, Assessment and Disease Monitoring, vol. 13, no. 1, e12124. https://doi.org/10.1002/dad2.12124

TY - JOUR

T1 - White matter microstructure disruption in early stage amyloid pathology

AU - Collij, L.E.

AU - Ingala, S.

AU - Top, H.

AU - Wottschel, V.

AU - Stickney, K.E.

AU - Tomassen, J.

AU - Konijnenberg, E.

AU - Kate, M.T.

AU - Sudre, C.

AU - Alves, I.L.

AU - Yaqub, M.M.

AU - Wink, A.M.

AU - Van ‘t Ent, D.

AU - Scheltens, P.

AU - van Berckel, B.N.M.

AU - Visser, P.J.

AU - Barkhof, F.

AU - Den Braber, A.

PY - 2021

Y1 - 2021

N2 - © 2021 The Authors. Alzheimer.Introduction: Amyloid beta (Aβ) accumulation is the first pathological hallmark of Alzheimer’s disease (AD), and it is associated with altered white matter (WM) microstructure. We aimed to investigate this relationship at a regional level in a cog-nitively unimpaired cohort. Methods: We included 179 individuals from the European Medical Information Framework for AD (EMIF-AD) preclinAD study, who underwent diffusion magnetic resonance (MR) to determine tract-level fractional anisotropy (FA); mean, radial, and axial diffusivity (MD/RD/AxD); and dynamic [18F]flutemetamol) positron emission tomogra-phy (PET) imaging to assess amyloid burden. Results: Regression analyses showed a non-linear relationship between regional amyloid burden and WM microstructure. Low amyloid burden was associated with increased FA and decreased MD/RD/AxD, followed by decreased FA and increased MD/RD/AxD upon higher amyloid burden. The strongest association was observed between amyloid burden in the precuneus and body of the corpus callosum (CC) FA and diffusivity (MD/RD) measures. In addition, amyloid burden in the anterior cingu-late cortex strongly related to AxD and RD measures in the genu CC. Discussion: Early amyloid deposition is associated with changes in WM microstruc-ture. The non-linear relationship might reflect multiple stages of axonal damage.

AB - © 2021 The Authors. Alzheimer.Introduction: Amyloid beta (Aβ) accumulation is the first pathological hallmark of Alzheimer’s disease (AD), and it is associated with altered white matter (WM) microstructure. We aimed to investigate this relationship at a regional level in a cog-nitively unimpaired cohort. Methods: We included 179 individuals from the European Medical Information Framework for AD (EMIF-AD) preclinAD study, who underwent diffusion magnetic resonance (MR) to determine tract-level fractional anisotropy (FA); mean, radial, and axial diffusivity (MD/RD/AxD); and dynamic [18F]flutemetamol) positron emission tomogra-phy (PET) imaging to assess amyloid burden. Results: Regression analyses showed a non-linear relationship between regional amyloid burden and WM microstructure. Low amyloid burden was associated with increased FA and decreased MD/RD/AxD, followed by decreased FA and increased MD/RD/AxD upon higher amyloid burden. The strongest association was observed between amyloid burden in the precuneus and body of the corpus callosum (CC) FA and diffusivity (MD/RD) measures. In addition, amyloid burden in the anterior cingu-late cortex strongly related to AxD and RD measures in the genu CC. Discussion: Early amyloid deposition is associated with changes in WM microstruc-ture. The non-linear relationship might reflect multiple stages of axonal damage.

U2 - 10.1002/dad2.12124

DO - 10.1002/dad2.12124

M3 - Article

SN - 2352-8729

VL - 13

JO - Alzheimer's and Dementia: Diagnosis, Assessment and Disease Monitoring

JF - Alzheimer's and Dementia: Diagnosis, Assessment and Disease Monitoring

IS - 1

M1 - e12124

ER -

White matter microstructure disruption in early stage amyloid pathology

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